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Mattiolo P, De Bellis M, Mafficini A, Fassan M, Bevere M, Ciulla C, Bersani S, Lawlor RT, Milella M, Scarpa A, Luchini C, Ruzzenente A. Long-Term Survivor of Intrahepatic Cholangiocarcinoma for over 18 Years: Case Study with Longitudinal Histo-molecular and Tumor Immune Microenvironment Characterization and Systematic Review of the Literature. J Gastrointest Cancer 2024; 55:1634-1646. [PMID: 39283582 PMCID: PMC11464565 DOI: 10.1007/s12029-024-01113-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/10/2024]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma is a biliary neoplasm usually showing a dismal prognosis. In early stages, surgical resection is the best treatment option, significantly increasing the overall survival. This approach is also recommended in the case of relapsing disease. In this study, we report the case of a patient affected by intrahepatic cholangiocarcinoma with multiple relapses and still alive for over 18 years. We also provide a systematic review regarding long-survivor (> 60 months) of intrahepatic cholangiocarcinoma. CASE PRESENTATION A 41-year-old woman with no pathological history was diagnosed with localized intrahepatic cholangiocarcinoma and surgically treated with left hepatectomy. After the first intervention, the patients underwent three further surgical resections because of locoregional recurrences. Histologically, there were some significant similarities among all neoplasms, including the tubule-glandular architecture, but also morphological heterogeneity. The tumor immune microenvironment remained stable across the different lesions. The molecular analysis with next-generation sequencing demonstrated that all neoplasms shared the same genomic profile, including NBN and NOTCH3 mutations and chromosomes 1 and 3 alterations. CONCLUSIONS This case study highlights the essential role of a stringent follow-up after resection of intrahepatic cholangiocarcinoma for detecting early relapsing tumors. Moreover, it shows the importance of the molecular characterization of multiple tumors for understanding their real nature. The accurate study of long-surviving patients highlights the features that are critical for outcome improvement.
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Affiliation(s)
- Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona, Italy.
| | - Mario De Bellis
- Division of General and Hepato-Biliary Surgery, Department of Surgery, Dentistry, Gynecology, and Pediatrics, University of Verona, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Mafficini
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
- Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
| | - Michele Bevere
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Calogero Ciulla
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona, Italy
| | - Samantha Bersani
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona, Italy
| | - Rita T Lawlor
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Michele Milella
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, University and Hospital Trust of Verona, Verona, Italy.
- ARC-Net Research Center, University of Verona, Verona, Italy.
| | - Andrea Ruzzenente
- Division of General and Hepato-Biliary Surgery, Department of Surgery, Dentistry, Gynecology, and Pediatrics, University of Verona, University and Hospital Trust of Verona, Verona, Italy
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Chiablaem K, Jinawath A, Nuanpirom J, Arora JK, Nasaree S, Thanomchard T, Singhto N, Chittavanich P, Suktitipat B, Charoensawan V, Chairoungdua A, Jinn-Chyuan Sheu J, Kiyotani K, Svasti J, Nakamura Y, Jinawath N. Identification of RNF213 as a Potential Suppressor of Local Invasion in Intrahepatic Cholangiocarcinoma. J Transl Med 2024; 104:102074. [PMID: 38723854 DOI: 10.1016/j.labinv.2024.102074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 04/08/2024] [Accepted: 04/30/2024] [Indexed: 06/14/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with poor survival especially when it spreads. The histopathology of its rare intraductal papillary neoplasm of the bile duct type (IPNB) characteristically shows cancer cells originating within the confined bile duct space. These cells eventually invade and infiltrate the nearby liver tissues, making it a good model to study the mechanism of local invasion, which is the earliest step of metastasis. To discover potential suppressor genes of local invasion in ICC, we analyzed the somatic mutation profiles and performed clonal evolution analyses of the 11 pairs of macrodissected locally invasive IPNB tissues (LI-IPNB) and IPNB tissues without local invasion from the same patients. We identified a protein-truncating variant in an E3 ubiquitin ligase, RNF213 (c.6967C>T; p.Gln2323X; chr17: 78,319,102 [hg19], exon 29), as the most common protein-truncating variant event in LI-IPNB samples (4/11 patients). Knockdown of RNF213 in HuCCT1 and YSCCC cells showed increased migration and invasion, and reduced vasculogenic mimicry but maintained normal proliferation. Transcriptomic analysis of the RNF213-knockdown vs control cells was then performed in the HuCCT1, YSCCC, and KKU-100 cells. Gene ontology enrichment analysis of the common differentially expressed genes revealed significantly altered cytokine and oxidoreductase-oxidizing metal ion activities, as confirmed by Western blotting. Gene Set Enrichment Analysis identified the most enriched pathways being oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, adipogenesis, and angiogenesis. In sum, loss-of-function mutation of RNF213 is a common genetic alteration in LI-IPNB tissues. RNF213 knockdown leads to increased migration and invasion of ICC cells, potentially through malfunctions of the pathways related to inflammation and energy metabolisms.
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Affiliation(s)
- Khajeelak Chiablaem
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand
| | - Artit Jinawath
- Molecular Histopathology Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jiratchaya Nuanpirom
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand
| | - Jantarika Kumar Arora
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Sirawit Nasaree
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanastha Thanomchard
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nilubon Singhto
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pamorn Chittavanich
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Bhoom Suktitipat
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Varodom Charoensawan
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Arthit Chairoungdua
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Jim Jinn-Chyuan Sheu
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kazuma Kiyotani
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Jisnuson Svasti
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand
| | - Yusuke Nakamura
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan; National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Natini Jinawath
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan, Thailand.
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Liu H, Lan T, Cai YS, Lyu YH, Zhu J, Xie SN, Hu FJ, Liu C, Wu H. Predicting prognosis in intrahepatic cholangiocarcinoma by the histopathological features. Asian J Surg 2024; 47:2589-2597. [PMID: 38604849 DOI: 10.1016/j.asjsur.2024.03.085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/23/2023] [Accepted: 03/06/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous liver tumor. The associations between histopathological feature and prognosis of ICC are limited. The present study aimed to investigate the prognostic significance of glandular structure and tumor budding in ICC. METHODS Patients received radical hepatectomy for ICC were included. Glandular structure and tumor budding were detected by Hematoxylin-eosin staining. The Kaplan-Meier method and the Cox proportional hazards regression model were used to calculate the survival and hazard ratio. Based on the results of multivariate analysis, nomograms of OS and DFS were constructed. C-index and Akaike information criterion (AIC) were used to assess accuracy of models. RESULTS A total of 323 ICC patients who underwent surgery were included in our study. Glandular structure was associated with worse overall survival (OS) [hazard ratio (HR): 2.033, 95% confidence interval (CI): 1.047 to 3.945] and disease-free survival (DFS) [HR: 1.854, 95% CI: 1.082 to 3.176]. High tumor budding was associated with worse DFS [HR: 1.636, 95%CI: 1.060 to 2.525]. Multivariate analysis suggested that glandular structure, tumor number, lymph node metastasis, and CA19-9 were independent risk factors for OS. Independent predictor factors for DFS were tumor budding, glandular structure, tumor number, and lymph node metastasis. The c-index (0.641 and 0.642) and AIC (957.69 and 1188.52) showed that nomograms of OS and DFS have good accuracy. CONCLUSION High tumor budding and glandular structure are two important histopathological features that serve as prognostic factors for ICC patients undergoing hepatectomy.
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Affiliation(s)
- Hu Liu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tian Lan
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yun-Shi Cai
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ying-Hao Lyu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiang Zhu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Si-Nan Xie
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Feng-Juan Hu
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chang Liu
- Division of Liver, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Minimal Invasive Surgery, Shangjin Nanfu Hospital, Chengdu, 610037, China.
| | - Hong Wu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Zou Y, Xu X, Wu T, Chen Q, Li Z, Yang Z, Wang K, Shen F. Sex disparity in clinical characteristics and long-term prognosis after liver resection for patients with intrahepatic cholangiocarcinoma: A propensity score matching analysis. Heliyon 2024; 10:e29910. [PMID: 38707344 PMCID: PMC11066329 DOI: 10.1016/j.heliyon.2024.e29910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/07/2024] Open
Abstract
Aim To compare the survival outcomes between male and female patients with intrahepatic cholangiocarcinoma who underwent liver resection. Methods Data from 976 consecutive intrahepatic cholangiocarcinoma patients undergoing liver resection between January 2005 and May 2013 at the Eastern Hepatobiliary Surgery Hospital were prospectively collected and retrospectively reviewed. Patient clinicopathological characteristics, overall survival, and cumulative recurrence rates were compared between male and female patients using propensity score matching. Results Propensity score matching generated 313 matched pairs of patients. Among the entire cohort, the 1-, 3-, and 5-year overall survival and recurrence rates of the male and female patients were 60.2 %, 37.3 %, and 27.7 % vs. 65.8 %, 40.4 %, and 31.0 % (P = 0.380) and 50.6 %, 67.4 %, and 74.2 % vs. 44.4 %, 63.5 %, and 69.6 % (P = 0.123), respectively. In the matched cohort, the 1-, 3-, and 5-year overall survival and recurrence rates of the male and female patients were 60.6 %, 35.9 % and 22.4 % vs. 66.4 %, 40.6 % and 31.1 % (P = 0.041) and 51.5 %, 69.3 % and 83.9 % vs. 44.3 %, 63.6 %, and 69.9 % (P = 0.041), respectively. After adjustment for other confounding variables by multivariate Cox regression analysis, male sex was independently associated with worse overall survival (hazard ratio = 1.322, 95 % confidence interval: 1.079-1.621, P = 0.007) and tumor recurrence (hazard ratio = 1.337, 95 % confidence interval: 1.088-1.645, P = 0.006). A subgroup analysis of patients younger than 55 years old after propensity score matching showed that male patients had significantly worse overall survival and higher recurrence rates than female patients after surgery, while no significant difference in long-term overall survival and recurrence was observed between male and female patients older than 55 years old after propensity score matching. Conclusion Male sex was an independent risk factor for overall survival and tumor recurrence in patients after liver resection for intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Yiran Zou
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xinfei Xu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Tanyang Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Qinjunjie Chen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zheng Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhishi Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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Khosla D, Misra S, Chu PL, Guan P, Nada R, Gupta R, Kaewnarin K, Ko TK, Heng HL, Srinivasalu VK, Kapoor R, Singh D, Klanrit P, Sampattavanich S, Tan J, Kongpetch S, Jusakul A, Teh BT, Chan JY, Hong JH. Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches. Cancers (Basel) 2024; 16:801. [PMID: 38398194 PMCID: PMC10887007 DOI: 10.3390/cancers16040801] [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: 01/11/2024] [Revised: 02/05/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.
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Affiliation(s)
- Divya Khosla
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shagun Misra
- Department of Radiotherapy and Oncology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Pek Lim Chu
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Peiyong Guan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rajesh Gupta
- Department of GI Surgery, HPB, and Liver Transplantation, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Khwanta Kaewnarin
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Tun Kiat Ko
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Hong Lee Heng
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Vijay Kumar Srinivasalu
- Department of Medical Oncology, Mazumdar Shaw Medical Center, NH Health City Campus, Bommasandra, Bangalore 560099, India
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deepika Singh
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Poramate Klanrit
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand
| | - Jing Tan
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Bin Tean Teh
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
| | - Jason Yongsheng Chan
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
- Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Division of Medical Oncology, National Cancer Center, Singapore 168583, Singapore
| | - Jing Han Hong
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
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Li Z, Gao Q, Wu Y, Ma X, Wu F, Luan S, Chen S, Shao S, Shen Y, Zhang D, Feng F, Yuan L, Wei S. HBV infection effects prognosis and activates the immune response in intrahepatic cholangiocarcinoma. Hepatol Commun 2024; 8:e0360. [PMID: 38206204 PMCID: PMC10786594 DOI: 10.1097/hc9.0000000000000360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/08/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND The impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features. METHODS We retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform. RESULTS The analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group. CONCLUSIONS The activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.
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Affiliation(s)
- Zhizhen Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Qingxiang Gao
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yingjun Wu
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaoming Ma
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
| | - Fangyan Wu
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Siyu Luan
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Sunrui Chen
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Siyuan Shao
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Yang Shen
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ding Zhang
- Department of Medical, 3D Medicines Inc., Shanghai, China
| | - Feiling Feng
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lei Yuan
- Department of Hepatobiliary Surgery, Quzhou People's Hospital, Quzhou, Zhejiang, China
| | - Shaohua Wei
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
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Yu L, Dai MG, Lu WF, Wang DD, Ye TW, Xu FQ, Liu SY, Liang L, Feng DJ. Preoperative prediction model for microvascular invasion in HBV-related intrahepatic cholangiocarcinoma. BMC Surg 2023; 23:239. [PMID: 37592274 PMCID: PMC10433593 DOI: 10.1186/s12893-023-02139-8] [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: 04/10/2023] [Accepted: 08/04/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND AND AIMS Preoperative prediction of microvascular invasion (MVI) using a noninvasive method remain unresolved, especially in HBV-related in intrahepatic cholangiocarcinoma (ICC). This study aimed to build and validate a preoperative prediction model for MVI in HBV-related ICC. METHODS Patients with HBV-associated ICC undergoing curative surgical resection were identified. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors of MVI in the training cohort. Then, a prediction model was built by enrolling the independent risk factors. The predictive performance was validated by receiver operator characteristic curve (ROC) and calibration in the validation cohort. RESULTS Consecutive 626 patients were identified and randomly divided into the training (418, 67%) and validation (208, 33%) cohorts. Multivariate analysis showed that TBIL, CA19-9, tumor size, tumor number, and preoperative image lymph node metastasis were independently associated with MVI. Then, a model was built by enrolling former fiver risk factors. In the validation cohort, the performance of this model showed good calibration. The area under the curve was 0.874 (95% CI: 0.765-0.894) and 0.729 (95%CI: 0.706-0.751) in the training and validation cohort, respectively. Decision curve analysis showed an obvious net benefit from the model. CONCLUSION Based on clinical data, an easy model was built for the preoperative prediction of MVI, which can assist clinicians in surgical decision-making and adjuvant therapy.
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Affiliation(s)
- Liang Yu
- Department of Radiology, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, Hangzhou, China
| | - Mu-Gen Dai
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Wen-Feng Lu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Dong-Dong Wang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery , General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, Hangzhou, China
| | - Tai-Wei Ye
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery , General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, Hangzhou, China
| | - Fei-Qi Xu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery , General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, Hangzhou, China
| | - Si-Yu Liu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
- Department of Laboratory Medicine, The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Lishui, Zhejiang, China
| | - Lei Liang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery , General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, Hangzhou, China
| | - Du-Jin Feng
- Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, 310014, Hangzhou, China.
- Department of Laboratory Medicine Center, Zhejiang Center for Clinical Laboratories, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
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8
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Zhang J, Dong W, Li Y, Fu J, Jia N. Prediction of microvascular invasion in combined hepatocellular-cholangiocarcinoma based on preoperative contrast-enhanced CT and clinical data. Eur J Radiol 2023; 163:110839. [PMID: 37121101 DOI: 10.1016/j.ejrad.2023.110839] [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: 02/15/2023] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 05/02/2023]
Abstract
OBJECTIVE Microvascular invasion (MVI) is significantly associated with prognosis in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. The study aimed to explore the value of preoperative contrast-enhanced CT (CECT) features and clinical data in predicting MVI of cHCC-CCA. METHODS A total of 33 patients with MVI-positive and 27 with MVI-negative were enrolled, and underwent preoperative CECT imaging from January 2016 to December 2021. Preoperative clinical data and CECT imaging features were retrospectively analyzed. Univariable and multivariable logistic regression analysis were performed to identify potential predictors of MVI in cHCC-CCA. The diagnostic performance was evaluated by the receiver operating characteristic (ROC) curve and its area under the curve (AUC) value. RESULTS The mean age of the patients was 54.0 ± 10.3 years, and 53 of the 60 patients (88.3%) were male. Preoperative imaging features on CECT (non-smooth contour and arterial phase peritumoral enhancement) and clinical data (hepatitis B virus (HBV) infection and protein induced by vitamin K absence or antagonist-II (PIVKA-II)) were highly distinct between those in MVI-positive group and MVI-negative group. On multivariable logistic analysis, arterial phase peritumoral enhancement (odds ratio (OR), 6.514; 95% confidence interval (CI), 1.588-26.728, p = 0.012) and high serum PIVKA-II level (OR, 6.810; 95% CI, 1.796-25.820, p = 0.005) were independent predictors associated with MVI of cHCC-CCA. The combination of these two predictors had high sensitivity (31/33, 93.9%; 95% CI, 80.4% - 98.3%) in the prediction of MVI with an area under the receiver operating characteristic (ROC) curve of 0.763 (95% CI, 0.635-0.863). CONCLUSIONS The findings indicated that arterial phase peritumoral enhancement on preoperative CECT and high serum PIVKA-II level were identified as potential predictors for MVI in cHCC-CCA patients.
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Affiliation(s)
- Juan Zhang
- Department of Radiology, Eastern Hepatobilliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobilliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China
| | - Yinqiao Li
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Jiazhao Fu
- Department of Organ Transplantation, Changhai Hospital, First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
| | - Ningyang Jia
- Department of Radiology, Eastern Hepatobilliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China.
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9
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Wang J, Huang M, Shen J, Li B, Wu Y, Xie W, Xiao H, Tan L. Development and external validation of a prognosis model to predict outcomes after curative resection of early-stage intrahepatic cholangiocarcinoma. Front Surg 2023; 10:1102871. [PMID: 36969753 PMCID: PMC10030709 DOI: 10.3389/fsurg.2023.1102871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/20/2023] [Indexed: 03/10/2023] Open
Abstract
BackgroundEarly-stage intrahepatic cholangiocarcinoma (ESICC) with curative resection and lymph node-negative still has the risk of poor prognosis, and there lacks prognosis-assessing tools for these patients. The objective of this study was to develop a prognosis model to predict outcomes and identify risk stratification for ESICC after resection.MethodsTotally 263 patients with ESICC after hepatectomy from January 2012 to January 2022 were analyzed. Clinicopathological factors were selected using multivariable Cox regression analysis and a prognosis model was developed. The performance of the model was evaluated by concordance index (C-index), calibration plots, decision curves analysis (DCA), and net reclassification index (NRI). Kaplan-Meier curves were analyzed for risk stratification of overall survival (OS) and recurrence-free survival (RFS) based on the prognosis model.ResultsThe clinicopathological features that were independently associated with OS of ESICC included carbohydrate antigen19-9, carcinoembryonic antigen, tumor size, tumor differentiation, and T stage. The prognosis model based on these prognostic factors demonstrated excellent discriminatory performance in both derivation cohort (C-index, 0.71) and external validation cohort (C-index, 0.78), which outperformed the TNM staging system (C-index, 0.59) and individual prognostic factors (all C-index < 0.7). Calibration plots, DCA and NRI also showed superior predictive performance. According to the risk for survival, the model stratified patients into low risk (median OS, 66.6 months; median RFS, 24.3 months) and high risk (median OS, 24.0 months; median RFS, 6.4 months) (P < 0.001).ConclusionsOur prognosis model can robustly predict the outcomes of ESICC after curative resection and provide precise evaluation on prognosis risk, facilitating clinicians to develop individualized postoperative treatment options.
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Affiliation(s)
- Jianping Wang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Manling Huang
- Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jingxian Shen
- Department of Medical Imaging, StateKey Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Bin Li
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanqing Wu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenxuan Xie
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Han Xiao
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Correspondence: Li Tan Han Xiao
| | - Li Tan
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Correspondence: Li Tan Han Xiao
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10
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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11
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Cochrane Hepato-Biliary Group, Tran A, Konstantinidis M, Moon J, El Sehemawi N, Ferreira K, Habibollahi P, Odisio BC, Nourouzpour S, Bassir A, Nezami N. Interventions for unresectable intrahepatic cholangiocarcinoma: a network meta‐analysis. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2022; 2022:CD015159. [PMCID: PMC9730740 DOI: 10.1002/14651858.cd015159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To establish the existence of differences in effectiveness and safety of intra‐arterial therapies (IATs) such as bland embolisation, conventional transarterial chemoembolisation (cTACE), drug‐eluting bead transarterial chemoembolisation (DEBTACE), yttrium‐90 (Y90), hepatic artery infusion (HAI), external beam radiotherapies (EBRTs), and immunotherapy versus systemic chemotherapy for unresectable intrahepatic cholangiocarcinoma through pairwise meta‐analysis and network meta‐analysis with subsequent treatment ranking.
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Affiliation(s)
| | - Andrew Tran
- UT Health McGovern Medical SchoolHoustonTexasUSA
| | - Menelaos Konstantinidis
- Institute of Health Policy, Management and Evaluation, University of TorontoTorontoCanada,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health TorontoTorontoCanada
| | - John Moon
- Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging SciencesEmory University School of MedicineAtlantaGeorgiaUSA
| | | | | | - Peiman Habibollahi
- Department of Interventional RadiologyDivision of Diagnostic Imaging, The University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Bruno C Odisio
- Department of Interventional RadiologyDivision of Diagnostic Imaging, The University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | | | - Ali Bassir
- Department of Radiological SciencesDavid Geffen School of Medicine, University of California Los AngelesLos AngelesCaliforniaUSA
| | - Nariman Nezami
- Department of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA,Experimental Therapeutics Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimoreMarylandUSA
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12
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Liu J, Xia Y, Xue F, Lu C, Wang J, Wang C, Wu Y, Bai S, Shen F, Wang K. Elevated serum neutrophil-lymphocyte ratio is associated with worse long-term survival in patients with HBV-related intrahepatic cholangiocarcinoma undergoing resection. Front Oncol 2022; 12:1012246. [PMID: 36324563 PMCID: PMC9618718 DOI: 10.3389/fonc.2022.1012246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/03/2022] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND This study aimed to examine the influence of serum inflammatory marker levels on long-term outcomes after liver resection in patients with intrahepatic cholangiocarcinoma (ICC). METHODS Data from 1189 consecutive ICC patients who underwent liver resection were reviewed. The serum neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) were measured before surgery. Overall survival (OS) and tumour recurrence were analysed using the Kaplan-Meier method and compared using the log-rank test. Independent risk factors for OS and tumour recurrence were analysed using the Cox hazard regression model. RESULTS We identified elevated serum NLR (≥ 2.15) as an independent risk factor for both OS and tumour recurrence (hazard ratio [HR]: 1.327, 95% confidence interval [CI]: 1.105-1.593; HR: 1.274, 95% CI: 1.074-1.510) among the three inflammatory markers assessed. Elevated NLR was associated with higher carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels, larger tumour size, multiple tumours, lymph node metastasis, vascular invasion, and more advanced tumour node metastasis (TNM) stage (III/IV). Subgroup analysis showed that elevated NLR was an independent risk factor for OS and tumour recurrence in patients with hepatitis B virus (HBV) infection compared with patients without HBV infection (HR: 1.347, 95% CI: 1.073-1.690; HR: 1.386, 95% CI: 1.112-1.726). CONCLUSIONS Elevated serum NLR was associated with worse prognosis among ICC patients who underwent liver resection, especially in patients with HBV infection.
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Affiliation(s)
- Jianwei Liu
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Feng Xue
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Caixia Lu
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jie Wang
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chunyan Wang
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yeye Wu
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Shilei Bai
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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13
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Value of Intravoxel Incoherent Motion (IVIM) Imaging for Differentiation between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:1504463. [PMID: 35615729 PMCID: PMC9113914 DOI: 10.1155/2022/1504463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/21/2022] [Accepted: 04/22/2022] [Indexed: 12/19/2022]
Abstract
Efficient noninvasive imaging techniques in the differentiation of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are very important because of their different management and prognosis. Our purpose was to evaluate the difference of parameters extracted from intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) between the two groups and their performance for the differentiation, as well as the significance of perfusion information. IVIM studies (9 b-values) in 41 patients with either ICC or HCC were reviewed retrospectively by two observers. Diffusion coefficient (D), pseudodiffusion coefficient (D∗), perfusion fraction (f), ADC, and the mean percentage of parenchymal enhancement (MPPE) at 30 s after contrast-enhancement were calculated and compared between ICC and HCC. The relationship between D∗, f values, and MPPE was evaluated by Spearman's correlation test. The diagnostic efficacy of all parameters was analyzed by the receiver operating characteristic (ROC) curve. Interobserver and intraobserver agreements were analyzed. The parameters (D and ADC) of ICC were distinctly higher than those of HCC; whereas the parameters (f and MPPE of arterial phase) were distinctly lower (all false discovery rate [FDR]-corrected P < 0.05). The metric D∗ value of ICC was slightly higher than that of HCC (71.44 vs 69.41) with FDR-corrected P > 0.05. Moreover, the value of parameter D was significantly lower than that of ADC (FDR-corrected P < 0.05). The parameters (D and f values) extracted from IVIM showed excellent diagnostic efficiency in the identification, and the diagnostic efficiency of D value was significantly higher than that of the ADC. There were positive correlations between perfusion-related parameters (D∗, f values) and MPPE. Interobserver and intraobserver agreements were excellent or perfect in measurements of all parameters. Parameters derived from IVIM were valuable for distinguishing ICC and HCC. Moreover, the D value showed better diagnostic efficiency for the differential diagnosis than monoexponential fitting-derived ADC value. Meanwhile, the significant correlation between perfusion-related parameters and MPPE demonstrates that specific IVIM metrics may serve as a noninvasive indicator for the vascular perfusion information of ICC and HCC.
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14
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Shen GL, Lu Y, Liang L, Lu WF, Diao YK, Xiao ZQ, Zhang KJ, Zhang JG, Zhang CW, Liu J. Impact of diabetes mellitus on the long-term prognosis of patients with hepatocellular carcinoma after hepatectomy. Expert Rev Gastroenterol Hepatol 2022; 16:473-478. [PMID: 35387530 DOI: 10.1080/17474124.2022.2063837] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The impact of diabetes mellitus (DM) on the survival of patients with hepatocellular carcinoma (HCC) is still unclear. The present study aims to draw a firm conclusion in terms of evaluating the impact of DM on the prognosis of HCC after hepatectomy. METHODS The pattern of recurrence for HCC was often stratified into early-stage (<2 years) and late-stage (≥2 years) recurrence. Because the early-stage recurrence was mainly attributed to aggressive tumor pathological characteristics, patients who recurrence or die within 2 years were excluded. Cumulative overall survival (OS) and recurrence-free survival (RFS) were determined by the method of Kaplan-Meier, and the independent risk factors of OS/RFS were determined by Cox regression analysis. RESULTS A total of 426 patients were eventually included. The 3- and 5-year OS in patients with and without DM was 83.7%, 55.1%; and 90.9%, 77.4%, respectively. Multivariate analysis showed that DM was an independent risk factor for OS (HR 1.166, 95% CI 1.056-2.036, P = 0.022) and RFS (HR 1.365, 95% CI 1.043-1.787, P = 0.023). CONCLUSION DM is an independent risk factor for long-term prognosis in patients with HCC. Patients with DM after hepatectomy for HCC, thus, need to actively control DM and closer follow-up.
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Affiliation(s)
- Guo-Liang Shen
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yi Lu
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lei Liang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Department of Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Wen-Feng Lu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, Zhejiang, China
| | - Yong-Kang Diao
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zun-Qiang Xiao
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Kang-Jun Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jun-Gang Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Cheng-Wu Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junwei Liu
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
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15
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Carotenuto M, Sacco A, Forgione L, Normanno N. Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:200-223. [PMID: 36046845 PMCID: PMC9400790 DOI: 10.37349/etat.2022.00079] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/22/2022] [Indexed: 11/22/2022] Open
Abstract
Improving the survival of patients with cholangiocarcinoma (CCA) has long proved challenging, although the treatment of this disease nowadays is on advancement. The historical invariability of survival outcomes and the limited number of agents known to be effective in the treatment of this disease has increased the number of studies designed to identify genetic targetable hits that can be efficacious for novel therapies. In this respect, the increasing feasibility of molecular profiling starting either from tumor tissue or circulating cell-free DNA (cfDNA) has led to an increased understanding of CCA biology. Intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) display different and typical patterns of actionable genomic alterations, which offer opportunity for therapeutic intervention. This review article will summarize the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease.
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Affiliation(s)
- Marianeve Carotenuto
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Alessandra Sacco
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Laura Forgione
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
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16
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Liu WW, Tu JF, Ying XH, Chen ZJ, Wang YB. Postoperative survival of extrahepatic and intrahepatic cholangiocarcinoma after surgery: a population-based cohort. BMJ Open 2022; 12:e049789. [PMID: 35414539 PMCID: PMC9006842 DOI: 10.1136/bmjopen-2021-049789] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES The study was designed to clarify the difference between extrahepatic cholangiocarcinoma (ECC) and intrahepatic cholangiocarcinoma (ICC) in postoperative cancer-specific death. DESIGN Patients diagnosed with ECC and ICC after surgery, who are identified from the Surveillance, Epidemiology and End Results programme, are eligible for this retrospective cohort study. SETTING Survival between groups was compared using the traditional Kaplan-Meier method and the cumulative incidence function (CIF) method. Propensity score-matched (PSM) analysis was conducted to balance the differences in vital variables between groups. The HR and 95% CI for ECC relative to ICC were used to quantify the risk of death. Subgroup analysis was further used to evaluate the stability of the differences between groups. RESULTS The study included 876 patients with ECC and 1194 patients with ICC. Before PSM, with the Kaplan-Meier method, postoperative overall survival and cancer-specific death for ECC were worse than those for ICC. However, with the CIF method, no difference in postoperative cancer-specific death was found. After PSM, all differences in the considered traits were balanced, and 173 pairs of patients were retained. Survival analysis found that there was no difference in postoperative all-cause death (Kaplan-Meier method, p=0.186) or cancer-specific death (Kaplan-Meier and CIF methods, p=0.500 and p=0.913, respectively), which was consistent with subgroup analysis. CONCLUSIONS ECC and ICC showed no difference in postoperative cancer-specific death, both in the natural state and in multiple variable-matched conditions. TRIAL REGISTRATION NUMBER researchregistry4175.
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Affiliation(s)
- Wei-Wen Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Jian-Fei Tu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Xi-Hui Ying
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Zheng-Ju Chen
- Laboratory of Pathology, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Yun-Bing Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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17
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Qian X, Lu X, Ma X, Zhang Y, Zhou C, Wang F, Shi Y, Zeng M. A Multi-Parametric Radiomics Nomogram for Preoperative Prediction of Microvascular Invasion Status in Intrahepatic Cholangiocarcinoma. Front Oncol 2022; 12:838701. [PMID: 35280821 PMCID: PMC8907475 DOI: 10.3389/fonc.2022.838701] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 01/24/2022] [Indexed: 02/06/2023] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with increasing incidence in the last decades. Microvascular invasion (MVI) is a poor prognostic factor for patients with ICC, which correlates early recurrence and poor prognosis, and it can affect the selection of personalized therapeutic regime. Purpose This study aimed to develop and validate a radiomics-based nomogram for predicting MVI in ICC patients preoperatively. Methods A total of 163 pathologically confirmed ICC patients (training cohort: n = 130; validation cohort: n = 33) with postoperative Ga-DTPA-enhanced MR examination were enrolled, and a time-independent test cohort (n = 24) was collected for external validation. Univariate and multivariate analyses were used to determine the independent predictors of MVI status, which were then incorporated into the MVI prediction nomogram. Least absolute shrinkage and selection operator logistic regression was performed to select optimal features and construct radiomics models. The prediction performances of models were assessed by receiver operating characteristic (ROC) curve analysis. The performance of the MVI prediction nomogram was evaluated by its calibration, discrimination, and clinical utility. Results Larger tumor size (p = 0.003) and intrahepatic duct dilatation (p = 0.002) are independent predictors of MVI. The final radiomics model shows desirable and stable prediction performance in the training cohort (AUC = 0.950), validation cohort (AUC = 0.883), and test cohort (AUC = 0.812). The MVI prediction nomogram incorporates tumor size, intrahepatic duct dilatation, and the final radiomics model and achieves excellent predictive efficacy in training cohort (AUC = 0.953), validation cohort (AUC = 0.861), and test cohort (AUC = 0.819), fitting well in calibration curves (p > 0.05). Decision curve and clinical impact curve further confirm the clinical usefulness of the nomogram. Conclusion The nomogram incorporating tumor size, intrahepatic duct dilatation, and the final radiomics model is a potential biomarker for preoperative prediction of the MVI status in ICC patients.
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Affiliation(s)
- Xianling Qian
- 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
| | - Xin Lu
- 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
| | - Xijuan Ma
- Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Ying Zhang
- Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Changwu Zhou
- 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
| | - Fang Wang
- Department of Research and Development, Shanghai United Imaging Intelligence Co., Ltd., Shanghai, China
| | - Yibing Shi
- Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 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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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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Zhou Y, Zhou G, Zhang J, Xu C, Zhu F, Xu P. DCE-MRI based radiomics nomogram for preoperatively differentiating combined hepatocellular-cholangiocarcinoma from mass-forming intrahepatic cholangiocarcinoma. Eur Radiol 2022; 32:5004-5015. [PMID: 35128572 DOI: 10.1007/s00330-022-08548-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To establish a radiomics nomogram based on dynamic contrast-enhanced (DCE) MR images to preoperatively differentiate combined hepatocellular-cholangiocarcinoma (cHCC-CC) from mass-forming intrahepatic cholangiocarcinoma (IMCC). METHODS A total of 151 training cohort patients (45 cHCC-CC and 106 IMCC) and 65 validation cohort patients (19 cHCC-CC and 46 IMCC) were enrolled. Findings of clinical characteristics and MR features were analyzed. Radiomics features were extracted from the DCE-MR images. A radiomics signature was built based on radiomics features by the least absolute shrinkage and selection operator algorithm. Univariate and multivariate analyses were used to identify the significant clinicoradiological variables and construct a clinical model. The radiomics signature and significant clinicoradiological variables were then incorporated into the radiomics nomogram by multivariate logistic regression analysis. Performance of the radiomics nomogram, radiomics signature, and clinical model was assessed by receiver operating characteristic and area under the curve (AUC) was compared. RESULTS Eleven radiomics features were selected to develop the radiomics signature. The radiomics nomogram integrating the alpha fetoprotein, background liver disease (cirrhosis or chronic hepatitis), and radiomics signature showed favorable calibration and discrimination performance with an AUC value of 0.945 in training cohort and 0.897 in validation cohort. The AUCs for the radiomics signature and clinical model were 0.848 and 0.856 in training cohort and 0.792 and 0.809 in validation cohort, respectively. The radiomics nomogram outperformed both the radiomics signature and clinical model alone (p < 0.05). CONCLUSION The radiomics nomogram based on DCE-MRI may provide an effective and noninvasive tool to differentiate cHCC-CC from IMCC, which could help guide treatment strategies. KEY POINTS • The radiomics signature based on dynamic contrast-enhanced magnetic resonance imaging is useful to preoperatively differentiate cHCC-CC from IMCC. • The radiomics nomogram showed the best performance in both training and validation cohorts for differentiating cHCC-CC from IMCC.
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Affiliation(s)
- Yang Zhou
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, No 300, Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Guofeng Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui District, Shanghai, 200032, China.,Shanghai Institute of Medical Imaging, No.180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Jiulou Zhang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, No 300, Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Feipeng Zhu
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, No 300, Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.
| | - Pengju Xu
- Department of Radiology, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui District, Shanghai, 200032, China. .,Shanghai Institute of Medical Imaging, No.180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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20
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Zhang G, Liu X, Sun Z, Feng X, Wang H, Hao J, Zhang X. A2M is a potential core gene in intrahepatic cholangiocarcinoma. BMC Cancer 2022; 22:5. [PMID: 34979994 PMCID: PMC8722218 DOI: 10.1186/s12885-021-09070-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 11/29/2021] [Indexed: 12/31/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a type of malignant tumor ranking the second in the incidence of primary liver cancer following hepatocellular carcinoma. Both the morbidity and mortality have been increasing in recent years. Small duct type of ICC has potential therapeutic targets. But overall, the prognosis of patients with ICC is usually very poor. Methods To search latent therapeutic targets for ICC, we programmatically selected the five most suitable microarray datasets. Then, we made an analysis of these microarray datasets (GSE26566, GSE31370, GSE32958, GSE45001 and GSE76311) collected from the Gene Expression Omnibus (GEO) database. The GEO2R tool was effective to find out differentially expressed genes (DEGs) between ICC and normal tissue. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were executed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v 6.8. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyze protein–protein interaction of these DEGs and protein–protein interaction of these DEGs was modified by Cytoscape3.8.2. Survival analysis was performed using Gene Expression Profiling Interactive Analysis (GEPIA) online analysis tool. Results A total of 28 upregulated DEGs and 118 downregulated DEGs were screened out. Then twenty hub genes were selected according to the connectivity degree. The survival analysis results showed that A2M was closely related to the pathogenesis and prognosis of ICC and was a potential therapeutic target for ICC. Conclusions According to our study, low A2M expression in ICC compared to normal bile duct tissue was an adverse prognostic factor in ICC patients. The value of A2M in the treatment of ICC needs to be further studied.
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Affiliation(s)
- Guanran Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Xuyue Liu
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Zhengyang Sun
- School of Information Engineering, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xiaoning Feng
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Haiyan Wang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jing Hao
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
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21
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Ghidini M, Ramai D, Facciorusso A, Singh J, Tai W, Rijavec E, Galassi B, Grossi F, Indini A. Metabolic disorders and the risk of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:999-1007. [PMID: 34423721 DOI: 10.1080/17474124.2021.1946393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy which arises from the biliary epithelium. Carcinogenesis of CCA is mainly linked to aberrant glucose metabolism and creation of an immunosuppressive environment around normal biliary epithelium. The incidence of CCA is higher in the East due to Opisthorchis viverrini, an endemic liver fluke. CCA has also be attributed to genetic, metabolic, and lifestyle risk factors.Areas covered: Differences in epidemiological risk factors are associated with varying phenotypes of CCA. Metabolic risk factors include diabetes, obesity, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome. Inherited metabolic risk factors include Wilson's disease and hemochromatosis. Metabolic disease is associated with a higher risk of CCA, with higher risk for the intrahepatic form. In this review, the authors provide an overview of available evidence regarding metabolic conditions associated with the development of CCA.Expert opinion: Metabolic disease is associated with a higher risk of intrahepatic CCA compared to its extrahepatic or hilar counterpart. As rates of obesity and metabolic syndrome increase, particularly in the West, it is conceivable that the incidence of CCA will also rise in the next years.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, USA
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Foggia, Italy
| | - Jameel Singh
- Department of Internal Medicine, Mather Hospital, Northwell Health, Port Jefferson, New York, USA
| | - Waqqas Tai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, USA
| | - Erika Rijavec
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Barbara Galassi
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Grossi
- Department of Medicine and Surgery, Medical Oncology Unit, ASST Sette Laghi, Varese, Italy
| | - Alice Indini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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22
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Jeong S, Luo G, Gao Q, Chen J, Liu X, Dong L, Zhang Y, Shen F, Cheng Q, Sui C, Liu J, Wang H, Xia Q, Chen L. A combined Cox and logistic model provides accurate predictive performance in estimation of time-dependent probabilities for recurrence of intrahepatic cholangiocarcinoma after resection. Hepatobiliary Surg Nutr 2021; 10:464-475. [PMID: 34430525 DOI: 10.21037/hbsn.2020.01.07] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/21/2019] [Indexed: 12/27/2022]
Abstract
Background Intrahepatic cholangiocarcinoma has heterogeneous outcomes after resection. There remains a need for broadly applicable recurrence-specific tool offering precise evaluation on curativeness of resection. Methods A four hospital-based clinical cohort involving 1,655 patients with intrahepatic cholangiocarcinoma who received surgical resection were studied. Cox and logistic models were networked into one system containing risk categories with distinctive probabilities of recurrence. Prediction of time-to-recurrence was performed by formulizing time-dependent risk probabilities. The model was validated in three clinical cohorts (n=332). Results From the training cohort, 10 and 11 covariates, including diabetes, cholelithiasis, albumin, platelet count, alpha fetoprotein, carbohydrate antigen 19-9, carcinoembryonic antigen, hepatitis B virus infection, tumor size and number, resection type, and lymph node metastasis, from Cox and logistic models were identified significant for recurrence-free survival (RFS). The combined Cox & logistic ranking system (CCLRS)-adjusted time-dependent probabilities were categorized into seven ranks (5-yr RFS for lowest and highest ranks were 75% vs. 0%; hazard ratio 18.5, 95% CI: 14.7-24.9, P<0.0001). The CCLRS was validated with a minimum area under curve value of 0.8086. Prediction of time-to-recurrence was validated to be excellent (Pearson r, 0.8204; P<0.0001). Conclusions The CCLRS allows precise estimation on risk of recurrence for intrahepatic cholangiocarcinoma after resection. It could be applicative when estimating time-dependent disease status and stratifying individuals who sole resection of the tumor would not be curative.
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Affiliation(s)
- Seogsong Jeong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Guijuan Luo
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jing Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Xiaolong Liu
- Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, China
| | - Liangqing Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yongjie Zhang
- Biliary Tract Department II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Qingbao Cheng
- Biliary Tract Department I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chengjun Sui
- Department of Special Medical Care & Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jingfeng Liu
- Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, China
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.,Shanghai Cancer Center, Shanghai Medical College, Fudan University; Shanghai, China
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23
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Park S, Lee JM, Park J, Lee J, Bae JS, Kim JH, Joo I. Volumetric CT Texture Analysis of Intrahepatic Mass-Forming Cholangiocarcinoma for the Prediction of Postoperative Outcomes: Fully Automatic Tumor Segmentation Versus Semi-Automatic Segmentation. Korean J Radiol 2021; 22:1797-1808. [PMID: 34402247 PMCID: PMC8546140 DOI: 10.3348/kjr.2021.0055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/08/2021] [Accepted: 04/27/2021] [Indexed: 11/15/2022] Open
Abstract
Objective To determine whether volumetric CT texture analysis (CTTA) using fully automatic tumor segmentation can help predict recurrence-free survival (RFS) in patients with intrahepatic mass-forming cholangiocarcinomas (IMCCs) after surgical resection. Materials and Methods This retrospective study analyzed the preoperative CT scans of 89 patients with IMCCs (64 male; 25 female; mean age, 62.1 years; range, 38–78 years) who underwent surgical resection between January 2005 and December 2016. Volumetric CTTA of IMCCs was performed in late arterial phase images using both fully automatic and semi-automatic liver tumor segmentation techniques. The time spent on segmentation and texture analysis was compared, and the first-order and second-order texture parameters and shape features were extracted. The reliability of CTTA parameters between the techniques was evaluated using intraclass correlation coefficients (ICCs). Intra- and interobserver reproducibility of volumetric CTTAs were also obtained using ICCs. Cox proportional hazard regression were used to predict RFS using CTTA parameters and clinicopathological parameters. Results The time spent on fully automatic tumor segmentation and CTTA was significantly shorter than that for semi-automatic segmentation: mean ± standard deviation of 1 minutes 37 seconds ± 50 seconds vs. 10 minutes 48 seconds ± 13 minutes 44 seconds (p < 0.001). ICCs of the texture features between the two techniques ranged from 0.215 to 0.980. ICCs for the intraobserver and interobserver reproducibility using fully automatic segmentation were 0.601–0.997 and 0.177–0.984, respectively. Multivariable analysis identified lower first-order mean (hazard ratio [HR], 0.982; p = 0.010), larger pathologic tumor size (HR, 1.171; p < 0.001), and positive lymph node involvement (HR, 2.193; p = 0.014) as significant parameters for shorter RFS using fully automatic segmentation. Conclusion Volumetric CTTA parameters obtained using fully automatic segmentation could be utilized as prognostic markers in patients with IMCC, with comparable reproducibility in significantly less time compared with semi-automatic segmentation.
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Affiliation(s)
- Sungeun Park
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Konkuk University Medical Center, Seoul, Korea
| | - Jeong Min Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
| | - Junghoan Park
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Jihyuk Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Jae Seok Bae
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Jae Hyun Kim
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
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Mar WA, Chan HK, Trivedi SB, Berggruen SM. Imaging of Intrahepatic Cholangiocarcinoma. Semin Ultrasound CT MR 2021; 42:366-380. [PMID: 34130849 DOI: 10.1053/j.sult.2021.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma is the second most common primary hepatic malignancy and is a heterogeneous tumor of biliary epithelium. We discuss the risk factors, anatomic classification of cholangiocarcinoma (CC) as well as the different morphologic subtypes of CC. Imaging findings of CC on different modalities are described, focusing on intrahepatic CC. Recently recognized imaging features that carry prognostic significance, such as a worse prognosis in tumors that have more desmoplastic stroma, are detailed. Other benign and malignant entities that should be considered in the differential diagnosis of CC will also be discussed.
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Affiliation(s)
- Winnie A Mar
- Department of Radiology, University of Illinois at Chicago
| | - Hing Kiu Chan
- Department of Radiology, University of Illinois at Chicago
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25
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Massani M, Bonariol L, Stecca T. Hepatic Arterial Infusion Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma, a Comprehensive Review. J Clin Med 2021; 10:2552. [PMID: 34207700 PMCID: PMC8228250 DOI: 10.3390/jcm10122552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/02/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials.
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Affiliation(s)
- Marco Massani
- HPB Hub Reference Center, First General Surgery Unit, Department of Surgery, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (L.B.); (T.S.)
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26
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Panayotova G, Lunsford KE, Latt NL, Paterno F, Guarrera JV, Pyrsopoulos N. Expanding indications for liver transplantation in the era of liver transplant oncology. World J Gastrointest Surg 2021; 13:392-405. [PMID: 34122730 PMCID: PMC8167850 DOI: 10.4240/wjgs.v13.i5.392] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/23/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.
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Affiliation(s)
- Guergana Panayotova
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Keri E Lunsford
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
- Center for Immunity and Inflammation, Institute for Infectious and Inflammatory Diseases, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nyan L Latt
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Flavio Paterno
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - James V Guarrera
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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Lu WF, Chen PQ, Yan K, Wu YC, Liang L, Yuan JY, Fu Y, Zhang HB. Synergistic impact of resection margin and microscopic vascular invasion for patients with HBV-related intrahepatic cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:575-582. [PMID: 33899638 DOI: 10.1080/17474124.2021.1913053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for intrahepatic cholangiocarcinoma (ICC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. METHODS A total of 711 consecutive patients who underwent curative liver resection for hepatitis B virus-related ICC were retrospectively analyzed. The different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive, +, or negative, -) on overall survival (OS) and recurrence-free survival (RFS) were analyzed. RESULTS The 1-, 3-, and 5-year OS rates were 67.6%, 42.5%, and 33.2% in wide RM & MVI (-), 58.0%, 36.1%, and 26.5% in narrow RM & MVI (-), 51.0%, 27.0%, and 24.3% in wide RM & MVI (+), and 39.0%, 20.4% and 14.3% in narrow RM & MVI (+) (p < 0.001). Multivariate analysis showed that RM & MVI were independent risk factors for the OS and RFS. CONCLUSION Combined analysis of RM and MVI can better stratify the risks of postoperative death and recurrence in patients with HBV-related ICC, which may help subsequent adjuvant therapy and closer follow-up.
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Affiliation(s)
- Wen-Feng Lu
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Pei-Qin Chen
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Kai Yan
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Ye-Chen Wu
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jian-Yong Yuan
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Yong Fu
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Hai-Bin Zhang
- Department of Hepatic Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
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28
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Li Q, Fu L, Han L, Li S, Zhang Y, Wang J. Long Noncoding RNA GAS5 Accelerates Cholangiocarcinoma Progression by Regulating hsa-miR-1297. Cancer Manag Res 2021; 13:2745-2753. [PMID: 33790648 PMCID: PMC8001187 DOI: 10.2147/cmar.s297868] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/26/2021] [Indexed: 12/28/2022] Open
Abstract
Background Long noncoding RNAs (lncRNAs) have been reported as important molecules in cholangiocarcinoma (CCA) occurrence and development. A previous study showed that lncRNA GAS5 (GAS5) was an oncogene in some tumors. But the role of GAS5 in CCA progression reminds unclear. This research was designed to study the expression and potential effects of GAS5 in the progression of CCA. Methods The expression of GAS5 in CCA tissues was evaluated through mining of the TCGA and GEPIA databases. qRT-PCR was applied to validate the results in our clinical samples. χ2 test was used to analyze the association between the expression level of tissue GAS5 and different clinicopathological parameters of CCA patients. The target gene of GAS5 was predicted by bioinformatic databases, and further verified by luciferase reporter assays. Finally, the role of GAS5 in CCA cells invasion and proliferation was detected by Transwell assay and CCK-8 assay. Results Compared to the adjacent nontumor tissues and the normal human intrahepatic biliary epithelial cell, the expression of GAS5 was markedly increased in CCA tissues (p<0.001) and cell lines (p<0.01), respectively. CCA patients with high GAS5 expression tended to present lymph node metastasis (p<0.001) and had advanced clinical stage (p=0.006). The bioinformatics analysis predicted that hsa-miR-1297 was the potential target gene of GAS5, which was validated by luciferase reporter assays. In addition, the function study showed that GAS5 acted as a “sponge” to downregulate hsa-miR-1297, thus modulating CCA cell proliferation and invasion. Conclusion GAS5 acts as an endogenous sponge of hsa-miR-1297 to promote CCA cell proliferation and invasion, which might be a potential biomarker and therapeutic target for CCA.
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Affiliation(s)
- Qian Li
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China
| | - Lei Fu
- Department of Oncology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, People's Republic of China
| | - Lili Han
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China
| | - Shuai Li
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China
| | - Yanling Zhang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China
| | - Jufeng Wang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China
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29
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Tavares I, Martins R, Ribeiro IP, Esteves L, Caramelo F, Abrantes AM, Neves R, Caetano-Oliveira R, Botelho MF, Barbosa de Melo J, Diogo D, Tralhão JG, Carreira IM. Development of a genomic predictive model for cholangiocarcinoma using copy number alteration data. J Clin Pathol 2021; 75:274-278. [PMID: 33649143 DOI: 10.1136/jclinpath-2020-207346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 01/03/2023]
Abstract
AIMS Cholangiocarcinoma (CC) is a rare tumour arising from the biliary tract epithelium. The aim of this study was to perform a genomic characterisation of CC tumours and to implement a model to differentiate extrahepatic (ECC) and intrahepatic (ICC) cholangiocarcinoma. METHODS DNA extracted from tumour samples of 23 patients with CC, namely 10 patients with ECC and 13 patients with ICC, was analysed by array comparative genomic hybridisation. A support vector machine algorithm for classification was applied to the genomic data to distinguish between ICC and ECC. A survival analysis comparing both groups of patients was also performed. RESULTS With these whole genome results, we observed several common alterations between tumour samples of the same CC anatomical type, namely gain of Xp and loss of 3p, 11q11, 14q, 16q, Yp and Yq in ICC tumours, and gain of 16p25.3 and loss of 3q26.1, 6p25.3-22.3, 12p13.31, 17p, 18q and Yp in ECC tumours. Gain of 2q37.3 was observed in the samples of both tumour subtypes, ICC and ECC. The developed genomic model comprised four chromosomal regions that seem to enable the distinction between ICC and ECC, with an accuracy of 71.43% (95% CI 43% to 100%). Survival analysis revealed that in our cohort, patients with ECC survived on average 8 months less than patients with ICC. CONCLUSIONS This genomic characterisation and the introduction of genomic models to clinical practice could be important for patient management and for the development of targeted therapies. The power of this genomic model should be evaluated in other CC populations.
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Affiliation(s)
- Inês Tavares
- University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal
| | - Ricardo Martins
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,Surgery Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal.,University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal
| | - Ilda Patrícia Ribeiro
- University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal.,University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Luísa Esteves
- University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal
| | - Francisco Caramelo
- University of Coimbra, Laboratory of Biostatistics and Medical Informatics, IBILI, Faculty of Medicine, Coimbra, Portugal
| | - Ana Margarida Abrantes
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Rita Neves
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal
| | - Rui Caetano-Oliveira
- Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,Pathology Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal
| | - Maria Filomena Botelho
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Joana Barbosa de Melo
- University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal.,University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
| | - Dulce Diogo
- Surgery Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal
| | - José Guilherme Tralhão
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,Surgery Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal.,University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal
| | - Isabel Marques Carreira
- University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal .,University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal.,Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
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30
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Radiomics signature on dynamic contrast-enhanced MR images: a potential imaging biomarker for prediction of microvascular invasion in mass-forming intrahepatic cholangiocarcinoma. Eur Radiol 2021; 31:6846-6855. [PMID: 33638019 DOI: 10.1007/s00330-021-07793-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/22/2021] [Accepted: 02/15/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To develop a radiomics signature based on dynamic contrast-enhanced (DCE) MR images for preoperative prediction of microvascular invasion (MVI) in patients with mass-forming intrahepatic cholangiocarcinoma (IMCC). METHODS One hundred twenty-six patients with surgically resected single IMCC (34 MVI-positive and 92 MVI-negative) were enrolled and allocated to training and validation cohorts (7:3 ratio). Findings of clinical characteristics and MR features were analyzed. A radiomics signature was built on the basis of reproducible features by using the least absolute shrinkage and selection operator (LASSO) regression algorithm in the training cohort. The prediction performance of radiomics signature was evaluated by receiver operating characteristics curve (ROC) analysis. Internal validation was performed on an independent cohort containing 38 patients. RESULTS Larger tumor size and higher radiomics score were positively correlated with MVI in both training cohort (p < 0.001, < 0.001, respectively) and validation cohort (p = 0.008, 0.001, respectively). The radiomics signature, consisting of seven wavelet features, showed optimal prediction performance in both training (AUC = 0.873) and validation cohorts (AUC = 0.850). CONCLUSION A radiomics signature derived from DCE-MRI of the liver can be a reliable imaging biomarker for predicting MVI of IMCC, which could aid in tailoring treatment strategies. KEY POINTS • The radiomics signature based on dynamic contrast-enhanced magnetic resonance imaging can be a useful tool to preoperatively predict MVI of IMCC. • Larger tumor size is positively correlated with MVI of IMCC.
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31
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Gentile D, Donadon M, Civilini E, Torzilli G. Total upper transversal hepatectomy with outflow reconstruction for advanced mass-forming cholangiocarcinoma. Updates Surg 2021; 73:769-773. [PMID: 33625678 DOI: 10.1007/s13304-020-00946-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/08/2020] [Indexed: 10/22/2022]
Abstract
We describe a complex case of extended hepatectomy with venous outflow reconstruction for the treatment of advanced mass-forming cholangiocarcinoma (MFCCC) invading the three main hepatic veins (HVs). A 50-year-old woman who received a diagnosis of MFCCC and judged unresectable, was referred to our hospital. After multidisciplinary team evaluation, the patient underwent abdominal computed tomography, gadoxetic acid-enhanced magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography. The radiological examinations showed a large mass located in S4s-8 and S1, in contact with the right hepatic vein (RHV), the inferior right hepatic vein, the anterior wall of the inferior vena cava (IVC), infiltrating the middle and left hepatic veins (MHV, LHV). Several communicating veins between the RHV, MHV and LHV were detected. The case was further investigated, and the surgical strategy planned by means of using three-dimensional simulation software. A total upper transversal hepatectomy with resection of the main HVs and outflow reconstruction was performed. The outflow of the remnant liver was restored performing a vascular anastomosis between the parenchymal stump of the RHV and the IVC. Meticulous review of pre-operative imaging techniques with three-dimensional simulation of hepatectomy together with advanced use of intra-operative ultrasound allowed us to offer the chance of cure to a patient otherwise considered unresectable.
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Affiliation(s)
- Damiano Gentile
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center - IRCCS, Via Manzoni, 56, 20089, Rozzano, Milano, Italy
| | - Matteo Donadon
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center - IRCCS, Via Manzoni, 56, 20089, Rozzano, Milano, Italy.,Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Efrem Civilini
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy.,Department of Vascular Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Guido Torzilli
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center - IRCCS, Via Manzoni, 56, 20089, Rozzano, Milano, Italy. .,Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy.
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32
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Lee DH. Current Status and Recent Update of Imaging Evaluation for Peri-Hilar Cholangiocarcinoma. JOURNAL OF THE KOREAN SOCIETY OF RADIOLOGY 2021; 82:298-314. [PMID: 36238748 PMCID: PMC9431946 DOI: 10.3348/jksr.2021.0018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/25/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
간문주변부의 해부학적 복잡성으로 인해 간문주변부 담관암은 그 진단과 치료가 어려운 질환으로 알려져 있다. 간문주변부 담관암이 의심되는 환자에 있어서, 영상 검사는 이상 소견의 발견 및 감별 진단, 종양의 종축 침범 부위의 파악, 인접 혈관 침범과 원격 전이 유무의 파악, 그리고 최종적으로 수술적 절제 가능 유무의 평가에 있어 핵심적인 역할을 하고 있다. 이 종설에서는 간문주변부 담관암의 분류 및 종양의 평가를 위해 권고되는 표준 영상 검사의 기법과 간문주변부 담관암의 전형적인 영상 소견에 대해 기술할 예정이다. 종축 방향의 종양 침범 파악, 인접 혈관 침범 및 원격 전이 유무의 평가에 있어서 각 영상 검사 소견과 그 진단능에 대해 논의할 예정이다. 이후 전통적인 절제 가능성 평가의 개념에 대해 고찰하고, 최근의 경향을 소개한다.
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Affiliation(s)
- Dong Ho Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
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33
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Mavilia MG, Sharma A, Forouhar F. Metastatic cholangiocarcinoma in a patient with undiagnosed Wilson disease. Ann Hepatol 2020; 18:929-931. [PMID: 31167735 DOI: 10.1016/j.aohep.2019.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 04/02/2019] [Accepted: 03/14/2019] [Indexed: 02/04/2023]
Abstract
Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. Although the frequency of malignancy is generally increased in chronic liver disease, CC rarely presents in Wilson disease (WD). The incidence of hepatic malignancy in WD is only 1.2%, with CC accounting for 0.5%. A 66 year old male with history of hypertension, diabetes, and compensated cryptogenic cirrhosis presented with acute onset dyspnea and pleuritic chest pain. He was incidentally found to have a sizeable mass in the right hepatic lobe. Ultimately, a liver biopsy revealed dense demoplasia and increased mucin production, consistent with diagnosis of CC. Biopsy also demonstrated increased copper deposition consistent with WD, explaining the patient's underlying cirrhosis. Unlike other forms of chronic liver disease where incidence of liver cancer is increased, the lower rate of malignancy seen in WD may be explained by a protective effect of copper in WD. Copper acts to both directly stabilize DNA and inhibit angiogenesis. In this case, it is possible that the degree of copper deposition in his liver was mild, causing cirrhosis and the chronic liver inflammation that caused his CC. However, it may not have been sufficient to "protect" against development of CC.
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Affiliation(s)
| | - Aniket Sharma
- Department of Medicine, University of Connecticut, Farmington, CT, USA
| | - Faripour Forouhar
- Department of Pathology, University of Connecticut, Farmington, CT, USA
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34
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Zhang XH, Huo L, Liu CF, Xu F, Lu XY, Huang B, Jia NY, Wu L, Shen F. Arterial hyperenhancement of small intrahepatic cholangiocarcinomas correlates with microvessel counts and patient survival. HPB (Oxford) 2020; 22:1197-1205. [PMID: 31843444 DOI: 10.1016/j.hpb.2019.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/12/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND To compare outcomes of patients with arterially hyperenhancing intrahepatic cholangiocarcinomas (ICC) and arterially hypoenhancing ICCs after partial hepatectomy in a cohort with an analysis of prognostic factors. METHODS From June 2009 to October 2011, a prospective cohort of 68 patients with single resectable ICCs (≤5 cm in diameter) underwent gadolinium contrast-enhanced dynamic-phase magnetic resonance imaging and were treated with partial hepatectomy. Patients were divided into those with arterially hyperenhancing ICCs (n = 28) or arterially hypoenhancing ICCs (n = 40). Clinic-radiologic-pathologic results and survival of these patients were compared and statistically analyzed. RESULTS The median overall survival (OS) time was significantly longer in the arterially hyperenhancing ICCs (56.8 vs. 37.0 months) (p = 0.044). At pathologic evaluation, arterially hyperenhancing ICCs showed significantly higher microvessel count (MVC) than arterially hypoenhancing ICCs (106.2 ± 47.5 vs. 46.9 ± 21.6/mm2, p = 0.001). Arterial enhancement of ICCs was found to be an independent prognostic factor for longer survival. CONCLUSION The presence of arterially hyperenhancing ICCs is related to higher MVC and exhibit a better OS time than arterially hypoenhancing ICCs after partial hepatectomy.
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Affiliation(s)
- Xiang-Hua Zhang
- The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lei Huo
- The Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Cai-Feng Liu
- The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Xu
- The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xin-Yuan Lu
- The Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Bin Huang
- The Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ning-Yang Jia
- The Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Lu Wu
- The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Feng Shen
- The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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35
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Current management of intrahepatic cholangiocarcinoma: from resection to palliative treatments. Radiol Oncol 2020; 54:263-271. [PMID: 32726292 PMCID: PMC7409608 DOI: 10.2478/raon-2020-0045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 06/29/2020] [Indexed: 01/06/2023] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is the second most common liver primary tumour after hepatocellular carcinoma and represents 20% of all the cholangiocarcinomas. Its incidence is increasing and mortality rates are rising. Surgical resection is the only option to cure the disease, despite the high recurrence rates reported to be up to 80%. Intrahepatic recurrences may be still treated with curative intent in a small percentage of the patients. Unfortunately, due to lack of specific symptoms, most patients are diagnosed in a late stage of disease and often unsuitable for resection. Liver transplantation for ICC is still controversial. After the first published poor results, improving outcomes have been reported in highly selected cases, including locally advanced ICC treated with neoadjuvant chemotherapy, when successful in controlling tumour progression. Thus, liver transplantation should be considered a possible option within study protocols. When surgical management is not possible, palliative treatments include chemotherapy, radiotherapy and loco-regional treatments such as radiofrequency ablation, trans-arterial chemoembolization or radioembolization. Conclusions This update on the management of ICC focusses on surgical treatments. Known and potential prognostic factors are highlighted in order to assist in treatment selection.
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36
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Ma X, Liu L, Fang J, Rao S, Lv L, Zeng M, Shi Y, Yang C. MRI features predict microvascular invasion in intrahepatic cholangiocarcinoma. Cancer Imaging 2020; 20:40. [PMID: 32576283 PMCID: PMC7310524 DOI: 10.1186/s40644-020-00318-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/15/2020] [Indexed: 01/02/2023] Open
Abstract
Background The presence of microvascular invasion (MVI) in intrahepatic cholangiocarcinoma (ICC) is a significant adverse prognostic factor. This study sought to investigate the correlation between preoperative imaging parameters and MVI in ICC. Methods A total of 108 patients with surgically resected single ICC tumors (34 MVI-positive and 74 MVI-negative lesions) who underwent MRI examination, including T1WI, T2WI, DWI, and dynamic enhancement imaging, were enrolled in this retrospective study. The following qualitative and quantitative characteristics were evaluated: tumor morphology, signal features on T1WI and T2WI, intrahepatic duct dilatation, hepatic capsule retraction, target sign on DWI, dynamic enhancement pattern, arterial phase enhancement pattern, dot−/band-like enhancement inside the tumor, visible vessel penetration inside the tumor (hepatic artery, portal vein, or hepatic vein), integrity of the enhancement edge of the arterial phase, peripheral hepatic enhancement, tumor size, maximum enhancement edge thickness, arterial edge enhancement ratio, and delayed phase enhancement ratio. Other clinicopathological features were also used to predict and evaluate MVI in ICC. Chi-square test, Fisher’s exact test, and independent t-test were used for univariate analysis to determine the relationships among the presence of MVI and these MR parameters. Logistic regression analysis was used to identify predictors of MVI among these MR parameters. Results Among MRI characteristics, tumor morphology, intrahepatic duct dilatation, arterial phase enhancement pattern, visible hepatic artery penetration sign, maximum diameter of the tumor and the arterial phase edge enhancement ratio were correlated with MVI (P = 0.007, 0.003, 0.008, 0.000, 0.003, and 0.002, respectively). Furthermore, higher CA19–9 levels (≥37 U/ml) and pathological tumor grade III were also related to MVI (P = 0.014 and 0.004, respectively). However, multivariate logistic regression analysis demonstrated that none of the parameters were independent risk factors for the diagnosis of MVI in ICCs. Conclusion For the preoperative prediction of MVI in ICC, six qualitative and quantitative data obtained on preoperative MRI, as well as one tumorigenic marker and the pathological tumor grade, were statistically significant. More research is needed to identify MR characteristics that can be used as independent risk factors.
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Affiliation(s)
- Xijuan Ma
- Department of Radiology, Zhongshan Hospital, Fudan University, Fenglin Road 180# , Xuhui District, Shanghai, 200032, P.R. China.,Shanghai Institute of Medical Imaging, Shanghai, 200032, P.R. China.,Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, No.199 Jiefang South Road, Quanshan District, Xuzhou, Jiangsu, 221009, P.R. China
| | - Liheng Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Fenglin Road 180# , Xuhui District, Shanghai, 200032, P.R. China.,Shanghai Institute of Medical Imaging, Shanghai, 200032, P.R. China
| | - Jun Fang
- Department of Radiology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, P.R. China
| | - Shengxiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Fenglin Road 180# , Xuhui District, Shanghai, 200032, P.R. China.,Shanghai Institute of Medical Imaging, Shanghai, 200032, P.R. China
| | - Lulu Lv
- Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, No.199 Jiefang South Road, Quanshan District, Xuzhou, Jiangsu, 221009, P.R. China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Fenglin Road 180# , Xuhui District, Shanghai, 200032, P.R. China.,Shanghai Institute of Medical Imaging, Shanghai, 200032, P.R. China
| | - Yibing Shi
- Department of Radiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, No.199 Jiefang South Road, Quanshan District, Xuzhou, Jiangsu, 221009, P.R. China.
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Fenglin Road 180# , Xuhui District, Shanghai, 200032, P.R. China. .,Shanghai Institute of Medical Imaging, Shanghai, 200032, P.R. China.
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Galangin Inhibits Cholangiocarcinoma Cell Growth and Metastasis through Downregulation of MicroRNA-21 Expression. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5846938. [PMID: 32626749 PMCID: PMC7306077 DOI: 10.1155/2020/5846938] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 04/25/2020] [Indexed: 02/06/2023]
Abstract
Galangin, a natural flavonoid product derived from the root of galangal, is emerging as a promising anticancer agent against multiple cancers. Yet, whether it also has antitumor effects on cholangiocarcinoma (CCA) and the underlying mechanism is still unknown. Herein, we demonstrate that galangin exhibits multiple antitumor effects on CCA cells including decreases cell viability; inhibits proliferation, migration, and invasion; and induces apoptosis. Moreover, those phenotypic changes are associated with downregulated microRNA-21 (miR-21) expression. To support, overexpression of miR-21 blocks galangin-mediated antisurvival and metastasis effects on CCA cells. Mechanically, galangin increases the expression of phosphatase and tensin homolog (PTEN), a direct target of miR-21, resulting in decreased phosphorylation of AKT, a protein kinase which plays a critical role in controlling survival and apoptosis. In contrast, overexpression of miR-21 abrogates galangin-regulated PTEN expression and AKT phosphorylation. Taken together, these findings indicate that galangin inhibits CCA cell proliferation and metastasis and induces cell apoptosis through a miR-21-dependent manner, and galangin may provide a novel potential therapeutic adjuvant to treat CCA.
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Ma J, Feng J, Zhou X. Long non-coding RNA HAGLROS regulates lipid metabolism reprogramming in intrahepatic cholangiocarcinoma via the mTOR signaling pathway. Exp Mol Pathol 2020; 115:104466. [PMID: 32446859 DOI: 10.1016/j.yexmp.2020.104466] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 05/09/2020] [Accepted: 05/14/2020] [Indexed: 02/08/2023]
Abstract
Alternation of long non-coding RNA (lncRNA) is implicated in intrahepatic cholangiocarcinoma (ICC) development. HAGLROS is a lncRNA with a length of 699 bp, which is involved in the progression of various cancers. But the mechanism of HAGLROS in ICC remains unknown. In this study, the sh-HAGLROS-1 or sh-HAGLROS-2 was transfected into QBC939 cells, and overexpressing HAGLROS vector was transfected into KMCH cells. HAGLROS expression in ICC tissues and cell lines was detected, and its association with ICC prognosis was further analyzed. Lipid accumulation and lipid-related indicators (TG, LDL-C, TC and HDLC) in QBC939 and KMCH cells were measured. ICC cell viability, invasion and migration were measured. Western blot analysis was used to detect levels of the mTOR axis-related proteins and autophagy-related proteins (LC3I, LC3II, Beclin and P62). The levels of serum lipids and SREBP1 positive expression in transplanted tumors of nude mice were detected. HAGLROS was highly expressed in ICC and negatively correlated with prognosis. QBC939 cells with knocking down HAGLROS exhibited reduced lipid-related protein levels, blocked ICC cellular processes, inactivated mTOR axis, and increased autophagy. QBC939 cells with overexpressing HAGLROS showed opposite trends. The lipid-related protein levels in serum of nude mice and SREBP1 positive expression in transplanted tumors were diminished. Taken together, sh-HAGLROS inactivated the mTOR axis and promoted autophagy, thereby improving lipid metabolism reprogramming in ICC. This study may offer novel ICC treatments.
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Affiliation(s)
- Jun Ma
- Department of General Surgery, Minhang Hospital, Fudan University, Shanghai 201100, PR China
| | - Jinfeng Feng
- Department of General Surgery, Minhang Hospital, Fudan University, Shanghai 201100, PR China
| | - Xiang Zhou
- Department of General Surgery, Minhang Hospital, Fudan University, Shanghai 201100, PR China.
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Panayotova GG, Paterno F, Guarrera JV, Lunsford KE. Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications. Curr Oncol Rep 2020; 22:49. [PMID: 32297105 DOI: 10.1007/s11912-020-00910-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Cholangiocarcinoma (CCA) is a rare malignancy of the biliary ducts that can be classified as intrahepatic, perihilar, or distal based on anatomic location. Although surgical resection can be curative, complete excision with negative margins is often difficult to achieve. In patients with unresectable disease, long-term survival is rarely seen with medical therapy alone. A multimodal treatment approach, including liver transplantation (LT) for select patients with unresectable CCA, should be considered. RECENT FINDINGS While currently only an approved indication for early, liver-limited, perihilar cholangiocarcinoma, promising results have been achieved for LT in localized intrahepatic disease. The absolute indication for transplant for intrahepatic tumors is currently the subject of multiple investigations. Continued advances in neoadjuvant/adjuvant therapy and better understanding of tumor biology may further augment the number of candidates for surgical therapies, with liver transplant acting as a promising tool to improve patient outcomes. Thorough consideration for any expansion in the indication for liver transplant in malignancy is necessary in order to balance patient outcomes with utilization of the scarce donor organ resources.
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Affiliation(s)
- Guergana G Panayotova
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - Flavio Paterno
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - James V Guarrera
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA
| | - Keri E Lunsford
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, 185 South Orange Ave, MSB G586, Newark, NJ, 07103, USA.
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Orlando G, Lai Q, Lerut J. Composite hepatocellular and hemangiosarcomatous tumor: The prognosis is determined by the sarcomatous component. Hepatobiliary Pancreat Dis Int 2020; 19:184-186. [PMID: 31899134 DOI: 10.1016/j.hbpd.2019.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 11/28/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Giuseppe Orlando
- Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Quirino Lai
- Starzl Unit of Abdominal Transplantation, Pôle de Chirurgie Expérimentale et Transplantation, Institute of Experimental and Clinical Research [IREC], Université catholique de Louvain, Brussels, Belgium; Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
| | - Jan Lerut
- Starzl Unit of Abdominal Transplantation, Pôle de Chirurgie Expérimentale et Transplantation, Institute of Experimental and Clinical Research [IREC], Université catholique de Louvain, Brussels, Belgium.
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Cai X, Li H, Kaplan DE. Murine hepatoblast-derived liver tumors resembling human combined hepatocellular-cholangiocarcinoma with stem cell features. Cell Biosci 2020; 10:38. [PMID: 32190288 PMCID: PMC7071781 DOI: 10.1186/s13578-020-00395-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. We describe a mouse model that exhibits the heterogenous histological and phenotypic finding similar to human CHC. METHODS We injected hepatoblasts isolated from p53-/- C57BL/6 mice into syngeneic wild-type pre-conditioned C57BL/6 mice. We confirmed that p53-/- murine hepatoblasts act as tumor-initiating cells (TICs) that generate CHC both in situ and within metastases. For comparative pathological study, 8 human cases of CHC with stem cell features were recruited by immunohistochemistry and multicolor fluorescence immunostaining. RESULTS We identified corresponding areas in murine tumors matching each WHO criteria-described subtype of human CHC. In both murine and human tumors, HPC-like cells in tumor nests and associated stem cell features/traits are suggested histologically to be the progenitor origin of the cancer. CONCLUSIONS The pathological characteristics of murine tumors recapitulate human CHC with stem cell features. These data provide additional comparative pathological evidence that CHC with stem cell features originate from HPCs and validate a model to study this cancer type in vivo.
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Affiliation(s)
- Xiong Cai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, 430022 China
| | - Heli Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
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Jiang W, Deng X, Zhu T, Wei Y, Lei Z, Guo M, Yang J. Identification of Cholangiocarcinoma Associated with Hepatolithiasis via the Combination of miRNA and Ultrasound. Cancer Manag Res 2020; 12:1845-1853. [PMID: 32210627 PMCID: PMC7075433 DOI: 10.2147/cmar.s241870] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Background Identification of cholangiocarcinoma (CCA) associated with hepatolithiasis (HL) is difficult. There is no effective method to discriminate CCA associated with HL (HL-CCA) from HL currently. Objective To explore the value of clinical data, ultrasonic characteristics and miRNA expression level in the identification of HL-CCA. Methods Thirty-one patients with HL-CCA in Huazhong University of Science and Technology Union Shenzhen Hospital were enrolled in the observation group, while 40 patients with HL alone were included in the control group. The clinical data, ultrasonic characteristics, and miRNA expression level of the two groups were recorded and analyzed to explore the potential indicators for the identification of HL-CCA. Results The accuracy of ultrasound in the diagnosis of HL-CCA was low (54.84%). Multivariate logistic regression analysis showed that liver abscess (P=0.021), indistinct border demarcation (P=0.015), non-homogenous echotexture (P=0.019), missed portal vein around lesion (P=0.032), miRNA-21 (P=0.018) and miRNA-221 (P=0.009) were the potential indicators for the identification of HL-CCA. The combined diagnosis based on logistic regression contained liver abscess, border demarcation, echotexture, portal vein around lesion, miRNA-21 and miRNA-221. The results showed that the accuracy of combined diagnosis identifying HL-CCA was the most accurate (AUC=0.911), which was significantly greater than the AUC of miRNA-21 or miRNA-221 individually (P<0.05), with a sensitivity and specificity of 77.42% and 97.50%, respectively. Conclusion Patients with HL-CCA show high incidence of hepatic abscess and elevated miRNA-21 and miRNA-221 expression level. The ultrasonic features are more likely to show indistinct border demarcation, non-homogenous echotexture, and missed portal vein around lesion. The combined diagnosis is more accurate in the identification of HL-CCA.
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Affiliation(s)
- Wei Jiang
- Department of Ultrasound, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Xiaofei Deng
- Department of Ultrasound, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Ting Zhu
- Department of Ultrasound, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Yuya Wei
- Department of Ultrasound, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Zhen Lei
- Department of Ultrasound, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Meimei Guo
- Department of Gastroenterology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
| | - Jiong Yang
- Department of Gastroenterology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, People's Republic of China
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Ma CH, Hwang DW, Song KB, Kim SC, Shin SH, Lee JH. Prognostic factors predicting survival rate over 10 years of patients with intrahepatic cholangiocarcinoma after hepatic resection. Ann Surg Treat Res 2020; 98:116-123. [PMID: 32158731 PMCID: PMC7052393 DOI: 10.4174/astr.2020.98.3.116] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/27/2019] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose Hepatic resection is considered as the optimal treatment for intrahepatic cholangiocarcinoma (IHCC); however, the survival rate after resection is low and the analysis of long-term (≥10 years) survivors is rare. This study aims to analyze the clinicopathological factors affecting the long-term survival of patients with IHCC. Methods Between January 2003 and December 2012, a single-institution cohort of 429 patients who underwent hepatic resection for IHCC were reviewed retrospectively. Surgical results, recurrence, and survival rates were investigated, and multivariate analyses were performed to identify prognostic factors. Results The overall 1- , 3- , 5- and 10-year survival rates of patients were 76.5%, 44.1%, 33.3%, and 25.1%, respectively. Multivariate analysis showed that the serum CA 19-9 level (≥38 U/mL) (P < 0.001), lymph node (LN) metastasis (P = 0.001), and lymphovascular invasion (LVI) (P = 0.012) were independent factors associated with overall survival. In particular, CA 19-9 level and histologic type were determined to be independent factors affecting survival for more than 10 years. Conclusion CA 19-9 (≥38 U/mL), LN metastasis, and LVI were identified as independent risk factors for survival after resection of IHCC. CA 19-9 (<38 U/mL) and histologic type were independent factors predicting survival for more than 10 years.
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Affiliation(s)
- Chung Hyeun Ma
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Hyun Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Jeong S, Ge Y, Chen J, Gao Q, Luo G, Zheng B, Sha M, Shen F, Cheng Q, Sui C, Liu J, Wang H, Xia Q, Chen L. Latent Risk Intrahepatic Cholangiocarcinoma Susceptible to Adjuvant Treatment After Resection: A Clinical Deep Learning Approach. Front Oncol 2020; 10:143. [PMID: 32140448 PMCID: PMC7042372 DOI: 10.3389/fonc.2020.00143] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 01/27/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Artificial Intelligence (AI) frameworks have emerged as a novel approach in medicine. However, information regarding its applicability and effectiveness in a clinical prognostic factor setting remains unclear. Methods: The AI framework was derived from a pooled dataset of intrahepatic cholangiocarcinoma (ICC) patients from three clinical centers (n = 1,421) by applying the TensorFlow deep learning algorithm to Cox-indicated pathologic (four), serologic (six), and etiologic (two) factors; this algorithm was validated using a dataset of ICC patients from an independent clinical center (n = 234). The model was compared to the commonly used staging system (American Joint Committee on Cancer; AJCC) and methodology (Cox regression) by evaluating the brier score (BS), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under curve (AUC) values. Results: The framework (BS, 0.17; AUC, 0.78) was found to be more accurate than the AJCC stage (BS, 0.48; AUC, 0.60; IDI, 0.29; NRI, 11.85; P < 0.001) and the Cox model (BS, 0.49; AUC, 0.70; IDI, 0.46; NRI, 46.11; P < 0.001). Furthermore, hazard ratios greater than three were identified in both overall survival (HR; 3.190; 95% confidence interval [CI], 2.150-4.733; P < 0.001) and disease-free survival (HR, 3.559; 95% CI, 2.500-5.067; P < 0.001) between latent risk and stable groups in validation. In addition, the latent risk subgroup was found to be significantly benefited from adjuvant treatment (HR, 0.459; 95% CI, 0.360-0.586; P < 0.001). Conclusions: The AI framework seems promising in the prognostic estimation and stratification of susceptible individuals for adjuvant treatment in patients with ICC after resection. Future prospective validations are needed for the framework to be applied in clinical practice.
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Affiliation(s)
- Seogsong Jeong
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Yang Ge
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Guijuan Luo
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Bo Zheng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Meng Sha
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Shen
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Qingbao Cheng
- Biliary Tract Department I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chengjun Sui
- Department of Special Medical Care and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.,Department of Oncology, Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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Pu XH, Yue S, Wu HY, Yang J, Fan XS, Fu Y, Ye Q, Chen J. C-MET in intrahepatic cholangiocarcinoma: High-Frequency amplification predicts protein expression and a unique molecular subtype. Pathol Res Pract 2020; 216:152857. [PMID: 32089411 DOI: 10.1016/j.prp.2020.152857] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/10/2020] [Accepted: 02/10/2020] [Indexed: 12/16/2022]
Abstract
As an increasing number of gene alterations have been discovered in intrahepatic cholangiocarcinoma (ICC), molecular targets are promising for the diagnosis and treatment of distinct subpopulations carrying unique molecular signatures. C-MET amplification is associated with a variety of tumors, including ICC; however, the characteristics of this alteration have not been assessed in ICC. By determining the ratios of C-MET/chromosome enumeration probe (CEP) 7 double-colour probes, we evaluated the presence of C-MET amplification in a cohort of 133 ICC tumors by fluorescence in situ hybridization (FISH). We further determined the levels of MET protein expression by immunohistochemistry (IHC) and analyzed clinicopathologic records. Of the samples, 21 (15.8 %) had high-frequency and 41 (30.8 %) had low-frequency C-MET genetic amplification, and 71 (53.4 %) had a normal C-MET gene. There were significant differences in gross classification (p = 0.045), microscopic cholangitis (p = 0.030), mucus level in tumors (p = 0.012) and T stage (p = 0.007) between the three groups. When we combined high-frequency and low-frequency amplifications of C-MET into one group, only microscopic cholangitis (p = 0.010) and stage (p = 0.016) showed significant differences compared to normal C-MET gene expression. However, when we combined the low-frequency C-MET amplification group with the normal C-MET group and compared this combined group with the high-frequency C-MET amplification group, the high-frequency group had more younger patients (p = 0.047), had more non-mass-forming (MF)-type cases according to gross classification (p = 0.015), secreted more mucus (p = 0.002) and appeared to have a higher T stage (p = 0.031) than the combined group. For IHC results, although only cluster C-MET amplification predicted protein overexpression, high-frequency amplification was associated with more protein expression than the other genetic statuses (p = 0.000). As low-frequency C-MET amplification exhibited similar biology to that of the normal gene, we regarded high-frequency amplification of C-MET as a unique molecular subtype. It may play important roles in tumor progression and may be used as a prognostic marker for targeted therapy.
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Affiliation(s)
- Xiao-Hong Pu
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Shen Yue
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Hong-Yan Wu
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Jun Yang
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Xiang-Shan Fan
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Yao Fu
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Qing Ye
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
| | - Jun Chen
- Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
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Saito Y. Establishment of an organoid bank of biliary tract and pancreatic cancers and its application for personalized therapy and future treatment. J Gastroenterol Hepatol 2019; 34:1906-1910. [PMID: 31264257 DOI: 10.1111/jgh.14773] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/31/2022]
Abstract
Biliary tract cancers and pancreatic cancers are aggressive malignancies that are difficult to diagnose early and have a poor prognosis. Patients with inoperable biliary tract and pancreatic cancers generally receive chemotherapy regimens including gemcitabine. However, the effects of these drugs are limited, and the 5-year survival rates of patients are very low. The newly developed three-dimensional culture system known as "organoid culture" allows long-term expansion of stem cells into cyst-like structures (organoids) with properties resembling those of the original tissues. We and other groups have successfully established long-term in vitro cultures of organoids derived from biliary tract and pancreatic cancers. Organoids derived from biliary tract and pancreatic cancers closely recapitulate the properties of the original tumors including genetic alterations, gene expression profiles, and histopathological structures. These patient-derived cancer organoids can be applied for drug sensitivity testing, drug screening, epigenetic therapy, and differentiation-inducing therapy to identify therapeutic agents optimal for each patient. We intend to further establish organoids derived from various cancer cases and construct an organoid bank of biliary tract and pancreatic cancers. These powerful in vitro preclinical models of refractory cancers may bridge the gap between basic research and clinical trials and allow personalized therapy for patients.
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Affiliation(s)
- Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
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Balitzer D, Joseph NM, Ferrell L, Shafizadeh N, Jain D, Zhang X, Yeh M, di Tommaso L, Kakar S. Immunohistochemical and molecular features of cholangiolocellular carcinoma are similar to well-differentiated intrahepatic cholangiocarcinoma. Mod Pathol 2019; 32:1486-1494. [PMID: 31186529 DOI: 10.1038/s41379-019-0290-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/29/2019] [Accepted: 04/29/2019] [Indexed: 02/08/2023]
Abstract
Cholangiolocellular carcinoma is characterized by low grade cytologic atypia, and anastomosing cords and glands resembling cholangioles or canals of Hering. Cholangiolocellular carcinoma has been variously regarded as a subtype of intrahepatic cholangiocarcinoma (World Health Organization 2000), combined hepatocellular-cholangiocarcinoma of stem cell subtype (World Health Organization 2010) and a distinct type of primary liver carcinoma. Capture-based next generation sequencing targeting the coding regions of 479 cancer genes and select introns was performed on 17 cases (5 cholangiolocellular carcinomas, 7 intrahepatic cholangiocarcinomas, 5 mixed cholangiolocellular-intrahepatic cholangiocarcinomas) along with immunohistochemistry for CK19, SALL4, CD56, CD117, and EMA. For 5 mixed cholangiolocellular-intrahepatic cholangiocarcinoma, the individual areas were micro-dissected prior to sequencing. CK19 and EMA were positive in all cases; both luminal and cytoplasmic EMA was seen in 3/5 cholangiolocellular carcinoma and 3/6 intrahepatic cholangiocarcinomas. CD117 and SALL4 were negative in all cases. CD56 was positive in 2/5 cholangiolocellular carcinoma, 4/6 intrahepatic cholangiocarcinoma and 2/5 mixed cases. Mutations typical of intrahepatic cholangiocarcinoma (IDH1/2, PBRM1, FGFR2) were present in 90% of cases with cholangiolocellular carcinoma component. The genomic profile (IDH1/2 mutations, FGFR2 fusions, chromatin-remodeling gene mutations such as ARID1A, PBRM1) and copy number alterations were similar in cholangiolocellular carcinoma, intrahepatic cholangiocarcinoma and mixed cholangiolocellular-intrahepatic cholangiocarcinoma. In all mixed cases, the immunohistochemistry results, mutational profile and copy number alterations in both components were similar. Cholangiolocellular carcinoma should be categorized as a histologic subtype of well-differentiated intrahepatic cholangiocarcinoma, and should not be considered a distinct entity, or combined hepatocellular-cholangiocarcinoma unless a distinct hepatocellular component is also present.
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Affiliation(s)
- Dana Balitzer
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Nancy M Joseph
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Linda Ferrell
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Nafis Shafizadeh
- Department of Pathology, Kaiser Permanente Woodland Hills Medical Center, Woodland Hills, CA, USA
| | - Dhanpat Jain
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Xuchen Zhang
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Matthew Yeh
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Luca di Tommaso
- Department of Pathology, Humanitas Clinical and Research Center, Rozzano-IRCCS, and Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, CA, USA.
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Li Z, Jiang X, Huang L, Li J, Ji D, Xu Y, Leng K, Cui Y. Up-regulation of ZFAS1 indicates dismal prognosis for cholangiocarcinoma and promotes proliferation and metastasis by modulating USF1 via miR-296-5p. J Cell Mol Med 2019; 23:8258-8268. [PMID: 31565837 PMCID: PMC6850950 DOI: 10.1111/jcmm.14698] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 08/09/2019] [Accepted: 08/27/2019] [Indexed: 12/13/2022] Open
Abstract
LncRNAs has been demonstrated to modulate neoplastic development by modulating downstream miRNAs and functional genes. In this study, we aimed to detect the interaction among lncRNA ZFAS1 miR‐296‐5p and USF1. We explored the proliferation, migration and invasion of cholangiocarcinoma. The differentially expressed ZFAS1 was discovered in both tissues and cell lines by qRT‐PCR. The targeting relationship between miR‐296‐5p and ZFAS1 or USF1 was validated by dual‐luciferase assay. The impact of ZFAS1 on CCA cell proliferation was observed by CCK‐8 assay. The protein expression of USF1 was determined by Western blot. The effects of ZFAS1, miR‐296‐5p and USF1 on tumour growth were further confirmed using xenograft model. LncRNA ZFAS1 expression was relatively up‐regulated in tumour tissues and cells while miR‐296‐5p was significantly down‐regulated. Knockdown of ZFAS1 significantly suppressed tumour proliferation, migration, invasion and USF1 expression. Overexpressed miR‐296‐5p suppressed cell proliferation and metastasis. Knockdown of USF1 inhibited cell proliferation and metastasis and xenograft tumour growth. In conclusion, ZFAS1 might promote cholangiocarcinoma proliferation and metastasis by modulating USF1 via miR‐296‐5p.
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Affiliation(s)
- Zhenglong Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingming Jiang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lining Huang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinglin Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Daolin Ji
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kaiming Leng
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Yang H, Wang J, Li Z, Yang Y, Yang L, Zhang Y, Shi Y, Cao Y, Zhou J, Wang Z, Chen Q. Risk Factors and Outcomes of Early Relapse After Curative Resection of Intrahepatic Cholangiocarcinoma. Front Oncol 2019; 9:854. [PMID: 31555597 PMCID: PMC6737003 DOI: 10.3389/fonc.2019.00854] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022] Open
Abstract
Early relapse after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a tremendous influence on the long-term survival outcomes of ICC patients. The purpose of our study was to investigate risk factors for early tumor relapse and confirm whether early relapse was correlated with ICC patients' long-term survival outcomes. Three hundred and twenty-two consecutive ICC patients undergoing partial hepatectomy at Liver Surgery Department of Zhongshan Hospital (Fudan University, Shanghai, China) between January 2005 and December 2011 were included in this retrospectively study. The definition of early relapse had been described as tumor relapse within 24 months after hepatectomy in ICC patients. We identified a total of 168 ICC patients with early relapse and 23 ICC patients with late relapse after hepatectomy. From the time of relapse, the long-term survival outcomes were worse among patients who had early vs. late relapse (median OS 16.5 vs. 44.7 months, respectively; P < 0.0001). The overall survival of the early relapse group was lower than that of the late relapse group (P < 0.0001). Multivariate Cox regression analysis indicated that multiple tumors (hazard ratio [HR], 1.951; 95% CI, 1.382-2.755; P < 0.001), lymphonodus metastasis (HR, 1.517; 95% CI, 1.061-2.168; P = 0.022), and higher serum CA19-9 levels (HR, 1.495; 95% CI, 1.095-2.039; P = 0.011) were independent risk factors of early relapse. Moreover, multiple tumors (HR, 1.641; 95% CI, 1.120-2.406; P = 0.011), lymphonodus metastasis (HR, 2.008; 95% CI, 1.367-2.949; P < 0.001), elevated NLR (HR, 1.921; 95% CI, 1.331-2.774; P < 0.001) and higher serum CA19-9 levels (HR, 1.990; 95% CI, 1.409-2.812; P < 0.001) were independent predictors of overall survival for ICC patients with early relapse. Collectively, our findings demonstrated that multiple tumors, lymphonodus metastasis, and higher serum CA19-9 levels were associated with the increased risks of early relapse and worse prognoses of ICC after curative-intent resection.
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Affiliation(s)
- Hua Yang
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai, China
| | - Jie Wang
- ENT Institute and Otorhinolaryngology Department, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Zehuan Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Yang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Liuxiao Yang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Yong Zhang
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai, China
| | - Yinghong Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China
| | - Jian Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Zheng Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Qing Chen
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai, China
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Intrahepatic Cholangiocarcinomas Have Histologically and Immunophenotypically Distinct Small and Large Duct Patterns. Am J Surg Pathol 2019; 42:1334-1345. [PMID: 30001234 DOI: 10.1097/pas.0000000000001118] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intrahepatic cholangiocarcinomas are histologically heterogenous. Using a cohort of 184 clinically defined, resected intrahepatic cholangiocarcinomas, we retrospectively classified the histology into 4 subtypes: large duct (LD), small duct (SD) (predominantly tubular [SD1] or predominantly anastomosing/cholangiolar, [SD2]), or indeterminate. Then, we tested the 4 subtypes for associations with risk factors, patient outcomes, histology, and immunophenotypic characteristics. SD was the most common (84%; 24% SD1 and 60% SD2) with lower proportions of LD (8%), and indeterminate (8%). Primary sclerosing cholangitis was rare (2%), but correlated with LD (P=0.005). Chronic hepatitis, frequent alcohol use, smoking, and steatosis had no histologic association. LD was associated with mucin production (P<0.001), perineural invasion (P=0.002), CA19-9 staining (P<0.001), CK7, CK19, CD56 immunophenotype (P=0.005), and negative albumin RNA in situ hybridization (P<0.001). SD was histologically nodular (P=0.019), sclerotic (P<0.001), hepatoid (P=0.042), and infiltrative at the interface with hepatocytes (P<0.001). Albumin was positive in 71% of SD and 18% of LD (P=0.0021). Most albumin positive tumors (85%) lacked extracellular mucin (P<0.001). S100P expression did not associate with subtype (P>0.05). There was no difference in disease-specific or recurrence-free survival among the subtypes. Periductal infiltration and American Joint Committee on Cancer eighth edition pT stage predicted survival by multivariable analysis accounting for gross configuration, pT stage, and histologic type. pT2 had worse outcome relative to other pT stages. Significant differences in histology and albumin expression distinguish LD from SD, but there is insufficient evidence to support further subclassification of SD.
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