{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:44:16Z","timestamp":1753893856552,"version":"3.41.2"},"reference-count":49,"publisher":"Open Exploration Publishing","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Explor Target Antitumor Ther"],"accepted":{"date-parts":[[2025,4,23]]},"abstract":"<jats:p xml:lang=\"en\">Aim: This research aims to guide future strategies for personalized treatment of primary mediastinal large B-cell lymphoma (PMBCL), particularly to identify high-risk patients who may benefit from incorporating immune checkpoint inhibitors (ICIs) in the first-line setting. Methods: A retrospective, single-center study included 254 newly diagnosed PMBCL patients treated with rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (R-DA-EPOCH), rituximab, modified protocol NHL-BFM-90 (RmNHL-BFM-90), or R-DA-EPOCH combined with nivolumab. Clinical parameters, immunohistochemical markers [programmed death ligand-1 (PD-L1), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), human leucocyte antigen (HLA)-DR, Ki-67, multiple myeloma oncogene 1 (MUM1)], molecular markers (mutations in tumor protein p53 (TP53), CD58, beta-2-microglobulin (B2M), and exportin 1 (XPO1) genes; short tandem repeats at 6p21.3 [major histocompatibility complex (MHC) class I\/II], 9p24.1 (PD-L1\/PD-L2), 16p13.13 [class II, MHC, transactivator gene (CIITA)]), and cytogenetic profiles [myelocytomatosis oncogene (MYC)\/8q24, B-cell lymphoma 2 (BCL2)\/18q21, BCL6\/3q27, del17p13, and karyotype abnormalities] were analyzed. Results: The addition of nivolumab to R-DA-EPOCH as a first-line regimen significantly improved event-free survival (EFS; P = 0.018). This study identified that adverse prognostic factors for PMBCL include allelic imbalance at specific loci 6p21.3 (MHC class I\/II), 9p24.1 (PD-L1\/PD-L2), and 16p13.13 (CIITA). Incorporating nivolumab into the R-DA-EPOCH regimen as a first-line therapy has shown potential in reducing adverse prognostic factors. Conclusions: These findings suggest that high-risk patients may benefit significantly from the early incorporation of ICIs into their treatment plans.<\/jats:p>","DOI":"10.37349\/etat.2025.1002318","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:50:41Z","timestamp":1747788641000},"update-policy":"https:\/\/doi.org\/10.37349\/open_exploration_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic impact of biomarkers in PMBCL: rationale for early integration of immune checkpoint inhibitors"],"prefix":"10.37349","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-5934","authenticated-orcid":false,"given":"Yana K.","family":"Mangasarova","sequence":"first","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russian 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(Noisy-le-grand)"},{"key":"ref26","unstructured":"ncbi.nlm.nih.gov\/gene [Internet]. Bethesda: Courtesy of the National Library of Medicine; [cited 2024 Dec 25]. Available from: https:\/\/www.ncbi.nlm.nih.gov\/gene\/"},{"key":"ref27","unstructured":"hgvs-nomenclature.org [Internet]. [cited 2024 Dec 25]. Available from: http:\/\/varnomen.hgvs.org\/"},{"key":"ref28","unstructured":"SIFT. Version 6.2.1 [Software]. [cited 2024 Dec 25]. Available from: https:\/\/sift.bii.a-star.edu.sg\/"},{"key":"ref29","unstructured":"PROVEAN. Version 1.1.5 [Software]. [cited 2024 Dec 25]. Available from: http:\/\/provean.jcvi.org\/"},{"key":"ref30","unstructured":"PolyPhen-2. Version 2.2.2 [Software]. [cited 2024 Dec 25]. Available from: http:\/\/genetics.bwh.harvard.edu\/pph2\/"},{"key":"ref31","unstructured":"MutationTaster [Software]. [cited 2024 Dec 25]. Available from: https:\/\/www.mutationtaster.org\/"},{"key":"ref32","unstructured":"ClinVar [Internet]. Bethesda: Courtesy of the National Library of Medicine; [cited 2024 Dec 25]. Available from: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/j.1600-0625.2011.01375.x","article-title":"A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays","volume":"21","author":"Sidorova","year":"2012","journal-title":"Exp Dermatol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw227","article-title":"VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research","volume":"44","author":"Lai","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"ref38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref39","unstructured":"RYR2:c.8162T>C [Internet]. [cited 2024 Nov 15]. Available from: https:\/\/franklin.genoox.com\/variant\/snp\/chr1-237821276-T-C"},{"key":"ref40","unstructured":"Seshat [Internet]. [cited 2024 Nov 15]. Available from: http:\/\/vps338341.ovh.net\/"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"297","DOI":"10.35754\/0234-5730-2024-69-3-297-318","article-title":"Analysis of microsatellite instability in primary mediastinal large B-cell lymphoma: Focus on PD-L1\/PD-L2 and CIITA","volume":"69","author":"Abdurashidova","year":"2024","journal-title":"Russ J Hematol Transfusiology"},{"key":"ref42","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00951","article-title":"Investigation of Cervical Tumor Biopsies for Chromosomal Loss of Heterozygosity (LOH) and Microsatellite Instability (MSI) at the","volume":"9","author":"Chambuso","year":"2019","journal-title":"Front Oncol"},{"key":"ref43","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5741-y","article-title":"Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review","volume":"19","author":"van Bussel","year":"2019","journal-title":"BMC Cancer"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"7331","DOI":"10.1182\/bloodadvances.2023011169","article-title":"High","volume":"7","author":"Camus","year":"2023","journal-title":"Blood Adv"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"778","DOI":"10.26442\/00403660.2021.07.200929","article-title":"Allogeneic hematopoietic stem cell transplantation in patients with multiple myeloma","volume":"93","author":"Firsova","year":"2021","journal-title":"Ter Arkh"},{"key":"ref46","doi-asserted-by":"publisher","DOI":"10.3390\/genes13030398","article-title":"Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL","volume":"13","author":"Risinskaya","year":"2022","journal-title":"Genes (Basel)"},{"key":"ref47","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179426","article-title":"Loss of Heterozygosity and Mutations in the RAS-ERK Pathway Genes in Tumor Cells of Various Loci in Multiple Myeloma","volume":"25","author":"Soloveva","year":"2024","journal-title":"Int J Mol Sci"},{"key":"ref48","doi-asserted-by":"publisher","DOI":"10.3390\/ijms251910482","article-title":"Biallelic Loss of 7q34 (","volume":"25","author":"Risinskaya","year":"2024","journal-title":"Int J Mol Sci"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.3390\/curroncol29050278","article-title":"STR Profiling Reveals Tumor Genome Instability in Primary Mediastinal B-Cell Lymphoma","volume":"29","author":"Risinskaya","year":"2022","journal-title":"Curr Oncol"}],"container-title":["Exploration of Targeted Anti-tumor Therapy"],"original-title":[],"language":"en","deposited":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:50:46Z","timestamp":1747788646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.explorationpub.com\/Journals\/etat\/Article\/1002318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":49,"URL":"https:\/\/doi.org\/10.37349\/etat.2025.1002318","archive":["Portico","Portico"],"relation":{},"ISSN":["2692-3114"],"issn-type":[{"type":"electronic","value":"2692-3114"}],"subject":[],"published":{"date-parts":[[2025,5,20]]},"assertion":[{"value":"2024-12-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-20","order":2,"name":"published","label":"Published Online","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"1002318"}}