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Harkins L, Vilarinho S, Saltzman WM. Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver. Biochemistry 2025; 64:1685-1697. [PMID: 40127248 DOI: 10.1021/acs.biochem.4c00712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.
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Affiliation(s)
- Lauren Harkins
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
| | - Silvia Vilarinho
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, United States
- Department of Genetics and Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States
| | - W Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Chemical & Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06520, United States
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut 06520, United States
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Cao JJ, Shon A, Yoon L, Kamaya A, Tse JR. Diagnostic performance of CT/MRI LI-RADS v2018 in non-cirrhotic hepatitis C virus infection. Abdom Radiol (NY) 2025; 50:1615-1623. [PMID: 39400590 DOI: 10.1007/s00261-024-04589-x] [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: 06/25/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 10/15/2024]
Abstract
PURPOSE To evaluate the diagnostic performance of LI-RADS among patients with non-cirrhotic hepatitis C virus (HCV) infection. METHODS This retrospective, IRB-approved, single-center study included 66 observations from 43 adult patients (11 women, 32 men; median age 65 years). All patients received liver protocol CT or MRI from 2010 to 2023, had HCV, and did not have cirrhosis based on histopathology. Three board-certified abdominal radiologists blinded to histopathology and imaging follow-up assessed each observation for major features and final LI-RADS category, and inter-reader agreements with weighted kappa were calculated. The positive predictive value, sensitivity, specificity, and accuracy of in diagnosing HCC and overall malignancy was calculated. RESULTS Of the 66 observations, 53 (80%) were malignant and 13 (20%) were benign. Positive predictive value for HCC was 0-0% for LR-1, 0-0% for LR-2, 0-33% for LR-3, 57-100% for LR-4, 98-100% for LR-5, 25-50% for LR-M, and 83-100% for LR-TIV. Positive predictive value for overall malignancy was 0-0% for LR-1, 0-0% for LR-2, 0-33% for LR-3, 57-100% for LR-4, 98-100% for LR-5, 100-100% for LR-M, and 100-100% for LR-TIV. For LR-5 in identifying HCC, sensitivity ranged from 74 to 90%, specificity from 94 to 100%, and accuracy from 80 to 91%. For the composite of LR-5, LR-M, or LR-TIV in identifying overall malignancy, sensitivity was 87-98%, specificity was 92-100%, and accuracy was 89-97%. The inter-reader agreement for major features varied from moderate to substantial, with substantial agreement for the final category. CONCLUSION CT/MRI LI-RADS v2018 criteria can be applied to non-cirrhotic HCV patients with near-perfect specificity.
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Affiliation(s)
- Jennie J Cao
- University of Pennsylvania, Perelman School of Medicine, Philadelphia, USA
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Cigliano A, Liao W, Deiana GA, Rizzo D, Chen X, Calvisi DF. Preclinical Models of Hepatocellular Carcinoma: Current Utility, Limitations, and Challenges. Biomedicines 2024; 12:1624. [PMID: 39062197 PMCID: PMC11274649 DOI: 10.3390/biomedicines12071624] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant primary liver tumor, remains one of the most lethal cancers worldwide, despite the advances in therapy in recent years. In addition to the traditional chemically and dietary-induced HCC models, a broad spectrum of novel preclinical tools have been generated following the advent of transgenic, transposon, organoid, and in silico technologies to overcome this gloomy scenario. These models have become rapidly robust preclinical instruments to unravel the molecular pathogenesis of liver cancer and establish new therapeutic approaches against this deadly disease. The present review article aims to summarize and discuss the commonly used preclinical models for HCC, evaluating their strengths and weaknesses.
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Affiliation(s)
- Antonio Cigliano
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.A.D.); (D.R.)
| | - Weiting Liao
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143, USA; (W.L.); (X.C.)
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Giovanni A. Deiana
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.A.D.); (D.R.)
| | - Davide Rizzo
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.A.D.); (D.R.)
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143, USA; (W.L.); (X.C.)
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Diego F. Calvisi
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.A.D.); (D.R.)
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Bihain C, Delwaide J, Meunier P, Gerard L, Jadoul A, Detry O. Successful multimodal management of a large hepatocellular carcinoma in a non-cirrhotic liver: a case report. Acta Chir Belg 2024; 124:229-233. [PMID: 37482686 DOI: 10.1080/00015458.2023.2234724] [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: 12/20/2022] [Accepted: 06/21/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) found in a non cirrhotic liver represents a minority of HCC cases and remains poorly studied. Due to its specific characteristics and evolution, this tumour requires a different management compared to HCC in a cirrhotic liver. CASE REPORT The authors describe the case of a 68-year-old man diagnosed with a large giant and only mildly symptomatic HCC in a non-cirrhotic liver. The 23 cm HCC was discovered when a thoracoabdominal computed tomography was performed following mild abdominal pain. After a multidisciplinary discussion the tumour was judged to be borderline, but potentially resectable after neoadjuvant therapy and preparation for surgery. The patient underwent selective internal radiation therapy radioembolization of the right hepatic artery lobe with 5,5 GBq of 90Y-labeled glass microspheres. It was followed by extended right hepatectomy after preparation by embolization of the right portal and the right hepatic veins. Thirty months after surgical resection the patient showed neither clinical, radiological nor biological signs of HCC recurrence. DISCUSSION HCC in non-cirrhotic liver is less common than in cirrhotic liver but has a better prognosis, thanks to a greater opportunity for surgical resection. The symptoms often emerge late and are unspecific, thus delaying the HCC diagnosis. Advances in surgical resection by laparotomy or laparoscopy, and neoadjuvant therapy in preparation for surgery, have proven to be effective. However, high mortality persists due to late diagnosis linked to the inability of identifying groups at risk of HCC in the non-cirrhotic population and inadequate screening.
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Affiliation(s)
- Clara Bihain
- Department of Abdominal Surgery and Transplantation, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
| | - Jean Delwaide
- Department of Hepatogastroenterology, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
| | - Paul Meunier
- Department of Radiology, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
| | - Laurent Gerard
- Department of Radiology, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
| | - Alexandre Jadoul
- Department of Imaging Oncology and Nuclear Medicine, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
| | - Olivier Detry
- Department of Abdominal Surgery and Transplantation, CHU Liege, University of Liege (CHU ULiege), Liege, Belgium
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Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de la Tijera F, Huitzil-Melendez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:362-379. [PMID: 35778341 DOI: 10.1016/j.rgmx.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/20/2022] [Indexed: 01/03/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this second part of the document, the topics related to the treatment of HCC are presented.
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Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico.
| | | | | | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, CDMX, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | - D Huitzil-Melendez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | | | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
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Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de la Tijera F, Huitzil-Melendez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:362-379. [DOI: 10.1016/j.rgmxen.2022.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/20/2022] [Indexed: 10/25/2022] Open
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Bredt LC, Felisberto IBG, Felisberto DEG. Is there a role for liver transplantation in the treatment of hepatocellular carcinoma in non-cirrhotic liver? World J Meta-Anal 2022; 10:46-51. [DOI: 10.13105/wjma.v10.i2.46] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/21/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Whether liver transplantation (LT) plays a role in the treatment of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver (NCL) is a matter of debate. The recommendations for LT in this setting are extremely fragile and less well-defined than for cirrhosis-associated HCC. All reports of LT for NCL-HCC revealed that long-term outcomes of these patients are poor, and these dismal figures are justified by the advanced tumor stage at the time of LT, suggesting the presence of systemic micrometastatic disease. The decision-making regarding LT for NCL-HCC is difficult, since specific selection criteria are scarce, and basically the potential candidates are those with unresectable only-liver tumor at admission, or unresectable intrahepatic recurrence post-resection. Besides the surgical aspects regarding the tumor resectability, other phenotypic and genetic characteristics of the tumor should be considered for the indication of LT in this scenario. The present minireview aims to discuss and analyze the last series of LT for NCL-HCC, in order to help clinicians in the decision-making process regarding the role of LT in NCL-HCC treatment.
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Affiliation(s)
- Luis Cesar Bredt
- Surgical Oncology and Hepatobiliary Surgery, Unioeste University, Cascavel 85819-110, Paraná, Brazil
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8
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Griffith DOL. Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers. Cancer Genet 2022; 264-265:90-99. [DOI: 10.1016/j.cancergen.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/07/2022] [Accepted: 04/20/2022] [Indexed: 11/26/2022]
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9
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Mahn R, Sadeghlar F, Bartels A, Zhou T, Weismüller T, Kupczyk P, Meyer C, Gaertner FC, Toma M, Vilz T, Knipper P, Glowka T, Manekeller S, Kalff J, Strassburg CP, Gonzalez-Carmona MA. Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes. Medicine (Baltimore) 2021; 100:e27082. [PMID: 34559100 PMCID: PMC8462617 DOI: 10.1097/md.0000000000027082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/12/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited. PATIENT CONCERNS In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain. DIAGNOSIS An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed. INTERVENTIONS Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed. OUTCOMES More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy. LESSONS In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.
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Affiliation(s)
- Robert Mahn
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | | | - Alexandra Bartels
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | - Taotao Zhou
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | - Tobias Weismüller
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | | | - Carsten Meyer
- Department of Radiology, University Hospital Bonn, Germany
| | | | - Marieta Toma
- Department of Pathology, University Hospital Bonn, Germany
| | - Tim Vilz
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | - Petra Knipper
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | - Tim Glowka
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | | | - Jörg Kalff
- Department of Visceral Surgery, University Hospital Bonn, Germany
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Baglieri J, Zhang C, Liang S, Liu X, Nishio T, Rosenthal SB, Dhar D, Su H, Cong M, Jia J, Hosseini M, Karin M, Kisseleva T, Brenner DA. Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1564-1579. [PMID: 34119473 PMCID: PMC8406794 DOI: 10.1016/j.ajpath.2021.05.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
Abstract
Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Colr/r mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Colr/r mice or Hepa 1-6 cells were engrafted into WT and Colr/r livers. The effect of hepatic stellate cells (HSCs) from WT and Colr/r mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Colr/r mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Colr/r mice. Although Colr/r HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Colr/r HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Colr/r phenotype into a WT phenotype. Although Colr/r mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.
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Affiliation(s)
- Jacopo Baglieri
- Department of Medicine, University of California San Diego, San Diego, California; Department of Surgery, University of California San Diego, San Diego, California
| | - Cuili Zhang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Shuang Liang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego, San Diego, California
| | - Takahiro Nishio
- Department of Medicine, University of California San Diego, San Diego, California
| | - Sara B Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, San Diego, California
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, San Diego, California
| | - Hua Su
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, San Diego, California
| | - Michael Karin
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, San Diego, California
| | - David A Brenner
- Department of Medicine, University of California San Diego, San Diego, California.
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11
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Uehara T, Pogribny IP, Rusyn I. The DEN and CCl 4 -Induced Mouse Model of Fibrosis and Inflammation-Associated Hepatocellular Carcinoma. Curr Protoc 2021; 1:e211. [PMID: 34370903 PMCID: PMC8744072 DOI: 10.1002/cpz1.211] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Human hepatocellular carcinoma (HCC) develops most often as a complication of fibrosis or cirrhosis. Although most human studies of HCC provide crucial insights into the molecular signatures of HCC, they seldom address its etiology. Mouse models provide essential tools for investigating the pathogenesis of HCC, but the majority of rodent cancer models do not feature liver fibrosis. Detailed here is a protocol for an experimental mouse model of HCC that arises in association with advanced liver fibrosis. The disease model is induced by a single injection of N-nitrosodiethylamine (DEN) at 2 weeks of age followed by repeated administration of carbon tetrachloride (CCl4 ) from 8 weeks of age for up to 14 consecutive weeks. A dramatic potentiation of liver tumor incidence is observed following administration of DEN and CCl4 , with 100% of mice developing liver tumors at 5 months of age. This model has been employed for studying the molecular mechanisms of fibrogenesis and HCC development, as well as for cancer hazard/chemotherapy testing of drug candidates. © 2021 Wiley Periodicals LLC. Basic Protocol: The DEN and CCl4 -induced mouse model of fibrosis and inflammation-associated hepatocellular carcinoma.
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Affiliation(s)
- Takeki Uehara
- Strategic Development Department, Shionogi & Co., Osaka, Japan
| | - Igor P. Pogribny
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
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12
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Lin E, Zou B, Zeng G, Cai C, Li P, Chen J, Li D, Zhang B, Li J. The impact of liver fibrosis on microvascular invasion and prognosis of hepatocellular carcinoma with a solitary nodule: a Surveillance, Epidemiology, and End Results (SEER) database analysis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1310. [PMID: 34532447 PMCID: PMC8422100 DOI: 10.21037/atm-21-3731] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The pathogenesis of non-cirrhotic hepatocellular carcinoma (HCC) with a high recurrence remains controversial, while microvascular invasion (MVI) is highly suggestive of tumor recurrence. This study aimed to investigate the effects of liver fibrosis on MVI and prognosis in HCC. METHODS Based on the data of HCC in the Surveillance, Epidemiology, and End Results (SEER) database [2004-2015], multivariate logistic regression was used for correlation analysis. Survival was analyzed by Log-Rank test and Cox regression, and decision curve analysis and receiver operating characteristic curves were established to evaluate alternative diagnostic and prognostic strategies. RESULTS The study included 1,492 patients with MVI (17.8%) or without MVI (82.2%) for HCC with a solitary nodule. Liver fibrosis was significantly correlated with the occurrence of MVI, and the risk of MVI in patients with a fibrosis score F5-6 was lower than in those with a score of F0-4 (OR =0.651, 95% CI: 0.492-0.860). Combining liver fibrosis could improve the prediction performance of MVI risk models, but liver fibrosis was less associated with survival outcomes in comparison with other tumor characteristics. CONCLUSIONS Lower liver fibrosis correlated with a higher risk of MVI in HCC with a solitary nodule and was a good indicator for improving the performance of MVI risk models. However, it was not a prognostic sensitive indicator.
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Affiliation(s)
- En Lin
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Baojia Zou
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Guifang Zeng
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Chaonong Cai
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Peiping Li
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Jiafan Chen
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Decheng Li
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Baimeng Zhang
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Jian Li
- Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
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Vázquez Rodríguez JA, Molina Villalba C, Estévez Escobar M. Alagille syndrome and hepatocellular carcinoma in a non-cirrhotic adult. Med Clin (Barc) 2021; 158:295-296. [PMID: 34256939 DOI: 10.1016/j.medcli.2021.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 11/16/2022]
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Abstract
Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related death worldwide.
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Martínez-Mier G, Esquivel-Torres S, Casanova-Sánchez I, Escobar-Ríos A, Troche-Gutiérrez J, Yoldi-Aguirre C. Carcinoma hepatocelular en hígado no cirrótico: características clínicas y resultados en Veracruz, México. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 86:4-12. [PMID: 32345506 DOI: 10.1016/j.rgmx.2019.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 10/29/2019] [Accepted: 11/28/2019] [Indexed: 02/06/2023]
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Hepatocellular carcinoma in the noncirrhotic liver: Clinical features and outcomes in Veracruz, Mexico. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2021. [DOI: 10.1016/j.rgmxen.2019.11.006] [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: 11/19/2022] Open
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Impact of diseased liver parenchyma on perioperative outcome among patients with hepatocellular carcinoma undergoing hepatectomy: Experience from a developing country. Surg Oncol 2020; 35:236-242. [PMID: 32932220 DOI: 10.1016/j.suronc.2020.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/25/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Limited data can be found about surgical outcome of patients with hepatocellular carcinoma (HCC) arising in non-diseased liver. The study aim was to compare short- and long-term outcomes among HCC patients with normal and diseased liver parenchyma, undergoing potentially curative liver resection in a developing country. MATERIALS AND METHODS From November 2001 until January 2017, 228 patients with HCC underwent curative-intent hepatectomy at the University Clinic for Digestive Surgery. From that number, 190 patients were eligible for analysis. Diseased liver (DL) was present in 112 patients while 78 patients had HCC in non-diseased liver (NDL). RESULTS Median age, sex, ASA score, the presence of extrahepatic disease and lobar distribution of tumors were similar in both groups. The number of tumors was higher in DL group, while tumor diameter was higher in NDL group. Anatomic liver resection and major liver resections were performed more commonly in NDL than in DL group (66.7 vs 47.4%, p = 0.008; 33.3 vs. 15.2%, p = 0.003). Postoperative morbidity was significantly higher in DL group (p = 0.004). Overall survival was statistically longer in NDL group (p = 0.024). By univariate analysis potential prognostic factors for long-term survival were identified: presence of chronic HCV infection, presence of cirrhosis, Child-Pugh score B and operative time longer than 240 min. The last two were confirmed by multivariate analysis as independent negative prognostic factors for overall survival. CONCLUSION Liver resection in patients with HCC arising in non-diseased livers, despite of need for extended hepatectomies, provides favorable long-term prognosis.
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Memon A, Pyao Y, Jung Y, Lee JI, Lee WK. A Modified Protocol of Diethylnitrosamine Administration in Mice to Model Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:5461. [PMID: 32751728 PMCID: PMC7432842 DOI: 10.3390/ijms21155461] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022] Open
Abstract
We aimed to create an animal model for hepatocellular carcinoma (HCC) with a short time, a high survival rate, as well as a high incidence of HCC in both males and females than previously reported. The Diethylnitrosamine (DEN) model has an age-related effect. A single dose of DEN treatment is not enough in young mice up to 50 weeks. The same pattern is shown in an adult with multiple-dose trials whether or not there is some promotion agent. In this study, two-week old C57BL6 mice were given a total of eight doses of DEN, initially 20mg/kg body weight, and then 30mg/kg in the third week, followed by 50mg/kg for the last six weeks. The first group is DEN treatment only and the other two groups received thioacetamide (TAA) treatment for four or eight weeks after one week of rest from the last DEN treatment. An autopsy was performed after 24 weeks of the initial dose of DEN in each group. The cellular arrangement of HCC in the entire group was well-differentiated carcinoma and tumor presence with no significant impact on the survival of mice. Increased levels of the biochemical markers in serum, loss of tissue architecture, hepatocyte death, and proliferation were highly activated in all tumor-induced groups. This finding demonstrates an improved strategy to generate an animal model with a high occurrence of tumors combined with cirrhosis in a short time regardless of sex for researchers who want to investigate liver cancer-related.
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Affiliation(s)
- Azra Memon
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Yuliya Pyao
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Yerin Jung
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Jung Il Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea;
| | - Woon Kyu Lee
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
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20
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Seok J, Suk KT. Gut-microbiome Taxonomic Profiling as Non-invasive Biomarkers for the Early Detection of Alcoholic Hepatocellular Carcinoma. JOURNAL OF LIVER CANCER 2020; 20:32-40. [PMID: 37383053 PMCID: PMC10035701 DOI: 10.17998/jlc.20.1.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 11/26/2019] [Accepted: 11/26/2019] [Indexed: 06/30/2023]
Abstract
Background/Aims Hepatocellular carcinoma (HCC) is a prevalent form of primary liver cancer and the fifth leading cause of worldwide cancer mortality. Though early diagnosis of HCC is important, so far lack of effective biomarkers for early diagnosis of HCC has been a problem. In this study, we searched for potential functional biomarkers of alcoholic HCC by using metagenomics approach. Methods Between September 2017 and April 2019, normal control (n=44), alcoholic liver cirrhosis (n=44), and alcoholic HCC (n=13) groups were prospectively enrolled and analyzed. Gut microbiota was analyzed using the 16S-based microbiome taxonomic profiling platform of EzBioCloud Apps and analyzing system. Results There was a statistically significant difference among groups in diversity (P<0.05). In the comparison of phylum between cirrhosis and HCC, Proteobacteria were increased and Bacteroidetes were decreased. Firmicutes were not significantly different among the three groups. In the taxonomic profiling, relative abundance of Lactobacillus in the cirrhosis and HCC groups showed richness (P<0.05). In the biomarker analysis between cirrhosis and HCC, obiquinome Fe-S protein 3, global nitrogen regulator, Vesicle-associated membrane protein 7, toxin YoeB, peroxisome-assembly ATPase, and nitrogen oxide reductase regulator were differently expressed (P<0.001). Conclusions Alcoholic HCC showed different expressions in the stool taxonomy and biomarker compared with that of cirrhosis and control. Therefore, new biomarkers using stool analysis for alcoholic HCC are necessary.
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Affiliation(s)
- Jun Seok
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, Korea
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, Korea
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
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21
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Liu Y, Li H, Ye N, Luo CJ, Hu YY, Wu H, Gong JP. Non-Cirrhotic Liver is Associated with Poor Prognosis of Hepatocellular Carcinoma: A Literature Review. Med Sci Monit 2019; 25:6615-6623. [PMID: 31479436 PMCID: PMC6752105 DOI: 10.12659/msm.915722] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 04/19/2019] [Indexed: 12/15/2022] Open
Abstract
Primary hepatocellular carcinoma (HCC) is the fifth most frequently reported malignancy, and it is also the second most common cause of cancer-related deaths worldwide. Although most HCC cases have been reported to develop from cirrhosis, accumulating data suggest that HCC is also closely related to non-cirrhotic chronic liver disease. Traditionally, HCC was thought to develop mostly from cirrhosis; however, an increasing number of reports have found that HCC can develop directly from inflammation without cirrhosis. The incidence of HCC in non-cirrhotic liver (HCC-NCL) is high, especially in developed countries. Studies have found that the most common cause of HCC-NCL is neglected fatty liver disease. This type of HCC has unique clinical characteristics and is closely related to metabolic disorders. Unfortunately, the prevention of HCC-NCL has not received enough attention worldwide, and there is also a lack of specific screening methods and clinical guidelines. This article mainly reviews the etiology, incidence, clinical characteristics, and screening markers of HCC-NCL to improve the understanding and prevention of this disease.
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Affiliation(s)
- Yan Liu
- Department of Gastroenterology, Chengdu Fifth People’s Hospital, Chengdu, Sichuan, P.R. China
| | - Hao Li
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Nan Ye
- Department of Hepatobiliary Surgery, Dongyang People’s Hospital, Jinhua, Zhejiang, P.R. China
| | - Cheng-Jun Luo
- Department of Gastroenterology, Chengdu Fifth People’s Hospital, Chengdu, Sichuan, P.R. China
| | - Ye-Yu Hu
- Department of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Jian-Ping Gong
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
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22
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Carling U, Røsok B, Line PD, Dorenberg EJ. ALBI and P-ALBI grade in Child-Pugh A patients treated with drug eluting embolic chemoembolization for hepatocellular carcinoma. Acta Radiol 2019; 60:702-709. [PMID: 30205701 DOI: 10.1177/0284185118799519] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Treatment outcome for hepatocellular carcinoma (HCC) is related to tumor burden and liver function. Grading systems assessing liver function need validation in different clinical settings. PURPOSE To evaluate drug-eluting embolic transarterial chemoembolization (DEE-TACE) in Child-Pugh A HCC with respect to albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (P-ALBI) grade. MATERIAL AND METHODS Forty-nine patients with Child-Pugh class A, diagnosed with HCC and allocated to DEE-TACE treatment, were retrospectively analyzed regarding tumor and treatment characteristics, radiological response (mRECIST) one month post treatment, overall survival (OS), and adverse events (AEs; CTCAE, grades ≥3) with respect to ALBI and P-ALBI grade. RESULTS There were 21 ALBI 1 patients, 29 P-ALBI 1 patients, and 19 patients were both ALBI and P-ALBI 1. Objective response rate was 74% with no statistically significant difference for ALBI (1 vs. 2; P = 0.08), or P-ALBI (1 vs. 2; P = 0.49). OS was 14.8 months (range = 1.7-62.0; ALBI 1 vs. 2: P = 0.08; P-ALBI 1 vs. 2: P = 0.003). OS in responders with ALBI 1 and 2 was 28.9 vs.10.2 months ( P = 0.02), and P-ALBI 1 and 2 was 26.7 vs. 8.6 months ( P < 0.001). In multivariate analyses, both ALBI 2 (HR = 2.4, P = 0.02) and P-ALBI 2 (HR = 3.3, P < 0.01) were negative prognostic factors for survival. There were 15 AEs in 13 patients, with hepatic failure only occurring in ALBI 2 and P-ALBI 2 patients. CONCLUSION P-ALBI grade 1 and 2 differentiated survival in Child-Pugh A patients treated with DEE-TACE. Both grading systems can differentiate survival in patients responding to treatment.
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Affiliation(s)
- Ulrik Carling
- 1 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Bård Røsok
- 2 Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Pål-Dag Line
- 3 Department of Transplantation, Oslo University Hospital, Oslo, Norway
| | - Eric J Dorenberg
- 1 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
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Role of Gut Microbiota in Hepatocarcinogenesis. Microorganisms 2019; 7:microorganisms7050121. [PMID: 31060311 PMCID: PMC6560397 DOI: 10.3390/microorganisms7050121] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/23/2019] [Accepted: 05/03/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulates over decades. Observations from recent studies have accounted for the involvement of the gut–liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis can cause the intestinal microbiome to serve as the main source of portal-vein endotoxins, such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on clinical as well as animal studies involving the gut microbiota, with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, which represent key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.
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24
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Imprialos KP, Stavropoulos K, Doumas M, Skalkou A, Zografou I, Athyros VG. The potential role of statins in treating liver disease. Expert Rev Gastroenterol Hepatol 2018; 12:331-339. [PMID: 29431526 DOI: 10.1080/17474124.2018.1439379] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins are commonly use for the management of dyslipidemia, worldwide. Various studies have demonstrated that statins offer significant reduction in the risk of cardiovascular morbidity and mortality. However, this class of drugs has been implicated in potential liver toxicity, thus has been considered as a 'forbidden-drug' in patients with increased liver enzymes. Areas covered: Studies have shown that statins might offer clinical benefits in the setting of viral hepatitis, progression of cirrhosis, and hepatocellular carcinoma. More importantly, this class of drugs was shown to ameliorate liver histological (in both imaging and biopsy studies) and functional alterations in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In addition, two large survival studies have demonstrated reduction in the risk for cardiovascular events with statin use in patients with elevated transaminase levels at baseline. Expert commentary: These benefits were of greater extent compared with patients with normal liver function tests at baseline. However, current international guidelines seem to neglect these findings and are not including statins in the management algorithm of patients with non-alcoholic fatty liver disease or steatohepatitis. Future randomized studies providing biopsy-proven benefits will establish the use of statins in the prevention of cardiovascular events and therapeutic algorithm of these patients.
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Affiliation(s)
- Konstantinos P Imprialos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Konstantinos Stavropoulos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Michael Doumas
- b Veterans Affairs Medical Center , George Washington University , Washington , DC , USA
| | - Anastasia Skalkou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Ioanna Zografou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Vasilios G Athyros
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
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Kabbage L, El Kouhen M, Taghy A, Znati K, Kabbaj N. A rare presentation of hepatocellular carcinoma in non-cirrhotic liver. Pan Afr Med J 2017; 28:69. [PMID: 29255539 PMCID: PMC5724728 DOI: 10.11604/pamj.2017.28.69.13512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/12/2017] [Indexed: 01/26/2023] Open
Abstract
Hepatocellular carcinoma is the most frequent type of liver malignancy. Most cases of hepatocellular carcinoma are secondary to either viral hepatitis (hepatitis B, C) or alcoholic cirrhosis. Liver cirrhosis due to any other causes is considered as a risk factor for development of hepatocellular carcinoma; however, hepatocellular carcinoma in non cirrhotic livers remains a rare condition. The present case report describes a 59-year-old woman patient admitted to explore right hypochondriac and epigastric pain, with no evidence of pre-existing liver disease and with a good general condition. The computed tomography was very suggestive of a gastro-intestinal stromal tumor. But, at laparotomy, a huge hepatic tumor was discovered. Histopathological study confirmed the presence of primary hepatocellular carcinoma. Hepatocellular carcinoma occurs more frequently on a cirrhotic liver. However, it can occur on a non cirrhotic liver and remains and extremely rare case.
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Affiliation(s)
- Lamia Kabbage
- Faculty of medicine, mohammed V Souissi University Rabat Morocco
- EFD-hepatogastroenterology Unit, ibn sina hospital, Rabat,Morocco
| | - Meryem El Kouhen
- EFD-hepatogastroenterology Unit, ibn sina hospital, Rabat,Morocco
| | - Ahmed Taghy
- Faculty of medicine, mohammed V Souissi University Rabat Morocco
- Clinique chirurgicale B, ibn sina hospital, Rabat, Morocco
| | - Kaoutar Znati
- Faculty of medicine, mohammed V Souissi University Rabat Morocco
- Pathology departement, ibn sina hospital, Rabat, Morocco
| | - Nawal Kabbaj
- Faculty of medicine, mohammed V Souissi University Rabat Morocco
- EFD-hepatogastroenterology Unit, ibn sina hospital, Rabat,Morocco
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26
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Shim CW, Park JW, Kim SH, Kim JS, Kim BH, Kim SH, Hong EK. Noncirrhotic hepatocellular carcinoma: etiology and occult hepatitis B virus infection in a hepatitis B virus-endemic area. Therap Adv Gastroenterol 2017; 10:529-536. [PMID: 28804513 PMCID: PMC5484439 DOI: 10.1177/1756283x17710247] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/04/2017] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Although hepatocellular carcinoma (HCC) usually develops in cirrhotic livers, a minority of cases occur in noncirrhotic livers (NCLs). We investigated etiology, clinicopathological features, and occult hepatitis B virus (HBV) infection (OBI) in patients with NCL HCC in an HBV-endemic area. METHODS A total of 710 patients who underwent resection or transplantation for HCC at the National Cancer Center (NCC), Korea, were enrolled. HCC and fibrosis stage were diagnosed pathologically. RESULTS A total of 178 patients (25%) did not have cirrhosis (NCL group). The main cause of HCC was HBV infection (77.2%), followed by cryptogenic disease (11.0%). The prevalence of NCL was 19.2%, 32.5%, 50.0%, and 48.7% among patients with HBV, hepatitis C virus (HCV), alcoholic, and cryptogenic disease, respectively (p < 0.05); corresponding nonfibrosis rates were 8.1%, 0%, 19.0%, and 24.3%, respectively. The NCL group was significantly older, with a larger tumor size, smaller tumor number, lower tumor stage, and more frequent non-HBV etiology. Among non-HBV HCC cases, 130 (80.2%) had antibodies against HBV core (HBc) and 55 (38.5%) had OBI. OBI-positive rates of 0%, 31.8%, and 52.6% were detected among HCV, alcoholic, and cryptogenic HCC cases, respectively. OBI did not correlate with advanced fibrosis. The NCL and liver cirrhosis (LC) groups did not differ in median overall survival. CONCLUSION Regardless of etiology, a significant number of HCC patients, including half of nonviral cases, did not have LC. Half of cryptogenic HCC cases had OBI. This study promotes an understanding of fibrosis and OBI among patients with HCC in an HBV-endemic area.
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Affiliation(s)
| | | | - So Hee Kim
- Biometric Research Branch, National Cancer Center, Korea
| | - Jin Sook Kim
- Liver and Pancreatobiliary Cancer Branch, National Cancer Center, Korea
| | - Bo Hyun Kim
- Center for Liver Cancer, National Cancer Center, Korea
| | - Sung Hoon Kim
- Center for Liver Cancer, National Cancer Center, Korea
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Large hepatocellular carcinoma in a non-cirrhotic liver with peritoneal and omental metastasis in a healthy man: a case report. J Med Case Rep 2017; 11:34. [PMID: 28173830 PMCID: PMC5297144 DOI: 10.1186/s13256-017-1203-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/06/2017] [Indexed: 12/19/2022] Open
Abstract
Background Liver cancer is the second leading cause of cancer death in men worldwide. Hepatocellular carcinoma usually develops in the setting of cirrhosis or chronic inflammation. Major risk factors for developing hepatocellular carcinoma are chronic hepatitis B or C virus infection, alcoholic cirrhosis, and nonalcoholic fatty liver disease. The most frequent locations for hepatocellular carcinoma to metastasize are the lungs, portal vein, bones, and regional lymph nodes. Case presentation A 41-year-old Sri Lankan man presented with progressive abdominal distension and on examination was found to have a palpable irregular mass in the left lobe of his liver with moderate ascites. His ascitic fluid was an exudate without malignant cells. An ultrasound scan and contrast-enhanced computed tomography of his abdomen showed a large contrast-enhancing lesion in the left lobe of his liver without features of cirrhosis. Laparoscopic assessment revealed peritoneal and omental deposits. Histology of the biopsies taken from the liver lesion, omental deposits, and peritoneal deposits supported a diagnosis of hepatocellular carcinoma. His liver biochemistry was normal and hepatitis serology was negative. He is abstinent from alcohol and did not have metabolic syndrome. Conclusions It is rare for a young patient to develop hepatocellular carcinoma with a normal liver without chronic hepatitis B or C infection, or any other risk factors. Intraperitoneal metastasis of non-ruptured hepatocellular carcinoma is also very rare. Here we report a rare case of a 41-year-old man with a large hepatocellular carcinoma in a non-cirrhotic liver without chronic hepatitis who presented with peritoneal and omental metastasis.
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28
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Carrilho FJ, Mattos AAD, Vianey AF, Vezozzo DCP, Marinho F, Souto FJ, Cotrim HP, Coelho HSM, Silva I, Garcia JHP, Kikuchi L, Lofego P, Andraus W, Strauss E, Silva G, Altikes I, Medeiros JE, Bittencourt PL, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and treatment of hepatocellular carcinoma. ARQUIVOS DE GASTROENTEROLOGIA 2016; 52 Suppl 1:2-14. [PMID: 26959803 DOI: 10.1590/s0004-28032015000500001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma is a malignancy of global importance and is associated with a high rate of mortality. Recent advances in the diagnosis and treatment of this disease make it imperative to update the recommendations on the management of the disease. In order to draw evidence-based recommendations concering the diagnosis and management of hepatocellular carcinoma, the Brazilian Society of Hepatology has sponsored a single-topic meeting in João Pessoa (PB). All the invited pannelists were asked to make a systematic review of the literature and to present topics related to the risk factors for its development, methods of screening, radiological diagnosis, staging systems, curative and palliative treatments and hepatocellular carcinoma in noncirrhotic liver. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript containing the recommendations of the Brazilian Society of Hepatology.
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Affiliation(s)
| | | | | | | | - Fábio Marinho
- Hospital Português de Beneficiência, Recife, PE, Brazil
| | | | | | | | - Ivonete Silva
- Faculdade de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | | | - Luciana Kikuchi
- Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | - Patricia Lofego
- Faculdade de Medicina, Universidade Federal do Espírito Santo, ES, Brazil
| | | | - Edna Strauss
- Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | | | | | | | | | - Edison R Parise
- Faculdade de Medicina, Universidade Federal de São Paulo, SP, Brazil
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Janicko M, Drazilova S, Pella D, Fedacko J, Jarcuska P. Pleiotropic effects of statins in the diseases of the liver. World J Gastroenterol 2016; 22:6201-6213. [PMID: 27468210 PMCID: PMC4945979 DOI: 10.3748/wjg.v22.i27.6201] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.
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Hadjittofi C, Athanasopoulos PG, Koti RS, Konstantinidou SK, Davidson BR. Long-term survival with repeated resections of recurrent hepatocellular carcinoma in a non-cirrhotic liver: case report and brief review of the literature. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:112. [PMID: 27127765 DOI: 10.21037/atm.2016.03.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A healthy and asymptomatic 55-year-old woman underwent a complete (R0) non-anatomical resection of an incidentally detected solitary hepatocellular carcinoma (HCC) in a non-cirrhotic liver. Six years following the initial R0 non-anatomical resection, intrahepatic recurrence was diagnosed and the patient underwent a second R0 non-anatomical resection. At 12.5 years following the initial resection, a further intrahepatic recurrence was diagnosed, which was once again completely resected by left lateral hepatectomy. This represents one of the longest reported periods between initial resection and HCC recurrence, following repeated R0 resections in the absence of cirrhosis. The appropriate surveillance period and genetic testing protocol for such cases remains to be established.
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Affiliation(s)
- Christopher Hadjittofi
- 1 Department of Cardiothoracic Surgery, King's College Hospital, Denmark Hill, London, UK ; 2 Department of HPB & Liver Transplant Surgery, Royal Free Hospital, London, UK ; 3 Department of Pharmacy & Forensic Science, King's College London, Strand, London, UK ; 4 Research Department of General Surgery, University College London, Gower Street, London, UK
| | - Panagiotis G Athanasopoulos
- 1 Department of Cardiothoracic Surgery, King's College Hospital, Denmark Hill, London, UK ; 2 Department of HPB & Liver Transplant Surgery, Royal Free Hospital, London, UK ; 3 Department of Pharmacy & Forensic Science, King's College London, Strand, London, UK ; 4 Research Department of General Surgery, University College London, Gower Street, London, UK
| | - Rahul S Koti
- 1 Department of Cardiothoracic Surgery, King's College Hospital, Denmark Hill, London, UK ; 2 Department of HPB & Liver Transplant Surgery, Royal Free Hospital, London, UK ; 3 Department of Pharmacy & Forensic Science, King's College London, Strand, London, UK ; 4 Research Department of General Surgery, University College London, Gower Street, London, UK
| | - Sofia K Konstantinidou
- 1 Department of Cardiothoracic Surgery, King's College Hospital, Denmark Hill, London, UK ; 2 Department of HPB & Liver Transplant Surgery, Royal Free Hospital, London, UK ; 3 Department of Pharmacy & Forensic Science, King's College London, Strand, London, UK ; 4 Research Department of General Surgery, University College London, Gower Street, London, UK
| | - Brian R Davidson
- 1 Department of Cardiothoracic Surgery, King's College Hospital, Denmark Hill, London, UK ; 2 Department of HPB & Liver Transplant Surgery, Royal Free Hospital, London, UK ; 3 Department of Pharmacy & Forensic Science, King's College London, Strand, London, UK ; 4 Research Department of General Surgery, University College London, Gower Street, London, UK
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Sukowati CHC, El-Khobar KE, Ie SI, Anfuso B, Muljono DH, Tiribelli C. Significance of hepatitis virus infection in the oncogenic initiation of hepatocellular carcinoma. World J Gastroenterol 2016; 22:1497-1512. [PMID: 26819517 PMCID: PMC4721983 DOI: 10.3748/wjg.v22.i4.1497] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/06/2015] [Accepted: 10/12/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, and DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Viral
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Viral
- Genotype
- Hepacivirus/genetics
- Hepacivirus/pathogenicity
- Hepatitis B virus/genetics
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Liver Neoplasms/epidemiology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/virology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/virology
- Oncogenes
- Risk Factors
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Mohamad B, Shah V, Onyshchenko M, Elshamy M, Aucejo F, Lopez R, Hanouneh IA, Alhaddad R, Alkhouri N. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. Hepatol Int 2015; 10:632-9. [DOI: 10.1007/s12072-015-9679-0] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 10/07/2015] [Indexed: 02/06/2023]
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Sheng RF, Zeng MS, Ji Y, Yang L, Chen CZ, Rao SX. MR features of small hepatocellular carcinoma in normal, fibrotic, and cirrhotic livers: a comparative study. ACTA ACUST UNITED AC 2015; 40:3062-9. [DOI: 10.1007/s00261-015-0536-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Liu ZM, Tseng HY, Tsai HW, Su FC, Huang HS. Transforming growth factor β-interacting factor-induced malignant progression of hepatocellular carcinoma cells depends on superoxide production from Nox4. Free Radic Biol Med 2015; 84:54-64. [PMID: 25841779 DOI: 10.1016/j.freeradbiomed.2015.03.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 03/09/2015] [Accepted: 03/25/2015] [Indexed: 01/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly malignancies worldwide because of its high recurrence rate, high metastatic potential, and resistance to drugs. Elucidation of the mechanisms underlying malignancy in HCC is needed to improve diagnosis, therapy, and prognosis. Previously, we showed that transforming growth factor β-interacting factor (TGIF) antagonizes arsenic trioxide-induced apoptosis of HepG2 cells and is associated with poor prognosis and progression of urothelial carcinoma in patients after radical nephroureterectomy. To determine whether TGIF plays a role in HCC tumorigenesis, we compared the expression of TGIF, its downstream targets, and reactive oxygen species levels between HCC HepG2 cells and the more invasive SK-Hep1 cells. Superoxide production, phosphorylation of c-Src(Y416) and AKT(S473), and expression of TGIF and NADPH oxidase (Nox) were higher in invasive SK-Hep1 cells than in HepG2 cells. TGIF-overexpressing HepG2 xenograft tumors markedly promoted tumor growth and metastasis to the lungs. Overexpression of TGIF in HepG2 cells increased superoxide production from Nox4, matrix metalloproteinase expression, invadopodia formation, and cellular migration/invasion ability. Conversely, knockdown of TGIF in SK-Hep1 cells attenuated these processes. Using gene knockdown and pharmacological inhibitors, we demonstrate that c-Src/AKT is the upstream signaling that regulates TGIF-induced Nox4 activation and subsequent superoxide production. Taken together, our results implicate TGIF as a potential biomarker for prognosis and target for clinical therapy in patients with advanced HCC.
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Affiliation(s)
- Zi-Miao Liu
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Hong-Yu Tseng
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Fang-Cheng Su
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Huei-Sheng Huang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
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Eskesen AN, Bjøro K, Aandahl EM, Line PD, Melum E. Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway--a population-based cohort study. Cancer Epidemiol 2014; 38:741-747. [PMID: 25454262 DOI: 10.1016/j.canep.2014.10.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 10/04/2014] [Accepted: 10/12/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC. METHODS All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed. RESULTS Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age ≤ 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics. CONCLUSION Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program.
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Affiliation(s)
- Arne Nørgaard Eskesen
- Department of Infectious Diseases, Medical Division, Akershus University Hospital, Lørenskog, Norway.
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Bouomrani S, Kilani I, Nouma H, Slama A, Beji M. [Non fibrolamellar hepatocellular carcinoma on a healthy liver]. Pan Afr Med J 2014; 18:155. [PMID: 25419293 PMCID: PMC4236843 DOI: 10.11604/pamj.2014.18.155.2762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 12/21/2013] [Indexed: 01/10/2023] Open
Abstract
Le carcinome hépatocellulaire (CHC) survient le plus souvent sur foie de cirrhose. Sa survenue sur un foie sain est exceptionnelle et pose un véritable défit diagnostique pour le clinicien. Nous rapportons l'observation d'un patient de 53 ans, sans antécédents pathologiques notables qui fût admis pour exploration d'une douleur de l'hypochondre droit évoluant depuis quelques mois avec une exacerbation récente, associée à un amaigrissement important et une altération de l’état général. L'examen clinique notait une hépatomégalie ferme et douloureuse. L’échographie abdominale montrait une masse hétérogène du secteur latéral droit du foie faisant 10 cm de grand axe. La TDM abdominale montrait une masse tissulaire, hétérogène, à vascularisation artérielle importante, mesurant 10 cm de diamètre et occupant le secteur latéral droit du foie. Cette tumeur comprime la branche portale droite sans signes d'extension. Il n'y avait pas d'adénopathie ni d’épanchement intra abdominal. La ponction biopsique écho-guidée avait conclu à un CHC non fibrolamellaire. Le bilan biologique, en particulier les transaminases, le taux de prothrombine, l’électrophorèse des protéines sanguine et l'alpha foeto-protéine, était sans anomalies. Les sérologies de l'hépatites virales B et C ainsi que la recherche des auto anticorps spécifiques des hépatites auto immunes et le bilan cuprique étaient aussi négatives. Vue l’âge, le stade avancé de la tumeur et l'altération de l’état général la conduite thérapeutique était de s'abstenir.
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Affiliation(s)
- Salem Bouomrani
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Ichrak Kilani
- Service de Gastroentérologie, Hôpital Militaire de Gabès 6000, Tunisie
| | - Hanène Nouma
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Alaeddine Slama
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Maher Beji
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
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Arnaoutakis DJ, Mavros MN, Shen F, Alexandrescu S, Firoozmand A, Popescu I, Weiss M, Wolfgang CL, Choti MA, Pawlik TM. Recurrence patterns and prognostic factors in patients with hepatocellular carcinoma in noncirrhotic liver: a multi-institutional analysis. Ann Surg Oncol 2014; 21:147-154. [PMID: 23959056 DOI: 10.1245/s10434-013-3211-3] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce. METHODS Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models. RESULTS Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51). CONCLUSIONS Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.
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Affiliation(s)
- Dean J Arnaoutakis
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael N Mavros
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Feng Shen
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Sorin Alexandrescu
- Institute for Digestive Diseases and Liver Transplantation Fundeni, Bucharest, Romania
| | - Amin Firoozmand
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Irinel Popescu
- Institute for Digestive Diseases and Liver Transplantation Fundeni, Bucharest, Romania
| | - Matthew Weiss
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher L Wolfgang
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael A Choti
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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Uehara T, Pogribny IP, Rusyn I. The DEN and CCl4 -Induced Mouse Model of Fibrosis and Inflammation-Associated Hepatocellular Carcinoma. CURRENT PROTOCOLS IN PHARMACOLOGY 2014; 66:14.30.1-14.30.10. [PMID: 25181010 PMCID: PMC4214366 DOI: 10.1002/0471141755.ph1430s66] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Human hepatocellular carcinoma (HCC) develops most often as a complication of fibrosis or cirrhosis. While most human studies of HCC provide crucial insights into the molecular signatures of HCC, seldom do they address the etiology of HCC. Mouse models are essential tools for investigating the pathogenesis of HCC; however, the overwhelming majority of cancer models in rodents do not feature liver fibrosis. Detailed in this unit is a protocol for an experimental mouse model of HCC that arises in association with advanced liver fibrosis. The disease model is induced by a single injection of N-nitrosodiethylamine (DEN) followed by repeated administration of carbon tetrachloride (CCl4 ). A dramatic potentiation of liver tumor incidence is observed following administration of DEN and CCl4 , with 100% of mice developing liver tumors at 5 months of age. This model can be employed for studying the molecular mechanisms of fibrogenesis and HCC development, and in cancer hazard/chemotherapy testing of drug candidates.
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Affiliation(s)
- Takeki Uehara
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431
| | - Igor P. Pogribny
- National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA; Phone: +1-870-543-7096; Fax: +1-870-543-7720
| | - Ivan Rusyn
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431,corresponding author: Ivan Rusyn, Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431; ; Phone/fax: +1-919-843-2596
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Characterization and prognosis of patients with hepatocellular carcinoma (HCC) in the non-cirrhotic liver. BMC Gastroenterol 2014; 14:117. [PMID: 24990270 PMCID: PMC4098694 DOI: 10.1186/1471-230x-14-117] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 06/26/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND HCC predominantly develops in the condition of chronic inflammation that has led to liver cirrhosis. A small proportion of patients with HCC is diagnosed in the non-cirrhotic liver (NCL). Data on patients with HCC in NCL in advanced stages are scarce. METHODS A retrospective analysis was performed comparing 93 patients with HCC in NCL to 571 patients with HCC in liver cirrhosis (LC) with respect to clinical and demographic characteristics. Also factors influencing survival in patients with HCC in NCL were analyzed. RESULTS Patients with HCC in NCL were diagnosed at older age and in more advanced tumor stages than patients with LC. More than 25% of patients with HCC in NCL presented with extrahepatic metastases. Only a minority of patients with HCC in NCL lacked any sign of hepatic damage. Risk factors for LC and risk factors for NAFLD are present in the majority of patients with HCC in NCL. The BCLC classification corresponded with the survival of patients with HCC in NCL although the therapeutic options differ from those for patients with liver cirrhosis. CONCLUSIONS It will be one of the major challenges in the future to awake awareness of carrying a risk of hepatic malignancies in patients with chronic liver diseases apart from liver cirrhosis, especially in NAFLD. Surveillance programs need to be implemented if these are cost-effective.
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Kornberg A. Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria: Multidisciplinary Approach to Improve Outcome. ISRN HEPATOLOGY 2014; 2014:706945. [PMID: 27335840 PMCID: PMC4890913 DOI: 10.1155/2014/706945] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/03/2014] [Indexed: 12/12/2022]
Abstract
The implementation of the Milan criteria (MC) in 1996 has dramatically improved prognosis after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Liver transplantation has, thereby, become the standard therapy for patients with "early-stage" HCC on liver cirrhosis. The MC were consequently adopted by United Network of Organ Sharing (UNOS) and Eurotransplant for prioritization of patients with HCC. Recent advancements in the knowledge about tumor biology, radiographic imaging techniques, locoregional interventional treatments, and immunosuppressive medications have raised a critical discussion, if the MC might be too restrictive and unjustified keeping away many patients from potentially curative LT. Numerous transplant groups have, therefore, increasingly focussed on a stepwise expansion of selection criteria, mainly based on tumor macromorphology, such as size and number of HCC nodules. Against the background of a dramatic shortage of donor organs, however, simple expansion of tumor macromorphology may not be appropriate to create a safe extended criteria system. In contrast, rather the implementation of reliable prognostic parameters of tumor biology into selection process prior to LT is mandatory. Furthermore, a multidisciplinary approach of pre-, peri-, and posttransplant modulating of the tumor and/or the patient has to be established for improving prognosis in this special subset of patients.
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Affiliation(s)
- A. Kornberg
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstraße 22, D-81675 Munich, Germany
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41
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Sheng RF, Zeng MS, Rao SX, Ji Y, Chen LL. MRI of small intrahepatic mass-forming cholangiocarcinoma and atypical small hepatocellular carcinoma (≤3 cm) with cirrhosis and chronic viral hepatitis: a comparative study. Clin Imaging 2014; 38:265-72. [PMID: 24559750 DOI: 10.1016/j.clinimag.2013.12.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 12/24/2013] [Accepted: 12/31/2013] [Indexed: 01/05/2023]
Abstract
OBJECTIVE The objective was to identify the decision-making magnetic resonance (MR) features in differentiating small intrahepatic mass-forming cholangiocarcinoma (sIMCC) from atypical small hepatocellular carcinoma (sHCC) (≤3 cm) in patients with cirrhosis and chronic viral hepatitis. METHODS Signal features and relative contrast of sHCCs and sIMCCs in T2-weighted and dynamic enhanced imaging were analyzed. A subgroup comparison between the cirrhosis and noncirrhosis chronic viral hepatitis group was also made. RESULTS Univariate analysis revealed that tumor contours (P<.001), signals in T2-weighted (P<.001) and each phase of contrast-enhanced scanning (P<.001), enhancement patterns (P<.001), as well as accompanying findings of tumor capsule (P<.001), hepatic capsule retraction (P<.001), bile duct dilation (P=.031), and transient hepatic intensity difference (P=.002) were different between sIMCC and atypical sHCC. Multivariate analysis indicated that dynamic enhancement patterns (P<.001) and signals in T2-weighted images (P=.024) were independent predictors for differentiation. Confusing MR features were more often observed in the cirrhosis group compared with those in the noncirrhosis chronic viral hepatitis group. CONCLUSION Dynamic enhancement patterns and signals in T2-weighted images were the most important MR features to differentiate sIMCC from atypical sHCC with cirrhosis and chronic viral hepatitis.
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Affiliation(s)
- Ruo-Fan Sheng
- Department of Radiology, Zhongshan Hospital, Shanghai Medical School, Fudan, University, Shanghai Medical Imaging Institute, No. 180 Fenglin Road, Xuhui, District, Shanghai 200032, China
| | - Meng-Su Zeng
- Department of Radiology, Zhongshan Hospital, Shanghai Medical School, Fudan, University, Shanghai Medical Imaging Institute, No. 180 Fenglin Road, Xuhui, District, Shanghai 200032, China.
| | - Sheng-Xiang Rao
- Department of Radiology, Zhongshan Hospital, Shanghai Medical School, Fudan, University, Shanghai Medical Imaging Institute, No. 180 Fenglin Road, Xuhui, District, Shanghai 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Shanghai Medical School, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Ling-Li Chen
- Department of Pathology, Zhongshan Hospital, Shanghai Medical School, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
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ZHANG LILI, YU SU, DUAN ZHIJUN, WANG QIUMING, TIAN GE, TIAN YAN, ZHAO WEI, WANG HUI, ZHANG CUILING, GUO SHIBIN, LIU QIGUI, HE GAOHONG, BIAN TENGFEI, CHANG JIUYANG, JIN XUE, CUI DONGSHENG. Treatment of liver cancer in mice by the intratumoral injection of an octreotide-based temperature-sensitive gel. Int J Mol Med 2013; 33:117-27. [DOI: 10.3892/ijmm.2013.1542] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 08/21/2013] [Indexed: 11/06/2022] Open
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Kim JM, Kwon CHD, Joh JW, Park JB, Lee JH, Kim SJ, Paik SW, Park CK, Yoo BC. Differences between hepatocellular carcinoma and hepatitis B virus infection in patients with and without cirrhosis. Ann Surg Oncol 2013; 21:458-65. [PMID: 24132624 DOI: 10.1245/s10434-013-3302-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND In patients with hepatitis B virus (HBV) infections, differences in hepatocellular carcinoma (HCC) between those with liver cirrhosis and those without cirrhosis have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between noncirrhotic and cirrhotic patients and to determine prognostic factors for tumor recurrence after hepatectomy in patients with HBV and HCC. METHODS Between 2005 and 2010, 441 curative hepatectomies for HCC in patients with cirrhosis and 454 for HCC in patients without cirrhosis were performed. RESULTS Cirrhotic patients had lower platelet counts, protein induced by vitamin K antagonist-II (PIVKA-II) levels, and tumor size than noncirrhotic patients. HCC differentiation in noncirrhotic patients was poorer than in cirrhotic patients. The 1-, 2-, and 3-year disease-free survival rates were 72.0, 65.6, and 61.0% in noncirrhotic patients, and 68.6, 56.5, and 51.5% in cirrhotic patients, respectively (P = 0.013). However, the 1-, 2-, and 3-year overall survival rates were 92.4, 85.5, and 81.7% in noncirrhotic patients, and 91.9, 86.1, and 82.4% in cirrhotic patients, respectively (P = 0.683). Risk factors for tumor recurrence in each group varied in multivariate analyses. Increased age, high platelet counts, microvascular invasion, serosal invasion, and intrahepatic metastasis predisposed to tumor recurrence in noncirrhotic patients, but elevated PIVKA-II and alkaline phosphatase levels, low serum albumin levels, portal vein invasion, intrahepatic metastasis, and tumor size were predisposing factors for recurrence in cirrhotic patients. CONCLUSIONS The clinicopathologic characteristics and risk factors for tumor recurrence in cirrhotic and noncirrhotic HCC patients with HBV infection differ.
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Affiliation(s)
- Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Ertle JM, Heider D, Wichert M, Keller B, Kueper R, Hilgard P, Gerken G, Schlaak JF. A combination of α-fetoprotein and des-γ-carboxy prothrombin is superior in detection of hepatocellular carcinoma. Digestion 2013; 87:121-31. [PMID: 23406785 DOI: 10.1159/000346080] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 11/20/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM The incidence of hepatocellular carcinoma (HCC) is increasing in western countries. Despite its low sensitivity, the diagnosis of HCC still depends on detection of α-fetoprotein (AFP). Therefore, the aim of this study was to evaluate the combined analysis of AFP and des-γ-carboxy prothrombin (DCP) in a European cohort. METHODS We performed a single-center study (164 HCC/422 controls), in which the serum concentrations of AFP and DCP were determined. RESULTS AFP and DCP were elevated in HCC patients compared to controls (p < 0.0001). By combination of AFP and DCP, the sensitivity was improved from 28.7% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 54.9%) to 78.0% using cutoffs of 10 ng/ml for AFP and 5 ng/ml for DCP (DCP alone, cutoff 5 ng/ml: 63.4%). Among early-stage patients, the sensitivity increased from 20% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 38%) to 55% in combination (DCP alone, cutoff 5 ng/ml: 47%). The area under the curve (AUC) for AFP and DCP was similar (AFP: 0.88; DCP: 0.87; combined: 0.91). Among non-cirrhotic patients, DCP (AUC: 0.93) showed a better performance than AFP (AUC: 0.84). Especially patients with non-alcoholic steatohepatitis had a high percentage of DCP-positive tumors. CONCLUSION The data suggest that AFP alone is not sufficient for the serological diagnosis of HCC in European patients, while a combination of AFP and DCP can increase the sensitivity even in early-stage patients.
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Affiliation(s)
- Judith M Ertle
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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Hepatocellular carcinoma in chronic hepatitis C in the absence of advanced fibrosis or cirrhosis. AJR Am J Roentgenol 2013; 200:W610-6. [PMID: 23701091 DOI: 10.2214/ajr.12.9151] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The objective of our study was to describe the cross-sectional imaging appearance of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection in the absence of advanced fibrosis and cirrhosis. MATERIALS AND METHODS This study is a retrospective review of our surgical database to identify patients with chronic HCV infection and HCC who underwent hepatectomy and who had undergone preoperative CT or MRI. Only patients with a Metavir fibrosis score of F0, F1, or F2 on pathology were included. Patients with hepatitis B virus coinfection or other causes of chronic liver disease and patients with histopathologic evidence of advanced fibrosis or cirrhosis (Metavir scores F3 and F4) were excluded. Contrast-enhanced CT or MRI examinations performed within 2 months before surgery were reviewed for the number, size, and location of tumors; tumor enhancement characteristics; and presence of macrovascular invasion. RESULTS Two hundred forty-five resections of HCC in patients with HCV were performed in our institution from 1987 to 2012. Of this group, 26 patients (10.6%) had a Metavir fibrosis score of F0, F1, or F2; of those patients, 19 (18 men and one woman; 18 non-Asian patients and one Asian patient; mean age, 64 years) had imaging studies available for review. Twenty-one HCCs (mean size, 4.5 cm; range, 0.9-14.8 cm) were evaluated at imaging. Typical wash-in and washout characteristics were seen in 16 of 19 viable lesions (84.2%). The remaining two HCCs were completely necrotic after transarterial chemoembolization. Eighteen patients had a solitary tumor. Most tumors (15/21, 71.4%) developed in the right hepatic lobe. CONCLUSION HCC can develop in patients with chronic HCV without advanced fibrosis or cirrhosis, most frequently in older non-Asian men, and usually appears as a large solitary tumor with a typical wash-in-washout enhancement pattern.
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Moy KA, Jiao L, Freedman ND, Weinstein SJ, Sinha R, Virtamo J, Albanes D, Stolzenberg-Solomon RZ. Soluble receptor for advanced glycation end products and risk of liver cancer. Hepatology 2013; 57:2338-45. [PMID: 23325627 PMCID: PMC3644530 DOI: 10.1002/hep.26264] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 12/27/2012] [Indexed: 12/14/2022]
Abstract
UNLABELLED Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by the AGE/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample between 1985 and 1988. During follow-up beginning 5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentrations of sRAGE, CML-AGE, glucose, and insulin were measured in case subjects and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available in most cases and in a subset of the study population. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) adjusted for age, years of smoking, and body mass index. sRAGE and CML-AGE concentrations were inversely associated with liver cancer. Further adjustment for glucose and insulin or exclusion of case subjects with chronic HBV or HCV did not change the associations. CONCLUSION Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and nonsmokers. (HEPATOLOGY 2013 ).
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Affiliation(s)
- Kristin A Moy
- Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Kim H, Kim K, Yu SJ, Jang ES, Yu J, Cho G, Yoon JH, Kim Y. Development of biomarkers for screening hepatocellular carcinoma using global data mining and multiple reaction monitoring. PLoS One 2013; 8:e63468. [PMID: 23717429 PMCID: PMC3661589 DOI: 10.1371/journal.pone.0063468] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 04/02/2013] [Indexed: 01/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases.
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Affiliation(s)
- Hyunsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyunggon Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Sun Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jiyoung Yu
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Geunhee Cho
- Departments of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail: (JHY); (YK)
| | - Youngsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail: (JHY); (YK)
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Witjes CDM, ten Kate FJW, Verhoef C, de Man RA, IJzermans JNM. Immunohistochemical characteristics of hepatocellular carcinoma in non-cirrhotic livers. J Clin Pathol 2013; 66:687-91. [PMID: 23585667 DOI: 10.1136/jclinpath-2012-201156] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers. In the absence of risk factors, for example, cirrhosis or hepatitis B or C virus infection, HCC diagnosis might be difficult. We aimed to explore the value of immunohistochemical characteristics to diagnostics and prognosis, and whether these immunohistochemical characteristics differ from those of HCC in a cirrhotic liver, possibly indicating an aberrant pathogenetic pathway. Paraffin-embedded, formalin-fixed tissue slides from liver resection specimens of the patients with HCC in a non-cirrhotic liver were analysed. From January 2000 through April 2011, 799 patients with HCC were admitted to our hospital; in total, 47 patients with 50 HCCs in a non-cirrhotic liver were operated. These tumours were stained positive for α-fetoprotein (AFP) in 30%, CD34 in 88%, cytokeratine 7 (CK7) in 44%, CK19 in 12%, glypican-3 (GPC-3) in 40%, glutamine synthetase in 62% and β-catenin in 32%. There was similarity in immunohistochemical expression of several markers comparing HCC in a non-cirrhotic liver with HCC in a cirrhotic liver. Moderate or poorly differentiated HCC more often expressed β-catenin and GPC-3 and showed a higher percentage of MIB-1-positive hepatocytes. A positive AFP immunohistochemical staining was significantly related with a high preoperative AFP serum level (p=0.001). None of the immunohistochemical stainings were associated with a worse overall survival. Of the patients treated with a surgical resection, 17 had recurrence of HCC and these patients more often had a positive CK19 staining (p=0.048). In conclusion, immunohistochemical expression of several markers in HCC in a non-cirrhotic and cirrhotic liver was comparable. Immunohistochemical markers have limited additional value to characterise HCC in non-cirrhoitc livers.
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Affiliation(s)
- Caroline D M Witjes
- Department of Hepatobiliary and Transplantation Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands.
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Witjes CDM, Polak WG, Verhoef C, Eskens FALM, Dwarkasing RS, Verheij J, de Man RA, Ijzermans JNM. Increased alpha-fetoprotein serum level is predictive for survival and recurrence of hepatocellular carcinoma in non-cirrhotic livers. Dig Surg 2013; 29:522-8. [PMID: 23548745 DOI: 10.1159/000348669] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 01/27/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) may be diagnosed in the absence of cirrhosis. However, little is known about prognostic factors for the survival of HCC patients with a non-cirrhotic liver in the absence of well-established risk factors. METHOD Survival rates and risk factors for survival and recurrence were analysed in all patients diagnosed between 2000 and 2010 with HCC in a non-cirrhotic liver and in the absence of well-established risk factors. RESULTS Ninety-four patients were analysed. Treatment with curative intent consisted of surgical resection in 43 patients (46%) and radiofrequency ablation in 4 patients (4%). In patients treated with curative intent and alive 30 days after treatment (n = 40), 1- and 5-year overall survival rates were 95 and 51%, respectively. Patients with a high preoperative α-fetoprotein (AFP) serum level, the presence of microvascular invasion in the resected specimen, a complicated postoperative course and a major resection, due to a greater tumour volume, had a significantly worse outcome and a higher recurrence rate. In multivariate analysis, a high AFP serum level at presentation was significantly associated with recurrence and a worse survival. CONCLUSION HCC presenting in a non-cirrhotic liver in the absence of well-established risk factors has a poor prognosis. Increased AFP serum levels are significantly associated with clinical outcome.
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Affiliation(s)
- Caroline D M Witjes
- Division of Hepatobiliary and Transplantation Surgery, Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands.
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Uehara T, Ainslie GR, Kutanzi K, Pogribny IP, Muskhelishvili L, Izawa T, Yamate J, Kosyk O, Shymonyak S, Bradford BU, Boorman GA, Bataller R, Rusyn I. Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis. Toxicol Sci 2013; 132:53-63. [PMID: 23288052 DOI: 10.1093/toxsci/kfs342] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood. This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells. First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age). Second, carbon tetrachloride (CCl(4); 0.2ml/kg, 2/week ip starting at 8 weeks of age) was administered for 9 or 14 weeks to develop advanced liver fibrosis. In animals treated with DEN as neonates, presence of liver fibrosis led to more than doubling (to 100%) of the liver tumor incidence as early as 5 months of age. This effect was associated with activation of cells with progenitor features in noncancerous liver tissue, including markers of replicative senescence (p16), oncofetal transformation (Afp, H19, and Bex1), and increased "stemness" (Prom1 and Epcam). In contrast, the dose of DEN used did not modify the extent of liver inflammation, fibrogenesis, oxidative stress, proliferation, or apoptosis induced by subchronic CCl(4) administration. This study demonstrates the potential role of liver stem-like cells in the mechanisms of chemical-induced, fibrosis-promoted HCC. We posit that the combination of genotoxic and fibrogenic insults is a sensible approach to model liver carcinogenesis in experimental animals. These results may contribute to identification of cirrhotic patients predisposed to HCC by analyzing the expression of hepatic progenitor cell markers in the noncancerous liver tissue.
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Affiliation(s)
- Takeki Uehara
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC, USA
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