5,557

Top 100 Cited Articles in the Field of Hepatocellular Carcinoma: A Bibliometric Analysis

Noureen Asghar, Rabbia Siddiqi, Mahnoor Islam, Hamza Mehmood, Nauman Hashmani

Noureen Asghar, Rabbia Siddiqi, Mahnoor Islam, Hamza Mehmood, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan
Nauman Hashmani, Hashmani’s Hospital, Karachi, Pakistan

Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Mahnoor Islam, Crystal View Apartments, P.EC.H.S. Block 6, 62/3, Dr. Mehmood Hussain Road, Karachi, Pakistan.
Email: mahnoorislam95@gmail.com
Telephone: +923408362337

Received: July 25, 2018
Revised: September 28, 2018
Accepted: September 30, 2018
Published online: December 21, 2018

ABSTRACT

AIM: Bibliometric analyses are used by funding agencies and researchers to identify major contributors to scientific progress. Citation classics have been identified in many gastrointestinal malignancies, but not yet for hepatocellular carcinoma (HCC). Thus we sought to analyze the 100 most cited articles in this field.

MATERIALS AND METHODS: The Scopus database was searched by two reviewers for articles concerning HCC. The 100 top cited papers were analyzed by topic, journal, author, year and institution.

RESULTS: The 100 most-cited articles in HCC were published between 1954 and 2012, with the most articles (n = 29) published in period 2006-2010. The total number of citations of these articles ranged from 618-4,833 (median = 934.5) citations. These articles originated from 21 countries, with nearly half from the USA (n = 49), followed by Spain and Italy (n = 19). The University of Barcelona, Spain contributed the most articles (n = 13). Hepatology contributed the greatest number of articles (n = 19), with New England Journal of Medicine having the greatest number of citations (n = 21,276). Seventy-five of the top 100 papers were original articles; most of these focused on genetics/pathophysiology (n = 27) or management (n = 24).

CONCLUSION: Our analysis serves as a reference for the most highly cited works in HCC and characterizes research trends in the field.

Key words: Bibliometrics; Citation classics; Liver cancer; Hepatocellular carcinoma; Scientometrics

© 2018 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Asghar N, Siddiqi R, Islam M, Mehmood H, Hashmani N. Top 100 Cited Articles in the Field of Hepatocellular Carcinoma: A Bibliometric Analysis. Journal of Gastroenterology and Hepatology Research 2018; 7(6): 2777-2784 Available from: URL: http: //www.ghrnet.org/index.php/joghr/article/view/2388

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and in 2015 it ranked as the sixth most common neoplasm and the fourth leading cause of cancer-related mortality[1]. Given this high global disease burden, it can be appreciated that significant resources are devoted to research in HCC. The association of several modifiable risk factors such as viral hepatitis infections and alcoholic liver disease with hepatocarcinogenesis has generated strong interest in preventive screening research and implementation. In addition, there is an urgent and expanding role for novel molecular therapies like sorafenib in the management of this chemo-resistant tumor. The promise of precision medicine in HCC has focused much research on genomic profiling to identify prognostic markers and targets for drug therapy.

With increasing emphasis on evidence-based medicine, recent years have seen a rise in the number of research publications[2]. Bibliometric methods of analyzing research meta-data can provide useful information to funding agencies, federal policymakers and individual researchers and clinicians. Citation analysis can also identify which areas should be prioritized by future research. For physicians, a list of citation classics enables them to efficiently navigate landmark developments in their field.

Despite criticism, citation rate and impact factor metrics are widely used to assess the scholarly impact of a scientific manuscript[3, 4]. Many medical and surgical specialties have utilized bibliometric techniques to identify their citation classics and characterize research trends, including several gastrointestinal malignancies[5-11]. However to our knowledge no such analysis has yet been published on HCC. The objective of our study was to present the 100 top cited articles and to gain insight on the evolution of HCC research.

Methods

In January 2018, two independent researchers (NA and RS) searched the Scopus database (www.scopus.com) for citations of articles published on HCC. As compared to PubMed, Web of Science or Google Scholar, Scopus is known to have a greater coverage where scientific publications are concerned[12]. In order to broaden the results, all article types, non-human studies and studies without abstract availability were included. No time restriction was applied and all the journals in the database were included in the search. Articles with their main focus on HCC, epidemiology, carcinogenesis, management, surgery and chemotherapy were included.

Our primary search phrases included “liver cancer”, “hepatocellular cancer”, “hepatic cancer”, “hepatocarcinogenesis” and “HCC”. All these terms were also searched using “carcinoma”, “neoplasm”, “tumor” and “malignancy” and their plural forms. All individual key phrases were searched for in the title, keywords and abstract.

The returned dataset was strictly related to HCC. Abstracts of all articles were thoroughly analyzed for relevance to the topic according to the inclusion and exclusion criteria, independently by both reviewers. Abstracts were obtained from other search engines if they were not available on Scopus and similarly analyzed for relevance. The top 100 selected articles were ordered using “cited by” option. A final list was made after comparing both reviewers’ lists. A difference of 5.5% was observed between the lists. Articles were only included after consensus and agreement of both reviewers.

The final list was exported to Microsoft Excel 2016. The list was analyzed for the following: article title, author, author affiliations, number of authors, journal, total citations, year of publication, citations per year, institution and country of origin of the first author. H index and affiliations of authors were obtained from their Scopus profiles. We calculated the median and inter-quartile range (IQR) for total number of citations and citations per year, as our data were not expected to be normally distributed. Thomson Reuters’ Journal Citation Reports 2017 was used to obtain the journal’s impact factor. Tables and charts were made using Microsoft Excel 2016 (Microsoft Corp., Redmond, WA, USA). Pearson product-moment correlation test was applied to determine the correlation between journal impact factor and the number of papers of that journal in the top 100 list, using IBM SPSS (Statistical Package for the Social Sciences; SPSS Inc., Chicago, IL, USA) version 22. A p value of < 0.05 was considered significant. No ethics approval was required for this study as all data are publicly available.

Table 1 Top 100 cited articles, their total citations, citations per year and rank according to citations per year.
RankArticleNumber of total citationsAverage citations per yearRank by average citations per year
1Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. New Engl J Med. 2008;359(4):378-90.48334832
2Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. New Engl J Med. 1996;334(11):693-9.4226192.110
3Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-36.4035310.45
4Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology. 2011;53(3):1020-2.3846579.41
5Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907-17.3140209.39
6El-Serag HB, Rudolph KL. Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis. Gastroenterology. 2007;132(7):2557-76.3106282.46
7Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the barcelona-2000 EASL conference. J Hepatol. 2001;35(3):421-30.3019177.612
8El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. New Eng J Med. 1999;340(10):745-50.2517132.517
9Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34.24122687
10European Association for the Study of the L, Llovet JM, Ducreux M, Lencioni R, Di Bisceglie AM, Galle PR, et al. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43.23223873
11Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer. 1954;7(3):462-503.225635.685
12Llovet JM, Real MI, Monta?a X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet. 2002;359(9319):1734-9.2123132.716
13Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37(2):429-42.1928128.518
14Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-55.19203204
15Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA Level. J Am Med Assoc. 2006;295(1):65-73.1892157.714
16Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis. 1999;19(3):329-37.180394.929
17Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. Lancet. 1981;2(8256):1129-32.176747.864
18El-Serag HB. Hepatocellular carcinoma. New Eng J Med. 2011;365(12):1118-27.1755250.78
19Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology. 2007;133(2):647-58. 1726156.913
20 Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 2004;127(SUPPL.):S5-S16.1687120.520
21Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RTP, et al. Randomized controlled trial of transarterialLipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164-71.1670104.426
22Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431(7007):461-6.1634116.721
23Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment study of 850 patients. Cancer. 1985;56(4):918-28.155947.267
24Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980;209(4455):497-9.13683684
25Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. New Engl J Med. 1997;336(26):1855-9.135164.349
26Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529-38.1322110.222
27Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hot spot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350(6317):427-8.128247.565
28Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 2004;127(SUPPL.):S35-S50.127591.131
29Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394-403.127374.937
30Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: Resection versus transplantation. Hepatology. 1999;30(6):1434-40.124965.748
31Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445(7128):656-60.1205109.523
32Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 2006;6(9):674-87.119899.827
33Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, et al. Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model. Cell. 2009;137(6):1005-17.1150127.819
34El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-73.e1.1147191.211
35Lencioni R, Llovet JM. Modified recist (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52-60.1147143.415
36Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: Treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999;210(3):655-61.111258.552
37Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, et al. Interrelationship of blood transfusion, non�\A, non�\B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus. Hepatology. 1990;12(4):671-5.111039.676
38Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991;350(6317):429-31.109940.772
39Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100(10):698-711.1089108.924
40Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339-46.107867.445
41Bugianesi E, Leone N, Vanni E, Rizzetto M, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: From cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134-40.106666.647
42Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988;61(10):1942-56.104034.789
43Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S, et al. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl AcadSci USA. 1990;87(17):6547-9.103837.181
44Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121-4.103594.130
45Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med. 1998;4(9):1065-7.99049.563
46Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 1982;42(9):3858-63.97627.194
47Curley SA, Izzo F, Delrio P, Ellis LM, Granchi J, Vallone P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: Results in 123 patients. Ann Surg. 1999;230(1):1-8.96150.661
48Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J ClinOncol. 2009;27(9):1485-91.953105.925
49Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351(6324):317-20.94835.188
50Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J ClinOncol. 2006;24(26):4293-300.9367836
51Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30(5):969-77.93314.6100
52Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: Complications encountered in a multicenter study. Radiology. 2003;226(2):441-51.93162.151
53Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk Factors for Hepatocellular Carcinoma among Patients with Chronic Liver Disease. New Engl J Med. 1993;328(25):1797-801.92937.280
54Aden DP, Fogel A, Plotkin S, Damjanov I, Knowles BB. Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line [15]. Nature. 1979;282(5739):615-6.91223.497
55Manghisi G, Elba S, Mossa A, Giorgio A, Aloisio V, Perrotta A, et al. A new prognostic system for hepatocellular carcinoma: A retrospective study of 435 patients. Hepatology. 1998;28(3):751-5.90445.269
56Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med. 1999;131(3):174-81.89647.268
57Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. New Engl J Med. 2002;347(3):168-74.87954.955
58Livraghi T, Giorgio A, Marin G, Salmi A, De Sio I, Bolondi L, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: Long-term results of percutaneous ethanol injection. Radiology. 1995;197(1):101-8.86937.879
59Tobe T, Endo Y, Hattori N, Ichida F, Mizumoto R, Mori W, et al. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Ann Surg. 1990;211(3):277-87.8673191
60Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Ierace T, Solbiati L, et al. Hepatocellular carcinoma: Radio-frequency ablation of medium and large lesions. Radiology. 2000;214(3):761-8.85147.366
61Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851-8.84770.642
62Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346(8982):1051-5.84436.782
63 De La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl AcadSci USA. 1998;95(15):8847-51.82841.471
64Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25(17):2537-45.82468.744
65Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35(3):519-24.82351.458
66Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243(3):321-8.80767.346
67El-Serag HB. Hepatocellular carcinoma: Recent trends in the United States. Gastroenterology. 2004;127(SUPPL.):S27-S34.79756.954
68Bosch FX, Ribes J, Borràs J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19(3):271-85.77240.673
69A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. New Engl J Med. 1995;332(19):1256-61.77133.590
70Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197-208.7689628
71Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, et al. Small hepatocellular carcinoma in cirrhosis: Randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003;228(1):235-40.76250.859
72Reddy JK, Azarnoff DL, Hignite CE. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature. 1980;283(5745):397-8.7612099
73Ma S, Chan K, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and Characterization of Tumorigenic Liver Cancer Stem/Progenitor Cells. Gastroenterology. 2007;132(7):2542-56.76069.143
74Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10(1):35-43.74983.234
75Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 1993;218(2):145-51.74729.992
76El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139(10):817-23.74649.762
77Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. New Engl J Med. 2008;359(19):1995-2004.74474.438
78Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, de Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. New Engl J Med. 1991;325(10):675-80.74227.593
79El-Serag HB, Tran T, Everhart JE. Diabetes Increases the Risk of Chronic Liver Disease and Hepatocellular Carcinoma. Gastroenterology. 2004;126(2):460-8.73852.757
80Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000;24(3):245-50.72540.374
81Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90+ Cancer Stem Cells in Human Liver Cancer. Cancer Cell. 2008;13(2):153-66.72472.439
82Llovet JM, Bustamante J, Castells A, Vilana R, Del Carmen Avuso M, Sala M, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29(1):62-7.72338.178
83Copur MS. Sorafenib in advanced hepatocellular carcinoma [3]. New Engl J Med. 2008;359(23):2498.72172.140
84Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: Results of the PRECISION v study. Cardiovasc Intervent Radiol. 2010;33(1):41-52.7209032
85Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48(4):1312-27.71871.841
86Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121(7):977-90.71354.856
87Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res ClinOncol. 2004;130(7):417-22.71150.860
88Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, et al. Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach. Cell. 2006;125(7):1253-67.6965853
89Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection. Hepatology. 2010;51(5):1820-32.68485.533
90Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229(6):790-800.67135.387
91Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001;33(5):1080-6.66739.277
92Curley SA, Izzo F, Ellis LM, Vauthey JN, Vallone P. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg. 2000;232(3):381-91.65936.683
93Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology. 1993;18(1):47-53.65426.295
94Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200-7.65043.370
95Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 1989;2(8670):1004-6.64622.398
96Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol. 2002;22(4):1184-93.63939.975
97Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356(9232):802-7.63635.386
98Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47(1):82-9.63463.450
99Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48 Suppl 1:S20-37.63178.935
100Nishiwaki-Matsushima R, Ohta T, Nishiwaki S, Suganuma M, Kohyama K, Ishikawa T, et al. Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR. J Cancer Res ClinOncol. 1992;118(6):420-4.61823.896

RESULTS

1. Citation Count and Citations per Year

Table 1 shows the top 100 cited articles in the field of HCC, along with their total citations, citation per year and rank according to total citations and citation per year. The citation count ranged from 618-4,833 for these 100 articles, with median of 934.5 (IQR = 582.5). The citations of all the articles sum up to 125,615, with approximately 3% (n = 3762) being self-citations. The number of citations per year ranged from 14.6 to 579.4. The median number of citations per year was 62.8 (IQR = 65.0).

2. Year of Publication, Origin and Authorship

The top ten articles were published after 1996. The 100 most cited articles were published between 1954 and 2012. During this 58 year span, the largest number of these articles (n = 29) were published in the 5-year period from 2006 to 2010, followed by 2001-2005 (n = 24) as shown in Figure 1. During 2006-2010, 5 articles out of the 29 published discussed sorafenib. In contrast, out of the 40 articles published during 1993-2003, 19 articles were based on HCC treatment; 10 articles from the aforementioned 19 were about chemoembolization and radiofrequency ablation, whereas 5 explored liver transplantation and resection. The remaining 4 covered other miscellaneous aspects of HCC treatment.

Twenty-one different countries contributed to the 100 most cited articles. Nearly half of the articles originated from USA (n = 49), followed by Italy and Spain with an equal number of articles (n = 19). Thirty-one articles had authors from more than one country. One article from the list had unidentified authorship nationality (Figure 2).

A total of 808 authors contributed to these 100 articles. The number of authors for each article ranged from 1 to 49, with each paper having a median of 7 authors (IQR = 7.25).Table 2 lists all the authors with 5 or more publications in top 100 cited articles along with their H-index. Jordi Bruix coauthored the greatest number of articles (n = 19) followed by Josep M Llovet (n = 17), and Hashem B El-Serag (n = 7).

Figure 1 Number of publications in each 5-year interval.

Table 2 Authors with ≥ 5 articles in the top 100 articles.
AuthorTotal articlesAuthorship positionAuthor affiliationsH-index
  FirstLastOther  
Bruix, J.195104Universitat de Barcelona, Barcelona Clinic Liver Cancer (BCLC) Group, Barcelona, Spain80
Llovet, J.M.171025Icahn School of Medicine at Mount Sinai, Department of Medicine, New York, United States95
El-Serag, H.B.7700Baylor College of Medicine, Department of Medicine, Houston, United States92
Lencioni, R.A.6213University of Miami Leonard M. Miller School of Medicine, Department of Vascular and Interventional Radiology, Miami, United States60
Livraghi, T.5500Istituto Clinico Humanitas, Rozzano, Italy49
Mazzaferro, V.5203Universita degli Studi di Milano, Gastrointestinal Surgery and Liver Transplantation, Milan, Italy60

3. Journal and Institutional Affiliations

The 100 most cited articles were published in 28 different journals, with top 5 producing nearly half of the articles (n = 49). These five journals included (1) Hepatology (2) New England Journal of Medicine (3) Gastroenterology (4) The Lancet, and (5) Nature. Hepatology published the most articles (n = 19), but New England Journal of Medicine generated the largest number of total citations (21,276) with 15 papers. The median impact factor for these 28 journals was 15.2 (range = 2.19-72.4). Thirty-five articles in our list were published in journals having impact factors of 30.0 or above. We found no significant correlation between the impact factor of a journal and the number of articles of that journal in the top 100 list (p = 0.146). Journals with more than 2 articles in top 100 are shown in Table 3.

A number of institutions contributed to the top 100 articles. University of Barcelona contributed the greatest number of articles (n = 13), followed by Baylor College of Medicine (n = 6). Based on first author institutional affiliations, institutions which contributed more than 2 articles in our list are shown in Table 4.

Table 3 Top-cited articles according to journal and their impact factors (only journals with >2 articles have been shown).
Journal NameNumber of articlesImpact factor 2017
Hepatology1513.2
New England Journal of Medicine1172.4
Gastroenterology918.4
Nature740.1
The Lancet747.8
Annals of Surgery68.98
Journal of Hepatology512.5
Radiology57.3
Cell430.4
Cancer35.99
Seminars in Liver Disease35.5

Table 4 Institutions that contributed ≥ 2 articles in the top 100 cited list.
Institute, countryNumber of articles
University of Barcelona, Spain13
Baylor College of Medicine, United States6
Ospedale Civile, Italy5
Institut Catala d'Oncologia, Spain2
Mount Sinai School of Medicine, United States2
National Cancer Institute, Italy2
University of Pisa, Italy2
University of Texas M.D. Anderson Cancer Center, United States2
University of Washington Medical Research Unit, Taiwan2

4. Type of Article and Topical Distribution

We divided the top 100 cited articles into 3 categories, according to the type of study: original articles (n = 75), review/expert opinion (n = 20) and official guidelines (n = 5). Figure 3 shows the temporal trend of publication by type of article. Original articles were further subdivided according to article’s main focus into 5 categories: genetics and pathophysiology (n = 27), management (n = 24), epidemiology/natural history (n = 19), prognostication (n = 3) and surveillance (n = 2).

Of the top 40 most cited articles, 35% (n = 14) were focused on management, while this figure rose to 70% (n = 7) among the top 10 articles. This pattern is also reflected in the citations-per-year ranking, indicating that the exceptionally high citation counts of management articles are not attributable to earlier publication.

Figure 3 The number of articles published over 5-year intervals, by study type.

DISCUSSION

Research Activity and Trends

As shown in Figures 1 and 3, the time period from 1991 to 2010 saw the publication of a large majority of the 100 most-cited articles in the list (n = 82); furthermore, the distribution of these articles through this period reflects an exponential increase in research activity. This pattern of literature growth has been identified by a variety of bibliometric analyses in the past-notably, by studies analyzing the literature on clinically relevant topics such as diabetes[5] or chikungunya[13], which suggests the modern significance of HCC as a disease entity to be dealt with in clinical practice. Additionally, as suggested by previous studies,[14] the increasing number of publications since 1991 may be also be linked to the establishment of the World Wide Web. Further analysis of the articles published in this interval pinpoints peak research activity to be in the period from 2006 to 2010. The specific subject matter of these articles provides valuable insight into potential breakthroughs in the field — most importantly, the emergence of sorafenib as a novel therapeutic agent for HCC.

During the 2006-2010 periods alone, 5 articles (out of the 29 published during these years) were seen to explore the therapeutic potential of sorafenib. Collectively, these randomized controlled trials (RCTs) and experimental studies served to highlight the significant survival benefit and acceptable tolerance to sorafenib, which may be responsible for a shift in treatment strategies. While sorafenib-based studies were found to predominate in the 2006-2010 period, the majority of articles focusing on liver transplantation or resection were published from 1993 to 2001, whereas articles exploring chemoembolization and radiofrequency ablation for unresectable tumors were published mainly from 1995 to 2003. Overall, this signifies a growing interest in applying targeted therapeutics to the field of HCC.

Additionally, analysis of the top-cited articles also shows a sudden decline in research activity from 2011 to 2015 after the exponential increase. This may simply be attributed to the temporal disadvantage of newer articles, given that they have had little time to garner citations. The introduction of a ranking by citations-per-year (Table 1) reduces this bias considerably and emphasizes the significance of recently-published articles higher up in this ranking. On the other hand, the past 5-6 years have also seen the publication and frequent updating of reviews and clinical guidelines in favor of original articles.

Content

Survey of the findings and rationale of the top 10 most-cited articles allows clear identification of the gaps in literature bridged by these studies, and puts their contribution to the field of HCC into perspective. Excluding clinical guidelines, 2 of the top 10 most-cited articles provide clinical evidence of the therapeutic benefit of sorafenib in advanced HCC, while another study highlights liver transplantation as an effective treatment. Apart from clinical studies, 3 of the highest-cited articles review the epidemiological aspects of HCC; proposing strategies for prevention and prognostication in view of known risk factors, defining molecular pathways, and underlining the shifting incidence of HCC from older to younger patient populations over time.

Among pathophysiology-based articles, the relationship between HCC incidence and hepatitis B or C seems to be of particular interest, as well as the role of genetic alterations such as p53 mutations. More importantly, the increasing number of citations garnered by management-based articles in recent years may align with attempts being made towards the development and assessment of curative procedures for HCC. Although the initial percentage of articles discussing management in the top 100 list is 24%, this increases to 35% in the top 40 most-cited articles and 70% in the top 10 most-cited articles. This pattern is also reflected in the citations-per-year ranking, indicating that the exceptionally high citation counts of management articles are not attributable to earlier publication. In comparison with bibliometric analyses of other hepatic pathologies, the literature exploring Budd-Chiari syndrome shows a similar focus on clinical reports[15], while studies on non-alcoholic fatty liver disease favor pathogenesis and epidemiology[16].

Journals

Table 3 summarizes the journals that most frequently contained the top-cited articles, along with their respective impact factors. The highest numbers of articles were found to be published in the specialty journal Hepatology. Overall, however, our analysis shows a fairly even distribution of articles to general versus specialty journals (52% vs. 48% respectively). Moreover, the broad readership and high impact factors of journals such as New England Journal of Medicine, The Lancet and Nature indicate the importance of these studies and their results to the scientific community as a whole. Such high-impact journals (impact factor ≥ 30) represent 35% of all publications in the list, while the median impact factor for journals in our list was 15.2. This figure is higher than that reported for citation classics in other fields such as gastric cancer[8] (median impact factor 9.28), reinforcing the relative impact of HCC in academic research.

Unlike several fields such as cardiovascular[7], diabetes[5] and thrombolytics[17] research, our analysis did not identify a correlation between journal impact factor and the number of top-cited articles published in that journal. This may be related to the near-equal contribution of specialty journals among the top 100 cited articles, as these journals tend to have narrower readership- indicating the need for and importance of sub-specialized expertise in the field of HCC.

Origins and Authors

As denoted in Figure 2, USA has contributed the highest number of top-cited articles to HCC literature by a large margin, followed by Western European countries. These findings are unsurprising, given the number of established research institutes in the US and the widespread availability of resources. Furthermore, 31% of articles were found to be multi-origin, thus implying open exchange of information across borders and solidifying the role of such international exchange in producing high-quality research. Apart from this, the overwhelming disease burden of HCC in sub-Saharan Africa and Eastern Asia[18] strongly encourages a global effort to increase the productivity of these countries so as to evaluate these populations more thoroughly.

In terms of authorship, it is interesting to note that the author and institute with the highest number of publications originate from Spain, rather than USA. The recognition of individual authors helps to identify significant influences in the field of research and potentially cements the increased value of their work. However, only 6 authors were found to contribute more than 5 articles to the top 100 list, which may indicate a lack of prominent thought leaders despite the high overall productivity of the field.

Figure 2 Number of articles originating from each country.

Limitations

As a citation classic, this analysis is subject to various types of bias that may interfere with accurate representation by citation count. This includes institutional bias, language bias, powerful person bias, and in-house bias[19]. We calculated self-citations among the total number of citations, and found them to be around 3%, indicating that bias resulting from self-citations is minimal in our analysis. Furthermore, we utilized only one database in our study to collect references, which may have resulted in the omission of articles not recognized by Scopus. Finally, despite the production of a separate list by citations-per-year, high-quality articles published in 2015 or later require a certain number of years to garner citation counts reflecting their impact, due to which any such recent articles would likely be excluded from our list.

ACKNOWLEDGMENTS

No conflict of commercial, personal, political, intellectual, or religious interests.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

REFERENCES

1. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Fürst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M6, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topór-Mądry R, Tran B, Ukwaja, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol 2017; 3: 1683-1691. [PMID: 28983565]; [PMCID: PMC5824275]; [DOI: 10.1001/jamaoncol.2017.3055]

2. Hung BT, Long NP, Hung le P, Luan NT, Anh NH, Nghi TD, Hieu MV, Trang NT, Rafidinarivo HF, Anh NK, Hawkes D, Huy NT, Hirayama K. Research trends in evidence-based medicine: a joinpoint regression analysis of more than 50 years of publication data. PLoS One 2015; 10: e0121054. [PMID: 25849641]; [PMCID: PMC4388379]; [DOI: 10.1371/journal.pone.0121054]

3. Moed HF. The impact-factors debate: the ISI’s uses and limits. Nature 2002; 415: 731-732. [PMID: 11845176]; [DOI: 10.1038/415731a]

4. Choudhri AF, Siddiqui A, Khan NR, Cohen HL. Understanding bibliometric parameters and analysis. Radiographics 2015; 35: 736-746. [PMID: 25969932]; [DOI: 10.1148/rg.2015140036]

5. Shuaib W, Costa JL. Anatomy of success: 100 most cited articles in diabetes research. Ther Adv Endocrinol Metab 2015; 6: 163-173. [PMID: 26301066]; [PMCID: PMC4525126]; [DOI: 10.1177/2042018815580254]

6. Li Q, Jiang Y. Top classic citations in pancreatic cancer research. World J Surg Oncol 2016; 14: 298. [PMID: 27899147]; [PMCID: PMC5129593]; [DOI: 10.1186/s12957-016-1061-8]

7. Shuaib W, Khan MS, Shahid H, Valdes EA, Alweis R. Bibliometric analysis of the top 100 cited cardiovascular articles. Am J Cardiol 2015; 115: 972-981. [PMID: 25670637]; [DOI: 10.1016/j.amjcard.2015.01.029]

8. Powell AG, Hughes DL, Wheat JR, Lewis WG. The 100 most influential manuscripts in gastric cancer: A bibliometric analysis. Int J Surg 2016; 28: 83-90. [PMID: 26873521]; [DOI: 10.1016/j.ijsu.2016.02.028]

9. Wrafter PF, Connelly TM, Khan J, Devane L, Kelly J, Joyce WP. The 100 most influential manuscripts in colorectal cancer: A bibliometric analysis. Surgeon 2016; 14: 327-336. [PMID: 27091391]; [DOI: 10.1016/j.surge.2016.03.001]

10. Powell AG, Hughes DL, Brown J, Larsen M, Witherspoon J, Lewis WG. Esophageal cancer’s 100 most influential manuscripts: a bibliometric analysis. Dis Esophagus 2017; 30: 1-8. [PMID: 28375483]; [DOI: 10.1093/dote/dow039]

11. Khan MS, Usman MS, Fatima K, Hashmani N, Siddiqi TJ, Riaz H, Khan AR, Khosa F. Characteristics of Highly Cited Articles in Interventional Cardiology. Am J Cardiol 2017; 120: 2100-2109. [PMID: 28964383]; [DOI: 10.1016/j.amjcard.2017.08.030]

12. Falagas ME, Pitsouni EI, Malietzis GA, Pappas G. Comparison of PubMed, Scopus, Web of Science, and Google Scholar: strengths and weaknesses. FASEB J 2008; 22: 338-342. [PMID: 17884971]; [DOI: 10.1096/fj.07-9492LSF]

13. Vera-Polania F, Munoz-Urbano M, Banol-Giraldo AM, Jimenez-Rincon M, Granados-Alvarez S, Rodriguez-Morales AJ. Bibliometric assessment of scientific production of literature on chikungunya. J Infect Public Health 2015; 8: 386-388. [PMID: 25937447]; [DOI: 10.1016/j.jiph.2015.03.006]

14. Schmidt S, Bundschuh M, Scutaru C, Klingelhoefer D, Groneberg DA, Gerber A: Hepatitis B. Global scientific development from a critical point of view. J Viral Hepat 2014; 21: 786-793. [PMID: 24205854]; [DOI: 10.1111/jvh.12205]

15. Qi X, Jia J, Ren W, Yang M, De Stefano V, Wang J, Fan D. Scientific publications on portal vein thrombosis and Budd-Chiari syndrome: a global survey of the literature. J Gastrointestin Liver Dis 2014; 23: 65-71. [PMID: 24689099]

16. Zhang TS, Qin HL, Wang T, Li HT, Li H, Xia SH, Xiang XH. Global publication trends and research hotspots of nonalcoholic fatty liver disease: a bibliometric analysis and systematic review. Springerplus 2015, 4: 776. [PMID: 26697286]; [PMCID: PMC4678134]; [DOI: 10.1186/s40064-015-1542-1]

17. Siddiqi TJ, Usman MS, Khan MS, Fatima K, Norbash A, Qureshi AI, Khan AR, Khosa F. The 100 Most Influential Papers in the Field of Thrombolytic Therapy: A Bibliometric Analysis. Am J Cardiovasc Drugs 2017; 17: 319-333. [PMID: 28349275]; [DOI: 10.1007/s40256-017-0227-2]

18. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013; 47 Suppl: S2-6. [PMID: 23632345]; [PMCID: PMC3683119]; [DOI: 10.1097/MCG.0b013e3182872f29]

19. Garfield E. Journal impact factor: a brief review. CMAJ 1999; 161: 979-980. [PMID: 10551195]; [PMCID: PMC1230709]

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.