Neuro-oncology advances最新文献

{"title":"Correction to: Recurrent fibroblast growth factor receptor3 fusion glioblastoma treated with pemigatinib: A case report and review of the literature.","authors":"","doi":"10.1093/noajnl/vdae116","DOIUrl":"https://doi.org/10.1093/noajnl/vdae116","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/noajnl/vdae072.].</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae116"},"PeriodicalIF":3.7,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling glioblastoma diversity: Insights into methylation subtypes and spatial relationships.","authors":"Martha Foltyn-Dumitru, Haidar Alzaid, Aditya Rastogi, Ulf Neuberger, Felix Sahm, Tobias Kessler, Wolfgang Wick, Martin Bendszus, Philipp Vollmuth, Marianne Schell","doi":"10.1093/noajnl/vdae112","DOIUrl":"10.1093/noajnl/vdae112","url":null,"abstract":"<p><strong>Background: </strong>The purpose of this study was to elucidate the relationship between distinct brain regions and molecular subtypes in glioblastoma (GB), focusing on integrating modern statistical tools and molecular profiling to better understand the heterogeneity of Isocitrate Dehydrogenase wild-type (IDH-wt) gliomas.</p><p><strong>Methods: </strong>This retrospective study comprised 441 patients diagnosed with new IDH-wt glioma between 2009 and 2020 at Heidelberg University Hospital. The diagnostic process included preoperative magnetic resonance imaging and molecular characterization, encompassing IDH-status determination and subclassification, through DNA-methylation profiling. To discern and map distinct brain regions associated with specific methylation subtypes, a support-vector regression-based lesion-symptom mapping (SVR-LSM) was employed. Lesion maps were adjusted to 2 mm³ resolution. Significance was assessed with beta maps, using a threshold of <i>P</i> < .005, with 10 000 permutations and a cluster size minimum of 100 voxels.</p><p><strong>Results: </strong>Of 441 initially screened glioma patients, 423 (95.9%) met the inclusion criteria. Following DNA-methylation profiling, patients were classified into RTK II (40.7%), MES (33.8%), RTK I (18%), and other methylation subclasses (7.6%). Between molecular subtypes, there was no difference in tumor volume. Using SVR-LSM, distinct brain regions correlated with each subclass were identified: MES subtypes were associated with left-hemispheric regions involving the superior temporal gyrus and insula cortex, RTK I with right frontal regions, and RTK II with 3 clusters in the left hemisphere.</p><p><strong>Conclusions: </strong>This study linked molecular diversity and spatial features in glioblastomas using SVR-LSM. Future studies should validate these findings in larger, independent cohorts to confirm the observed patterns.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae112"},"PeriodicalIF":3.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early prognostication of overall survival for pediatric diffuse midline gliomas using MRI radiomics and machine learning: A two-center study.","authors":"Xinyang Liu, Zhifan Jiang, Holger R Roth, Syed Muhammad Anwar, Erin R Bonner, Aria Mahtabfar, Roger J Packer, Anahita Fathi Kazerooni, Miriam Bornhorst, Marius George Linguraru","doi":"10.1093/noajnl/vdae108","DOIUrl":"10.1093/noajnl/vdae108","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors that are diagnosed and monitored through MRI. We developed an automatic pipeline to segment subregions of DMG and select radiomic features that predict patient overall survival (OS).</p><p><strong>Methods: </strong>We acquired diagnostic and post-radiation therapy (RT) multisequence MRI (T1, T1ce, T2, and T2 FLAIR) and manual segmentations from 2 centers: 53 from 1 center formed the internal cohort and 16 from the other center formed the external cohort. We pretrained a deep learning model on a public adult brain tumor data set (BraTS 2021), and finetuned it to automatically segment tumor core (TC) and whole tumor (WT) volumes. PyRadiomics and sequential feature selection were used for feature extraction and selection based on the segmented volumes. Two machine learning models were trained on our internal cohort to predict patient 12-month survival from diagnosis. One model used only data obtained at diagnosis prior to any therapy (baseline study) and the other used data at both diagnosis and post-RT (post-RT study).</p><p><strong>Results: </strong>Overall survival prediction accuracy was 77% and 81% for the baseline study, and 85% and 78% for the post-RT study, for internal and external cohorts, respectively. Homogeneous WT intensity in baseline T2 FLAIR and larger post-RT TC/WT volume ratio indicate shorter OS.</p><p><strong>Conclusions: </strong>Machine learning analysis of MRI radiomics has potential to accurately and noninvasively predict which pediatric patients with DMG will survive less than 12 months from the time of diagnosis to provide patient stratification and guide therapy.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae108"},"PeriodicalIF":3.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11255990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141725422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.","authors":"","doi":"10.1093/noajnl/vdae100","DOIUrl":"https://doi.org/10.1093/noajnl/vdae100","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/noajnl/vdae036.].</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae100"},"PeriodicalIF":3.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From bench to bedside: Advancing towards therapeutic treatment of vestibular schwannomas.","authors":"Shaolei Guo, Xuan Zheng, Wenli Chen, Umar Raza, Ailiang Zeng, Farhana Akter, Quan Huang, Shun Yao","doi":"10.1093/noajnl/vdae107","DOIUrl":"10.1093/noajnl/vdae107","url":null,"abstract":"<p><p>Vestibular schwannomas are rare intracranial tumors originating from Schwann cells of the vestibular nerve. Despite their benign nature, these tumors can exert significant mass effects and debilitating symptoms, including gradual hearing loss, vertigo, facial nerve dysfunction, and headaches. Current clinical management options encompass wait-and-scan, surgery, radiation therapy, and off-label medication. However, each approach exhibits its own challenges and harbors limitations that underscore the urgent need for therapeutic treatments. Over the past 2 decades, extensive elucidation of the molecular underpinnings of vestibular schwannomas has unraveled genetic anomalies, dysregulated signaling pathways, downstream of receptor tyrosine kinases, disrupted extracellular matrix, inflammatory tumor microenvironment, and altered cerebrospinal fluid composition as integral factors in driving the development and progression of the disease. Armed with this knowledge, novel therapeutic interventions tailored to the unique molecular characteristics of those conditions are actively being pursued. This review underscores the urgency of addressing the dearth of Food and Drug Administration-approved drugs for vestibular schwannoma, highlighting the key molecular discoveries and their potential translation into therapeutics. It provides an in-depth exploration of the evolving landscape of therapeutic development, which is currently advancing from bench to bedside. These ongoing efforts hold the promise of significantly transforming the lives of vestibular schwannoma patients in the future.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae107"},"PeriodicalIF":3.7,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathways to hypermutation in high-grade gliomas: Mechanisms, syndromes, and opportunities for immunotherapy.","authors":"Tuesday Haynes, Mark R Gilbert, Kevin Breen, Chunzhang Yang","doi":"10.1093/noajnl/vdae105","DOIUrl":"10.1093/noajnl/vdae105","url":null,"abstract":"<p><p>Despite rapid advances in the field of immunotherapy, including the success of immune checkpoint inhibition in treating multiple cancer types, clinical response in high-grade gliomas (HGGs) has been disappointing. This has been in part attributed to the low tumor mutational burden (TMB) of the majority of HGGs. Hypermutation is a recently characterized glioma signature that occurs in a small subset of cases, which may open an avenue to immunotherapy. The substantially elevated TMB of these tumors most commonly results from alterations in the DNA mismatch repair pathway in the setting of extensive exposure to temozolomide or, less frequently, from inherited cancer predisposition syndromes. In this review, we discuss the genetics and etiology of hypermutation in HGGs, with an emphasis on the resulting genomic signatures, and the state and future directions of immuno-oncology research in these patient populations.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae105"},"PeriodicalIF":3.7,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential gene expression underlying epileptogenicity in patients with gliomas.","authors":"Armin Mortazavi, Anas U Khan, Edwin Nieblas-Bedolla, Ujwal Boddeti, Muzna Bachani, Alexander Ksendzovsky, Kory Johnson, Kareem A Zaghloul","doi":"10.1093/noajnl/vdae103","DOIUrl":"10.1093/noajnl/vdae103","url":null,"abstract":"<p><strong>Background: </strong>Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences.</p><p><strong>Methods: </strong>Total RNA sequencing was obtained from The Cancer Genome Atlas-Lower-Grade Glioma project, comprised of 2021 World Health Organization classification low-grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to characterize differential expression.</p><p><strong>Results: </strong>Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and semaphorin neuronal repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis.</p><p><strong>Conclusions: </strong>In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae103"},"PeriodicalIF":3.7,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma vulnerability to neddylation inhibition is dependent on PTEN status, and dysregulation of the cell cycle and DNA replication.","authors":"Brett Taylor, Nanyun Tang, Yue Hao, Matthew Lee, Sen Peng, Rita Bybee, Lauren Hartman, Krystine Garcia-Mansfield, Ritin Sharma, Patrick Pirrotte, Jianhui Ma, Alison D Parisian, Frank Furnari, Harshil D Dhruv, Michael E Berens","doi":"10.1093/noajnl/vdae104","DOIUrl":"10.1093/noajnl/vdae104","url":null,"abstract":"<p><strong>Background: </strong>Neddylation (NAE) inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report the cytotoxic vulnerability to NAE inhibitors in a subset of glioblastoma (GBM) preclinical models and identify genetic alterations and biological processes underlying differential response.</p><p><strong>Methods: </strong>GBM DNA sequencing and transcriptomic data were queried for genes associated with response to NAE inhibition; candidates were validated by molecular techniques. Multi-omics and functional assays revealed processes implicated in NAE inhibition response.</p><p><strong>Results: </strong>Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and DNA repair pathways as significant differentiators between sensitive and resistant models. Vulnerability to MLN4924, a NAE inhibitor, is associated with elevated S-phase populations, DNA re-replication, and DNA damage. In a panel of GBM models, loss of WT <i>PTEN</i> is associated with resistance to different NAE inhibitors. A NAE inhibition response gene set could segregate the GBM cell lines that are most resistant to MLN4924.</p><p><strong>Conclusions: </strong>Loss of WT <i>PTEN</i> is associated with non-sensitivity to 3 different compounds that inhibit NAE in GBM. A NAE inhibition response gene set largely consisting of DNA replication genes could segregate GBM cell lines most resistant to NAEi and may be the basis for future development of NAE inhibition signatures of vulnerability and clinical trial enrollment within a precision medicine paradigm.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae104"},"PeriodicalIF":3.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update on central nervous system tumors in germline replication-repair deficiency syndromes.","authors":"Anirban Das, Ayse Bahar Ercan, Uri Tabori","doi":"10.1093/noajnl/vdae102","DOIUrl":"10.1093/noajnl/vdae102","url":null,"abstract":"<p><p>DNA replication-repair deficiency (RRD) arises from pathogenic variants in the mismatch repair and/or polymerase-proofreading genes. Multiple germline cancer predisposition syndromes in children and young adults, including constitutional mismatch repair deficiency (CMMRD), Lynch, polymerase-proofreading deficiency, and rare digenic syndromes can lead to RRD cancers. The most frequent brain tumors in these children are high-grade gliomas. Embryonal tumors like medulloblastoma have also been described. Lower-grade tumors are reported from cancer surveillance initiatives. The latter has an extremely high rate of malignant transformation. Novel functional assays quantifying the genomic microsatellite indel load have been demonstrated to be highly sensitive and specific for the diagnosis of RRD cancers and children with germline CMMRD. Importantly, RRD brain tumors uniformly harbor high mutation and microsatellite burden. High T-cell infiltration makes these aggressive cancers amenable to immune checkpoint inhibition, irrespective of their germline genetic background. Synergistic combinations are reported to be successful in patients failing checkpoint inhibitor monotherapy. Future directions include the development of innovative approaches to improve immune surveillance for RRD brain cancers. Additionally, the use of novel tools including circulating tumor DNA and quantifying microsatellite indel load over time can be useful to monitor disease burden and treatment responses in patients.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae102"},"PeriodicalIF":3.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.","authors":"Radu O Minea, Thu Zan Thein, Zhuoyue Yang, Mihaela Campan, Pamela M Ward, Axel H Schönthal, Thomas C Chen","doi":"10.1093/noajnl/vdae095","DOIUrl":"10.1093/noajnl/vdae095","url":null,"abstract":"<p><strong>Background: </strong>The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations.</p><p><strong>Methods: </strong>We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow.</p><p><strong>Results: </strong>In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity.</p><p><strong>Conclusions: </strong>NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":"6 1","pages":"vdae095"},"PeriodicalIF":3.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}