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Chaudhary N, Kiranmayee B. Non-receptor Type PTPases and their Role in Controlling Pathways Related to Diabetes and Liver Cancer Signalling. Curr Pharm Biotechnol 2025; 26:654-664. [PMID: 38424416 DOI: 10.2174/0113892010288624240213072415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/22/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
The role of non-receptor type Protein Tyrosine Phosphatase (PTPases) in controlling pathways related to diabetes and Hepatocellular Carcinoma (HCC) is significant. The insulin signal transduction pathway is regulated by the steady-state phosphorylation of tyrosyl residues of the insulin receptor and post-receptor substrates. PTPase has been shown to have a physiological role in the regulation of reversible tyrosine phosphorylation. There are several non-receptor type PTPases. PTPase containing the SH-2 domain (SHP-2) and the non-receptor type PTPase (PTP1B; encoded by the PTPN1 gene) are involved in negative regulation of the insulin signaling pathway, thereby indicating that the pathway can be made more efficient by the reduction in the activity of specific PTPases. Reduction in insulin resistance may be achieved by drugs targeting these specific enzymes. The modifications in the receptor and post-receptor events of insulin signal transduction give rise to insulin resistance, and a link between insulin-resistant states and HCC has been established. The cancer cells thrive on higher levels of energy and their growth gets encouraged since insulin-resistant states lead to greater glucose levels. Cancer, hyperglycemia, and hypoglycemia are highly linked through various pathways hence, clarifying the molecular mechanisms through which non-receptor type PTPase regulates the insulin signal transduction is necessary to find an effective target for cancer. Targeting the pathways related to PTPases; both receptor and non-receptor types, may lead to an effective candidate to fight against diabetes and HCC.
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Affiliation(s)
- Nidhee Chaudhary
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
| | - Bellam Kiranmayee
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
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Zeng RW, Ong CEY, Ong EYH, Chung CH, Lim WH, Xiao J, Danpanichkul P, Law JH, Syn N, Chee D, Kow AWC, Lee SW, Takahashi H, Kawaguchi T, Tamaki N, Dan YY, Nakajima A, Wijarnpreecha K, Muthiah MD, Noureddin M, Loomba R, Ioannou GN, Tan DJH, Ng CH, Huang DQ. Global Prevalence, Clinical Characteristics, Surveillance, Treatment Allocation, and Outcomes of Alcohol-Associated Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2024; 22:2394-2402.e15. [PMID: 38987014 DOI: 10.1016/j.cgh.2024.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/25/2024] [Accepted: 06/02/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes. CONCLUSIONS Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.
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Affiliation(s)
| | - Christen En Ya Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Elden Yen Hng Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Charlotte Hui Chung
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Jia Hao Law
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Alfred Wei Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore; Division of Surgical Oncology, National University Cancer Institute, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | | | - Takumi Kawaguchi
- Department of Digestive Disease Information & Research, School of Medicine, Kurume University, Fukuoka, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Atsushi Nakajima
- Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Banner University Medical Center, Phoenix, Arizona
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | | | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Digestive Disease Information & Research, School of Medicine, Kurume University, Fukuoka, Japan
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore.
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3
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Berardi G, Cucchetti A, Sposito C, Ratti F, Nebbia M, D’Souza DM, Pascual F, Dogeas E, Tohme S, Vitale A, D’Amico FE, Alessandris R, Panetta V, Simonelli I, Colasanti M, Russolillo N, Moro A, Fiorentini G, Serenari M, Rotellar F, Zimitti G, Famularo S, Ivanics T, Donando FG, Hoffman D, Onkendi E, Essaji Y, Giuliani T, Lopez Ben S, Caula C, Rompianesi G, Chopra A, Abu Hilal M, Sapisochin G, Torzilli G, Corvera C, Alseidi A, Helton S, Troisi RI, Simo K, Conrad C, Cescon M, Cleary S, Kwon DCH, Ferrero A, Ettorre GM, Cillo U, Geller D, Cherqui D, Serrano PE, Ferrone C, Aldrighetti L, Kingham TP, Mazzaferro V. Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome. JHEP Rep 2024; 6:101075. [PMID: 38961853 PMCID: PMC11220535 DOI: 10.1016/j.jhepr.2024.101075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND & AIMS Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. METHODS Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. RESULTS In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). CONCLUSIONS Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. IMPACT AND IMPLICATIONS Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.
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Affiliation(s)
- Giammauro Berardi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, San Camillo Forlanini Hospital, Rome, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences-DIME, Alma Mater Studiorum, University of Bologna, Italy
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, Forlì, Italy
| | - Carlo Sposito
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Surgery, HPB Surgery and Liver Transplantation, Istituto Nazionale Tumori IRCCS, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, San Raffaele Hospital Department of Surgery, Milan, Italy
| | - Martina Nebbia
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | | | - Franco Pascual
- Department of Surgery, Paul Brousse Hospital, Villejuif, Paris, France
| | - Epameinondas Dogeas
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Samer Tohme
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Alessandro Vitale
- Department of Surgical Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Padua, Italy
| | - Francesco Enrico D’Amico
- Department of Surgical Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Padua, Italy
| | - Remo Alessandris
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgical Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Padua, Italy
| | - Valentina Panetta
- Laltrastatistica Consultancy and Training, Biostatistics Department, Rome, Italy
| | - Ilaria Simonelli
- Laltrastatistica Consultancy and Training, Biostatistics Department, Rome, Italy
| | - Marco Colasanti
- Department of Surgery, San Camillo Forlanini Hospital, Rome, Italy
| | | | - Amika Moro
- Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
| | | | - Matteo Serenari
- Hepato-biliary and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | - Giuseppe Zimitti
- Department of Surgery, Poliambulanza Foundation Hospital, Brescia, Italy
| | - Simone Famularo
- Department of General Surgery, Humanitas University and Research Hospital, IRCCS, Milan, Italy
| | - Tommy Ivanics
- Department of Surgery, University of Toronto, Toronto, ON, Canada
| | | | - Daniel Hoffman
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Edwin Onkendi
- Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Yasmin Essaji
- Department of Surgery, Virginia Mason Hospital, Seattle, WA, USA
- Department of Surgery, Seattle Medical Center, Seattle, WA, USA
| | - Tommaso Giuliani
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Santiago Lopez Ben
- Department of Surgery, Hospital Universitari Dr Josep Trueta de Girona, Girona, Spain
| | - Celia Caula
- Department of Surgery, Hospital Universitari Dr Josep Trueta de Girona, Girona, Spain
| | - Gianluca Rompianesi
- Department of Clinical Medicine and Surgery, Università Federico Secondo, Naples, Italy
| | | | - Mohammed Abu Hilal
- Department of Surgery, Poliambulanza Foundation Hospital, Brescia, Italy
| | | | - Guido Torzilli
- Department of General Surgery, Humanitas University and Research Hospital, IRCCS, Milan, Italy
| | - Carlos Corvera
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Adnan Alseidi
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Scott Helton
- Department of Surgery, Virginia Mason Hospital, Seattle, WA, USA
| | - Roberto I. Troisi
- Department of Clinical Medicine and Surgery, Università Federico Secondo, Naples, Italy
| | - Kerri Simo
- Department of Surgery, Hospital, Toledo, OH, USA
| | - Claudius Conrad
- Department of Surgery, Saint Elizabeth Medical Center, Boston, MA, USA
| | - Matteo Cescon
- Hepato-biliary and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Sean Cleary
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Umberto Cillo
- Department of Surgical Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Padua, Italy
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Daniel Cherqui
- Department of Surgery, Paul Brousse Hospital, Villejuif, Paris, France
| | - Pablo E. Serrano
- Department of Surgery, McMaster University, Hamilton, ONT, Canada
| | - Cristina Ferrone
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, San Raffaele Hospital Department of Surgery, Milan, Italy
| | - T. Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vincenzo Mazzaferro
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Surgery, HPB Surgery and Liver Transplantation, Istituto Nazionale Tumori IRCCS, Milan, Italy
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Chang B, Tian H, Huang A, Zhai X, Wang Q, Han L, Jin X, Gao L, Liang Q, Li B, Lu Y, Xie H, Ji D, Zou Z. Prevalence and prediction of hepatocellular carcinoma in alcohol-associated liver disease: a retrospective study of 136 571 patients with chronic liver diseases. EGASTROENTEROLOGY 2024; 2:e100036. [PMID: 39944749 PMCID: PMC11731072 DOI: 10.1136/egastro-2023-100036] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 11/15/2023] [Indexed: 03/27/2025]
Abstract
Background and aims To explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated liver disease (ALD)-related HCC risk. Methods A database of 136 571 inpatients in the Fifth Medical Center of Chinese PLA General Hospital from 2002 to 2018 with chronic liver disease was established. Data were collected by medical records review. Multivariate logistic regression was used to identify the independent high-risk factors associated with HCC, and then were incorporated into a novel nomogram. Afterward, the new established model was validated using external cohort by receiver operating characteristic curves analysis. For external cohort, 1646 patients with ALD admitted to our hospital from 2019 to 2021 were included. ALD was diagnosed on the basis of a history of sustained heavy alcohol intake greater than 40 g/day for men and 20 g/day for women for >5 years, clinical evidence of liver disease and supporting laboratory abnormalities. Results Over the last 17 years, trends showed obviously increases in ALD. ALD-related HCC experienced a significant increase from 5.8% to 30.7%, whereas hepatitis B virus (HBV)-related HCC declined from 77.6% to 52.0%. In patients with ALD-related HCC (5119), 3816 (74.54%) cases had HBV infection, 493 (9.63%) cases had hepatitis C virus (HCV) infection, 71 (1.39%) cases were coinfected with both HBV and HCV, and 739 (14.44%) cases had neither HBV nor HCV infection. Drinking years (OR 1.009, 95% CI (1.000 to 1.017)), age (OR 1.060, 95% CI (1.051 to 1.069)), diabetes mellitus (OR 1.314, 95% CI (1.123 to 1.538)), HBV infection (OR 4.905, 95% CI (4.242 to 5.671)), liver cirrhosis (OR 4.922, 95% CI (3.887 to 6.232)) and male sex (OR 17.011, 95%CI (2.296 to 126.013)) were associated with increased risk of HCC in patients with ALD. A nomogram had a concordance index of 0.786 (95% CI 0.773 to 0.799) and had well-fitted calibration curves. These results were successfully validated both in the internal cohort and external cohort. Conclusion The prevalence of ALD and ALD-related HCC has been increased dramatically. The nomogram model established here with its high accuracy and easy-to-use features achieved an optimal prediction of HCC development in patients with ALD, which can help clinicians to develop an individualised and precise treatment strategy.
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Affiliation(s)
- Binxia Chang
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hui Tian
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ang Huang
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xingran Zhai
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Qiaoling Wang
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Lin Han
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xueyuan Jin
- Quality Control Department, The Fifth Medical Center of Chinese PLA General Hospital, Fengtai-qu, China
| | - Li Gao
- Second Internal Department, Huanghua Boai Hospital, Cangzhou, China
| | - Qingsheng Liang
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Baosen Li
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yinying Lu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Huan Xie
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Dong Ji
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Chen T, Zhang Y, Liu J, Rao Z, Wang M, Shen H, Zeng S. Trends in liver cancer mortality in China from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open 2023; 13:e074348. [PMID: 38159955 PMCID: PMC10759138 DOI: 10.1136/bmjopen-2023-074348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 11/08/2023] [Indexed: 01/03/2024] Open
Abstract
OBJECTIVE We aimed to examine trends in overall mortality rates for liver cancer and those within subgroups according to sex, age, aetiological factors and modifiable risk factors in China from 1990 to 2019. DESIGN The design of this study involved analysing liver cancer mortality rates in China from 1990 to 2019 using joinpoint regression analysis to identify significant changes in mortality rates. Annual percentage changes (APCs) and 95% CIs were used to quantify the magnitude of changes in mortality rates. The study also conducted subgroup analyses based on sex, age, aetiological factors and risk factors to better understand trends in liver cancer mortality rates. RESULTS The age-standardised mortality from liver cancer in China first increased from 28.12 to 31.54 deaths per 100 000 population in 1990-1996 (APC=2.1%, 95% CI: 1.5% to 2.6%), then dropped at varying rates (1996-2000, APC=-3.7%, 95% CI: -5.2% to -2.1%; 2000-2004, APC=-17.4%, 95% CI: -18.7% to -16.1%; 2004-2007, APC=-5.4%, 95% CI: -8.3% to -2.3%; and 2007-2012, APC=-1.4%, 95% CI: -2.3% to -0.4%), and began to increase again after 2012 (APC=1.3%, 95% CI: 0.9% to 1.7%). Hepatitis B and C virus infections accounted for 63% and 18% of liver cancer-related deaths, respectively, in China from 1990 to 2019. Smoking, drug use, alcohol use and elevated body mass index were the four leading risk factors for liver cancer mortality in China during the study period. Notable variations in both liver cancer mortality rates and changes in mortality rates were observed across sexes and age groups. CONCLUSIONS The age-standardised liver cancer mortality rate in China significantly decreased from 1996 to 2019. The major differences in liver cancer mortality rates and inconsistent changes in mortality rates between 1990 and 2019 merit the attention of researchers and policymakers.
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Affiliation(s)
- Taili Chen
- Department of Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Yan Zhang
- Department of Oncology, Yueyang People's Hospital, Yueyang, Hunan, China
| | - Jiayi Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | | | - Mian Wang
- Department of Epidemiology and Health Statistics, University of South China, Hengyang, Hunan, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, China
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Ventura I, Sanchiz L, Legidos-García ME, Murillo-Llorente MT, Pérez-Bermejo M. Atezolizumab and Bevacizumab Combination Therapy in the Treatment of Advanced Hepatocellular Cancer. Cancers (Basel) 2023; 16:197. [PMID: 38201624 PMCID: PMC10777975 DOI: 10.3390/cancers16010197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
Liver cancer, particularly hepatocellular carcinoma, is a global concern. This study focuses on the evaluation of Atezolizumab and Bevacizumab combination therapy as a promising alternative in the treatment of advanced hepatocellular carcinoma. The objectives of this systematic review include evaluating the efficacy of Atezolizumab and Bevacizumab combination therapy compared to conventional therapies with Sorafenib and other conventional therapies, analyzing the associated adverse effects, and exploring prognostic factors in the setting of advanced hepatocellular carcinoma. A systematic literature review was carried out using the PubMed and Web of Science databases. Fifteen related articles were included and evaluated according to their level of evidence and recommendation. Results: The combination therapy of Atezolizumab and Bevacizumab, along with Sorafenib, showed positive results in the treatment of patients with advanced hepatocellular carcinoma. Significant adverse effects were identified, such as gastrointestinal bleeding, arterial hypertension, and proteinuria, which require careful attention. In addition, prognostic factors, such as transforming growth factor beta (TGF-β), alpha-fetoprotein (AFP), and vascular invasion, were highlighted as key indicators of hepatocellular carcinoma progression. Conclusions: The combination of Atezolizumab and Bevacizumab is shown to be effective in the treatment of advanced hepatocellular carcinoma, although it is essential to take into consideration the associated adverse effects. The prognostic factors identified may provide valuable information for the clinical management of this disease. This study provides a comprehensive overview of a promising emerging therapy for liver cancer.
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Affiliation(s)
- Ignacio Ventura
- Molecular and Mitochondrial Medicine Research Group, School of Medicine and Health Sciences, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain;
- Translational Research Center San Alberto Magno CITSAM, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain
| | - Lorena Sanchiz
- School of Medicine and Health Sciences, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain;
| | - María Ester Legidos-García
- SONEV Research Group, Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain; (M.E.L.-G.); (M.T.M.-L.)
| | - María Teresa Murillo-Llorente
- SONEV Research Group, Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain; (M.E.L.-G.); (M.T.M.-L.)
| | - Marcelino Pérez-Bermejo
- SONEV Research Group, Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente Mártir, C/Quevedo nº 2, 46001 Valencia, Spain; (M.E.L.-G.); (M.T.M.-L.)
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Xiong KG, Ke KY, Chen LF, Kong JF, Lin TS, Lin QB, Lin S, Zhu YY. The impact of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with hepatocellular carcinoma after radical resection. Hepatobiliary Pancreat Dis Int 2023; 22:366-372. [PMID: 35466065 DOI: 10.1016/j.hbpd.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 03/22/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is recently proposed an entity by a group of international experts. However, the impact of MAFLD on the prognosis of patients with hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the influence of MAFLD for the prognosis of HCC after radical resection. METHODS HCC patients who received radical resection were enrolled. The recurrence-free survival (RFS) and overall survival (OS) were compared between MAFLD and non-MAFLD. RESULTS A total of 576 HCC patients were included, and among them 114 (19.8%) met the diagnostic criteria of MAFLD. The median RFS was 34.0 months in the MAFLD group and 19.0 months in the non-MAFLD group. The 1-, 3-, and 5-year RFS rates were 64.9%, 49.1% and 36.1% in the MAFLD group, which were higher than those of the non-MAFLD group (59.4%, 35.3% and 26.5%, respectively, P = 0.01). The mean OS was 57.0 months in the MAFLD group and 52.2 months in the non-MAFLD group. There was no statistical difference in OS rate between the MAFLD group and non-MAFLD group. Similar results were found in HBV-related HCC patients in the subgroup analysis. Univariate analysis revealed that MAFLD was a protective factor for RFS in HCC patients after radical resection (P < 0.05), and there was no association between MAFLD and OS rate (P > 0.05). Multivariate analysis demonstrated that MAFLD was not an independent protective factor for HCC patients with radical resection. CONCLUSIONS MAFLD improves RFS rate in HCC patients with radical resection, but is not an independent protective factor and not associated with OS rate.
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Affiliation(s)
- Ke-Gong Xiong
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Kun-Yu Ke
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Li-Fang Chen
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Jin-Feng Kong
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Tai-Shun Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Qing-Biao Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Su Lin
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Yue-Yong Zhu
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China; Fujian Clinical Research Center for Liver and Intestinal Diseases, Fuzhou 350001, China.
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8
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Komaniecki G, Camarena MDC, Gelsleichter E, Mendoza R, Subler M, Windle JJ, Dozmorov MG, Lai Z, Sarkar D, Lin H. Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity. Biochemistry 2023; 62:543-553. [PMID: 36548985 PMCID: PMC9850907 DOI: 10.1021/acs.biochem.2c00583] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/01/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments lipid accumulation (steatosis), inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for nonalcoholic steatohepatitis (NASH) and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue cysteine 75 (Cys75). Mutation of Cys75 to serine (Ser) completely abolished AEG-1 palmitoylation. We identified ZDHHC6 as a palmitoyltransferase catalyzing the process in HEK293T cells. To obtain insight into how palmitoylation regulates AEG-1 function, we generated knock-in mice by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation, angiogenesis, and lipid accumulation, were activated in AEG-1-C75S hepatocytes compared to AEG-1-WT. These findings suggest that AEG-1-C75S functions as dominant positive and that palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. We thus identify a previously unknown regulatory mechanism of AEG-1, which might help design new therapeutic strategies for NASH and HCC.
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Affiliation(s)
- Garrison Komaniecki
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
- C.
Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Maria Del Carmen Camarena
- C.
Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Eric Gelsleichter
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
| | - Rachel Mendoza
- Department
of Human and Molecular Genetics, Virginia
Commonwealth University, Richmond, Virginia 23298, United States
| | - Mark Subler
- Department
of Human and Molecular Genetics, Virginia
Commonwealth University, Richmond, Virginia 23298, United States
| | - Jolene J. Windle
- Department
of Human and Molecular Genetics, Virginia
Commonwealth University, Richmond, Virginia 23298, United States
- Massey
Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, United States
- VCU
Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Mikhail G. Dozmorov
- Department
of Biostatistics, Virginia Commonwealth
University, Richmond, Virginia 23298, United States
- Department
of Pathology, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Zhao Lai
- Greehy
Children’s Cancer Research Institute, University of Texas Health
Science Center San Antonio, San Antonio, Texas 78229, United States
| | - Devanand Sarkar
- Department
of Human and Molecular Genetics, Virginia
Commonwealth University, Richmond, Virginia 23298, United States
- Massey
Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, United States
- VCU
Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Hening Lin
- Department
of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
- Howard
Hughes Medical Institute, Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States
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9
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Teng PC, Huang DQ, Lin TY, Noureddin M, Yang JD. Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease. Gut Liver 2023; 17:24-33. [PMID: 36530125 PMCID: PMC9840929 DOI: 10.5009/gnl220357] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/09/2022] [Accepted: 09/19/2022] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.
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Affiliation(s)
- Pai-Chi Teng
- Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, Taiwan,Department of Urology, National Taiwan University Hospital, Taipei, Taiwan,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Daniel Q. Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore,Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Ting-Yi Lin
- Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ju Dong Yang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Corresponding AuthorJu Dong Yang, ORCIDhttps://orcid.org/0000-0001-7834-9825, E-mail
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10
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Capuno J, Kraft A, Calicdan KG, O’Donnell O. Associations between health-related quality of life and measures of adiposity among Filipino adults. PLoS One 2022; 17:e0275798. [PMID: 36288388 PMCID: PMC9605333 DOI: 10.1371/journal.pone.0275798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/23/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Estimate associations between the health-related quality of life (HRQoL) and adiposity in a low-income population. METHODS In a cluster random sample of 3796 Filipinos aged 40-70 years in Nueva Ecija province, we measured body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and six dimensions of HRQoL using the 20-item Short Form Health Survey. We stratified by sex and used nonparametric regression to graph mean HRQoL in each dimension by BMI, WC, and WHR. We used ordinary least squares regression to estimate differences in each HRQoL dimension by categories of BMI, WC, and WHR adjusted for sociodemographic characteristics and smoking. RESULTS Mean HRQoL was lowest for health perception (Males: 67.5 (SD = 15.9); Females: 66.7 (15.8)) and highest for role functioning (Males: 97.5 (12.9); Females: 97.4 (13.3)). Mean (SD) values of BMI, WC, and WHR were 22.1 (3.6), 84.8 cm (9.5), and 0.9 (0.1), respectively for males, and 23.7 (4.2), 86.5 cm (10.2), and 0.9 (0.1), respectively, for females. There was no evidence that higher BMI was associated with lower HRQoL. Adjusted mean social functioning was 4.92 (p = 0.076) higher for males with high BMI risk (8.6% prevalence) compared with acceptable BMI risk (50.3%). Mean social functioning was 3.61 (p = 0.012) and 5.48 (p = 0.017) lower for females with high WC (44.7%) and WHR (83.1%), respectively, compared with those with low WC (23.8%) and WHR (3.6%). Mean physical functioning was lower by 2.70 (p = 0.204) and 1.07 (p = 0.198) for males and females, respectively, with high compared with low WC. Mean physical functioning was 3.93 (p = 0.037) lower for males with high (7.6%) compared with low (38.8%) WHR. Mean role functioning was 1.09 (p = 0.124) and 2.46 (p = 0.158) lower for males with borderline and high WHR, respectively. CONCLUSIONS There is discordance between future adiposity-related health risk and current experience of HRQoL.
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Affiliation(s)
- Joseph Capuno
- School of Economics, University of the Philippines, Diliman, Quezon City, Philippines
| | - Aleli Kraft
- School of Economics, University of the Philippines, Diliman, Quezon City, Philippines
| | - Kayleen Gene Calicdan
- School of Economics, University of the Philippines, Diliman, Quezon City, Philippines
| | - Owen O’Donnell
- Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, Netherlands
- Tinbergen Institute, Amsterdam, Netherlands
- University of Lausanne, Lausanne, Switzerland
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11
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Ding L, Ning S, Hu W, Xue Y, Yu S. Distinctive Metabolism-Associated Gene Clusters That Are Also Prognostic in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6595989. [PMID: 36199423 PMCID: PMC9527115 DOI: 10.1155/2022/6595989] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/22/2022] [Accepted: 08/29/2022] [Indexed: 11/29/2022]
Abstract
Objective To offer new prognostic evaluations by exploring potentially distinctive genetic features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods There were 12 samples for gene expression profiling processes in this study. These included three HCC lesion samples and their matched adjacent nontumor liver tissues obtained from patients with HCC, as well as three ICC samples and their controls collected similarly. In addition to the expression matrix generated on our own, profiles of other cohorts from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus (GEO) were also employed in later bioinformatical analyses. Differential analyses, functional analyses, protein interaction network analyses, and gene set variation analyses were used to identify key genes. To establish the prognostic models, univariate/multivariate Cox analyses and subsequent stepwise regression were applied, with the Akaike information criterion evaluating the goodness of fitness. Results The top three pathways enriched in HCC were all metabolism-related; they were fatty acid degradation, retinol metabolism, and arachidonic acid metabolism. In ICC, on the other hand, additional pathways related to fat digestion and absorption and cholesterol metabolism were identified. Consistent characteristics of such a metabolic landscape were observed across different cohorts. A prognostic risk score model for calculating HCC risk was constructed, consisting of ADH4, ADH6, CYP2C9, CYP4F2, and RDH16. This signature predicts the 3-year survival with an AUC area of 0.708 (95%CI = 0.644 to 0.772). For calculating the risk of ICC, a prognostic risk score model was built upon the expression levels of CYP26A1, NAT2, and UGT2B10. This signature predicts the 3-year survival with an AUC area of 0.806 (95% CI = 0.664 to 0.947). Conclusion HCC and ICC share commonly abrupted pathways associated with the metabolism of fatty acids, retinol, arachidonic acids, and drugs, indicating similarities in their pathogenesis as primary liver cancers. On the flip side, these two types of cancer possess distinctive promising biomarkers for predicting overall survival or potential targeted therapies.
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Affiliation(s)
- Linchao Ding
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shilong Ning
- Department of Clinical Nutrition, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Weijian Hu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Yadong Xue
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shi'an Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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12
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Shigematsu Y, Kanda H, Amori G, Takahashi Y, Takazawa Y, Inamura K. Nonalcoholic non-virus-related hepatocellular carcinoma arising from nonsteatotic liver: Clinical and pathological features. Medicine (Baltimore) 2022; 101:e28746. [PMID: 35119029 PMCID: PMC8812618 DOI: 10.1097/md.0000000000028746] [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: 04/26/2021] [Accepted: 01/07/2022] [Indexed: 01/04/2023] Open
Abstract
Nonalcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is considered to occur in steatotic livers; however, emerging evidence indicates that a subset of NANV-HCC occurs in nonsteatotic livers. Currently, little information is available regarding this subset. This study sought to provide the clinical and pathological features of NANV-HCC in nonsteatotic livers.We retrospectively investigated the clinicopathological features of 101 consecutive patients with NANV-HCC treated with a curative-intent hepatectomy. A background liver with <5% steatosis by area was regarded as a nonsteatotic liver. Survivals of patient subgroups were estimated using the Kaplan-Meier method, and log-rank tests were conducted to assess the survival difference. Multivariate analysis was performed with the Cox proportional hazards method.Overall, 34 of 101 patients with NANV-HCC were found to have a nonsteatotic liver. Vascular invasion of the tumor was more frequently observed in patients with a nonsteatotic liver than in those with a steatotic liver (P = .03). The extent of lobular inflammation and fibrosis did not differ between patients with and without steatosis in the liver. NANV-HCC with a nonsteatotic liver was independently associated with a shorter disease-free survival (DFS) (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.21-3.80; P = .009) and a shorter overall survival (OS) (HR 2.79; 95% CI 1.27-6.16; P = .01) than NANV-HCC with a steatotic liver.The absence of steatosis in the liver is independently associated with shorter DFS and OS in patients with NANV-HCC. Our findings indicate that nonsteatotic liver can be a surrogate phenotype of aggressive NANV-HCC.
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Affiliation(s)
- Yasuyuki Shigematsu
- Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, 780 Komuro, Ina, Kita-adachi-gun, Saitama, Japan
| | - Gulanbar Amori
- Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
| | - Yutaka Takazawa
- Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon Minato, Tokyo, Japan
| | - Kentaro Inamura
- Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, Japan
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13
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Luna-Cuadros MA, Chen HW, Hanif H, Ali MJ, Khan MM, Lau DTY. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol 2022; 28:96-107. [PMID: 35125821 PMCID: PMC8793019 DOI: 10.3748/wjg.v28.i1.96] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/12/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a significant cause of hepatocellular carcinoma (HCC). The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95% cure rate. Successful treatment of chronic hepatitis C greatly reduces the risk of HCC. A proportion of patients, especially those with pre-existing cirrhosis, remain at risk for HCC despite sustained virologic response (SVR). Diabetes mellitus, hepatic steatosis, alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure. Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis. More recently, various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR. These models still need to be validated and standardized prior to applying to routine clinical care.
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Affiliation(s)
- Maria Alejandra Luna-Cuadros
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Hao-Wei Chen
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Hira Hanif
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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14
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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15
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Association of weight change in young adulthood with subsequent risk of hepatocellular carcinoma: a national cohort study. Eur J Cancer Prev 2021; 30:211-219. [PMID: 32925510 DOI: 10.1097/cej.0000000000000610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Risk of hepatocellular carcinoma (HCC) in young adults might be clinically overlooked for future HCC risk. Thus, we examined the association between weight change and future risk of developing HCC in young adults. We collected a nationwide and population-based cohort data of more than 2.2 million men and women aged between 20 and 39 who were without previous cancer diagnosis and underwent two consecutive biennial national health screening between 2002 and 2005 from the National Health Insurance Service database. The individuals were categorized as weight loss (≥5.0 kg and 2.0-4.9 kg), stable weight (weight gain or loss <2.0 kg), and weight gain (2.0-4.9 kg and ≥5.0 kg) and were followed-up for incident HCC from 1 January 2006 to 31 December 2018. During 12 years of follow-up, there were 2694 HCCs in men and 306 HCCs in women. In the multivariable Cox proportional hazards model adjusted for socioeconomic, health behavior, medical characteristics, and family history, weight gain of more than 5.0 kg and between 2.0 and 4.9 kg were associated with significantly increased risk in young men [hazard ratio (HR) 1.16, 95% confidence intervals (95% CI) 1.01-1.32] and young women (HR 1.34, 95% CI 1.01-1.77), respectively. Protective association of weight loss with HCC was not observed. The association of weight gain and HCC risk was stronger in young adults with underlying liver diseases compared to those without any liver disease (Pheterogeneity < 0.001). Weight gain during young adulthood should not be clinically overlooked for future HCC risk, especially among those with underlying liver diseases.
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16
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Hepatocellular Carcinoma in India. Indian J Surg 2021. [DOI: 10.1007/s12262-021-02762-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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17
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Zhao Y, Bilal M, Raza A, Khan MI, Mehmood S, Hayat U, Hassan STS, Iqbal HMN. Tyrosine kinase inhibitors and their unique therapeutic potentialities to combat cancer. Int J Biol Macromol 2021; 168:22-37. [PMID: 33290765 DOI: 10.1016/j.ijbiomac.2020.12.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 02/05/2023]
Abstract
Cancer is one of the leading causes of death with a mortality rate of 12%. Although significant progress has been achieved in cancer research, the effective treatment of cancer remains the greatest global challenge in medicine. Dysregulation of tyrosine kinases (TK) is one of the characteristics of several types of cancers. Thus, drugs that target and inhibit these enzymes, known as TK inhibitors (TKIs), are considered vital chemotherapeutics to combat various types of cancer. The oral bioavailability of available TKIs and their targeted therapy are their potential benefits. Based on these characteristics, most TKIs are included in first/second-line therapy for the treatment of different cancers. This review aims to shed light on orally-active TKIs (natural and synthetic molecules) and their promising implication in the therapy of numerous types of tumors along with their mechanisms of action. Further, recent progress in the development of synthetic and isolation of natural TKIs is reviewed. A significant growth in research regarding the development of new-generation TKIs is made with time (23 FDA-approved TKIs from 2018) due to their better therapeutic response. Oral bioavailability should be considered as an important parameter while developing of new-generation TKIs; however, drug delivery systems can also be used to address issue of poor bioavailability to a certain extent. Moreover, clinical trials should be designed in consideration of the development of resistance and tumor heterogeneity.
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Affiliation(s)
- Yuping Zhao
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China.
| | - Muhammad Bilal
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China.
| | - Ali Raza
- School of Biomedical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Muhammad Imran Khan
- Hefei National Lab for Physical Sciences at the Microscale and the Centers for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Shahid Mehmood
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Uzma Hayat
- School of Biomedical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Sherif T S Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 6-Suchdol, 165 21 Prague, Czech Republic
| | - Hafiz M N Iqbal
- Tecnologico de Monterrey, School of Engineering and Sciences, Monterrey, 64849, Mexico.
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18
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Processes exacerbating apoptosis in non-alcoholic steatohepatitis. Clin Sci (Lond) 2020; 133:2245-2264. [PMID: 31742325 DOI: 10.1042/cs20190068] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, owing to its high prevalence, progressive nature and lack of effective medical therapies. NAFLD is a complex and multifactorial disease involving the progressive and concerted action of factors that contribute to the development of liver inflammation and eventually fibrosis. Here, we summarize fundamental molecular mechanisms underlying the pathogenesis of non-alcoholic steatohepatitis (NASH), how they are interrelated and possible translation to clinical applications. We focus on processes triggering and exacerbating apoptotic signalling in the liver of NAFLD patients and their metabolic and pathological implications. Indeed, liver injury and inflammation are cardinal histopathological features of NASH, a duo in which derailment of apoptosis is of paramount importance. In turn, the liver houses a very high number of mitochondria, crucial metabolic unifiers of both extrinsic and intrinsic signals that converge in apoptosis activation. The role of lifestyle options is also dissected, highlighting the management of modifiable risk factors, such as obesity and harmful alcohol consumption, influencing apoptosis signalling in the liver and ultimately NAFLD progression. Integrating NAFLD-associated pathologic mechanisms in the cell death context could provide clues for a more profound understating of the disease and pave the way for novel rational therapies.
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19
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Berkan-Kawińska A, Piekarska A. Hepatocellular carcinoma in non-alcohol fatty liver disease - changing trends and specific challenges. Curr Med Res Opin 2020; 36:235-243. [PMID: 31631714 DOI: 10.1080/03007995.2019.1683817] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background and Aims: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. The etiology of this disease is known in 90% of the patients, and it is viral in most of the cases. According to recent predictions, nearly half of the world population will be suffering from obesity by 2030. Consequently, non-alcoholic fatty liver disease (NAFLD) may play a growing role in HCC epidemiology. In this review, we sought to explore the relationship between liver steatosis and HCC.Methods: A narrative review was conducted using the PubMed MeSH search. The eligible papers were identified using a standard PubMed search with relevant key terms and various synonyms.Results: According to the results, patients with NAFLD-HCC tended to be older than those with hepatitis C virus (HCV)-HCC, and they were more often obese and had concomitant diseases, such as diabetes. On the other hand, the synthetic liver function was better preserved in NAFLD-HCC patients, who also obtained lower scores on the Model for End-stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP). However, it has to be noted that HCC in patients with non-alcoholic steatohepatitis (NASH) may develop without underlying cirrhosis. Although NASH-HCC is usually smaller and well-differentiated compared to HCV-HCC, the prognosis is similar in both groups. Efficient HCC screening in NASH cirrhosis poses a challenge because it is difficult to perform ultrasound examination in obese patients and alfa-fetoprotein level is no longer considered reliable.Conclusions: The constantly increasing prevalence of NAFLD in the general population can contribute to a growing role of NAFLD/NASH in HCC epidemiology. Moreover, some particular challenges specific for patients with liver steatosis may impede proper HCC diagnosis, treatment and follow-up.
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Affiliation(s)
| | - Anna Piekarska
- Infectious Diseases and Hepatology Department, Medical University of Lodz, Lodz, Poland
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20
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Lin YH, Wu MH, Huang YH, Yeh CT, Lin KH. TUG1 Is a Regulator of AFP and Serves as Prognostic Marker in Non-Hepatitis B Non-Hepatitis C Hepatocellular Carcinoma. Cells 2020; 9:cells9020262. [PMID: 31973032 PMCID: PMC7072672 DOI: 10.3390/cells9020262] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/17/2020] [Accepted: 01/19/2020] [Indexed: 02/07/2023] Open
Abstract
Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is associated with significantly elevated risk of hepatocellular carcinoma (HCC). Levels of the glycoprotein alpha-fetoprotein (AFP) are increased in the majority of patients with HCC and may be useful in diagnosis and follow-up. However, the relationship between T3/TR and AFP levels in HCC is currently unclear. The expression profiles of long non-coding RNAs (lncRNAs) were compared in microarrays of HepG2-TRα1 cells treated with/without T3 and HCC specimens. The effects of T3 on taurine upregulated gene 1 (TUG1) and AFP expression were validated using qRT-PCR. A correlation between TUG1 and AFP was confirmed via RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) strategies. Finally, overall and recurrence-free survival rates were analyzed using the Kaplan–Meier method and confirmed in online datasets. T3/TR treatment reduced TUG1 expression in vitro, resulting in the downregulation of AFP mRNA. Knockdown of TUG1 suppressed cell cycle progression and soft agar colony formation and induced cellular senescence. Our data support the involvement of TUG1 in the T3/TR-mediated suppression of cell growth. AFP mRNA levels showed strong positive correlations with TUG1 and unfavorable prognosis in patients with non-hepatitis B/non-hepatitis C HCC (NBNC-HCC). T3/TR, TUG1, and AFP may potentially serve as effective prognostic markers for NBNC-HCC.
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Affiliation(s)
- Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
| | - Meng-Han Wu
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Correspondence: (C.-T.Y.); (K.-H.L.); Tel./Fax: +886-3-2118263 (K.-H.L.)
| | - Kwang-Huei Lin
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (C.-T.Y.); (K.-H.L.); Tel./Fax: +886-3-2118263 (K.-H.L.)
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21
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Dhamija E, Paul SB, Kedia S. Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern. Indian J Med Res 2019; 149:9-17. [PMID: 31115369 PMCID: PMC6507546 DOI: 10.4103/ijmr.ijmr_1456_17] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.
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Affiliation(s)
- Ekta Dhamija
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Shashi Bala Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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22
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Gawrieh S, Dakhoul L, Miller E, Scanga A, deLemos A, Kettler C, Burney H, Liu H, Abu-Sbeih H, Chalasani N, Wattacheril J. Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study. Aliment Pharmacol Ther 2019; 50:809-821. [PMID: 31475372 DOI: 10.1111/apt.15464] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/30/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States. AIM To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres METHODS: Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non-cirrhotic patients, non-alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non-cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non-cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). CONCLUSIONS Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non-cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non-cirrhotic patients presented with more advanced HCC, their survival was better.
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Affiliation(s)
- Samer Gawrieh
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Lara Dakhoul
- Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Andrew Scanga
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - Carla Kettler
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Heather Burney
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Hao Liu
- Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Julia Wattacheril
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York
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23
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Farcas M, Gavrea AA, Gulei D, Ionescu C, Irimie A, Catana CS, Berindan-Neagoe I. SIRT1 in the Development and Treatment of Hepatocellular Carcinoma. Front Nutr 2019; 6:148. [PMID: 31608282 PMCID: PMC6773871 DOI: 10.3389/fnut.2019.00148] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide–dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.
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Affiliation(s)
- Marius Farcas
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andrei-Alexandru Gavrea
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Calin Ionescu
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,5th Surgical Department, Municipal Hospital, Cluj-Napoca, Romania
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.,Department of Surgery, The Oncology Institute "Prof. Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
| | - Cristina S Catana
- Department of Medical Biochemistry, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
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24
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Liu T, Wang W, Cui H, Sun M, Wang Y, Liu X, Cao L, Liu H, Liu S. Elevated fasting serum glucose levels increase the risk of hepatocellular carcinoma: A prospective cohort study. Medicine (Baltimore) 2019; 98:e16369. [PMID: 31348238 PMCID: PMC6709261 DOI: 10.1097/md.0000000000016369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Previous studies have demonstrated a positive relationship between liver cancer and diabetes mellitus. However, elevated fasting blood glucose (FBG) itself may be a risk factor for the development of hepatocellular carcinoma (HCC) rather than diabetes, and during the follow-up period, death is an event that may occur before the occurrence of HCC, which should be dealt with competing risk models. Our study aims to investigate the relationship between FBG and new-onset HCC by using competing risk regression models.We prospectively studied the relationship between FBG concentrations and risk of HCC in a cohort of 93,447 participants who were free of prior HCC, and whose demographic characteristics and biochemical parameters were recorded. Cox proportional hazards regression models and competing risk regression models were used to evaluate the association between FBG concentrations and risk of incident HCC.A total of 302 participants were diagnosed with HCC among 93,447 subjects during 810,499 person-years of follow-up. The multivariable hazard ratios (HRs) [95% confidence interval (95% CI)] for the association of FBG and log(FBG) with HCC were 1.07 (1.01∼1.12), 1.84 (1.23∼2.74) in an analysis adjusted for other potential variables. In the multivariable adjusted analysis, participants who were in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group would have increased the risk of HCC by 47% and 69%, respectively. In a cause-specific hazard model (CS model), the multivariable HRs (95% CI) for the association of FBG with HCC were 1.46 (1.09∼1.98), 1.69 (1.27∼2.27) in the multivariable adjusted analysis. Similar results were also observed in sub-distribution hazard function model (SD model) with corresponding multivariate HRs (95% CI) of 1.46 (1.09∼2.00), 1.69 (1.25∼2.27) in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group, respectively.Higher FBG concentrations itself were positively associated with new-onset HCC in the Cox proportional hazards regression models and competing risk models. FBG concentrations can be used as a scientific and important way to identify individuals with a higher risk of HCC and control of FBG concentrations might serve as a possible way to decrease the risk of HCC among Chinese population.Trial registration: ChiCTR-TNRC-11001489. Registered August 24, 2011 (retrospectively registered).
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Affiliation(s)
- Tong Liu
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Wanchao Wang
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Haozhe Cui
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
- Department of Graduate School, North China University of Science and Technology
| | - Miaomiao Sun
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
- Department of Graduate School, North China University of Science and Technology
| | - Yiming Wang
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Xining Liu
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Liying Cao
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Hai Liu
- Department of Anesthesiology, Kailuan General Hospital Affiliated to North China University of Science and Technology, Tangshan, Hebei, China
| | - Siqing Liu
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
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Marchio A, Dhifallah I, Bahri O, Pineau P. Circulating Aflatoxin B1-Related TP53 Mutation Detected by Digital PCR in Tunisian Patients with and Without Hepatocellular Carcinoma. HEPATITIS MONTHLY 2019; In Press. [DOI: 10.5812/hepatmon.85775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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26
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Liang S, Ma HY, Zhong Z, Dhar D, Liu X, Xu J, Koyama Y, Nishio T, Karin D, Karin G, Mccubbin R, Zhang C, Hu R, Yang G, Chen L, Ganguly S, Lan T, Karin M, Kisseleva T, Brenner DA. NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice. Gastroenterology 2019; 156:1156-1172.e6. [PMID: 30445007 PMCID: PMC6409207 DOI: 10.1053/j.gastro.2018.11.019] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 11/06/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen. METHODS Fourteen-day-old Nox1-/- mice, Nox4-/- mice, Nox1-/-Nox4-/- (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1ΔHep), hepatic stellate cells (Nox1ΔHep), or macrophages (Nox1ΔMac). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8-12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots. RESULTS Nox4-/- mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1-/- mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1ΔHep and Nox1ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1ΔMac developed fewer and smaller tumors, similar to Nox1-/- mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1-/- or Nox1ΔMac, mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle. CONCLUSIONS In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.
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Affiliation(s)
- Shuang Liang
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Hsiao-Yen Ma
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Zhenyu Zhong
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Debanjan Dhar
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Xiao Liu
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jun Xu
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yukinori Koyama
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Nishio
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daniel Karin
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Gabriel Karin
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Ryan Mccubbin
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cuili Zhang
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,School of Public Health, Shandong University, Jinan, 250012, China
| | - Ronglin Hu
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guizhi Yang
- Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Li Chen
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Souradipta Ganguly
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Tian Lan
- Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Michael Karin
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, School of Medicine, University of California San Diego, La Jolla, California.
| | - David A. Brenner
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.,Correspondence: To whom correspondence should be addressed. ;
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Lawson-Ananissoh LM, Bouglouga O, Bagny A, El-Hadji Yakoubou R, Kaaga L, Redah D. DIGESTIVE DISEASES IN ELDERLY AND FACTORS ASSOCIATED WITH LENGTH OF STAY IN THE HEPATOLOGY AND GASTROENTEROLOGY UNIT OF THE CAMPUS TEACHING HOSPITAL OF LOME (TOGO). ARQUIVOS DE GASTROENTEROLOGIA 2019; 55:369-374. [PMID: 30785520 DOI: 10.1590/s0004-2803.201800000-80] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/28/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND The digestive pathologies are frequent in the elderly and often have a latent and atypical symptomatology. OBJECTIVE To assess the epidemiological and evolutionary current data on digestive diseases in the elderly, and look for factors associated with length of hospital stay. METHODS Retrospective study of 10 years, including patients aged 60 and over hospitalized for digestive diseases in the Gastroenterology Department of the Campus Teaching Hospital of Lome, Togo. RESULTS Of 5933 hospitalized patients, there were 1054 patients (17.8%) aged 60 years and over with a digestive pathology (526 men and 528 women). The average age was 69.5 years ±7.9 ranging from 60 to 105 years. The average length of hospital stay was 7.45 days ±6.2 ranging from 1 to 44 days. HIV prevalence was 2.4%. In order of decreasing frequency, there were hepatobiliary pathologies (54.3%) with a predominance of cirrhosis and liver cancer, eso-gastroduodenal pathologies (23.1%) with predominance of ulcers, gastric cancer and esophageal cancer, intestinal pathologies (8.7%) with a predominance of food poisoning, pancreatic pathologies (4.2%) with a predominance of pancreatic cancer and peritoneal pathologies (1.4%). Gastric cancer was the second digestive cancer found after liver cancer. Pancreatic head cancer was the second disease after gastric cancer which need a transfer in a surgical ward (P=0.031). There were 204 deaths (19.4%). The longest duration of hospitalization was due to gastric cancer (9.16 days). CONCLUSION Hepatobiliary diseases were the most frequent and associated with a high death rate and a long hospital stay.
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Affiliation(s)
| | - Oumboma Bouglouga
- Hepatology and Gastroenterology Unit of the Campus Teaching Hospital of Lome, Togo
| | - Aklesso Bagny
- Hepatology and Gastroenterology Unit of the Campus Teaching Hospital of Lome, Togo
| | | | - Laconi Kaaga
- Hepatology and Gastroenterology Unit of the Campus Teaching Hospital of Lome, Togo
| | - Datouda Redah
- Hepatology and Gastroenterology Unit of the Campus Teaching Hospital of Lome, Togo
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Comparison of Hepatocellular Carcinoma in Patients with Cryptogenic Versus Hepatitis B Etiology: A Study of 1079 Cases Over 3 Decades. Dig Dis Sci 2019; 64:585-590. [PMID: 30327962 DOI: 10.1007/s10620-018-5331-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 10/09/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Traditionally in Asia, hepatitis B (HBV) accounts for the majority of hepatocellular carcinoma (HCC), but increasingly, non-viral or nonalcoholic steatohepatitis (NASH) etiology may play a more prominent role with current socioeconomic changes. There remains a paucity in data comparing NASH-HCC to HBV-related HCC. In this study, we explored the differences in clinical characteristics between HBV- and cryptogenic-related HCC. METHODS Patients with HCC seen in the Department of Gastroenterology and Hepatology, Singapore General Hospital were enrolled in an ongoing database since 1980. Patients with HCC attributed to HBV or cryptogenic etiology were identified. Comparison of clinical characteristics was performed between the two groups. RESULTS There were 916 HBV-HCC patients and 163 cryptogenic HCC patients, accounting for 70.9% and 12.6% of the total HCC cases (1292 patients), respectively. Out of the total cohort enrolled from 1980 to 2005, the ratio of cryptogenic to HBV patients was 1:6.7, while from 2006 to the current year, the ratio of cryptogenic to HBV patients has increased significantly to 1:3.9. Relative to patients with HBV, cryptogenic HCC patients were older (67.6 vs. 59.4 years old; p < 0.001), had lower proportion of male patients (69.9% vs. 83.8%; p < 0.001), and had higher incidence of smoking (32.2% vs. 25.8%; p = 0.008). HBV group had higher alanine transaminase (60.9 ± 85.7 U/L vs. 48.0 ± 52.1 U/L; p = 0.003), hemoglobin (12.7 ± 2.28 g/dL vs. 12.0 ± 2.46 g/dL, p < 0.001), albumin (32.9 ± 6.8 g/L vs. 31.3 ± 7.7 g/L; p = 0.007), and prothrombin time (13.2 ± 2.95 s vs. 12.7 ± 2.01 s, p = 0.023), as compared to the cryptogenic group. Cryptogenic HCC patients presented more frequently with unifocal HCC (55.2% vs. 46.5%; p = 0.002). There was no difference in the proportions of patients receiving surgical resection in both groups (23.5% in HBV group vs. 17.9% in cryptogenic group; p = 0.202). Cox regression analysis revealed no survival difference between cryptogenic-related HCC and HBV-related HCC (p = 0.367). CONCLUSION Temporal trends suggest that HCC attributed to HBV is on the decline, while cryptogenic- or NASH-related HCC is an emerging clinical entity. A paradigm shift in approach to screening, surveillance, and management of HCC may be required in view of the changing landscape of HCC epidemiology into an increasing non-viral etiology.
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Bertot LC, Adams LA. Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2019; 13:179-187. [PMID: 30791782 DOI: 10.1080/17474124.2019.1549989] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is associated with hepatocellular carcinoma (HCC), the most frequent malignant liver tumor. The increasing prevalence of obesity and diabetes is influencing the epidemiology of HCC with the most dramatic increases in NAFLD-related HCC seen in Western countries. Although cirrhosis is the major risk factor for HCC in NAFLD, there is increasing recognition that NAFLD-HCC occurs in the absence of cirrhosis. Areas covered: The epidemiology of NAFLD related HCC and its impact on changing the incidence of HCC globally. We overview risk factors for NAFLD-HCC in the presence and absence of cirrhosis and examine trends in liver transplantation (LT) related to NAFLD-HCC. Expert commentary: The incidence of NAFLD-related cirrhosis will continue to rise globally in parallel with risk factors of obesity and diabetes. Consequently, NAFLD-related HCC will become an increasingly important cause of liver-related morbidity and mortality and a common indication for LT worldwide. Further identification of risk factors for NAFLD-HCC and effective treatments for NAFLD are required to reduce this future burden of disease.
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Affiliation(s)
| | - Leon A Adams
- a Medical School , University of Western Australia , Nedlands , Australia.,b Department of Hepatology and Liver Transplant Unit , Sir Charles Gairdner Hospital , Nedlands , Australia
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Jindal A, Thadi A, Shailubhai K. Hepatocellular Carcinoma: Etiology and Current and Future Drugs. J Clin Exp Hepatol 2019; 9:221-232. [PMID: 31024205 PMCID: PMC6477125 DOI: 10.1016/j.jceh.2019.01.004] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/14/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.
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Key Words
- AMP, adenosine monophosphate
- AMPK, AMP-activated protein kinase
- ATP, adenosine 5′-triphosphate
- BMF, Bcl2 modifying factor
- BMI, body mass index
- CDK, cyclin-dependent kinase
- CTGF, connective tissue growth factor
- CTL, cytotoxic T lymphocyte
- CTLA, cytotoxic T-lymphocyte-associated protein
- ECM, extracellular matrix
- EFGR, endothelial growth factor receptor
- EGFR, epidermal growth factor receptor
- EMT, Epithelial–mesenchymal transition
- ERK, extracellular signal-regulated kinase
- FDA, Food and Drug Administration
- GFG, fibroblast growth factor
- HBV, hepatitis B virus
- HBcAg, hepatitis B core antibody
- HBsAg, HBV surface antigen
- HCC, Hepatocellular carcinoma
- HCV, hepatitis B virus
- HDV, hepatitis D virus
- HIF, hypoxia-inducible factor
- HIV, human immunodeficiency virus
- IGFR, insulin-like growth factor
- JAK, janus kinase
- MAPK, mitogen-activated protein kinase
- MDSC, myeloid-derived suppressor cell
- NASH, nonalcoholic steatohepatitis
- NK, natural killer
- NKT, natural killer T cell
- ORR, objective response rate
- OS, overall survival
- PAPSS1, 3′-phosphoadenosine 5′-phosphosulfate synthase 1
- PD-L1, programmed death ligand1
- PD1, programmed cell death protein 1
- PDGFR, platelet-derived growth factor receptor
- PEDF, pigment epithelium-derived factor
- PFS, progression-free survival
- PI3K, phosphoinositide 3-kinases
- PTEN, phosphatase and tensin homolog
- PUMA, p53 upregulated modulator of apoptosis
- RFA, radiofrequency ablation
- Rb, retinoblastoma protein
- SCF, stem cell factor
- SHP1, src homology 2 domain–containing phosphatase 1
- STAT3, signal transducer and activator of transcription 3
- TACE, transarterial chemoembolization
- TGF 1, transforming growth factor-1
- TK, tyrosine kinase
- TKI, Tyrosine kinase inhibitor
- TRKA, tropomyosin receptor kinase A
- Treg, regulatory T cells
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- bFGF, basic fibroblast growth factor
- combination therapy
- cyclin-dependent kinase inhibitors
- hepatocellular carcinoma
- hepatology
- tyrosine kinase inhibitors
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Affiliation(s)
- Aastha Jindal
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Address for correspondence: Aastha Jindal, Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA.
| | - Anusha Thadi
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Kunwar Shailubhai
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Research & Development, Tiziana Lifesciences, Doylestown, PA 18902, USA
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31
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Flores YN, Zhang ZF, Bastani R, Leng M, Crespi CM, Ramírez-Palacios P, Stevens H, Salmerón J. Risk factors for liver disease among adults of Mexican descent in the United States and Mexico. World J Gastroenterol 2018; 24:4281-4290. [PMID: 30310261 PMCID: PMC6175761 DOI: 10.3748/wjg.v24.i37.4281] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 08/01/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To compare the prevalence of chronic liver disease (CLD) risk factors in a representative sample of Mexican-Americans born in the United States (US) or Mexico, to a sample of adults in Mexico.
METHODS Data for Mexican-Americans in the US were obtained from the 1999-2014 National Health and Nutrition Examination Survey (NHANES), which includes persons of Mexican origin living in the US (n = 4274). The NHANES sample was restricted to Mexican-American participants who were 20 years and older, born in the US or Mexico, not pregnant or breastfeeding, and with medical insurance. The data in Mexico were obtained from the 2004-2013 Health Worker Cohort Study in Cuernavaca, Mexico (n = 9485). The following known risk factors for liver disease/cancer were evaluated: elevated aminotransferase levels (elevated alanine aminotransferase was defined as > 40 IU/L for males and females; elevated aspartate aminotransferase was defined as > 40 IU/L for males and females), infection with hepatitis B or hepatitis C, metabolic syndrome, high total cholesterol, diabetes, obesity, abdominal obesity, and heavy alcohol use. The main independent variables for this study classified individuals by country of residence (i.e., Mexico vs the US) and place of birth (i.e., US-born vs Mexico-born). Regression analyses were used to investigate CLD risk factors.
RESULTS After adjusting for socio-demographic characteristics, Mexican-American males were more likely to be obese, diabetic, heavy/binge drinkers or have abdominal obesity than males in Mexico. The adjusted multivariate results for females also indicate that Mexican-American females were significantly more likely to be obese, diabetic, be heavy/binge drinkers or have abdominal obesity than Mexican females. The prevalence ratios and prevalence differences mirror the multivariate analysis findings for the aforementioned risk factors, showing a greater risk among US-born as compared to Mexico-born Mexican-Americans.
CONCLUSION In this study, Mexican-Americans in the US had more risk factors for CLD than their counterparts in Mexico. These findings can be used to design and implement more effective health promotion policies and programs to address the specific factors that put Mexicans at higher risk of developing CLD in both countries.
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Affiliation(s)
- Yvonne N Flores
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Delegación Morelos, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos 62000, México
- UCLA Department of Health Policy and Management and Kaiser Permanente Center for Health Equity, Fielding School of Public Health, Los Angeles, CA 90095, United States
- UCLA Cancer Prevention and Control Research Center, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, United States
| | - Zuo-Feng Zhang
- UCLA Department of Epidemiology, Fielding School of Public Health, Los Angeles, CA 90095, United States
| | - Roshan Bastani
- UCLA Department of Health Policy and Management and Kaiser Permanente Center for Health Equity, Fielding School of Public Health, Los Angeles, CA 90095, United States
- UCLA Cancer Prevention and Control Research Center, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, United States
| | - Mei Leng
- UCLA Division of General Internal Medicine and Health Services Research, Los Angeles, CA 90095, United States
| | - Catherine M Crespi
- UCLA Cancer Prevention and Control Research Center, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, United States
- UCLA Department of Biostatistics, Fielding School of Public Health, Los Angeles, CA 90095, United States
| | - Paula Ramírez-Palacios
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Delegación Morelos, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos 62000, México
| | - Heather Stevens
- University of Washington, School of Medicine, Seattle, WA 98195, United States
| | - Jorge Salmerón
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Delegación Morelos, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos 62000, México
- Universidad Nacional Autónoma de México, Academic Epidemiology Research Unit, Avenida Universidad 3000, Ciudad Universitaria, Coyoacán, Mexico City 04510, México
- Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Morelos 62100, México
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Jiang K, Centeno BA. Primary Liver Cancers, Part 2: Progression Pathways and Carcinogenesis. Cancer Control 2018; 25:1073274817744658. [PMID: 29353494 PMCID: PMC5933573 DOI: 10.1177/1073274817744658] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) have been increasing in incidence worldwide and are leading causes of cancer death. Studies of the molecular alterations leading to these carcinomas provide insights into the key mechanisms involved. A literature review was conducted to identify articles with information relevant to current understanding of the etiologies and molecular pathogenesis of HCC and ICC. Chronic inflammatory diseases are the key etiological risk factors for both HCC and ICC, although other diseases play a role, and for many ICCs, an underlying risk factor is not identified. Mutations in catenin beta 1 ( CTNBB1) and tumor protein 53 (P53) are the main genetic alterations in HCC. Isocitrate dehydrogenases 1 and 2 (IDH1/2), KRAS protooncogene GTPase (KRAS), a RAS Viral Oncogene Homolog in neoroblastoma (NRAS) and P53 are primary genetic alterations in ICC. In both diseases, the mutational landscape is dependent on the underlying etiology. The most significant etiologies and genetic processes involved in the carcinogenesis of HCC and ICC are reviewed.
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Affiliation(s)
- Kun Jiang
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
| | - Barbara A Centeno
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
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Guo W, Tan HY, Wang N, Wang X, Feng Y. Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation. Cancer Manag Res 2018; 10:715-734. [PMID: 29692630 PMCID: PMC5903488 DOI: 10.2147/cmar.s156837] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer, with increasing prevalence worldwide. The mortality rate of HCC is similar to its incidence rate, which reflects its poor prognosis. At present, the diagnosis of HCC is still mostly dependent on invasive biopsy, imaging methods, and serum α-fetoprotein (AFP) testing. Because of the asymptomatic nature of early HCC, biopsy and imaging methods usually detect HCC at the middle-late stages. AFP has limited sensitivity and specificity, as many other nonmalignant liver diseases can also result in a very high serum level of AFP. Therefore, better biomarkers with higher sensitivity and specificity at earlier stages are greatly needed. Since metabolic reprogramming is an essential hallmark of cancer and the liver is the metabolic hub of living systems, it is useful to investigate HCC from a metabolic perspective. As a noninvasive and nondestructive approach, metabolomics provides holistic information on dynamically metabolic responses of living systems to both endogenous and exogenous factors. Therefore, it would be conducive to apply metabolomics in investigating HCC. In this review, we summarize recent metabolomic studies on HCC cellular, animal, and clinicopathologic models with attention to metabolomics as a biomarker in cancer diagnosis. Recent applications of metabolomics with respect to therapeutic and prognostic evaluation of HCC are also covered, with emphasis on the potential of treatment by drugs from natural products. In the last section, the current challenges and trends of future development of metabolomics on HCC are discussed. Overall, metabolomics provides us with novel insight into the diagnosis, prognosis, and therapeutic evaluation of HCC.
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Affiliation(s)
- Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
- Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
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Massoud O, Charlton M. Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. Clin Liver Dis 2018; 22:201-211. [PMID: 29128057 DOI: 10.1016/j.cld.2017.08.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although hepatocellular carcinoma (HCC) is more common in the setting of cirrhosis, there is increasing evidence that it can develop in the setting of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and that steatosis alone can promote carcinogenesis. In addition, obesity, diabetes, and metabolic syndrome are recognized risks for the development of HCC. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. The surveillance for HCC in the setting of noncirrhotic NAFLD/NASH, obesity, diabetes, and metabolic syndrome remains an area of uncertainty.
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Affiliation(s)
- Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama, 1720 2nd Avenue South, BDB 380, Birmingham, AL 35233, USA
| | - Michael Charlton
- Division of Gastroenterology and Hepatology, University of Chicago, Center for Liver Diseases, The University of Chicago Biological Sciences, 5841 South Maryland Avenue, Room M-454, Chicago, IL 60637, USA.
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Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment. Biochim Biophys Acta Mol Basis Dis 2018; 1864:607-617. [PMID: 29197664 DOI: 10.1016/j.bbadis.2017.11.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 11/14/2017] [Accepted: 11/28/2017] [Indexed: 12/14/2022]
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Li Y, Zhang W, Doughtie A, Cui G, Li X, Pandit H, Yang Y, Li S, Martin R. Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma. Oncotarget 2018; 7:52329-52339. [PMID: 27447573 PMCID: PMC5239555 DOI: 10.18632/oncotarget.10750] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 06/12/2016] [Indexed: 12/20/2022] Open
Abstract
Background Human fibroblast growth factor 19 (FGF19), its receptor (FGFR4) and EpCAM play an important role in cell proliferation, differentiation, motility, and overexpression have been linked to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the FGF19 signals responsible for the progression of HCC arising from fatty liver. Results FGF19 level was significantly increased in the HCC patients' serum compared to non-HCC controls. The IHC results demonstrated significant increases of protein expressions of FGF19, FGFR4 and EpCAM in specimens with fatty liver, NASH, cirrhosis, and HCC compared to healthy liver tissue. There was a significant positive correlation between the protein expressions (FGF19, FGFR4, and EpCAM) and histopathologic changes from FL to HCC. Furthermore, FGF19 was positively correlated with FGFR4 and with EpCAM. Materials and Methods FGF19 protein levels in serum and tissues were determined by ELISA assay. The FGFR4, and EpCAM expression and tissue distribution were further evaluated by immunohistochemical staining in tissue array samples. FGF19, FGFR4 and EpCAM expressions between the different histologic stages of fatty liver steatohepatitis-cirrhosis-HCC carcinogenesis sequence were compared to healthy hepatic tissue. Conclusions Overexpression of FGF19/FGFR4 significantly correlated with EpCAM as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence. Impact This is the first study to elucidate FGF19/FGFR4 signaling in favor of HCC cells developing as indicated by increased EpCAM within the carcinogenesis sequence from fatty liver to hepatocellular carcinoma. Our study has the potential to yield novel and cost effective screening strategies for HCC patients.
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Affiliation(s)
- Yan Li
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Weizhong Zhang
- Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, 130022, China
| | - Anne Doughtie
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Guozhen Cui
- Department of Hepatology, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Xuanyi Li
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Harshul Pandit
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Yingbin Yang
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Suping Li
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Robert Martin
- Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
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Ome Y, Hashida K, Yokota M, Nagahisa Y, Okabe M, Kawamoto K. The safety and efficacy of laparoscopic hepatectomy in obese patients. Asian J Surg 2017; 42:180-188. [PMID: 29273265 DOI: 10.1016/j.asjsur.2017.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 10/09/2017] [Accepted: 10/30/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is generally reported to increase the risk of surgical complications. There have been few reports of laparoscopic hepatectomy (LH) in obese patients. The purpose of this study was to compare the safety and efficacy of (1) LH versus open hepatectomy (OH) in obese patients and (2) LH in obese patients versus LH in non-obese patients. METHODS We introduced LH at our institution in April 2014. LH was performed in 63 obese patients and 108 non-obese patients from April 2014 to May 2017. OH was performed in 79 obese patients from January 2010 to May 2017. This study retrospectively compared the short-term outcomes of the LH obese group with those of the OH obese group and the LH non-obese group. RESULTS In patient characteristics, the LH obese group included a significantly higher percentage of patients with liver cirrhosis than the OH obese group. The LH obese group had fewer patients with a history of abdominal surgery but more with liver cirrhosis than the LH non-obese group. For short-term outcomes, the LH obese group had significantly less blood loss, fewer intraoperative transfusions, fewer positive surgical margins, and shorter postoperative hospital stays than the OH obese group. In contrast, only operation time was significantly different (longer) in the LH obese group than in the LH non-obese group. There were no significant differences in morbidity or mortality between the LH obese group and either the OH obese or the LH non-obese groups. CONCLUSION LH in obese patients is safe and effective.
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Affiliation(s)
- Yusuke Ome
- Department of Surgery, Kurashiki Central Hospital, Okayama, Japan.
| | - Kazuki Hashida
- Department of Surgery, Kurashiki Central Hospital, Okayama, Japan
| | - Mitsuru Yokota
- Department of Surgery, Kurashiki Central Hospital, Okayama, Japan
| | - Yoshio Nagahisa
- Department of Surgery, Kurashiki Central Hospital, Okayama, Japan
| | - Michio Okabe
- Department of Surgery, Kurashiki Central Hospital, Okayama, Japan
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38
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Ribback S, Sonke J, Lohr A, Frohme J, Peters K, Holm J, Peters M, Cigliano A, Calvisi DF, Dombrowski F. Hepatocellular glycogenotic foci after combined intraportal pancreatic islet transplantation and knockout of the carbohydrate responsive element binding protein in diabetic mice. Oncotarget 2017; 8:104315-104329. [PMID: 29262643 PMCID: PMC5732809 DOI: 10.18632/oncotarget.22234] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/05/2017] [Indexed: 01/01/2023] Open
Abstract
Aims The intraportal pancreatic islet transplantation (IPIT) model of diabetic rats is an insulin mediated model of hepatocarcinogenesis characterized by the induction of clear cell foci (CCF) of altered hepatocytes, which are pre-neoplastic lesions excessively storing glycogen (glycogenosis) and exhibiting activation of the AKT/mTOR protooncogenic pathway. In this study, we transferred the IPIT model to the mouse and combined it with the knockout of the transcription factor carbohydrate responsive element binding protein (chREBP). Methods C57BL/6J Wild-type (WT) and chREBP-knockout (chREBP-KO) mice (n = 297) were matched to 16 groups (WT/ chREBP-KO, experimental/control, streptozotocine-induced diabetic/not diabetic, one/four weeks). Experimental groups received the intraportal transplantation of 70 pancreatic islets. Liver and pancreatic tissue was examined using histology, morphometry, enzyme- and immunohistochemistry and electron microscopy. Results CCF emerged in the liver acini downstream of the transplanted islets. In comparison to WT lesions, CCF of chREBP-KO mice displayed more glycogen accumulation, reduced activity of the gluconeogenic enzyme glucose-6-phosphatase, decreased glycolysis, lipogenesis and reduced levels of the AKT/mTOR cascade members. Proliferative activity of CCF was ∼two folds higher in WT mice than in chREBP-KO mice. Conclusions The IPIT model is applicable to mice, as murine CCF resemble preneoplastic liver lesions from this hepatocarcinogenesis model in the rat in terms of morphological, metabolic and molecular alterations and proliferative activity, which is diminished after chREBP knockout. chREBP appears to be an essential component of AKT/mTOR mediated cell proliferation and the metabolic switch from a glycogenotic to lipogenic phenotype in precursor lesions of hepatocarcinogenesis.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Jenny Sonke
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Andrea Lohr
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Josephine Frohme
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Kristin Peters
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Johannes Holm
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Michele Peters
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Antonio Cigliano
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Diego F Calvisi
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
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39
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Zhen Y, Xinghui Z, Chao W, Yi Z, Jinwen C, Ruifang G, Chao Z, Min Z, Chunlei G, Yan F, Lingfang D, Long S, Wenzhi S, Xiaohe L, Rong X. Several microRNAs could predict survival in patients with hepatitis B-related liver cancer. Sci Rep 2017; 7:45195. [PMID: 28322348 PMCID: PMC5359660 DOI: 10.1038/srep45195] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 02/20/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs as biomarkers play an important role in the tumorigenesis process, including hepatocellular carcinomas (HCCs). In this paper, we used The Cancer Genome Atlas (TCGA) database to mine hepatitis B-related liver cancer microRNAs that could predict survival in patients with hepatitis B-related liver cancer. There were 93 cases of HBV-HCC and 49 cases of adjacent normal controls included in the study. Kaplan–Meier survival analysis of a liver cancer group versus a normal control group of differentially expressed genes identified eight genes with statistical significance. Compared with the normal liver cell line, hepatocellular carcinoma cell lines had high expression of 8 microRNAs, albeit at different levels. A Cox proportional hazards regression model for multivariate analysis showed that four genes had a significant difference. We established classification models to distinguish short survival time and long survival time of liver cancers. Eight genes (mir9-3, mir10b, mir31, mir519c, mir522, mir3660, mir4784, and mir6883) were identified could predict survival in patients with HBV-HCC. There was a significant correlation between mir10b and mir31 and clinical stages (p < 0.05). A random forests model effectively estimated patient survival times.
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Affiliation(s)
- Ye Zhen
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China.,School of public health, Taishan Medical University, Tai'an 271016, China.,Department of Infectious Disease, Tai'an Central Hospital, Tai'an 271000, China
| | - Zhao Xinghui
- Laboratory of Vaccine and Antibody Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Wu Chao
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Zhao Yi
- Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Chen Jinwen
- Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Gao Ruifang
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Zhang Chao
- College of Information Science and Engineering, Shandong Agriculture University, Tai'an 271000, China
| | - Zhao Min
- Department of Infectious Disease, Tai'an Central Hospital, Tai'an 271000, China
| | - Guo Chunlei
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Fang Yan
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Du Lingfang
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Shen Long
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Shen Wenzhi
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Luo Xiaohe
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China
| | - Xiang Rong
- Department of Tumor Molecular Biology, Nankai University School of Medicine, Tianjin 371000, China.,The 2011 Project Collaborative Innovation Center for Biological Therapy, Nankai University School of Medicine, Tianjin 371000, China.,The International Collaborative Laboratory for Biological Medicine of the Ministry of Education, Nankai University School of Medicine, Tianjin 371000, China
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40
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Du J, Cheng X, Shen L, Tan Z, Luo J, Wu X, Liu C, Yang Q, Jiang Y, Tang G, Li X, Zhang S, Zhu L. Methylation of miR-145a-5p promoter mediates adipocytes differentiation. Biochem Biophys Res Commun 2016; 475:140-8. [PMID: 27179777 DOI: 10.1016/j.bbrc.2016.05.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 05/10/2016] [Indexed: 12/30/2022]
Abstract
MicroRNAs (miRNAs, miR) play important roles in adipocyte development. Recent studies showed that the expression of several miRNAs is closely related with promoter methylation. However, it is not known whether miRNA mediates adipocytes differentiation by means of DNA methylation. Here, we showed that miR-145a-5p was poorly expressed in adipose tissue from mice fed a high fat diet (HFD). Overexpression or inhibition of miR-145a-5p was unfavorable or beneficial, respectively, for adipogenesis, and these effects were achieved by regulating adipocyte-specific genes involved in lipogenic transcription, fatty acid synthesis, and fatty acid transportation. Particularly, we first suggested that miR-145a-5p mimics or inhibitors promoted or repressed adipocytes proliferation by regulating p53 and p21, which act as cell cycle regulating factors. Surprisingly, the miR-145a-5p-repressed adipocyte differentiation was enhanced or rescued when cells treated with 5-Aza-dC were transfected with miR-145a-5p mimics or inhibitors, respectively. These data indicated that, as a new mean to positively regulate adipocyte proliferation, the process of miR-145a-5p-inhibited adipogenesis may be regulated by DNA methylation.
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Affiliation(s)
- Jingjing Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiao Cheng
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Zhendong Tan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Jia Luo
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaoqian Wu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Chendong Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Qiong Yang
- Department of Animal Husbandry and Veterinary Medicine, Chengdu Agricultural College, Chengdu 611100, Sichuan, China
| | - Yanzhi Jiang
- College of Life and Science, Sichuan Agricultural University, Chengdu 611130, China
| | - Guoqing Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
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41
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Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Res 2016; 5. [PMID: 27239288 PMCID: PMC4870992 DOI: 10.12688/f1000research.6946.1] [Citation(s) in RCA: 148] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2016] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development.
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Affiliation(s)
| | - Salome Bandoh
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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42
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Flores YN, Auslander A, Crespi CM, Rodriguez M, Zhang ZF, Durazo F, Salmerón J. Longitudinal association of obesity, metabolic syndrome and diabetes with risk of elevated aminotransferase levels in a cohort of Mexican health workers. J Dig Dis 2016; 17:304-12. [PMID: 26991251 PMCID: PMC4956543 DOI: 10.1111/1751-2980.12341] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 12/14/2015] [Accepted: 03/07/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In Mexico, chronic liver disease have been increasingly found along with the rapidly growing prevalence of obesity, diabetes and metabolic syndrome (MS). We aimed to investigate the longitudinal association between these three factors and risk of elevated alanine aminotransferase (ALT) levels (>40 U/L), a marker for liver damage, in a cohort of Mexican adults. METHODS Data were obtained from two separate waves of the Mexican Health Worker Cohort Study: Wave 1 (2004-2006) and Wave 2 (2011-2013). Unconditional logistic regression models were employed to determine the cross-sectional and longitudinal association between these risk factors and elevated ALT levels. RESULTS The prevalence of elevated ALT was significantly higher among men, individuals aged under 60 years, those who were overweight or obese, diabetic, with MS or heavy/binge drinkers. The longitudinal results indicated that weight gain between waves that resulted in a change in body mass index, along with remaining overweight or obese, were significantly associated with an increased risk of elevated ALT levels. A significantly increased risk of developing elevated ALT was also observed among those who acquired diabetes or MS from Wave 1 to Wave 2. CONCLUSIONS Weight gain and acquiring diabetes or MS are associated with a significant risk of having elevated ALT. These results, within the context of the rapid increase in global obesity rates, call urgently for programs to help to prevent chronic liver disease.
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Affiliation(s)
- Yvonne N Flores
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, México
- Department of Health Policy and Management, Center for Cancer Prevention and Control Research, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, California, USA
| | - Allyn Auslander
- Department of Epidemiology, Fielding School of Public Health, UCLA, Los Angeles, California, USA
| | - Catherine M Crespi
- Department of Biostatistics, Center for Cancer Prevention and Control Research, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
| | - Michael Rodriguez
- Department of Family Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
| | - Zuo-Feng Zhang
- Department of Epidemiology, Fielding School of Public Health, UCLA, Los Angeles, California, USA
| | - Francisco Durazo
- Department of Digestive Diseases, David Geffen School of Medicine and Pfleger Liver Institute, UCLA, Los Angeles, California, USA
| | - Jorge Salmerón
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, México
- Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico
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Abstract
Liver-related mortality is the third cause of death in patients with nonalcoholic fatty liver disease, but the long-term prognosis basically depends on the presence and severity of liver damage. Thus, life expectancy in patients with simple steatosis is not different from the general population, but liver-related mortality is significantly higher in patients with nonalcoholic steatohepatitis (NASH), particularly in those with advanced fibrosis. Progression of liver disease is observed in up to one-third of patients with NASH. The long-term hepatic prognosis mostly depends on the histologic stage at initial liver biopsy, but multiple risk factors may concur.
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44
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NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/s11901-016-0297-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Makarova-Rusher OV, Altekruse SF, McNeel TS, Ulahannan S, Duffy AG, Graubard BI, Greten TF, McGlynn KA. Population attributable fractions of risk factors for hepatocellular carcinoma in the United States. Cancer 2016; 122:1757-65. [PMID: 26998818 DOI: 10.1002/cncr.29971] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/29/2016] [Accepted: 02/01/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..
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Affiliation(s)
- Oxana V Makarova-Rusher
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sean F Altekruse
- Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Tim S McNeel
- Information Management Services Inc, Calverton, Maryland
| | - Susanna Ulahannan
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Austin G Duffy
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Barry I Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, Sastre J, Martí-Bonmati L, Llovet JM, Bilbao JI, Sangro B, Pardo F, Ayuso C, Bru C, Tabernero J, Bruix J. [Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH]. Med Clin (Barc) 2016; 146:511.e1-511.e22. [PMID: 26971984 DOI: 10.1016/j.medcli.2016.01.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/22/2016] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociación Española para el Estudio del Hígado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Española de Trasplante Hepático, Sociedad Española de Radiología Médica, Sociedad Española de Radiología Vascular e Intervencionista y Sociedad Española de Oncología Médica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (www.cancer.gov) and the strength of recommendation is based on the GRADE system.
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Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, España
| | - Marta Burrel
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Jaime Feliu
- Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, España
| | - Javier Briceño
- Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Javier Sastre
- Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, España
| | - Luis Martí-Bonmati
- Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Josep María Llovet
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, Estados Unidos
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Carmen Ayuso
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Concepció Bru
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, España
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España.
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Ma S, Wu J, Wu J, Wei Y, Zhang L, Ning Q, Hu D. Relationship between HLA-DRB1 allele polymorphisms and familial aggregations of hepatocellular carcinoma. ACTA ACUST UNITED AC 2016; 23:e1-7. [PMID: 26966407 DOI: 10.3747/co.23.2839] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc). METHODS Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc. RESULT Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05). CONCLUSIONS Our research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C.
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Affiliation(s)
- S Ma
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - J Wu
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - J Wu
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - Y Wei
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - L Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - Q Ning
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
| | - D Hu
- Department of Infectious Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning, P.R.C
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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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Hamdy K, Al Swaff R, Hussein HA, Gamal M. Assessment of serum adiponectin in Egyptian patients with HCV-related cirrhosis and hepatocellular carcinoma. J Endocrinol Invest 2015; 38:1225-31. [PMID: 26359143 DOI: 10.1007/s40618-015-0379-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 08/05/2015] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIM Hepatitis C-associated insulin resistance is involved in the development of various complications including hepatocarcinogenesis. Low plasma levels of adiponectin contribute to the pathogenesis of insulin resistance and type II diabetes mellitus. The aim of this study was to determine the value of serum adiponectin in Egyptian patients with hepatitis C-related cirrhosis and hepatocellular carcinoma. PATIENTS AND METHODS 90 Egyptian patients with hepatitis C-related liver cirrhosis were enrolled in this study. Patients were divided into two groups as follows: group I: 61 patients with hepatitis C-related cirrhosis and hepatocellular carcinoma, group II: 29 patients with hepatitis C-related cirrhosis (hepatocellular carcinoma was excluded in these patients at the time of recruitment in the study). Serum adiponectin level was measured and correlated with all other studied parameters. RESULTS Serum adiponectin was significantly lower in patients with hepatocellular carcinoma and it had significant negative correlations with both the overall tumor size and the number of tumor foci. Highly significant negative correlations were found between adiponectin and all markers of insulin resistance in both groups. At a cut-off value ≤5.4 μg/ml, adiponectin had a sensitivity of 60.7%, a specificity of 93.1%, a positive predictive value of 94.9%, and a negative predictive value of 52.9% for detection of hepatocellular carcinoma (with an overall accuracy of 77.6%). CONCLUSION An independent association exists between serum adiponectin and hepatocellular carcinoma in Egyptian patients with hepatitis C-related cirrhosis. Therapy to increase circulating adiponectin concentration might represent a novel strategy to prevent hepatitis C-related hepatic complications.
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Affiliation(s)
- K Hamdy
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - R Al Swaff
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - H A Hussein
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - M Gamal
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Abstract
The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlying this complex relationship.
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Affiliation(s)
- Andrea Marengo
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy; , ,
| | - Chiara Rosso
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy; , ,
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy; , ,
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