Knowledge mapping of immunotherapy for thyroid cancer from 1980 to 2022: A review

With the gradual development of immunotherapy for thyroid cancer, relevant research has increased. To better understand the current situation, development trend, evolution process, and research hotspots of this field, we conducted this comprehensive bibliometrics visual analysis. We retrieved papers published from 1980 to 2022 from Web of Science Core Collection on January 31, 2023. CiteSpace, Pajek, VOSviewer, R-Bibliometrix, and Scimago Graphics are the tools to perform the analysis. Analysis methods mainly include co-occurrence analysis and cluster analysis. Analysis objects are countries or regions, institutions, authors, journals, and keywords, etc. In terms of publication number, the recent decade has witnessed rapid growth. USA was the most prolific country and has the most influence in the cooperation team. Sweden took the lead in focus on this research field and lasted for 21 years. Garden State Cancer Center was released most papers (28). INSERM played a major role in institutional cooperation. Goldenberg DM published the most papers (48), with H-Index 25 and G-Index 43. Journal of Nuclear Medicine has the greatest papers published (41). The average impactor factor of the top 10 journals is 7.2058. The top keywords with high burst strength are: radioimmunotherapy (14.85), monoclonal antibody (13.78), non hodgkins lymphoma (12.54). The research field of immunotherapy for thyroid cancer will be further developed. This study provides a valuable reference for future research in the field.


Introduction
Thyroid cancer (TC) is a very common endocrine malignant tumor, unlike many other malignant tumors, TC has the unique characteristic of being able to affect individuals of all age groups, including children, with the median age at diagnosis being 51 years, approximately 43% of new cases occur in individuals aged between 45 and 64 years.TC often presents with neck nodules, lumps, swelling, pain, and swallowing, dyspnea, cough and other symptoms.There are 3 most common histologic subtypes of thyroid cancer, that is, papillary thyroid cancer, follicular thyroid cancer, and Hurthle cell cancer.Papillary thyroid cancer is the most common type, accounting for about 90% of new cases and the prognosis is good.Depending on a survey, the morbidity of TC has tripled in the last 30 years. [1]owever, due to its slow growth and hidden symptoms.[4][5] A small number of thyroid nodules were detected during physical examination.Most thyroid nodules can be identified by ultrasonography. [6][9] Technologies like computed tomography, magnetic resonance imaging and fine needle aspiration cytology are often used to diagnose TC. [10] At present, whether there are suitable biomarkers to diagnose TC is still controversial. [11]here are many therapies to intervene in TC, such as thyroidectomy and lymph node dissection when the disease is limited to local structures.For different TC, radioactive iodine is used for treating radiosensitive TC. [12] For metastatic TC, Adriamycin is used in cytotoxic chemotherapy. [13]Targeted agents are part of the current standard treatment methods for TC when it has spread beyond the thyroid gland (metastatic disease) and cannot be effectively treated with surgery or radioactive iodine therapy. [14][17] Since approval of immune checkpoint inhibitors as the main immunotherapy for cancers by Food and Drug Administration of USA in 2011, it has become one of the pillar therapies for cancer treatment. [18][21] It has also been widely applied in TC. [12,[22][23][24][25][26] With the wide application of immunotherapy in TC, a large number of related studies have emerged, accompanied by the publication of scientific papers.Bibliometrics is the application of mathematical and statistical methods to analyze data in relevant research fields.Some bibliometric analyses have analyzed immunotherapy for different cancers, [27][28][29][30] but as far as we know, there is no bibliometric analysis of immunotherapy for TC.In order to clearly understand the development status of this field, this study applies the bibliometric method to visualize and analyze the relevant papers of immunotherapy for TC.

Materials and methods
Figure 1 shows the flow chart of this study.First, search and download relevant paper data from the database.The visualization software programs of bibliometrics are used for co-occurrence analysis, frequency analysis and cluster analysis to analyze the relevant contents of countries or regions, institutions, journals, keywords, etc.The purpose of the research is to obtain the overview, development trend, cooperation team, and research hotspot of the research field.

Analysis methods and tools
We used descriptive and co-occurrence analysis methods to analyze the obtained data. [31,32]CiteSpace (6.1.R6), Pajek (64 5.16), VOSviewer (1.6.17), and Scimago Graphics (Beta 1.0.26)35][36][37][38][39][40][41] These software programs are based on co-occurrence analysis and cluster analysis to analyze the cooperation relationship between items such as countries or regions, institutions, authors and the cluster of keywords. [34,42]In general, the size of items (nodes) in the map indicates the value of the item, such as the number of published papers or citation.The number and thickness of links between nodes shows the relationship between them.Centrality shows the importance of a member of a cooperative team.][45][46] R-Bibliometrix was utilized to analyze the thematic evolution and trend. [47,48] Results

Publication output analysis
In all 963 articles, the first article appeared in 1983. [49]Figure 2 shows the trend of publishing volume changes by year.The period from 1984 to 1989 showed that there was not any relevant paper published.From 2 papers in 1990 to 13 papers in 1997, it is a slow growth process.From 1999 to 2009, it was a plateau period, with an annual volume of about 20 papers.There was a slight decline in the next 3 years after 2010.Then the number of papers increased rapidly from 13 in 2013 to 157 in 2022.In the last 10 years, it accounted for 66% of the total number of papers published.

Analysis of countries or regions
A total of 963 papers have been produced in 56 countries or regions.Table 1 shows the top 10 countries in terms of the publication number.USA is the 1 with the highest volume of documents (365).It is greater than twice that of China (168), which ranks second.Figure 3 shows the map of national or regional cooperation.Each node represents a country or region.The size of each node represents the number of published papers.The number and thickness of links between nodes indicate the strength of their cooperation relationship.Figure 3A shows the map of countries or regions according to the proportion of published papers.Different colors represent different clusters, and countries or regions with the same color represent closer cooperation.The size of the area of each country or region indicates the number of published papers in this research field.Figure 3B shows the world distribution map of national or regional cooperation.The research in this field is distributed in all continents, but mainly concentrated in economically developed countries or regions.Figure 3C shows the cooperation relationship between countries in a circular map.Countries or regions with close cooperation constitute a cluster in the same color.Those that do not constitute a cooperative relationship with other countries or regions form their own clusters.There are 17 clusters in total, and 10 clusters are relatively large and representative, clusters representing different cooperation teams.The first cluster is green, its main members are Italy, Netherlands, Canada; The second cluster is blue, its members are France, Spain, Australia, Belgium, Brazil; The third cluster is orange, its members are USA, Romania, Argentina; The 4th cluster is purple, its members are Switzerland, Poland, Portugal, Singapore; The fifth cluster is dark orange, its members are Japan, India, Iran.The nodes in Figure 3D show the change of the country or region from the inside to the outside, transition from dark blue to green and then yellow, and the time from far to near.Each ring represents a year.The purple circle around the node indicates that the centrality of the country or region is relatively strong (Table 1).Top prolific countries or regions with high centrality are USA (0.45), France (0.24), Italy (0.16), Germany (0.14), and England (0.14).They play an important connecting role in the cooperative team.The red ring in the node indicates that the burst value of the node is relatively large, and the corresponding ring position indicates the period with high burst value (Fig. 3E).This indicates that they began to pay great attention to this research field at a certain period.Among them, Sweden, USA, Germany, Austria and France began to draw attention to this field relatively early (from 1995 to 2005).China began to focus attention on this research relatively late (2021).However, China has the largest burst strength (29.66), indicating that China has recently invested more in this research field.

Analysis of institutions
A total of 1283 institutions participated in writing of these 963 papers.Table 2 displays the top 10 institutions in terms of publication number, the top 10 institutions published 22.74% of the total.Six of them come from the USA, 2 from France, and the other 2 from Italy and China.Mayo Clin and Univ Texas MD Anderson Canc Ctr have greater academic influence.The average number of citations per paper is 82 and 85 respectively.From the perspective of centrality, the values of INSERM (0.11) and Memorial Sloan Kettering Cancer Center and (0.07) are the highest, indicating that they occupy an important position in the cooperation team.Sixty-seven institutions with cooperative relationships that have published more than or equal to 5 papers were incorporated into the cluster map (Fig. 4).There are 8 clusters in total.Each cluster represents a cooperative team, indicating that their cooperation between the members of the same cluster is relatively close.The first cluster includes institutions sort by frequency: Mayo Clin, Univ Chicago, Wayne State Univ, Inst Gustave Roussy, Gustave Roussy, Stanford Univ, Univ Paris Saclay, Univ Sydney, Univ Pittsburgh, Albert Einstein Coll Med, Univ Bordeaux, Univ Oxford; The second cluster includes: Garden State Canc Ctr, INSERM, Univ Nantes, Univ Hosp, Ctr Mol Med & Immunol, Immunotech Sa, Ibc Pharmaceut Inc, Immunomedics Inc, Gip Arronax, Chu Nantes, Inst Biol; The third cluster includes: Fudan Univ, China Med Univ, Shanghai Jiao Tong Univ, Chinese Acad Med Sci, Chinese Acad Med Sci and Peking Union Med Coll, Huazhong Univ Sci & Technol, Zhejiang Univ, Chinese Acad Sci, Nanjing Med Univ, Zhengzhou Univ; The 4th cluster includes: Univ Texas MD Anderson Canc Ctr, Harvard Med Sch, Univ Calif San Francisco, Univ Michigan, Vanderbilt Univ, Harvard Univ, Sun Yat Sen Univ, Univ Calif Davis, Brigham and Womens Hosp; The 5th cluster includes: Univ Pisa, Univ Naples Federico Ii, Sapienza Univ Rome, Univ Messina, Univ Padua, Univ Perugia, Univ Toronto, CNR.

Analysis of authors
A total of 5280 authors participated in the creation of 963 papers.Table 3 lists the top 10 authors in the number of publishing articles.Indicators such as h-index, g-index and m-index are listed respectively.[52][53][54] In terms of the number and influence of published papers, the top 6 authors are all ranked high.Bodet-milin C, ranked 10th in the number of published papers, started late (2006).Although the number of papers is not large (12), the M-Index is high (0.5), which indicates that this author has great impact.
Figure 5 displays the author's clustering map.It shows the author's cooperation.A total of 99 authors who have published more than 2 articles and have cooperative relations are illustrated in the figure.There are 6 clusters.Different colors represent different cooperation teams (Fig. 5A). Figure 5B shows the cooperation happened between different authors or teams timely.The change of time from far to near is purple, green, and yellow respectively.Figure 5C and Figure 5D are expanded maps of the teams.From the comparison of the 2 figures (Figure 5C and Figure 5D), the links between the authors are not strong.It shows that mature cooperation between authors in this field has not yet been formed.

Analysis of journals
A total of 384 journals have included the 963 papers.Table 4 displays the top 10 journals with the highest productivity.The papers printed in the top 10 journals account for 22.74% of all papers.Journal of Nuclear Medicine has the greatest papers published, with 41 articles.It holds the highest H-Index (25) and G-Index (41)

Analysis of keywords
A total of 4121 keywords were extracted from 963 papers, including 2358 Keywords Plus and 1763 author's keywords.Figure 6A shows the word cloud of the top 200 Keywords.The size of the font indicates the frequency.The top 10 keywords are: immunotherapy (232), thyroid cancer (76), radioimmunotherapy (70), immune checkpoint inhibitors (54), cancer (41), nivolumab (37), anaplastic thyroid cancer (33), prognosis (33).Figure 6B shows the thematic evolution map.Each column represents a time slice.With the change of time, different keywords

Analysis of burst keywords
Burst keyword indicates that a topic has received more attention in a certain period of time. [55]Figure 7 displays the top 25 keywords with the strongest bursts.The first burst keyword appeared in 1990 was the activated killer cell, which lasted 16 years until 2005.In terms of burst strength, the top 3 are: radioimmunotherapy (14.85), monoclonal antibody (13.78), non hodgkins lymphoma (12.54).The keywords that have received  more attention in the past 2 decades include bivalent hapten, dendritic cell, positron-emission tomography, regulatory t cell, metastatic melanoma, ipilimumab, advanced melanoma, adverse event, immune checkpoint inhibitor, management, papillary, blockade, nivolumab.

Analysis of citation
All 963 papers were cited 26,991 time.The average citations per paper was 28.03.The h-index was 82.The top 10 highly cited articles are presented in Table 5. Six of the top 10 articles were published after 2015, indicating that research in this field has made rapid progress and that very new articles can receive more attention in a short period of time.These highly cited papers have confirmed the efficacy of immunotherapy, and also discussed the side effects or adverse effects of immunotherapy.The mechanism and safety of immunotherapy are the main topics that scholars take an interest in.The article with the highest number of citations was published by Marabelle, Aurelien et al in 2020. [34]They performed a retrospective study of pembrolizumab monotherapy in 1066 patients with 10 types of unresectable or metastatic tumors, including thyroid cancer.They concluded that high tissue tumor mutational burden may be a new and useful predictive biomarker for the response to the therapy.The second article is a review of the adverse events profile of anti-programmed cell death-1 or anti cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibodies. [56]The third high cited article believed that the treatment of low-grade or transformed non-Hodgkin lymphoma with iodine I-131 tositumomab has good responses. [57]The 4th article is  Osmani, Lais et al [58] review of World Health Organization's classification of non-small cell lung-cancer published in 2018.They think accurate subclassification is very important.Biomarkers is necessary to determine the subclassification of lung-cancer patients in the process of targeted therapies and immunotherapy or monitoring the response of the therapies.Byun, David J. et al [59] discussed in their review about the clinical management of the endocrinopathies including thyroid dysfunctions base on the mechanisms of immune-related adverse events.The research of Ances, BM et al [60] was based on Brain MRI and [F-18] fluorodeoxyglucose -PET assisted imaging suggested several antigens were strongly expressed in the hippocampus neuropil, and the immune marker pattern is sufficient to prompt the diagnosis and predict the treatment response of relate diseases.Another system review written by Abdel-Wahab, Noha et al [61] is about cancer treatment by using  antibodies like immune checkpoint blockade adverse effect of immunotherapy.They found out that these types of immunotherapies can lead to autoimmune systemic diseases such as autoimmune colitis, hepatitis, lupus, celiac disease, endocrinopathy, cutaneous, sarcoidosis, polyarthritis, polymyalgia rheumatica, dermatomyositis.Corsello, Salvatore Maria et al [62] introduced the endocrine adverse effects, such as hypophysitis, abnormal thyroid function caused by immunotherapy in their review.However, research on the mechanism and epidemiological investigation of these side effects are not enough.Loibl, S.; Untch, M. et al [63] randomized phase-II study showed that pathological complete response can be increased by the application of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy.Goldenberg, DM et al [64] have obtained positive clinical efficacy in the treatment of malignant thyroid with tumor expressing carcinoembryonic antigen by using bispecific antibodies with hapten-radionuclides.

Discussion
TC is a very common endocrine tumor.More than 90% of TC has a good prognosis.Recently, the 5-year survival rate reached 98%. [65]The cause of TC is not clear.It says that environmental pollution can cause thyroid disease. [66]Most TC were discovered by ultrasonography, computed tomography, magnetic resonance imaging and fine needle aspiration cytology. [6,10]Artificial intelligence is also for imaging diagnosis of TC. [67] With the increase of TC screening, the morbidity of TC once increased. [1,68]However, due to the change in the scope of screening, the morbidity of TC is on the decline. [69]The morbidity of TC has a certain relationship with countries or regions, and some regions have higher morbidity of TC. [70] In recent years, immunotherapy has been extensively used in cancer treatment including TC. [26,[71][72][73][74][75][76][77][78][79][80][81] In this study, papers on immunotherapy for TC were studied by using bibliometric method.
From 1983, relevant research papers began to appear (Fig. 2).In the first 3 decades, the publication of relevant research papers showed a relatively stable period of sluggish growth.The number of papers published during this period accounts for 1 third of the total number of papers.After that, it began to show a rapid growth process, from 13 papers in 2013 to 157 papers in 2022, an increase of more than 12 times.
From the perspective of national or regional output, the top 5 countries or regions are USA, China, France, Italy, Germany.Output of USA papers exceeds twice that of China.In terms of national and regional cooperation, there are 10 cooperation teams (Fig. 3).The highest 5 cooperation teams are the Europe-America cooperation team composed of Italy, Netherlands and Canada.The second is France, Spain, Australia, Belgium and Brazil constituted the Europe-Oceania-South America cooperation team.The third cooperation team includes USA, Romania and Argentina; the 4th includes Switzerland, Poland, Portugal, Singapore.The fifth includes Japan, India and Iran.In terms of the importance of members in the cooperation team, USA has the highest centrality, which indicates that USA is in the most prominent position in the cooperation relationship.From the perspective of immunotherapy for TC, Sweden, USA, Germany, Austria and France began to pay attention to this research earlier.Sweden attention went on a long time, with a span of more than 20 years from 1995 to 2015.China started to pay more attention to this field late, from 2021 to 2022, but it is burst strength is 29.66.This shows that China's attention to immunotherapy for TC has increased rapidly in the past 2 years.
Of the 1283 institutions that published 963 papers, the top 10 institutions make up about 1, 5th of the total number of papers.Top 10 institutions are mainly from the United States, France, China and Italy.Mayo Clin and Univ Texas MD Anderson Canc Ctr have greater academic influence.INSERM and Memorial Sloan Kettering Cancer Center played a major role in team cooperation.Association of tumor mutational burden with outcomes in patients with advanced solid tumors treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study [51] Marabelle, Aurelien et al Lancet Oncology 54.433 2020 698 174.5 2 Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination [52] Boutros Moving from targeted therapy to immunotherapy [54] Osmani Adverse events associated with immune checkpoint blockade in patients with cancer: A systematic review of case reports [56] Abdel A total of 5280 authors participated in the creation of all papers.Top 99 authors who have published papers equal to or greater than 2 constitute 6 cooperative teams.The strength of cooperation relationship within and between teams is quite weak.This is shown that the large-scale author cooperation team in the field of immunotherapy for TC is relatively immature.
The average citations per paper was 28.03.The h-index of the papers was 82.Six of the top 10 articles were published after 2015 (Table 5), indicating that the highly cited articles in this field are quite new.These highly cited literatures have confirmed the efficacy of immunotherapy, and also discussed the side effects or adverse effects of immunotherapy. [56,59,61,62,64]The mechanism and safety of immunotherapy are the main topics that scholars pay heed to. [57]As well as biomarkers for the response to immunotherapy are discussed. [34,58,63]Some scholars discovered that the combination of lenvatinib and pembrolizumab has a longterm positive effect on Anaplastic thyroid carcinoma and metastatic poorly differentiated thyroid carcinomas, [82] Dabrafenib plus trametinib has a good effect for anaplastic TC. [83] This study is a bibliometric analysis based on mathematical and statistical methods to analyze the literature; it has its limitations.Although the WoSCC is recognized as the authoritative scientific literature database, only using the WoSCC data may lead to some data omission.If other database such as Google Scholar and other databases can be included, the analysis results may be more comprehensive.In terms of data standardization, it is difficult to take care of all data because of the large amount of data.For example, the different writing methods of the same institution led to inaccurate data, such as "Ctr Mol Med and Immunol" and "Ctr Molec Med and Immunol" are processed as 2 different institutions.These could result in bias in the analysis results.However, as the first bibliometric study on immunotherapy for TC, it analyzes the development trend and hotspots of this research field and can provide reference for researchers in this field.

Conclusion
Holistically, a large number of studies have emerged on immunotherapy for TC, especially in the last decade.USA is in a leading position in this research field from the perspective of scientific research output and cooperation.China, which ranks second in the number of published articles, has performed well in this research field in the past 2 years.Among the institutions, the Garden State Cancer Center has the largest number of papers published.Mayo Clinic and University of Texas MD Anderson Cancer Center have greater academic influence.Journal of Nuclear Medicine is the most prolific journal.The research hotspots in the last 5 years include t-cells, carcinoma, expression, cells, adverse events, survival, management, nivolumab, pembrolizumab, blockade, association guidelines, acquired-resistance, dabrafenib.These research hotspots will continue for a while.
In summary, this is the first study on immunotherapy for TC in the way of knowledge map and visualization through bibliometrics.Compared with the conventional reviews, this study uses the research method of bibliometrics to analyze this field.This study provides a valuable reference for future research in the field of immunotherapy for TC.

2. 1 .
Data collection web of science core collection (WoSCC) was selected as the data source.The search queries were: [TS = (thyroid cancer*) OR TS = (thyroid Carcinoma*) OR TS = (thyroid Neoplasm*) OR TS = (thyroid Adenoma*) OR TS = (thyroid tumor*)] AND TS=(*immunotherap*), Time span = January 01, 1980 to December 31, 2022.Searching date: January 01, 2023.A total of 1033 results were obtained.Since the data included in the article does not contain any personal information of patients, ethical approval is not required.

Figure 2 .
Figure 2. The annual output of publication on immunotherapy for thyroid cancer.

Figure 3 .
Figure 3. Map of national or regional cooperation.(A) Map of countries or regions according to the proportion of published papers.(B) World distribution map of national or regional cooperation.(C) Circular chart of national or regional cooperation.(D) The map of cooperation relationship of countries or regions over time.(E) Top 6 Countries with the strongest bursts strength.

Figure 4 .
Figure 4. Institution cluster vertical distribution map on immunotherapy for thyroid cancer.

Figure 5 .
Figure 5. Author cooperation network map on immunotherapy for thyroid cancer.(A) The author's cooperative relationship.(B) The author's cooperative relationship changes over time.(C) The author's cooperative relationship expanded map (links ≥ 1).(D) The author's cooperative relationship expanded map (links ≥ 2).

Figure 6 .
Figure 6.Keyword analysis.(A) Word cloud of the top 200 keywords on immunotherapy for thyroid cancer.(B) Thematic evolution of five time slices on immunotherapy for thyroid cancer.(C) The top 30 keywords of the latest trend topics on immunotherapy for thyroid cancer.(D) Keywords clustering map on immunotherapy for thyroid cancer.

Figure 7 .
Figure 7. Top 25 keywords with the strongest bursts.
. Clinical Cancer Research has the highest impactor factor (IF) 11.082.The average IF of the top 10 journals is 7.2058.In terms of SCI subject category, The Journal of Nuclear Medicine belongs to Radiology, Nuclear Medicine and Medical Imaging category; 4 of the top Journals are in Endocrinology and Metabolism category; 3 of them are in Oncology category; The categories of the other 2 Journals are Immunology and Medicine, Research and Experimental.From the position of journals in SCI subject category, 2 journals rank in the top 10% (2.94%, 6.94%) of the category; 5 in the top 25%; 2 ranking around 30%; this shows that the research field is relatively influential in the industry.

Table 1
Ranking of Top 10 countries or regions on immunotherapy for thyroid cancer.
appear, which represent the emergence of new topics.From 1983 to 2005, the time slice's immunotherapy, radioimmunotherapy, and thyroid cancer was a preliminary development process from the concept.By 2006 to 2016, the molecular imaging, and to 2019, anaplastic thyroid cancer, anaplastic thyroid carcinoma, checkpoint inhibitor, pd-1 (programmeddeath-1), are the

Table 2
Top 10 institutions on Immunotherapy for Thyroid Cancer.

Table 3
Top Ten Authors on Immunotherapy for Thyroid Cancer.

Table 4
Top 10 Journals Publishing Papers on Immunotherapy for Thyroid Cancer.

Table 5
Top ten Cited papers on Immunotherapy for Thyroid Cancer.
. Clinical Cancer Research has the highest IF 11.082.The average IF of the top 10 journals is 7.2058.This shows that the field has received considerable attention.In terms of SCI subject category, The Journal of Nuclear Medicine belongs to Radiology, Nuclear Medicine and Medical Imaging category; 4 of them are in Endocrinology and Metabolism category; 3 of them are in Oncology category.From the position of journals in SCI subject category, most journals rank high in SCI category.Two journals rank in the top 10% (2.94%, 6.94%) of their categories; 5 in the highest 25%; 2 ranking around 30%; this shows that the research field is relatively influential in the industry.