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Yahia Y, Qasem M, Abbarh S, Saffo H, Obeidat IM, Barjas HH, Faisal MM, Halabiya M, Chandra P, Derbala M. Risk of Malignancy in Indeterminate Liver Nodules Among Patients with Cirrhosis: A Retrospective Cohort Study. J Gastrointest Cancer 2024; 56:1. [PMID: 39414724 PMCID: PMC11485135 DOI: 10.1007/s12029-024-01122-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2024] [Indexed: 10/18/2024]
Abstract
BACKGROUND Several studies have shown a higher risk of liver cancer from indeterminate liver nodules, but the exact occurrence and predictors of liver cancer in this group are still unclear. Our aim is to study the development of liver cancer in this population and identify any potential risk factors. METHODS This retrospective study evaluated cirrhotic patients with indeterminate liver nodules from 2013 to 2023.Data from electronic patient records was analyzed to assess the association between HCC and baseline factors. Subgroup exploratory analysis compared characteristics of patients with de novo HCC and those with nodule transformation HCC. RESULTS Out of 116 patients with liver nodules, 19 (16%) developed HCC in up to 7.5-year follow-up. Univariate Cox regression analysis showed a significant association between HCC incidence and smoking [hazard ratio (HR) 2.60, 95% Confidence Interval [CI] 1.01-6.74), nodule diameter exceeding 2 cm (HR 5.41, 95% CI 1.45-20.18), and baseline LI-RADS score 3 (HR 3.78, 95% CI 1.36-19.52). Multivariate Cox regression analysis revealed significant independent associations with nodule diameters 1 cm to < 2 cm (adjusted HR 3.35, 95% CI 1.06-10.60) and greater than 2 cm (adjusted HR 5.85, 95% CI 1.10-31.16), as well as with LI-RADS 3 lesions (adjusted HR 3.75, 95% CI 1.16-12.11) with adjusting other potential predictors and covariates. CONCLUSION Our findings show a higher incidence of HCC in patients with indeterminate liver nodules, increasing over time and reaching 30% at seven years. Nodules larger than 1-2 cm or LI-RADS 3 lesions pose increased risk for HCC. Enhanced surveillance is necessary given the lack of clear management guidelines.
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Affiliation(s)
- Yousef Yahia
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar.
| | - Ma'mon Qasem
- Radiology Department, Hamad Medical Corporation, Doha, Qatar
| | - Shahem Abbarh
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | - Husam Saffo
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Ibrahim M Obeidat
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | | | | | - Malik Halabiya
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Prem Chandra
- Medical Research Centre, Hamad Medical Corporation, Doha, Qatar
| | - Moutaz Derbala
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
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Xiao Y, Wu F, Hou K, Wang F, Zhou C, Huang P, Yang C, Zeng M. MR radiomics to predict microvascular invasion status and biological process in combined hepatocellular carcinoma-cholangiocarcinoma. Insights Imaging 2024; 15:172. [PMID: 38981992 PMCID: PMC11233482 DOI: 10.1186/s13244-024-01741-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 06/09/2024] [Indexed: 07/11/2024] Open
Abstract
OBJECTIVES To establish an MRI-based radiomics model for predicting the microvascular invasion (MVI) status of cHCC-CCA and to investigate biological processes underlying the radiomics model. METHODS The study consisted of a retrospective dataset (82 in the training set, 36 in the validation set) and a prospective dataset (25 patients in the test set) from two hospitals. Based on the training set, logistic regression analyses were employed to develop the clinical-imaging model, while radiomic features were extracted to construct a radiomics model. The diagnosis performance was further validated in the validation and test sets. Prognostic aspects of the radiomics model were investigated using the Kaplan-Meier method and log-rank test. Differential gene expression analysis and gene ontology (GO) analysis were conducted to explore biological processes underlying the radiomics model based on RNA sequencing data. RESULTS One hundred forty-three patients (mean age, 56.4 ± 10.5; 114 men) were enrolled, in which 73 (51.0%) were confirmed as MVI-positive. The radiomics model exhibited good performance in predicting MVI status, with the area under the curve of 0.935, 0.873, and 0.779 in training, validation, and test sets, respectively. Overall survival (OS) was significantly different between the predicted MVI-negative and MVI-positive groups (median OS: 25 vs 18 months, p = 0.008). Radiogenomic analysis revealed associations between the radiomics model and biological processes involved in regulating the immune response. CONCLUSION A robust MRI-based radiomics model was established for predicting MVI status in cHCC-CCA, in which potential prognostic value and underlying biological processes that regulate immune response were demonstrated. CRITICAL RELEVANCE STATEMENT MVI is a significant manifestation of tumor invasiveness, and the MR-based radiomics model established in our study will facilitate risk stratification. Furthermore, underlying biological processes demonstrated in the radiomics model will offer valuable insights for guiding immunotherapy strategies. KEY POINTS MVI is of prognostic significance in cHCC-CCA, but lacks reliable preoperative assessment. The MRI-based radiomics model predicts MVI status effectively in cHCC-CCA. The MRI-based radiomics model demonstrated prognostic value and underlying biological processes. The radiomics model could guide immunotherapy and risk stratification in cHCC-CCA.
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Affiliation(s)
- Yuyao Xiao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fei Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kai Hou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fang Wang
- Shanghai United Imaging Intelligence Co. Ltd, Shanghai, China
| | - Changwu Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng Huang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Institute of Medical Imaging, Shanghai, China.
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Wang J, Guan X, Shang N, Wu D, Liu Z, Guan Z, Zhang Z, Jin Z, Wei X, Liu X, Song M, Zhu W, Dai G. Dysfunction of CCT3-associated network signals for the critical state during progression of hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167054. [PMID: 38360074 DOI: 10.1016/j.bbadis.2024.167054] [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: 08/24/2023] [Revised: 01/25/2024] [Accepted: 01/30/2024] [Indexed: 02/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is a serious threat to human health; thus, early diagnosis and adequate treatment are essential. However, there are still great challenges in identifying the tipping point and detecting early warning signals of early HCC. In this study, we aimed to identify the tipping point (critical state) of and key molecules involved in hepatocarcinogenesis based on time series transcriptome expression data of HCC patients. The phase from veHCC (very early HCC) to eHCC (early HCC) was identified as the critical state in HCC progression, with 143 genes identified as key candidate molecules by combining the DDRTree (dimensionality reduction via graph structure learning) and DNB (dynamic network biomarker) methods. Then, we ranked the candidate genes to verify their mRNA levels using the diethylnitrosamine (DEN)-induced HCC mouse model and identified five early warning signals, namely, CCT3, DSTYK, EIF3E, IARS2 and TXNRD1; these signals can be regarded as the potential early warning signals for the critical state of HCC. We identified CCT3 as an independent prognostic factor for HCC, and functions of CCT3 involving in the "MYCtargets_V1" and "E2F-Targets" are closely related to the progression of HCC. The predictive method combining the DDRTree and DNB methods can not only identify the key critical state before cancer but also determine candidate molecules of critical state, thus providing new insight into the early diagnosis and preemptive treatment of HCC.
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Affiliation(s)
- Jianwei Wang
- School of Computer and Artificial Intelligence, Zhengzhou University, Zhengzhou 45001, China; School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Xiaowen Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Ning Shang
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Di Wu
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Zihan Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Zhenzhen Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Zhizi Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Zhongzhen Jin
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Xiaoyi Wei
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Xiaoran Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Mingzhu Song
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China
| | - Weijun Zhu
- School of Computer and Artificial Intelligence, Zhengzhou University, Zhengzhou 45001, China.
| | - Guifu Dai
- School of Life Sciences, Zhengzhou University, Zhengzhou 45001, China.
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Sayed GI, Solyman M, El Gedawy G, Moemen YS, Aboul-Ella H, Hassanien AE. Circulating miRNA's biomarkers for early detection of hepatocellular carcinoma in Egyptian patients based on machine learning algorithms. Sci Rep 2024; 14:4989. [PMID: 38424116 PMCID: PMC10904762 DOI: 10.1038/s41598-024-54795-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
Liver cancer, which ranks sixth globally and third in cancer-related deaths, is caused by chronic liver disorders and a variety of risk factors. Despite therapeutic improvements, the prognosis for Hepatocellular Carcinoma (HCC) remains poor, with a 5-year survival rate for advanced cases of less than 12%. Although there is a noticeable decrease in the frequency of cases, liver cancer remains a significant worldwide health concern, with estimates surpassing one million cases by 2025. The prevalence of HCC has increased in Egypt, and it includes several neoplasms with distinctive messenger RNA (mRNA) and microRNA (miRNA) expression profiles. In HCC patients, certain miRNAs, such as miRNA-483-5P and miRNA-21, are upregulated, whereas miRNA-155 is elevated in HCV-infected people, encouraging hepatocyte proliferation. Short noncoding RNAs called miRNAs in circulation have the potential as HCC diagnostic and prognostic markers. This paper proposed a model for examining circulating miRNAs as diagnostic and predictive markers for HCC in Egyptian patients and their clinical and pathological characteristics. The proposed HCC detection model consists of three main phases: data preprocessing phase, feature selection based on the proposed Binary African Vulture Optimization Algorithm (BAVO) phase, and finally, classification as well as cross-validation phase. The first phase namely the data preprocessing phase tackle the main problems associated with the adopted datasets. In the feature selection based on the proposed BAVO algorithm phase, a new binary version of the BAVO swarm-based algorithm is introduced to select the relevant markers for HCC. Finally, in the last phase, namely the classification and cross-validation phase, the support vector machine and k-folds cross-validation method are utilized. The proposed model is evaluated on three studies on Egyptians who had HCC. A comparison between the proposed model and traditional statistical studies is reported to demonstrate the superiority of using the machine learning model for evaluating circulating miRNAs as diagnostic markers of HCC. The specificity and sensitivity for differentiation of HCC cases in comparison with the statistical-based method for the first study were 98% against 88% and 99% versus 92%, respectively. The second study revealed the sensitivity and specificity were 97.78% against 90% and 98.89% versus 92.5%, respectively. The third study reported 83.2% against 88.8% and 95.80% versus 92.4%, respectively. Additionally, the results show that circulating miRNA-483-5p, 21, and 155 may be potential new prognostic and early diagnostic biomarkers for HCC.
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Affiliation(s)
- Gehad Ismail Sayed
- School of Computer Science, Canadian International College (CIC), Cairo, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Mona Solyman
- Faculty of Computers and Artificial Intelligence, Cairo University, Giza, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Gamalat El Gedawy
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menofia University, Menofia, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Yasmine S Moemen
- Clinical Pathology Department, National Liver Institute, Menofia University, Menofia, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Hassan Aboul-Ella
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Aboul Ella Hassanien
- Faculty of Computers and Artificial Intelligence, Cairo University, Giza, Egypt
- College of Business Administration, Kuwait University, Al Shadadiya, Kuwait
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
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Brandi N, Renzulli M. Liver Lesions at Risk of Transformation into Hepatocellular Carcinoma in Cirrhotic Patients: Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement. J Clin Transl Hepatol 2024; 12:100-112. [PMID: 38250460 PMCID: PMC10794268 DOI: 10.14218/jcth.2023.00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/04/2023] [Accepted: 07/25/2023] [Indexed: 01/23/2024] Open
Abstract
Recent technical advances in liver imaging and surveillance for patients at high risk for developing hepatocellular carcinoma (HCC) have led to an increase in the detection of borderline hepatic nodules in the gray area of multistep carcinogenesis, particularly in those that are hypointense at the hepatobiliary phase (HBP) and do not show arterial phase hyperenhancement. Given their potential to transform and advance into hypervascular HCC, these nodules have progressively attracted the interest of the scientific community. To date, however, no shared guidelines have been established for the decision management of these borderline hepatic nodules. It is therefore extremely important to identify features that indicate the malignant potential of these nodules and the likelihood of vascularization. In fact, a more complete knowledge of their history and evolution would allow outlining shared guidelines for their clinical-surgical management, to implement early treatment programs and decide between a preventive curative treatment or a watchful follow-up. This review aims to summarize the current knowledge on hepatic borderline nodules, particularly focusing on those imaging features which are hypothetically correlated with their malignant evolution, and to discuss current guidelines and ongoing management in clinical practice.
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Affiliation(s)
- Nicolò Brandi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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6
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Kim HS, Yoon JH, Baek GO, Yoon MG, Han JE, Cho HJ, Kim SS, Jeong JY, Cheong JY, Eun JW. Tumor Endothelial Cells-Associated Integrin Alpha-6 as a Promising Biomarker for Early Detection and Prognosis of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4156. [PMID: 37627184 PMCID: PMC10453423 DOI: 10.3390/cancers15164156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/08/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset encompassing various stages of liver disease, identifying 972 differentially expressed genes in HCC. A refined analysis yielded 59 genes specifically differentially expressed in early HCC, including ITGA6. Subsequent validation in multiple datasets confirmed the consistent upregulation of ITGA6 in HCC. In addition, when analyzing progression-free survival (PFS) within the entire patient cohort and overall survival (OS) specifically among patients classified as tumor grade G1, the group of patients characterized by high expression levels of ITGA6 displayed an elevated risk ratio in relation to prognosis. Further analyses demonstrated the predominant expression of ITGA6 in TECs and its enrichment in angiogenesis-related pathways. Additionally, positive correlations were found between ITGA6 expression and pro-tumorigenic immune cells, but not with anti-tumorigenic immune cells. Our study elucidates the potential of ITGA6 as a blood-based marker for HCC early detection and diagnosis and its complex interplay with the tumor microenvironment. Further research may lead to novel strategies for HCC management and patient care.
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Affiliation(s)
- Hyung Seok Kim
- Department of Biochemistry, College of Medicine, Kosin University, Seo-gu, Busan 49267, Republic of Korea; (H.S.K.); (J.-Y.J.)
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea;
| | - Geum Ok Baek
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Moon Gyeong Yoon
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Jee-Yeong Jeong
- Department of Biochemistry, College of Medicine, Kosin University, Seo-gu, Busan 49267, Republic of Korea; (H.S.K.); (J.-Y.J.)
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
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7
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Kudo M. Surveillance, Diagnosis, and Treatment Outcome of Hepatocellular Carcinoma in Japan: 2023 Update. Liver Cancer 2023; 12:95-102. [PMID: 37325491 PMCID: PMC10267513 DOI: 10.1159/000530079] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/06/2023] [Indexed: 06/17/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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8
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Shen C, Cao Y, Qi GQ, Huang J, Liu ZP. Discovering pathway biomarkers of hepatocellular carcinoma occurrence and development by dynamic network entropy analysis. Gene 2023; 873:147467. [PMID: 37164125 DOI: 10.1016/j.gene.2023.147467] [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: 02/03/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/12/2023]
Abstract
OBJECTIVE Gene expression profiling techniques measure the transcription of thousands of genes in a parallel manner. With more and more hepatocellular carcinoma (HCC) transcriptomic data becoming available, the high-throughput data provides an unprecedented opportunity to discover HCC diagnostic biomarkers. In this work, we propose a bioinformatics method based on dynamic network entropy analysis, called DNEA, to identify potential pathway biomarkers for HCC occurrence and development by integrating transcriptome and interactome. METHODS We firstly collect the pathways documented in different knowledge-bases and then impose the genome-wide human transcriptomic data of multistage cancerous tissues during the development and progression of HCC. After linking the gene sets of pathways into individual connected networks, we map the corresponding gene expression information onto these pathways. The dynamic network entropy of individual pathways is calculated to evaluate its activities and dysfunctionalities during the disease occurrence and development. We use the overall significant difference in the entropic dynamics during the time course to prioritize distinctive pathways during disease progression. Then machine learning classification methods are employed to screen out pathway biomarkers with the classification ability to distinguish different-stage samples of HCC progression. RESULTS Pathway biomarkers discovered based on DNEA demonstrate good classification performance in measuring HCC progression. The classification accuracy is as follows: DNA replication pathway (mean AUC= 0.82, 20 genes) from KEGG, FMLP pathway (mean AUC=0.84, 14 genes) from BioCarta, and downstream signaling of activated FGFR pathway (mean AUC =0.80, 15 genes) from Reactome. At the same time, previous studies have shown that these genes and pathways screened are closely related to the occurrence and development of HCC in terms of oncogenesis dysfunctions. CONCLUSIONS Our method for cancer biomarker discovery based on dynamic network entropy analysis is effective and efficient in identifying pathway biomarkers related to the progression of complex diseases.
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Affiliation(s)
- Chen Shen
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China; Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Yi Cao
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China; Center for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Guo-Qiang Qi
- Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Jian Huang
- Department of Data and Information, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China; Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, Zhejiang 310052, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
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9
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Liu P, Zhu Z, Ma J, Wei L, Han Y, Shen E, Tan X, Chen Y, Cai C, Guo C, Peng Y, Gao Y, Liu Y, Huang Q, Gao L, Li Y, Jiang Z, Wu W, Liu Y, Zeng S, Li W, Feng Z, Shen H. Prognostic stratification based on m 5C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma. Front Immunol 2022; 13:951529. [PMID: 36159831 PMCID: PMC9505913 DOI: 10.3389/fimmu.2022.951529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/22/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified. METHODS In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models. RESULTS The 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis. CONCLUSION In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.
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Affiliation(s)
- Ping Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ziqing Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Jiayao Ma
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Le Wei
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Edward Shen
- Department of Life Science, McMaster University, Hamilton, ON, Canada
| | - Xiao Tan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yihong Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Cao Guo
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yinghui Peng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yongting Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Qiaoqiao Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Le Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaohui Jiang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyang Feng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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10
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Lu CH, Hsiao JK. Diagnostic and therapeutic roles of iron oxide nanoparticles in biomedicine. Tzu Chi Med J 2022; 35:11-17. [PMID: 36866343 PMCID: PMC9972926 DOI: 10.4103/tcmj.tcmj_65_22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/03/2022] [Accepted: 06/08/2022] [Indexed: 11/04/2022] Open
Abstract
Nanotechnology changed our understanding of physics and chemics and influenced the biomedical field. Iron oxide nanoparticles (IONs) are one of the first emerging biomedical applications of nanotechnology. The IONs are composed of iron oxide core exhibiting magnetism and coated with biocompatible molecules. The small size, strong magnetism, and biocompatibility of IONs facilitate the application of IONs in the medical imaging field. We listed several clinical available IONs including Resovist (Bayer Schering Pharma, Berlin, Germany) and Feridex intravenous (I.V.)/Endorem as magnetic resonance (MR) contrast agents for liver tumor detection. We also illustrated GastroMARK as a gastrointestinal contrast agent for MR imaging. Recently, IONs named Feraheme for treating iron-deficiency anemia have been approved by the Food and Drug Administration. Moreover, tumor ablation by IONs named NanoTherm has also been discussed. In addition to the clinical application, several potential biomedical applications of IONs including cancer-targeting capability by conjugating IONs with cancer-specific ligands, cell trafficking tools, or tumor ablation agents have also been discussed. With the growing awareness of nanotechnology, further application of IONs is still on the horizon that would shed light on biomedicine.
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Affiliation(s)
- Chia-Hung Lu
- Department of Medical Imaging, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Jong-Kai Hsiao
- Department of Medical Imaging, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan,School of Medicine, Tzu Chi University, Hualien, Taiwan,Address for correspondence: Dr. Jong-Kia Hsiao, Department of Medical Imaging, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289, Jianguo Road, Xindian District, New Taipei, Taiwan. E-mail:
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11
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Sheng X, Qin JM. Clinical features and diagnostic and therapeutic strategies of hepatic dysplastic nodules. Shijie Huaren Xiaohua Zazhi 2022; 30:169-181. [DOI: 10.11569/wcjd.v30.i4.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic dysplastic nodules (DNs) are a group of neoplastic lesions with a diameter of more than 1 cm that belong to precancerous lesions, with abnormal cytoplasm and cells but without malignant basis in histology. Hepatic DNs lack typical tumor markers and clinical symptoms, and their clinical diagnosis relys mainly on imaging or/and tissue pathological examination. Thanks to the further research on the pathogenesis of hepatic DNs and the development of imaging technology, the combination of medical history, various examinationss, individual tumor markers, and imaging and histopathology techniques can significantly improve the early detection and diagnosis accuracy for hepatic DNs, and reduce the rate of missed and false diagnosis. Due to the potential malignancy risk of hepatic DNs, intervention measures should be carried out on hepatic DNs at all stages, in order to block the transformation process of DNs into hepatocellular carcinoma (HCC), which is of great clinical significance to reduce the incidence and mortality of HCC.
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Affiliation(s)
- Xia Sheng
- Department of Pathology, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China
| | - Jian-Min Qin
- Department of General Surgery, The Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
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12
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Zhang J, Liu Z, Liu L, Huang M, Huang Y. Th22/IL-22 mediates the progression of HBV-related hepatocellular carcinoma via STAT3. Cytotechnology 2022; 74:203-216. [PMID: 35464167 PMCID: PMC8975974 DOI: 10.1007/s10616-021-00517-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022] Open
Abstract
T helper cell 22 are abundant in Hepatitis B Virus-related hepatocellular carcinoma tissue, and the main cytokine interleukin 22 produced by Th22 cells is closely related to the initiation and development of HCC. Understanding the role of Th22/IL-22 in the progression of HBV-related HCC will facilitate new therapeutic development. Th22 cells were isolated from peripheral blood of healthy donors and co-cultured with HBV positive HepG2.2.15 cells. IL-22 secretion and HepG2.2.15 cell proliferation and apoptosis were monitored. Expressions of p-STAT3, Cyclin D1, Bcl-2, and cleaved caspase 3 were detected by Western blot analysis. Th22 cells significantly promoted the proliferation and inhibited the apoptosis of HepG2.2.15 cells; up-regulated expression of p-STAT3, Cyclin D1 and Bcl-2, and down-regulated cleaved caspase 3 in HepG2.2.15 cells. These effects were significantly attenuated when IL-22 and STAT3 was knockdown in Th22 and HepG2.2.15 cells, respectively. Our data suggests that HBV induces host Th22 cells to overexpress IL-22, which in turn triggers over-activation of STAT3 and its downstream signaling proteins to promote HCC progression. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-021-00517-9.
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Affiliation(s)
- Jia Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Zhou Liu
- Department of Internal Medicine, Jiangxi Provincial Chest Hospital, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Lingpeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Mingwen Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Yong Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
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13
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Tang B, Zhu J, Zhao Z, Lu C, Liu S, Fang S, Zheng L, Zhang N, Chen M, Xu M, Yu R, Ji J. Diagnosis and prognosis models for hepatocellular carcinoma patient's management based on tumor mutation burden. J Adv Res 2021; 33:153-165. [PMID: 34603786 PMCID: PMC8463909 DOI: 10.1016/j.jare.2021.01.018] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023] Open
Abstract
Introduction The development and prognosis of HCC involve complex molecular mechanisms, which affect the effectiveness of its treatment strategies. Tumor mutational burden (TMB) is related to the efficacy of immunotherapy, but the prognostic role of TMB-related genes in HCC has not yet been determined clearly. Objectives In this study, we identified TMB-specific genes with good prognostic value to build diagnostic and prognostic models and provide guidance for the treatment of HCC patients. Methods Weighted gene co-expression network analysis (WGCNA) was applied to identify the TMB-specific genes. And LASSO method and Cox regression were used in establishing the prognostic model. Results The prognostic model based on SMG5 and MRPL9 showed patients with higher prognostic risk had a remarkedly poorer survival probability than their counterparts with lower prognostic risk in both a TCGA cohort (P < 0.001, HR = 1.93) and an ICGC cohort (P < 0.001, HR = 3.58). In addition, higher infiltrating fractions of memory B cells, M0 macrophages, neutrophils, activated memory CD4 + T cells, follicular helper T cells and regulatory T cells and higher expression of B7H3, CTLA4, PD1, and TIM3 were present in the high-risk group than in the low-risk group (P < 0.05). Patients with high prognostic risk had higher resistance to some chemotherapy and targeted drugs, such as methotrexate, vinblastine and erlotinib, than those with low prognostic risk (P < 0.05). And a diagnostic model considering two genes was able to accurately distinguish patients with HCC from normal samples and those with dysplastic nodules. In addition, knockdown of SMG5 and MRPL9 was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion Our study helps to select patients suitable for chemotherapy, targeted drugs and immunotherapy and provide new ideas for developing treatment strategies to improve disease outcomes in HCC patients.
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Affiliation(s)
- Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinyu Zhu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Chenying Lu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Siyu Liu
- Department of Laboratory, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Shiji Fang
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Liyun Zheng
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Nannan Zhang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
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14
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Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H, Imai Y, Hiraoka A, Ikeda M, Izumi N, Moriguchi M, Ogasawara S, Minami Y, Ueshima K, Murakami T, Miyayama S, Nakashima O, Yano H, Sakamoto M, Hatano E, Shimada M, Kokudo N, Mochida S, Takehara T. Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 2021; 10:181-223. [PMID: 34239808 PMCID: PMC8237791 DOI: 10.1159/000514174] [Citation(s) in RCA: 434] [Impact Index Per Article: 108.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan,*Masatoshi Kudo,
| | | | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Osaka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Michihisa Moriguchi
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Shiro Miyayama
- Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Etsuro Hatano
- Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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15
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Kovac JD, Ivanovic A, Milovanovic T, Micev M, Alessandrino F, Gore RM. An overview of hepatocellular carcinoma with atypical enhancement pattern: spectrum of magnetic resonance imaging findings with pathologic correlation. Radiol Oncol 2021; 55:130-143. [PMID: 33544992 PMCID: PMC8042819 DOI: 10.2478/raon-2021-0004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the setting of cirrhotic liver, the diagnosis of hepatocellular carcinoma (HCC) is straightforward when typical imaging findings consisting of arterial hypervascularity followed by portal-venous washout are present in nodules larger than 1 cm. However, due to the complexity of hepatocarcinogenesis, not all HCCs present with typical vascular behaviour. Atypical forms such as hypervascular HCC without washout, isovascular or even hypovascular HCC can pose diagnostic dilemmas. In such cases, it is important to consider also the appearance of the nodules on diffusion-weighted imaging and hepatobiliary phase. In this regard, diffusion restriction and hypointensity on hepatobiliary phase are suggestive of malignancy. If both findings are present in hypervascular lesion without washout, or even in iso- or hypovascular lesion in cirrhotic liver, HCC should be considered. Moreover, other ancillary imaging findings such as the presence of the capsule, fat content, signal intensity on T2-weighted image favour the diagnosis of HCC. Another form of atypical HCCs are lesions which show hyperintensity on hepatobiliary phase. Therefore, the aim of the present study was to provide an overview of HCCs with atypical enhancement pattern, and focus on their magnetic resonance imaging (MRI) features. CONCLUSIONS In order to correctly characterize atypical HCC lesions in cirrhotic liver it is important to consider not only vascular behaviour of the nodule, but also ancillary MRI features, such as diffusion restriction, hepatobiliary phase hypointensity, and T2-weighted hyperintensity. Fat content, corona enhancement, mosaic architecture are other MRI feautures which favour the diagnosis of HCC even in the absence of typical vascular profile.
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Affiliation(s)
- Jelena Djokic Kovac
- Center for Radiology and MRI, Clinical Center Serbia, School of Medicine, University of Belgrade; Belgrade, Serbia
| | - Aleksandar Ivanovic
- Center for Radiology and MRI, Clinical Center Serbia, School of Medicine, University of Belgrade; Belgrade, Serbia
| | - Tamara Milovanovic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia School of Medicine, University of Belgrade; Belgrade, Serbia
| | - Marjan Micev
- Departament of Digestive Pathology, Clinical Center of Serbia, Belgrade, Serbia
| | - Francesco Alessandrino
- Division of Abdominal Imaging, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Richard M. Gore
- Department of Gastrointestinal Radiology, NorthShore University, Evanston, Pritzker School of Medicine at the University of Chicago, ChicagoUSA
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16
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Kurebayashi Y, Kubota N, Sakamoto M. Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications. Hepatol Res 2021; 51:5-18. [PMID: 32573056 DOI: 10.1111/hepr.13539] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/13/2020] [Accepted: 06/18/2020] [Indexed: 01/24/2023]
Abstract
Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.
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Affiliation(s)
- Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine.,Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Naoto Kubota
- Department of Pathology, Keio University School of Medicine
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17
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Zuo D, Yang K, Wu S. Diagnostic performance of intravascular perfusion based contrast-enhanced ultrasound LI-RADS in the evaluation of hepatocellular carcinoma. Clin Hemorheol Microcirc 2021; 78:429-437. [PMID: 33867358 DOI: 10.3233/ch-211164] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) is a relative new algorithm for hepatocellular carcinoma (HCC) assessment. OBJECTIVE To validate the diagnostic efficiency of the intravascular perfusion based CEUS LI-RADS for HCC. METHODS Archives of 873 patients with focal liver lesions (FLLs) undergoing CEUS were reviewed, and target images were read by two sonologists independently according to the CEUS LI-RADS. The diagnostic performance was calculated and compared. RESULTS Assessment with reference to CEUS LI-RADS, 87 of 218 FLLs (39.9%) were categorized as LR-5, 131 of 218 FLLs (60.1%) were categorized as non-LR-5, 19 of 99 HCCs were categorized as non-LR-5, and 7 of 119 non-HCCs were categorized as LR-5. The sensitivity, specificity, AUROC, positive and negative predictive values of CEUS LI-RADS for diagnosing HCC were 80.81%(95%CI: 71.7%-88.0%), 94.1%(95%CI: 88.3%-97.6%), 0.87 (95%CI: 0.82-0.92), 91.9%(95%CI: 84.1%-96.7%), and 85.5%(95%CI: 78.3%-91.0%), respectively. CONCLUSIONS The diagnostic efficiency of the intravascular perfusion based CEUS LI-RADS for the evaluation of HCCs is very good.
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Affiliation(s)
- Dongsheng Zuo
- Department of Ultrasound, The First Affiliated Hospital of Hainan Medical University, Haikou, China
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kefeng Yang
- Department of Ultrasound, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Size Wu
- Department of Ultrasound, The First Affiliated Hospital of Hainan Medical University, Haikou, China
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18
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Takeda H, Takai A, Kumagai K, Iguchi E, Arasawa S, Eso Y, Shimizu T, Ueda Y, Taura K, Uemoto S, Kita R, Haga H, Marusawa H, Fujimoto A, Seno H. Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution. J Pathol 2020; 252:398-410. [PMID: 32815153 DOI: 10.1002/path.5533] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/22/2020] [Accepted: 08/10/2020] [Indexed: 01/04/2025]
Abstract
Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eriko Iguchi
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryuichi Kita
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Akihiro Fujimoto
- Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Kancharla J, Dariya B, Momin S, Prasad IDV, Bhaskar L, Bramhachari PV, Alam A. HIF1A C1772T genetic variation is associated with the elevated risk of breast cancer among Asians: An updated meta-analysis. Meta Gene 2020; 25:100722. [DOI: 10.1016/j.mgene.2020.100722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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20
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Wilson SR, Barr RG. Contrast-Enhanced Ultrasonography of the Abdomen. ADVANCES IN CLINICAL RADIOLOGY 2020; 2:213-233. [DOI: 10.1016/j.yacr.2020.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Midorikawa Y, Yamamoto S, Tatsuno K, Renard-Guillet C, Tsuji S, Hayashi A, Ueda H, Fukuda S, Fujita T, Katoh H, Ishikawa S, Covington KR, Creighton CJ, Sugitani M, Wheeler DA, Shibata T, Nagae G, Takayama T, Aburatani H. Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression. Cancer Res 2020; 80:3810-3819. [DOI: 10.1158/0008-5472.can-20-0225] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/01/2020] [Accepted: 07/02/2020] [Indexed: 11/16/2022]
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Kwa WT, Effendi K, Yamazaki K, Kubota N, Hatano M, Ueno A, Masugi Y, Sakamoto M. Telomerase reverse transcriptase (TERT) promoter mutation correlated with intratumoral heterogeneity in hepatocellular carcinoma. Pathol Int 2020; 70:624-632. [PMID: 32559017 DOI: 10.1111/pin.12974] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/21/2020] [Accepted: 05/31/2020] [Indexed: 12/23/2022]
Abstract
Telomerase reverse transcriptase (TERT) promoter mutations are frequently observed in hepatocellular carcinoma (HCC); however, the impact of TERT promoter mutations (TPMs) on clinical features and morphological patterns in HCC remains unresolved. Using DNA extracted from 97 HCCs, correlations between TPM status and both the clinical features of HCC and the immunohistochemically-based subgroups were evaluated. Morphological tumor patterns were semi-quantitatively analyzed using hematoxylin and eosin-stained slides of the whole tumor cross-sectional area. The percentages of tumor area occupied by early, well, moderate and poor histological patterns were calculated as a homogeneity index. TPMs were observed in 53 of 97 (55%) HCCs and were significantly associated with older age (P = 0.018) and HCV-related background (P = 0.048). The biliary/stem cell marker-positive subgroup was less likely to have TPMs (29%) compared to the Wnt/β-catenin signaling marker-positive subgroup (60%). In contrast to TPM-negative HCCs, TPM-positive HCCs clearly exhibited intratumoral morphological heterogeneity (0.800 ± 0.117 vs 0.927 ± 0.096, P < 0.0001), characterized by two or more heterogeneous histological patterns (P < 0.0001) and had more well or early differentiated histological patterns (P = 0.024). Our findings showed that intratumoral heterogeneity was strongly related to TPM-positive HCCs, which established novel roles of TPMs, and may improve our understanding particularly about HCC development and diagnosis.
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Affiliation(s)
- Wit Thun Kwa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kathryn Effendi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Ken Yamazaki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Naoto Kubota
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Mami Hatano
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Akihisa Ueno
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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Wooddell CI, Blomenkamp K, Peterson RM, Subbotin VM, Schwabe C, Hamilton J, Chu Q, Christianson DR, Hegge JO, Kolbe J, Hamilton HL, Branca-Afrazi MF, Given BD, Lewis DL, Gane E, Kanner SB, Teckman JH. Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease. JCI Insight 2020; 5:135348. [PMID: 32379724 DOI: 10.1172/jci.insight.135348] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.
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Affiliation(s)
| | - Keith Blomenkamp
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | | | | | | | | | - Qili Chu
- Arrowhead Pharmaceuticals, Madison, Wisconsin, USA
| | | | | | - John Kolbe
- Auckland Clinical Studies, Auckland, New Zealand
| | | | | | - Bruce D Given
- Arrowhead Pharmaceuticals, Pasadena, California, USA
| | | | - Edward Gane
- Auckland Clinical Studies, Auckland, New Zealand
| | | | - Jeffrey H Teckman
- Departments of Pediatrics and Biochemistry, St. Louis University School of Medicine, Cardinal Glennon Children's Hospital, St. Louis, Missouri, USA
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Shimizu Y, Arai K, Yamashita T, Yamashita T, Shimakami T, Kawaguchi K, Kitamura K, Sakai Y, Mizukoshi E, Honda M, Kitao A, Kozaka K, Kobayashi S, Kaneko S. Direct-Acting Antiviral Agents Reduce the Risk of Malignant Transformation of Hepatobiliary Phase-Hypointense Nodule without Arterial Phase Hyperenhancement to Hepatocellular Carcinoma on Gd-EOB-DPTA-Enhanced Imaging in the Hepatitis C Virus-Infected Liver. Liver Cancer 2020; 9:261-274. [PMID: 32647630 PMCID: PMC7325122 DOI: 10.1159/000504889] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 10/26/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Hepatobiliary phase-hypointense nodules without arterial phase hyperenhancement (HHNs without APHE) on gadolinium-ethoxybenzyl-diethylenetriamine-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) are considered to be dysplastic nodules or early hepatocellular carcinoma (HCC) and have high risk of undergoing malignant transformation and progression to hypervascular HCC. The aim of this study was to evaluate the clinical outcome of HHNs without APHE diagnosed by Gd-EOB-DTPA-enhanced MRI before the eradication of HCV by direct-acting antiviral agents (DAAs). METHODS We retrospectively investigated 221 consecutive patients with HCV infection who were treated with DAAs. Thirty patients with 65 HHNs without APHE were enrolled in a sustained virologic response (SVR) cohort and 22 with 43 HHNs without APHE who did not receive DAAs or had failed HCV eradication therapy were enrolled in a non-SVR cohort. Fifty-seven percent of patients in the SVR group and 64% of those in the non-SVR group had a history of HCC. The primary endpoint of this study was the development of hypervascular HCC from HHNs without APHE detected on imaging. The cumulative incidence and relative risk of progression to hypervascular HCC in relation to clinical characteristics were compared between the two cohorts. RESULTS The 2-year cumulative incidence of progression to hypervascular HCC was 8.5 and 21.9% in the SVR and non-SVR cohorts, respectively. There was a significant reduction in progression of HHNs without APHE to HCC after the eradication of HCV (p = 0.022, log-rank test). Multivariate Cox regression analysis identified hyperintensity on T2-weighted images (relative risk 14.699, p < 0.001) and achieving SVR (relative risk 0.290, p = 0.043) as independent factors associated with the risk of HCC. During follow-up, 6 (9.2%) of the HHNs without APHE in the SVR cohort became undetectable on hepatocyte-phase images. CONCLUSIONS Eradication of HCV by DAAs could reduce the hypervascularization rate of HHNs without APHE, and some of these nodules disappeared.
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Affiliation(s)
- Yoshiaki Shimizu
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan,*Kuniaki Arai, MD, PhD, Department of Gastroenterology, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641 (Japan), E-Mail , Taro Yamashita, MD, PhD, Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641 (Japan), E-Mail
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Azusa Kitao
- Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan
| | - Satoshi Kobayashi
- Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
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Does quantitative assessment of arterial phase hyperenhancement and washout improve LI-RADS v2018–based classification of liver lesions? Eur Radiol 2020; 30:2922-2933. [DOI: 10.1007/s00330-019-06596-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/18/2022]
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26
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Ueno A, Masugi Y, Yamazaki K, Kurebayashi Y, Tsujikawa H, Effendi K, Ojima H, Sakamoto M. Precision pathology analysis of the development and progression of hepatocellular carcinoma: Implication for precision diagnosis of hepatocellular carcinoma. Pathol Int 2020; 70:140-154. [PMID: 31908112 DOI: 10.1111/pin.12895] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 12/11/2019] [Indexed: 12/25/2022]
Abstract
Outcomes for patients with hepatocellular carcinoma (HCC) remain poor because the condition is often unresponsive to the available treatments. Consequently, the early and precise diagnosis of HCC is crucial to achieve improvements in prognosis. For patients with chronic liver disease, the assessment of liver fibrosis is also important to ascertain both the staging of fibrosis and the risk of HCC occurrence. Early HCC was first described in 1991 in Japan and was defined internationally in 2009. As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted. Consequently, improvements in imaging technology made the early diagnosis of HCC possible. At present, the most appropriate therapeutic strategy for HCC is determined using an integrated staging system that assesses the tumor burden, the degree of liver dysfunction and the patient performance status; however, pathological and molecular features are not taken into account. The recent introduction of several new therapeutic agents will change the treatment strategy for HCC. Against this background, HCC subclassification based on tumor cellular and microenvironmental characteristics will become increasingly important. In this review, we give an overview of how pathological analysis contributes to understanding the development and progression of HCC and establishing a precision diagnosis of HCC.
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Affiliation(s)
- Akihisa Ueno
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Ken Yamazaki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kathryn Effendi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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Hu J, Bhayana D, Burak KW, Wilson SR. Resolution of indeterminate MRI with CEUS in patients at high risk for hepatocellular carcinoma. Abdom Radiol (NY) 2020; 45:123-133. [PMID: 31440801 DOI: 10.1007/s00261-019-02181-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE To show the contribution of CEUS to characterization of indeterminate MRI observations in high-risk patients for hepatocellular carcinoma (HCC). METHODS From July to December 2015, 42 consecutive patients referred to CEUS with indeterminate MRI scans comprise our study cohort. There are 50 indeterminate nodule-like observations and 10 arterial phase hyperenhancing foci, suggesting pseudolesions/arterio-portal shunts. MRI and CEUS lesions are classified according to their enhancement features in all phases and Liver Imaging and Reporting Data System (LI-RADS) in a blind read format. Clinical pathologic correlation and 24 months follow-up are performed. RESULTS A majority, 37/50 (74%), of indeterminate nodule-like observations have arterial phase enhancement without washout on MRI. CEUS further characterizes enhancement and shows washout in 14/37 (38%). In total, CEUS diagnoses 16 malignant lesions in 14 patients including 14 HCC and 2 ICC. 12/16 (75%) malignant lesions are confirmed by biopsy or follow-up. Ultrasound identification of a nodule differentiates real nodules from pseudolesions. Of the ten suspected arterial-portal shunts on MRI, two show a real nodule on ultrasound, confirmed as an HCC and a regenerative nodule. 15/42 (36%) patients have LI-RADS escalated from LR-3 or 4 on MRI to LR-4 or 5 on CEUS. Overall, the sensitivity of CEUS is (13/16) 81.3% and specificity is (37/37) 100% for malignant diagnosis. CONCLUSION Grayscale ultrasound detects true nodules. Dynamic CEUS detects and characterizes washout, correctly predicting HCC. CEUS is complimentary to MRI and can serve as a problem-solving tool when MRI is indeterminate.
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28
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Shin H, Jung YW, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Kim YY, Choi JY, Kim SU. Risk assessment of hepatocellular carcinoma development for indeterminate hepatic nodules in patients with chronic hepatitis B. Clin Mol Hepatol 2019; 25:390-399. [PMID: 31146508 PMCID: PMC6933117 DOI: 10.3350/cmh.2018.0103] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/19/2019] [Accepted: 03/04/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS A risk prediction model for the development of hepatocellular carcinoma (HCC) from indeterminate nodules detected on computed tomography (CT) (RadCT score) in patients with chronic hepatitis B (CHB)-related cirrhosis was proposed. We validated this model for indeterminate nodules on magnetic resonance imaging (MRI). METHODS Between 2013 and 2016, Liver Imaging Reporting and Data System (LI-RADS) 2/3 nodules on MRI were detected in 99 patients with CHB. The RadCT score was calculated. RESULTS The median age of the 72 male and 27 female subjects was 58 years. HCC history and liver cirrhosis were found in 47 (47.5%) and 44 (44.4%) patients, respectively. The median RadCT score was 112. The patients with HCC (n=41, 41.4%) showed significantly higher RadCT scores than those without (median, 119 vs. 107; P=0.013); the Chinese university-HCC and risk estimation for HCC in CHB (REACH-B) scores were similar (both P>0.05). Arterial enhancement, T2 hyperintensity, and diffusion restriction on MRI were not significantly different in the univariate analysis (all P>0.05); only the RadCT score significantly predicted HCC (hazard ratio [HR]=1.018; P=0.007). Multivariate analysis showed HCC history was the only independent HCC predictor (HR=2.374; P=0.012). When the subjects were stratified into three risk groups based on the RadCT score (<60, 60-105, and >105), the cumulative HCC incidence was not significantly different among them (all P>0.05, log-rank test). CONCLUSION HCC history, but not RadCT score, predicted CHB-related HCC development from LI-RADS 2/3 nodules. New risk models optimized for MRI-defined indeterminate nodules are required.
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Affiliation(s)
- Haneulsaem Shin
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Yeon Woo Jung
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yeun-Yoon Kim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Young Choi
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine and Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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29
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Long J, Chen P, Lin J, Bai Y, Yang X, Bian J, Lin Y, Wang D, Yang X, Zheng Y, Sang X, Zhao H. DNA methylation-driven genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma. Am J Cancer Res 2019; 9:7251-7267. [PMID: 31695766 PMCID: PMC6831284 DOI: 10.7150/thno.31155] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 08/05/2019] [Indexed: 12/21/2022] Open
Abstract
In this study, we performed a comprehensively analysis of gene expression and DNA methylation data to establish diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC). Methods: We collected gene expression and DNA methylation datasets for over 1,200 clinical samples. Integrated analyses of RNA-sequencing and DNA methylation data were performed to identify DNA methylation-driven genes. These genes were utilized in univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to build a prognostic model. Recurrence and diagnostic models for HCC were also constructed using the same genes. Results: A total of 123 DNA methylation-driven genes were identified. Two of these genes (SPP1 and LCAT) were chosen to construct the prognostic model. The high-risk group showed a markedly unfavorable prognosis compared to the low-risk group in both training (HR = 2.81; P < 0.001) and validation (HR = 3.06; P < 0.001) datasets. Multivariate Cox regression analysis indicated the prognostic model to be an independent predictor of prognosis (P < 0.05). Also, the recurrence model successfully distinguished the HCC recurrence rate between the high-risk and low-risk groups in both training (HR = 2.22; P < 0.001) and validation (HR = 2; P < 0.01) datasets. The two diagnostic models provided high accuracy for distinguishing HCC from normal samples and dysplastic nodules in the training and validation datasets, respectively. Conclusions: We identified and validated prognostic, recurrence, and diagnostic models that were constructed using two DNA methylation-driven genes in HCC. The results obtained by integrating multidimensional genomic data offer novel research directions for HCC biomarkers and new possibilities for individualized treatment of patients with HCC.
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Inchingolo R, Faletti R, Grazioli L, Tricarico E, Gatti M, Pecorelli A, Ippolito D. MR with Gd-EOB-DTPA in assessment of liver nodules in cirrhotic patients. World J Hepatol 2018; 10:462-473. [PMID: 30079132 PMCID: PMC6068846 DOI: 10.4254/wjh.v10.i7.462] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/25/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023] Open
Abstract
To date the imaging diagnosis of liver lesions is based mainly on the identification of vascular features, which are typical of overt hepatocellular carcinoma (HCC), but the hepatocarcinogenesis is a complex and multistep event during which, a spectrum of nodules develop within the liver parenchyma, including benign small and large regenerative nodule (RN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC, and well differentiated HCC. These nodules may be characterised not only on the basis of their respective different blood supplies, but also on their different hepatocyte function. Recently, in liver imaging the introduction of hepatobiliary magnetic resonance imaging contrast agent offered the clinicians the possibility to obtain, at once, information not only related to the vascular changes of liver nodules but also information on hepatocyte function. For this reasons this new approach becomes the most relevant diagnostic clue for differentiating low-risk nodules (LGDN-RN) from high-risk nodules (HGDN/early HCC or overt HCC) and consequently new diagnostic algorithms for HCC have been proposed. The use of hepatobiliary contrast agents is constantly increasing and gradually changing the standard of diagnosis of HCC. The main purpose of this review is to underline the added value of Gd-EOB-DTPA in early-stage diagnoses of HCC. We also analyse the guidelines for the diagnosis and management of HCC, the key concepts of HCC development, growth and spread and the imaging appearance of precursor nodules that eventually may transform into overt HCC.
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Affiliation(s)
- Riccardo Inchingolo
- Division of Interventional Radiology, Department of Radiology, Madonna delle Grazie Hospital, Matera 75100, Italy.
| | - Riccardo Faletti
- Department of Surgical Sciences, Radiology Unit, University of Turin, Turin 10126, Italy
| | - Luigi Grazioli
- Department of Radiology, University of Brescia "Spedali Civili", Brescia 25123, Italy
| | - Eleonora Tricarico
- Division of Interventional Radiology, Department of Radiology, Madonna delle Grazie Hospital, Matera 75100, Italy
| | - Marco Gatti
- Department of Surgical Sciences, Radiology Unit, University of Turin, Turin 10126, Italy
| | - Anna Pecorelli
- Department of Diagnostic Radiology, School of Medicine, University of Milano-Bicocca, Monza 20900, Italy
| | - Davide Ippolito
- Department of Diagnostic Radiology, School of Medicine, University of Milano-Bicocca, Monza 20900, Italy
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31
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Shen Q, Eun JW, Lee K, Kim HS, Yang HD, Kim SY, Lee EK, Kim T, Kang K, Kim S, Min DH, Oh SN, Lee YJ, Moon H, Ro SW, Park WS, Lee JY, Nam SW. Barrier to autointegration factor 1, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3, and splicing factor 3b subunit 4 as early-stage cancer decision markers and drivers of hepatocellular carcinoma. Hepatology 2018; 67:1360-1377. [PMID: 29059470 DOI: 10.1002/hep.29606] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 09/20/2017] [Accepted: 10/16/2017] [Indexed: 01/05/2023]
Abstract
UNLABELLED An accurate tool enabling early diagnosis of hepatocellular carcinoma (HCC) is clinically important, given that early detection of HCC markedly improves survival. We aimed to investigate the molecular markers underlying early progression of HCC that can be detected in precancerous lesions. We designed a gene selection strategy to identify potential driver genes by integrative analysis of transcriptome and clinicopathological data of human multistage HCC tissues, including precancerous lesions, low- and high-grade dysplastic nodules. The gene selection process was guided by detecting the selected molecules in both HCC and precancerous lesion. Using various computational approaches, we selected 10 gene elements as a candidate and, through immunohistochemical staining, showed that barrier to autointegration factor 1 (BANF1), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3), and splicing factor 3b subunit 4 (SF3B4) are HCC decision markers with superior capability to diagnose early-stage HCC in a large cohort of HCC patients, as compared to the currently popular trio of HCC diagnostic markers: glypican 3, glutamine synthetase, and heat-shock protein 70. Targeted inactivation of BANF1, PLOD3, and SF3B4 inhibits in vitro and in vivo liver tumorigenesis by selectively modulating epithelial-mesenchymal transition and cell-cycle proteins. Treatment of nanoparticles containing small-interfering RNAs of the three genes suppressed liver tumor incidence as well as tumor growth rates in a spontaneous mouse HCC model. We also demonstrated that SF3B4 overexpression triggers SF3b complex to splice tumor suppressor KLF4 transcript to nonfunctional skipped exon transcripts. This contributes to malignant transformation and growth of hepatocyte through transcriptional inactivation of p27Kip1 and simultaneously activation of Slug genes. CONCLUSION The findings suggest molecular markers of BANF1, PLOD3, and SF3B4 indicating early-stage HCC in precancerous lesion, and also suggest drivers for understanding the development of hepatocarcinogenesis. (Hepatology 2018;67:1360-1377).
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Affiliation(s)
- Qingyu Shen
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Woo Eun
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyungbun Lee
- Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hyung Seok Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Doo Yang
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Yean Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Kyung Lee
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Taemook Kim
- Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, Republic of Korea
| | - Keunsoo Kang
- Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, Republic of Korea
| | - Seongchan Kim
- Center for RNA Research, Institute for Basic Science (IBS), Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Dal-Hee Min
- Center for RNA Research, Institute for Basic Science (IBS), Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Soon-Nam Oh
- Department of Radiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Joon Lee
- Department of Radiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyuk Moon
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Simon Weonsang Ro
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Young Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Republic of Korea
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32
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Yang D, Li R, Zhang XH, Tang CL, Ma KS, Guo DY, Yan XC. Perfusion Characteristics of Hepatocellular Carcinoma at Contrast-enhanced Ultrasound: Influence of the Cellular differentiation, the Tumor Size and the Underlying Hepatic Condition. Sci Rep 2018; 8:4713. [PMID: 29549368 PMCID: PMC5856788 DOI: 10.1038/s41598-018-23007-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 03/05/2018] [Indexed: 12/12/2022] Open
Abstract
This study aimed to analyze the influence of the cellular differentiation, the tumor size and the underlying hepatic condition on the enhancement pattern of hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS). 276 patients with single lesion ≤ 5 cm who underwent CEUS exam and were pathologically confirmed as HCC were retrospectively enrolled. Enhancement patterns, washout patterns, wash-in time and washout time were observed and recorded. During the arterial phase, more poorly differentiated HCCs (42.5%) and lesions > 3 cm (35.2%) performed inhomogeneous enhancement (p < 0.05). More well differentiated HCCs (63.4%) performed late washout or no washout while compared with moderately (37.8%) or poorly (24.1%) differentiated HCCs (p < 0.05). Poorly differentiated HCCs showed the shortest washout time (83.0 ± 39.8 s), moderately differentiated HCCs showed the moderate washout time (100.4 ± 52.1 s), and well differentiated HCCs showed the longest washout time (132.3 ± 54.2 s) (p < 0.05). Lesions > 3 cm (97.2 ± 51.3 s) washed out more rapidly than lesions ≤ 3 cm (113.9 ± 53.5 s) (p < 0.05). The dynamic enhancement procedure of HCC was influenced by the cellular differentiation and the tumor size. While, hepatic background showed no influence on the dynamic enhancement of HCC.
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Affiliation(s)
- Dan Yang
- Department Ultrasound, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
| | - Rui Li
- Department Ultrasound, the Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Xiao-Hang Zhang
- Department Ultrasound, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
| | - Chun-Lin Tang
- Department Ultrasound, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
| | - Kuan-Sheng Ma
- Department Hepato-biliary-Pancreatic Surgery, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
| | - De-Yu Guo
- Department Pathology, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
| | - Xiao-Chu Yan
- Department Pathology, Southwest Hospital Affiliated to Third Military Medical University, Chongqing, China
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33
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Cucchetti A, Vitale A. Personalized management of patients with very early hypovascular hepatocellular carcinoma. Liver Int 2018; 38:415-416. [PMID: 29469211 DOI: 10.1111/liv.13699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Affiliation(s)
- Alessandro Cucchetti
- Department of Medical and Surgical Sciences - DIMEC, S.Orsola-Malpighi Hospital, Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
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34
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Takayasu K, Arii S, Sakamoto M, Matsuyama Y, Kudo M, Kaneko S, Nakashima O, Kadoya M, Izumi N, Takayama T, Ku Y, Kumada T, Kubo S, Kokudo T, Hagiwara Y, Kokudo N. Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting. Liver Int 2018; 38:484-493. [PMID: 29266722 DOI: 10.1111/liv.13670] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 12/09/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. METHODS The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. RESULTS The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. CONCLUSIONS For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA.
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Affiliation(s)
- Kenichi Takayasu
- Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan
| | - Shigeki Arii
- Department of Hepato-Biliary-Pancreatic Surgery, Hamamatsu Rosai Hospital, Japan Labor Health and Welfare Organization, Hamamatsu, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Matsuyama
- Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Sayama, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University School of Medical Science, Kanazawa, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan
| | - Masumi Kadoya
- Department of Radiology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yonson Ku
- Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takashi Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yasuhiro Hagiwara
- Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
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35
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Rizzo F, Rinaldi A, Marchese G, Coviello E, Sellitto A, Cordella A, Giurato G, Nassa G, Ravo M, Tarallo R, Milanesi L, Destro A, Torzilli G, Roncalli M, Di Tommaso L, Weisz A. Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma. Oncotarget 2018; 7:54650-54661. [PMID: 27429044 PMCID: PMC5342370 DOI: 10.18632/oncotarget.10567] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/06/2016] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the result of a stepwise process, often beginning with development within a cirrhotic liver of premalignant lesions, morphologically characterized by low- (LGDN) and high-grade (HGDN) dysplastic nodules. PIWI-interacting RNAs (piRNAs) are small noncoding RNAs (sncRNAs), 23-35 nucleotide-long, exerting epigenetic and post-transcriptional regulation of gene expression. Recently the PIWI-piRNA pathway, best characterized in germline cells, has been identified also in somatic tissues, including stem and cancer cells, where it influences key cellular processes.Small RNA sequencing was applied to search for liver piRNAs and to profile their expression patterns in cirrhotic nodules (CNs), LGDN, HGDN, early HCC and progressed HCC (pHCC), analyzing 55 samples (14 CN, 9 LGDN, 6 HGDN, 6 eHCC and 20 pHCC) from 17 patients, aiming at identifying possible relationships between these sncRNAs and liver carcinogenesis. We identified a 125 piRNA expression signature that characterize HCC from matched CNs, correlating also to microvascular invasion in HCC. Functional analysis of the predicted RNA targets of deregulated piRNAs indicates that these can target key signaling pathways involved in hepatocarcinogenesis and HCC progression, thereby affecting their activity. Interestingly, 24 piRNAs showed specific expression patterns in dysplastic nodules, respect to cirrhotic liver and/or pHCC.The results demonstrate that the PIWI-piRNA pathway is active in human liver, where it represents a new player in the molecular events that characterize hepatocarcinogenesis, from early stages to pHCC. Furthermore, they suggest that piRNAs might be new disease biomarkers, useful for differential diagnosis of dysplastic and neoplastic liver lesions.
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Affiliation(s)
- Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | - Antonio Rinaldi
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | | | - Elena Coviello
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | - Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | | | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.,Genomix4life, University of Salerno, Baronissi (SA), Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.,Genomix4life, University of Salerno, Baronissi (SA), Italy
| | - Maria Ravo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
| | - Luciano Milanesi
- Institute for Biomedical Technologies, National Research Council, Milano, Italy
| | - Anna Destro
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano-Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy.,Hepatobiliary and General Surgery Division, Humanitas Clinical and Research Center, Rozzano-Milan, Italy
| | - Massimo Roncalli
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano-Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy
| | - Luca Di Tommaso
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano-Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, Baronissi (SA), Italy
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36
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Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from patients with hepatocellular carcinoma. Cell Oncol (Dordr) 2017; 41:169-184. [PMID: 29204978 DOI: 10.1007/s13402-017-0364-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Recently, Glypican-3 (GPC3) has been identified as a potential hepatocellular carcinoma (HCC) diagnostic and/or therapeutic target. GPC3 has been found to be up-regulated in HCC and to be absent in normal and cirrhotic liver. As yet, however, the molecular characteristics of GPC3 and its role in HCC cell physiology and development are still undefined. METHODS Human hepatocyte cultures were established from 10 HCC patients. Additional liver samples were obtained from 5 patients without cirrhosis and/or HCC. Soft agar colony formation, (co-)immunofluorescence and Western blot assays were used to characterize the hapatocyte cultures. The expression of GPC3 in the hepatocytes was silenced using siRNA, after which, apoptosis, scratch wound migration and transwell invasion assays were performed. RESULTS We found that in HCC precursor hepatocytes GPC3 is increasingly expressed in different forms and at different locations, i.e., a non-cleaved form (70 kDa) was found to be localized in the cytoplasm while a N-terminal cleaved form (N-GPC3: 40 kDa) was fond to be localized in the cytoplasm and at the extracellular side of hepatocyte membranes. In addition, we found that the non-cleaved form of GPC3 co-localizes with Furin-Convertase in the Golgi apparatus. We also found that, similar to GPC3, Furin-Convertase is expressed in HCC precursor cells, suggesting a role in GPC3 processing. Subsequent siRNA-mediated GPC3 silencing resulted in a temporary inhibition of cell proliferation, migration and ivasion, while inducing apoptosis in transformed hepatocytes. CONCLUSION Our data reveal new aspects of the role of GPC3 in early hepatocyte transformation. In addition we conclude that GPC3 may serve as a new HCC immune-therapeutic target.
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37
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Imai Y, Katayama K, Hori M, Yakushijin T, Fujimoto K, Itoh T, Igura T, Sakakibara M, Takamura M, Tsurusaki M, Takahashi H, Nakanishi K, Usuki N, Tsuji K, Ohashi H, Kim T, Takehara T, Murakami T. Prospective Comparison of Gd-EOB-DTPA-Enhanced MRI with Dynamic CT for Detecting Recurrence of HCC after Radiofrequency Ablation. Liver Cancer 2017; 6:349-359. [PMID: 29234638 PMCID: PMC5704682 DOI: 10.1159/000481416] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND We prospectively compared the efficacy of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) with that of dynamic multidetector computed tomography (MDCT) for detection of recurrent hypervascular hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). METHODS Institutional review board approval and written informed consent were obtained for this multicenter study. Ninety-seven HCC patients treated with curative RFA underwent both Gd-EOB-DTPA-enhanced MRI and dynamic MDCT every 3-4 months. HCC diagnosis was made based on the typical enhancement pattern of HCC on MRI and/or CT by on-site consensus reading. Two blinded observers independently assessed image datasets to compare diagnostic accuracy, sensitivity, specificity, and the areas under the receiver operating characteristic curve (AUROC). RESULTS Recurrence was observed in 48 of 97 patients. Among these, 22 were diagnosed by both Gd-EOB-DTPA-enhanced MRI and MDCT; the remainder were diagnosed by only one of these 2 modalities. Recurrence was diagnosed in more patients by Gd-EOB-DTPA-enhanced MRI than by MDCT (44 vs. 26 patients, p < 0.001). Patient-based analysis revealed that the accuracy, sensitivity, and AUROC of Gd-EOB-DTPA-enhanced MRI were significantly higher than those of MDCT for both observers (p < 0.005). The AUROC of Gd-EOB-DTPA- enhanced MRI and MDCT was 0.95 and 0.76 for observer 1 and 0.90 and 0.74 for observer 2, respectively. The κ values for MRI and MDCT were 0.83 and 0.70, respectively. CONCLUSIONS Compared with dynamic MDCT, Gd-EOB-DTPA-enhanced MRI had higher diagnostic accuracy and sensitivity for detection of recurrent hypervascular HCC and may be a better tool for following patients after RFA.
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Affiliation(s)
- Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan,*Yasuharu Imai, MD, PhD, Department of Gastroenterology, Ikeda Municipal Hospital, 3-1-18, Johnan, Ikeda, Osaka 563-8510 (Japan), E-Mail
| | - Kazuhiro Katayama
- Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Masatoshi Hori
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kenji Fujimoto
- Department of Internal Medicine, National Hospital Organization Minamiwakayama Medical Center, Tanabe, Japan,Division of Clinical Research, National Hospital Organization Minamiwakayama Medical Center, Tanabe, Japan
| | - Toshifumi Itoh
- Department of Gastroenterology and Hepatology, JCHO Osaka Hospital, Osaka, Japan
| | - Takumi Igura
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Mitsuru Sakakibara
- Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Manabu Takamura
- Department of Radiology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Masakatsu Tsurusaki
- Department of Radiology, Faculty of Medicine, Kindai University, Sayama, Japan
| | - Hiroto Takahashi
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Katsuyuki Nakanishi
- Department of Diagnostic Radiology, Osaka International Cancer Institute, Osaka, Japan
| | - Noriaki Usuki
- Department of Radiology, JCHO Osaka Hospital, Osaka, Japan
| | - Koh Tsuji
- Department of Radiology, National Hospital Organization Minamiwakayama Medical Center, Tanabe, Japan
| | - Hiroshi Ohashi
- Department of Pathology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Tonsok Kim
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takamichi Murakami
- Department of Radiology, Faculty of Medicine, Kindai University, Sayama, Japan
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38
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Radiologically Undetected Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation: An Immunohistochemical Correlation With LI-RADS Score. Am J Surg Pathol 2017; 41:1466-1472. [PMID: 28914714 DOI: 10.1097/pas.0000000000000955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Orthotopic liver transplantation is the best option for patients with carefully selected unresectable disease because of underlying liver dysfunction. The 5-year survival rate after orthotopic liver transplantation for early detected hepatocellular carcinoma (HCC) is high, and a similar or even higher rate is reported in those with radiologically undetected HCC. This study evaluated and compared the histologic features of pretransplant radiologically undetected (14 patients, 25 tumors) versus detected (36 patients, 45 tumors) HCCs. Tumor size, tumor differentiation, number of unpaired arteries, mitotic count per 10 high-power fields, CD34 immunostain to assess microvessel density, and Ki67 immunostain were compared with the Liver Imaging Reporting and Data System score, which was retrospectively assigned to each tumor in both groups. The Liver Imaging Reporting and Data System score was significantly higher in the HCC detected group (P<0.001). The vast majority of the undetected HCCs (88%) was <2 cm in size. Only 12% of the undetected HCCs were ≥2 cm, whereas 51% of the detected HCCs were ≥2 cm in size. Higher rate of moderate to poor tumor differentiation was noted in the detected HCCs compared with the undetected group (89% vs. 60%; P=0.004). No statistically significant difference in the number and distribution of unpaired arteries, or mitotic count was observed in 2 groups (although fewer unpaired arteries were identified in the undetected group). The detected HCCs had a higher rate of 2+ CD34 staining compared with the undetected HCCs (68% vs. 27%; P=0.002), whereas the opposite was observed for 1+ CD34 staining (59% undetected HCCs vs. 17% detected HCCs; P=0.002). Ki67 proliferative index was not statistically different between the 2 groups (120.8/1000 cells detected HCCs vs. 81.8/1000 cells undetected HCCs; P=0.36). The factors associated with failing to detect HCCs pretransplant by radiologic studies include small tumor size (<2 cm), low-grade histologic differentiation, and low microvessel density (low CD34 staining). A significant association between the number and distribution of unpaired arteries and HCC detection has not been established by our study.
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Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017; 11:317-370. [PMID: 28620797 PMCID: PMC5491694 DOI: 10.1007/s12072-017-9799-9] [Citation(s) in RCA: 1612] [Impact Index Per Article: 201.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 05/02/2017] [Indexed: 02/06/2023]
Abstract
There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.
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Affiliation(s)
- Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-city, Yamanashi, Japan.
- The University of Tokyo, Tokyo, Japan.
| | - Ann-Lii Cheng
- Department of Oncology and Internal Medicine, National Taiwan University Hospital, National Taiwan University Cancer Center and Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka-Sayama, Osaka, Japan
| | - Jeong Min Lee
- Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jidong Jia
- Beijing Key Laboratory of Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoghesh K Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University and Hospital, Karachi, Pakistan
| | | | - Takamasa Ohki
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cosmas Rinaldi A Lesmana
- Digestive Disease and GI Oncology Center, Medistra Hospital, University of Indonesia, Jakarta, Indonesia
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Laurentius A Lesmana
- Digestive Disease and GI Oncology Center, Medistra Hospital, University of Indonesia, Jakarta, Indonesia
| | - Rino A Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Shuntaro Obi
- Third Department of Internal Medicine, Teikyo University School of Medicine, Chiba, Japan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Park HJ, Choi BI, Lee ES, Park SB, Lee JB. How to Differentiate Borderline Hepatic Nodules in Hepatocarcinogenesis: Emphasis on Imaging Diagnosis. Liver Cancer 2017; 6:189-203. [PMID: 28626731 PMCID: PMC5473078 DOI: 10.1159/000455949] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Rapid advances in liver imaging have improved the evaluation of hepatocarcinogenesis and early diagnosis and treatment of hepatocellular carcinoma (HCC). In this situation, detection of early-stage HCC in its development is important for the improvement of patient survival and optimal treatment strategies. Because early HCCs are considered precursors of progressed HCC, precise differentiation between a dysplastic nodule (DN), especially a high-grade DN, and early HCC is important. In clinical practice, these nodules are frequently called "borderline hepatic nodules." SUMMARY This article discusses radiological and pathological characteristics of these borderline hepatic nodules and offers an understanding of multistep hepatocarcinogenesis by focusing on the descriptions of the imaging changes in the progression of DN and early HCC. Detection and accurate diagnosis of borderline hepatic nodules are still a challenge with contrast enhanced ultrasonography, CT, and MRI with extracellular contrast agents. However, gadoxetic acid-enhanced MRI may be useful for improving the diagnosis of these borderline nodules. KEY MESSAGES Since there is a net effect of incomplete neoangiogenesis and decreased portal venous flow in the early stage of hepatocarcinogenesis, borderline hepatic nodules commonly show iso- or hypovascularity. Therefore, precise differentiation of these nodules remains a challenging issue. In MRI using hepatobiliary contrast agents, signal intensity of HCCs on hepatobiliary phase (HBP) is regarded as a potential imaging biomarker. Borderline hepatic nodules are seen as nonhypervascular and hypointense nodules on the HBP, which is important for predicting tumor behavior and determining appropriate therapeutic strategies.
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Affiliation(s)
| | - Byung Ihn Choi
- Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
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Jo PC, Jang HJ, Burns PN, Burak KW, Kim TK, Wilson SR. Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It. Radiology 2017; 282:317-331. [PMID: 28099108 DOI: 10.1148/radiol.2016151732] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material-enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. © RSNA, 2017 Online supplemental material is available for this article.
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Affiliation(s)
- Patricia C Jo
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
| | - Hyun-Jung Jang
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
| | - Peter N Burns
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
| | - Kelly W Burak
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
| | - Tae Kyoung Kim
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
| | - Stephanie R Wilson
- From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, 1403 29 St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.)
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Development of Risk Prediction Model for Hepatocellular Carcinoma Progression of Indeterminate Nodules in Hepatitis B Virus-Related Cirrhotic Liver. Am J Gastroenterol 2017; 112:460-470. [PMID: 27779194 DOI: 10.1038/ajg.2016.480] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 09/01/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study was performed to evaluate long-term outcome of indeterminate nodules detected on cirrhotic liver and to develop risk prediction model for hepatocellular carcinoma (HCC) progression of indeterminate nodules on hepatitis B virus (HBV)-related cirrhotic liver. METHODS Indeterminate nodules up to 2 cm with uncertain malignant potential detected on computed tomography of cirrhotic liver during HCC surveillance were analyzed retrospectively. HCC risk prediction model of indeterminate nodules in HBV-related cirrhotic liver was deduced based on result of Cox regression analysis. RESULTS A total of 494 indeterminate nodules were included. Independent risk factors of HCC progression were old age, arterial enhancement, large nodule size, low serum albumin level, high serum α-fetoprotein (AFP) level, and prior HCC history in all included subjects. In subjects with chronic hepatitis B, old age (year; hazard ratio (HR)=1.06; P<0.001), arterial enhancement (HR=2.62; P=0.005), large nodule size (>1 cm; HR=7.34; P<0.001), low serum albumin level (≤3.5 g/dl; HR=3.57; P=0.001), high serum AFP level (≥100 ng/ml; HR=6.04; P=0.006), prior HCC history (HR=4.24; P=0.001), and baseline hepatitis B e antigen positivity (HR=2.31; P=0.007) were associated with HCC progression. We developed a simple risk prediction model using these risk factors and identified patients at low, intermediate, and high risk for HCC; 5-year cumulative incidences were 1%, 14.5%, and 63.1%, respectively. The developed risk score model showed good performance with area under the curve at 0.886 at 3 years, and 0.920 at 5 years in leave-one-out cross-validation. CONCLUSIONS We developed a useful and accurate risk score model for predicting HCC progression of indeterminate nodules detected on HBV-related cirrhotic liver.
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An Anti-Human Lutheran Glycoprotein Phage Antibody Inhibits Cell Migration on Laminin-511: Epitope Mapping of the Antibody. PLoS One 2017; 12:e0167860. [PMID: 28060819 PMCID: PMC5218393 DOI: 10.1371/journal.pone.0167860] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 11/21/2016] [Indexed: 11/24/2022] Open
Abstract
The Lutheran glycoprotein (Lu), also known as basal cell adhesion molecule (B-CAM), is an Ig superfamily (IgSF) transmembrane receptor for laminin α5. Although Lu is not present in normal hepatocytes, its expression is significantly increased in hepatocellular carcinoma (HCC). In this study, we isolated thirteen phage antibodies to Lu from a phage library of peripheral blood from HCC patients, suggesting that these patients produced autoantibodies against endogenous Lu. To characterize the phage antibodies, we determined the Lu domains they recognize. The extracellular domain of Lu contains five IgSF domains, D1-D2-D3-D4-D5. The epitope of one phage antibody (A7) was localized to the D5 domain. The other phage antibodies recognized the D2 domain, which is also recognized by a function blocking mouse monoclonal antibody. One of the antibodies to D2 (C7) inhibited the binding of Lu to ligand, and it also prevented tumor cell migration on laminin-511 (LM-511). However, the C7 scFv purified from the periplasm fraction of bacteria did not exhibit the inhibitory effects, indicating that the scFv form could not sterically inhibit the binding of Lu to LM-511. We also identified the amino acid residues that form the epitope recognized by the C7 phage antibody. Mutagenesis studies showed that Arg247 is necessary for forming the epitope. The C7 phage antibody and its epitope may be useful for developing drugs to prevent HCC progression and/or metastasis.
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Yue WW, Wang S, Xu HX, Sun LP, Guo LH, Bo XW, Li XL, Zhao CK, Wang D, Liu BJ. Parametric imaging with contrast-enhanced ultrasound for differentiating hepatocellular carcinoma from metastatic liver cancer. Clin Hemorheol Microcirc 2016; 64:177-188. [PMID: 27258196 DOI: 10.3233/ch-162060] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Wen-Wen Yue
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Shuo Wang
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
- Department of Ultrasound, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui-Xiong Xu
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
- State Key Laboratory of High Performance Ceramic and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Science, Shanghai, China
| | - Li-Ping Sun
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Le-Hang Guo
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Xiao-Wan Bo
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Xiao-Long Li
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Chong-Ke Zhao
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Dan Wang
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
| | - Bo-Ji Liu
- Department of Medical Ultrasound, Tenth People’s Hospital of Tongji University, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai, China
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Lin MT, Wang CC, Cheng YF, Eng HL, Yen YH, Tsai MC, Tseng PL, Chang KC, Wu CK, Hu TH. Comprehensive Comparison of Multiple-Detector Computed Tomography and Dynamic Magnetic Resonance Imaging in the Diagnosis of Hepatocellular Carcinoma with Varying Degrees of Fibrosis. PLoS One 2016; 11:e0166157. [PMID: 27829060 PMCID: PMC5102357 DOI: 10.1371/journal.pone.0166157] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 10/23/2016] [Indexed: 01/27/2023] Open
Abstract
Background & Aims Liver computed tomography and dynamic magnetic resonance imaging play an important role in the early detection of hepatocellular carcinoma. However, the American Association for the Study of Liver Diseases (AASLD) recommend the use of applied imaging studies for HCC diagnosis only in cirrhotic patients. This study aimed to comprehensively compare liver CT and dynamic MRI for HCC diagnosis before surgical resection over years in clinical practice, and also to compare the diagnostic differences between liver CT and dynamic MRI in HCCs with varying degrees of fibrosis. Methods 841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification. Results Among the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies. Conclusions The application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary.
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Affiliation(s)
- Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chih-Chi Wang
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yu-Fan Cheng
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- * E-mail:
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Tada T, Kumada T, Toyoda H, Sone Y, Kaneoka Y, Maeda A, Okuda S, Otobe K, Tsuji N. Utility of combined gray-scale and perflubutane contrast-enhanced ultrasound for diagnosing early hepatocellular carcinomas: Comparison of well differentiated and distinctly nodular types. Hepatol Res 2016; 46:1214-1225. [PMID: 26860925 DOI: 10.1111/hepr.12670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/27/2016] [Accepted: 02/04/2016] [Indexed: 12/13/2022]
Abstract
AIM To clarify the value of gray-scale ultrasound (US) combined with contrast-enhanced US (CEUS) with perflubutane in diagnosing early hepatocellular carcinoma (HCC). METHODS A total of 57 surgically resected, well differentiated HCCs were analyzed. Hepatocellular carcinomas were macroscopically diagnosed as vaguely nodular or distinctly nodular types, which correspond to early HCC or progressed HCC, respectively. Gray-scale US findings were evaluated in terms of shape (round or roundish, or irregular), border and contour (well-defined and smooth, or poorly defined), and intratumor echo levels (hyper, hypo, iso, heterogeneous, or mosaic). Contrast-enhanced US findings were evaluated during the arterial phase (vascularity [finely homogeneous, dendritic, or chaotic] and perfusion enhancement [homogeneous or heterogeneous]), portal phase (presence or absence of washout), and post-vascular phase (echo intensity level [defect, incomplete defect, or iso-enhancing]). RESULTS Eighteen HCCs were categorized as early HCCs and the remaining 39 were categorized as progressed HCCs. Receiver operating characteristic curve analysis for the diagnosis of early HCC yielded area under the receiver operating characteristic curve (Az ) values for border and contour on gray-scale US and echo intensity level in the CEUS post-vascular phase of 0.782 and 0.828, respectively. Multiple logistic regression analysis also indicated that both of these gray-scale US and CEUS findings were independently associated with early HCC. The Az value for the combination of border and contour and echo intensity for the diagnosis of early HCC was 0.907, corresponding to a high diagnostic value. CONCLUSION The combination of gray-scale US and CEUS can provide high-quality imaging assessment for diagnosing early HCC.
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Affiliation(s)
- Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yasuhiro Sone
- Department of Radiology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yuji Kaneoka
- Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsuyuki Maeda
- Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan
| | - Seiji Okuda
- Department of Pathological Diagnosis, Ogaki Municipal Hospital, Ogaki, Japan
| | | | - Nozomi Tsuji
- Imaging Diagnosis, Ogaki Municipal Hospital, Ogaki, Japan
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Kowalik MA, Sulas P, Ledda-Columbano GM, Giordano S, Columbano A, Perra A. Cytokeratin-19 positivity is acquired along cancer progression and does not predict cell origin in rat hepatocarcinogenesis. Oncotarget 2016; 6:38749-63. [PMID: 26452031 PMCID: PMC4770734 DOI: 10.18632/oncotarget.5501] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 09/21/2015] [Indexed: 02/06/2023] Open
Abstract
Although the expression of the stem/progenitor cell marker cytokeratin-19 (CK-19) has been associated with the worst clinical prognosis among all HCC subclasses, it is yet unknown whether its presence in HCC is the result of clonal expansion of hepatic progenitor cells (HPCs) or of de-differentiation of mature hepatocytes towards a progenitor-like cell phenotype. We addressed this question by using two rat models of hepatocarcinogenesis: the Resistant-Hepatocyte (R-H) and the Choline-methionine deficient (CMD) models. Our data indicate that the expression of CK-19 is not the result of a clonal expansion of HPCs (oval cells in rodents), but rather of a further step of preneoplastic hepatocytes towards a less differentiated phenotype and a more aggressive behavior. Indeed, although HCCs were positive for CK-19, very early preneoplastic foci (EPFs) were completely negative for this marker. While a few weeks later the vast majority of preneoplastic nodules remained CK-19 negative, a minority became positive, suggesting that CK-19 expression is the result of de-differentiation of a subset of EPFs, rather than a marker of stem/progenitor cells. Moreover, the gene expression profile of CK-19-negative EPFs clustered together with CK-19-positive nodules, but was clearly distinct from CK-19 negative nodules and oval cells.
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Affiliation(s)
- Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Pia Sulas
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | | | - Silvia Giordano
- University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo, Torino, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
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Prognostic Significance of Concurrent Hypovascular and Hypervascular Nodules in Patients with Hepatocellular Carcinoma. PLoS One 2016; 11:e0163119. [PMID: 27649084 PMCID: PMC5029907 DOI: 10.1371/journal.pone.0163119] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 09/03/2016] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hypovascular nodules often occur together with hypervascular hepatocellular carcinoma (HCC). However, it remains controversial whether hypovascular nodules associated with hypervascular HCC have any prognostic value. This study evaluated the prognostic impact of hypovascular nodules co-existing with hypervascular HCC as diagnosed by computed tomography during arterial portography (CTAP) and computed tomography during hepatic arteriography (CTHA), which can sensitively capture the dynamic changes in blood flow through the portal vein and hepatic artery in patients with early stage HCC. METHODS A total of 152 patients with hypervascular HCC (≤ 30 mm, ≤ 3 nodules), who underwent initial local ablation, were analyzed retrospectively. All patients received CTAP and CTHA prior to treatment. Overall survival (OS) was compared among group A (hypervascular HCC only, 107 patients) and group B (hypovascular nodules and hypervascular HCC, 45 patients). RESULTS Among all hypovascular nodules, 81% (46 of 57) developed hypervascularization within the follow-up period. The 1- and 2-year hypervascularization rates were 17% and 51%, respectively. OS was significantly longer for group A than for group B (P < 0.001). A Cox proportional-hazards model identified the presence of hypovascular nodules concurrent with hypervascular HCC as an independent poor prognostic factor. CONCLUSION The prognosis of hypervascular HCC patients with hypovascular nodules detected during CTAP and CTHA is poor. Clinical HCC categories seem to be dissimilar between patients with and without hypovascular nodules.
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Sano K. [8．Imaging of Hepatocellular Carcinoma]. Nihon Hoshasen Gijutsu Gakkai Zasshi 2016; 72:930-938. [PMID: 27647600 DOI: 10.6009/jjrt.2016_jsrt_72.9.930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Affiliation(s)
- Katsuhiro Sano
- Department of Diagnostic Radiology, Saitama Medical University International Medical Center
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Piras-Straub K, Khairzada K, Kocabayoglu P, Paul A, Gerken G, Herzer K. A -1573T>C SNP within the human TRAIL promoter determines TRAIL expression and HCC tumor progression. Cancer Med 2016; 5:2942-2952. [PMID: 27580702 PMCID: PMC5083748 DOI: 10.1002/cam4.854] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 07/04/2016] [Accepted: 07/14/2016] [Indexed: 12/23/2022] Open
Abstract
The cytokine tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis in liver cancer cells but not in normal liver cells. Therefore, TRAIL got credited to play a role in hepatocellular carcinoma (HCC) development and progression. Impaired expression of TRAIL in HCC cells and sequence variations in the TRAIL promoter may facilitate development, growth, and spread . The TRAIL promoter was sequenced from liver tissue of 93 patients undergoing partial liver resection (PRT) or liver transplantation (LT) for HCC. TRAIL mRNA expression was investigated by quantitative real‐time PCR. A variant ‐1573T>C (single‐nucleotide polymorphism; C, cytosine) SNP was characterized by electron mobility shift assay and supershift assays. Functionality of the ‐1573T>C SNP was analyzed in reporter gene assays and cell migration assays. In approximately 30% of HCC samples, a loss‐of‐function shift of the binding pattern due to a ‐1573T>C SNP was found within the human TRAIL promoter. Correlation analysis revealed significantly lower TRAIL expression in HCC samples with the ‐1573C sequence (P ≤ 0.05). Reporter gene assays revealed significantly reduced inducibility of the TRAIL promoter due to the ‐1573C sequence. The variant ‐1573C sequence impaired not only binding of transcription factors but also expression of TRAIL. Interestingly, this impairment resulted in enhanced migration activity and colony formation of the liver tumor cells. Our findings suggest that loss of function of the human TRAIL promoter due to the ‐1573T>C SNP leads to reduced expression and impaired inducibility of TRAIL, with the consequence of enhanced growth and migration of tumor cells, ultimately resulting in the progression of the HCC.
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Affiliation(s)
- Katja Piras-Straub
- Department of General, Visceral, and Transplantation Surgery, University Hospital Germany, Essen, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Khaleda Khairzada
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Peri Kocabayoglu
- Department of General, Visceral, and Transplantation Surgery, University Hospital Germany, Essen, Germany
| | - Andreas Paul
- Department of General, Visceral, and Transplantation Surgery, University Hospital Germany, Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Kerstin Herzer
- Department of General, Visceral, and Transplantation Surgery, University Hospital Germany, Essen, Germany. .,Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
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