The 100 top-cited studies in cancer immunotherapy

Abstract Objective The objective of the current study was to identify the 100 top-cited studies in cancer immunotherapy. Materials and methods A retrospective bibliometric analysis was performed in March 2019. Studies were searched on the Web of Science to identify the 100 top-cited studies in cancer immunotherapy. Studies were identified and analysed for authorship, journal, study type, year of publication and institution. Results The 100 top-cited papers were cited from 591 to 5332 times and were published between 1986 and 2016. They were published in 27 journals, and New England Journal of Medicine published most of the studies (n = 14), followed by Nature (n = 11) and Journal of Clinical Oncology (n = 10). They were published from 10 countries, and the USA published most of the studies (n = 82), followed by France (n = 5) and Netherlands (n = 3). National Cancer Institute in USA was the leading institution and Rosenberg, SA was the most productive author. Conclusions This study provides insights into development and most important papers in cancer immunotherapy and will provide evidence for future research in cancer immunotherapy.


Introduction
Cancer immunotherapy is a therapy used to combat cancer by involving or using the components of the immune system [1]. The current cancer immunotherapy involves three approaches including the blockage of immune checkpoints, adoptive cellular therapy and vaccination [2][3][4][5]. In the past 20 years, significant progress has been achieved in cancer immunotherapy. Notably, the Nobel Prize in Physiology or Medicine 2018 awarded the discovery of cancer immunotherapy [6,7]. Up to now, advancements of cancer immunotherapy are mainly reflected by scientific articles, especially by using the bibliometrics analysis [7].
Bibliometrics is an analysis of written publications such as books and articles [8]. It has been used to quantitative research assessment exercise of academic output and provides evidence for funding [9,10]. Citation analysis is the main bibliometrics method [11]. The number of citations is not only the indicator of the impact of an article in the scientific community but also the basis of impact factor [12]. Highly cited papers are considered as the fundamental of research fields [13,14]. Therefore, analysis of highly cited or top cited articles can provide information about scientific progress and research trends in a specific discipline [12].
There have been some studies which were used to assess the top-cited articles in various research fields, such as tuberculosis [15], diabetes [16], surgery [17], anaesthesiology [18], rehabilitation [19], vaccine [20], etc. However, no such study for cancer immunotherapy has been published. Therefore, we performed the current bibliometric analysis to assess the 100 top-cited articles for cancer immunotherapy.

Materials and methods
This was a retrospective bibliometric analysis which did not involve human subjects [12], thus it was not needed to be approved by the institutional review board.
immunotherapy. Disagreements were resolved by discussion. Only articles that focused on the subject of cancer immunotherapy were included. A cancer immunotherapy article was defined as any study that focused on any immunotherapy for any cancer. Articles about studies conducted using other therapy for cancer but mentioned immunotherapy was excluded. In addition, studies that analysed the immune factors which have potential effect for cancer were also excluded.

Data extraction
After all 100 top-cited articles were selected, data were extracted by two authors [13]. The following data were extracted [13], including title, citation number, publication year, number of authors, name of first author and corresponding author, source journal, impact factor of the journal, article types.

Data analysis
Data analyses were performed to determine study type, country, year of publication, journal title, authorship, institution, as previously described [13]. All of the data were presented by using only descriptive statistics, and no statistical significance tests were performed [12].

Results
The 100 top-cited articles are listed in Table 1. The 100 topcited articles were identified on the basis of their citations, and the number of citations ranged from 591 to 5332 with a total number of citations equal to 103,763 and a median number of citations equal to 812.5.
These papers were published in 27 journals ( Table 2). The highest number was from the New England Journal of Medicine (n ¼ 14), followed by Nature (n ¼ 11) and Journal of Clinical Oncology (n ¼ 10). Other journals like Science Translational Medicine, Nature Reviews Cancer, Journal of Experimental Medicine, Nature Medicine and Nature Reviews Immunology had at least five but less than 10 articles. The other 19 journals had less than five articles. The impact factors of all the journals ranged from 4.225 to 79.26. All articles were published during a span of 31 years from 1986 to 2016 (Table 3). The maximum number of articles were published in 2011 and 2012 (n ¼ 9), and for a five-year period, the maximum contribution was made by 2011-2015 (n ¼ 32).
Of all the 100 articles, 72 articles were original articles, 28 were reviews (Table 4). Among the 72 original articles, there were 43 basic researches, 28 trials and one case report. The average citations of trials were much higher those of the basic researches.
A total of 10 countries contributed to the top 100 cited articles ( Table 5). The USA contributed most of the articles with 83 papers, France contributed five papers, while Argentina, China, Australia, Belgium, England, Germany, Japan and Netherlands each contributed less than five studies.
Among the 100 articles, 17 institutions contributed more than one article ( Table 6). The 17 institutions were from four countries, including USA (n ¼ 14), France (n ¼ 1), Netherlands (n ¼ 1) and Belgium (n ¼ 1). The top four contributors were National Cancer Institute in USA (n ¼ 21), Johns Hopkins University in USA (n ¼ 6), Baylor Institution Immunology Research in USA (n ¼ 4) and French National Institute of Health and Medical Research in France (n ¼ 4).
There were 11 authors contributed more than one article as first author, and 12 authors contributed more than one article as the corresponding author (Table 7). Rosenberg, SA contributed the highest number of papers as both corresponding author (n ¼ 13) and first author (n ¼ 8).

Discussion
Given the high burden of cancer, there has been great productivity of cancer research. In the past two decades, cancer immunotherapy is the most promise research field for the treatment of cancer. Although there have been several citation analyses concerning various cancers [117][118][119], yet there has been no such study for cancer immunotherapy to describe the research trends. Given cancer immunotherapy awarded by Nobel Prize last year, thus, we performed the current study.
The top 100 most-cited articles were published in 33 different journals between 1986 and 2016. New England Journal of Medicine was the most frequent journal in our list, with 14 articles, followed by Nature and Journal of Clinical Oncology. Other top journals include Science Translational Medicine, Nature Reviews Cancer, Journal of Experimental Medicine, Nature Medicine and Nature Reviews Immunology.
Our study encompasses a wide variety of authors, institutions and countries. The USA had a powerful influence, 83% of articles were originated from the institution in that country, whereas the other several countries contributed the remaining papers. When we examined the publications by individual authors, we found Rosenberg SA contributed most of the topcited papers as first author and corresponding author. It is very surprising that both the two Nobel prize winners James P. Allison and Tasuku Honjo were not listed in top-cited papers as contact author and first author. In the 100 top-cited papers, there were only four papers co-authored by Allison [41,46,89,99], while there was no paper co-authored by Tasuku Honjo. It was possible that their papers might have not so many citations. However, their papers would be cited more time in the next few years, because everyone knows them now and would like to cite their studies.
Like many previous bibliometric analyses, our study also has some limitations [120]. First, citation analysis was based on the Web of Science, citation numbers might be misleading [11,120], owing to self-citations, sub-publications and time of publications, we may have missed some important papers which have been indexed by other databases, such as Scopus and Google [19]. Second, as for the authorship, we only included the first author and corresponding author. It is possible that several authors will have co-authored papers The blockade of immune checkpoints in cancer immunotherapy [21] Nature Reviews Cancer  Review  3887  2012  13  22437870 Safety and activity of anti-PD-L1 antibody in patients with advanced cancer [3] New England Journal of Medicine   Trial  3440  2012  11  22658128 Sipuleucel-T immunotherapy for castrationresistant prostate cancer [22] New England Journal of Medicine   Trial  2759  2010  12  20818862 Vaccination of melanoma patients with peptideor tumor lysate-pulsed dendritic cells [23] Nature Medicine Basic research 2349 1998 5 9500607 Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion [24] Nature  Oncology meets immunology: the cancerimmunity cycle [50] Immunity Review 995 2013 10 23890059 Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer [51] New England Journal of Medicine      and therefore be underrepresented in the current study [11]. Third, searching based on title and contents means a small number of manuscripts which involving cancer immunotherapy might not have been identified [12].
In conclusion, our study provides a comprehensive list of the true landmark publication in cancer immunotherapy and recognizes contributions made by essential authors, institutions, published scientific journals, research types. Given the high burden of cancer, cancer immunotherapy remains an important research area. Increased research productivity is clearly indicated on numerous fronts of cancer immunotherapy.

Disclosure statement
No potential conflict of interest was reported by the authors.

Ethics committee approval
This is a bibliometric analysis, so ethics approval is not applicable.