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Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: a multicenter prospective study. 基于DNA甲基化的脑膜瘤复发预测指标的验证和下一代更新:一项多中心前瞻性研究。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-06 DOI: 10.1093/neuonc/noae236
Alexander P Landry, Justin Z Wang, Vikas Patil, Chloe Gui, Mamatjan Yasin, Zeel Patel, Rebecca Yakubov, Ramneet Kaloti, Parnian Habibi, Mark Wilson, Andrew Ajisebutu, Yosef Ellenbogen, Qingxia Wei, Olivia Singh, Julio Sosa, Sheila Mansouri, Christopher Wilson, Aaron A Cohen-Gadol, Piiamaria Virtanen, Noah Burket, Matthew Blackwell, Jenna Koenig, Anthony Alfonso, Joseph Davis, Mohamed A Zaazoue, Ghazaleh Tabatabai, Marcos Tatagiba, Felix Behling, Jill S Barnholtz-Sloan, Andrew E Sloan, Silky Chotai, Lola B Chambless, Alireza Mansouri, Felix Ehret, David Capper, Derek S Tsang, Kenneth Aldape, Andrew Gao, Farshad Nassiri, Gelareh Zadeh
{"title":"Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: a multicenter prospective study.","authors":"Alexander P Landry, Justin Z Wang, Vikas Patil, Chloe Gui, Mamatjan Yasin, Zeel Patel, Rebecca Yakubov, Ramneet Kaloti, Parnian Habibi, Mark Wilson, Andrew Ajisebutu, Yosef Ellenbogen, Qingxia Wei, Olivia Singh, Julio Sosa, Sheila Mansouri, Christopher Wilson, Aaron A Cohen-Gadol, Piiamaria Virtanen, Noah Burket, Matthew Blackwell, Jenna Koenig, Anthony Alfonso, Joseph Davis, Mohamed A Zaazoue, Ghazaleh Tabatabai, Marcos Tatagiba, Felix Behling, Jill S Barnholtz-Sloan, Andrew E Sloan, Silky Chotai, Lola B Chambless, Alireza Mansouri, Felix Ehret, David Capper, Derek S Tsang, Kenneth Aldape, Andrew Gao, Farshad Nassiri, Gelareh Zadeh","doi":"10.1093/neuonc/noae236","DOIUrl":"10.1093/neuonc/noae236","url":null,"abstract":"<p><strong>Background: </strong>We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays.</p><p><strong>Methods: </strong>Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection.</p><p><strong>Results: </strong>A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (p<0.05), while all WHO grade 3 tumours were considered high-risk. Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays.</p><p><strong>Conclusions: </strong>This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool which will improve prognostication, inform patient selection for RT, and allow for molecularly-stratified clinical trials.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583595","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}
引用次数: 0
Potential of ex vivo organotypic slice cultures in neuro-oncology. 体外有机切片培养在神经肿瘤学中的潜力。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-06 DOI: 10.1093/neuonc/noae195
Ariane Steindl, Manuel Valiente
{"title":"Potential of ex vivo organotypic slice cultures in neuro-oncology.","authors":"Ariane Steindl, Manuel Valiente","doi":"10.1093/neuonc/noae195","DOIUrl":"https://doi.org/10.1093/neuonc/noae195","url":null,"abstract":"<p><p>Over recent decades, in vitro and in vivo models have significantly advanced brain cancer research; however, each presents distinct challenges for accurately mimicking in situ conditions. In response, organotypic slice cultures have emerged as a promising model recapitulating precisely specific in vivo phenotypes through an ex vivo approach. Ex vivo organotypic brain slice models can integrate biological relevance and patient-specific variability early in drug discovery, thereby aiming for more precise treatment stratification. However, the challenges of obtaining representative fresh brain tissue, ensuring reproducibility, and maintaining essential central nervous system (CNS)-specific conditions reflecting the in situ situation over time have limited the direct application of ex vivo organotypic slice cultures in robust clinical trials. In this review, we explore the benefits and possible limitations of ex vivo organotypic brain slice cultures in neuro-oncological research. Additionally, we share insights from clinical experts in neuro-oncology on how to overcome these current limitations and improve the practical application of organotypic brain slice cultures beyond academic research.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591325","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}
引用次数: 0
Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1). 关于 1 型神经纤维瘤病 (NF1) 周围神经鞘瘤综合诊断方法的共识建议。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-06 DOI: 10.1093/neuonc/noae235
Calixto-Hope G Lucas, Andrea M Gross, Carlos G Romo, Carina A Dehner, Alexander J Lazar, Markku Miettinen, Melike Pekmezci, Martha Quezado, Fausto J Rodriguez, Anat Stemmer-Rachamimov, David Viskochil, Arie Perry
{"title":"Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1).","authors":"Calixto-Hope G Lucas, Andrea M Gross, Carlos G Romo, Carina A Dehner, Alexander J Lazar, Markku Miettinen, Melike Pekmezci, Martha Quezado, Fausto J Rodriguez, Anat Stemmer-Rachamimov, David Viskochil, Arie Perry","doi":"10.1093/neuonc/noae235","DOIUrl":"https://doi.org/10.1093/neuonc/noae235","url":null,"abstract":"<p><p>Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a \"Symposium on Atypical Neurofibroma: State of the Science\". Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming \"low-grade MPNST\" to \"ANNUBP with increased proliferation\" to avoid the use of the \"malignant\" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583591","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}
引用次数: 0
Automated segmentation of brain metastases with deep learning: A multi-center, randomized crossover, multi-reader evaluation study. 利用深度学习自动分割脑转移瘤:一项多中心、随机交叉、多阅读器评估研究。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae113
Xiao Luo, Yadi Yang, Shaohan Yin, Hui Li, Ying Shao, Dechun Zheng, Xinchun Li, Jianpeng Li, Weixiong Fan, Jing Li, Xiaohua Ban, Shanshan Lian, Yun Zhang, Qiuxia Yang, Weijing Zhang, Cheng Zhang, Lidi Ma, Yingwei Luo, Fan Zhou, Shiyuan Wang, Cuiping Lin, Jiao Li, Ma Luo, Jianxun He, Guixiao Xu, Yaozong Gao, Dinggang Shen, Ying Sun, Yonggao Mou, Rong Zhang, Chuanmiao Xie
{"title":"Automated segmentation of brain metastases with deep learning: A multi-center, randomized crossover, multi-reader evaluation study.","authors":"Xiao Luo, Yadi Yang, Shaohan Yin, Hui Li, Ying Shao, Dechun Zheng, Xinchun Li, Jianpeng Li, Weixiong Fan, Jing Li, Xiaohua Ban, Shanshan Lian, Yun Zhang, Qiuxia Yang, Weijing Zhang, Cheng Zhang, Lidi Ma, Yingwei Luo, Fan Zhou, Shiyuan Wang, Cuiping Lin, Jiao Li, Ma Luo, Jianxun He, Guixiao Xu, Yaozong Gao, Dinggang Shen, Ying Sun, Yonggao Mou, Rong Zhang, Chuanmiao Xie","doi":"10.1093/neuonc/noae113","DOIUrl":"10.1093/neuonc/noae113","url":null,"abstract":"<p><strong>Background: </strong>Artificial intelligence has been proposed for brain metastasis (BM) segmentation but it has not been fully clinically validated. The aim of this study was to develop and evaluate a system for BM segmentation.</p><p><strong>Methods: </strong>A deep-learning-based BM segmentation system (BMSS) was developed using contrast-enhanced MR images from 488 patients with 10338 brain metastases. A randomized crossover, multi-reader study was then conducted to evaluate the performance of the BMSS for BM segmentation using data prospectively collected from 50 patients with 203 metastases at 5 centers. Five radiology residents and 5 attending radiologists were randomly assigned to contour the same prospective set in assisted and unassisted modes. Aided and unaided Dice similarity coefficients (DSCs) and contouring times per lesion were compared.</p><p><strong>Results: </strong>The BMSS alone yielded a median DSC of 0.91 (95% confidence interval, 0.90-0.92) in the multi-center set and showed comparable performance between the internal and external sets (P = .67). With BMSS assistance, the readers increased the median DSC from 0.87 (0.87-0.88) to 0.92 (0.92-0.92) (P < .001) with a median time saving of 42% (40-45%) per lesion. Resident readers showed a greater improvement than attending readers in contouring accuracy (improved median DSC, 0.05 [0.05-0.05] vs 0.03 [0.03-0.03]; P < .001), but a similar time reduction (reduced median time, 44% [40-47%] vs 40% [37-44%]; P = .92) with BMSS assistance.</p><p><strong>Conclusions: </strong>The BMSS can be optimally applied to improve the efficiency of brain metastasis delineation in clinical practice.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590872","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}
引用次数: 0
Expanding therapeutic options for people with NF2-related schwannomatosis: Encouraging results with brigatinib. 扩大NF2相关分裂瘤病患者的治疗选择:布加替尼取得令人鼓舞的结果
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae137
Scott R Plotkin, Jaishri O Blakeley
{"title":"Expanding therapeutic options for people with NF2-related schwannomatosis: Encouraging results with brigatinib.","authors":"Scott R Plotkin, Jaishri O Blakeley","doi":"10.1093/neuonc/noae137","DOIUrl":"10.1093/neuonc/noae137","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa-Results of the HIT 2000 trial. 后窝脑肿瘤儿科幸存者特定领域神经认知结果的风险因素 - HIT 2000 试验结果。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae092
Martin Mynarek, Anne Rossius, Anika Guiard, Holger Ottensmeier, Katja von Hoff, Denise Obrecht-Sturm, Lisa Bußenius, Carsten Friedrich, Andre O von Bueren, Nicolas U Gerber, Thomas Traunwieser, Rolf-Dieter Kortmann, Monika Warmuth-Metz, Brigitte Bison, Ulrich-W Thomale, Juergen Krauss, Torsten Pietsch, Steven C Clifford, Stefan M Pfister, Dominik Sturm, Felix Sahm, Tanja Tischler, Stefan Rutkowski
{"title":"Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa-Results of the HIT 2000 trial.","authors":"Martin Mynarek, Anne Rossius, Anika Guiard, Holger Ottensmeier, Katja von Hoff, Denise Obrecht-Sturm, Lisa Bußenius, Carsten Friedrich, Andre O von Bueren, Nicolas U Gerber, Thomas Traunwieser, Rolf-Dieter Kortmann, Monika Warmuth-Metz, Brigitte Bison, Ulrich-W Thomale, Juergen Krauss, Torsten Pietsch, Steven C Clifford, Stefan M Pfister, Dominik Sturm, Felix Sahm, Tanja Tischler, Stefan Rutkowski","doi":"10.1093/neuonc/noae092","DOIUrl":"10.1093/neuonc/noae092","url":null,"abstract":"<p><strong>Background: </strong>Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization, and biology in pediatric survivors of a posterior fossa tumor.</p><p><strong>Methods: </strong>Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic tool based on Cattell-Horn-Carroll's model for intelligence were analyzed.</p><p><strong>Results: </strong>Cognitive performance 5.14 years (mean; range = 1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had a strong impact on most subtests. pCMS was associated with psychomotor abilities (β = -0.25 to -0.16) and processing speed (β = -0.32). Postoperative hydrocephalus correlated with crystallized intelligence (β = -0.20) and short-term memory (β = -0.15), age with crystallized intelligence (β = 0.15) and psychomotor abilities (β = -0.16 and β = -0.17). Scores for fluid intelligence (β = -0.23), short-term memory (β = -0.17) and visual processing (β = -0.25) declined, and scores for selective attention improved (β = 0.29) with time after diagnosis.</p><p><strong>Conclusions: </strong>The dose of CSI was strongly associated with neurocognitive outcomes. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI dose and toxicity caused by other treatment modalities.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Outcomes and relapse patterns in primary central nervous system lymphoma: Longitudinal analysis of 559 patients diagnosed from 1983 to 2020. 原发性中枢神经系统淋巴瘤的预后和复发模式:对 1983-2020 年间确诊的 559 例患者的纵向分析。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae115
Kathryn R Tringale, Michael Scordo, Joachim Yahalom, Charlie White, Zhigang Zhang, Behroze Vachha, Gustav Cederquist, Lauren Schaff, Lisa DeAngelis, Christian Grommes, Brandon S Imber
{"title":"Outcomes and relapse patterns in primary central nervous system lymphoma: Longitudinal analysis of 559 patients diagnosed from 1983 to 2020.","authors":"Kathryn R Tringale, Michael Scordo, Joachim Yahalom, Charlie White, Zhigang Zhang, Behroze Vachha, Gustav Cederquist, Lauren Schaff, Lisa DeAngelis, Christian Grommes, Brandon S Imber","doi":"10.1093/neuonc/noae115","DOIUrl":"10.1093/neuonc/noae115","url":null,"abstract":"<p><strong>Background: </strong>Contemporary outcomes and relapse patterns in primary CNS lymphoma (PCNSL) are lacking. We analyzed factors associated with relapse in a large cohort with extensive follow-up.</p><p><strong>Methods: </strong>T1-post-contrast-enhancing disease was characterized in immunocompetent PCNSL (diffuse large B-cell) patients from 1983 to 2020. Patients were stratified by response to induction and consolidation (complete/unconfirmed [CR/CRu], partial, stable, progression [POD]). Refractory was POD during (or relapse ≤3 months of) induction. Initial relapse site was categorized as local (involving/adjacent to baseline), distant intraparenchymal, leptomeningeal, or other. Progression-free (PFS) and overall survival (OS) were assessed with proportional hazards. Cumulative incidence with competing risks was used to assess local relapse.</p><p><strong>Results: </strong>Median follow-up was 7.4 years (N = 559). Most (321, 57%) were recursive partitioning analysis class 2 (age ≥50, Karnosfky Performance Status [KPS] ≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received methotrexate-based induction (532, 95%). There was no difference in PFS or OS from consolidation based on initial response to induction (CR/CRu vs PR) in patients who ultimately achieved a CR/CRu to consolidation. PFS at 1-, 5 years for 351 patients with CR/CRu to consolidation was 80% (95% confidence interval [95% CI]: 76%-84%) and 46% (95% CI: 41%-53%), respectively; 1-year cumulative incidence of local versus nonlocal relapse was 1.8% versus 15%, respectively. For 97 refractory patients, 1-year cumulative incidence of local versus nonlocal relapse was 57% versus 42%, respectively. Deep structure involvement (HR 1.89, 95% CI: 1.10%-3.27%) was associated with local relapse in refractory patients.</p><p><strong>Conclusions: </strong>We report the first comprehensive relapse patterns in a large PCNSL cohort. While relapses post-CR to consolidation are typically distant and unpredictable, refractory patients had a relatively high incidence of local relapse. These findings can help optimize multimodality therapy for this highest-risk population.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma. 抑制 PERK 介导的 UPR 可作为逆转残余衰老的开关和胶质母细胞瘤的衰老疗法。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae134
Madhura Ketkar, Sanket Desai, Pranav Rana, Rahul Thorat, Sridhar Epari, Amit Dutt, Shilpee Dutt
{"title":"Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.","authors":"Madhura Ketkar, Sanket Desai, Pranav Rana, Rahul Thorat, Sridhar Epari, Amit Dutt, Shilpee Dutt","doi":"10.1093/neuonc/noae134","DOIUrl":"10.1093/neuonc/noae134","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma due to recurrence is clinically challenging with 10-15 months overall survival. Previously we showed that therapy-induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate the TIS reversal mechanism for potential therapeutic intervention to prevent glioblastoma (GBM) recurrence.</p><p><strong>Methods: </strong>Residual senescent (RS) and end of residual senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenarios. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays, and IHCs were performed for the mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model.</p><p><strong>Results: </strong>Transcriptome analysis showed co-expression of endoplasmic reticulum (ER) stress-unfolded protein response (UPR) and senescence-associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, Reactive oxygen specis (ROS), DNA damage, and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP, and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in ER, RS cells displayed stressed ER morphology, upregulated ER stress markers, and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21, and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival.</p><p><strong>Conclusion: </strong>We demonstrate that PERK-mediated UPR regulates senescence reversal and its inhibition can be exploited as a potential seno-therapeutic option in glioblastoma.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhancing neuro-oncology care through equity-driven applications of artificial intelligence. 通过公平驱动的人工智能应用,加强神经肿瘤治疗。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae127
Mulki Mehari, Youssef Sibih, Abraham Dada, Susan M Chang, Patrick Y Wen, Annette M Molinaro, Ugonma N Chukwueke, Joshua A Budhu, Sadhana Jackson, J Ricardo McFaline-Figueroa, Alyx Porter, Shawn L Hervey-Jumper
{"title":"Enhancing neuro-oncology care through equity-driven applications of artificial intelligence.","authors":"Mulki Mehari, Youssef Sibih, Abraham Dada, Susan M Chang, Patrick Y Wen, Annette M Molinaro, Ugonma N Chukwueke, Joshua A Budhu, Sadhana Jackson, J Ricardo McFaline-Figueroa, Alyx Porter, Shawn L Hervey-Jumper","doi":"10.1093/neuonc/noae127","DOIUrl":"10.1093/neuonc/noae127","url":null,"abstract":"<p><p>The disease course and clinical outcome for brain tumor patients depend not only on the molecular and histological features of the tumor but also on the patient's demographics and social determinants of health. While current investigations in neuro-oncology have broadly utilized artificial intelligence (AI) to enrich tumor diagnosis and more accurately predict treatment response, postoperative complications, and survival, equity-driven applications of AI have been limited. However, AI applications to advance health equity in the broader medical field have the potential to serve as practical blueprints to address known disparities in neuro-oncologic care. In this consensus review, we will describe current applications of AI in neuro-oncology, postulate viable AI solutions for the most pressing inequities in neuro-oncology based on broader literature, propose a framework for the effective integration of equity into AI-based neuro-oncology research, and close with the limitations of AI.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Thrombosis, brain metastasis formation, and the perivascular metastatic niche-Novel insights from the tumor microvascular circulation. 血栓形成、脑转移瘤形成和血管周围转移龛--来自肿瘤微血管循环的新见解。
IF 16.4 1区 医学
Neuro-oncology Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae168
Christopher Alvarez-Breckenridge, Priscilla K Brastianos, Daniel P Cahill
{"title":"Thrombosis, brain metastasis formation, and the perivascular metastatic niche-Novel insights from the tumor microvascular circulation.","authors":"Christopher Alvarez-Breckenridge, Priscilla K Brastianos, Daniel P Cahill","doi":"10.1093/neuonc/noae168","DOIUrl":"10.1093/neuonc/noae168","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534314/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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