Felix Sahm, Kenneth D Aldape, Priscilla K Brastianos, Daniel J Brat, Sonika Dahiya, Andreas von Deimling, Caterina Giannini, Mark R Gilbert, David N Louis, David R Raleigh, Guido Reifenberger, Sandro Santagata, Chitra Sarkar, Gelareh Zadeh, Pieter Wesseling, Arie Perry
Meningiomas are the most frequent primary intracranial tumors. Hence, they constitute a major share of diagnostic specimens in neuropathology practice. The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") has introduced the first molecular grading parameters for meningioma with oncogenic variants in the TERT promoter and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3. However, after publication of the new classification volume, clarifications were requested, not only on novel but also on long-standing questions in meningioma grading that were beyond the scope of the WHO "blue book". In addition, more recent research into possible new molecular grading parameters could not yet be implemented in the 2021 classification but constitute a compelling body of literature. Hence, the cIMPACT-NOW Steering Committee convened a working group to provide such clarification and assess the evidence of possible novel molecular criteria. As a result, this cIMPACT-NOW update provides guidance for more standardized morphological evaluation and interpretation, most prominently pertaining to brain invasion, identifies scenarios in which advanced molecular testing is recommended, proposes to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants, and discusses areas in which the current evidence is not yet sufficient to result in new recommendations.
{"title":"cIMPACT-NOW Update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas.","authors":"Felix Sahm, Kenneth D Aldape, Priscilla K Brastianos, Daniel J Brat, Sonika Dahiya, Andreas von Deimling, Caterina Giannini, Mark R Gilbert, David N Louis, David R Raleigh, Guido Reifenberger, Sandro Santagata, Chitra Sarkar, Gelareh Zadeh, Pieter Wesseling, Arie Perry","doi":"10.1093/neuonc/noae170","DOIUrl":"https://doi.org/10.1093/neuonc/noae170","url":null,"abstract":"<p><p>Meningiomas are the most frequent primary intracranial tumors. Hence, they constitute a major share of diagnostic specimens in neuropathology practice. The 2021 WHO Classification of Central Nervous System Tumors (\"CNS5\") has introduced the first molecular grading parameters for meningioma with oncogenic variants in the TERT promoter and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3. However, after publication of the new classification volume, clarifications were requested, not only on novel but also on long-standing questions in meningioma grading that were beyond the scope of the WHO \"blue book\". In addition, more recent research into possible new molecular grading parameters could not yet be implemented in the 2021 classification but constitute a compelling body of literature. Hence, the cIMPACT-NOW Steering Committee convened a working group to provide such clarification and assess the evidence of possible novel molecular criteria. As a result, this cIMPACT-NOW update provides guidance for more standardized morphological evaluation and interpretation, most prominently pertaining to brain invasion, identifies scenarios in which advanced molecular testing is recommended, proposes to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants, and discusses areas in which the current evidence is not yet sufficient to result in new recommendations.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109998","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}
Liliana Santos, Francesca Tomatis, Hugo R S Ferreira, Sara F F Almeida, Edward Ciputra, José Sereno, Rui Almeida, Paulo Teixeira, Ana Sofia Ribeiro, João N Moreira, Ana P Silva, Lino Ferreira, Antero J Abrunhosa, Célia M Gomes
Background: Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation.
Methods: We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model.
Results: Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival.
Conclusions: We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.
{"title":"ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.","authors":"Liliana Santos, Francesca Tomatis, Hugo R S Ferreira, Sara F F Almeida, Edward Ciputra, José Sereno, Rui Almeida, Paulo Teixeira, Ana Sofia Ribeiro, João N Moreira, Ana P Silva, Lino Ferreira, Antero J Abrunhosa, Célia M Gomes","doi":"10.1093/neuonc/noae169","DOIUrl":"https://doi.org/10.1093/neuonc/noae169","url":null,"abstract":"<p><strong>Background: </strong>Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation.</p><p><strong>Methods: </strong>We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model.</p><p><strong>Results: </strong>Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival.</p><p><strong>Conclusions: </strong>We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110000","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}
Maryamalsadat Mahootiha, Divyanshu Tak, Zezhong Ye, Anna Zapaishchykova, Jirapat Likitlersuang, Juan Carlos Climent Pardo, Aidan Boyd, Sridhar Vajapeyam, Rishi Chopra, Sanjay P Prabhu, Kevin X Liu, Hesham Elhalawani, Ali Nabavizadeh, Ariana Familiar, Sabine Mueller, Hugo J W L Aerts, Pratiti Bandopadhayay, Keith L Ligon, Daphne Haas-Kogan, Tina Y Poussaint, Hemin Ali Qadir, Ilangko Balasingham, Benjamin H Kann
Background: Postoperative recurrence risk for pediatric low-grade gliomas (pLGGs) is challenging to predict by conventional clinical, radiographic, and genomic factors. We investigated if deep learning of MRI tumor features could improve postoperative pLGG risk stratification.
Methods: We used pre-trained deep learning (DL) tool designed for pLGG segmentation to extract pLGG imaging features from preoperative T2-weighted MRI from patients who underwent surgery (DL-MRI features). Patients were pooled from two institutions: Dana Farber/Boston Children's Hospital (DF/BCH) and the Children's Brain Tumor Network (CBTN). We trained three DL logistic hazard models to predict postoperative event-free survival (EFS) probabilities with 1) clinical features, 2) DL-MRI features, and 3) multimodal (clinical and DL-MRI features). We evaluated the models with a time-dependent Concordance Index (Ctd) and risk group stratification with Kaplan Meier plots and log-rank tests. We developed an automated pipeline integrating pLGG segmentation and EFS prediction with the best model.
Results: Of the 396 patients analyzed (median follow-up: 85 months, range: 1.5-329 months), 214 (54%) underwent gross total resection and 110 (28%) recurred. The multimodal model improved EFS prediction compared to the DL-MRI and clinical models (Ctd: 0.85 (95% CI: 0.81-0.93), 0.79 (95% CI: 0.70-0.88), and 0.72 (95% CI: 0.57-0.77), respectively). The multimodal model improved risk-group stratification (3-year EFS for predicted high-risk: 31% versus low-risk: 92%, p<0.0001).
Conclusions: DL extracts imaging features that can inform postoperative recurrence prediction for pLGG. Multimodal DL improves postoperative risk stratification for pLGG and may guide postoperative decision-making. Larger, multicenter training data may be needed to improve model generalizability.
{"title":"Multimodal Deep Learning Improves Recurrence Risk Prediction in Pediatric Low-Grade Gliomas.","authors":"Maryamalsadat Mahootiha, Divyanshu Tak, Zezhong Ye, Anna Zapaishchykova, Jirapat Likitlersuang, Juan Carlos Climent Pardo, Aidan Boyd, Sridhar Vajapeyam, Rishi Chopra, Sanjay P Prabhu, Kevin X Liu, Hesham Elhalawani, Ali Nabavizadeh, Ariana Familiar, Sabine Mueller, Hugo J W L Aerts, Pratiti Bandopadhayay, Keith L Ligon, Daphne Haas-Kogan, Tina Y Poussaint, Hemin Ali Qadir, Ilangko Balasingham, Benjamin H Kann","doi":"10.1093/neuonc/noae173","DOIUrl":"https://doi.org/10.1093/neuonc/noae173","url":null,"abstract":"<p><strong>Background: </strong>Postoperative recurrence risk for pediatric low-grade gliomas (pLGGs) is challenging to predict by conventional clinical, radiographic, and genomic factors. We investigated if deep learning of MRI tumor features could improve postoperative pLGG risk stratification.</p><p><strong>Methods: </strong>We used pre-trained deep learning (DL) tool designed for pLGG segmentation to extract pLGG imaging features from preoperative T2-weighted MRI from patients who underwent surgery (DL-MRI features). Patients were pooled from two institutions: Dana Farber/Boston Children's Hospital (DF/BCH) and the Children's Brain Tumor Network (CBTN). We trained three DL logistic hazard models to predict postoperative event-free survival (EFS) probabilities with 1) clinical features, 2) DL-MRI features, and 3) multimodal (clinical and DL-MRI features). We evaluated the models with a time-dependent Concordance Index (Ctd) and risk group stratification with Kaplan Meier plots and log-rank tests. We developed an automated pipeline integrating pLGG segmentation and EFS prediction with the best model.</p><p><strong>Results: </strong>Of the 396 patients analyzed (median follow-up: 85 months, range: 1.5-329 months), 214 (54%) underwent gross total resection and 110 (28%) recurred. The multimodal model improved EFS prediction compared to the DL-MRI and clinical models (Ctd: 0.85 (95% CI: 0.81-0.93), 0.79 (95% CI: 0.70-0.88), and 0.72 (95% CI: 0.57-0.77), respectively). The multimodal model improved risk-group stratification (3-year EFS for predicted high-risk: 31% versus low-risk: 92%, p<0.0001).</p><p><strong>Conclusions: </strong>DL extracts imaging features that can inform postoperative recurrence prediction for pLGG. Multimodal DL improves postoperative risk stratification for pLGG and may guide postoperative decision-making. Larger, multicenter training data may be needed to improve model generalizability.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110029","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}
Emilie Le Rhun, Lakshmi Nayak, Mary Jane Lim-Fat, Roberta Rudà, Elena Pentsova, Peter Forsyth, Barbara J O'Brien, Matthias Preusser, Priya Kumthekar, Dieta Brandsma, Michael Weller
Background: There are no validated tools for the clinical neurological assessment of patients with leptomeningeal metastases (LM). However, clinical examination during the course of the disease guides medical management and is part of response assessment in clinical trials. Because neuroimaging may not always be obtained owing to rapid clinical deterioration, clinical neurological assessment of LM is essential, and standardization Is important to minimize rater disagreement.
Methods: The RANO-LM group launched a 2-steps process, aiming at improving and standardizing the clinical assessment of patients with LM. We report here on the first step: the establishment of a consensus scorecard. The task force had 9 virtual meetings to define general recommendations on neurological assessment and selected domains of interest that should be tested.
Results: Fourteen domains of neurological symptoms and signs were selected: level of consciousness, cognition, nausea and vomiting, vision, eye movement, facial strength, hearing, swallowing, speech, limb strength, limb ataxia, walking, bladder bowel functions. For each item, a clear instruction on how to perform the assessment is provided with scoring criteria between 0 and 2. The general clinical status of the patient and use of steroids, pain medications, and anti-emetics should be documented. Neurological sequelae from previous brain metastases or cancer treatment should be rated at the baseline evaluation; it should be specified when symptoms or signs may be related to a condition other than LM.
Discussion: A revised NANO-LM consensus scorecard for clinical assessment has been established. An international prospective validation study of the proposal is currently ongoing (NCT06417710).
{"title":"NANO-LM: An updated scorecard for the clinical assessment of patients with leptomeningeal metastases.","authors":"Emilie Le Rhun, Lakshmi Nayak, Mary Jane Lim-Fat, Roberta Rudà, Elena Pentsova, Peter Forsyth, Barbara J O'Brien, Matthias Preusser, Priya Kumthekar, Dieta Brandsma, Michael Weller","doi":"10.1093/neuonc/noae171","DOIUrl":"https://doi.org/10.1093/neuonc/noae171","url":null,"abstract":"<p><strong>Background: </strong>There are no validated tools for the clinical neurological assessment of patients with leptomeningeal metastases (LM). However, clinical examination during the course of the disease guides medical management and is part of response assessment in clinical trials. Because neuroimaging may not always be obtained owing to rapid clinical deterioration, clinical neurological assessment of LM is essential, and standardization Is important to minimize rater disagreement.</p><p><strong>Methods: </strong>The RANO-LM group launched a 2-steps process, aiming at improving and standardizing the clinical assessment of patients with LM. We report here on the first step: the establishment of a consensus scorecard. The task force had 9 virtual meetings to define general recommendations on neurological assessment and selected domains of interest that should be tested.</p><p><strong>Results: </strong>Fourteen domains of neurological symptoms and signs were selected: level of consciousness, cognition, nausea and vomiting, vision, eye movement, facial strength, hearing, swallowing, speech, limb strength, limb ataxia, walking, bladder bowel functions. For each item, a clear instruction on how to perform the assessment is provided with scoring criteria between 0 and 2. The general clinical status of the patient and use of steroids, pain medications, and anti-emetics should be documented. Neurological sequelae from previous brain metastases or cancer treatment should be rated at the baseline evaluation; it should be specified when symptoms or signs may be related to a condition other than LM.</p><p><strong>Discussion: </strong>A revised NANO-LM consensus scorecard for clinical assessment has been established. An international prospective validation study of the proposal is currently ongoing (NCT06417710).</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110030","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}
Christopher Alvarez-Breckenridge, Priscilla Brastianos, Daniel Cahill
{"title":"Thrombosis, brain metastasis formation, and the perivascular metastatic niche-novel insights from the tumor microvascular circulation.","authors":"Christopher Alvarez-Breckenridge, Priscilla Brastianos, Daniel Cahill","doi":"10.1093/neuonc/noae168","DOIUrl":"https://doi.org/10.1093/neuonc/noae168","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110032","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}
Kanish Mirchia, Abrar Choudhury, Tara Joseph, Janeth Ochoa Birrueta, Joanna J Phillips, Aparna Bhaduri, Elizabeth E Crouch, Arie Perry, David R Raleigh
Background: Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with local recurrence and hematogenous metastasis. The cell states and spatial transcriptomic architecture underlying the unique clinical behavior of meningeal SFTs are unknown.
Methods: Single-cell (n=4), spatial (n=8), and bulk RNA sequencing (n=22) was used to define the cell states and spatial transcriptomic architecture of meningeal SFTs across histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. Immunofluorescence, immunohistochemistry, and comparison of single-cell types to meningiomas, or to cerebral vascular development or homeostasis, were used for validation.
Results: Here we show meningeal SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development or homeostasis. Single-cell trajectory analysis and pseudotemporal ordering of single-cells suggest that meningeal SFT cell fate decisions are dynamic and interchangeable. Cell-cell communication analyses demonstrate receptor-ligand interactions throughout the meningeal SFT microenvironment, particularly between SFT cells, endothelia, and immature neurons. Direct comparison of single-cell transcriptomes from meningeal SFTs versus meningiomas shows that SFT cells are enriched in expression of endothelial markers while meningiomas cells are enriched in expression of mural cells markers. Meningeal SFT spatial transcriptomes show regionally distinct intratumor heterogeneity in cell states, gene expression programs, and cell-cell interactions across WHO histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples.
Conclusions: These results shed light on pathways underlying meningeal SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell, spatial, and bulk RNA sequencing data across human cancers and normal tissues.
{"title":"Meningeal solitary fibrous tumor cell states phenocopy cerebral vascular development and homeostasis.","authors":"Kanish Mirchia, Abrar Choudhury, Tara Joseph, Janeth Ochoa Birrueta, Joanna J Phillips, Aparna Bhaduri, Elizabeth E Crouch, Arie Perry, David R Raleigh","doi":"10.1093/neuonc/noae172","DOIUrl":"10.1093/neuonc/noae172","url":null,"abstract":"<p><strong>Background: </strong>Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with local recurrence and hematogenous metastasis. The cell states and spatial transcriptomic architecture underlying the unique clinical behavior of meningeal SFTs are unknown.</p><p><strong>Methods: </strong>Single-cell (n=4), spatial (n=8), and bulk RNA sequencing (n=22) was used to define the cell states and spatial transcriptomic architecture of meningeal SFTs across histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. Immunofluorescence, immunohistochemistry, and comparison of single-cell types to meningiomas, or to cerebral vascular development or homeostasis, were used for validation.</p><p><strong>Results: </strong>Here we show meningeal SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development or homeostasis. Single-cell trajectory analysis and pseudotemporal ordering of single-cells suggest that meningeal SFT cell fate decisions are dynamic and interchangeable. Cell-cell communication analyses demonstrate receptor-ligand interactions throughout the meningeal SFT microenvironment, particularly between SFT cells, endothelia, and immature neurons. Direct comparison of single-cell transcriptomes from meningeal SFTs versus meningiomas shows that SFT cells are enriched in expression of endothelial markers while meningiomas cells are enriched in expression of mural cells markers. Meningeal SFT spatial transcriptomes show regionally distinct intratumor heterogeneity in cell states, gene expression programs, and cell-cell interactions across WHO histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples.</p><p><strong>Conclusions: </strong>These results shed light on pathways underlying meningeal SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell, spatial, and bulk RNA sequencing data across human cancers and normal tissues.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110028","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}
Shaoping Shen, Yong Cui, Mingxiao Li, Kefu Yu, Qinghui Zhu, Xiaokang Zhang, Weicheng Shen, Haoyi Li, Haihui Jiang, Ming Li, Xijie Wang, Xuzhe Zhao, Xiaohui Ren, Song Lin
Background: Glioma, characterized by limited lymphocytic infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune-resistant to an activated state.
Methods: TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted.
Results: TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of "LTo" and "LTi" cells, respectively, interaction through LTα/β-LTβR promoted TLS induction. Post-TLS formation, CD4+ and CD8+ T cells but not CD19+ B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled switch from naïve to mature, some B cells highlighted an enrichment of CSR-associated genes, V gene usage and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME.
Conclusion: TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.
{"title":"TLR agonists promote formation of Tertiary Lymphoid Structure and improve anti-glioma immunity.","authors":"Shaoping Shen, Yong Cui, Mingxiao Li, Kefu Yu, Qinghui Zhu, Xiaokang Zhang, Weicheng Shen, Haoyi Li, Haihui Jiang, Ming Li, Xijie Wang, Xuzhe Zhao, Xiaohui Ren, Song Lin","doi":"10.1093/neuonc/noae167","DOIUrl":"https://doi.org/10.1093/neuonc/noae167","url":null,"abstract":"<p><strong>Background: </strong>Glioma, characterized by limited lymphocytic infiltration, constitutes an \"immune-desert\" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune-resistant to an activated state.</p><p><strong>Methods: </strong>TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted.</p><p><strong>Results: </strong>TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of \"LTo\" and \"LTi\" cells, respectively, interaction through LTα/β-LTβR promoted TLS induction. Post-TLS formation, CD4+ and CD8+ T cells but not CD19+ B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled switch from naïve to mature, some B cells highlighted an enrichment of CSR-associated genes, V gene usage and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME.</p><p><strong>Conclusion: </strong>TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073426","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}
Ji Eun Park, Joo Young Oh, Do Hoon Park, Ho-Su Lee, Shinkyo Yoon, Nak Young Kim, Seo Young Park, Sang Woo Song, Young-Hoon Kim, Chang-Ki Hong, Jeong Hoon Kim, Ho Sung Kim
Background: To spatially validate intratumoral subregions (tumor habitat) using physiologic MRI on pathology of the isocitrate dehydrogenase (IDH)-wildtype whole-glioblastoma sample.
Methods: Data of 20 patients (168 slides) were obtained from the Ivy Glioblastoma Atlas Project. On MRI, tumor habitats were defined using voxel-wise clustering of apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps for contrast-enhancing lesion (CEL) and non-enhancing lesion (NEL). On pathology slides, normalized areas of leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen was co-registered on MRI and correlation between pathology-MRI habitats was calculated. RNA sequencing of 67 samples was assessed using 4 Neftel subtypes and further correlated with pathology.
Results: Six tumor habitats were identified: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was correlated with hypovascular cellular habitat in CEL (r= 0.238, p =.005). IT was correlated with hypovascular cellular habitat in NEL (r= 0.294, p =.017). CThypervascular was correlated with hypervascular habitat in NEL (r= 0.195, p = .023). CTperinecrotic was correlated with imaging necrosis (r= 0.199, p =.005). Astrocyte-like subtypes were correlated with IT (r= 0.256, p <.001), while mesenchymal-like subtypes were correlated with CTperinecrotic area (r= 0.246, p <.001).
Conclusion: Pathologically matched tumor subregions were cellular tumor with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive as well as infiltrative tumor portion can be achieved using non-invasive MRI tumor habitats.
背景:利用生理学磁共振成像对异柠檬酸脱氢酶(IDH)-野生型全胶质母细胞瘤样本的病理学进行空间验证瘤内亚区域(肿瘤栖息地):方法:从常春藤胶质母细胞瘤图谱项目中获取了20名患者(168张切片)的数据。在核磁共振成像中,通过对对比增强病灶(CEL)和非增强病灶(NEL)的表观弥散系数(ADC)和脑血容量(CBV)图进行体素聚类,确定肿瘤的分布区。在病理切片上,获得前缘(LE)、浸润性肿瘤(IT)、细胞肿瘤(CT)、高血管性病变(CThypervascular)和坏死周围病变(CTperinecrotic)的归一化区域。大体标本在核磁共振成像上进行联合登记,并计算病理学与核磁共振成像之间的相关性。使用 4 个 Neftel 亚型对 67 个样本的 RNA 测序进行评估,并进一步与病理学进行关联:结果:确定了六种肿瘤生境:CEL和NEL的高血管生境、低血管细胞生境和低血管低细胞生境。CT与CEL的低血管细胞栖息地相关(r= 0.238,p =.005)。在 NEL 中,IT 与血管下细胞栖息地相关(r= 0.294,p =.017)。CThypervascular 与 NEL 的高血管生境相关(r= 0.195,p = .023)。CTperinecrotic 与成像坏死相关(r= 0.199,p =.005)。星形胶质细胞样亚型与 IT 相关(r= 0.256,p=0.005):病理匹配的肿瘤亚区在CEL中为低血管细胞生境的细胞性肿瘤,在NEL中为低血管细胞生境的浸润性肿瘤。使用非侵入性磁共振成像肿瘤生境可识别最具侵袭性和浸润性的肿瘤部分。
{"title":"Mapping Tumor Habitats in IDH-Wild Type Glioblastoma: Integrating MR Imaging, Pathologic, and RNA Data from Ivy Glioblastoma Atlas Project.","authors":"Ji Eun Park, Joo Young Oh, Do Hoon Park, Ho-Su Lee, Shinkyo Yoon, Nak Young Kim, Seo Young Park, Sang Woo Song, Young-Hoon Kim, Chang-Ki Hong, Jeong Hoon Kim, Ho Sung Kim","doi":"10.1093/neuonc/noae161","DOIUrl":"https://doi.org/10.1093/neuonc/noae161","url":null,"abstract":"<p><strong>Background: </strong>To spatially validate intratumoral subregions (tumor habitat) using physiologic MRI on pathology of the isocitrate dehydrogenase (IDH)-wildtype whole-glioblastoma sample.</p><p><strong>Methods: </strong>Data of 20 patients (168 slides) were obtained from the Ivy Glioblastoma Atlas Project. On MRI, tumor habitats were defined using voxel-wise clustering of apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps for contrast-enhancing lesion (CEL) and non-enhancing lesion (NEL). On pathology slides, normalized areas of leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen was co-registered on MRI and correlation between pathology-MRI habitats was calculated. RNA sequencing of 67 samples was assessed using 4 Neftel subtypes and further correlated with pathology.</p><p><strong>Results: </strong>Six tumor habitats were identified: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was correlated with hypovascular cellular habitat in CEL (r= 0.238, p =.005). IT was correlated with hypovascular cellular habitat in NEL (r= 0.294, p =.017). CThypervascular was correlated with hypervascular habitat in NEL (r= 0.195, p = .023). CTperinecrotic was correlated with imaging necrosis (r= 0.199, p =.005). Astrocyte-like subtypes were correlated with IT (r= 0.256, p <.001), while mesenchymal-like subtypes were correlated with CTperinecrotic area (r= 0.246, p <.001).</p><p><strong>Conclusion: </strong>Pathologically matched tumor subregions were cellular tumor with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive as well as infiltrative tumor portion can be achieved using non-invasive MRI tumor habitats.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036505","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}
Denise Obrecht-Sturm, Melanie Schoof, Alicia Eckhardt, Martin Mynarek, Mark R Gilbert, Kenneth Aldape, Terri S Armstrong, Vijay Ramaswamy, Michael Bockmayr, Katja von Hoff, Gudrun Fleischhack, Jonas E Adolph, Stephan Tippelt, Stefan M Pfister, Kristian Pajtler, Dominik Sturm, Richard Drexler, Franz L Ricklefs, Natalia Stepien, Johannes Gojo, Torsten Pietsch, Monika Warmuth-Metz, Rolf Kortmann, Beate Timmermann, Christine Haberler, Stefan Rutkowski, Ulrich Schüller
Background: Ependymoma (EPN) is not a uniform disease but represents different disease types with biological and clinical heterogeneity. However, the pattern of when and where different types of EPN relapse is not yet comprehensively described.
Methods: We assembled 269 relapsed intracranial EPN from pediatric (n=233) and adult (n=36) patients from European and Northern American cohorts and correlated DNA methylation patterns and copy-number alterations with clinical information.
Results: The cohort comprised the following molecular EPN types: PF-EPN-A (n=177), ST-EPN-ZFTA (n=45), PF-EPN-B (n=31), PF-EPN-SE (n=12), and ST-EPN-YAP (n=4). First relapses of PF-EPN-B (PF: posterior-fossa) and PF-EPN-SE (SE: subependymoma) occurred later than of PF-EPN-A, ST-EPN-YAP (ST: supratentorial), or ST-EPN-ZFTA (median time to relapse: 4.3 and 6.0 years vs. 1.9/1.0/2.4 years; p<0.01). Metastatic or combined recurrences in PF-EPN-B and -A more often involved the spinal cord than in ST-EPN-ZFTA (72.7% and 40.0 vs. 12.5%; p<0.01). No distant relapses were observed in ST-EPN-YAP (n=4) or PF-EPN-SE (n=12). Post-relapse survival (PRS) was poor for PF-EPN-A and ST-EPN-ZFTA (5-year PRS: 44.5±4.4/47.8±9.1%), whereas PF-EPN-B and PF-EPN-SE displayed a 5-year PRS of 89.5±7.1/90.0±9.5% (p=0.03). However, 10-year PRS for PF-EPN-B dropped to 45.8±17.3%. Neither between radiation field and relapse pattern nor between radiation field and spinal involvement at relapse an impact was identified. Notably, all patients with relapsed ST-EPN-YAP did not receive upfront radiotherapy, but were successfully salvaged using irradiation at relapse.
Conclusions: Relapse patterns of specific EPN types are different. Future clinical trials, treatment adaptions, duration of surveillance and diagnostics should be planned incorporating entity-specific relapse information.
背景:脑上皮瘤(EPN)并不是一种统一的疾病,而是具有生物学和临床异质性的不同疾病类型。然而,不同类型的EPN何时何地复发的模式尚未得到全面描述:我们收集了来自欧洲和北美队列的 269 例复发的颅内 EPN 儿童患者(n=233)和成人患者(n=36),并将 DNA 甲基化模式和拷贝数改变与临床信息相关联:结果:该队列包括以下分子 EPN 类型:PF-EPN-A(177人)、ST-EPN-ZFTA(45人)、PF-EPN-B(31人)、PF-EPN-SE(12人)和ST-EPN-YAP(4人)。PF-EPN-B(PF:后窝)和PF-EPN-SE(SE:肢端瘤下)的首次复发时间晚于PF-EPN-A、ST-EPN-YAP(ST:幕上)或ST-EPN-ZFTA(中位复发时间分别为4.3年和6.0年):中位复发时间:4.3 年和 6.0 年 vs. 1.9/1.0/2.4 年;p 结论:特定 EPN 类型的复发模式各不相同。在规划未来的临床试验、治疗调整、监测持续时间和诊断时,应纳入特定实体的复发信息。
{"title":"Distinct relapse pattern across molecular ependymoma types.","authors":"Denise Obrecht-Sturm, Melanie Schoof, Alicia Eckhardt, Martin Mynarek, Mark R Gilbert, Kenneth Aldape, Terri S Armstrong, Vijay Ramaswamy, Michael Bockmayr, Katja von Hoff, Gudrun Fleischhack, Jonas E Adolph, Stephan Tippelt, Stefan M Pfister, Kristian Pajtler, Dominik Sturm, Richard Drexler, Franz L Ricklefs, Natalia Stepien, Johannes Gojo, Torsten Pietsch, Monika Warmuth-Metz, Rolf Kortmann, Beate Timmermann, Christine Haberler, Stefan Rutkowski, Ulrich Schüller","doi":"10.1093/neuonc/noae166","DOIUrl":"https://doi.org/10.1093/neuonc/noae166","url":null,"abstract":"<p><strong>Background: </strong>Ependymoma (EPN) is not a uniform disease but represents different disease types with biological and clinical heterogeneity. However, the pattern of when and where different types of EPN relapse is not yet comprehensively described.</p><p><strong>Methods: </strong>We assembled 269 relapsed intracranial EPN from pediatric (n=233) and adult (n=36) patients from European and Northern American cohorts and correlated DNA methylation patterns and copy-number alterations with clinical information.</p><p><strong>Results: </strong>The cohort comprised the following molecular EPN types: PF-EPN-A (n=177), ST-EPN-ZFTA (n=45), PF-EPN-B (n=31), PF-EPN-SE (n=12), and ST-EPN-YAP (n=4). First relapses of PF-EPN-B (PF: posterior-fossa) and PF-EPN-SE (SE: subependymoma) occurred later than of PF-EPN-A, ST-EPN-YAP (ST: supratentorial), or ST-EPN-ZFTA (median time to relapse: 4.3 and 6.0 years vs. 1.9/1.0/2.4 years; p<0.01). Metastatic or combined recurrences in PF-EPN-B and -A more often involved the spinal cord than in ST-EPN-ZFTA (72.7% and 40.0 vs. 12.5%; p<0.01). No distant relapses were observed in ST-EPN-YAP (n=4) or PF-EPN-SE (n=12). Post-relapse survival (PRS) was poor for PF-EPN-A and ST-EPN-ZFTA (5-year PRS: 44.5±4.4/47.8±9.1%), whereas PF-EPN-B and PF-EPN-SE displayed a 5-year PRS of 89.5±7.1/90.0±9.5% (p=0.03). However, 10-year PRS for PF-EPN-B dropped to 45.8±17.3%. Neither between radiation field and relapse pattern nor between radiation field and spinal involvement at relapse an impact was identified. Notably, all patients with relapsed ST-EPN-YAP did not receive upfront radiotherapy, but were successfully salvaged using irradiation at relapse.</p><p><strong>Conclusions: </strong>Relapse patterns of specific EPN types are different. Future clinical trials, treatment adaptions, duration of surveillance and diagnostics should be planned incorporating entity-specific relapse information.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018181","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}
Hia S Ghosh, Ruchit V Patel, Eleanor Woodward, Noah F Greenwald, Varun M Bhave, Eduardo A Maury, Gregory Cello, Samantha E Hoffman, Yvonne Li, Hersh Gupta, Gilbert Youssef, Liam F Spurr, Jayne Vogelzang, Mehdi Touat, Frank Dubois, Andrew D Cherniack, Xiaopeng Guo, Sherwin Tavakol, Gino Cioffi, Neal I Lindeman, Azra H Ligon, E Antonio Chiocca, David A Reardon, Patrick Y Wen, David Meredith, Sandro Santagata, Jill S Barnholtz-Sloan, Keith L Ligon, Rameen Beroukhim, Wenya Linda Bi
Background: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received.
Methods: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival.
Results: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received.
Conclusions: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations.
背景:随着胶质瘤的分类、风险分层和治疗标准发生重大变化,我们试图了解分子特征、临床指标和接受的治疗如何影响这些肿瘤患者的总体生存率:我们从癌症基因组图谱(The Cancer Genome Atlas)、基因组学证据肿瘤信息交换项目(Project Genomics Evidence Neoplasia Information Exchange)和丹娜-法伯癌症研究所/布里格姆妇女医院(Dana-Farber Cancer Institute/Brigham and Women's Hospital)收集了一批经组织病理学诊断的胶质瘤患者。这项研究结合了回顾性临床、组织学和分子数据,以及对患者生存情况的前瞻性评估:结果:共发现 4400 例胶质瘤:结果:共发现 4400 例胶质瘤:2195 例胶质母细胞瘤、1198 例 IDH1/2 突变星形细胞瘤、531 例少突胶质细胞瘤、271 例其他 IDH1/2 野生型胶质瘤和 205 例儿童型胶质瘤。分子分类更新了27.2%胶质瘤的原始组织病理学诊断。通过研究胶质瘤亚型的分子改变分布,发现了致瘤通路中相互排斥的改变。与TCGA患者相比,非TCGA患者的总生存率明显提高,胶质母细胞瘤、IDH1/2突变星形细胞瘤和少突胶质细胞瘤的生存率分别提高了26.7%、55.6%和127.8%(均为p结论:通过应用现代分子标准,我们描述了胶质瘤亚型的基因组多样性,确定了临床适用的预后特征,并提供了患者生存率的最新情况,为正在进行的研究提供了参考。
{"title":"Contemporary Prognostic Signatures and Refined Risk Stratification of Gliomas: An Analysis of 4,400 Tumors.","authors":"Hia S Ghosh, Ruchit V Patel, Eleanor Woodward, Noah F Greenwald, Varun M Bhave, Eduardo A Maury, Gregory Cello, Samantha E Hoffman, Yvonne Li, Hersh Gupta, Gilbert Youssef, Liam F Spurr, Jayne Vogelzang, Mehdi Touat, Frank Dubois, Andrew D Cherniack, Xiaopeng Guo, Sherwin Tavakol, Gino Cioffi, Neal I Lindeman, Azra H Ligon, E Antonio Chiocca, David A Reardon, Patrick Y Wen, David Meredith, Sandro Santagata, Jill S Barnholtz-Sloan, Keith L Ligon, Rameen Beroukhim, Wenya Linda Bi","doi":"10.1093/neuonc/noae164","DOIUrl":"https://doi.org/10.1093/neuonc/noae164","url":null,"abstract":"<p><strong>Background: </strong>With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received.</p><p><strong>Methods: </strong>We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival.</p><p><strong>Results: </strong>4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received.</p><p><strong>Conclusions: </strong>By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009084","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}