{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T16:36:54Z","timestamp":1766507814265,"version":"3.48.0"},"reference-count":68,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: Astrocytoma IDH-mutant CNS WHO grade 4 is a malignant tumor of the central nervous system characterized by tumor necrosis, microvascular proliferation, and\/or homozygous CDKN2A\/B deletion. This study aims to investigate the prognostic role of the consequences of hypoxic events leading to necrosis and microvascular density, observing their associations with clinical-imaging parameters and morphogenetics. Methods: We performed a retrospective analysis over a 10-year period. Clinical and imaging data were collected from observation sheets and electronic databases. Six immunohistochemical markers and FISH testing were used to evaluate the prognosis and neoformation of blood vessels. Based on the whole slide image, the necrotic percentage was assessed, and the microvascular density was quantified. All data were statistically analyzed. Results: We identified 44 cases, with a mean age of 57.86 years. From a clinical perspective, advanced age, arterial hypertension, diabetes mellitus, and acute onset of clinical manifestations represent negative prognostic factors. In imaging, the increased rate of resectability is a protective factor, while the presence of residual volume and an increased residual volume have a negative impact on survival. The consequences of hypoxic events (tumor necrosis and microvascular density) are negative risk factors for survival. Added to these are p53 overexpression, loss of PTEN, deletion, and amplification of the CDKN2A gene. Conclusions: We observed that necrosis and increased microvascular density resulting from microvascular proliferation are both defining features of the tumor and impact patient prognosis and survival. In addition, they induce or are associated with other essential changes (p53, PTEN, CDKN2A) that promote tumor aggressiveness.<\/jats:p>","DOI":"10.3390\/medsci14010006","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:27:47Z","timestamp":1766500067000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Consequences of Hypoxic Events, Necrosis, and Microvascular Density, in Astrocytoma IDH-Mutant, CNS WHO Grade 4"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8039-3200","authenticated-orcid":false,"given":"Cristian Ionut","family":"Orasanu","sequence":"first","affiliation":[{"name":"Department of Pathology, Clinical Service of Pathology, \u201cSf. Apostol Andrei\u201d Emergency County Hospital, 900591 Constanta, Romania"},{"name":"Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), \u201cOvidius\u201d University, 900591 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madalina","family":"Bosoteanu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Service of Pathology, \u201cSf. Apostol Andrei\u201d Emergency County Hospital, 900591 Constanta, Romania"},{"name":"Faculty of Medicine, \u201cOvidius\u201d University of Constanta, 900470 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sorin","family":"Vamesu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Service of Pathology, \u201cSf. Apostol Andrei\u201d Emergency County Hospital, 900591 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9396-2350","authenticated-orcid":false,"given":"Raluca Ioana","family":"Voda","sequence":"additional","affiliation":[{"name":"Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), \u201cOvidius\u201d University, 900591 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anamaria","family":"Sincu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Service of Pathology, \u201cSf. Apostol Andrei\u201d Emergency County Hospital, 900591 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9251-3297","authenticated-orcid":false,"given":"Mariana","family":"Deacu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Service of Pathology, \u201cSf. Apostol Andrei\u201d Emergency County Hospital, 900591 Constanta, Romania"},{"name":"Faculty of Medicine, \u201cOvidius\u201d University of Constanta, 900470 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e13062","DOI":"10.1111\/bpa.13062","article-title":"Classification of adult-type diffuse gliomas: Impact of the World Health Organization 2021 update","volume":"32","author":"Whitfield","year":"2022","journal-title":"Brain Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/cco-22-120","article-title":"2021 updates to the World Health Organization classification of adult-type and pediatric-type diffuse gliomas: A clinical practice review","volume":"12","author":"Thomas","year":"2023","journal-title":"Chin. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"154163","DOI":"10.1016\/j.prp.2022.154163","article-title":"IDH-mutant astrocytoma with an evolutional progression to CDKN2A\/B homozygous deletion and NTRK fusion during recurrence: A case report","volume":"239","author":"Kirishima","year":"2022","journal-title":"Pathol. Res. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2100029","DOI":"10.1002\/bies.202100029","article-title":"Tumor necrosis: A synergistic consequence of metabolic stress and inflammation","volume":"43","author":"Yee","year":"2021","journal-title":"Bioessays"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.7150\/thno.41692","article-title":"Glioma stem cells and their roles within the hypoxic tumor microenvironment","volume":"11","author":"Boyd","year":"2021","journal-title":"Theranostics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Shan, F.Y., Zhao, D., Tirado, C.A., Fonkem, E., Zhang, Y., Feng, D., and Huang, J.H. (2022). Glioblastomas: Molecular Diagnosis and Pathology. Glioblastoma\u2014Current Evidence, IntechOpen.","DOI":"10.5772\/intechopen.105472"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1158\/0008-5472.CAN-03-2073","article-title":"Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population","volume":"64","author":"Brat","year":"2004","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1007\/s12035-020-01892-8","article-title":"Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma","volume":"57","author":"Ahir","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1369\/00221554211058098","article-title":"Proteomic Distributions in CD34+ Microvascular Niche Patterns of Glioblastoma","volume":"70","author":"Chen","year":"2022","journal-title":"J. Histochem. Cytochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4132\/jptm.2024.03.11","article-title":"The spectrum of microvascular patterns in adult diffuse glioma and their correlation with tumor grade","volume":"58","author":"Soni","year":"2024","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.trecan.2015.10.009","article-title":"Glioblastoma: Defining Tumor Niches","volume":"1","author":"Hambardzumyan","year":"2015","journal-title":"Trends Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.3390\/clinpract12060108","article-title":"Implications of Cellular Immaturity in Necrosis and Microvascularization in Glioblastomas IDH-Wild-Type","volume":"12","author":"Orasanu","year":"2022","journal-title":"Clin. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/jnen\/nlv009","article-title":"The Diagnostic Use of Immunohistochemical Surrogates for Signature Molecular Genetic Alterations in Gliomas","volume":"75","author":"Tanboon","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/bpa.12173","article-title":"Revisiting TP53 Mutations and Immunohistochemistry\u2014A Comparative Study in 157 Diffuse Gliomas","volume":"25","author":"Takami","year":"2015","journal-title":"Brain Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/jnen\/nlaf024","article-title":"Isocitrate dehydrogenase-mutant astrocytoma in persons aged 55 years and older: Survival differences versus the young","volume":"84","author":"Siddiq","year":"2025","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","first-page":"367","article-title":"Treatment and outcomes of IDH1-mutant gliomas in elderly patients","volume":"140","author":"Yu","year":"2023","journal-title":"J. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/bpa.12801","article-title":"IDH mutant lower grade (WHO Grades II\/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations","volume":"30","author":"Yang","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_18","unstructured":"(2021). Central Nervous System Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/neuonc\/noac207","article-title":"Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions","volume":"25","author":"Miller","year":"2023","journal-title":"Neuro Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s11060-022-04114-4","article-title":"Sex as a prognostic factor in adult-type diffuse gliomas: An integrated clinical and molecular analysis according to the 2021 WHO classification","volume":"159","author":"Kim","year":"2022","journal-title":"J. Neurooncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1001\/jama.2013.280319","article-title":"Glioblastoma and other malignant gliomas: A clinical review","volume":"310","author":"Omuro","year":"2013","journal-title":"JAMA"},{"key":"ref_22","first-page":"3","article-title":"Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment","volume":"18","author":"Hanif","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2217\/cns.13.12","article-title":"Retrospective analysis of the effects of steroid therapy and antidiabetic medication on survival in diabetic glioblastoma patients","volume":"2","author":"Welch","year":"2013","journal-title":"CNS Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/ANA.0000000000000339","article-title":"Association Between Perioperative Hyperglycemia and Survival in Patients with Glioblastoma","volume":"29","author":"Hagan","year":"2017","journal-title":"J. Neurosurg. Anesth."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Guarnaccia, L., Marfia, G., Masseroli, M.M., Navone, S.E., Balsamo, M., Caroli, M., Valtorta, S., Moresco, R.M., Campanella, R., and Garzia, E. (2021). Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma. Cancers, 14.","DOI":"10.20944\/preprints202111.0531.v1"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Valerius, A.R., Webb, L.M., Thomsen, A., Lehrer, E.J., Breen, W.G., Campian, J.L., Riviere-Cazaux, C., Burns, T.C., and Sener, U. (2024). Review of Novel Surgical, Radiation, and Systemic Therapies and Clinical Trials in Glioblastoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910570"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1093\/annonc\/mdh306","article-title":"Hypertension as a risk factor for glioma? Evidence from a population-based study of comorbidity in glioma patients","volume":"15","author":"Houben","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Aboubechara, J.P., and Aboud, O. (2024). Metabolic Risk Factors and Survival in Patients with Glioblastoma. Cancers, 16.","DOI":"10.20944\/preprints202409.0546.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"vi1","DOI":"10.1093\/neuonc\/noae145","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017-2021","volume":"26","author":"Price","year":"2024","journal-title":"Neuro Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e14019","DOI":"10.1200\/JCO.2024.42.16_suppl.e14019","article-title":"Prognostic factors of grade 4 IDH-mutant astrocytoma","volume":"42","author":"Maqbool","year":"2024","journal-title":"JCO"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e448","DOI":"10.1016\/j.wneu.2018.04.067","article-title":"Preoperative Two-Dimensional Size of Glioblastoma is Associated with Patient Survival","volume":"115","author":"Leu","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Porz, N., Bauer, S., Pica, A., Schucht, P., Beck, J., Verma, R.K., Slotboom, J., Reyes, M., and Wiest, R. (2014). Multi-modal glioblastoma segmentation: Man versus machine. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096873"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109663","DOI":"10.1016\/j.radonc.2023.109663","article-title":"ESTRO-EANO guideline on target delineation and radiotherapy details for glioblastoma","volume":"184","author":"Niyazi","year":"2023","journal-title":"Radiother. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ohmura, K., Tomita, H., and Hara, A. (2023). Peritumoral Edema in Gliomas: A Review of Mechanisms and Management. Biomedicines, 11.","DOI":"10.3390\/biomedicines11102731"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fang, Z., Shu, T., Luo, P., Shao, Y., Lin, L., Tu, Z., Zhu, X., and Wu, L. (2024). The peritumoral edema index and related mechanisms influence the prognosis of GBM patients. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1417208"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s11060-020-03428-5","article-title":"Disparities in glioblastoma survival by case volume: A nationwide observational study","volume":"147","author":"Raj","year":"2020","journal-title":"J. Neuro-Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1055\/s-0040-1701635","article-title":"Importance and Evidence of Extent of Resection in Glioblastoma","volume":"82","author":"Wykes","year":"2021","journal-title":"J. Neurol. Surg. A Cent. Eur. Neurosurg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/s41598-020-79829-3","article-title":"Precise enhancement quantification in post-operative MRI as an indicator of residual tumor impact is associated with survival in patients with glioblastoma","volume":"11","author":"Ligero","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11060-023-04409-0","article-title":"Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: Systematic review and meta-analysis","volume":"164","author":"Ma","year":"2023","journal-title":"J. Neuro-Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/neuonc\/not137","article-title":"Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma","volume":"16","author":"Chaichana","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41571-020-00447-z","article-title":"EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood","volume":"18","author":"Weller","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1093\/neuonc\/noad100","article-title":"Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline","volume":"25","author":"Sahm","year":"2023","journal-title":"Neuro-Oncology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"549412","DOI":"10.1155\/2015\/549412","article-title":"Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies","volume":"2015","author":"Zimna","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dom\u00e8nech, M., Hern\u00e1ndez, A., Plaja, A., Mart\u00ednez-Balibrea, E., and Bala\u00f1\u00e0, C. (2021). Hypoxia: The Cornerstone of Glioblastoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212608"},{"key":"ref_45","first-page":"75","article-title":"The origin of circumscribed necroses and perinecrotic niches in glioblastoma multiforme: An additional hypothesis","volume":"2","author":"Schiffer","year":"2015","journal-title":"Integr. Cancer Sci. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"208","DOI":"10.62347\/YXVS6225","article-title":"Significance of Nestin and CD133 as cancer stem cell markers in diffuse glioma and association with p53 expression and IDH status","volume":"17","author":"Selvaraj","year":"2024","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1111\/cas.12691","article-title":"Nestin as a marker of cancer stem cells","volume":"106","author":"Neradil","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_48","first-page":"17","article-title":"Mechanisms of temozolomide resistance in glioblastoma\u2014A comprehensive review","volume":"4","author":"Singh","year":"2021","journal-title":"Cancer Drug Resist."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"318","DOI":"10.15386\/mpr-1951","article-title":"Immunohistochemical expression of MGMT in gliomas and its role in ascertaining patient survival","volume":"94","author":"Butta","year":"2021","journal-title":"Med. Pharm. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.31557\/APJCP.2021.22.12.3803","article-title":"Diagnostic Accuracy of Immunohistochemistry in Detecting MGMT Methylation Status in Patients with Glioma","volume":"22","author":"Sahara","year":"2021","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/jnr.24776","article-title":"Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events","volume":"99","author":"Ibarra","year":"2021","journal-title":"J. Neurosci. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s12031-024-02240-4","article-title":"Characterizing the Linkage of Systemic Hypoxia and Angiogenesis in High-Grade Glioma to Define the Changes in Tumor Microenvironment for Predicting Prognosis","volume":"74","author":"Shrivastava","year":"2024","journal-title":"J. Mol. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1158\/1535-7163.MCT-22-0595","article-title":"Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem","volume":"22","author":"Siddhartha","year":"2023","journal-title":"Mol. Cancer Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1093\/neuonc\/noae033","article-title":"Sexual-biased necroinflammation is revealed as a predictor of bevacizumab benefit in glioblastoma","volume":"26","author":"Sepulveda","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e5004","DOI":"10.1002\/nbm.5004","article-title":"Vascular differences between IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 at imaging and transcriptomic levels","volume":"36","author":"Andreu","year":"2023","journal-title":"NMR Biomed."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ers\u00f6z, C.C., Berber, H., and Heper, A. (2024). Grade 4 astrocytoma vs. grade 4 glioblastoma: Is there any clue in H&E?. Int. J. Neurosci., 1\u20136.","DOI":"10.1080\/00207454.2024.2441994"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"452","DOI":"10.37897\/RJN.2021.4.7","article-title":"Relationship between phosphatase and tensin homolog (PTEN) expression in high grade glioma and histopathologic findings","volume":"20","author":"Hayati","year":"2021","journal-title":"Ro. J. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1158\/0008-5472.CAN-04-3376","article-title":"PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma","volume":"65","author":"Rong","year":"2005","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/ncpneuro0661","article-title":"Mechanisms of disease: The PI3K-Akt-PTEN signaling node\u2014An intercept point for the control of angiogenesis in brain tumors","volume":"3","author":"Castellino","year":"2007","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5484","DOI":"10.1074\/jbc.M108302200","article-title":"PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy","volume":"277","author":"Mayo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_61","first-page":"1001","article-title":"The MDM2-p53 interaction","volume":"1","author":"Moll","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.3390\/cimb44090284","article-title":"Prognostic Impact of Low-Level p53 Expression on Brain Astrocytomas Immunopositive for Epidermal Growth Factor Receptor","volume":"44","author":"Tsai","year":"2022","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1080\/07357900902783211","article-title":"Association between MGMT promoter hypermethylation and p53 mutation in glioblastoma","volume":"27","author":"Shamsara","year":"2009","journal-title":"Cancer Investig."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Huang, L.E. (2022). Impact of CDKN2A\/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020246"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Kim, T.G., Ryu, K.H., Kim, S.H., and Kim, Y.Z. (2024). CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1\/2-Mutation in CNS WHO Grade 4 Gliomas. Biomedicines, 12.","DOI":"10.3390\/biomedicines12102256"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s11060-020-03528-2","article-title":"The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: A systematic review of the contemporary literature","volume":"148","author":"Lu","year":"2020","journal-title":"J. Neuro-Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s11060-025-05078-x","article-title":"CDKN2A\/B status versus morphology in diagnosing WHO grade 4 IDH-mutated astrocytomas: What is the clinical relevance?","volume":"174","author":"Lipatnikova","year":"2025","journal-title":"J. Neuro-Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1093\/neuonc\/noz126.000","article-title":"CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas","volume":"21","author":"Appay","year":"2019","journal-title":"Neuro-Oncology"}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/1\/6\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:44:25Z","timestamp":1766501065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/1\/6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["medsci14010006"],"URL":"https:\/\/doi.org\/10.3390\/medsci14010006","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}