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63 (); 181-195
doi:
10.1016/j.jor.2025.03.053

Exploration of research hotspots and evolutionary trends in osteosarcoma pulmonary metastasis: A comprehensive bibliometric analysis spanning five decades

, , , , , ,
a Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
b Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
c Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
d Department of Rheumatology and Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China

⁎Corresponding author: Chaojie Yu. h2021020@sr.gxmu.edu.cn

⁎⁎Corresponding author: Zhiping Su. h202109011@sr.gxmu.edu.cn

Received: , Accepted: ,
Professor P K Surendran Memorial Education Foundation
Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Pulmonary metastasis frequently complicates osteosarcoma, making the investigation of its mechanisms and therapeutic strategies a focal point in both clinical medicine and biosciences. The explosive growth of the relevant literature has still not been systematically sorted out and summarized.

Bibliometric methods were used in this study, Literature was retrieved from the Web of Science Core Collection, SCOPUS, and PubMed up until July 1, 2024. Bibliometric indicators were analyzed and research trends and hotspots in the field visualized using the Bibliometrix package, VOSviewer 1.6.19 and Citespace 6.3.R1 software.

A total of 1148 publications were reviewed, revealing that over the past five decades, the cumulative number of publications on pulmonary metastasis of osteosarcoma has gradually increased. China leads in the number of published papers, while the United States exhibits the most collaborative relationships with other countries. Italy is noted for the highest quality of research. Sun Yat-sen University is the most prolific institution, and the most productive author is Eugenie S. Kleinerman from the University of Texas MD Anderson Cancer Center. “Cancer” is the journal with the most publications, and Zhou Yan's 2020 paper received the highest local citations. Keywords such as “angiogenesis,” “tumor microenvironment,” and “surgery” appeared frequently, suggesting these topics are current research hotspots.

“Immunotherapy”, “survival”, “chemotherapy”, “prognosis”, “biomarkers”, “metastasectomy”, “microRNA”, “angiogenesis”, “tumor microenvironment”, and “surgery” define key research areas. Current hot topics include tumor-associated macrophages and the tumor microenvironment, which may hold the key to future therapeutic breakthroughs.

1

1 Introduction

Osteosarcoma represents the most common primary malignant bone tumor, predominantly affecting the limbs and showing a higher incidence in males compared to females. Classical osteosarcoma predominantly affects adolescents, with approximately 75 % of cases diagnosed between ages 15–25, with a median age of onset at 20 years. Incidence rates are notably lower in individuals younger than six or older than 60.1–3 Its aggressive clinical behavior often results in rapid pulmonary metastases in 90 % of patients, increasing mortality risk by 2.34 times compared to those without lung metastasis.4 Thus, addressing pulmonary metastasis in osteosarcoma management is critical.

Quantitative analysis of the current status, key areas, and prospects of pulmonary metastasis in osteosarcoma holds significant importance. Given the explosive growth of scientific literature, new methodologies like bibliometrics—analyzing quantitative features of bibliographic data—are essential for understanding the development trends and knowledge flow within fields, providing comprehensive knowledge maps for researchers.5–7

While studies on pulmonary metastasis of osteosarcoma continue to evolve, no previous work has conducted a complete bibliometric review and objective assessment. Our study aims to fill this gap by comprehensively analyzing publications using bibliometric methods combined with various visualization tools, offering valuable references for both basic research and clinical practice.

2

2 Methods

2.1

2.1 Data sources and search strategy

To ensure the comprehensiveness of the data and that the research findings accurately reflect the reality of the field, data were sourced from the Web of Science Core Collection (WOSCC), SCOPUS, and PubMed databases. Each database was independently searched, and duplicates were removed post-retrieval. Literature identified in multiple databases was downloaded primarily from WOSCC and PubMed, whereas records from PubMed and SCOPUS lacking citation information were excluded.

In bibliometrics, WOSCC is considered the “gold standard” due to its comprehensive and complete dataset.8,9 SCOPUS offers extensive coverage of medical literature, effectively portraying global trends within research domains, which has garnered increased attention among researchers in recent years. The cutoff date for relevant studies was set as July 1, 2024, with all searches conducted on the same day to avoid discrepancies due to database updates. Publication types were restricted to “articles” and “reviews,” and language was limited to “English.” Given author preferences and database search engine limitations, advanced search functionalities were employed in WOSCC using thematic queries and Boolean logic to enhance search precision. In SCOPUS, the search was conducted across “title, abstract, and author keywords.”

For WOSCC, the search formula was: ((((TS=(“osteosarcoma")) OR TS=(“osteoma sarcomatosum")) OR TS=(“osteogenic sarcoma")) OR TS=(“osteogenic s.")) OR TS=(“o. sarcomatosum”) AND ((TS=(“lung metastasis")) OR TS=(“lung metastatic")) OR TS=(“lung metastases").

For Pubmed, the search formula was: (((“lung metastasis”) OR (“lung metastatic")) OR (“lung metastases"))AND(“osteosarcoma"[Mesh]).

For SCOPUS, the search formula was: ((TITLE-ABS-KEY(“lung metastasis”) OR TITLE-ABS-KEY(“lung metastatic ") OR TITLE-ABS-KEY (“lung metastases"))) AND ((TITLE-ABS-KEY(“osteosarcoma”) OR TITLE-ABS-KEY(“osteoma sarcomatosum”) OR TITLE-ABS-KEY(“osteogenic sarcoma”) OR TITLE-ABS-KEY(“osteogenic s.”) OR TITLE-ABS-KEY(“o. sarcomatosum"))).

2.2

2.2 Data inclusion and exclusion criteria

Data collection adhered to a double-blind principle where each article's title and abstract were independently reviewed by three authors. Only records meeting predefined criteria (Fig. 1) were included, with disputed cases resolved through consensus or majority vote among the reviewers. Results from WOSCC were exported as plain text files containing full records and cited references, while SCOPUS results were exported in CSV format. After manual filtering and removal of duplicates using Citespace, all data were verified for compatibility with bibliometric software including Citespace, VOSviewer, and R before proceeding with further analysis.

Flowchart of Literature Inclusion and Exclusion. This flowchart illustrates the process of literature inclusion and exclusion criteria applied during the systematic review.
Fig. 1 Flowchart of Literature Inclusion and Exclusion. This flowchart illustrates the process of literature inclusion and exclusion criteria applied during the systematic review.
2.3

2.3 Bibliometric analysis

VOSviewer 1.6.19 10 was utilized for the analysis and visualization of networks related to countries, authors, citations, institutions, journal collaborations, keyword co-occurrence, clusters, and citation and co-citation networks. These analyses were presented using VOSviewer 1.6.19 and R 4.2.1.11 Overlay maps of journals and burst detection were performed using Citespace 6.3.R1.12 Microsoft Excel 2021 was used for statistical analysis and graphical representation of annual publication trends and distribution patterns, as well as for data organization and chart presentation.

3

3 Results

3.1

3.1 Overview

In the final dataset, we included 1148 English articles related to pulmonary metastasis of osteosarcoma. Among these, 1096 (95.47 %) were research articles, and 52 (4.53 %) were review articles.

3.2

3.2 Publication trends and distribution

The data span from 1974 to 2024. The publication trend is illustrated in Fig. 2, showing that the peak year for publications was 2021 with 93 articles. Overall, there has been a fluctuating upward trend, with a slight decrease in 2019 compared to 2018. Due to the data collection cutoff date of July 1, 2024, the number of publications for this year is relatively limited. To further explore the maturity and prospects of research in this field, we performed statistical analysis and model fitting on cumulative publication numbers, achieving an R2 value of 0.8182, indicating excellent model fit. This suggests that cumulative publications are expected to continue growing, reflecting the broad prospects and research value in the study of pulmonary metastasis of osteosarcoma.

Publication Distribution in Osteosarcoma Lung Metastasis Research (1974–2024). Orange bars indicate the cumulative growth trend of publications, blue curves depict the annual number of publications, and dashed lines represent the fitted curve model.
Fig. 2 Publication Distribution in Osteosarcoma Lung Metastasis Research (1974–2024). Orange bars indicate the cumulative growth trend of publications, blue curves depict the annual number of publications, and dashed lines represent the fitted curve model.
3.3

3.3 Country analysis

Pulmonary metastasis of osteosarcoma has attracted global attention, with contributions from 53 countries (Fig. 3B). We listed the top 10 countries by publication count (Table 1) and visualized their collaboration networks (Fig. 3A). China had the highest number of publications (478, 41.64 %), followed by the United States (281, 24.48 %) and Japan (183, 15.94 %). The international collaboration network was divided into 17 clusters (Fig. 3C and D), with some countries not collaborating with others shown separately. The United States (total link strength = 130), China (total link strength = 82), and France (total link strength = 55) were central nodes in the collaboration network. Average citations per article, a metric used to gauge article quality, indicated that Italy (average citations = 48.288), Germany (average citations = 43.150), and the United States (average citations = 41.758) ranked first, second, and third, respectively. Notably, China (average citations = 24.948) and Japan (average citations = 29.508) showed a significant discrepancy between publication volume and citation impact. Considering all factors, the United States holds a central position in osteosarcoma research. Additionally, Fig. 3E and F shows the temporal overlay of country collaboration networks, where yellow nodes represent later average publication times and purple nodes represent earlier ones. The results indicate that developed countries like Norway, the United States, and Japan started researching earlier, while developing countries such as China and Iran began later.

Network of Top Ten Contributing National Collaborations in Osteosarcoma Lung Metastasis. A. National Collaboration Network: Line widths represent the strength of connections, with wider bands indicating stronger collaborations. Countries with wider bands and more diverse line colors indicate that they have established collaborations with more countries. B. Geographic Visualization of Country Collaborations: The size of the circle represents the country's contribution to osteosarcoma lung metastasis research, the width of the line indicates the strength of the connection, and the color denotes different clusters identified by VOSviewer. C. Country Collaboration Network: Line widths represent the strength of connections, with wider bands indicating stronger collaborations. The size of the circle represents the country's contribution to the field, and colors represent different clusters of country collaborations. D. Partial Collaborative Network of Country Relationships: Highlights selected national collaborations within the field. E. Analysis of Main Research Countries (1974–2024): The size of the circle represents the number of publications, and the width of the line indicates the strength of the association. F. Local Analysis of Main Research Countries (1974–2024): Provides a detailed view of key contributing countries.
Fig. 3 Network of Top Ten Contributing National Collaborations in Osteosarcoma Lung Metastasis. A. National Collaboration Network: Line widths represent the strength of connections, with wider bands indicating stronger collaborations. Countries with wider bands and more diverse line colors indicate that they have established collaborations with more countries. B. Geographic Visualization of Country Collaborations: The size of the circle represents the country's contribution to osteosarcoma lung metastasis research, the width of the line indicates the strength of the connection, and the color denotes different clusters identified by VOSviewer. C. Country Collaboration Network: Line widths represent the strength of connections, with wider bands indicating stronger collaborations. The size of the circle represents the country's contribution to the field, and colors represent different clusters of country collaborations. D. Partial Collaborative Network of Country Relationships: Highlights selected national collaborations within the field. E. Analysis of Main Research Countries (1974–2024): The size of the circle represents the number of publications, and the width of the line indicates the strength of the association. F. Local Analysis of Main Research Countries (1974–2024): Provides a detailed view of key contributing countries.
Table 1 Leading countries in osteosarcoma pulmonary metastasis research (top 10).
id country documents citations total link strength average citatons Proportion of publications(%)
1 china 478 11925 82 24.948 41.64 %
2 united states 281 11734 130 41.758 24.48 %
3 japan 183 5400 47 29.508 15.94 %
4 italy 66 3187 34 48.288 5.75 %
5 france 56 2272 55 40.571 4.88 %
6 germany 40 1726 39 43.150 3.48 %
7 united kingdom 37 1474 47 39.838 3.22 %
8 switzerland 26 683 9 26.269 2.26 %
9 spain 23 728 25 31.652 2.00 %
10 australia 21 761 10 36.238 1.83 %
3.4

3.4 Institutional and author analysis

From the WOSCC and SCOPUS datasets, 982 institutions contributed to research on pulmonary metastasis of osteosarcoma. The top 10 institutions by publication count are presented in Table 2. Sun Yat-sen University (116 articles, 10.10 %) was the most productive institution, followed by the Texas State University System (110 articles, 9.58 %) and MD Anderson Cancer Center (102 articles, 8.89 %). Among the top 10 institutions, four were from the United States, three from China, two from France, and one from the Rizzoli Orthopedic Institute in Italy. The top 50 institutions were analyzed for collaboration networks(Fig. 4), forming 12 clusters identified by different colors. The largest cluster (blue) includes 20 institutions centered around Harvard University, the Texas State University System, MD Anderson Cancer Center, and Ohio University System. Clusters centered around Wuhan University (red) and Sun Yat-sen University and Shanghai Jiao Tong University (green) were particularly prominent. Overall, domestic institutional collaborations were close, but international collaborations need to be strengthened both in breadth and depth.

Table 2 Leading institutions in osteosarcoma pulmonary metastasis research (top 10).
ID Affiliation Articles Country Proportion of publications(%)
1 SUN YAT SEN UNIVERSITY 116 China 10.10 %
2 UNIVERSITY OF TEXAS SYSTEM 110 USA 9.58 %
3 UTMD ANDERSON CANCER CENTER 102 USA 8.89 %
4 SHANGHAI JIAO TONG UNIVERSITY 80 China 6.97 %
5 UNIVERSITY OF CALIFORNIA SYSTEM 65 USA 5.66 %
6 IRCCS ISTITUTO ORTOPEDICO RIZZOLI 51 Italy 4.44 %
7 CHINA MEDICAL UNIVERSITY TAIWAN 50 China 4.36 %
8 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM) 44 France 3.83 %
9 NANTES UNIVERSITE 42 France 3.66 %
10 UNIVERSITY SYSTEM OF OHIO 41 USA 3.57 %
Institutional Collaboration Network in Osteosarcoma Lung Metastasis. Line widths represent the strength of institutional collaborations, with wider bands indicating stronger collaborations. Circle sizes represent institutional contributions to osteosarcoma lung metastasis research, and colors denote different clusters of institutional collaborations.
Fig. 4 Institutional Collaboration Network in Osteosarcoma Lung Metastasis. Line widths represent the strength of institutional collaborations, with wider bands indicating stronger collaborations. Circle sizes represent institutional contributions to osteosarcoma lung metastasis research, and colors denote different clusters of institutional collaborations.

A total of 5968 authors contributed to osteosarcoma pulmonary metastasis research. The top 10 authors by publication count are listed in Table 3. The most prolific author was Eugenie S. Kleinerman from MD Anderson Cancer Center, with 45 publications in this field, followed by Bruno Fuchs (Switzerland), Dominique Heymann (France), and Robert M. Hoffman (USA), each with 21 publications. For evaluating author quality, we included Average Citations in our analysis. Gaetano Bacci (n = 19, Average Citations = 74.789) ranked first, followed by Stefano Ferrari (n = 19, Average Citations = 67.000) and Shu-Fang Jia (n = 16, Average Citations = 58.688). These authors mainly come from the United States, Italy, and the Netherlands. According to Price's Law,13 authors with ≥5 publications were identified as core contributors to osteosarcoma research, totaling 197 individuals. Using VOSviewer, we visualized author relationships (Fig. 5A). These 197 authors were divided into 32 clusters, with some authors without collaborative relationships grouped separately. The largest cluster, consisting of 19 authors centered around Eugenie S. Kleinerman and Shu-Fang Jia, also featured Kleinerman as the author with the highest collaboration strength. Fig. 5B illustrates the temporal overlay of author collaboration networks, revealing key clusters and their contributions to osteosarcoma pulmonary metastasis research. The findings indicate that the cluster centered around Konishi, Y and Morishita, T from Nara Medical University (depicted in pink) and the cluster led by Bacci, Gaetano and Picci, Piero from Istituto Ortopedico Rizzoli (depicted in green) initiated their research efforts earlier. Additionally, the cluster centered around Guo, Wei from Peking University (depicted in orange) and the cluster led by Hu, Zhaohui from Liuzhou People's Hospital (depicted in light purple) have achieved significant milestones in recent years within the field of osteosarcoma pulmonary metastasis. These emerging clusters have made notable contributions, reflecting the dynamic growth and increasing impact of research efforts from these institutions.

Table 3 Leading authors in osteosarcoma pulmonary metastasis research by publication volume (top 10).
ID Author documents Total citations Average citations Country
1 kleinerman, eugenie s 45 2063 45.844 USA
2 fuchs, bruno 21 626 29.810 Switzerland
3 heymann, dominique 21 909 43.286 France
4 hoffman, robert m 21 602 28.667 USA
5 bacci, gaetano 19 1421 74.789 Italy
6 ferrari, stefano 19 1273 67.000 Italy
7 born, walter 17 546 32.118 Switzerland
8 shen, jingnan 17 796 46.824 China
9 tsuciya, hiroyuki 17 564 33.176 Japan
10 jia, shu-fang 16 939 58.688 USA
Author Collaboration Network in Osteosarcoma Lung Metastasis Research. A. Author Collaboration Network: Different colors represent different author clusters, and line widths indicate the strength of connections, with wider bands representing stronger collaborations. B. Analysis of Main Research Authors (1974–2024): The size of the circles represents the number of papers, and the width of the curves corresponds to the strength of the connections.
Fig. 5 Author Collaboration Network in Osteosarcoma Lung Metastasis Research. A. Author Collaboration Network: Different colors represent different author clusters, and line widths indicate the strength of connections, with wider bands representing stronger collaborations. B. Analysis of Main Research Authors (1974–2024): The size of the circles represents the number of papers, and the width of the curves corresponds to the strength of the connections.
3.5

3.5 Journal analysis

Based on Bradford's Law14 (Fig. 6A), there are 23 core journals in the field of osteosarcoma pulmonary metastasis research. We present the top 10 journals by publication count, as shown in Table 4. The journal with the highest number of publications is Cancer (n = 40, IF = 6.100), followed by Cancer Letters (n = 31, IF = 9.100) and Oncotarget (n = 29, IF = 2.700), along with other journals with publication counts greater than or equal to 16. Among the 1148 included studies, approximately 20.12 % were published in these top 10 journals. Notably, five of these journals are classified as Q1 in the Journal Citation Reports (JCR 2023) and have impact factors greater than 5, underscoring their significant influence in this research domain.

Core Journals in Osteosarcoma Lung Metastasis Research. A. Core Journals as Determined by Bradford's Law: The gray shaded area includes journals that have made significant contributions to the field, listed in descending order based on the number of articles published. B. Collaborative Journal Relationship Network: Identically colored nodes represent the same cluster. C. Dual Graph Mapping Overlay of Journals: Citing journals are on the left, cited journals are on the right, and the width of the connecting lines represents the strength of citation relationships.
Fig. 6 Core Journals in Osteosarcoma Lung Metastasis Research. A. Core Journals as Determined by Bradford's Law: The gray shaded area includes journals that have made significant contributions to the field, listed in descending order based on the number of articles published. B. Collaborative Journal Relationship Network: Identically colored nodes represent the same cluster. C. Dual Graph Mapping Overlay of Journals: Citing journals are on the left, cited journals are on the right, and the width of the connecting lines represents the strength of citation relationships.
Table 4 High-impact journals in osteosarcoma pulmonary metastasis research based on publication frequency (top 10).
ID Journal Pblications Citations Average citatons IF/JIF Qartile h_index g_index
1 cancer 40 3077 76.925 6.100/Q1 31 40
2 cancer letters 31 1280 41.290 9.100/Q1 18 31
3 oncotarget 29 887 30.586 2.700/Q2 19 29
4 frontiers in oncology 22 415 18.864 3.500/Q2 10 20
5 international journal of cancer 21 1132 53.905 5.700/Q1 15 21
6 cancer research 19 1285 67.632 12.500/Q1 17 19
7 clinical cancer research 19 1333 70.158 10.000/Q1 18 19
8 clinical & experimental metastasis 17 809 47.588 4.200/Q2 13 17
9 plos one 17 614 36.118 2.900/Q2 15 17
10 anticancer research 16 237 14.813 1.600/Q4 10 16

To further assess the centrality of journals in osteosarcoma pulmonary metastasis research, we considered multiple metrics, including average citations per article, H-index, and G-index. Our analysis indicates that Cancer, Cancer Research, and Clinical Cancer Research more accurately represent the core content of this field.

VOSviewer conducted a co-citation network analysis of the top 50 journals by publication count, as illustrated in Fig. 6B. Clusters of journals were formed based on their similarities and interrelationships, resulting in five distinct clusters, each identified by a unique color. Fig. 6C presents an overlay map of citing and cited journals. The left cluster represents citing journals, often considered the forefront of research in the field, while the right cluster comprises cited journals, typically reflecting the foundational knowledge. The connections between citing and cited journals are depicted by colored bands, indicating citation relationships. This overlay helps to better understand the relationships and dynamic changes within the field of osteosarcoma pulmonary metastasis research, highlighting the prospects and citation patterns of academic publications. In Fig. 6C, citing journals primarily originate from “molecular biology, immunology,” whereas cited journals predominantly come from “molecular biology, genetics."

3.6

3.6 Literature analysis

In Table 5, we summarize and present the top 11 most locally cited studies in the field of osteosarcoma pulmonary metastasis. The highest-cited study is a 2020 publication by Zhou Yan in Nature Communications (IF = 14.700/Q1), titled “Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma,” with 270 citations. Following this, the second most cited study is a 2007 publication by Thomas Volker in Journal of Clinical Oncology (IF = 42.100/Q1), titled “Positron Emission Tomography for Staging of Pediatric Sarcoma Patients: Results of a Prospective Multicenter Trial,” which has been cited 268 times. These studies provide invaluable insights into the development and metastasis of osteosarcoma and offer critical evidence for clinical diagnosis and treatment.

Table 5 Top citations in osteosarcoma pulmonary metastasis research (1974–2024, top 11).
ID Tilte Citations Year Author Journal IF JCR Qartile
1 Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma 270 2020 Zhou Yan Nature communications 14.700 Q1
2 Positron Emission Tomography for Staging of Pediatric Sarcoma Patients: Results of a Prospective Multicenter Trial 268 2007 Thomas volker JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
3 MicroRNA-143 Regulates Human Osteosarcoma Metastasis by Regulating Matrix Metalloprotease-13 Expression 229 2011 Mitsuhiko Osaki MOLECULAR THERAPY 12.100 Q1
4 Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Survival 224 2003 Stefano Ferrari JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
5 The metastatic patterns of osteosarcoma 220 1975 G M Jeffree British Journal of Cancer 6.400 Q1
6 Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases 208 2008 Su Young Kim CLINICAL & EXPERIMENTAL METASTASIS 4.200 Q2
7 Development and Treatment of Pulmonary Metastases in Adult Patients with Extremity Soft Tissue Sarcoma 194 1993 Gadd, Michele A. M.D. ANNALS OF SURGERY 7.500 Q1
8 MicroRNA-34a Inhibits the Proliferation and Metastasis of Osteosarcoma Cells Both In Vitro and In Vivo 194 2012 Kang Yan PLoS One 2.900 Q2
9 Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis 192 2008 Sue C. Kaste D.O. CANCER 6.100 Q1
10 An Orthotopic Model of Human Osteosarcoma Growth and Spontaneous Pulmonary Metastasis 190 2005 Hue H. Luu CLINICAL & EXPERIMENTAL METASTASIS 4.200 Q2
11 ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma 190 1996 Masanori Onda M.D. CANCER 6.100 Q2

Citation analysis often reveals the flow of knowledge within a field. Among the 1148 studies reviewed, a total of 31,380 references were identified. Table 6 lists the top 10 most frequently cited references. The most cited reference is Bielack, SS's 2002 study published in Journal of Clinical Oncology (Q1, IF = 42.000), titled “Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols,” which has been cited 106 times. This study provides an in-depth analysis of prognostic factors in newly diagnosed high-grade osteosarcoma patients. The second most cited reference is Mirabello, Lisa's 2009 study in Cancer (Q1, IF = 6.100), titled “Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program,” which received 83 citations. This study analyzed the incidence and survival rates of 3482 osteosarcoma patients between 1973 and 2004, revealing significant differences among various age groups, races, genders, pathological subtypes, stages, and anatomical locations. Notably, four out of the top 10 most cited references were published in Journal of Clinical Oncology (IF = 42.100/Q1).

Table 6 Most cited references (top 10).
ID Tilte Citations Year Author Journal IF JCR Qartile
1 Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols 106 2002 Bielack, SS JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
2 Osteosarcoma Incidence and Survival Rates From 1973 to 2004 Data From the Surveillance, Epidemiology, and End Results Program 83 2009 Mirabello, Lisa CANCER 6.100 Q1
3 Primary metastatic osteosarcoma: Presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols 74 2003 Kager, L JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
4 Translational biology of osteosarcoma 71 2014 Kansara, Maya NATURE REVIEWS CANCER 72.500 Q1
5 The Epidemiology of Osteosarcoma 67 2009 Ottaviani, Giulia PEDIATRIC AND ADOLESCE NT OSTEOSARCOMA / /
6 Osteosarcoma: Current Treatment and a Collaborative Pathway to Success 66 2015 Isakoff, Michael S. JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
7 Osteosarcoma relapse after combined modality therapy: An analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS) 52 2005 Kempf-Bielack, B JOURNAL OF CLINICAL ONCOLOGY 42.100 Q1
8 Osteosarcoma 52 2010 Ritter, J. ANNALS OF ONCOLOGY 56.700 Q1
9 THE EFFECT OF ADJUVANT CHEMOTHERAPY ON RELAPSE-FREE SURVIVAL IN PATIENTS WITH OSTEOSARCOMA OF THE EXTREMITY 51 1986 LINK, MP NEW ENGLAND JOURNAL OF MEDICINE 96.200 Q1
10 Osteosarcoma treatment - Where do we stand? A state of the art review 48 2014 Luetke, Anja CANCER TREATMENT REVIEWS 9.600 Q1

Burst detection was employed to identify sudden increases in citation counts over time. We listed the top 25 references based on burst strength (Fig. 7B). Among these, the earliest burst reference is Bielack, SS's 2002 study, which also holds the highest citation count in osteosarcoma pulmonary metastasis research. The reference with the highest burst strength is Isakoff, Michael S.'s 2015 publication in Journal of Clinical Oncology, titled “Osteosarcoma: Current Treatment and a Collaborative Pathway to Success,” with a burst strength of 12.13. This article is also among the top 10 most cited references. Currently, nine articles are still in their burst phase, indicating ongoing relevance and impact.

Co-cited References in Osteosarcoma Lung Metastasis. A. Co-cited Reference Network: Node sizes represent the number of citations, connecting lines indicate relationships between co-cited references, and the width of connecting lines represents the intensity of co-citation. Different colors denote different clusters. B. Top 25 References with the Highest Citation Burst Intensity for Osteosarcoma Lung Metastasis: Highlights the most impactful references in the field.
Fig. 7 Co-cited References in Osteosarcoma Lung Metastasis. A. Co-cited Reference Network: Node sizes represent the number of citations, connecting lines indicate relationships between co-cited references, and the width of connecting lines represents the intensity of co-citation. Different colors denote different clusters. B. Top 25 References with the Highest Citation Burst Intensity for Osteosarcoma Lung Metastasis: Highlights the most impactful references in the field.

To further explore the thematic sources of major citations, we conducted a co-citation network analysis using VOSviewer. Given the vast number of references, we included those with at least 20 citations, resulting in 45 references for network analysis (Fig. 7A). The size of each node represents the citation frequency, and the lines connecting nodes indicate that the two references were simultaneously cited in the same article, with shorter lines indicating closer relationships between the papers.Cluster 1 (Red) includes 14 references focusing on chemotherapy for osteosarcoma pulmonary metastasis. Cluster 2 (Green) discusses cellular and molecular mechanisms of osteosarcoma lung metastasis. Cluster 3 (Blue) examines the efficacy of adjuvant chemotherapy in treating osteosarcoma pulmonary metastasis. Cluster 4 (Yellow) does not have a clearly defined theme but generally relates to the prognosis and treatment of osteosarcoma pulmonary metastasis.

3.7

3.7 Keyword hotspot analysis

Keywords represent the core themes and subjects of research articles. By conducting a keyword co-occurrence network analysis using VOSviewer, we can clearly identify the primary research focuses and trends within the field. Analyzing frequently occurring keywords helps in highlighting prominent themes, concepts, and cutting-edge research areas.

Table 7 lists the top 25 most frequent keywords from the 1148 reviewed articles. The most common keywords are “osteosarcoma” (731 occurrences), “proliferation/metastasis” (253 occurrences), and “lung metastasis” (212 occurrences). Given that these terms overlap with the search query, they will not be analyzed further. To ensure that the statistically derived keywords provide representative insights into osteosarcoma pulmonary metastasis research, we incorporated data from the top 100 highly cited studies in the Web of Science Core Collection (WOSCC) and performed synonym consolidation and statistical analysis. Table 8 presents the top 25 most frequent keywords from these 100 studies.

Table 7 Keywords by frequency of occurrence from common screening methods (top 25).
id keyword occurrences total link strength
1 osteosarcoma 731 837
2 proliferation/metastasis 253 413
3 lung metastasis 212 277
4 prognosis 56 106
5 invasion 34 70
6 chemotherapy 30 71
7 mouse model 23 35
8 survival 23 55
9 apoptosis 22 47
10 immunotherapy 21 36
11 bone neoplasm 20 29
12 biomarker 18 32
13 epithelial-mesenchymal transition 18 32
14 metastasectomy 18 54
15 lung 16 38
16 sarcoma 16 16
17 exosome 15 26
18 microrna 14 22
19 surgery 14 38
20 tumor microenvironment 14 23
21 angiogenesis 13 25
22 computed tomography 13 28
23 target therapy 13 24
24 recurrence 12 28
25 autophagy 11 14
Table 8 Keywords by frequency of occurrence from the top 100 cited studies (top 25).
id keyword occurrences total link strength
1 osteosarcoma 47 84
2 metastasis 16 38
3 lung metastasis 14 27
4 surgery 5 12
5 chemotherapy 4 13
6 mesenchymal stem cell 4 8
7 metastasectomy 4 17
8 survival 4 11
9 tumor microenvironment 4 11
10 extremity 3 8
11 immunotherapy 3 9
12 limb salvage 3 12
13 neoadjuvant chemotherapy 3 12
14 tumour-associated macrophage 3 7
15 angiogenesis 2 5
16 axl 2 2
17 biomarker 2 4
18 lung 2 6
19 macrophages 2 6
20 microrna 2 4
21 necroptosis 2 2
22 pd-l1 2 6
23 pediatric oncology 2 7
24 primary bone tumor 2 5
25 prognosis 2 2

To enhance the breadth and representativeness of our findings, we intersected the keywords from both tables. The resulting keywords, as shown in Fig. 8A, include “immunotherapy,” “survival,” “chemotherapy,” “prognosis,” “biomarker,” “metastasectomy,” “microRNA,” “angiogenesis,” “tumor microenvironment,” and “surgery.” These terms define the broad and representative focus areas of osteosarcoma pulmonary metastasis research.

Keyword Analysis in Osteosarcoma Lung Metastasis Research.A. Intersection of Data Obtained via Common Screening Methods and Top 25 Keywords from the Top 100 Cited Studies: Blue represents data obtained through common screening methods, and orange represents data from the top 100 cited studies.B. Word Cloud Visualization: Note: After removing search terms.C. Keyword Network Derived from Classical Screening Methods: Illustrates keyword relationships in osteosarcoma lung metastasis research.D. Keyword Network Derived from Classical Screening Methods:Node Separation Clustering.E. Keyword Network for the Top 100 Cited Studies on Osteosarcoma Lung Metastasis: Shows keyword patterns in high-impact studies.F. Trends in Osteosarcoma Lung Metastasis Research: Circle sizes represent the frequency of occurrence of keywords.G. Top 25 Keywords with the Highest Citation Burst Intensity: Identifies emerging research topics and trends.
Fig. 8 Keyword Analysis in Osteosarcoma Lung Metastasis Research.A. Intersection of Data Obtained via Common Screening Methods and Top 25 Keywords from the Top 100 Cited Studies: Blue represents data obtained through common screening methods, and orange represents data from the top 100 cited studies.B. Word Cloud Visualization: Note: After removing search terms.C. Keyword Network Derived from Classical Screening Methods: Illustrates keyword relationships in osteosarcoma lung metastasis research.D. Keyword Network Derived from Classical Screening Methods:Node Separation Clustering.E. Keyword Network for the Top 100 Cited Studies on Osteosarcoma Lung Metastasis: Shows keyword patterns in high-impact studies.F. Trends in Osteosarcoma Lung Metastasis Research: Circle sizes represent the frequency of occurrence of keywords.G. Top 25 Keywords with the Highest Citation Burst Intensity: Identifies emerging research topics and trends.

Beyond frequency analysis, we also constructed a keyword clustering network based on author-provided keywords. From the 1148 articles, keywords with at least five occurrences were included, totaling 103 keywords (Fig. 8C). To distinguish between clusters, we separated nodes for better visualization (Fig. 8D). Cluster 1 (Red) primarily addresses the “diagnosis, treatment, and prognosis assessment of osteosarcoma lung metastasis.” Cluster 2 (Green) focuses on “experimental models and molecular mechanisms of osteosarcoma lung metastasis.” Cluster 3 (Blue) emphasizes “targeted therapy and immunotherapy for osteosarcoma.” Clusters 4 (Yellow) and 5 (Purple) concentrate on “molecular markers, tumor microenvironment, and therapeutic resistance in osteosarcoma” and “molecular therapy, immunotherapy, and cell death mechanisms in osteosarcoma,” respectively. It is important to note that the interconnections between clusters cannot be entirely distinct, reflecting the interconnected nature of these research areas.

To further analyze the evolving trends in osteosarcoma pulmonary metastasis research, we conducted trend analysis and burst detection on extracted keywords. The thematic trends over time are illustrated in Fig. 8F, where “mouse osteosarcoma” was an early research topic, while “tumor-associated macrophage” and “nomogram” have gained significant attention in recent years.

Burst detection quantifies the intensity of keyword bursts, revealing the evolution of research hotspots (Fig. 8G). Early bursts include topics such as “rat osteosarcoma,” “neoadjuvant chemotherapy,” “gene therapy,” and “lung cancer,” consistent with the trends depicted in Fig. 8F. More recently, there has been a strong burst in topics like “tumor microenvironment,” “risk factor,” and “SEER program,” indicating current researcher interest in tumor microenvironment, risk assessment, and big data analysis. This shift in focus aligns with recent advancements in understanding the role of macrophages in the tumor microenvironment.

4

4 Discussion

In this study, we employed bibliometric software including VOSviewer, CiteSpace, and Bibliometrix to analyze 1148 documents retrieved from SCOPUS, WOSCC, and PubMed, providing an in-depth exploration of the hotspots and research dynamics in the field of pulmonary metastasis of osteosarcoma over the past five decades. The increasing number of studies on pulmonary metastasis of osteosarcoma reflects growing concern about the health issues it poses, particularly among adolescents.

The publication count in 2019 saw a decline compared to the previous year, which may be attributed to the global impact of the COVID-19 pandemic, similar to findings by Marc Raynaud et al.15 Factors such as reduced logistical convenience leading to shortages of reagents,16 shifts in research priorities,15 and decreased scientific funding due to economic downturns17 likely contributed to this trend.

Country analysis revealed that while 53 countries participated in osteosarcoma pulmonary metastasis research, international collaboration remains limited. Most institutional clusters are confined within national borders, highlighting the insularity of many research efforts. Core institutions largely align with core countries, with the United States hosting four top institutions, China three, but notably absent is Japan, despite its significant publication output.

After a comprehensive evaluation of various factors, it is evident that the United States remains at the core of osteosarcoma research, a position that is difficult to challenge. However, the increasing number of research outputs and the notable recent surge in research activity from China cannot be overlooked. The level of academic capability is often closely linked to economic capacity. For instance, in 2022, the United States allocated 4.4 trillion to healthcare expenditures, amounting to 13,493 per capita and representing 17.3 % of its GDP.18 Additionally, the U.S. ranks among the top countries in terms of investment in scientific research infrastructure, which may partly explain its dominant position in the field of osteosarcoma research.

China's growth can be attributed to two main factors: its large population necessitating urgent attention to diseases like osteosarcoma, and robust governmental support for scientific research, especially in foundational studies. However, discrepancies between publication quantity and quality in China and Japan highlight the need for these nations to focus on enhancing paper quality.

Institutional analysis revealed that Harvard Medical School, despite not being the most prolific publisher, occupies a central position in its collaboration cluster. Clusters centered around Wuhan University, Sun Yat-sen University, and Shanghai Jiao Tong University have made significant contributions, reflecting China's rising influence in medical research. This trend underscores the competitive dynamics between China and the U.S. in the global scientific landscape.

Italy's Rizzoli Orthopedic Institute, as the sole Italian institution among the top 10 publishers, exemplifies high-quality research, ranking first globally in article quality. It was ranked fifth in “The World's Best Hospitals 2023″ by Newsweek for orthopedics, underscoring its expertise and international reputation.

High-impact journals like Cancer, Cancer Research, and Clinical Cancer Research are pivotal in the osteosarcoma pulmonary metastasis field, with Cancer featuring prominently among the most cited studies. These publications focus on oncology research, emphasizing their significance in guiding future directions.

Author analysis highlighted Eugenie S. Kleinerman's prominent role, both in publication count and collaboration intensity. His affiliation with MD Anderson Cancer Center and central position in the largest author cluster underscore his influential status. Kleinerman's pioneering work dates back to 2001, focusing on aerosol-based treatments and later on interleukin therapy and Fas pathway expression.

Jia Shu-Fang ranks third in article quality, collaborating extensively with Kleinerman. To quantify authors' contributions, average citations were considered, with Gaetano Bacci leading at 74.789 average citations, focusing on diagnosis, treatment, and prognosis of osteosarcoma pulmonary metastasis, advocating combined surgery and chemotherapy strategies.

The classical treatment for osteosarcoma is a multidisciplinary approach primarily centered around surgical interventions, with “surgical procedures” and “metastasectomy” being frequently identified as high-frequency keywords in both routine screening data and the top 100 most cited studies (Fig. 8A). Pulmonary metastasis is not uncommon among osteosarcoma patients.19,20 Historically, distant metastases were considered a contraindication for surgery,21,22 but many researchers have challenged these “taboos.” The first documented case of surgical resection of pulmonary metastases from osteosarcoma dates back to 1882, when Weinlechner reported the local excision of a rib osteosarcoma and the removal of lung metastases.

A series of retrospective studies23–25 now suggest that proper evaluation and resection of pulmonary metastases are crucial for improving survival rates. In cases of recurrence, resection should not only ensure the absence of metastatic lesions outside the lungs but also consider whether the patient's pulmonary function can be adequately preserved.20 Pfannschmidt et al. 26 found that the extent of resection does not significantly impact survival time, while Pastorino et al. 24 demonstrated that wedge resection achieves outcomes comparable to those of anatomical resection. Consequently, wedge resection has become the preferred method for pulmonary metastasectomy when indicated. However, due to the highly malignant nature of osteosarcoma, many patients do not achieve the same prognosis as those with other types of tumors post-surgery.27

The effectiveness of primary tumor treatment is closely related to the occurrence of pulmonary metastasis. The term “limb salvage” is frequently mentioned in keyword analyses, reflecting ongoing interest and debate regarding whether limb preservation is feasible. While there is no definitive consensus, successful limb-salvage surgery is widely recognized for its potential to improve patient quality of life and functional outcomes. Safe surgical margins and favorable chemotherapy responses are prerequisites for limb-salvage surgery. Bacci et al. 28 found that, given a good chemotherapy response, there is no significant difference in survival and recurrence rates between limb-salvage and amputation surgeries. For patients with poor chemotherapy responses, achieving safe margins through amputation remains the optimal choice.

Neoadjuvant chemotherapy is employed preoperatively to enhance limb-salvage rates,29 although it has not been shown to improve overall survival.30 Compared to surgery alone, the combination of chemotherapy and surgery has been proven to significantly enhance treatment efficacy.31 The term “chemotherapy” and “neoadjuvant chemotherapy” frequently appear in keyword analyses, reflecting the widespread adoption of a comprehensive treatment regimen involving preoperative chemotherapy, surgical intervention, and postoperative chemotherapy. This approach, known as neoadjuvant chemotherapy, aims to maximize therapeutic benefits by integrating multiple modalities.

This treatment paradigm improves patients' five-year survival rates and limb-salvage rates.32 Currently, five chemotherapy drugs known to be effective against osteosarcoma include methotrexate (MTX), doxorubicin, cisplatin, ifosfamide, and etoposide. Various combinations of these drugs are employed in chemotherapy regimens.

Substantial evidence from clinical studies33–35 indicates that the MAP regimen, which includes doxorubicin, cisplatin, and high-dose methotrexate as part of a neoadjuvant chemotherapy-surgery-adjuvant chemotherapy integrated treatment model, demonstrates higher response rates and better long-term outcomes compared to other multi-drug combinations. However, elderly patients often experience delayed metabolism of high-dose MTX, leading to more severe adverse effects, making MTX less favorable for this demographic.36

The advent of targeted therapies and immunotherapies offers new hope for patients with osteosarcoma pulmonary metastasis who have failed first-line chemotherapy. Frequently mentioned terms such as “immunotherapy,” “biomarkers,” “microRNA,” “targeted therapy,” and “PD-1″ highlight the growing interest in these innovative therapeutic approaches.

Research on the “tumor microenvironment” in osteosarcoma pulmonary metastasis is at the forefront of current investigations. Our study explicitly identifies that “tumor microenvironment,” “tumor-associated macrophages (TAMs)," and related research will be central to future studies in this field. Other frequently occurring keywords such as “angiogenesis,” “PD-1,” and “AXL” are also integral components of this research focus.

The tumor microenvironment in osteosarcoma primarily consists of T lymphocytes and macrophages, although it also includes other subpopulations. TAMs are present in the vicinity of tumor cells, and their modulation of the tumor microenvironment plays a critical role in the development and progression of pulmonary metastasis. These cells not only participate in tumor angiogenesis and metastasis but also influence tumor immune evasion and drug resistance through various mechanisms. The polarization process of TAMs, transitioning from the M1 to the M2 phenotype, promotes pulmonary metastasis in osteosarcoma37 and assists in establishing immune tolerance during tumor growth.38

Relevant studies indicate that M2-TAMs may exacerbate intratumoral T lymphocyte immunosuppression, facilitating the occurrence of pulmonary metastasis.39 Factors such as zinc finger protein ZIM3,40 IL-8,41 PD-1,42 and HMGB1,43 which are highly expressed, contribute to this polarization shift. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (l-MTP-PE) has been designed for therapeutic targeting of TAM polarization.44 When combined with chemotherapy, particularly regimens containing ifosfamide, it has been shown to significantly improve overall survival and disease-free survival rates.45–47

Mifamurtide activates antitumor immune activity by binding to Toll-like receptor 4 (TLR4) on the surface of monocytes and macrophages, thereby enhancing their immunological response against tumor cells. Additionally, mifamurtide can activate the innate immune system by binding to the NOD2 receptor within macrophages. When used in combination with chemotherapy, mifamurtide effectively eliminates minimal residual disease and inhibits the development of pulmonary metastases.48

Inhibiting tumor angiogenesis is also a new therapeutic approach. Angiogenesis is considered fundamental for providing nutritional support to malignant tumors. M2-polarized tumor-associated macrophages (TAMs) play a pivotal role in driving angiogenesis by releasing fibroblast growth factor (FGF), matrix metalloproteinase 9 (MMP-9), and vascular endothelial growth factor (VEGF).49,50 These factors promote the formation of new blood vessels, which are essential for tumor growth and metastasis.

Several anti-angiogenic agents, such as Apatinib,51 Sorafenib,52 Regorafenib,53 Bevacizumab,54 and recombinant human endostatin 55, have been used in combination with chemotherapy for the treatment of resectable pulmonary metastases in osteosarcoma patients, achieving notable efficacy. Additionally, other drugs target different pathways. For instance, Z-GP-DAVLBH,56 associated with the keywords “epithelial-mesenchymal transition” and “AXL,” and Pembrolizumab,57 related to “PD-1,” are being explored in clinical practice for their therapeutic potential.

Furthermore, “microRNA” represents another significant focus of research. As the subject of the 2024 Nobel Prize in Biology, this gene regulatory process also profoundly influences the occurrence of pulmonary metastasis in osteosarcoma. In osteosarcoma patients, mesenchymal stem cells (MSCs) closely interact with osteosarcoma cells within the bone and bone marrow microenvironment. However, compared to osteoblasts, MSCs lack functional gap junctions that enable communication with osteosarcoma cells.58

Extracellular vesicles (EVs) have emerged as an effective means of communication between cells. Mesenchymal stem cells secrete EVs containing a variety of nucleic acids besides proteins, including DNA, mRNA, microRNA, and non-coding RNA (ncRNA). These EVs guide the proliferation of osteosarcoma cells and confer stem cell-like properties, accelerating tumor angiogenesis and immune suppression. Compared to normal osteoblast-derived EVs, osteosarcoma-derived EVs contain immunomodulatory substances that significantly reduce T-cell proliferation rates and promote regulatory T-cell phenotypes, thereby facilitating osteosarcoma progression.59

MicroRNAs (miRNAs), which are now recognized as the most prevalent carriers within EVs mediating pulmonary metastasis in osteosarcoma, play a crucial regulatory role in this process. Research by Mitsuhiko Osaki et al. has identified miR-143 as one of the most downregulated miRNAs associated with lung metastasis. It influences osteosarcoma pulmonary metastasis by regulating the expression of matrix metalloproteinase-13 (MMP-13).60 Additionally, Shu-Nan Wang et al. found that overexpression of miR-491 inhibits osteosarcoma cell lung metastasis while enhancing cisplatin-induced tumor growth inhibition and apoptosis.61 Furthermore, miR-67562 and miR-130763 have also been shown to promote osteosarcoma pulmonary metastasis through epithelial-mesenchymal transition (EMT). Targeting the regulatory mechanisms of miRNAs holds promise as an innovative therapeutic strategy.

5

5 Conclusion

Our bibliometric analysis of the last fifty years reveals a steadily increasing publication trend in osteosarcoma pulmonary metastasis research. China leads in publication volume, while the U.S. remains the global core, and Italy excels in research quality. Sun Yat-sen University and Eugenie S. Kleinerman stand out as leading contributors. High-impact journals like Cancer play pivotal roles, with Zhou Yan's 2020 paper receiving the highest local citations.

Keywords such as “immunotherapy,” “survival rate,” “chemotherapy,” “prognosis,” “biomarkers,” “metastasectomy,” “microRNA,” “angiogenesis,” “tumor microenvironment,” and “surgery” define key research focuses. Current hot topics include tumor-associated macrophages and tumor microenvironment, underscoring their importance.

5.1

5.1 Limitations

This study reviewed three databases but encountered format incompatibilities. We mitigated this by integrating data across databases. The fixed retrieval date and database updates pose challenges in replicating results. Different software tools used for analysis may yield slightly varied outcomes, but aggregating these results enhances reliability. Despite these limitations, our findings provide valuable insights into osteosarcoma pulmonary metastasis research.

CRediT authorship contribution statement

Chaojie Yu: Conceptualization, Supervision, Funding acquisition. Xiaohua Jiang: Conceptualization, Data curation, Writing – original draft, Visualization, Writing – review & editing. Shutian Wei: Data curation, Writing – review & editing. Chengxing Zhou: Data curation, Writing – review & editing. Chengyu Zhou: Data curation, Writing – review & editing. Yanshan Wei: Writing – review & editing. Zhiping Su: Writing – original draft, Visualization, Writing – review & editing.

Institutional review board statement

This research does not require ethical review.

Data availability statement

All data that support the findings of this study are included in this manuscript and its supplementary information files. Further enquiries can be directed to the corresponding author.

Ethical statement

This study did not involve human participants, animal experiments, or patient data. Therefore, informed consent from patients/guardians was not required. All data analyzed were anonymized and derived from publicly available sources/simulations. The study complies with ethical standards outlined in the Declaration of Helsinki.

Funding

The research was supported by Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation under Grant No. 2023GXNSFBA026238, and Guangxi Zhuang Autonomous Region Health Commission Self-funded Research Project (No. Z-A20230715).The First Batch of Medical Young Reserve Talent Training Program in Guangxi Zhuang Autonomous Region (Gui Wei Ren Fa No. [2025]5).

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