Neuro-oncologyPub Date : 2025-07-12DOI: 10.1093/neuonc/noaf165
Edward K Avila, Anne S Reiner, Terri S Armstrong, Ashley E Aaroe, Elizabeth M Cunningham, Julie G Brown, Francesco Bruno, Jose Diarte, Aya Haggiagi, Rebecca A Harrison, Adela Joanta-Gomez, Johan A F Koekkoek, Eudocia Q Lee, Emilie Le Rhun, Hope Miller, Katherine S Panageas, Edwin N Peguero, Roberta Ruda, Riccardo Soffietti, Jessica W Templer, Steven Tobochnik, Elizabeth Vera, Michael A Vogelbaum, Michael Weller, Martin van den Bent
{"title":"RANO seizure working group-Tumor Related Epilepsy Assessment Tool (RANO-TREAT) to assess seizure control for glioma treatment trials and clinical practice.","authors":"Edward K Avila, Anne S Reiner, Terri S Armstrong, Ashley E Aaroe, Elizabeth M Cunningham, Julie G Brown, Francesco Bruno, Jose Diarte, Aya Haggiagi, Rebecca A Harrison, Adela Joanta-Gomez, Johan A F Koekkoek, Eudocia Q Lee, Emilie Le Rhun, Hope Miller, Katherine S Panageas, Edwin N Peguero, Roberta Ruda, Riccardo Soffietti, Jessica W Templer, Steven Tobochnik, Elizabeth Vera, Michael A Vogelbaum, Michael Weller, Martin van den Bent","doi":"10.1093/neuonc/noaf165","DOIUrl":"https://doi.org/10.1093/neuonc/noaf165","url":null,"abstract":"<p><strong>Background: </strong>No standardized method exists for seizure assessment in glioma clinical trials. We describe the development and evaluation of RANO-TREAT (Tumor Related Epilepsy Assessment Tool) for seizure assessment and its association with changes on brain MRI.</p><p><strong>Methods: </strong>Patients with glioma/glioneuronal tumors and ≥1 prior seizure along with clinicians completed RANO-TREAT in conjunction with brain MRIs, yielding multiple RANO-TREAT scores at clinic visits over time. Unweighted (primary) and weighted (post-hoc) scores were correlated with disease progression via MRI in all patients and patients with IDHmt tumors, separately. Cohorts were randomly split by patient into cohort-specific training and validation sets. Weights for RANO-TREAT items were defined by multivariable generalized estimating equation models in cohort-specific training sets and validated in cohort-specific validation sets. A nomogram was developed using overall cohort training and validation sets.</p><p><strong>Results: </strong>490 patients (310 IDHmt tumors) had ≥1 visits and 285 patients (168 IDHmt tumors) had ≥2 visits. Unweighted RANO-TREAT scores (OR:1.01; 95%CI:0.998-1.02; P=0.13) and score changes (OR:1.00; 95%CI:0.99-1.02; P=0.63) were not associated with progressive disease on MRI. Post-hoc analysis using training and validation sets demonstrated weighted RANO-TREAT scores were correlated with progressive disease in both overall cohort validation set (OR:2.51; 95%CI:1.80-3.52; P<0.0001) and IDHmt cohort validation set (OR:4.53; 95%CI:2.11-9.75; P=0.0001). Weighted analyses for patients with ≥2 visits showed similar associations in validation sets.</p><p><strong>Conclusions: </strong>This prospective study suggests an association of seizure control evaluated by a new standardized tool with disease progression in glioma. This tool requires further systematic evaluation in glioma clinical trials alongside more traditional endpoints.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619457","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}
Neuro-oncologyPub Date : 2025-07-11DOI: 10.1093/neuonc/noaf162
Yanhong Zhang, Rosalia Rabinovsky, Evgeny Deforzh, Ami Kobayashi, Anastasia Kuzkina, Johnna Francis Varghese, Damita Rai, Joanna A Korecka, Vikram Khurana, Gopal Murugaiyan, David Morrissey, Erik J Uhlmann, Anna M Krichevsky
{"title":"Lipid nanoparticle formulation for gene editing and RNA-based therapies for glioblastoma.","authors":"Yanhong Zhang, Rosalia Rabinovsky, Evgeny Deforzh, Ami Kobayashi, Anastasia Kuzkina, Johnna Francis Varghese, Damita Rai, Joanna A Korecka, Vikram Khurana, Gopal Murugaiyan, David Morrissey, Erik J Uhlmann, Anna M Krichevsky","doi":"10.1093/neuonc/noaf162","DOIUrl":"https://doi.org/10.1093/neuonc/noaf162","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM), one of the deadliest cancers, resists current therapies, with drug development hindered by its high heterogeneity. However, GBM consistently relies on microRNA-10b (miR-10b), a key driver of glioma growth and a promising therapeutic target. miR-10b gene editing represents a potential treatment, but effective delivery strategies for gene editing systems in GBM remain unexplored.</p><p><strong>Methods: </strong>We developed lipid nanoparticles (LNPs) encapsulating Cas9 mRNA and a miR-10b-targeting sgRNA (termed miRTEN). miRTEN was tested in glioma stem cells (GSCs) and orthotopic GBM models to assess therapeutic efficacy, immune responses, and safety.</p><p><strong>Results: </strong>Intracerebroventricular (ICV) injections of miRTEN enabled broad and durable Cas9 mRNA expression and miR-10b gene editing in tumor core and invasive areas across diverse GBM models. miRTEN significantly suppressed tumor growth, reduced GSC proliferation and viability, with therapeutic outcomes correlating with dose-dependent miR-10b suppression. Combining miRTEN with temozolomide (TMZ) further enhanced tumor suppression, overcoming TMZ resistance and improving survival. In immunocompetent models, miRTEN activated anti-tumor immune responses, increased cytotoxic CD8+ T cells infiltration, and promoted durable immune memory, enabling tumor rejection upon rechallenge. Safety assessments demonstrated that miRTEN selectively targets GBM cells, sparing normal brain tissues and causing no significant off-target toxicity.</p><p><strong>Conclusion: </strong>As in vivo CRISPR-based drugs advance toward clinical applications, our findings demonstrate the potential of LNPs-mediated CRISPR-Cas9 systems for targeted miR-10b editing and, more generally, gene editing and RNA therapies for GBM. miRTEN monotherapy, as well as its combination with standard care, offers a promising, safe, and effective approach to improving outcomes in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626798","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}
Neuro-oncologyPub Date : 2025-07-08DOI: 10.1093/neuonc/noaf160
Guillaume Bourmeau, Oceane Anezo, Jeremy Raymond, Alberto Ballestín, Cathy Pichol-Thievend, Juliette Reveilles, Adrien Thomas, Lin Wang, Melanie Miranda, Eve Moutaux, Stephane Liva, Valentino Ribecco, Laetitia Besse, Florent Dingli, Damarys Loew, Celine Vallot, Gaetano Gargiulo, Vidhya M Ravi, Kevin Joseph, Giorgio Seano
{"title":"Proneural-Mesenchymal hybrid glioblastoma cells are resistant to therapy and dependent on nuclear import.","authors":"Guillaume Bourmeau, Oceane Anezo, Jeremy Raymond, Alberto Ballestín, Cathy Pichol-Thievend, Juliette Reveilles, Adrien Thomas, Lin Wang, Melanie Miranda, Eve Moutaux, Stephane Liva, Valentino Ribecco, Laetitia Besse, Florent Dingli, Damarys Loew, Celine Vallot, Gaetano Gargiulo, Vidhya M Ravi, Kevin Joseph, Giorgio Seano","doi":"10.1093/neuonc/noaf160","DOIUrl":"https://doi.org/10.1093/neuonc/noaf160","url":null,"abstract":"<p><strong>Background: </strong>Despite extensive research efforts, glioblastoma (GBM) remains a deadly disease with poor prognosis. Although previous studies have identified various cell states within GBM tumors, the molecular mechanism underlying adaptive GBM cell plasticity induced by conventional therapy remains unclear.</p><p><strong>Methods: </strong>We used fluorescent reporters for proneural (PN) and mesenchymal (MES) subtypes to monitor GBM cell plasticity in real-time across multiple patient-derived cell lines. This approach revealed cells that concurrently expressed both proneural and mesenchymal markers. To investigate this unique hybrid population, we implemented a comprehensive methodological approach encompassing bulk and single-cell RNA sequencing, single-cell ChIP sequencing, nuclear proteomics, high-resolution imaging, orthotopic mouse models, clinical dataset analysis, and pharmacological and genetic techniques. This multifaceted strategy allowed us to gain functional and molecular insights into this distinct cellular population.</p><p><strong>Results: </strong>We showed that these hybrid cells are increased by conventional therapies, and are resistant to these therapies. At the molecular level, hybrid cells display significant alterations in chromatin structure and nuclear protein composition, elevated transcriptional activity, Myc activation, and improved transport between the nucleus and cytoplasm. Genetic and pharmaceutical inhibition of the nuclear import/export shuttling machinery, increased in hybrid cells, effectively suppressed adaptive GBM cell plasticity and hybrid identity, thereby enhancing the sensitivity of GBM cells to therapies.</p><p><strong>Conclusion: </strong>Our results indicate that GBM hybrid cells play a crucial role in chemoradiation resistance. The nuclear transport machinery presents a potential therapeutic target for hybrid cells, offering a way to counteract the typical resistance to treatment observed in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591857","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}
Neuro-oncologyPub Date : 2025-07-04DOI: 10.1093/neuonc/noaf126
Emilie Le Rhun, Barbara J O'Brien, Elena Pentsova, Matthias Preusser, Michael Weller, Adrienne Boire
{"title":"Point/counterpoint: intrathecal therapy for patients with leptomeningeal metastases from solid tumors.","authors":"Emilie Le Rhun, Barbara J O'Brien, Elena Pentsova, Matthias Preusser, Michael Weller, Adrienne Boire","doi":"10.1093/neuonc/noaf126","DOIUrl":"10.1093/neuonc/noaf126","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560641","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}
Neuro-oncologyPub Date : 2025-07-01DOI: 10.1093/neuonc/noaf149
{"title":"Correction to: Erratum to: TRLS-11. PNOC005: ONCOLYTIC MEASLES VIRUS FOR THE TREATMENT OF CHILDREN AND YOUNG ADULTS WITH RECURRENT MEDULLOBLASTOMA OR ATYPICAL TERATOID RHABDOID TUMOR.","authors":"","doi":"10.1093/neuonc/noaf149","DOIUrl":"https://doi.org/10.1093/neuonc/noaf149","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144541649","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}
Neuro-oncologyPub Date : 2025-07-01DOI: 10.1093/neuonc/noaf148
{"title":"Erratum to: A hitchhiker's guide to cerebrospinal fluid biomarkers for neuro-oncology.","authors":"","doi":"10.1093/neuonc/noaf148","DOIUrl":"https://doi.org/10.1093/neuonc/noaf148","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144541650","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}
Neuro-oncologyPub Date : 2025-06-28DOI: 10.1093/neuonc/noaf155
Rishab Ramapriyan, Fred G Barker, Leland G Richardson, Jing Sun, Gust Vandecandelaere, Jane M Shim, Guillaume De Vlaminck, Matthew Gaffey, Eric P Grewal, Masih Tazhibi, Kourosh Morshedy, Amir R Aref, Syeda M Batool, Xiaopeng Guo, Nazanin Ijad, Leonora Balaj, Hiroaki Wakimoto, Maria Martinez-Lage, Matthew J Frigault, Mark B Leick, Joshua D Bernstock, Wenya Linda Bi, Bob S Carter, E Antonio Chiocca, Jorg Dietrich, Elizabeth R Gerstner, Genevieve M Boland, Brian V Nahed, Scott R Plotkin, Russell W Jenkins, Priscilla K Brastianos, William T Curry, Marcela V Maus, Bryan D Choi
{"title":"Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells.","authors":"Rishab Ramapriyan, Fred G Barker, Leland G Richardson, Jing Sun, Gust Vandecandelaere, Jane M Shim, Guillaume De Vlaminck, Matthew Gaffey, Eric P Grewal, Masih Tazhibi, Kourosh Morshedy, Amir R Aref, Syeda M Batool, Xiaopeng Guo, Nazanin Ijad, Leonora Balaj, Hiroaki Wakimoto, Maria Martinez-Lage, Matthew J Frigault, Mark B Leick, Joshua D Bernstock, Wenya Linda Bi, Bob S Carter, E Antonio Chiocca, Jorg Dietrich, Elizabeth R Gerstner, Genevieve M Boland, Brian V Nahed, Scott R Plotkin, Russell W Jenkins, Priscilla K Brastianos, William T Curry, Marcela V Maus, Bryan D Choi","doi":"10.1093/neuonc/noaf155","DOIUrl":"https://doi.org/10.1093/neuonc/noaf155","url":null,"abstract":"<p><strong>Background: </strong>Meningioma is the most common primary CNS tumor, with high-grade cases exhibiting aggressive behavior, frequent recurrence, and poor prognosis. Currently, no systemic therapies are approved for recurrent or malignant meningiomas. Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in hematologic malignancies and promise for solid tumors but its use for meningiomas has been underexplored. Mesothelin, a glycoprotein overexpressed in several solid tumors of mesodermal origin, may serve as a viable immunotherapeutic target. This study aimed to evaluate mesothelin as a CAR T-cell target in meningiomas.</p><p><strong>Methods: </strong>Mesothelin expression was analyzed in patient-derived meningioma samples using immunohistochemistry, flow cytometry, and droplet digital PCR. Mesothelin-specific CAR T-cells were generated and evaluated in vitro, ex vivo using patient-derived organotypic tumor spheroids (PDOTS), and in vivo using orthotopic meningioma mouse models of human xenografts. Cytotoxicity, T-cell proliferation, cytokine secretion, and tumor clearance were assessed.</p><p><strong>Results: </strong>Mesothelin was detected in a subset of tumors across all meningioma grades at the transcript and protein levels, with surface expression confirmed in patient-derived primary cells. Mesothelin-specific CAR T-cells exhibited potent and specific cytotoxicity, T-cell activation, and cytokine secretion in vitro and effectively eliminated PDOTS. In orthotopic human xenograft models, mesothelin CAR T-cell therapy led to significant tumor regression and prolonged survival.</p><p><strong>Conclusions: </strong>Mesothelin is a viable CAR T-cell target for meningiomas, and mesothelin-specific CAR T-cell therapy shows strong preclinical efficacy. These findings provide a rationale for early-phase clinical trials of mesothelin CAR T-cell therapy in patients with refractory meningiomas.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529080","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}
Neuro-oncologyPub Date : 2025-06-28DOI: 10.1093/neuonc/noaf147
{"title":"Erratum to: Multi-site retrospective analysis of diffusion and perfusion magnetic resonance imaging correlates to glioma characteristics derived from radio-pathomic map.","authors":"","doi":"10.1093/neuonc/noaf147","DOIUrl":"https://doi.org/10.1093/neuonc/noaf147","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529077","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":"Assessing time-trend bias in glioblastoma prognosis over two decades of clinical trials.","authors":"Giacomo Sferruzza, Karthik Desingu, Andrés Cubero Cruz, Gaetano Finocchiaro","doi":"10.1093/neuonc/noaf158","DOIUrl":"https://doi.org/10.1093/neuonc/noaf158","url":null,"abstract":"<p><strong>Background: </strong>The time-trend bias represents a potential limitation in the use of external controls in glioblastoma (GBM) trials. In this study, we assessed whether outcomes for newly diagnosed GBM (ndGBM) patients treated with the standard Stupp protocol in clinical trials have changed over the past two decades.</p><p><strong>Methods: </strong>We retrieved individual patient survival pseudo-data from Stupp protocol arms reported in trials published over the last twenty years. Survival distributions were approximated using Weibull distributions, and an Accelerated Failure Time (AFT) model was used to evaluate any potential time trend by correcting for identified key prognostic factors.</p><p><strong>Results: </strong>MGMT methylation status and Karnofsky Performance Status emerged as the main determinants of survival differences among clinical trials. Both in a multivariable regression that included all candidate prognostic factors and after adjustment for the main determinants, publication year showed no impact on the outcome of the Stuppprotocol control arms. The performance of the model was validated using three independent Phase 3 cohorts, providing additional evidence for the absence of time-trend bias.</p><p><strong>Conclusions: </strong>No evidence of time-trend bias was observed in Phase 3 GBM trials over the past two decades once major prognostic factors were accounted for.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529076","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}