Neuro-oncology最新文献

{"title":"IRS2 as a driver of brain metastasis in colorectal cancer: A potential target for novel therapeutic strategies.","authors":"Inbal Greenberg, Fayhaa Khair-Dabour, Keren Merenbakh-Lamin, Ethan S Sokol, Anat Klein Goldberg, Dor Simkin, Avishay Spitzer, Moshe Benhamou, Shai Bar-Shira, Michal Raz, Rachel Grossman, Eilam Yeini, Paula Ofek, Tomer Meirson, Ronit Satchi-Fainaro, Hadas Reuveni, Ido Wolf, Tami Rubinek","doi":"10.1093/neuonc/noaf028","DOIUrl":"10.1093/neuonc/noaf028","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) ranks as the fourth most common cause of brain metastasis (BM), with its incidence on the rise. However, the molecular mechanisms driving the formation of these lesions from CRC remain unclear.</p><p><strong>Methods: </strong>We analyzed the Foundation Medicine genomic database, which includes over 35,000 CRC samples from both local and metastatic sites. The role of insulin receptor substrate 2 (IRS2) in CRC brain tropism was investigated using various in vitro (co-culture systems and 3D sphere formation assays), in vivo (intracranial and subcutaneous mouse models), and ex vivo (CRC Patient-Derived Explants) models. The molecular and metabolic effects of IRS2 were examined through RNA sequencing and Seahorse analysis. The therapeutic potential of a combined treatment with NT219, an IRS2 inhibitor, and 5-fluorouracil (5-FU) was assessed using our CRC BM mouse model.</p><p><strong>Results: </strong>Our research reveals a distinctive genomic profile of CRC BM and highlights the role of IRS2 in promoting CRC BM. IRS2 mediates its effect by modulating the β-catenin and oxidative phosphorylation (OXPHOS) pathways. We developed a mouse model of BM from CRC and demonstrated that treatment with the IRS2 inhibitor NT219, in combination with 5-FU, significantly suppresses BM development and prolongs survival.</p><p><strong>Conclusions: </strong>Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1729-1745"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the cancer cell proteome: A delicate equilibrium with the genome and epigenome.","authors":"Ryan J Duchatel, Javad Nazarian","doi":"10.1093/neuonc/noaf120","DOIUrl":"10.1093/neuonc/noaf120","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1847-1848"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of MAPK and TORC1 signaling retards development of radiation resistance in pediatric BRAFV600E glioma models.","authors":"Fuyang Li, Kathryn M Bondra, Hanzhou Wang, Dias Kurmashev, Bipasha Mukherjee, Suman Kanji, Amyn A Habib, Yidong Chen, Siyuan Zheng, Sandeep Burma, Peter J Houghton","doi":"10.1093/neuonc/noaf068","DOIUrl":"10.1093/neuonc/noaf068","url":null,"abstract":"<p><strong>Background: </strong>MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but the development of XRT resistance is a challenge.</p><p><strong>Methods: </strong>XRT resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT.</p><p><strong>Results: </strong>Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control compared to XRT alone, but resistance to combined therapy developed rapidly. RNA sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active Akt or TSC2 deletion, conferred in vitro XRT resistance. The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development.</p><p><strong>Conclusion: </strong>PI3K-mTOR activation promotes the development of XRT resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT and can potentially prevent the development of XRT resistance.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1787-1800"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHP2 inhibition reduces somatotroph tumor growth in a pre-clinical model.","authors":"Facundo García Barberá, Florencia Picech, Laura Cecenarro, Gilda Florencia Mezger, Erica Faure, Natacha Zlocowski, Patricia Calafat, Juan Carlos De Battista, Jorge Humberto Mukdsi, Liliana Del Valle Sosa, Juan Pablo Petiti","doi":"10.1093/neuonc/noaf057","DOIUrl":"10.1093/neuonc/noaf057","url":null,"abstract":"<p><strong>Background: </strong>In somatotroph tumors, over 50% of patients do not respond satisfactorily to the octreotide (OCT) treatment. Stimulation of SSTR2 with OCT triggers anti-proliferative signaling pathways mediated by the phosphatase SHP2. This phosphatase can exercise its functions through the STAT3, with the SHP2/STAT3 subcellular localization being crucial for understanding its mechanisms of action. We investigated the expression of SHP2 in somatotrophs tumors, the role of SHP2 on cell proliferation, its effects on STAT3 phosphorylation, and SHP2/STAT3 subcellular localization, using in vitro and a pre-clinical model.</p><p><strong>Methods: </strong>Protein and mRNA expression of SHP2 were evaluated in PitNETs by bioinformatic analysis, IHC and WB. The effect of SHP099 on cell proliferation was determined in GH3 cells, patient derived tumor cells and in a PDX model. The effect of SHP2 on STAT3, AKT, and ERK1/2 activation was analyzed by WB, and SHP2/STAT3 subcellular localization was evaluated by IF and MET.</p><p><strong>Results: </strong>We observed increased SHP2 expression in somatotroph tumors being associated with invasiveness. The anti-proliferative effect of OCT and its adaptation after long-term exposure may be driven by the expression of SSTR2 and SHP2. The treatment with SHP099 decreased cell proliferation, tumor volume growth, necrosis as well as the phosphorylation of STAT3-Tyr705, AKT, and ERK1/2.</p><p><strong>Conclusion: </strong>We have demonstrated that SHP2 is more expressed in somatotroph tumors, with its pharmacological inhibition resulting in a reduction of both in vitro and in vivo cell proliferation via STAT3 phosphorylation, making this phosphatase a novel clinical target with promising effects on somatotroph tumors.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1702-1714"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation of tumor versus peritumoral cortex in gliomas by intraoperative electrocorticography.","authors":"Belén Díaz-Fernández, David Henao-Herreno, Juan Nieto, Alesya Evstratova, Silvia Cases-Cunillera, Louise Deboeuf, Alexandre Roux, Edouard Dezamis, Marc Zanello, Bertrand Mathon, Carine Karachi, Alexandre Carpentier, Pascale Varlet, Johan Pallud, Laurent Capelle, Catalina Alvarado-Rojas, Michel Le Van Quyen, Gilles Huberfeld","doi":"10.1093/neuonc/noaf082","DOIUrl":"10.1093/neuonc/noaf082","url":null,"abstract":"<p><strong>Background: </strong>Brain diffuse gliomas are highly epileptic and infiltrative tumors. Glioma surgery consists of the resection of the tumor core and the maximum of the peritumoral zone, infiltrated by tumor cells, guided by the intraoperative assessment of brain functionality and connectivity. However, its electrophysiological characteristics are poorly characterized.</p><p><strong>Methods: </strong>We studied the characteristics of electrocorticographic (ECoG) signals, in the context of glioma surgery in awake conditions on 29 patients, using EEG activity sampled on the tumor itself versus on its borders and in healthy areas. We assessed the features of frequency bands and aperiodic components (offset and slope) of ECoG power spectra during awake glioma surgery, according to cortical tumoral versus peritumoral and healthy status.</p><p><strong>Results: </strong>We found that tumor contacts present a decrease in activity for all the frequency bands except for delta activity, which was increased. Second, the peritumoral cortex was characterized by an increase in relative beta activity and slopes between 20 and 40 Hz. Low cortical tumor cell infiltration was directly correlated with a reduction in the production of physiological brain rhythms. Finally, an automatic classifier based on neural networks allowed the classification of the electrodes based on their power spectrum characteristics.</p><p><strong>Conclusions: </strong>This intraoperative study shows that ECoG during glioma surgery in awake condition may characterize the peritumoral cortices, key for pathophysiology and therapy, and deepens our knowledge of the effects of tumor cell infiltration on nervous tissue activity. Its assessment during the surgical procedure should better delineation of the cortical areas to be removed.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1758-1771"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCOR loss promotes both retinoblastoma growth and susceptibility to IGF1R inhibition.","authors":"Su-Chan Lee, Satoshi Nakata, Lujain Alaali, Kaixuan Wang, Pei-Chi Tsai, Khoa Pham, Brent A Orr, Quynh T Tran, Laura Asnaghi, Eric Raabe, Charles G Eberhart","doi":"10.1093/neuonc/noaf096","DOIUrl":"10.1093/neuonc/noaf096","url":null,"abstract":"<p><strong>Background: </strong>BCL-6 corepressor (BCOR) loss-of-function alterations are common in clinically aggressive retinoblastoma. The study aim was to determine if BCOR loss promotes the growth and dissemination of retinoblastoma cells, and identify the pathways it regulates in these retinal tumors of childhood.</p><p><strong>Methods: </strong>Gain- and loss-of-function strategies were used to modulate BCOR levels in a panel of retinoblastoma cell lines, and the effects on proliferation, clonogenicity, apoptosis, and migration were assessed in vitro and in murine xenograft models.</p><p><strong>Results: </strong>BCOR knockdown or knockout in retinoblastoma lines with high protein levels increased tumor growth, invasion, clonogenicity, and chemoresistance in vitro, while increased expression in low BCOR lines slowed growth. Growth of retinoblastoma xenografts was similarly sensitive to BCOR gain or loss. BCOR reduction resulted in upregulation of IGF1 and activation of IGF1 receptor (IGF1R) signaling, and the effects of IGF1R inhibition were dependent on BCOR level. In vitro, reduction of retinoblastoma growth and induction of apoptosis by the IGF1R inhibitors linsitinib and AEW541 were also significantly stronger in cells with low BCOR as compared to controls. Both linsitinib and AEW541 suppressed colony formation in a dose-dependent manner in BCOR knockout or knockdown cells. Finally, high BCOR levels rendered retinoblastoma xenografts insensitive to linsitinib.</p><p><strong>Conclusions: </strong>Loss of BCOR function is associated with more aggressive retinoblastoma cell line growth and chemoresistance, at least in part due to increased IGF1R signaling. Inhibiting IGF1R pharmacologically had a marked anti-tumor effect in aggressive retinoblastoma lacking BCOR, suggesting it as a new therapeutic target, although this still needs to be confirmed in clinical samples with BCOR mutations.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1715-1728"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synapsin III promotes neuronal-like transdifferentiation of glioblastoma stem cells by disrupting JAG1-Notch1 interaction.","authors":"Yilin Deng, Zheng Yuan, Xiong Jin, Zekun Wang, Rui Gong, Shuai Ren, Jong Bae Park, Bingyang Shi, Jinlong Yin","doi":"10.1093/neuonc/noaf056","DOIUrl":"10.1093/neuonc/noaf056","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM), a formidable and highly aggressive form of brain cancer, is predominantly driven by GBM stem cells (GSCs), which are characterized by their ability for self-renewal and aberrant differentiation. Targeting the terminal differentiation of GSCs represents a promising therapeutic strategy. This study aimed to elucidate the role of synapsin III (SYN3) in driving the differentiation of GSCs into neuron-like cells and its effect on the tumor-suppressive pathways in GBM.</p><p><strong>Methods: </strong>Proliferation assays, limited dilution assays, immunocytochemistry, western blot, RT-qPCR, and GSC tumor models were used to determine gene function and assess the role of γ-secretase inhibitors. Co-immunoprecipitation and microscale thermophoresis were conducted to explore the underlying regulatory mechanisms. Intracranial orthotopic injection of adeno-associated virus (AAV) was performed to evaluate therapeutic potential.</p><p><strong>Results: </strong>We demonstrate that SYN3, uniquely within the synapsin family, acts as a tumor suppressor by steering GSCs toward neuronal-like transdifferentiation. Mechanistically, SYN3 enhances the expression of Neuregulin 3 (NRG3), which serves as a non-canonical antagonist of Notch signaling by competitively binding to specific epitopes within the EGF-like domain of JAG1, a critical site for the canonical engagement of Notch receptors. This critical interaction disrupts the JAG1-Notch1 signaling pathway, a key mechanism driving GSCs toward neuronal-like transdifferentiation, thereby reducing their stemness. Furthermore, SYN3 demonstrated significant antineoplastic activity in a mouse model harboring GSCs. AAV-mediated overexpression of SYN3 markedly impeded GBM progression.</p><p><strong>Conclusions: </strong>Our research reveals the therapeutic potential of SYN3 in regulating GSC fate and offers a novel differentiation-based approach for GBM therapy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1686-1701"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXR2 activation is not exclusive of CNS neuroblastoma.","authors":"Alexa N Siskar, Emily Hanzlik, Maria F Cardenas, Mohammad K Eldomery, Soniya Pinto, Christopher L Tinkle, Qunyu Zhang, Xiaoyu Li, Tong Lin, Sandeep K Dhanda, Gerald Reis, Daphne Li, Ravi Raghavan, Alexander Vortmeyer, Matthias A Karajannis, Giles W Robinson, Arzu Onar-Thomas, Patrick R Blackburn, David A Wheeler, Jason Chiang","doi":"10.1093/neuonc/noaf076","DOIUrl":"10.1093/neuonc/noaf076","url":null,"abstract":"<p><strong>Background: </strong>FOXR2 activation is regarded as pathognomonic for CNS neuroblastoma (NB). However, a comprehensive understanding of the landscape for CNS tumors exhibiting FOXR2 activation is lacking.</p><p><strong>Methods: </strong>Histopathologic, molecular, imaging, and clinical data of 42 CNS tumors with FOXR2 overexpression identified through screening institutional datasets and published institutional cases were analyzed.</p><p><strong>Results: </strong>Among the 42 tumors, 21 (50.0%) were high-grade gliomas (HGGs), and 18 (42.9%) were embryonal tumors. The HGGs included ten H3 K27M-mutant diffuse midline gliomas (DMGs) and eight radiation-associated tumors. The embryonal tumors included 11 CNS NBs and six pineoblastomas (PBs). FOXR2 expression was similar between CNS NB and other tumor types (P = 0.82). HGGs with FOXR2 overexpression, unlike NBs and PBs, displayed diverse concomitant genetic alterations. The most common mechanisms of FOXR2 activation involved structural alterations causing promoter donation and enhancer hijacking from active genes essential for brain development, followed by alternative promoter activation or truncated LINE-1 retrotransposition. The preferential activation mechanism varied by tumor type. All but two aberrant FOXR2 transcripts incorporated non-canonical, non-coding exons. Gene set enrichment analysis demonstrated shared downstream effects of FOXR2 activation at the epigenome and transcriptome levels across tumor types. DMGs and PBs with FOXR2 overexpression were aggressive, with 0% 2-year overall survival, whereas CNS NBs responded well to combined chemotherapy and radiation.</p><p><strong>Conclusions: </strong>CNS tumors with FOXR2 overexpression manifest significant histological, molecular, imaging, and clinical diversity. While HGGs and PBs with FOXR2 overexpression demonstrated inferior prognosis, CNS NBs showed favorable outcomes. Integrating histologic and molecular diagnostic approaches is imperative for accurate prognostication and optimal therapeutic decision-making.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1801-1812"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The proteomic landscape of diffuse midline glioma highlights the therapeutic potential of non-histone protein methyltransferases.","authors":"Arun Kumaran Anguraj Vadivel, Sanja Pajovic, Robert Siddaway, Sabrina Zhu, Stefanie-Grace Sbergio, Olivera Matic, Lauren Phillips, Yong Jia Bu, Mark Nitz, Cynthia Hawkins","doi":"10.1093/neuonc/noaf033","DOIUrl":"10.1093/neuonc/noaf033","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor with limited treatment options despite extensive genomic characterization. The aim of this study was to investigate the proteomic landscape of DMG to identify potential therapeutic targets.</p><p><strong>Methods: </strong>We conducted a comprehensive proteomic analysis using LC-MS3, along with DNA methylation and DNA/RNA sequencing in 55 DMG patients' samples. post-translational modification profiling (phosphoproteome and methylproteome) was conducted in 30 patient samples. We then investigated the effects of modulating key protein targets on protein methylation, protein synthesis, and DMG cell growth in vitro and in vivo.</p><p><strong>Results: </strong>DMGs exhibited high global protein methylation, with significant enrichment of translation machinery proteins and factors involved in apoptosis regulation. Surprisingly, while targets of key kinases were highly phosphorylated, overall protein phosphorylation was lower in DMG compared to normal brain tissues. Non-histone methyltransferases METTL13 and METTL21B, along with protein kinases PAK2, PRKACA, and AKT1, were identified as key players in DMG methylproteome and phosphoproteome, respectively. METTL13 knockdown led to reduced EEF1A1 protein methylation, a shift in oncoprotein synthesis, and inhibited DMG cell growth in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings highlight the dependency of DMG on methyl-signaling pathways, particularly involving METTL13, which regulates EEF1A1 protein methylation and oncoprotein synthesis. Targeting the non-histone methyltransferases offers a promising therapeutic strategy for DMG. This study underscores the potential of post-translational modifications, specifically methyl-signaling pathways, as novel therapeutic targets for DMG and possibly other currently incurable cancers.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1829-1846"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathological and molecular characteristics of IDH-wildtype glioblastoma without contrast enhancement: Implications for clinical outcomes.","authors":"Martha Foltyn-Dumitru, Rouzbeh Banan, Marianne Schell, Mustafa Ahmed Mahmutoglu, Tobias Kessler, Wolfgang Wick, Gianluca Brugnara, Martin Bendszus, Felix Sahm, Philipp Vollmuth","doi":"10.1093/neuonc/noaf070","DOIUrl":"10.1093/neuonc/noaf070","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GB) heterogeneity poses substantial challenges for diagnosis and treatment. Isocitrate dehydrogenase (IDH)-wildtype GB may lack contrast enhancement on MRI and exhibit a \"low-grade radiologic appearance\" (non-contrast-enhancing [CE] GB), a phenomenon with unclear clinical implications. This study investigates the histopathological and molecular differences and survival outcomes between CE and non-CE GB.</p><p><strong>Methods: </strong>This retrospective study at Heidelberg University Hospital analyzed 457 IDH-wildtype GB cases (09/2009-01/2021). Contrast enhancement on preoperative MRI was volumetrically assessed, classifying tumors as non-CE/CE GB using a 1 cm³ cutoff. Molecular and histopathological features, including microvascular proliferation, necrosis, and overall survival (OS), were compared between the groups.</p><p><strong>Results: </strong>Of the initial cohort, 352 (77%) patients met the inclusion criteria, with 44 (12.5%) non-CE and 308 (87.5%) CE GB. The histopathological assessment revealed that non-CE GB was less likely to present traditional hallmarks of GB, such as microvascular proliferation (39% vs. 94%) and necrosis (25% vs. 92%) (P < .001). In the non-CE group, 24 patients (55%) were diagnosed as molecular GB, compared to only 8 patients (3%) in the CE group (P < .001). A significant difference was observed in Ki-67 levels, with non-CE GBs having a lower mean Ki-67 index of 18% ± 12% compared to 26% ± 13% in CE tumors (P < .001). The median OS was 27.2 months (95% CI, 19.8-NA) for non-CE and 14.7 months (95% CI, 13.2-17.1) for CE GB (P = .0049).</p><p><strong>Conclusions: </strong>IDH-wildtype GBs without contrast enhancement are often diagnosed based on molecular criteria due to less frequent histopathological hallmarks and are associated with prolonged OS.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1878-1887"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}