1. Introduction

Bone malignancies (BM) include osteosarcoma, Ewing’s sarcoma, chondrosarcoma, and chordoma, among others. BM typically arises from genetic mutations and epigenetic changes, including DNA methylation and histone modifications that are correlated with an unfavorable prognosis in the condition.[1,2] BM can induce a range of symptoms, including bone pain and fractures, leading to a substantial impact on the patients’ quality of life. Moreover, the elevated mortality rate associated with BM can result in emotional distress, depression, and even suicidal tendencies among patients.[3] Common treatment modalities for BM encompass surgical intervention, neoadjuvant chemotherapy, and adjuvant chemotherapy.[4,5] The advancement of molecular biomarker research has paved the way for the gradual integration of targeted therapy in BM treatment. Multifaceted antiangiogenic targeted drugs comprising small molecules, including sorafenib, apatinib, and others, such as tyrosine kinase inhibitors, have demonstrably enhanced patient survival rates. Nevertheless, treatments for patients with metastatic or recurrent BM continue to stagnate,[6] and the prognosis has not experienced substantial improvement.

Over the past decade, immunotherapy, including the interaction between immune checkpoints, has demonstrated promising therapeutic effects in treating various malignant tumors.[7] This approach holds significant potential for cancer treatment. Tumor immunotherapy reactivates and sustains the body’s immune system by reinstating the “tumor-immune cycle” and eliminating tumor cells.[8] However, in inoperable BM, the overall survival rate is currently low, possibly due to resistance and early hematogenous metastasis. Additionally, chemotherapy resistance and tumor immune evasion are common challenges in current treatment methods. These limitations are further compounded by cancer stem cells and the microenvironment.[9] Immunotherapy encompasses the use of cytokines, tumor vaccines, immune checkpoint inhibitors, and immune regulators.[10] Notably, Zheng et al discovered a close association between the expression of programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) in osteosarcoma and patient prognosis. Their in vitro and animal experiments revealed that PD-1/PD-L1 inhibitors partially alleviate the malignant progression of osteosarcoma.[11] Moreover, Ghisoli et al[12] reported a significant improvement in the survival rate of Ewing’s Sarcoma patients following treatment with the FANG (Vigil) vaccine. Furthermore, the PD-1 inhibitor nivolumab was found to alleviate the progression of Chondrosarcoma and Chordoma.[13,14] Currently, ongoing clinical trials are being conducted on immunotherapy for BM, cementing its place as an integral component of future treatment strategies. However, the existing literature on immunotherapy for BM lacks systematic organization, resulting in confusion regarding relevant knowledge gaps and inhibiting researchers from effectively comprehending the development trends in this field.

Bibliometrics is a mathematical and statistical approach that integrates keywords, journals, authors, and their affiliations to describe, evaluate, and predict the current status and future trends of scientific and technological development. Its wide application in solving medical issues is well-documented.[15–17] The publication of research studies on immunotherapy for BM is increasing. Nevertheless, there is currently no specific bibliometric research focusing on BM immunotherapy. This study seeked to evaluate the literature on BM immunotherapy from 2010 to 2023, aiming to utilize immunotherapy more effectively to enhance the prognosis of BM patients in future clinical practice. The insights gained from this study have the potential to introduce new perspectives to the treatment strategies for BM in the clinical setting.

2. Materials and methods 2.1. Data collection

Utilized the following search formula to query the Web of Science Core Collection (WoSCC) on July 15, 2023, for articles related to BM immunotherapy from 2010 to July 14, 2023: TS=(“Bone Sarcoma” OR “Osteosarcoma” OR “Ewing Sarcoma” OR “Chondrosarcoma” OR “Chordoma”) AND TS=(“Immunotherapy” OR “Immunotherapies” OR “Immunotherapeutic”). The inclusion criteria for the literature were as follows: Manuscripts needed to relate to BM immunotherapy; only original articles and reviews were considered; the language of the literature had to be English; the WoS index type used was Science Citation Index-Expanded; nonoriginal literature such as conference abstracts, book chapters, editorial material, online publications, conference proceedings papers, and letters were excluded. The following information was extracted after identifying each article: title, keywords, author’s country, institution, abstract, and references. Items from Taiwan were classified as belonging to China in the country analysis, whereas items from England, Scotland, Northern Ireland, and Wales were classified as belonging to the United Kingdom. Download the text in TXT file format. Data collection was independently performed by 2 authors (SKY and KSY), who subsequently resolved any disagreements through negotiation.

2.2. Bibliometric analysis

The main software tools utilized in this study were R (version 4.1.0) with the “bibliometrix” package, VOSviewer (version 1.6.19),[18] Citespace (version 6.2.R4),[19] the Literature Econometrics Online Analysis Platform (http://bibliometric.com/), and Microsoft Excel 2019. Among them, R (version 4.1.0) with the “bibliometrix” package, Microsoft Excel 2019, and VOSviewer (version 1.6.19) were used for data extraction, analysis, and visualization of country, institution, and coauthor information. These tools facilitated the generation of analysis graphs, journal co-citation analysis, and keyword co-occurrence analysis. Citespace (version 6.2.R4) was specifically selected to create keyword and reference co-occurrence detection maps. The following parameters were set for the CiteSpace (version 6.2.R4) software: The time period was set to run from January 2010 to July 2023, with 1 year per slice. Keywords, categories, cited authors, and references were the node types. The top 50 results for each slice were the selection criteria. Pathfinder, sliced networks pruning, and merged network pruning were among the pruning options used. The default settings applied to the remaining parameters. Pruning techniques for sliced networks and merged networks were used. The default settings applied to the remaining parameters. For the VOSviewer (version 1.6.19) software, the following parameter settings were used: the normalization method was set to strength of association; 5 was the minimum threshold for the number of publications from the institution, author, and country/region; 100 was the minimum threshold for the number of journal citations; and 20 was the minimum threshold for the frequency of keyword occurrence. Additionally, the Bibliometrics Online Analysis Platform was employed to determine the number of literature publications per year.

3. Results

A total of 785 articles were initially identified in the WoSCC database. After applying the exclusion criteria, 27 articles were excluded as they were not published between 2010 and 2023. Furthermore, 7 conference abstracts, 10 book chapters, 9 editorial materials, 8 online publications, 2 conference proceedings papers, 1 letter, and 1 meeting were also excluded. Additionally, 1 article written in Polish was excluded. Ultimately, 719 articles that fulfilled the inclusion criteria were included in this study, comprising of 528 treatises and 191 reviews (Fig. 1).

Figure 1.:

Flow chart of literature inclusion and exclusion.

3.1. Country distribution

All articles included in this study originated from 51 different countries. The analysis of annual publications from 2010 to 2022 revealed a general upward trend (Fig. 2A), indicating a growing focus on immunotherapy for BM research. However, there was a decrease in the number of publications in 2023, possibly due to the timing of the statistics. Table 1 presents the top 10 countries in terms of publications during the 2010 to 2023 period. According to the statistical analysis, China ranked first in terms of publications (n = 284, 39.50%), followed by the United States (n = 251, 34.91%), Japan (n = 54, 7.51%), Germany (n = 53, 7.37%), and Italy (n = 41, 5.70%). The trend of national publications over time is illustrated in Figure 2B, with a significant increase observed in China in 2022. Notably, the United States had the highest total number of citations (8013), while Canada had the highest average citations (41.11). In order to explore inter-country collaboration, VOSviewer (version 1.6.19) software was employed, revealing that China and the United States had the closest collaboration (Fig. 2C). Furthermore, Figure 2D presents a temporal overlay of the national/regional cooperation networks, wherein the color of the yellow nodes indicates later average publication timings, while the purple nodes indicate earlier average publication times. The findings indicate that while China, Australia, and Canada began their BM research later, nations like Germany, Japan, and the Netherlands began their research sooner.

Table 1 - Top 10 countries contributing to publications of immunotherapy for bone malignancies. Rank Country Articles Percentage (N/719) Total citations Average citations 1 China 284 39.50 3855 13.57 2 United States of America 251 34.91 8013 31.92 3 Japan 54 7.51 1258 23.30 4 Germany 53 7.37 1907 35.98 5 Italy 41 5.70 1014 24.73 6 France 31 4.31 890 28.70 7 England 27 3.76 888 32.89 8 Netherlands 20 2.78 884 36.83 9 Spain 20 2.78 522 26.10 10 Canada 18 2.50 740 41.11
Figure 2.:

Country analyses of the BM immunotherapy study. (A) The annual number of publications on BM immunotherapy from 2010 to 2023. (B) The number of publications in the top 10 countries for BM immunotherapy from 2010 to 2023. (C) Analysis of the cooperation network among countries in the field of BM immunotherapy. (D) Analysis of major research countries over the period from 2010 to 2023. The circle size represents the number of papers. The breadth of the curves represents the connection strength.

3.2. Institution distribution

A total of 1055 institutions participated in the study on immunotherapy for BM, with 67 of them publishing at least 5 papers (Fig. 3A). These 67 institutions were categorized into 5 groups. The red cluster consisted of Chinese institutions, including Zhejiang University, Shanghai Jiao Tong University, Zhengzhou University, and Sichuan University. The blue cluster included Memorial Sloan Kettering Cancer Center, University of Washington Seattle, and Technical University of Munich. The yellow cluster consisted of the University of Texas MD Anderson Cancer Center, Central South University, and the University of Pittsburgh. The green cluster included Nationwide Children’s Hospital, the University of California Davis, and the University of Minnesota System. Finally, the purple cluster consisted of the National Cancer Institute and Harvard Medical School. There was a close collaboration between institutions in China and the U.S., with the University of Texas MD Anderson Cancer Center being the core institution in the field of BM immunotherapy research and having close links with research centers in many other countries. Additionally, the top 3 institutions in terms of literature publication were the University of Texas MD Anderson Cancer Center (n = 30), Zhejiang University (n = 28), and Memorial Sloan Kettering Cancer Center (n = 24) (Table 2). Chinese and U.S. institutions made major contributions in this area. Among the top 3 institutions in terms of total citations in the literature, the University of Texas MD Anderson Cancer Center ranked first, followed by the National Cancer Institute and Baylor College of Medicine (with 1638, 1015, and 973 citations, respectively) (Table 2). It is evident that most of the high-quality papers come from U.S. institutions. Overlay visualization analysis revealed that during the early years (around 2016), major institutions studying immunotherapy for BM were Memorial Sloan Kettering Cancer Center, Leiden University, and Harvard University. However, in recent years (around 2022), Shanghai Jiao Tong University and Sichuan University have emerged as significant forces (Fig. 3B).

Table 2 - Top 10 contributed institutions in the field of immunotherapy for bone malignancies. Rank Organization Articles Country Rank Organization Citations Country 1 University of Texas MD Anderson Cancer Center 30 United States of America 1 University of Texas MD Anderson Cancer Center 1638 United States of America 2 Zhejiang University 28 China 2 National Cancer Institute 1015 United States of America 3 Memorial Sloan Kettering Cancer Center 24 United States of America 3 Baylor College of Medicine 973 United States of America 4 National Cancer Institute 23 United States of America 4 Texas Children’s Cancer Center 959 United States of America 5 Central South University 23 China 5 Texas Children’s Cancer Center 879 United States of America 6 Shanghai Jiao Tong University 21 China 6 Zhejiang University 689 China 7 Harvard Medical School 13 United States of America 7 University of Pennsylvania 631 United States of America 8 University of California Davis 12 United States of America 8 St Jude Children’s Research Hospital 520 United States of America 9 Peking University 12 China 9 Leiden University 495 Netherlands 10 University of Pennsylvania 11 United States of America 10 Nationwide Children’s Hospital 465 United States of America
Figure 3.:

Network visualization maps of organizations. (A) Analysis of the cooperation network among institutions in the field of BM immunotherapy. (B) Analysis of major research institutions over the period from 2010 to 2023. The circle size represents the number of papers. The breadth of the curves represents the connection strength.

3.3. Analysis of authors and cited authors

All papers sampled on immunotherapy for BM were authored by a total of 4432 individuals. We visualized the collaborations among 73 authors who have published more than 5 studies in this field. The top 5 most prolific authors were Dean A. Lee (n = 12), Zhaoming Ye (n = 11), Binghao Li (n = 10), Toshihiko Torigoe (n = 10), and Tomohide Tsukahara (n = 10) (Table 3). Additionally, the top 5 most cited authors were Richard Gorlick, Nai-Kong V. Cheung, Eugenie S. Kleinerman, Yi Huang, and Wei Guo, with a total of 576, 401, 399, 352, and 349 citations respectively. These authors primarily hail from the United States, China, and Japan. Moreover, as illustrated in Figure 4A, the author group centered around Zhaoming Ye from China and Dean A. Lee from the US exhibited close collaborations with other author groups. Figure 4B depicts the graph of author impact over time. Based on the number of publications and citation, Wei Guo may be regarded as an influential researcher in the field of immunotherapy for BM after 2020. Subsequently, we employed Bibliometrix in R software (v4.1.0) to generate the “author output over time” graph (Fig. 4C), which revealed that Zhaoming Ye, Yong Zhou, Toshihiko Torigoe, and Tomohide Tsukahara have been conducting research in this field for the longest period of 13 years and have continued to publish new works this year.

Table 3 - Top 10 most productive and cited authors in the field of bone malignancies immunotherapy. Rank Author Articles Country Rank Author Citations Country 1 Dean A. Lee 12 United States of America 1 Richard Gorlick 576 United States of America 2 Zhaoming Ye 11 China 2 Nai-Kong V. Cheung 401 United States of America 3 Binghao Li 10 China 3 Eugenie S. Kleinerman 399 United States of America 4 Toshihiko Torigoe 10 Japan 4 Yi Huang 352 China 5 Tomohide Tsukahara 10 Japan 5 Wei Guo 349 China 6 Wei Guo 10 China 6 Zhenfeng Duan 347 China 7 Hiroyuki Tsuchiya 9 Japan 7 Marco W. Schilham 337 Netherlands 8 Robert J canter 9 United States of America 8 Dean A. Lee 320 United States of America 9 Eugenie S Kleinerman 8 United States of America 9 Zhaoming Ye 318 China 10 William J Murphy 8 United States of America 10 Pancras C W Hogendoorn 306 Netherlands
Figure 4.:

Author network analysis. (A) Analysis of the cooperation network among authors in the field of BM immunotherapy. (B) Analysis of major research authors over the period from 2010 to 2023. The size of the circle is indicative of the number of papers. The width of the curves corresponds to the strength of the connections. (C) Top 10 authors over time.

3.4. Analysis of journals and co-cited journals

We conducted a co-cited journal analysis using the Bibliometrix package of R software (v4.1.0) and VOSviewer (v1.6.19) with a minimum citation threshold of ≥100. The study included a total of 3254 journals, 91 of which were co-cited at least 100 times. The top 10 journals for studies related to immunotherapy for BM are listed in Table 4. The top 5 journals with the highest number of publications were Frontiers in Oncology (n = 39, impact factor [IF] = 4.7), Frontiers in Immunology (n = 33, IF = 7.3), Cancers (n = 32, IF = 5.2), Journal for the ImmunoTherapy of Cancer (n = 21, IF = 10.9), and OncoImmunology (n = 19, IF = 7.2), with Clinical Cancer Research having the highest IF. Additionally, the top 5 journals with the most co-citations were Journal of Clinical Oncology (IF = 45.3), Clinical Cancer Research (IF = 11.5), Cancer Research (IF = 11.2), New England Journal of Medicine (IF = 158.5), and Lancet Oncology (IF = 51.1). These journals had total citations of 1878, 1808, 1363, 776, and 767, respectively (Table 5), with the New England Journal of Medicine having the highest IF. Figure 5A depicts the connection between the journals Journal of Clinical Oncology, Clinical Cancer Research, and Cancer Research, suggesting they may be core journals in the field of immunotherapy for BM. Additionally, we utilized a bimap overlay of journals to analyze the connections between journals that cite each other across different research areas (Fig. 5B). The sample waves from left to right represented the citation paths. Orange paths indicated that studies published in molecular, biology, and immunology journals often cite studies in molecular/biology/genetics journals, while green paths showed that the majority of citations for studies published in medicine/medical/clinical journals originate from health/nursing/medicine journals.

Table 4 - Top 10 journals with the most published articles. Rank Journals Articles IF (2022) JCR (2022) 1 Frontiers in Oncology 39 4.7 Q2 2 Frontiers in Immunology 33 7.3 Q1 3 Cancers 32 5.2 Q2 4 Journal for ImmunoTherapy of Cancer 21 10.9 Q1 5 OncoImmunology 19 7.2 Q1 6 Clinical Cancer Research 16 11.5 Q1 7 International Journal of Molecular Sciences 14 5.6 Q1 8 Oncotarget 12 – – 9 Cancer Immunology Immunotherapy 11 5.8 Q1 10 Oncology Letters 10 2.9 Q4
Table 5 - Top 10 journals with the most cited journals. Rank Co-cited Journals Total citations IF (2022) JCR (2022) 1 Journal of Clinical Oncology 1878 45.3 Q1 2 Clinical Cancer Research 1808 11.5 Q1 3 Cancer Research 1363 11.2 Q1 4 New England Journal of Medicine 776 158.5 Q1 5 Lancet Oncology 767 51.1 Q1 6 PLoS One 712 3.7 Q2 7 Cancer 683 6.2 Q1 8 Blood 674 20.3 Q1 9 Oncotarget 653 – – 10 Journal of Immunology 644 4.4 Q2
Figure 5.:

Journal analysis of BM immunotherapy. (A) A network map depicting academic journals that publish research on immunotherapy associated with BM. (B) A dual-map overlay depicting journals associated with research on immunotherapy in BM.

3.5. Analysis of references and co-cited references

The present study conducted a comprehensive literature analysis, and the findings are summarized in Table 6. This table highlighted the top 5 most frequently cited publications out of the 719 articles included in the analysis. Notably, the article titled “Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma” received the highest number of citations, with a total of 706. The publication titled “CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors” ranked second, with 282 citations. Furthermore, “Future directions in the treatment of osteosarcoma” was the third-ranked publication, garnering 223 citations. These studies focusing on immune therapy had made significant contributions to enhancing the prognosis of BM patients.

Table 6 - Top 5 highly cited articles in the field of immunotherapy for bone malignancies. Rank Title DOI Journal IF (2022) Publication year Total citations 1 Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma 10.1200/JCO.2014.58.0225 Journal of Clinical Oncology 45.3 2015 706 2 CAR-T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors 10.1158/1078-0432.CCR-18-0432 Clinical Cancer Research 11.5 2019 282 3 Future directions in the treatment of osteosarcoma 10.1097/MOP.0000000000000298 Current Opinion in Pediatrics 3.6 2016 223 4 Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma 10.1038/srep30093 Scientific Reports 4.6 2016 200 5 Novel insights and therapeutic interventions for pediatric osteosarcoma 10.2217/fon-2016-0261 Future Oncology 3.4 2017 174

Subsequently, we employed VOSviewer software (version 1.6.19) for co-citation analysis of the 719 articles. From a pool of 29,545 citations, we identified 47 articles that exceeded 30 citations (