Neuro-oncology最新文献

{"title":"A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients.","authors":"Mary Jane Lim-Fat, Jennifer A Cotter, Mehdi Touat, Jayne Vogelzang, Cecilia Sousa, Will Pisano, Jack Geduldig, Varun Bhave, Joseph Driver, Pei-Chi Kao, Alana McGovern, Clement Ma, Ashley S Margol, Kristina Cole, Amy Smith, Stewart Goldman, Kristiyana Kaneva, AiLien Truong, Kellie J Nazemi, Matthew D Wood, Karen D Wright, Wendy B London, Katherine E Warren, Patrick Y Wen, Wenya Linda Bi, Sanda Alexandrescu, David A Reardon, Keith L Ligon, Kee Kiat Yeo","doi":"10.1093/neuonc/noae142","DOIUrl":"10.1093/neuonc/noae142","url":null,"abstract":"<p><strong>Background: </strong>The frequency and significance of IDH mutations in glioma across age groups are incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes.</p><p><strong>Methods: </strong>Clinical, histologic, and sequencing data from patients with IDH-mutant, grades 2-4 gliomas, were collected from collaborating institutions between 2013 and 2019. Patients were categorized as pediatric (<19 years), young adult (YA; 19-39 years), or older adult (≥40 years). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine the association of age and other covariates with overall (OS) and progression-free survival (PFS).</p><p><strong>Results: </strong>We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS.</p><p><strong>Conclusions: </strong>IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approaches varied significantly by patient age and warrant further study as addressable age-associated outcome drivers.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2364-2376"},"PeriodicalIF":16.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856131","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":"Risk of new tumor, carotid stenosis, and stroke after stereotactic radiosurgery for pituitary tumor: A multicenter study of 2254 patients with imaging follow-up.","authors":"Chloe Dumot, Georgios Mantziaris, Sam Dayawansa, Carson Brantley, Cheng-Chia Lee, Huai-Che Yang, Selcuk Peker, Yavuz Samanci, David Mathieu, Jean-Nicolas Tourigny, Nuria Martinez Moreno, Roberto Martinez Alvarez, Thomas Chytka, Roman Liscak, Herwin Speckter, Erwin Lazo, Anderson Brito, Piero Picozzi, Andrea Franzini, Juan Alzate, Elad Mashiach, Kenneth Bernstein, Douglas Kondziolka, Manjul Tripathi, Greg N Bowden, Ronald E Warnick, Darrah Sheehan, Kimball Sheehan, Angelica Fuentes, John A Jane, Mary Lee Vance, Jason P Sheehan","doi":"10.1093/neuonc/noae133","DOIUrl":"10.1093/neuonc/noae133","url":null,"abstract":"<p><strong>Background: </strong>A higher risk of secondary brain tumor, carotid stenosis, and stroke has been reported after conventional sella irradiation for pituitary neuroendocrine tumors (PitNET). Stereotactic radiosurgery (SRS), which is a more focused approach, is now increasingly used instead. The aim was to assess the risk of secondary brain tumor, carotid stenosis/occlusion, and stroke after SRS.</p><p><strong>Methods: </strong>In this multicentric retrospective study, 2254 patients with PitNET were studied, 1377 in the exposed group, and 877 in the control group.</p><p><strong>Results: </strong>There were 9840.1 patient-years at risk for the SRS and 5266.5 for the control group. The 15-year cumulative probability of secondary intracranial tumor was 2.3% (95% CI: 0.5%, 4.1%) for SRS and 3.7% (95% CI: 0%, 8.7%) for the control group (P = .6), with an incidence rate of 1.32 per 1000 and 0.95 per 1000, respectively. SRS was not associated with an increased risk of tumorigenesis when stratified by age (HR: 1.59 [95% CI: 0.57, 4.47], Pp = .38). The 15-year probability of new carotid stenosis/occlusion was 0.9% (95% CI: 0.2, 1.6) in the SRS and 2% (95% CI: 0, 4.4) in the control group (P = .8). The 15-year probability of stroke was 2.6% (95% CI: 0.6%, 4.6%) in the SRS and 11.1% (95% CI: 6%, 15.9%) in the control group (P < .001). In Cox multivariate analysis stratified by age, SRS (HR 1.85 [95% CI:0.64, 5.35], P = .26) was not associated with risk of new stroke.</p><p><strong>Conclusions: </strong>No increased risk of long-term secondary brain tumor, new stenosis or occlusion, and stroke was demonstrated in the SRS group compared to the control in this study with imaging surveillance.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2328-2338"},"PeriodicalIF":16.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727599","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":"Defining neuroblastoma: From origin to precision medicine.","authors":"Lourdes Sainero-Alcolado, Tomas Sjöberg Bexelius, Giuseppe Santopolo, Ye Yuan, Judit Liaño-Pons, Marie Arsenian-Henriksson","doi":"10.1093/neuonc/noae152","DOIUrl":"10.1093/neuonc/noae152","url":null,"abstract":"<p><p>Neuroblastoma (NB), a heterogenous pediatric tumor of the sympathetic nervous system, is the most common and deadly extracranial solid malignancy diagnosed in infants. Numerous efforts have been invested in understanding its origin and in development of novel curative targeted therapies. Here, we summarize the recent advances in the identification of the cell of origin and the genetic alterations occurring during development that contribute to NB. We discuss current treatment regimens, present and future directions for the identification of novel therapeutic metabolic targets, differentiation agents, as well as personalized combinatory therapies as potential approaches for improving the survival and quality of life of children with NB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2174-2192"},"PeriodicalIF":16.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889803","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":"Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.","authors":"Johnny Duerinck, Louise Lescrauwaet, Iris Dirven, Jacomi Del'haye, Latoya Stevens, Xenia Geeraerts, Freya Vaeyens, Wietse Geens, Stefanie Brock, Anne-Marie Vanbinst, Hendrik Everaert, Ben Caljon, Michaël Bruneau, Laetitia Lebrun, Isabelle Salmon, Marc Kockx, Sandra Tuyaerts, Bart Neyns","doi":"10.1093/neuonc/noae177","DOIUrl":"10.1093/neuonc/noae177","url":null,"abstract":"<p><strong>Background: </strong>Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG.</p><p><strong>Materials and methods: </strong>Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles.</p><p><strong>Results: </strong>42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015).</p><p><strong>Conclusion: </strong>Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2208-2221"},"PeriodicalIF":16.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471116","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":"A low level of tumor necrosis factor α in tumor microenvironment maintains the self-renewal of glioma stem cells by Vasorin-mediated glycolysis.","authors":"Yang Zhang, Tianxu Kang, Yuxi Wang, Chao Song, Huan Li, Hailong Mi, Yachao Li, Minhai Dong, Xiaoyu Ma, Hongtao Zhu, Lidong Cheng, Po Zhang, Zhiye Chen, Lin Zhou, Qiulian Wu, Feng Mao, Baofeng Wang, Suojun Zhang, Kai Shu, Feng Wan, Wenchao Zhou, Jeremy N Rich, Jianying Shen, Qungen Xiao, Xingjiang Yu","doi":"10.1093/neuonc/noae147","DOIUrl":"10.1093/neuonc/noae147","url":null,"abstract":"<p><strong>Background: </strong>Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy resistance and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on the Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patients.</p><p><strong>Methods: </strong>Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single-cell RNA sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal.</p><p><strong>Results: </strong>A low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα at a low level.</p><p><strong>Conclusions: </strong>TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. A combination of targeting VASN and TNFα antitumor effect may be an effective approach for treating GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2256-2271"},"PeriodicalIF":16.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879213","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":"Canonical Amplifications and CDKN2A/B Loss Refine IDH1/2-mutant Astrocytoma Prognosis.","authors":"Hia S Ghosh, Ruchit V Patel, Elizabeth B Claus, L Nicolas Gonzalez Castro, Patrick Y Wen, Keith L Ligon, David M Meredith, Wenya Linda Bi","doi":"10.1093/neuonc/noae258","DOIUrl":"https://doi.org/10.1093/neuonc/noae258","url":null,"abstract":"<p><strong>Background: </strong>Molecular features have been incorporated alongside histologic criteria to improve glioma diagnostics and prognostication. CDKN2A/B homozygous-loss associates with worse survival in IDH1/2-mutant astrocytomas (IDHmut-astrocytomas), the presence of which denotes grade 4 tumor independent of histologic features. However, no molecular features distinguish survival amongst histologically-defined grade 2 and 3 IDHmut-astrocytomas.</p><p><strong>Methods: </strong>We assembled a cohort of patients ≥19 years old diagnosed with an IDHmut-astrocytoma between 1989-2020 from public datasets and several academic medical centers. Multivariate modeling and unbiased clustering were used to stratify risk.</p><p><strong>Results: </strong>We identified 998 IDHmut-astrocytoma patients (41.5% female; 85.6% white). Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification was associated with reduced survival. Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived the longest (OS 205.7 months). Survival for grade 2/3 cases with either CDKN2A/B hemizygous-loss or focal amplifications (80.4, 88.7 months respectively) did not differ significantly from grade 4 cases with intact CDKN2A/B and no amplifications (91.5 months, p=0.93). Grade 4 patients with either hemizygous or homozygous loss of CDKN2A/B had the shortest survival (OS 31.9, 32.5 months respectively), followed by grade 4 cases with intact CDKN2A/B and focal gene amplifications (OS 55.9 months). Integrating CDKN2A/B status and amplifications alongside histopathologic grade refined overall survival prediction. Unbiased clustering revealed 9 distinct molecular profiles, with differential survival. IDHmut-astrocytomas with any CDKN2A/B-loss clustered together, regardless of grade, and exhibited the poorest outcomes.</p><p><strong>Conclusions: </strong>Combining CDKN2A/B hemizygous-loss and focal gene amplifications reveals a group of IDHmut-astrocytoma patients with intermediate prognosis, refining IDHmut-astrocytoma classification.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic contrast-enhanced and diffusion-weighted MR imaging for predicting tumor growth of sporadic vestibular schwannomas: a prospective study.","authors":"S M Schouten Sammy, D Lewis Daniel, S Cornelissen Stefan, K Li Ka-Loh, X Zhu Xiaoping, M C Maas Marnix, S Pegge Sjoert, T T G Jansen Thijs, J J S Mulder Jef, J J Waterval Jérôme, A A Postma Alida, O Pathmanaban Omar, D J Coope David, J M M Derks Jolanda, P P J H Langenhuizen Patrick, A T King Andrew, J B Verheul Jeroen, H P M Kunst Dirk","doi":"10.1093/neuonc/noae252","DOIUrl":"https://doi.org/10.1093/neuonc/noae252","url":null,"abstract":"<p><strong>Background: </strong>Advanced MR imaging, such as diffusion-weighted (DWI) and dynamic contrast-enhanced (DCE) imaging, may provide valuable non-invasive information on intrinsic tumor biology. This study aims to evaluate apparent diffusion coefficient (ADC) and DCE-MRI-derived microvascular parameter values (Ktrans, ve, and vp) as potential imaging predictors for future sporadic vestibular schwannoma (VS) growth.</p><p><strong>Methods: </strong>In this prospective cohort study, patients with newly diagnosed unilateral sporadic VS and an initial wait-and-scan strategy were enrolled between January 2021 and January 2023. Patients underwent a single timepoint comprehensive MRI protocol, including DWI and DCE-MRI sequences. The estimated values of ADC, Ktrans, ve, and vp were calculated using established pipelines on a voxelwise basis within the delineated tumor region of interest. Associations of the estimated parameter values with volumetric growth were evaluated in uni- and multivariable logistic regression and survival analyses.</p><p><strong>Results: </strong>Of the 110 analyzed patients, 70 (64%) exhibited growth during follow-up. A significant correlation was primarily observed between the DCE-MRI-derived parameters and VS growth. The combination of mean Ktrans (P<0.001) and ve (P<0.001) tumor values provided an internally validated model with an AUC of 0.85 for growth, yielding a sensitivity of 89% and specificity of 73% at the optimized cutoff value. Only the mean ADC values were found to be significantly higher in shrinking tumors (P=0.04).</p><p><strong>Conclusions: </strong>The strongly significant correlation observed between VS growth and Ktrans and ve tumor values indicates great potential of the non-invasive DCE-MRI for individualized VS management in clinical practice. External validation is needed to further substantiate these findings.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.","authors":"Han Shen, Faiqa Mudassar, Shiyong Ma, Xingyu Wang, Sandy Nguyen, Neha Bal, Quy-Susan Huynh, Dongwei Wang, Cecilia Chang, Prunella Ing, Winny Varikatt, Joey Lai, Brian Gloss, Jeff Holst, Geraldine M O'Neill, Harriet Gee, Kristina M Cook, Eric Hau","doi":"10.1093/neuonc/noae255","DOIUrl":"https://doi.org/10.1093/neuonc/noae255","url":null,"abstract":"<p><strong>Background: </strong>Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. DIPGs often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity.</p><p><strong>Method: </strong>Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated.</p><p><strong>Results: </strong>Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models.</p><p><strong>Conclusion: </strong>DIPG cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct epigenetic and transcriptional profiles of Epstein-Barr virus (EBV) positive and negative primary CNS lymphomas.","authors":"Ling Hai, Dennis Friedel, Felix Hinz, Dirk C Hoffmann, Sofia Doubrovinskaia, Hannah Rohdjess, Katharina Weidenauer, Evgeniya Denisova, Georg T Scheffler, Tobias Kessler, Alexandros Kourtesakis, Christel Herold-Mende, Octavian Henegariu, Joachim M Baehring, Jorg Dietrich, Benedikt Brors, Wolfgang Wick, Felix Sahm, Leon D Kaulen","doi":"10.1093/neuonc/noae251","DOIUrl":"https://doi.org/10.1093/neuonc/noae251","url":null,"abstract":"<p><strong>Background: </strong>Epstein-Barr virus (EBV)+ and EBV- primary CNS lymphomas (PCNSL) carry distinct mutational landscapes, but their transcriptional and epigenetic profiles have not been integrated and compared. This precludes further insights into pathobiology and molecular differences, relevant for classification and targeted therapy.</p><p><strong>Methods: </strong>23 EBV- and 15 EBV+ PCNSL, histologically classified as diffuse large B-cell lymphomas, were subjected to RNA-Sequencing and EPIC methylation arrays. Unsupervised clustering analyses were performed. Differentially expressed and differentially methylated genes were identified and integrated.</p><p><strong>Results: </strong>Two distinct transcriptional clusters were found, which separated EBV-and EBV+PCNSL (p < 0.0001). The EBV+ transcriptional signature contained genes (GPR15, FCER2/CD23, SLAMF1/CD150) closely regulated by EBV oncogenes in B-cells. Pathway enrichment analysis uncovered enhanced B-cell receptor (BCR) and WNT/beta-catenin signaling in EBV-lymphomas, whereas Interleukin-10, NOTCH, and viral life cycle pathways were upregulated in EBV+PCNSL. Correspondingly, BCR-associated SYK kinase activity was enriched in EBV-tumors while JAK2 was overrepresented in EBV+PCNSL. Epigenetic profiling revealed reduced global promoter methylation in EBV+PCNSL. Two methylation clusters were recognized, which separated EBV-and EBV+PCNSL (p < 0.0001). Epigenetic profiles were distinct from 2,788 other brain tumor and non-malignant reference samples. Promoter region hypermethylation of CD79B, a BCR subunit critical for sustained proliferation in EBV-disease, highly correlated (R = -0.7) with its transcriptional downregulation in EBV+PCNSL.</p><p><strong>Conclusions: </strong>EBV+ and EBV- PCNSL harbor distinct transcriptional and epigenetic profiles, corroborating them as distinctive biological subtypes. Uncovered differences provide novel insights into their pathobiology, may guide molecular diagnostics and targeted therapies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EANO guideline on molecular testing of meningiomas for targeted therapy selection.","authors":"Felix Sahm, Luca Bertero, Sebastian Brandner, David Capper, Roland Goldbrunner, Michael D Jenkinson, Michel Kalamarides, Katrin Lamszus, Nathalie L Albert, Maximilian J Mair, Anna S Berghoff, Christian Mawrin, Hans-Georg Wirsching, Sybren Ln Maas, David R Raleigh, Guido Reifenberger, Leonille Schweizer, Abigail K Suwala, Ghazaleh Tabatabai, Emeline Tabouret, Susan Short, Patrick Y Wen, Michael Weller, Emilie Le Rhun, Pieter Wesseling, Martin van den Bent, Matthias Preusser","doi":"10.1093/neuonc/noae253","DOIUrl":"https://doi.org/10.1093/neuonc/noae253","url":null,"abstract":"<p><p>Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4, ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGFR, PDGFR, as well as homologous recombination deficiency (HRD), genomic copy number variations, DNA methylation classes and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence level criteria, no molecular target reached ESCAT I (\"ready for clinical use\") classification and only mTOR pathway activation and NF2 alterations reached ESCAT II (\"investigational\") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}