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Welle CL, Khot R, Venkatesh SK, Paspulati RM, Ganeshan D, Fulcher AS. Benign biliary conditions with increased risk of malignant lesions. Abdom Radiol (NY) 2025; 50:2038-2052. [PMID: 39433602 DOI: 10.1007/s00261-024-04630-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/01/2024] [Accepted: 10/04/2024] [Indexed: 10/23/2024]
Abstract
Numerous conditions and pathologies affect the biliary system, many of which have underlying benign courses. However, these overall benign conditions can predispose the patient to malignant pathologies, often due to malignancy arising from abnormal biliary ducts (such as with cholangiocarcinoma) or due to malignancy arising from end-stage liver disease caused by the biliary condition (such as with hepatocellular carcinoma). While these malignancies can at times be obvious, some pathologies can be very difficult to detect and distinguish from the underlying benign biliary etiology. This paper discusses various benign biliary pathologies, with discussion of epidemiology, imaging features, malignant potential, and treatment considerations, with the goal of educating radiologists and referring clinicians to the risk and appearance of hepatobiliary malignancies associated with benign biliary conditions.
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Affiliation(s)
| | | | | | | | | | - Ann S Fulcher
- Virginia Commonwealth University Medical Center, Richmond, USA
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Anderson CM, Welle CL, Ludwig DR, Anderson MA, Khot R, Itani M, Zulfiqar M, Torbenson MS, Venkatesh SK. Autoimmune Disorders of the Liver and Biliary Tract. Radiographics 2025; 45:e240126. [PMID: 40111901 DOI: 10.1148/rg.240126] [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] [Indexed: 03/22/2025]
Abstract
Several autoimmune diseases (primary and secondary) can affect the liver and bile ducts. While the exact cause remains unclear, early diagnosis is crucial to prevent complications. The authors' main objective is to review imaging features of various autoimmune disorders, including autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, immunoglobulin G4 (IgG4)-related diseases, and drug-induced autoimmune injury. These disorders are chronic inflammatory conditions causing destruction of hepatocytes or cholangiocytes, destruction of the latter potentially leading to cholestasis and associated ductopenia. Complications related to untreated autoimmune disorders include sequelae of chronic liver failure or cirrhosis, such as portal hypertension and ascites. Neoplasms arising in the setting of cirrhosis related to autoimmune diseases include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder cancer. As these autoimmune disorders of the liver and biliary tract characteristically involve bile ducts and cause cholestasis, MRI or MR cholangiopancreatography (MRCP) is the preferred imaging modality, given its ability to provide excellent anatomic details of the bile ducts and demonstrate changes in the liver parenchyma. Understanding the imaging appearance of each of the autoimmune disorders affecting the liver and biliary tract allows a particular diagnosis to be suggested. Imaging studies often provide the first clues to an autoimmune disorder of the liver and bile ducts, enabling early diagnosis to halt progression and prevent complications. In addition, imaging studies are also useful for monitoring progression of disease, assessing treatment response, and detecting complications during follow-up. ©RSNA, 2025.
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Affiliation(s)
- Cody M Anderson
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Christopher L Welle
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Daniel R Ludwig
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Mark A Anderson
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Rachita Khot
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Malak Itani
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Maria Zulfiqar
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Michael S Torbenson
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
| | - Sudhakar K Venkatesh
- From the Department of Radiology, Abdominal Imaging Division (C.M.A., C.L.W., S.K.V.), and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Mo (D.R.L., M.I.); Department of Diagnostic Radiology, Massachusetts General Hospital, Boston, Mass (M.A.A.); Department of Diagnostic Radiology, University of Virginia, Charlottesville, Va (R.K.); and Department of Radiology, Abdominal Imaging Division, Mayo Clinic, Scottsdale, Ariz (M.Z.)
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Zerunian M, Polidori T, Palmeri F, Nardacci S, Del Gaudio A, Masci B, Tremamunno G, Polici M, De Santis D, Pucciarelli F, Laghi A, Caruso D. Artificial Intelligence and Radiomics in Cholangiocarcinoma: A Comprehensive Review. Diagnostics (Basel) 2025; 15:148. [PMID: 39857033 PMCID: PMC11763775 DOI: 10.3390/diagnostics15020148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/01/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant biliary system tumor and the second most common primary hepatic neoplasm, following hepatocellular carcinoma. CCA still has an extremely high unfavorable prognosis, regardless of type and location, and complete surgical resection remains the only curative therapeutic option; however, due to the underhanded onset and rapid progression of CCA, most patients present with advanced stages at first diagnosis, with only 30 to 60% of CCA patients eligible for surgery. Recent innovations in medical imaging combined with the use of radiomics and artificial intelligence (AI) can lead to improvements in the early detection, characterization, and pre-treatment staging of these tumors, guiding clinicians to make personalized therapeutic strategies. The aim of this review is to provide an overview of how radiological features of CCA can be analyzed through radiomics and with the help of AI for many different purposes, such as differential diagnosis, the prediction of lymph node metastasis, the defining of prognostic groups, and the prediction of early recurrence. The combination of radiomics with AI has immense potential. Still, its effectiveness in practice is yet to be validated by prospective multicentric studies that would allow for the development of standardized radiomics models.
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Affiliation(s)
- Marta Zerunian
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Tiziano Polidori
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Federica Palmeri
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Stefano Nardacci
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Antonella Del Gaudio
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Benedetta Masci
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Giuseppe Tremamunno
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Michela Polici
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
- PhD School in Translational Medicine and Oncology, Department of Medical and Surgical Sciences and Translational Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Domenico De Santis
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Francesco Pucciarelli
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Andrea Laghi
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
| | - Damiano Caruso
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza–University of Rome, Radiology Unit–Sant’Andrea University Hospital, 00189 Rome, Italy; (T.P.); (F.P.); (S.N.); (A.D.G.); (B.M.); (G.T.); (M.P.); (D.D.S.); (F.P.); (A.L.); (D.C.)
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Tan N, Ngu N, Worland T, Lee T, Abrahams T, Freeman E, Hannah N, Gazelakis K, Madden RG, Lynch KD, Valaydon Z, Sood S, Dev A, Bell S, Thompson AJ, Ding JN, Nicoll AJ, Liu K, Pandya K, Gow P, Lubel J, Kemp W, Roberts SK, Majeed A. Surveillance MRI is associated with improved survival in patients with primary sclerosing cholangitis. Hepatol Commun 2024; 8:e0442. [PMID: 38696372 PMCID: PMC11068143 DOI: 10.1097/hc9.0000000000000442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/16/2024] [Indexed: 05/04/2024] Open
Abstract
BACKGROUND The benefits of regular surveillance imaging for cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC) are unclear. Hence, we aimed to evaluate the impact of regular magnetic resonance cholangiopancreatography (MRCP) on outcomes of patients with PSC in Australia, where the practice of MRCP surveillance is variable. METHODS The relationship between MRCP surveillance and survival outcomes was assessed in a multicenter, retrospective cohort of patients with PSC from 9 tertiary liver centers in Australia. An inverse probability of treatment weighting approach was used to balance groups across potentially confounding covariates. RESULTS A total of 298 patients with PSC with 2117 person-years of follow-up were included. Two hundred and twenty patients (73.8%) had undergone MRCP surveillance. Regular surveillance was associated with a 71% reduced risk of death on multivariate weighted Cox analysis (HR: 0.29, 95% CI: 0.14-0.59, p < 0.001) and increased likelihood of having earlier endoscopic retrograde cholangiopancreatography from the date of PSC diagnosis in patients with a dominant stricture (p < 0.001). However, survival posthepatobiliary cancer diagnosis was not significantly different between both groups (p = 0.74). Patients who had surveillance of less than 1 scan a year (n = 41) had comparable survival (HR: 0.46, 95% CI 0.16-1.35, p = 0.16) compared to patients who had surveillance at least yearly (n = 172). CONCLUSIONS In this multicenter cohort study that employed inverse probability of treatment weighting to minimize selection bias, regular MRCP was associated with improved overall survival in patients with PSC; however, there was no difference in survival after hepatobiliary cancer diagnosis. Further prospective studies are needed to confirm the benefits of regular MRCP and optimal imaging interval in patients with PSC.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
- Central Clinical School, Monash University, Melbourne, Australia
| | - Natalie Ngu
- Central Clinical School, Monash University, Melbourne, Australia
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Australia
| | - Thomas Worland
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Tanya Lee
- Department of Gastroenterology and Hepatology, St Vincent’s Health, Melbourne, Australia
| | - Tobie Abrahams
- Department of Gastroenterology and Hepatology, St Vincent’s Health, Melbourne, Australia
| | - Elliot Freeman
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
| | - Nicholas Hannah
- Department of Gastroenterology and Hepatology, Melbourne Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Kathryn Gazelakis
- Department of Gastroenterology and Hepatology, Western Health, Melbourne, Australia
| | - Richie G Madden
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Kate D Lynch
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Zina Valaydon
- Department of Gastroenterology and Hepatology, Western Health, Melbourne, Australia
| | - Siddharth Sood
- Department of Gastroenterology and Hepatology, Melbourne Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Anouk Dev
- Central Clinical School, Monash University, Melbourne, Australia
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Australia
| | - Sally Bell
- Central Clinical School, Monash University, Melbourne, Australia
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Australia
| | - Alexander J Thompson
- Department of Gastroenterology and Hepatology, St Vincent’s Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - John Nik Ding
- Department of Gastroenterology and Hepatology, St Vincent’s Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Amanda J Nicoll
- Central Clinical School, Monash University, Melbourne, Australia
- Department of Gastroenterology and Hepatology, Eastern Health, Melbourne, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Keval Pandya
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Paul Gow
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
- Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
- Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart K Roberts
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
- Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, The Alfred, Melbourne, Australia
- Central Clinical School, Monash University, Melbourne, Australia
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Huang J, Bai X, Qiu Y, He X. Application of AI on cholangiocarcinoma. Front Oncol 2024; 14:1324222. [PMID: 38347839 PMCID: PMC10859478 DOI: 10.3389/fonc.2024.1324222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024] Open
Abstract
Cholangiocarcinoma, classified as intrahepatic, perihilar, and extrahepatic, is considered a deadly malignancy of the hepatobiliary system. Most cases of cholangiocarcinoma are asymptomatic. Therefore, early detection of cholangiocarcinoma is significant but still challenging. The routine screening of a tumor lacks specificity and accuracy. With the application of AI, high-risk patients can be easily found by analyzing their clinical characteristics, serum biomarkers, and medical images. Moreover, AI can be used to predict the prognosis including recurrence risk and metastasis. Although they have some limitations, AI algorithms will still significantly improve many aspects of cholangiocarcinoma in the medical field with the development of computing power and technology.
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Affiliation(s)
| | | | | | - Xiaodong He
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Catanzaro E, Gringeri E, Burra P, Gambato M. Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies. Cancers (Basel) 2023; 15:4947. [PMID: 37894314 PMCID: PMC10604939 DOI: 10.3390/cancers15204947] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2-8% of cases and being the leading cause of death in these patients. The majority of PSC-associated CCAs (PSC-CCA) develop within the first few years after PSC diagnosis. Older age and male sex, as well as concomitant inflammatory bowel disease (IBD) or high-grade biliary stenosis, are some of the most relevant risk factors. A complex combination of molecular mechanisms involving inflammatory pathways, direct cytopathic damage, and epigenetic and genetic alterations are involved in cholangiocytes carcinogenesis. The insidious clinical presentation makes early detection difficult, and the integration of biochemical, radiological, and histological features does not always lead to a definitive diagnosis of PSC-CCA. Surveillance is mandatory, but current guideline strategies failed to improve early detection and consequently a higher patient survival rate. MicroRNAs (miRNAs), gene methylation, proteomic and metabolomic profile, and extracellular vesicle components are some of the novel biomarkers recently applied in PSC-CCA detection with promising results. The integration of these new molecular approaches in PSC diagnosis and monitoring could contribute to new diagnostic and surveillance strategies.
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Affiliation(s)
- Elisa Catanzaro
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Center, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Patrizia Burra
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Martina Gambato
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
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7
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Yıldırım HÇ, Kavgaci G, Chalabiyev E, Dizdar O. Advances in the Early Detection of Hepatobiliary Cancers. Cancers (Basel) 2023; 15:3880. [PMID: 37568696 PMCID: PMC10416925 DOI: 10.3390/cancers15153880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/23/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Hepatocellular cancer (HCC) and biliary tract cancers (BTCs) have poor survival rates and a low likelihood of a cure, especially in advanced-stage disease. Early diagnosis is crucial and can significantly improve survival rates through curative treatment approaches. Current guidelines recommend abdominal ultrasonography (USG) and alpha-fetoprotein (AFP) monitoring for HCC screening in high-risk groups, and abdominal USG, magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) monitoring for biliary tract cancer. However, despite this screening strategy, many high-risk individuals still develop advanced-stage HCC and BTC. Blood-based biomarkers are being developed for use in HCC or BTC high-risk groups. Studies on AFP, AFP-L3, des-gamma-carboxy prothrombin, glypican-3 (GPC3), osteopontin (OPN), midkine (MK), neopterin, squamous cell carcinoma antigen (SCCA), Mac-2-binding protein (M2BP), cyclic guanosine monophosphate (cGMP), and interleukin-6 biomarkers for HCC screening have shown promising results when evaluated individually or in combination. In the case of BTCs, the potential applications of circulating tumor DNA, circulating microRNA, and circulating tumor cells in diagnosis are also promising. These biomarkers have shown potential in detecting BTCs in early stages, which can significantly improve patient outcomes. Additionally, these biomarkers hold promise for monitoring disease progression and evaluating response to therapy in BTC patients. However, further research is necessary to fully understand the clinical utility of these biomarkers in the diagnosis and management of HCC and BTCs.
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Affiliation(s)
| | | | | | - Omer Dizdar
- Department of Medical Oncology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey; (H.Ç.Y.); (G.K.); (E.C.)
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8
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Assis DN, Bowlus CL. Recent Advances in the Management of Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2023; 21:2065-2075. [PMID: 37084929 DOI: 10.1016/j.cgh.2023.04.004] [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: 01/20/2023] [Revised: 04/05/2023] [Accepted: 04/10/2023] [Indexed: 04/23/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study.
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Lapitz A, Azkargorta M, Milkiewicz P, Olaizola P, Zhuravleva E, Grimsrud MM, Schramm C, Arbelaiz A, O'Rourke CJ, La Casta A, Milkiewicz M, Pastor T, Vesterhus M, Jimenez-Agüero R, Dill MT, Lamarca A, Valle JW, Macias RIR, Izquierdo-Sanchez L, Pérez Castaño Y, Caballero-Camino FJ, Riaño I, Krawczyk M, Ibarra C, Bustamante J, Nova-Camacho LM, Falcon-Perez JM, Elortza F, Perugorria MJ, Andersen JB, Bujanda L, Karlsen TH, Folseraas T, Rodrigues PM, Banales JM. Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma. J Hepatol 2023; 79:93-108. [PMID: 36868481 PMCID: PMC10292605 DOI: 10.1016/j.jhep.2023.02.027] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). METHODS EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. RESULTS High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients' survival, respectively. CONCLUSIONS Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. IMPACT AND IMPLICATIONS The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.
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Affiliation(s)
- Ainhoa Lapitz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Mikel Azkargorta
- Proteomics Platform, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed ISCIII, Bizkaia Science and Technology Park, Derio, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain
| | - Ekaterina Zhuravleva
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marit M Grimsrud
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christoph Schramm
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany; 1st Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ander Arbelaiz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Colm J O'Rourke
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Tania Pastor
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Michael T Dill
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Heidelberg, Germany; Experimental Hepatology, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain
| | - Ylenia Pérez Castaño
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Osakidetza Basque Health Service, Bidasoa IHO, Bidasoa Hospital, Department of Digestive System, Irun, Spain
| | - Francisco Javier Caballero-Camino
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Ioana Riaño
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Clinical Research Unit, Spanish Clinical Research Network (SCReN) - ISCIII, Biodonostia Health Research Institute, San Sebastián, Spain
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Centre, Saarland University, Homburg, Germany
| | - Cesar Ibarra
- Osakidetza Basque Health Service, Ezkerraldea-Enkarterri-Cruces IHO, Cruces University Hospital, Barakaldo, Spain
| | - Javier Bustamante
- Osakidetza Basque Health Service, Ezkerraldea-Enkarterri-Cruces IHO, Cruces University Hospital, Barakaldo, Spain
| | - Luiz M Nova-Camacho
- Osakidetza Basque Health Service, Donostialdea IHO, Donostia University Hospital, Department of Pathology, San Sebastian, Spain
| | - Juan M Falcon-Perez
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Exosomes Laboratory, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Felix Elortza
- Proteomics Platform, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed ISCIII, Bizkaia Science and Technology Park, Derio, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
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10
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Villard C, Friis-Liby I, Rorsman F, Said K, Warnqvist A, Cornillet M, Kechagias S, Nyhlin N, Werner M, Janczewska I, Hagström T, Nilsson E, Bergquist A. Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis. J Hepatol 2023; 78:604-613. [PMID: 36410555 DOI: 10.1016/j.jhep.2022.11.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND & AIMS The evidence for hepatobiliary tumour surveillance in patients with primary sclerosing cholangitis (PSC) is scarce. In this study, we aimed to prospectively evaluate cholangiocarcinoma (CCA) surveillance with yearly MRI with cholangiopancreatography (MRI/MRCP) in a nationwide cohort. METHODS In total, 512 patients with PSC from 11 Swedish hospitals were recruited. The study protocol included yearly clinical follow-ups, liver function tests and contrast-enhanced MRI/MRCP and carbohydrate antigen (CA) 19-9. Patients with severe/progressive bile duct changes on MRI/MRCP were further investigated with endoscopic retrograde cholangiopancreatography. Patients were followed for 5 years or until a diagnosis of CCA, liver transplantation (LT) and/or death. Risk factors associated with CCA were analysed with Cox regression. RESULTS Eleven patients (2%) were diagnosed with CCA, and two (0.5%) with high-grade bile duct dysplasia. Severe/progressive bile duct changes on MRI/MRCP were detected in 122 patients (24%), of whom 10% had an underlying malignancy. The primary indication for LT (n = 54) was biliary dysplasia in nine patients (17%) and end-stage liver disease in 45 patients (83%), of whom three patients (7%) had unexpected malignancy in the explants. The median survival for patients with CCA was 13 months (3-22 months). Time to diagnosis of high-grade dysplasia and/or hepatobiliary malignancy was significantly associated with severe/progressive bile duct changes on MRI/MRCP (hazard ratio 10.50; 95% CI 2.49-44.31) and increased levels of CA19-9 (hazard ratio 1.00; 95% CI 1.00-1.01). CONCLUSION In an unselected cohort of patients with PSC, yearly CA19-9 and MRI/MRCP surveillance followed by ERCP was ineffective in detecting cancer early enough to support long-term survival. Given the low occurrence of CCA, studies on individualised strategies for follow-up and improved diagnostic methods for PSC-related CCA are warranted. IMPACT AND IMPLICATIONS A prospective nationwide 5-year study was conducted to evaluate yearly cholangiocarcinoma surveillance using MRI and CA19-9 in patients with primary sclerosing cholangitis. Only 2% of the patients were diagnosed with cholangiocarcinoma during follow-up and their prognosis remained poor despite surveillance. This surveillance strategy failed to detect cancer early enough to support long-term survival. Therefore, individualised strategies and improved diagnostic methods will be required to improve the early detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.
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Affiliation(s)
- Christina Villard
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
| | | | - Fredrik Rorsman
- Department of Hepatology, Akademiska University Hospital, Uppsala, Sweden
| | - Karouk Said
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Warnqvist
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Martin Cornillet
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Stergios Kechagias
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Nils Nyhlin
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Mårten Werner
- Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | | | - Therese Hagström
- Department of Gastroenterology, Stockholm South General Hospital, Stockholm, Sweden
| | - Emma Nilsson
- Gastroenterology Clinic, Skåne University Hospital, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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11
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Identification and validation of volatile organic compounds in bile for differential diagnosis of perihilar cholangiocarcinoma. Clin Chim Acta 2023; 541:117235. [PMID: 36716909 DOI: 10.1016/j.cca.2023.117235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/12/2023] [Accepted: 01/24/2023] [Indexed: 01/29/2023]
Abstract
Early and differential diagnosis of perihilar cholangiocarcinoma (PHCCA) is highly challenging. This study aimed to evaluate whether volatile organic compounds (VOCs) in bile samples could be emerging diagnostic biomarkers for PHCCA. We collected 200 bile samples from patients with PHCCA and benign biliary diseases (BBD), including a 140-patient training cohort and an 60-patient test cohort. Gas chromatography-ion mobility spectrometry (GC-IMS) was used for VOCs detection. The predictive models were constructed using machine learning algorithms. Our analysis detected 19 VOC substances using GC-IMS in the bile samples and resulted in the identification of three new VOCs, 2-methoxyfuran, propyl isovalerate, and diethyl malonate that were found in bile. Unsupervised hierarchical clustering analysis supported that VOCs detected in the bile could distinguish PHCCA from BBD. Twelve VOCs defined according to 32 signal peaks had significant statistical significance between BBD and PHCCA, including four up-regulated VOCs in PHCCA, such as 2-ethyl-1-hexanol, propyl isovalerate, cyclohexanone, and acetophenone, while the rest eight VOCs were down-regulated. ROC curve analysis revealed that machine learning models based on VOCs could help diagnosing PHCCA. Among them, SVM provided the highest AUC of 0·966, with a sensitivity and specificity of 93·1% and 100%, respectively. The diagnostic model based on different VOC spectra could be a feasible method for the differential diagnosis of PHCCA.
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12
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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13
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Bergquist A, Weismüller TJ, Levy C, Rupp C, Joshi D, Nayagam JS, Montano-Loza AJ, Lytvyak E, Wunsch E, Milkiewicz P, Zenouzi R, Schramm C, Cazzagon N, Floreani A, Liby IF, Wiestler M, Wedemeyer H, Zhou T, Strassburg CP, Rigopoulou E, Dalekos G, Narasimman M, Verhelst X, Degroote H, Vesterhus M, Kremer AE, Bündgens B, Rorsman F, Nilsson E, Jørgensen KK, von Seth E, Cornillet Jeannin M, Nyhlin N, Martin H, Kechagias S, Wiencke K, Werner M, Beretta-Piccoli BT, Marzioni M, Isoniemi H, Arola J, Wefer A, Söderling J, Färkkilä M, Lenzen H. Impact on follow-up strategies in patients with primary sclerosing cholangitis. Liver Int 2023; 43:127-138. [PMID: 35535655 PMCID: PMC10084018 DOI: 10.1111/liv.15286] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/22/2022] [Accepted: 05/06/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. METHODS We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. RESULTS A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. CONCLUSIONS Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.
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Affiliation(s)
- Annika Bergquist
- Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,European Reference Network for Hepatological Diseases, Stockholm, Sweden
| | - Tobias J Weismüller
- Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami, Florida, USA.,Schiff Center for Liver Diseases, University of Miami, Florida, USA
| | - Christian Rupp
- Department of Gastroenterology, Infectious Diseases, Intoxication, Heidelberg University Hospital, Heidelberg, Germany
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ellina Lytvyak
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Piotr Milkiewicz
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.,Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Roman Zenouzi
- Department of Medicine and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.,European Reference Network on Hepatological Disease, European Reference Network for Hepatological Diseases, Azienda Ospedaliera-Università di Padova, Padova, Italy
| | - Annarosa Floreani
- Studiosa Senior University of Padova, Italy and Scientific Consultant IRCCS Negrar, Verona, Italy
| | - Ingalill Friis Liby
- Department of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Miriam Wiestler
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network for Hepatological Diseases, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network for Hepatological Diseases, Hannover, Germany
| | - Taotao Zhou
- Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | | | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.,Ghent Liver Research Center, Ghent University, Ghent, Belgium.,European Reference Network for Hepatological Diseases, Ghent, Belgium
| | - Helena Degroote
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.,Ghent Liver Research Center, Ghent University, Ghent, Belgium.,European Reference Network for Hepatological Diseases, Ghent, Belgium
| | - Mette Vesterhus
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Andreas E Kremer
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.,Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Bennet Bündgens
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Fredrik Rorsman
- Department of Gastroenterology and Hepatology, University Hospital, Uppsala, Sweden
| | - Emma Nilsson
- Department of Clinical Sciences, Lund University, Lund, Sweden.,Gastroenterology Clinic, Skåne University Hospital, Sweden
| | | | - Erik von Seth
- Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,European Reference Network for Hepatological Diseases, Stockholm, Sweden
| | - Martin Cornillet Jeannin
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Nils Nyhlin
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Harry Martin
- Department of Gastroenterology, University College Hospitals NHS Foundation Trust, London, UK
| | - Stergios Kechagias
- Unit of Internal Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Kristine Wiencke
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Mårten Werner
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | | | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti - University Hospital, Ancona, Italy
| | - Helena Isoniemi
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology and Huslab, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Agnes Wefer
- Division of Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Söderling
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Martti Färkkilä
- Clinic of Gastroenterology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network for Hepatological Diseases, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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14
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Morgan MA, Khot R, Sundaram KM, Ludwig DR, Nair RT, Mittal PK, Ganeshan DM, Venkatesh SK. Primary sclerosing cholangitis: review for radiologists. Abdom Radiol (NY) 2023; 48:136-150. [PMID: 36063181 PMCID: PMC9852001 DOI: 10.1007/s00261-022-03655-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 01/22/2023]
Abstract
Primary sclerosing cholangitis is a rare chronic inflammatory disease affecting the bile ducts, which can eventually result in bile duct strictures, cholestasis and cirrhosis. Patients are often asymptomatic but may present with clinical features of cholestasis. Imaging plays an important role in the diagnosis and management. This review covers the pathophysiology, clinical features, imaging findings as well as methods of surveillance and post-transplant appearance.
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Affiliation(s)
- Matthew A. Morgan
- Department of Radiology, University of Pennsylvania Health System, 1 Silverstein, 3400 Spruce Street, Philadelphia, PA, USA
| | - Rachita Khot
- Radiology and Medical Imaging, University of Virginia Health, 1215 Lee Street, Charlottesville, VA, USA
| | - Karthik M. Sundaram
- Department of Radiology, University of Pennsylvania Health System, 1 Silverstein, 3400 Spruce Street, Philadelphia, PA, USA
| | - Daniel R. Ludwig
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, Campus Box 8131, Saint Louis, MO, USA
| | - Rashmi T. Nair
- Department of Radiology, University of Kentucky, 800 Rose Street, Room HX 313B, Lexington, KY 40536-0293, USA
| | - Pardeep K. Mittal
- Medical College of Georgia at Augusta University, 1120 15th street BA −1411, Augusta, GA 30912, USA
| | - Dhakshina M. Ganeshan
- The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Unit 1473, Houston, TX 77030, USA
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15
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Connor AA, Kodali S, Abdelrahim M, Javle MM, Brombosz EW, Ghobrial RM. Intrahepatic cholangiocarcinoma: The role of liver transplantation, adjunctive treatments, and prognostic biomarkers. Front Oncol 2022; 12:996710. [PMID: 36479082 PMCID: PMC9719919 DOI: 10.3389/fonc.2022.996710] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/31/2022] [Indexed: 08/01/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a primary epithelial cell malignancy of the liver with rising incidence rate globally. Its insidious presentation, heterogeneous and aggressive biology, and recalcitrance to current therapies results in unacceptably high morbidity and mortality. This has spurred research efforts in the last decade to better characterize it molecularly with translation to improved diagnostic tools and treatments. Much of this has been driven by patient advocacy. This has renewed interest in orthotopic liver transplantation (LT) with adjunctive therapies for iCCA, which was historically disparaged due to poor recipient outcomes and donor organ scarcity. However, the optimal use of LT as a treatment for iCCA care remains unclear. Here, we review the epidemiology of iCCA, the history of LT as a treatment modality, alternative approaches to iCCA local control, the evidence for peri-operative systemic therapies, and the potential roles of biomarkers and targeted agents. In doing so, we hope to prioritize areas for continued research and identify areas where multidisciplinary care can improve outcomes.
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Affiliation(s)
- Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- Section of Gastrointestinal Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
- Cockrell Center Phase 1 Unit, Cockrell Center for Advanced Therapeutics, Houston Methodist Hospital, Houston, TX, United States
| | - Milind M. Javle
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, United States
| | | | - R. Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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16
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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17
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Gleeson D, Walmsley M, Trivedi PJ, Joshi D, Rea B. Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: Can we be more proactive? Frontline Gastroenterol 2022; 14:162-166. [PMID: 36818795 PMCID: PMC9933607 DOI: 10.1136/flgastro-2022-102172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/17/2022] [Indexed: 02/24/2023] Open
Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals Sheffield UK, Sheffield, UK
| | | | - Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom, Birmingham, UK
| | - Deepak Joshi
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, UK
| | - Ben Rea
- Department of Clinical Radiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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18
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Eaton JE, Welle CL, Monahan H, Tahboub Amawi AD, Idilman I, Harmsen WS, Dzyubak B, Beiermann EW, Bakhshi Z, Gores GJ, LaRusso NF, Gossard AA, Lazaridis KN, Venkatesh SK. Comparative Performance of Quantitative and Qualitative Magnetic Resonance Imaging Metrics in Primary Sclerosing Cholangitis. GASTRO HEP ADVANCES 2022; 1:287-295. [PMID: 39131684 PMCID: PMC11307538 DOI: 10.1016/j.gastha.2022.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 01/05/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Several quantitative and qualitative magnetic resonance imaging (MRI) metrics have been reported to predict outcomes among those with primary sclerosing cholangitis (PSC). We aimed to compare the reproducibility and prognostic performances of MRI biomarkers and examine if combining these measurements adds value. Methods We performed a retrospective review of 388 patients with PSC who underwent a magnetic resonance elastography and magnetic resonance cholangiopancreatography. Liver stiffness (LS) was determined by validated automated software, whereas spleen volume was calculated by semiautomated software, and radiologists manually determined the ANALI scores. The primary endpoint was hepatic decompensation. Results LS and spleen volume values had perfect and near-perfect agreement (intraclass correlation coefficient of 1.00 and 0.9996, respectively), whereas ANALI with and without gadolinium had a moderate inter-rater agreement between 3 radiologists (kappa = 0.42-0.54 and 0.46-0.57, respectively). As a continuous variable, LS alone was the best predictor of hepatic decompensation (concordance score = 0.90; 95% confidence interval, 0.87-0.93). A quantitative-only MRI model [LS (>4.70 kPa = 2 or ≤4.70 kPa = 0) + spleen volume (>600 mm3 = 1 or ≤600 mm3 = 0)] had the optimal reproducibility and performance (concordance score = 0.85; 95% confidence interval = 0.80-0.89) and enabled patient risk stratification by estimating the 5-year incidence of hepatic decompensation: 7.49%, 44.50%, 70.00%, and 91.30% (score 0-3). Conclusion Quantitative MRI markers of fibrosis and portal hypertension generated by automated and semiautomated software are highly reproducible. LS is the single best imaging predictor of hepatic decompensation. However, a quantitative MRI score using LS and spleen volume is well suited to risk stratify those with PSC.
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Affiliation(s)
- John E. Eaton
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Hannah Monahan
- Department of Radiology, Mayo Clinic, Rochester, Minnesota
| | | | - Ilkay Idilman
- Department of Radiology, Mayo Clinic, Rochester, Minnesota
| | - William S. Harmsen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Bogdan Dzyubak
- Department of Radiology, Mayo Clinic, Rochester, Minnesota
| | | | - Zeinab Bakhshi
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Andrea A. Gossard
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
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19
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Núñez F P, Castro F, Mezzano G, Quera R, Diaz D, Castro L. Hepatobiliary manifestations in inflammatory bowel disease: A practical approach. World J Hepatol 2022; 14:319-337. [PMID: 35317174 PMCID: PMC8891676 DOI: 10.4254/wjh.v14.i2.319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/10/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. They can occur at any moment in the course of the disease or associated with the treatment. The prevalence of liver dysfunction can reach up to 50% in different studies. Nonalcoholic fatty liver disease is considered the most common hepatobiliary complication in IBD, while primary sclerosing cholangitis is the most specific. Management of hepatic manifestations in IBD involves a multidisciplinary approach that includes a high index of suspicion and joint management with hepatologists. The medical confrontation with abnormal liver tests must include an exhaustive study to determine if these patterns can be related to IBD, associated diseases or to the therapies used.
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Affiliation(s)
- Paulina Núñez F
- Universidad de los Andes,Inflammatory Bowel Disease Program, Digestive Disease Center, Santiago 7600976, RM, Chile
- Inflammatory Bowel Disease Program, Hospital San Juan de Dios, Universidad de Chile, Santiago 7701230, RM, Chile
| | - Fabiola Castro
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
| | - Gabriel Mezzano
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
- Department of Gastroenterology, Hospital del Salvador/Universidad de Chile, Santiago 7600976, RM, Chile
| | - Rodrigo Quera
- Universidad de los Andes,Inflammatory Bowel Disease Program, Digestive Disease Center, Santiago 7600976, RM, Chile
| | - Diego Diaz
- Medicine, Universidad de los Andes, Santiago 770976, RM, Chile
| | - Lorena Castro
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
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20
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Vedeld HM, Grimsrud MM, Andresen K, Pharo HD, von Seth E, Karlsen TH, Honne H, Paulsen V, Färkkilä MA, Bergquist A, Jeanmougin M, Aabakken L, Boberg KM, Folseraas T, Lind GE. Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology 2022; 75:59-73. [PMID: 34435693 PMCID: PMC9300181 DOI: 10.1002/hep.32125] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. APPROACH AND RESULTS Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77-0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels. CONCLUSIONS Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
| | - Marit M. Grimsrud
- Norwegian PSC Research Center, Department of Transplantation MedicineOslo University HospitalOsloNorway,Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Kim Andresen
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
| | - Heidi D. Pharo
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
| | - Erik von Seth
- Department of Medicine HuddingeUnit of Gastroenterology and RheumatologyKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Department of Transplantation MedicineOslo University HospitalOsloNorway,Institute of Clinical MedicineUniversity of OsloOsloNorway,Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University Hospital–RikshospitaletOsloNorway
| | - Hilde Honne
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
| | - Vemund Paulsen
- Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University Hospital–RikshospitaletOsloNorway
| | - Martti A. Färkkilä
- Department of MedicineDivision of GastroenterologyHelsinki University Hospital and Helsinki UniversityHelsinkiFinland
| | - Annika Bergquist
- Department of Medicine HuddingeUnit of Gastroenterology and RheumatologyKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Marine Jeanmougin
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
| | - Lars Aabakken
- Institute of Clinical MedicineUniversity of OsloOsloNorway,Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University Hospital–RikshospitaletOsloNorway
| | - Kirsten M. Boberg
- Norwegian PSC Research Center, Department of Transplantation MedicineOslo University HospitalOsloNorway,Institute of Clinical MedicineUniversity of OsloOsloNorway,Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University Hospital–RikshospitaletOsloNorway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation MedicineOslo University HospitalOsloNorway,Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University Hospital–RikshospitaletOsloNorway
| | - Guro E. Lind
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–Norwegian Radium HospitalOsloNorway,K. G. Jebsen Colorectal Cancer Research CentreOslo University HospitalOsloNorway
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21
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Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, Teh BT, Wongkham S, Gores GJ. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7:65. [PMID: 34504109 PMCID: PMC9246479 DOI: 10.1038/s41572-021-00300-2] [Citation(s) in RCA: 417] [Impact Index Per Article: 104.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2021] [Indexed: 02/08/2023]
Abstract
Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.
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Affiliation(s)
- Paul J. Brindley
- Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA
| | | | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Shahid A. Khan
- Liver Unit, Division of Digestive Diseases, Imperial College London, London, UK
| | - Alex Loukas
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia
| | - Alphonse E. Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,
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22
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Reporting standards for primary sclerosing cholangitis using MRI and MR cholangiopancreatography: guidelines from MR Working Group of the International Primary Sclerosing Cholangitis Study Group. Eur Radiol 2021; 32:923-937. [PMID: 34363134 DOI: 10.1007/s00330-021-08147-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/30/2021] [Accepted: 06/06/2021] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder affecting the bile ducts and is characterized by biliary strictures, progressive liver parenchymal fibrosis, and an increased risk of hepatobiliary malignancies primarily cholangiocarcinoma (CCA). PSC may lead to portal hypertension, liver decompensation, and liver failure with the need for liver transplantation. Magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) are considered the imaging standard for diagnosis and follow-up in patients with PSC. Currently, there are no universally accepted reporting standards and definitions for MRI/MRCP features. Controversies exist about the definition of a high-grade stricture and there is no widely agreed approach to their management. The members of the MRI working group of the International Primary Sclerosing Cholangitis Study Group (IPSCSG) sought to define terminologies and reporting standards for describing MRI/MRCP features that would be applied to diagnosis and surveillance of disease progression, and potentially for evaluating treatment response in clinical trials. In this extensive review, the technique of MRI/MRCP and assessment of image quality for the evaluation of PSC is briefly described. The definitions and terminologies for severity and length of strictures, duct wall thickening and hyperenhancement, and liver parenchyma signal intensity changes are outlined. As CCA is an important complication of PSC, standardized reporting criteria for CCA developing in PSC are summarized. Finally, the guidelines for reporting important changes in follow-up MRI/MRCP studies are provided. KEY POINTS: • Primary sclerosing cholangitis is a chronic inflammatory disorder affecting the bile ducts, causing biliary strictures and liver fibrosis and an increased risk of cholangiocarcinoma. • This consensus document provides definitions and suggested reporting standards for MRI and MRCP features of primary sclerosing cholangitis, which will allow for a standardized approach to diagnosis, assessment of disease severity, follow-up, and detection of complications. • Standardized definitions and reporting of MRI/MRCP features of PSC will facilitate comparison between studies, promote longitudinal assessment during management, reduce inter-reader variability, and enhance the quality of care and communication between health care providers.
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23
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Yang JD, Ghoz H, Aboelsoud MM, Taylor WR, Yab TC, Berger CK, Cao X, Foote PH, Giama NH, Barr Fritcher EG, Mahoney DW, Moser CD, Smyrk TC, Kipp BR, Gores GJ, Roberts LR, Kisiel JB. DNA Methylation Markers for Detection of Cholangiocarcinoma: Discovery, Validation, and Clinical Testing in Biliary Brushings and Plasma. Hepatol Commun 2021; 5:1448-1459. [PMID: 34430788 PMCID: PMC8369938 DOI: 10.1002/hep4.1730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/03/2021] [Accepted: 03/22/2021] [Indexed: 02/04/2023] Open
Abstract
Cholangiocarcinoma (CCA) has poor prognosis due to late-stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced-representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin-fixed, paraffin-embedded CCA tumors and adjacent hepatobiliary control tissues using methylation-specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95-1.0). In the clinical pilot on plasma, a cross-validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81-0.95]) but not for primary sclerosing cholangitis-associated eCCA (AUC, 0.54 [0.35-0.73]). Conclusion: Next-generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and HepatologyCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Hassan Ghoz
- Division of Gastroenterology and HepatologyMayo ClinicJacksonvilleFLUSA
| | | | - William R. Taylor
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Tracy C. Yab
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Calise K. Berger
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Xiaoming Cao
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Patrick H. Foote
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Nasra H. Giama
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | | | - Douglas W. Mahoney
- Department of Biomedical Statistics and InformaticsMayo ClinicRochesterMNUSA
| | - Catherine D. Moser
- Department of Pathology and Laboratory MedicineChildren’s Healthcare of AtlantaAtlantaGAUSA
| | | | | | - Gregory J. Gores
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Lewis R. Roberts
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - John B. Kisiel
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
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24
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Affiliation(s)
- John E Eaton
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | | | - Gregory J Gores
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
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25
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Li I, Ye X, He S. Letter to the Editor: Imaging Monitoring of Patients With Primary Sclerosing Cholangitis. Hepatology 2021; 74:534-535. [PMID: 33427311 DOI: 10.1002/hep.31709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Iangfa Li
- Division of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaofei Ye
- Division of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Songqing He
- Division of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Fung BM, Tabibian JH. Primary sclerosing cholangitis-associated cholangiocarcinoma: special considerations and best practices. Expert Rev Gastroenterol Hepatol 2021; 15:487-496. [PMID: 33682586 DOI: 10.1080/17474124.2021.1900732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Primary sclerosing cholangitis (PSC) is a rare, heterogenous, chronic cholestatic liver disease that causes fibro-inflammatory destruction of the intra- and/or extrahepatic bile ducts. The disease course may be variable, though in many cases it ultimately leads to biliary cirrhosis and its associated complications. PSC is also associated with malignancies, in particular cholangiocarcinoma (CCA), a dreaded neoplasm of the biliary tract with a poor prognosis. Risk stratification and surveillance for this malignancy are important components of the care of patients with PSC.Areas covered: In this review, we discuss important considerations in the clinical epidemiology, risk factors, diagnosis, and surveillance of PSC-associated CCA.Expert opinion: Despite growing awareness of PSC, high-quality evidence regarding the management of PSC and its associated risk of CCA remains limited. Early diagnosis of PSC-associated CCA remains difficult, and treatment options are limited, especially when diagnosed at later stages. The recent introduction of recommendations for CCA surveillance will likely improve outcomes, though an optimal surveillance approach has yet to be validated prospectively. Further research is needed in the development of high-accuracy (and noninvasive) surveillance and diagnostic tools that may facilitate earlier diagnosis of CCA and potential disease cure.
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Affiliation(s)
- Brian M Fung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Kawasaki H, Akazawa Y, Razumilava N. Progress toward improving outcomes in patients with cholangiocarcinoma. ACTA ACUST UNITED AC 2021; 19:153-168. [PMID: 33883870 PMCID: PMC8054970 DOI: 10.1007/s11938-021-00333-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Purpose of review: To provide an update on latest advances in treatment of cholangiocarcinoma. Recent findings: Incidence of cholangiocarcinoma has been increasing over the past decade. A better understanding of the genetic landscape of cholangiocarcinoma and its risk factors resulted in earlier diagnosis and treatment option expansion to targeted therapy with FGFR inhibitors, and liver transplantation for early perihilar cholangiocarcinoma and early intrahepatic cholangiocarcinoma. IDH1/2 inhibition for intrahepatic cholangiocarcinoma is an emerging targeted therapy approach. Data supports benefits of adjuvant therapy for a subset of patients undergoing surgical resection. Approaches combining different treatment modalities such as chemotherapy, surgery, radiation therapy appear promising. Summary: Earlier diagnosis and genetic characterization provided additional treatment options for patients with previously incurable cholangiocarcinoma. A precision medicine approach with a focus on actionable genetic alterations and combination of treatment modalities are actively being explored and will further improve outcomes in our patients with cholangiocarcinoma.
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Affiliation(s)
- Hiroko Kawasaki
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yuko Akazawa
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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