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1
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Filippi R, Brandi G, Casadei-Gardini A, Leone F, Silvestris N, Satolli MA, Salani F, Sperti E, Lutrino SE, Aprile G, Santini D, Scartozzi M, Faloppi L, Palloni A, Deserti M, Tavolari S, Rimini M, Brunetti O, Spadi R, Ilaria D, Di Maio M. Viral Hepatitis in Western Patients with Advanced Intrahepatic Cholangiocarcinoma: Retrospective Assessment of Prevalence, Prognostic and Predictive Significance. Cancer Invest 2025; 43:59-69. [PMID: 39601419 DOI: 10.1080/07357907.2024.2432013] [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: 03/14/2024] [Revised: 10/29/2024] [Accepted: 11/17/2024] [Indexed: 11/29/2024]
Abstract
Despite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/- platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139-194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41-1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation.
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Affiliation(s)
- Roberto Filippi
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesco Leone
- Department of Oncology, ASL BI, Ospedale degli Infermi di Biella, Ponderano, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - Maria Antonietta Satolli
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Francesca Salani
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Pisa, Italy
- Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
| | - Elisa Sperti
- Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | | | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Daniele Santini
- Medical Oncology A, Policlinico Umberto I, La Sapienza Università di Roma, Rome, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital, Cagliari, Italy
| | - Luca Faloppi
- Medical Oncology Unit, Ospedali "Santa Maria della Pietà" e "Bartolomeo Eustachio", AST di Macerata, Camerino, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marzia Deserti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Simona Tavolari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Rosella Spadi
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Depetris Ilaria
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
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Sathitruangsak C, Pattarapuntakul T, Kaewdech A, Thongkan T, Prisutkul A, Thongwatchara P, Sriplung H, Kongkamol C, Kanokwiroon K, Obchoei S, Sripongpun P. Impact of Clinical Characteristics and Treatment on Cholangiocarcinoma Prognosis in Southern Thailand. Cancer Med 2024; 13:e70491. [PMID: 39692215 DOI: 10.1002/cam4.70491] [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: 03/17/2024] [Revised: 11/12/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is most commonly seen in Northeastern Thailand and other parts of Asia where liver flukes are prevalent. However, it is unknown whether CCA patients in low and high liver fluke prevalence areas are similar. This study aimed to analyze the clinical characteristics and outcomes of CCA patients in Southern Thailand. METHODS We retrospectively reviewed 223 patients diagnosed with CCA between 2018 and 2021 in a tertiary-care center. Clinicopathologic data were reviewed and compared between intrahepatic, perihilar, and distal CCA (iCCA, pCCA, and dCCA, respectively). Overall survivals (OS) were determined by Kaplan-Meier method and multivariable Cox regressions. RESULTS The mean age was 63.9 years; 50.7% were men. The most common subtype was iCCA (49.3%), followed by pCCA (36.3%) and dCCA (14.3%). Most patients were diagnosed at a later stage: 59.4% TMN stage IV and 23.3% stage III. Cirrhosis was present in 6.3%, while the presence of liver fluke was not detected. Only 15.1% of the cohort were deemed resectable. The median OS for iCCA, pCCA, and dCCA patients were 27.3, 22.0, and 19.3 weeks, respectively (p = 0.9). One-year survival rate differed significantly between resectable and unresectable patients (85.2% vs. 21.2%, p < 0.0001). TMN stage (aHR 1.88), palliative biliary drainage (aHR 0.31), and systemic chemotherapy (aHR 0.19) were independent predictors for mortality in unresectable pCCA and dCCA patients. In unresectable iCCA patients, only systemic chemotherapy was significant (aHR 0.30). CONCLUSION Most patients were diagnosed late, and the median OS was only 5-6 months. Unresectable CCA patients with systemic chemotherapy and palliative biliary drainage had better survival rates.
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Affiliation(s)
- Chirawadee Sathitruangsak
- Holistic Center for Cancer Study and Care (HOCC-PSU) and Medical Oncology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Tanawat Pattarapuntakul
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Tortrakoon Thongkan
- Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Apinya Prisutkul
- Holistic Center for Cancer Study and Care (HOCC-PSU) and Medical Oncology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Phatcharaporn Thongwatchara
- Holistic Center for Cancer Study and Care (HOCC-PSU) and Medical Oncology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Hutcha Sriplung
- Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Chanon Kongkamol
- Division of Digital Innovation and Data Analytics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Kanyanatt Kanokwiroon
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Sumalee Obchoei
- Division of Health and Applied Sciences, Biochemistry Graduate Program, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
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Ciobica ML, Sandulescu BA, Chicea LM, Iordache M, Groseanu ML, Carsote M, Nistor C, Radu AM. The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review). BIOLOGY 2024; 13:662. [PMID: 39336089 PMCID: PMC11429066 DOI: 10.3390/biology13090662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/07/2024] [Accepted: 08/24/2024] [Indexed: 09/30/2024]
Abstract
Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20-30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.
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Affiliation(s)
- Mihai-Lucian Ciobica
- Department of Internal Medicine and Gastroenterology, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, "Dr. Carol Davila" Central Military University Emergency Hospital, 010825 Bucharest, Romania
| | - Bianca-Andreea Sandulescu
- Department of Internal Medicine and Gastroenterology, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, "Dr. Carol Davila" Central Military University Emergency Hospital, 010825 Bucharest, Romania
- PhD Doctoral School of "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Liana-Maria Chicea
- Clinical Medical Department, University "Lucian Blaga" Sibiu, 550024 Sibiu, Romania
| | - Mihaela Iordache
- 1st Internal Medicine Department, "Dr. Carol Davila" Central Military University Emergency Hospital, 010825 Bucharest, Romania
| | - Maria-Laura Groseanu
- Internal Medicine and Rheumatology Department, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mara Carsote
- Department of Endocrinology, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Clinical Endocrinology V, C.I. Parhon National Institute of Endocrinology, 011863 Bucharest, Romania
| | - Claudiu Nistor
- Department 4-Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Thoracic Surgery Department, "Dr. Carol Davila" Central Emergency University Military Hospital, 010825 Bucharest, Romania
| | - Ana-Maria Radu
- Department of Internal Medicine and Gastroenterology, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, "Dr. Carol Davila" Central Military University Emergency Hospital, 010825 Bucharest, Romania
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Mashiko T, Carreras J, Ogasawara T, Masuoka Y, Ei S, Takahashi S, Nomura T, Mori M, Koyanagi K, Yamamoto S, Nakamura N, Nakagohri T. Intrahepatic cholangiocarcinoma with arterial phase hyperenhancement and specialized tumor microenvironment associated with good prognosis after radical resection: A single-center retrospective study. Surgery 2024; 176:259-266. [PMID: 38796389 DOI: 10.1016/j.surg.2024.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 02/06/2024] [Accepted: 03/17/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND This single-center retrospective study aimed to clarify the clinical and pathologic background of mass-forming intrahepatic cholangiocarcinomas. METHODS A total of 53 patients with mass-forming intrahepatic cholangiocarcinomas were selected from 2007 to 2021 and analyzed based on several parameters, including the preoperative computed tomography pattern (enhancement in the arterial phase of dynamic contrast-enhanced computed tomography), clinical data, and tumor microenvironment evaluated by immunohistochemistry. The hyperenhancement (n = 13) and hypoenhancement (n = 40) groups were defined using the 50% cutoff of tumors with higher attenuation than the liver parenchyma. RESULTS The hyperenhancement group was characterized by a better overall survival than the hypoenhancement group (5-year survival: 86% vs 27%, respectively; P < .001) and by a higher infiltration of peritumoral (92% vs 58%; P = .020) and intratumoral CD3-positive T lymphocytes (85% vs 35%; P = .002). Conversely, the hypoenhancement group was characterized by a higher infiltration versus peritumoral CD163-positive tumor-associated macrophages (60% vs 8%; P = .001), peritumoral pentraxin 3-positive tumor-associated macrophages (50% vs 15%; P = .024), and intratumoral α-smooth muscle actin-positive cancer-associated fibroblasts (15% vs 68%; P = .001). A multiple regression analysis was performed to predict overall survival from the microenvironment, and the independent poor predictor factors were low intratumoral CD3-positive T lymphocytes (hazard ratio = 2.75), high peritumoral (hazard ratio = 2.38), and intratumoral CD163-positive tumor-associated macrophages (hazard ratio = 2.81) (all P values < 0.05). CONCLUSION Compared with hypovascular, hypervascular mass-forming intrahepatic cholangiocarcinomas have better tumor immunity and prognosis.
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Affiliation(s)
- Taro Mashiko
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Joaquim Carreras
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Toshihito Ogasawara
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Yoshihito Masuoka
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Shigenori Ei
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Shinichiro Takahashi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Takakiyo Nomura
- Department of Radiology, Tokai University School of Medicine, Isehara, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Kazuo Koyanagi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Seiichiro Yamamoto
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Toshio Nakagohri
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan.
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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] [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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Volesky-Avellaneda KD, Morais S, Walter SD, O’Brien TR, Hildesheim A, Engels EA, El-Zein M, Franco EL. Cancers Attributable to Infections in the US in 2017: A Meta-Analysis. JAMA Oncol 2023; 9:1678-1687. [PMID: 37856141 PMCID: PMC10587828 DOI: 10.1001/jamaoncol.2023.4273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/09/2023] [Indexed: 10/20/2023]
Abstract
Importance Infections are largely modifiable causes of cancer. However, there remains untapped potential for preventing and treating carcinogenic infections in the US. Objective To estimate the percentage and number of incident cancers attributable to infections in the US among adults and children for the most recent year cancer incidence data were available (2017). Data Sources A literature search from 1946 onward was performed in MEDLINE on January 6, 2023, to obtain the data required to calculate population attributable fractions for 31 infection-cancer pairs. National Health and Nutrition Examination Survey data were used to estimate the population prevalence of hepatitis B and C viruses and Helicobacter pylori. Study Selection Studies conducted in the US or other Western countries were selected according to specific infection-cancer criteria. Data Extraction and Synthesis Data from 128 studies were meta-analyzed to obtain the magnitude of an infection-cancer association or prevalence of the infection within cancer cells. Main Outcomes and Measures The proportion of cancer incidence attributable to 8 infections. Results Of the 1 666 102 cancers diagnosed in 2017 among individuals aged 20 years or older in the US, 71 485 (4.3%; 95% CI, 3.1%-5.3%) were attributable to infections. Human papillomavirus (n = 38 230) was responsible for the most cancers, followed by H pylori (n = 10 624), hepatitis C virus (n = 9006), Epstein-Barr virus (n = 7581), hepatitis B virus (n = 2310), Merkel cell polyomavirus (n = 2000), Kaposi sarcoma-associated herpesvirus (n = 1075), and human T-cell lymphotropic virus type 1 (n = 659). Cancers with the most infection-attributable cases were cervical (human papillomavirus; n = 12 829), gastric (H pylori and Epstein-Barr virus; n = 12 565), oropharynx (human papillomavirus; n = 12 430), and hepatocellular carcinoma (hepatitis B and C viruses; n = 10 017). The burden of infection-attributable cancers as a proportion of total cancer incidence ranged from 9.6% (95% CI, 9.2%-10.0%) for women aged 20 to 34 years to 3.2% (95% CI, 2.4%-3.8%) for women aged 65 years or older and from 6.1% (95% CI, 5.2%-7.0%) for men aged 20 to 34 years to 3.3% (95% CI, 1.9%-4.4%) for men aged 65 years or older. Among those aged 19 years or younger, 2.2% (95% CI, 1.3%-3.0%) of cancers diagnosed in 2017 were attributable to Epstein-Barr virus. Conclusions and Relevance Infections were estimated to be responsible for 4.3% of cancers diagnosed among adults in the US in 2017 and, therefore, represent an important target for cancer prevention efforts.
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Affiliation(s)
- Karena D. Volesky-Avellaneda
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Samantha Morais
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
- ICES, Toronto, Ontario, Canada
| | - Stephen D. Walter
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Thomas R. O’Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Allan Hildesheim
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Eric A. Engels
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Mariam El-Zein
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
| | - Eduardo L. Franco
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
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Pascale A, Rosmorduc O, Duclos-Vallée JC. New epidemiologic trends in cholangiocarcinoma. Clin Res Hepatol Gastroenterol 2023; 47:102223. [PMID: 37797807 DOI: 10.1016/j.clinre.2023.102223] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/14/2023] [Accepted: 10/02/2023] [Indexed: 10/07/2023]
Abstract
Cholangiocarcinoma (CCA) is the most common biliary tract malignancy and the second most frequent primary hepatic malignancy after hepatocellular carcinoma. During the past three decades, the incidence of intrahepatic cholangiocarcinoma (iCCA) has risen in Western Europe, while the incidence of extrahepatic cholangiocarcinoma (eCCA) has remained stable or fallen. The mortality rates of iCCA, which are greater than those of eCCA, showed also an increasing trend, while those of eCCA remained stable. Well-known risk factors like hepatobiliary flukes, hepatolithiasis and choledochal cysts are important in the development of iCCA particularly in Asian countries. In Western countries, the primary sclerosing cholangitis is the most common risk factor for CCA. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cirrhosis are considered to be risk factors for iCCA. Emergent risk factors such as obesity, diabetes and MAFLD are increasingly associated mostly with iCCA.
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Affiliation(s)
- Alina Pascale
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, 14 Avenue Paul Vaillant Couturier, 94800 Villejuif, France; INSERM U1193, Université Paris-Saclay, France; FHU Hepatinov, France.
| | - Olivier Rosmorduc
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, 14 Avenue Paul Vaillant Couturier, 94800 Villejuif, France; INSERM U1193, Université Paris-Saclay, France; FHU Hepatinov, France; Sorbonne Université, Paris, France
| | - Jean-Charles Duclos-Vallée
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, 14 Avenue Paul Vaillant Couturier, 94800 Villejuif, France; INSERM U1193, Université Paris-Saclay, France; FHU Hepatinov, France
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8
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Shaik MR, Shaik NA, Bilgrami Z, Wheeler E, Chow RT. A Call To Action: Cholangiocarcinoma in the Setting of Sustained Hepatitis C Virologic Response - Case Report and Review of Literature. J Community Hosp Intern Med Perspect 2023; 13:35-41. [PMID: 37868248 PMCID: PMC10589012 DOI: 10.55729/2000-9666.1198] [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: 02/03/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 10/24/2023] Open
Abstract
The incidence of cholangiocarcinoma, an aggressive malignancy with poor prognosis, is increasing. Hepatitis B and C have been well established as predisposing factors for this malignancy. The availability and efficacy of treatment for hepatitis C infection has led to a substantial reduction in viral hepatitis-related cholangiocarcinoma mortality. Despite treatment, the potential for developing cholangiocarcinoma continues to exist for patients with underlying cirrhosis. We present a patient who was effectively treated for hepatitis C with direct-acting antiviral therapy eight years prior. He presented with malaise, fatigue, and an unintentional weight loss of 40 pounds. Imaging revealed a metastatic malignancy, and a liver biopsy confirmed the diagnosis of cholangiocarcinoma and the absence of underlying cirrhosis in the background liver. This case highlights the persistent risk of developing cholangiocarcinoma despite achieving sustained virological response to treatment for hepatitis C. We review the associated literature and briefly discuss the predisposing conditions that might result in such an outcome. We also encourage the need for long-term surveillance for such patients and the importance of conducting more multi-center studies to identify at-risk patients and develop cost-effective screening protocols.
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Affiliation(s)
- Mohammed R. Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD,
United States
| | - Nishat A. Shaik
- Department of Medicine, Guntur Medical College, Guntur, Andhra Pradesh,
India
| | - Zaid Bilgrami
- Department of Radiology, New York Presbyterian Hospital Columbia Campus, New York,
United States
| | - Erika Wheeler
- Department of Pathology, University of Maryland Medical Center, Baltimore, MD,
United States
| | - Robert Td Chow
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD,
United States
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD,
United States
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9
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Shi GM, Huang XY, Wen TF, Song TQ, Kuang M, Mou HB, Bao LQ, Zhao HT, Zhao H, Feng XL, Zhang BX, Peng T, Zhang YB, Li XC, Yu HS, Cao Y, Liu LX, Zhang T, Wang WL, Ran JH, Liu YB, Gong W, Chen MX, Cao L, Luo Y, Wang Y, Zhou H, Yang GH, Fan J, Zhou J. Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study. Cancer Med 2023; 12:4137-4146. [PMID: 36127767 PMCID: PMC9972033 DOI: 10.1002/cam4.5273] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/13/2022] [Accepted: 08/08/2022] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly <grade 3, except for 2 events ≥grade 3. CONCLUSIONS The encouraging antitumor activity and favorable safety profile support the use of pemigatinib as a treatment in previously treated Chinese patients with cholangiocarcinoma and FGFR2 rearrangements.
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Affiliation(s)
- Guo-Ming Shi
- Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Yong Huang
- Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tian-Fu Wen
- Hepatobiliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Tian-Qiang Song
- Hepatobiliary Surgery, Tianjin Cancer Hospital, Tian Jin, China
| | - Ming Kuang
- Department of Oncology, Hepatobiliary and Pancreatic Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hai-Bo Mou
- Medical Oncology, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Le-Qun Bao
- Hepatobiliary Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Hai-Tao Zhao
- Liver Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Hong Zhao
- Hematological Surgery Department, Cancer Hospital of Chinese Academy of Medical Science, Beijing, China
| | - Xie-Lin Feng
- Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital, Chengdu, China
| | - Bi-Xiang Zhang
- Hepatobiliary Surgery, Tongji Hospital, Tongji Medical College of HUST, Wuhan, China
| | - Tao Peng
- Hepatological Surgery Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yu-Bao Zhang
- Hepatobiliary and Pancreatic Surgery, Cancer Hospital Affiliated to Harbin Medical University, Harbin, China
| | - Xiang-Cheng Li
- Liver Surgery, Jiangsu Province Hospital, Nanjing, China
| | - Hong-Sheng Yu
- Oncology Department, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yu Cao
- Phase 1 Clinical Research Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lian-Xin Liu
- Hepatobiliary Surgery Department, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Ti Zhang
- Hepatobiliary Surgery Department, Tianjin Cancer Hospital, Tianjin, China
| | - Wei-Lin Wang
- Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jiang-Hua Ran
- Hepatopancreatobiliary Surgery, The First Hospital of Kunming, Kunming, China
| | - Ying-Bin Liu
- General Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Gong
- General Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Xia Chen
- Department of Medical Science and Oncological Strategy, Innovent Biologics Inc., Suzhou, China
| | - Lian Cao
- Department of Medical Science and Oncological Strategy, Innovent Biologics Inc., Suzhou, China
| | - Yang Luo
- Department of Medical Science and Oncological Strategy, Innovent Biologics Inc., Suzhou, China
| | - Yan Wang
- Department of Medical Science and Oncological Strategy, Innovent Biologics Inc., Suzhou, China
| | - Hui Zhou
- Department of Medical Science and Oncological Strategy, Innovent Biologics Inc., Suzhou, China
| | - Guo-Huan Yang
- Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
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10
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Analysis of viral integration reveals new insights of oncogenic mechanism in HBV-infected intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma. Hepatol Int 2022; 16:1339-1352. [PMID: 36123506 DOI: 10.1007/s12072-022-10419-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/24/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Integration of HBV DNA into the human genome could progressively contribute to hepatocarcinogenesis. Both intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC) are known to be associated with HBV infection. However, the integration of HBV and mechanism of HBV-induced carcinogenesis in ICC and CHC remains unclear. METHODS 41 patients with ICC and 20 patients with CHC were recruited in the study. We conducted HIVID analysis on these 61 samples to identify HBV integration sites in both the tumor tissues and adjacent non-tumor liver tissues. To further explore the effect of HBV integration on gene alteration, we selected paired tumors and adjacent non-tumor liver tissues from 3 ICC and 4 CHC patients for RNA-seq and WGS. RESULTS We detected 493 HBV integration sites in ICC patients, of which 417 were from tumor samples and 76 were from non-tumor samples. And 246 HBV integration sites were detected in CHC patients, of which 156 were located in the genome of tumor samples and 90 were in non-tumor samples. Recurrent HBV integration events were detected in ICC including TERT, ZMAT4, MET, ANKFN1, PLXNB2, and in CHC like TERT, ALKBH5. Together with our established data of HBV-infected hepatocellular carcinoma, we found that HBV preferentially integrates into the specific regions which may affect the gene expression and regulation in cells and involved in carcinogenesis. We further performed genomic and transcriptomic sequencing of three ICC and four CHC patients, and found that HBV fragments could integrate near some important oncogene like TERT, causing large-scale genome variations on nearby genomic sequences, and at the same time changing the expression level of the oncogenes. CONCLUSION Comparative analysis demonstrates numerous newly discovered mutational events in ICC and CHC resulting from HBV insertions in the host genome. Our study provides an in-depth biological and clinical insights into HBV-induced ICC and CHC.
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11
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Wang Y, Yuan Y, Gu D. Hepatitis B and C virus infections and the risk of biliary tract cancers: a meta-analysis of observational studies. Infect Agent Cancer 2022; 17:45. [PMID: 36030232 PMCID: PMC9420284 DOI: 10.1186/s13027-022-00457-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Background Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important risk factors for hepatocellular carcinoma. However, their effect on other hepatobiliary cancers, such as biliary tract cancers (BTCs), is not well established. We aimed to investigate associations between HBV or HCV infection and BTCs risk by conducting a systematic review and meta-analysis. Methods We searched PubMed to identify all relevant articles published before June 9, 2021. Meta-analysis was performed to calculate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The meta-analysis was evaluated by heterogeneity testing, sensitivity analyses, and publication bias assessment. Results In total, 48 articles involving 69,723 cases and 4,047,574 controls were obtained to calculate the associations between HBV or HCV infection and the risk of BTCs. We found that both HBV and HCV infections were associated with the risk of BTCs, with pooled ORs of 2.16 (95% CI 1.73–2.69) and 2.12 (95% CI 1.62–2.77), respectively. Subgroup analyses by ethnicity suggested that HBV infection could increase the risk of BTCs in both Asian (OR = 2.29, 95% CI 1.76–2.97) and Caucasian (OR = 1.80, 95% CI 1.18–2.75) populations. In addition, HCV infection resulted in a higher increased risk of BTCs in Caucasian populations than in Asian populations (OR = 3.93 vs. 1.51, P = 0.014). In particular, significantly increased risks of intrahepatic cholangiocarcinoma (ICC) were identified in individuals with HBV (OR = 3.96, 95% CI 3.05–5.15) or HCV infection (OR = 2.90, 95% CI 2.07–4.08). Conclusions This study suggests that both HBV and HCV infections are risk factors for BTCs, particularly ICC, highlighting the necessity of cancer screening for BTCs in patients with either HBV or HCV infection. Supplementary Information The online version contains supplementary material available at 10.1186/s13027-022-00457-9.
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Affiliation(s)
- Yizhou Wang
- Department of Pathology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, 621000, China
| | - Ye Yuan
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Dongqing Gu
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
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12
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Lin CR, Lee YK, Chiang CJ, Yang YW, Chang HC, You SL. Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study. World J Gastroenterol 2022; 28:3695-3705. [PMID: 36161044 PMCID: PMC9372811 DOI: 10.3748/wjg.v28.i28.3695] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/30/2022] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignancies. However, because of its scarcity there are limited population-based data available for investigations into its epidemiologic characteristics. In Taiwan, we have a national cancer registry database that can be used to evaluate the secular trends of ICC.
AIM To evaluate secular trends of ICC according to age, sex, and risk factors in Taiwan.
METHODS In this population-based study, we used the national Taiwan Cancer Registry database. Age-standardized and relative percent changes in incidence rates were used to describe secular trends in incidence rates and sex ratios of ICC in Taiwan.
RESULTS The age-standardized ICC incidence rate among males increased from 1.51 per 100000 in 1993-1997 to 4.07 per 100000 in 2013-2017 and among female from 1.73 per 100000 to 2.95 per 100000. The incidence in females tended to plateau after 2008-2012. For males, the ICC incidence increased as age increased. In the long-term incidence trend of ICC in females, the incidence of the four age groups (40-44, 45-49, 50-54 and 55-59 years) remained stable in different years; although, the incidence of the 60-64 group had a peak in 2003-2007, and the peak incidence of the 65-69 and 70-74 groups occurred in 2008-2012. Among males, beginning at the age of 65, there were increases in the incidence of ICC for the period of 2003-2017 as compared with females in the period of 2003-2017.
CONCLUSION Increased incidence of ICC occurred in Taiwan over the past two decades. The increased incidence has progressively shifted toward younger people for both males and females.
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Affiliation(s)
- Chun-Ru Lin
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242008, Taiwan
| | - Yu-Kwang Lee
- Department of Surgery, National Taiwan University Hospital, Taipei 100229, Taiwan
| | - Chun-Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
| | - Ya-Wen Yang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
| | - Hung-Chuen Chang
- Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan
| | - San-Lin You
- School of Medicine and Data Science Center, Fu Jen Catholic University, New Taipei City 242008, Taiwan
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13
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Cytological Comparison between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Image Analysis Software Using Touch Smear Samples of Surgically Resected Specimens. Cancers (Basel) 2022; 14:cancers14092301. [PMID: 35565430 PMCID: PMC9102894 DOI: 10.3390/cancers14092301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/01/2022] [Accepted: 05/04/2022] [Indexed: 02/05/2023] Open
Abstract
To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of HCC and 16 of ICC. The results indicated that the major/minor axis ratio of ICC is significantly larger than that of HCC (1.67 ± 0.27 vs. 1.32 ± 0.11, p < 0.0001) in Papanicolaou staining. This result means that the nucleus of HCC is close to round and the nucleus of ICC is close to an oval. This significant difference in the major/minor axis ratio between ICC and HCC was consistently observed by the same analyses using clinical samples of cytology (4 cases of HCC and 13 cases of ICC) such a fine-needle aspiration, brushing and ascites (ICC: 1.45 ± 0.13 vs. HCC: 1.18 ± 0.056, p = 0.004). We also confirmed that nuclear position center-positioned nucleus (p < 0.0001) and granular cytoplasm (p < 0.0001) are typical features of HCC tumor cells compared to ICC tumor cells. The research study found a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding will be very useful for the differential cytodiagnosis of HCC and ICC.
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [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] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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15
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Gheorghe G, Diaconu CC, Ionescu V, Constantinescu G, Bacalbasa N, Bungau S, Gaman MA, Stan-Ilie M. Risk Factors for Pancreatic Cancer: Emerging Role of Viral Hepatitis. J Pers Med 2022; 12:83. [PMID: 35055398 PMCID: PMC8780367 DOI: 10.3390/jpm12010083] [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: 10/27/2021] [Revised: 12/09/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive malignant neoplastic diseases. The incidence and mortality rates of this disease vary depending on geographical area, which might be explained by the different exposure to risk factors. To improve the prognosis of patients with pancreatic cancer, different approaches are needed for an earlier diagnosis. Identification of risk factors and implementation of screening strategies are essential for a better prognosis. Currently, the risk factors for pancreatic cancer fall into two broad categories, namely extrinsic and intrinsic factors. Extrinsic factors include alcohol consumption, smoking, a diet rich in saturated fats, and viral infections such as chronic infection with hepatitis B and C viruses. The pathophysiological mechanisms explaining how these hepatotropic viruses contribute to the development of pancreatic cancer are not fully elucidated. The common origin of hepatocytes and pancreatic cells in the multipotent endodermal cells, the common origin of the blood vessels and biliary ducts of the pancreas and the liver, or chronic inflammatory changes may be involved in this interaction. A careful monitoring of patients with viral liver infections may contribute to the early diagnosis of pancreatic cancer and improve the prognosis of these patients.
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Affiliation(s)
- Gina Gheorghe
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Camelia Cristina Diaconu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Vlad Ionescu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Gabriel Constantinescu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Nicolae Bacalbasa
- Department of Visceral Surgery, “Carol Davila” University of Medicine and Pharmacy, Center of Excellence in Translational Medicine “Fundeni” Clinical Institute, 022328 Bucharest, Romania;
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Mihnea-Alexandru Gaman
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Madalina Stan-Ilie
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
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16
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Hormati A, Hajrezaei Z, Jazi K, Aslani Kolur Z, Rezvan S, Ahmadpour S. Gastrointestinal and Pancratohepatobiliary Cancers: A Comprehensive Review on Epidemiology and Risk Factors Worldwide. Middle East J Dig Dis 2022; 14:5-23. [PMID: 36619733 PMCID: PMC9489325 DOI: 10.34172/mejdd.2022.251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 11/01/2021] [Indexed: 01/11/2023] Open
Abstract
A significant number of cancer cases are afflicted by gastrointestinal cancers annually. Lifestyle and nutrition have a huge effect on gastrointestinal function, and unhealthy habits have become quite widespread in recent decades, culminating in the rapid growth of gastrointestinal cancers. The most prevalent cancers are lip and mouth cancer, esophageal cancer, gastric cancer, liver and bile duct cancer, pancreatic cancer, and colorectal cancer. Risk factors such as red meat consumption, alcohol consumption, tea, rice, viruses such as Helicobacter pylori and Ebstein Bar Virus (EBV), along with reduced physical activity, predispose the gastrointestinal tract to damage and cause cancer. According to the rapid increase of cancer incidence and late diagnosis of gastrointestinal malignancies, further epidemiological researches remain necessary in order to make appropriate population-based preventive policies. In this study, we reviewed clinical symptoms, risk factors, preventative measures, as well as incidence and mortality rates of gastrointestinal malignancies worldwide with focus on Iranian population.
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Affiliation(s)
- Ahmad Hormati
- Assistant Professor of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Assistant Professor of Gastroenterology and Hepatology, Disease Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Zahra Hajrezaei
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Zahra Aslani Kolur
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Sajjad Rezvan
- Radiology Resident, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Sajjad Ahmadpour
- Gastroenterology and Hepatology Diseases Research Center, Qom University of Medical Sciences, Qom, Iran
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17
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Understanding the genetic basis for cholangiocarcinoma. Adv Cancer Res 2022; 156:137-165. [DOI: 10.1016/bs.acr.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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18
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Broecker F, Moelling K. The Roles of the Virome in Cancer. Microorganisms 2021; 9:microorganisms9122538. [PMID: 34946139 PMCID: PMC8706120 DOI: 10.3390/microorganisms9122538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/22/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Viral infections as well as changes in the composition of the intestinal microbiota and virome have been linked to cancer. Moreover, the success of cancer immunotherapy with checkpoint inhibitors has been correlated with the intestinal microbial composition of patients. The transfer of feces-which contain mainly bacteria and their viruses (phages)-from immunotherapy responders to non-responders, known as fecal microbiota transplantation (FMT), has been shown to be able to convert some non-responders to responders. Since phages may also increase the response to immunotherapy, for example by inducing T cells cross-reacting with cancer antigens, modulating phage populations may provide a new avenue to improve immunotherapy responsiveness. In this review, we summarize the current knowledge on the human virome and its links to cancer, and discuss the potential utility of bacteriophages in increasing the responder rate for cancer immunotherapy.
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Affiliation(s)
- Felix Broecker
- Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
- Correspondence: (F.B.); (K.M.)
| | - Karin Moelling
- Institute of Medical Microbiology, University of Zurich, Gloriastr. 30, CH-8006 Zurich, Switzerland
- Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany
- Correspondence: (F.B.); (K.M.)
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Bao M, Zhu Q, Aji T, Wei S, Tuergan T, Ha X, Tulahong A, Hu X, Hu Y. Development of Models to Predict Postoperative Complications for Hepatitis B Virus-Related Hepatocellular Carcinoma. Front Oncol 2021; 11:717826. [PMID: 34676160 PMCID: PMC8523990 DOI: 10.3389/fonc.2021.717826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/13/2021] [Indexed: 01/27/2023] Open
Abstract
Background Surgical treatment remains the best option for patients with hepatocellular carcinoma (HCC) caused by chronic hepatitis B virus (HBV) infection. However, there is no optimal tool based on readily accessible clinical parameters to predict postoperative complications. Herein, our study aimed to develop models that permitted risk of severe complications to be assessed before and after liver resection based on conventional variables. Methods A total of 1,047 patients treated by hepatectomy for HCC with HBV infection at three different centers were recruited retrospectively between July 1, 2014, and July 1, 2018. All surgical complications were recorded and scored by the Comprehensive Complication Index (CCI). A CCI ≥26.2 was used as a threshold to define patients with severe complications. We built two models for the CCI, one using preoperative and one using preoperative and postoperative data. Besides, CCI and other potentially relevant factors were evaluated for their ability to predict early recurrence and metastasis. All the findings were internally validated in the Hangzhou cohort and then externally validated in the Lanzhou and Urumqi cohorts. Results Multivariable analysis identified National Nosocomial Infections Surveillance (NNIS) index, tumor number, gamma-glutamyltransferase (GGT), total cholesterol (TC), potassium, and thrombin time as the key preoperative parameters related to perioperative complications. The nomogram based on the preoperative model [preoperative CCI After Surgery for Liver tumor (CCIASL-pre)] showed good discriminatory performance internally and externally. A more accurate model [postoperative CCI After Surgery for Liver tumor (CCIASL-post)] was established, combined with the other four postoperative predictors including leukocyte count, basophil count, erythrocyte count, and total bilirubin level. No significant association was observed between CCI and long-term complications. Conclusion Based on the widely available clinical data, statistical models were established to predict the complications after hepatectomy in patients with HBV infection. All the findings were extensively validated and shown to be applicable nationwide. Such models could be used as guidelines for surveillance follow-up and the design of post-resection adjuvant therapy.
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Affiliation(s)
- Mingyang Bao
- State Key Laboratory of Genetic Engineering, Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai, China
| | - Qiuyu Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Surgery, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tuerganaili Aji
- Department of Hepatobiliary and Hydatid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Shuyao Wei
- Clinical Laboratory Diagnostics, School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Talaiti Tuergan
- Department of Hepatobiliary and Hydatid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaoqin Ha
- Department of Clinical Laboratory, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, China
| | - Alimu Tulahong
- Department of Hepatobiliary and Hydatid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaoyi Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yueqing Hu
- State Key Laboratory of Genetic Engineering, Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai, China.,Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China
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20
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Fragkou N, Sideras L, Panas P, Emmanouilides C, Sinakos E. Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence? World J Gastroenterol 2021; 27:4252-4275. [PMID: 34366604 PMCID: PMC8316913 DOI: 10.3748/wjg.v27.i27.4252] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/12/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.
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Affiliation(s)
- Nikolaos Fragkou
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Lazaros Sideras
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panteleimon Panas
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Emmanouil Sinakos
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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21
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Ma Z, Li H, Liu L. Combining PD-1 Inhibitor with VEGF/VEGFR2 Inhibitor in Chemotherapy: Report of a Patient with End-Stage Cholangiocarcinoma and Review of Literature. Recent Pat Anticancer Drug Discov 2021; 16:101-107. [PMID: 33390149 DOI: 10.2174/1574892815999201231215311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/06/2020] [Accepted: 10/14/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Cholangiocarcinoma is the second-largest liver cancer, and develops from the biliary epithelium, where it discretely progresses. Unfortunately, many patients miss the opportunity of performing surgery when diagnosed with cholangiocarcinoma, and due to its chemotherapeutic insensitivity, its control has always been considered difficult. OBJECTIVE Here, we present a case of stage 4 cholangiocarcinoma being controlled by the combination of chemotherapy with PD-1 and VEGF/VEGFR2 inhibitors. CASE PRESENTATION The patient is a 58-year-old male who was diagnosed with a progressed cholangiocarcinoma 2 years ago. From the beginning, metastases were discovered in multiple places, and the patient was unsuccessfully treated with 3 chemotherapy regimens. Therefore, a new therapeutic method was considered, and that involved the testing of a new combination of chemotherapy with PD-1 and VEGF/VEGFR2 inhibitors. RESULTS After 6 courses of treatment with this combination, the patient's lesions became smaller and stable. CONCLUSION Our case highlights the possibility of combining chemotherapy with PD-1 and VEGF/ VEGFR2 inhibitors for the treatment of cholangiocarcinoma patients. This combination may herald new hope for patients who run out of regimens.
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Affiliation(s)
- Zhenjiang Ma
- The First Affiliated Hospital of Sun Yat sen University No.183 Huangpu East Road, Huangpu District, Guangzhou City, Guangdong Province, China
| | - Heping Li
- The First Affiliated Hospital of Sun Yat sen University No.183 Huangpu East Road, Huangpu District, Guangzhou City, Guangdong Province, China
| | - Liangshuai Liu
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital) No. 36 Mingxin Road, Liwan District, Guangzhou City, Guangdong Province, China
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22
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Wang H, Chen X, Chen X, Zhang W, Liu K, Wang Y, Tang H, Hu J. Associations between hepatitis B virus exposure and the risk of extrahepatic digestive system cancers: A hospital-based, case-control study (SIGES). Cancer Med 2021; 10:3741-3755. [PMID: 33934530 PMCID: PMC8178500 DOI: 10.1002/cam4.3901] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/29/2020] [Accepted: 03/14/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES This case-control study was aimed to investigate associations between HBV infection and extrahepatic digestive system cancers. METHODS The patients of gastric, small intestinal, colonic, rectal, anal, biliary tract, and pancreatic cancers were retrospectively collected between 2016.5 and 2017.12. Simultaneously, the healthy controls were collected from the health check-up registry, and cancer-free status was confirmed based on medical records. Propensity score matching was performed to reduce bias. Multinomial logit model and conditional logistic regression model were used to assess the risk of individual cancer according to HBV serological markers and classifications. RESULTS Totally, 4748 patients involving seven cancers, and 57,499 controls were included. After matching, HBsAg was associated with increased risk of gastric cancer (aOR = 1.39, 95% CI: 1.05-1.85), and anti-HBs served as a protective factor for gastric (aOR = 0.72, 95% CI: 0.61-0.85), colonic (aOR = 0.73, 95% CI: 0.60-0.89), rectal (aOR = 0.73, 95% CI: 0.63-0.85), and pancreatic (aOR = 0.58, 95% CI: 0.42-0.82) cancers. Compared to subgroups with non-infection and vaccination status, inactive HBsAg carriers and active HBV infection subgroup were correlated with gastric carcinogenesis (aOR = 1.41, 95% CI: 1.03-1.93). However, no clear association was found between HBV infection and other cancers. CONCLUSIONS HBV infection was potentially associated with an increased risk of gastric cancer. The development mechanism of HBV-associated gastric cancer needs to investigate further.
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Affiliation(s)
- Hui Wang
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
- Department of Gastrointestinal SurgeryThe Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xin‐Zu Chen
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
- Department of Gastrointestinal and Hernia SurgerySecond People’s Hospital of Yibin City West China Yibin HospitalSichuan UniversityYibinChina
| | - Xiao‐Long Chen
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Wei‐Han Zhang
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Kai Liu
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - You‐Juan Wang
- Health Management CenterWest China HospitalSichuan UniversityChengduChina
| | - Huai‐Rong Tang
- Health Management CenterWest China HospitalSichuan UniversityChengduChina
| | - Jian‐Kun Hu
- Department of Gastrointestinal Surgery and Laboratory of Gastric CancerState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
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Lleo A, Colapietro F, Maisonneuve P, Aloise M, Craviotto V, Ceriani R, Rimassa L, Badalamenti S, Donadon M, Pedicini V, Repici A, Di Tommaso L, Voza A, Torzilli G, Aghemo A. Risk Stratification of Cholangiocarcinoma Patients Presenting with Jaundice: A Retrospective Analysis from a Tertiary Referral Center. Cancers (Basel) 2021; 13:cancers13092070. [PMID: 33922972 PMCID: PMC8123266 DOI: 10.3390/cancers13092070] [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: 03/26/2021] [Revised: 04/15/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Jaundice is a common clinical presentation of cholangiocarcinoma; however, the prognostic impact of this symptom is poorly understood. We retrospectively analyzed all consecutive cases presenting with jaundice between January 2010 and December 2017. During the study period, 200 patients (0.049% of all admissions) with CCA were identified. Most of them presented with advance disease, and median survival was 4.5 months. Age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis were associated with better survival. A nomogram was constructed that significantly predicts short term survival and could be used to tailor management. Abstract Cholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract. Jaundice is a common clinical presentation; however, the prognostic impact of this symptom is poorly understood, and current management recommendations lack solid evidence. We aim to assess the clinical outcomes and predictive factors of CCA patients presenting with jaundice in the Emergency Room (ER). We retrospectively analyzed all consecutive ER cases presenting with jaundice between January 2010 and December 2017. During the study period, 403,766 patients were admitted to the ER, 1217 (0.3%) presented with jaundice, and in 200 (0.049%), the diagnosis was CCA. CCA cases increased during the study period (p for trend 0.026). Most of them presented with advance disease (stage III 46.5%, stage IV 43.5%) and median survival was 4.5 months (95% CI 3.4–6.0). Factors associated with better survival were age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis. A nomogram was constructed that significantly predicts 1-month, 6-month, and 1-year survival after patients’ admission. In conclusion, the majority of CCA patients presenting with jaundice to the ER have advanced disease and poor prognosis. Risk stratification of these patients can allow tailored management.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
- Correspondence: ; Tel.: +39-02-8224-7231
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, 20132 Milan, Italy;
| | - Monia Aloise
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Vincenzo Craviotto
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Roberto Ceriani
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Salvatore Badalamenti
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Matteo Donadon
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Divisionof Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Vittorio Pedicini
- Department of Interventional Radiology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy;
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Digestive Endoscopy Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Luca Di Tommaso
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Pathology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Antonio Voza
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Divisionof Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (F.C.); (L.R.); (M.D.); (A.R.); (L.D.T.); (A.V.); (G.T.); (A.A.)
- Internal Medicine Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (M.A.); (V.C.); (R.C.); (S.B.)
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Long-term risk of primary liver cancers in entecavir versus tenofovir treatment for chronic hepatitis B. Sci Rep 2021; 11:1365. [PMID: 33446835 PMCID: PMC7809351 DOI: 10.1038/s41598-020-80523-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66–1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65–1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30–0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54–6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31–3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.
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Li M, Du M, Cong H, Gu Y, Fang Y, Li J, Gan Y, Tu H, Gu J, Xia Q. Characterization of hepatitis B virus DNA integration patterns in intrahepatic cholangiocarcinoma. Hepatol Res 2021; 51:102-115. [PMID: 33037855 DOI: 10.1111/hepr.13580] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/19/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022]
Abstract
AIM Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV-related ICC. METHODS The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high-throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. RESULTS Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high-throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV-DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV-DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para-ICC tissues. CONCLUSIONS Taken together, HBV integration is a common event in HBV-related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC.
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Affiliation(s)
- Mengge Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Du
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Cong
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyuan Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Emergency, Nanjing First Hospital, Nanjing, China
| | - Yuan Fang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jin Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Gan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Tu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinyang Gu
- Department of Transplantation, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Salem PES, Ghazala RA, El Gendi AM, Emara DM, Ahmed NM. The association between circulating MicroRNA-150 level and cholangiocarcinoma. J Clin Lab Anal 2020; 34:e23397. [PMID: 33161598 PMCID: PMC7676191 DOI: 10.1002/jcla.23397] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/06/2019] [Accepted: 11/24/2019] [Indexed: 12/17/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare tumor which requires a multimodality approach for its diagnosis. Carbohydrate antigen 19‐9 (CA19‐9) is currently the most commonly used tumor marker for CCA; nevertheless, it has certain limitations which need to be considered when using it as a tumor marker. MiRNA‐150 altered expression has been linked to the development and tumorigenesis of several cancers including CCA. This work aimed to study the serum level of CA19‐9 and miRNA‐150 expression in CCA patients and, also, to correlate their levels with tumor staging and different studied clinical and laboratory parameters. This work included 35 patients with CCA who were admitted to Hepatobiliary Unit, Alexandria Main University Hospital (Group I). Also, 35 age‐ and sex‐matched healthy subjects were included as a control group (Group II). All included subjects were submitted to measurement of serum CA19‐9 and MiRNA‐150 expression levels. Serum CA19‐9 levels showed an evident high median among CCA patients, while serum miRNA‐150 expression levels were evidently low among those patients. Moreover, combining miRNA‐150 with CA19‐9 made the accuracy of diagnosis of CCA much more reliable. Thus, miRNA‐150 can be considered as a non‐invasive, sensitive serum biomarker for the diagnosis of CCA especially when combined with CA 19‐9.
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Affiliation(s)
- Perihan El Sayed Salem
- Internal Medicine Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | | | - Doaa Mokhtar Emara
- Department of Radiodiagnosis and Intervention Radiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Nesma Mahmoud Ahmed
- Internal Medicine Department, Fever Hospital, Alexandria University, Alexandria, Egypt
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Marônek M, Link R, Monteleone G, Gardlík R, Stolfi C. Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders? Int J Mol Sci 2020; 21:ijms21218133. [PMID: 33143318 PMCID: PMC7663754 DOI: 10.3390/ijms21218133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia;
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
- Division of Clinical Biochemistry and Clinical Molecular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-06-72596163
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Morita S, Suda T, Kishi Y, Iwasaki T, Hiraoka N, Nagayama I, Hoshi T, Abe S, Yagi K, Hasegawa G, Ikarashi T, Terai S. Synchronous Double Bile Duct Cancers with Distinct Genetic Features. Intern Med 2020; 59:2129-2134. [PMID: 32493852 PMCID: PMC7516326 DOI: 10.2169/internalmedicine.4613-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.
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Affiliation(s)
- Shinichi Morita
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Takeshi Suda
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Yoji Kishi
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
- Department of Surgery, National Defense Medical College, Japan
| | - Toshimitsu Iwasaki
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
- Department of Surgery, National Defense Medical College, Japan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
| | - Itsuo Nagayama
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Takahiro Hoshi
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Satoshi Abe
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Kazuyoshi Yagi
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine Niigata University Hospital, Japan
| | - Go Hasegawa
- Department of Pathology, Uonuma institute of Community Medicine Niigata University Hospital, Japan
| | | | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
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Seo JW, Kwan BS, Cheon YK, Lee TY, Shim CS, Kwon SY, Choe WH, Yoo BC, Yoon JM, Lee JH. Prognostic impact of hepatitis B or C on intrahepatic cholangiocarcinoma. Korean J Intern Med 2020; 35:566-573. [PMID: 31916422 PMCID: PMC7214366 DOI: 10.3904/kjim.2018.062] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 07/11/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND/AIMS Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy, arising from the peripheral intrahepatic bile duct epithelium. Hepatitis B virus (HBV) or hepatitis C virus (HCV) may be involved in the development of ICC. We explored the prognostic value of hepatitis virus infection, as well as other prognostic factors affecting survival in patients with ICC. METHODS A retrospective chart review was performed for patients diagnosed with ICC between August 2005 and December 2018 at Konkuk University Medical Center. We identified a total of 131 patients with ICC. Overall survival rates of patients with and without hepatitis were determined. Univariate and multivariate analyses were used to estimate factors influencing survival outcomes. RESULTS A total of 17.6% (23/131) of patients were positive for HBV or HCV. Hepatitis B positive ICC patients were significantly younger with higher albumin and higher α-fetoprotein than those without hepatitis viral infections. The median survival of hepatitis-positive and hepatitis-negative groups was 280 and 213 days, respectively. Survival rates were not significantly different between the two groups (p = 0.279). Multivariate analyses indicated that lower serum carbohydrate antigen 19-9 (CA 19-9) (p < 0.001), lower T stage (p = 0.042), the absence of lymph-node metastasis (p = 0.043), and receiving curative surgery (p = 0.033) were independent predictors of better outcomes. CONCLUSION While hepatitis influenced a number of clinical features in ICC patients, it did not affect survival rate. Prognostic factors influencing survival outcomes with ICC were CA 19-9 level, T stage, the presence of lymph node metastasis, and curative surgery.
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Affiliation(s)
- Jung Woong Seo
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Byung Soo Kwan
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Young Koog Cheon
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
- Correspondence to Young Koog Cheon, M.D. Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea Tel: +82-2-2030-7490 Fax: +82-2-2030-7458 E-mail:
| | - Tae Yoon Lee
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Chan Sup Shim
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - So Young Kwon
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Min Yoon
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jung Hoon Lee
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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30
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Wu Y, Wang W, Shu B, Li M, Xu J, Zheng Q. Long-term surveillance of intrahepatic cholangiocarcinoma diagnosed after 20 years follow-up for hepatic hemangioma: a case report and literature review. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1206-1211. [PMID: 32509096 PMCID: PMC7270674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/27/2020] [Indexed: 06/11/2023]
Abstract
Intrahepatic cholangiocarcinoma is the second most common primary malignancy of liver with poor prognosis. Four patients of intrahepatic cholangiocarcinoma were diagnosed after several years' observation with hepatic hemangioma in recent reports. Herein, we present a rare case of much longer surveillance of intrahepatic cholangiocarcinoma diagnosed after 20 years follow up for hepatic hemangioma. An asymptomatic 74-year old Chinese man was admitted to our hospital for a recent enlarged liver mass lesion, after 20 years follow-up for hepatic hemangioma. He was first diagnosed with a hemangioma in segment 8 of liver by abdominal ultrasound in February 1994, on basis of slightly hyperechoic feature with 1.6 × 1.1 cm in size. The mass lesion has enlarged markedly since 2013, which was confirmed by ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography. Thus, hepatectomy was performed and histological characteristic revealed that the mass lesion was intrahepatic cholangiocarcinoma. This is the longest disease course of intrahepatic cholangiocarcinoma ever reported, which may change the former understanding of the biological behavior of intrahepatic cholangiocarcinoma and is worthy of further study.
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Affiliation(s)
- Yuzhe Wu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, China
| | - Weimin Wang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, China
| | - Bin Shu
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Tsinghua Changgung HospitalBeijing 102218, China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, China
| | - Jianjun Xu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, China
| | - Qichang Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, China
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31
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Intrahepatic cholangiocellular carcinoma with radiological enhancement patterns mimicking hepatocellular carcinoma. Updates Surg 2020; 72:413-421. [PMID: 32323164 DOI: 10.1007/s13304-020-00750-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/18/2020] [Indexed: 02/07/2023]
Abstract
Non-invasive diagnosis of hepatocellular carcinoma (HCC) in cirrhotic patients requires demonstration of wash-in and wash-out on contrast-enhanced imaging. Recent studies have reported misclassification of mass-forming intrahepatic cholangiocarcinoma (MFCCC) as HCC. We aimed to analyze the contrast enhancement patterns of MFCCC, focusing especially on lesions mimicking HCC. We retrospectively evaluated all consecutive patients with MFCCC who underwent surgery between 2007 and 2017. Patients with mixed HCC-MFCCC were excluded. Two expert radiologists reviewed preoperative CT and MRI. Full-nodule hyperenhancement in the arterial phase in conjunction with hypoenhancement in the portal/late phase was classified as an "HCC-like pattern". Imaging of MFCCCs with an HCC-like pattern was reviewed by an additional radiologist blinded to clinical data. Ninety-two patients were analyzed. All patients were investigated with multiphase CT and 85 with MRI. Twelve tumors (13%) showed full-nodule arterial hyperenhancement. Of these, four were hypoenhancing in the portal/late phase. Overall, 4/92 (4%) MFCCCs (4/45 in patients with cirrhosis/hepatitis, 9%) showed an HCC-like pattern accounting for misclassification as HCC on imaging review. HCC-like MFCCCs accounted for 9% of single tumors ≤ 50 mm. All HCC-like MFCCCs occurred in patients with cirrhosis or hepatitis, whereas only 47% of non-HCC-like MFCCCs did so (p = 0.053). After a median follow-up of 29 months, all patients with HCC-like MFCCCs are alive and disease free (median 64 months). In conclusion, MFCCC was misdiagnosed as typical HCC in 4% of all cases and in 9% of patients with single tumors ≤ 50 mm or with cirrhosis/hepatitis. The risk of misdiagnosis should be considered prior to treatment planning.
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Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis. J Hepatol 2020; 72:95-103. [PMID: 31536748 DOI: 10.1016/j.jhep.2019.09.007] [Citation(s) in RCA: 312] [Impact Index Per Article: 62.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 08/04/2019] [Accepted: 09/03/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA) carries a poor prognosis, is increasing in incidence and its causes are poorly understood. Although some risk factors are known, they vary globally and collectively account for a minority of cases. The aim of this study was to perform a comprehensive meta-analysis of risk factors for intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), from Eastern and Western world studies. METHODS A literature search of case-control studies was performed to identify potential risk factors for iCCA and eCCA. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Funnel plots were used to assess publication bias, and meta-regression was used to select risk factors for comparison between Eastern and Western studies. RESULTS A total of 13 risk factors were selected from 25 case-control studies in 7 geographically diverse countries. The strongest risk factors for both iCCA and eCCA were biliary cysts and stones, cirrhosis, hepatitis B and hepatitis C. Choledochal cysts conferred the greatest risk of both iCCA and eCCA with pooled ORs of 26.71 (95% CI 15.80-45.16) and 34.94 (24.36-50.12), respectively. No significant associations were found between hypertension and obesity for either iCCA or eCCA. Comparing Eastern and Western populations, there was a difference for the association of hepatitis B with iCCA (coefficient = -0.15195; 95% CI -0.278 to -0.025; p = 0.022). CONCLUSION This is the most comprehensive meta-analysis of CCA risk factors to date. Some risk factors, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of this cancer. LAY SUMMARY Cholangiocarcinoma (CCA) is a cancer arising in the bile ducts inside (intrahepatic CCA) and connected to the liver (extrahepatic CCA). It is a very aggressive cancer: 95% of patients die within 5 years. CCA rates are increasing globally, but the causes of CCA are poorly understood. The few risk factors that are known account for only a minority of cases. In this study, we found that the strongest risk factors for both intrahepatic and extrahepatic CCA are cysts and stones in the bile ducts, cirrhosis, and hepatitis B and C viruses. Some risk factors for CCA, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of CCA.
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Affiliation(s)
- Oliver Clements
- Division of Digestive Diseases; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Joseph Eliahoo
- Statistical Advisory Service, Imperial College London, London, United Kingdom
| | - Jin Un Kim
- Division of Digestive Diseases; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Simon D Taylor-Robinson
- Division of Digestive Diseases; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Shahid A Khan
- Division of Digestive Diseases; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
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Kim D, Adejumo AC, Yoo ER, Iqbal U, Li AA, Pham EA, Cholankeril G, Glenn JS, Ahmed A. Trends in Mortality From Extrahepatic Complications in Patients With Chronic Liver Disease, From 2007 Through 2017. Gastroenterology 2019; 157:1055-1066.e11. [PMID: 31251928 DOI: 10.1053/j.gastro.2019.06.026] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 05/28/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Trends of mortality associated with extrahepatic complications of chronic liver disease might be changing. We studied trends in mortality from extrahepatic complications of viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease in the United States. METHODS We performed a population-based study using US Census and the National Center for Health Statistics mortality records from 2007 through 2017. We identified trends in age-standardized mortality using Joinpoint trend analysis with estimates of annual percent change. RESULTS The liver-related mortality among patients with hepatitis C virus (HCV) infection increased from 2007 through 2013 and then decreased once patients began receiving treatment with direct-acting antiviral (DAA) agents, from 2014 through 2017. Among patients with HCV infection, the age-standardized mortality for extrahepatic cancers was 2.6%, for cardiovascular disease was 1.9%, and for diabetes was 3.3%. Among individuals with hepatitis B virus infection, liver-related mortality decreased steadily from 2007 through 2017. During the study, age-standardized mortality from hepatitis B virus-related extrahepatic complications increased by an average of 2.0% each year. Although liver-related mortality from ALD continued to increase, mortality from extrahepatic complications of ALD did not change significantly during the 11-year study. Among patients with nonalcoholic fatty liver disease, the cause of death was most frequently cardiovascular disease, which increased gradually over the study period, whereas liver-related mortality increased rapidly. CONCLUSIONS In an analysis of US Census and the National Center for Health Statistics mortality records, we found that after widespread use of DAA agents for treatment of viral hepatitis, cause-specific mortality from extrahepatic cancers increased, whereas mortality from cardiovascular disease or diabetes increased only among patients with HCV infection. These findings indicate the need to reassess risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals successfully treated for HCV infection with DAA agents.
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Affiliation(s)
- Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
| | | | - Eric R Yoo
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, California
| | - Umair Iqbal
- Department of Medicine, Geisinger Medical Center, Danville, Pennsylvania
| | - Andrew A Li
- Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Edward A Pham
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Jeffrey S Glenn
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
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34
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Pollicino T, Musolino C, Saitta C, Tripodi G, Lanza M, Raffa G, Tocco FCD, Raggi C, Bragazzi MC, Barbera A, Navarra G, Invernizzi P, Alvaro D, Raimondo G. Free episomal and integrated HBV DNA in HBsAg-negative patients with intrahepatic cholangiocarcinoma. Oncotarget 2019; 10:3931-3938. [PMID: 31231470 PMCID: PMC6570464 DOI: 10.18632/oncotarget.27002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023] Open
Abstract
There is evidence that chronic hepatitis B virus (HBV) infection is associated with an increased risk of intrahepatic cholangiocarcinoma (ICC) development, and it has been hypothesized an etiological role of HBV in the development of this tumor. Very little is known about occult HBV infection (OBI) in ICC. Aims of the study were to investigate the OBI prevalence and to characterize the HBV molecular status at intrahepatic level in OBI-positive cases with ICC. Frozen liver tumor specimens from 47 HBV surface-antigen-negative patients with ICC and 41 paired non-tumor liver tissues were tested for OBI by 4 different HBV-specific nested PCR. Covalently closed circular HBV DNA (HBV cccDNA) and viral integrations were investigated in OBI-positive cases. HBV DNA was detected in tumor and/or non-tumor specimens from 29/47 (61.7%) ICC patients. HBV cccDNA was found in tissues from 5/17 (34.5%) cases examined. HBV integration was detected in 4/10 (40%) tumor tissues tested and involved HBx and HBV-core gene sequences in 3 and 1 cases, respectively. Viral integration occurred: (a) 9,367 nucleotides upstream of the cat-eye-syndrome critical region protein-5-isoform coding sequence; (b) within the cystinosin isoform-1-precursor gene; (c) within the thromboxane-A-synthase-1 gene; (d) within the ATPase phospholipid transporting 9B gene. Occult HBV infection is highly prevalent in patients with ICC. Both free viral genomes and integrated HBV DNA can be present in these cases. These results suggest an involvement of HBV in the carcinogenic process leading to ICC development even in cases with occult infection.
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Affiliation(s)
- Teresa Pollicino
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Human Pathology, University of Messina, Italy
| | - Cristina Musolino
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Carlo Saitta
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy
| | - Gianluca Tripodi
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Marika Lanza
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Giuseppina Raffa
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Clinical and Experimental Medicine, University of Messina, Italy
| | | | - Chiara Raggi
- Humanitas Research and Clinical Center, Rozzano, Milan, Italy.,Present address: Department of Experimental and Clinical Medicine, University of Florence, Italy
| | | | - Adalberto Barbera
- Department of Human Pathology, University of Messina, Italy.,Division of Surgical Oncology, University Hospital of Messina, Italy
| | - Giuseppe Navarra
- Department of Human Pathology, University of Messina, Italy.,Division of Surgical Oncology, University Hospital of Messina, Italy
| | - Pietro Invernizzi
- Humanitas Research and Clinical Center, Rozzano, Milan, Italy.,Present address: Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Clinical and Experimental Medicine, University of Messina, Italy
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Yang F, Ma L, Yang Y, Liu W, Zhao J, Chen X, Wang M, Zhang H, Cheng S, Shen F, Wang H, Zhou W, Cao G. Contribution of Hepatitis B Virus Infection to the Aggressiveness of Primary Liver Cancer: A Clinical Epidemiological Study in Eastern China. Front Oncol 2019; 9:370. [PMID: 31179237 PMCID: PMC6537574 DOI: 10.3389/fonc.2019.00370] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 04/23/2019] [Indexed: 12/25/2022] Open
Abstract
Background and aims: The contribution of hepatitis B virus (HBV) infection to the aggressiveness of primary liver cancer (PLC) remains controversial. We aimed to characterize this in eastern China. Methods: We enrolled 8,515 PLC patients whose specimens were reserved at the BioBank of the hepatobiliary hospital (Shanghai, China) during 2007-2016. Of those, 3,124 who received primary radical resection were involved in survival analysis. A nomogram was constructed to predict the survivals using preoperative parameters. Results: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (CHC) accounted for 94.6, 3.7, and 1.7%, respectively. The rates of HBV infection were 87.5, 49.2, and 80.6%, respectively. HBV infection was significantly associated with 10-year earlier onset, more cirrhosis, higher α-fetoprotein, higher carbohydrate antigen 19-9 (CA19-9), more microvascular invasion (MVI), lower neutrophil-to-lymphocyte ratio (NLR), and lower platelet-to-lymphocyte ratio (PLR) in HCC. HBV infection was also associated with 7-year earlier onset, more cirrhosis, higher α-fetoprotein, more MVI, and lower PLR in ICC. In the multivariate Cox analysis, high circulating HBV DNA, α-fetoprotein, CA19-9, NLR, tumor size, number, encapsulation, Barcelona Clinic Liver Cancer (BCLC) stage, and MVI predicted an unfavorable prognosis in HCC; only CA19-9 and BCLC stage, rather than HBV-related parameters, had prognostic values in ICC. A nomogram constructed with preoperative HBV-related parameters including HBV load, ultrasonic cirrhosis, and α-fetoprotein perform better than the current staging systems in predicting postoperative survival in HCC. Conclusion: HBV promotes the aggressiveness of HCC in Chinese population. The contributions of HBV to ICC and other etiological factors to HCC might be indirect via arousing non-resolving inflammation.
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Affiliation(s)
- Fan Yang
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Longteng Ma
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yuan Yang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wenbin Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Jun Zhao
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xi Chen
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Mengchao Wang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongwei Zhang
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Shuqun Cheng
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongyang Wang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weiping Zhou
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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36
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Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int 2019; 39 Suppl 1:19-31. [PMID: 30851228 DOI: 10.1111/liv.14095] [Citation(s) in RCA: 464] [Impact Index Per Article: 77.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/09/2019] [Accepted: 02/24/2019] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co-occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide.
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Affiliation(s)
- Shahid A Khan
- Department of Hepatology, St Mary's Hospital, Imperial College London, London, United Kingdom
| | - Simona Tavolari
- Center of Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy
- G.I.CO. (Italian Group of Cholangiocarcinoma), Bologna, Italy
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Navas MC, Glaser S, Dhruv H, Celinski S, Alpini G, Meng F. Hepatitis C Virus Infection and Cholangiocarcinoma: An Insight into Epidemiologic Evidences and Hypothetical Mechanisms of Oncogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1122-1132. [PMID: 30953604 DOI: 10.1016/j.ajpath.2019.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/14/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial-mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.
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Affiliation(s)
- Maria-Cristina Navas
- Grupo Gastrohepatologia, School of Medicine, University of Antioquia, Medellin, Colombia; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Harshil Dhruv
- Translational Genomics Research Institute, Phoenix, Arizona
| | - Scott Celinski
- Department of Surgery, Baylor University Medical Center, Dallas, Texas
| | - Gianfranco Alpini
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Fanyin Meng
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas.
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Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
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Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
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Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70:151-171. [PMID: 30266282 DOI: 10.1016/j.jhep.2018.09.014] [Citation(s) in RCA: 2157] [Impact Index Per Article: 359.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 02/06/2023]
Abstract
Liver disease accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma. Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. Though these numbers are sobering, they highlight an important opportunity to improve public health given that most causes of liver diseases are preventable.
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Affiliation(s)
| | | | - John Eaton
- Mayo Clinic College of Medicine, Rochester, MN, USA
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40
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Mahale P, Engels EA, Koshiol J. Hepatitis B virus infection and the risk of cancer in the elderly US population. Int J Cancer 2018; 144:431-439. [DOI: 10.1002/ijc.31643] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/08/2018] [Accepted: 05/22/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Parag Mahale
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer Institute Rockville MD
| | - Eric A. Engels
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer Institute Rockville MD
| | - Jill Koshiol
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer Institute Rockville MD
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Huang J, Wang X, Zhu Y, Wang Z, Li J, Xu D, Wang S, Li TE, Lu L. Specific prognostic factors in hepatitis B virus-related and non-hepatitis B virus-related intrahepatic cholangiocarcinoma after macroscopic curative resection. J Surg Oncol 2018; 119:40-46. [PMID: 30480811 DOI: 10.1002/jso.25303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 10/29/2018] [Indexed: 01/19/2023]
Abstract
BACKGROUND The hepatitis B virus (HBV)-related intrahepatic cholangiocarcinoma (iCCA) was recognized as a unique subtype of iCCA, within particular features in demography, clinicopathology, and genealogy. However, how they predict prognosis, in particular, for HBV- and non-HBV-related iCCA is still unclear. METHODS Demographic, clinicopathologic, and genetic features were retrospectively collected and reviewed to determine the specific prognostic factors, precisely predicting the overall survival (OS) in HBV-related (n = 119) and non-HBV-related ( n = 149) iCCA patients, respectively. RESULTS In HBV-related iCCA, TP53 mutation, vascular invasion, extrahepatic metastasis, and serum levels of alpha-fetoprotein (AFP) were independent prognostic factors for OS. In non-HBV-related iCCA, RAS/ RAF mutation and lymphatic metastasis independently predicted the OS of patients. Tumor differentiation and serum levels of CA19-9 were significantly associated with OS in both HBV- and non-HBV-related iCCA patients. In a subset analysis, TP53 and RAS/RAF mutations were consistently related to poorer outcome in HBV- and non-HBV-related iCCA, respectively. CONCLUSIONS The HBV- and non-HBV-related iCCA have different prognostic factors for the OS.
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Affiliation(s)
- Jianbo Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiangyu Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zheng Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jianhua Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Da Xu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Shenghao Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Lendvai G, Szekerczés T, Illyés I, Dóra R, Kontsek E, Gógl A, Kiss A, Werling K, Kovalszky I, Schaff Z, Borka K. Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis. Pathol Oncol Res 2018; 26:3-15. [PMID: 30448973 DOI: 10.1007/s12253-018-0491-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 10/10/2018] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
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Affiliation(s)
- Gábor Lendvai
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Tímea Szekerczés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Idikó Illyés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Réka Dóra
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Endre Kontsek
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Alíz Gógl
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Klára Werling
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, 1085, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary.
| | - Katalin Borka
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
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Xiong J, Lu X, Xu W, Bai Y, Huang H, Bian J, Zhang L, Long J, Xu Y, Wang Z, Zhao H. Metabolic syndrome and the risk of cholangiocarcinoma: a hospital-based case-control study in China. Cancer Manag Res 2018; 10:3849-3855. [PMID: 30288116 PMCID: PMC6161710 DOI: 10.2147/cmar.s175628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Metabolic syndrome is regarded as a risk factor for hepatocellular carcinoma. However, no research has been conducted to investigate the association between metabolic syndrome and cholangiocarcinoma (CCA), especially in the Chinese population. Herein, a hospital-based case–control study was carried out in China to explore the association between metabolic syndrome and CCA risk. Patients and methods In this study, 303 CCA patients (136 intrahepatic cholangiocarcinoma [ICC] and 167 extrahepatic cholangiocarcinoma [ECC]) were included, who were observed at Peking Union Medical College Hospital (PUMCH), from 2002 to 2014. Healthy controls were randomly selected from the database of PUMPH Health Screening Center. We retrospectively extracted metabolic syndrome and other possible risk factors from clinical records, followed by investigation of the relationship with CCA via calculation of ORs and 95% CIs using logistic regression analysis. Results Metabolic syndrome was significantly and positively correlated with all CCA subtypes, with adjusted ORs (AORs) of 0.35 (95% CI =0.29–0.42) and 0.29 (95% CI =0.19–0.44) for ICC and ECC, respectively (both P<0.001). Dyslipoproteinemia harbored a stronger relationship with ICC (OR =3.16; 95% CI =2.12–4.71) than ECC (OR =1.87; 95% CI =1.27–2.77), whereas hypertension harbored a stronger association with ECC (OR =3.09; 95% CI =2.09–4.58) than ICC (OR =2.06; 95% CI =1.32–3.21). Obesity was related to both ICC and ECC, with similar ORs, while diabetes was only related to ICC (OR =4.59; 95% CI =2.78–7.58), but not ECC (OR =0.97; 95% CI =0.49–1.94). Conclusion Metabolic syndrome was significantly related to a 1.86-fold elevated CCA risk.
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Affiliation(s)
- Jianping Xiong
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Weiyu Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Hanchun Huang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Jin Bian
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Lei Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Junyu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Yiyao Xu
- Health Screening Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Zhenjie Wang
- Health Screening Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China,
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Chae H, Cho H, Yoo C, Kim KP, Jeong JH, Chang HM, Kang J, Lee HC, Lim YS, Kim KM, Shim JH, Lee SS, Park DH, Song TJ, Hwang S, Song GW, Moon DB, Lee YJ, Lee JH, Ryoo BY. Prognostic implications of hepatitis B virus infection in intrahepatic cholangiocarcinoma treated with first-line gemcitabine plus cisplatin. Int J Biol Markers 2018; 33:432-438. [PMID: 29874985 DOI: 10.1177/1724600818777239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE: Hepatitis B virus infection is a well-known risk factor for intrahepatic cholangiocarcinoma. However, its prognostic impact has rarely been investigated in advanced intrahepatic cholangiocarcinoma. METHODS: Between April 2010 and May 2015, 296 patients with unresectable or metastatic intrahepatic cholangiocarcinoma who received gemcitabine plus cisplatin (GemCis) were categorized into a hepatitis B virus group (n=62; 21%) and a non-hepatitis B virus group (n=234; 79%). Clinicopathological features and survival outcomes were retrospectively reviewed and analyzed. RESULTS: The median age of patients was 59 years (range, 27-78). The median overall survival with first-line GemCis was 9.4 months (95% CI 8.4, 10.4). Compared to the non-hepatitis B virus group, the hepatitis B virus group was younger (median age, 57 vs. 61 years, P = 0.001), mainly male (74% vs. 57%, P = 0.02), and had lower frequency of elevated cancer antigen (CA) 19-9 (34% vs. 59%, P = 0.001) and alkaline phosphatase (43% vs. 61%, P = 0.01). In a univariate analysis, the hepatitis B virus infection showed a marginal relationship with poor overall survival compared to the non-hepatitis B virus infection (median, 8.3 vs. 10.0 months; P=0.13). A multivariate analysis of potential prognostic factors revealed a significant association with poor overall survival in the hepatitis B virus group (hazard ratio (HR) =1.50, P = 0.02). Initial metastatic disease (vs. recurrent/unresectable disease; HR=1.50), metastatic sites ⩾ 2 (vs. 0-1; HR=1.51), Eastern Cooperative Oncology Group performance status ⩾ 2 (vs. 0-1; HR=1.93), elevated total bilirubin (vs. normal; HR=1.83), and low albumin (vs. normal; HR=1.52) were significantly related to an unfavorable overall survival. CONCLUSIONS: This study suggests that the hepatitis B virus infection may be associated with distinctive clinicopathological characteristics and poor outcome in advanced intrahepatic cholangiocarcinoma treated with GemCis.
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Affiliation(s)
- Heejung Chae
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyungwoo Cho
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyu-Pyo Kim
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Ho Jeong
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Heung-Moon Chang
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jihoon Kang
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Soo Lee
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Do Hyun Park
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae Jun Song
- 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Shin Hwang
- 3 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gi-Won Song
- 3 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Deok-Bog Moon
- 3 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Joo Lee
- 3 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- 3 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Baek-Yeol Ryoo
- 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Lei Z, Xia Y, Si A, Wang K, Li J, Yan Z, Yang T, Wu D, Wan X, Zhou W, Liu J, Wang H, Cong W, Wu M, Pawlik TM, Lau WY, Shen F. Antiviral therapy improves survival in patients with HBV infection and intrahepatic cholangiocarcinoma undergoing liver resection. J Hepatol 2018; 68:655-662. [PMID: 29155069 DOI: 10.1016/j.jhep.2017.11.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 10/19/2017] [Accepted: 11/01/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The impact of hepatitis B virus (HBV) infection on outcomes after resection of intrahepatic cholangiocarcinoma (ICC) has not been reported. The aim of this study was to examine the impact of antiviral therapy on survival outcomes after liver resection for patients with ICC and underlying HBV infection. METHODS Data on 928 patients with ICC and HBV infection who underwent liver resection at two medical centers between 2006 and 2011 were analyzed. Data on viral reactivation, tumor recurrence, cancer-specific survival (CSS) and overall survival (OS) were obtained. Survival rates were analyzed using the time-dependent Cox regression model adjusted for potential covariates. RESULTS Postoperative viral reactivation occurred in 3.3%, 8.3% and 15.7% of patients who received preoperative antiviral therapy, who did not receive preoperative antiviral therapy with a low, or a high HBV-DNA level (< or ≥2,000 IU/ml), respectively (p <0.001). A high viral level and viral reactivation were independent risk factors of recurrence (hazard ratio [HR] 1.22 and 1.34), CSS (HR 1.36 and 1.46) and OS (HR1.23 and 1.36). Five-year recurrence, CSS and OS were better in patients who received antiviral therapy (70.5%, 46.9% and 43.0%) compared with patients who did not receive antiviral therapy and had a high viral level (86.5%, 20.9% and 20.5%, all p <0.001), respectively. The differences in recurrence, CSS and OS were minimal compared with no-antiviral therapy patients with a low viral level (71.7%, 35.5% and 33.5%, p = 0.057, 0.051 and 0.060, respectively). Compared to patients with a high viral level who received no antiviral therapy, patients who initiated antiviral therapy either before or after surgery had better long-term outcomes (HR 0.44 and 0.54 for recurrence; 0.38 and 0.57 for CSS; 0.46 and 0.54 for OS, respectively). CONCLUSIONS Viral reactivation was associated with worse prognoses after liver resection for HBV-infected patients with ICC. Antiviral therapy decreased viral reactivation and prolonged long-term survival for patients with ICC and a high viral level. LAY SUMMARY Postoperative hepatitis B virus reactivation was associated with an increased complication rate and a decreased survival rate after liver resection in patients with ICC and hepatitis B virus infection. Antiviral therapy before liver resection reduced the risk of postoperative viral reactivation. Both pre- and postoperative antiviral therapy was effective in prolonging patient survival.
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Affiliation(s)
- Zhengqing Lei
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Anfeng Si
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Jun Li
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhenlin Yan
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Dong Wu
- Department of Hepatic Surgery I, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xuying Wan
- Department of Chinese Traditional Medicine, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weiping Zhou
- Department of Hepatic Surgery III, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jingfeng Liu
- Department of Hepatobiliary Surgery, The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University, Fuzhou, China
| | - Hongyang Wang
- National Scientific Center for Liver Cancer, Shanghai, China
| | - Wenming Cong
- Department of Pathology, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengchao Wu
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Scientific Center for Liver Cancer, Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Wan Yee Lau
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Feng Shen
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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Hoyos S, Navas MC, Restrepo JC, Botero RC. Current controversies in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1461-1467. [PMID: 28756216 DOI: 10.1016/j.bbadis.2017.07.027] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma represents 10% of primary liver malignancies and accounts for less than 3% of all gastrointestinal malignant tumors, with an enormous geographical variation. This neoplasia can arise from the biliary tract epithelium or hepatic progenitor cells. Depending on the anatomic localization, it is classified into three subtypes: intrahepatic, perihilar and distal. This fact is one of the main difficulties, because there are many studies that indistinctly include the results in the management of these different types of cholangiocarcinoma, without differentiating its location and even including gallbladder cancer. There are many controversial points in epidemiology, liver transplantation as a treatment, limitations of different results by group and type of treatment, histological testing and chemotherapy. This is a narrative review about topics in cholangiocarcinoma. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Sergio Hoyos
- Hepatobiliary and Liver Transplant Program, Hospital Pablo Tobon Uribe-Universidad de Antioquia, Medellín, Colombia; Grupo Gastrohepatologia, Facultad de Medicina, Universidad of Antioquía UdeA, Calle 70 No. 52-21, Medellin, Colombia; Epidemiology, University CES, Medellin, Colombia.
| | - Maria-Cristina Navas
- Grupo Gastrohepatologia, Facultad de Medicina, Universidad of Antioquía UdeA, Calle 70 No. 52-21, Medellin, Colombia
| | - Juan-Carlos Restrepo
- Hepatobiliary and Liver Transplant Program, Hospital Pablo Tobon Uribe-Universidad de Antioquia, Medellín, Colombia; Grupo Gastrohepatologia, Facultad de Medicina, Universidad of Antioquía UdeA, Calle 70 No. 52-21, Medellin, Colombia
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The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget 2018; 7:46750-46767. [PMID: 27102149 PMCID: PMC5216834 DOI: 10.18632/oncotarget.8775] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 04/10/2016] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.
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Shiao MS, Chiablaem K, Charoensawan V, Ngamphaiboon N, Jinawath N. Emergence of Intrahepatic Cholangiocarcinoma: How High-Throughput Technologies Expedite the Solutions for a Rare Cancer Type. Front Genet 2018; 9:309. [PMID: 30158952 PMCID: PMC6104394 DOI: 10.3389/fgene.2018.00309] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 07/23/2018] [Indexed: 12/16/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the cancer of the intrahepatic bile ducts, and together with hepatocellular carcinoma (HCC), constitute the majority of primary liver cancers. ICC is a rare disorder as its overall incidence is < 1/100,000 in the United States and Europe. However, it shows much higher incidence in particular geographical regions, such as northeastern Thailand, where liver fluke infection is the most common risk factor of ICC. Since the early stages of ICC are often asymptomatic, the patients are usually diagnosed at advanced stages with no effective treatments available, leading to the high mortality rate. In addition, unclear genetic mechanisms, heterogeneous nature, and various etiologies complicate the development of new efficient treatments. Recently, a number of studies have employed high-throughput approaches, including next-generation sequencing and mass spectrometry, in order to understand ICC in different biological aspects. In general, the majority of recurrent genetic alterations identified in ICC are enriched in known tumor suppressor genes and oncogenes, such as mutations in TP53, KRAS, BAP1, ARID1A, IDH1, IDH2, and novel FGFR2 fusion genes. Yet, there are no major driver genes with immediate clinical solutions characterized. Interestingly, recent studies utilized multi-omics data to classify ICC into two main subgroups, one with immune response genes as the main driving factor, while another is enriched with driver mutations in the genes associated with epigenetic regulations, such as IDH1 and IDH2. The two subgroups also show different hypermethylation patterns in the promoter regions. Additionally, the immune response induced by host-pathogen interactions, i.e., liver fluke infection, may further stimulate tumor growth through alterations of the tumor microenvironment. For in-depth functional studies, although many ICC cell lines have been globally established, these homogeneous cell lines may not fully explain the highly heterogeneous genetic contents of this disorder. Therefore, the advent of patient-derived xenograft and 3D patient-derived organoids as new disease models together with the understanding of evolution and genetic alterations of tumor cells at the single-cell resolution will likely become the main focus to fill the current translational research gaps of ICC in the future.
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Affiliation(s)
- Meng-Shin Shiao
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Khajeelak Chiablaem
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Varodom Charoensawan
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
- Integrative Computational BioScience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand
- Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nuttapong Ngamphaiboon
- Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - 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
- *Correspondence: Natini Jinawath ;
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Abstract
Cholangiocarcinomas (CC) are rare tumors which usually present late and are often difficult to diagnose and treat. CCs are categorized as intrahepatic, hilar, or extrahepatic. Epidemiologic studies suggest that the incidence of intrahepatic CCs may be increasing worldwide. In this chapter, we review the risk factors, clinical presentation, and management of cholangiocarcinoma.
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Zhang XF, Beal EW, Bagante F, Chakedis J, Weiss M, Popescu I, Marques HP, Aldrighetti L, Maithel SK, Pulitano C, Bauer TW, Shen F, Poultsides GA, Soubrane O, Martel G, Koerkamp BG, Itaru E, Pawlik TM. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg 2017; 105:848-856. [PMID: 29193010 DOI: 10.1002/bjs.10676] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/06/2017] [Accepted: 07/11/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND The objective of this study was to investigate the characteristics, treatment and prognosis of early versus late recurrence of intrahepatic cholangiocarcinoma (ICC) after hepatic resection. METHODS Patients who underwent resection with curative intent for ICC were identified from a multi-institutional database. Data on clinicopathological characteristics, initial operative details, timing and sites of recurrence, recurrence management and long-term outcomes were analysed. RESULTS A total of 933 patients were included. With a median follow-up of 22 months, 685 patients (73·4 per cent) experienced recurrence of ICC; 406 of these (59·3 per cent) developed only intrahepatic disease recurrence. The optimal cutoff value to differentiate early (540 patients, 78·8 per cent) versus late (145, 21·2 per cent) recurrence was defined as 24 months. Patients with early recurrence had extrahepatic disease more often (44·1 per cent versus 28·3 per cent in those with late recurrence; P < 0·001), whereas late recurrence was more often only intrahepatic (71·7 per cent versus 55·9 per cent for early recurrence; P < 0·001). From time of recurrence, overall survival was worse among patients who had early versus late recurrence (median 10 versus 18 months respectively; P = 0·029). In multivariable analysis, tumour characteristics including tumour size, number of lesions and satellite lesions were associated with an increased risk of early intrahepatic recurrence. In contrast, only the presence of liver cirrhosis was independently associated with an increased likelihood of late intrahepatic recurrence (hazard ratio 1·99, 95 per cent c.i. 1·11 to 3·56; P = 0·019). CONCLUSION Early and late recurrence after curative resection for ICC are associated with different risk factors and prognosis. Data on the timing of recurrence may inform decisions about the degree of postoperative surveillance, as well as help counsel patients with regard to their risk of recurrence.
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Affiliation(s)
- X-F Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - E W Beal
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - F Bagante
- Deparment of Surgery, University of Verona, Verona, Italy
| | - J Chakedis
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - M Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - I Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - H P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - L Aldrighetti
- Department of Surgery, Ospedale San Raffaele, Milan, Italy
| | - S K Maithel
- Department of Surgery, Emory University, Atlanta, USA
| | - C Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - T W Bauer
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - F Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - G A Poultsides
- Department of Surgery, Stanford University, Stanford, California, USA
| | - O Soubrane
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Assistance Publique - Hôpitaux de Paris, Beaujon Hospital, Clichy, France
| | - G Martel
- Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
| | - B G Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - E Itaru
- Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - T M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
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