{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:20Z","timestamp":1788415940654,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatoblastoma (HB) is the most common childhood liver malignancy, yet its research trajectory and trial landscape remain uncharacterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 219 trials from 16 international registries and 2,635 PubMed publications (2005\u20132024) using joinpoint regression, Gini coefficient, and diversity indices.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Trial activity peaked in 2013 and 2016, driven by risk-stratified protocols and the emergence of targeted therapies. Phase III\/IV trials were scarce. Cisplatin dominated drug utilization, with 54\u201380% resistance after 4\u20135 cycles. Targets concentrated on VEGFR\/TOP1\/RET\/BRAF, while Hippo\/YAP and immune checkpoints were underrepresented despite mechanistic relevance. AFP (n=607), CTNNB1 (&amp;gt;80% mutation frequency), TP53, AKT1, and MYC were top-reported genes. Geographic inequality correlated with healthcare infrastructure rather than disease burden.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The HB research ecosystem exhibits robust early-phase activity but constrained late-stage validation, narrow target diversity, and geographic inequity. Multi-omics integration and pediatric-specific preclinical platforms are urgently needed to bridge translational gaps.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1890288","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:13:56Z","timestamp":1788412436000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bibliometric and clinical trial landscape of hepatoblastoma (2000\u20132024): a multi-database analysis of global research"],"prefix":"10.3389","volume":"16","author":[{"given":"Xu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]},{"name":"School of Clinical Medicine, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Lou","sequence":"additional","affiliation":[{"name":"School of Ophthalmology & Optometry, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibo","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Imaging, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Imaging, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zining","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Stomatology, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiebin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.04.035","article-title":"Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults","volume":"77","author":"Sumazin","year":"2022","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115373","article-title":"State of the art and perspectives in pediatric hepatocellular carcinoma","volume":"207","author":"Digiacomo","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.71163","article-title":"Global burden of hepatoblastoma from 1990 to 2021 and projection to 2030","volume":"14","author":"Huang","year":"2025","journal-title":"Cancer Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4103\/0971-9261.142001","article-title":"The treatment of hepatoblastoma: its evolution and the current status as per the SIOPEL trials","volume":"19","author":"Aronson","year":"2014","journal-title":"J Indian Assoc Pediatr Surg"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810613","article-title":"Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma","volume":"361","author":"Perilongo","year":"2009","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801109","article-title":"Sodium thiosulfate for protection from cisplatin-induced hearing loss","volume":"378","author":"Brock","year":"2018","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2022.01.063","article-title":"Metastatic human hepatoblastoma cells exhibit enhanced tumorigenicity, invasiveness and a stem cell-like phenotype","volume":"57","author":"Marayati","year":"2022","journal-title":"J Pediatr Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11030407","article-title":"Mechanisms of anticancer drug resistance in hepatoblastoma","volume":"11","author":"Marin","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e41483","article-title":"Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells","volume":"11","author":"Maharati","year":"2025","journal-title":"Heliyon"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/\u03b2-catenin signalling: function, biological mechanisms, and therapeutic opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20192466","article-title":"Wnt\/\u03b2-catenin signaling as a useful therapeutic target in hepatoblastoma","volume":"39","author":"Sha","year":"2019","journal-title":"Biosci Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.70168","article-title":"Effective therapeutic targeting of CTNNB1-mutant hepatoblastoma with WNTinib","volume":"20","author":"Balaseviciute","year":"2026","journal-title":"Mol Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1714448","article-title":"Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children","volume":"378","author":"Drilon","year":"2018","journal-title":"N Engl J Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0113-0","article-title":"NTRK fusion-positive cancers and TRK inhibitor therapy","volume":"15","author":"Cocco","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3892\/ijo.2024.5676","article-title":"Targeting the Hippo\/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review)","volume":"65","author":"Li","year":"2024","journal-title":"Int J Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/j.1478-3231.2011.02646.x","article-title":"Deregulation of Hippo kinase signalling in human hepatic Malignancies","volume":"32","author":"Li","year":"2012","journal-title":"Liver Int"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N Engl J Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.70422","article-title":"Outcomes of patients with hepatocellular carcinoma treated with durvalumab plus tremelimumab in real-world clinical practice who met or did not meet the inclusion criteria for the phase 3 HIMALAYA trial","author":"Matono","year":"2026","journal-title":"J Gastroenterol Hepatol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092668","article-title":"A human organoid model of aggressive hepatoblastoma for disease modeling and drug testing","volume":"12","author":"Saltsman","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1186\/s12889-025-24407-3","article-title":"Global trends and regional differences of hepatoblastoma: a systematic analysis and predictions to 2035 based on the Global Burden of Disease study 2021","volume":"25","author":"Shi","year":"2025","journal-title":"BMC Public Health"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2025.1611187","article-title":"Bridging the gap: cancer scientific equity, global child health, and distribution of CAR T-cell therapy clinical trials in childhood cancer","volume":"13","author":"Montoya-Quintero","year":"2025","journal-title":"Front Pediatr"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2025.7733","article-title":"Barriers and opportunities for cancer clinical trials in low- and middle-income countries","volume":"8","author":"Eldridge","year":"2025","journal-title":"JAMA Netw Open"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2022.2032664","article-title":"The RACE for Children Act at one year: progress in pediatric development of molecularly targeted oncology drugs","volume":"22","author":"Zettler","year":"2022","journal-title":"Expert Rev Anticancer Ther"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2771","article-title":"FDA approval summary: Entrectinib for the treatment of NTRK gene fusion solid tumors","volume":"27","author":"Marcus","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/nrclinonc.2018.40","article-title":"Larotrectinib effective against TRK-fusion-positive cancers","volume":"15","author":"Sidaway","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2024-066920","article-title":"The RACE Act and pediatric trials of adult cancer drugs","volume":"154","author":"Liu","year":"2024","journal-title":"Pediatrics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.4_suppl.tps624","article-title":"A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC)","volume":"41","author":"Xie","year":"2023","journal-title":"J Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2021.39.15_suppl.4088","article-title":"Phase I trial of fourth-generation chimeric antigen receptor T-cells targeting glypican-3 for advanced hepatocellular carcinoma","volume":"39","author":"Fang","year":"2021","journal-title":"J Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.35.15_suppl.3049","article-title":"A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r\/r GPC3+ HCC)","volume":"35","author":"Zhai","year":"2017","journal-title":"J Clin Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2018.36.4_suppl.270","article-title":"A phase 2 and biomarker study of sorafenib combined with FOLFOX in patients with advanced hepatocellular carcinoma (HCC)","volume":"36","author":"Goyal","year":"2018","journal-title":"J Clin Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.16_suppl.e14658","article-title":"A pilot trial of personalized neoantigen pulsed autologous dendritic cell vaccine as adjuvant treatment in hepatocellular carcinoma","volume":"41","author":"Wu","year":"2023","journal-title":"J Clin Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2024.42.16_suppl.4125","article-title":"Utilization of tumor-informed circulating tumor DNA in detecting minimal residual disease and guiding adjuvant therapy in liver cancer","volume":"42","author":"Guo","year":"2024","journal-title":"J Clin Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70272-9","article-title":"Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study","volume":"14","author":"Zsiros","year":"2013","journal-title":"Lancet Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2016.34.15_suppl.10516","article-title":"Vincristine\/irinotecan upfront window treatment of high-risk hepatoblastoma: a report from the Children\u2019s Oncology Group (COG) AHEP0731 study committee","volume":"34","author":"Katzenstein","year":"2016","journal-title":"J Clin Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.60.2250","article-title":"Hepatocellular carcinoma in children: Does modified platinum- and doxorubicin-based chemotherapy increase tumor resectability and change outcome? Lessons learned from the SIOPEL 2 and 3 studies","volume":"34","author":"Murawski","year":"2016","journal-title":"J Clin Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.34.15_suppl.10514","article-title":"Two-year results of clinical efficacy of cisplatin in combination with sodium thiosulfate (STS) vs cisplatin alone in a randomized phase III trial for standard risk hepatoblastoma (SR-HB): SIOPEL 6","volume":"34","author":"Brock","year":"2016","journal-title":"J Clin Oncol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1186\/s13046-023-02824-9","article-title":"Correction: LncRNA MYLK-as1 facilitates tumor progression and angiogenesis by targeting miR-424-5p\/E2F7 axis and activating VEGF R-2 signaling pathway in hepatocellular carcinoma","volume":"42","author":"Teng","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"11208","DOI":"10.1038\/s41598-020-67693-0","article-title":"Propofol suppresses hepatocellular carcinoma by inhibiting NET1 through downregulating ERK\/VEGF signaling pathway","volume":"10","author":"Fei","year":"2020","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.02.002","article-title":"\u03b2-Catenin and Yes-Associated Protein 1 cooperate in hepatoblastoma pathogenesis","volume":"189","author":"Min","year":"2019","journal-title":"Am J Pathol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20622","article-title":"Central role of mTORC1 downstream of YAP\/TAZ in hepatoblastoma development","volume":"8","author":"Liu","year":"","journal-title":"Oncotarget"},{"key":"B41","doi-asserted-by":"publisher","first-page":"5347","DOI":"10.3390\/cancers14215347ER","article-title":"Clinical outcomes in fibrolamellar hepatocellular carcinoma treated with immune checkpoint inhibitors","author":"Chen","year":"2022","journal-title":"Cancers"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-22-0335","article-title":"Identification of IGF2 as genomic driver and actionable therapeutic target in hepatoblastoma","volume":"22","author":"Abril-Fornaguera","year":"2023","journal-title":"Mol Cancer Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2022-4005","article-title":"Abstract 4005: Identification of IGF2 as genomic driver and actionable therapeutic target in hepatoblastoma","volume":"82","author":"Abril-Fornaguera","year":"2022","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28621","article-title":"Patient\u2010derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management","volume":"64","author":"Cairo","year":"2016","journal-title":"Hepatology"},{"key":"B45","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1097\/01.COT.0000294783.17277.40","article-title":"Two pediatric liver cancers respond very differently to chemotherapy: Current regimens good for hepatoblastoma, but not hepatocellular carcinoma","volume":"28","author":"Carlson","year":"2006","journal-title":"Oncol Times"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1890288\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:13:57Z","timestamp":1788412437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1890288\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":45,"alternative-id":["10.3389\/fonc.2026.1890288"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1890288","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"1890288"}}