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Dynamics of tumor evolution after Gammaknife radiosurgery for sporadic vestibular schwannoma: defining volumetric patterns characterizing individual trajectory. 伽玛刀放射外科治疗散发性前庭裂隙瘤后肿瘤演变的动力学:确定个体轨迹的体积模式。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-16 DOI: 10.1093/neuonc/noae187
Anne Balossier, Madalina Olteanu, Christine Delsanti, Lucas Troude, Jean-Marc Thomassin, Pierre-Hugues Roche, Marie Chavent, Jean Régis

Background: Definition of tumor control and treatment failure after Gammaknife radiosurgery (GKRS) for vestibular schwannoma (VS) is still debated. The lack of knowledge on the dynamics of tumor evolution can lead to misinterpretation and subsequent inappropriate second treatment. The aim of this study was to evaluate the post-GKRS dynamics of evolution of tumor volume, and characterize volumetric patterns.

Methods: We included patients with sporadic VS treated by GKRS with an MRI follow-up of minimum 3 years. A clustering in 2 steps was performed: definition of the patterns of evolution based on a subset of patients with the most comprehensive follow-up, then assignment of the remaining patients on a best fit basis. The minimum length of follow-up was assessed by measuring the consistency of the clusters over time (Adjusted Rand Index and Normalized Mutual Information). An analysis of the discriminant variables was finally performed.

Results: 1,607 patients were included (median follow-up: 67 months). Five patterns were defined with one pattern gathering almost all cases of treatment failure. The clustering at 5 years afforded the highest consistency with long-term follow-up. Discriminant variables for clusters were: sex, initial symptoms, delay of diagnosis, Koos grading, fundus invasion, and number of isocenters.

Conclusions: The definition of these robust distinct patterns is likely to help tremendously the physicians to distinguish tumor control from potential failure. We advocate for no retreatment decision before 5 years post-GKRS. Further investigations are required to decide if the dynamics of evolution can be predicted at GKRS on an individual basis.

背景:前庭分裂瘤(VS)伽玛刀放射外科手术(GKRS)后肿瘤控制和治疗失败的定义仍存在争议。由于缺乏对肿瘤演变动态的了解,可能会导致误解和不恰当的二次治疗。本研究旨在评估 GKRS 术后肿瘤体积的动态演变,并描述肿瘤体积模式:我们纳入了接受 GKRS 治疗、磁共振成像随访至少 3 年的散发性 VS 患者。我们分两步进行了聚类:根据随访最全面的患者子集定义演变模式,然后根据最佳拟合原则分配其余患者。通过测量聚类随时间变化的一致性(调整后的兰德指数和归一化互信息)来评估随访的最短时间。最后进行了判别变量分析:共纳入 1,607 名患者(中位随访时间:67 个月)。共确定了五种模式,其中一种模式聚集了几乎所有的治疗失败病例。5 年的分组与长期随访的一致性最高。聚类的判别变量包括:性别、初始症状、诊断延迟、Koos分级、眼底侵犯和等中心数量:这些强大的独特模式的定义可能会极大地帮助医生区分肿瘤控制和潜在的失败。我们主张在 GKRS 术后 5 年前不做再治疗决定。我们还需要进一步的研究,以确定是否可以根据个体情况预测 GKRS 的演变动态。
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引用次数: 0
Erratum to: The biological significance of tumor grade, age, enhancement, and extent of resection in IDH-mutant gliomas: How should they inform treatment decisions in the era of IDH inhibitors? 勘误:IDH突变胶质瘤的肿瘤分级、年龄、增强程度和切除范围的生物学意义:在IDH抑制剂时代,它们应如何指导治疗决策?
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-14 DOI: 10.1093/neuonc/noae185
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引用次数: 0
MGMT promoter methylation and survival following chemotherapy for WHO grade 4 IDH-mutant astrocytoma. MGMT启动子甲基化与WHO 4级IDH突变星形细胞瘤化疗后的生存率
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-11 DOI: 10.1093/neuonc/noae157
Mary Jane Lim-Fat, Patrick Y Wen, Mehdi Touat, Vinay K Puduvalli, J Bryan Iorgulescu
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引用次数: 0
Brain tumoroids: treatment prediction and drug development for brain tumors with fast, reproducible and easy-to-use personalized models 脑肿瘤:利用快速、可重复和易用的个性化模型进行脑肿瘤的治疗预测和药物开发
IF 15.9 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-10 DOI: 10.1093/neuonc/noae184
Aurélie Soubéran, Carine Jiguet-Jiglaire, Soline Toutain, Philippe Morando, Nathalie Baeza-Kallee, Romain Appay, Céline Boucard, Thomas Graillon, Mikael Meyer, Kaissar Farah, Dominique Figarella-Branger, Emeline Tabouret, Aurélie Tchoghandjian
Background generation of patient avatar is critically needed in neuro-oncology for treatment prediction and preclinical therapeutic development. Our objective was to develop a fast, reproducible, low-cost and easy-to-use method of tumoroids generation and analysis, efficient for all types of brain tumors, primary and metastatic. Methods tumoroids were generated from 89 patients: 81 primary tumors including 77 gliomas, and 8 brain metastases. Tumoroids morphology, cellular and molecular characteristics were compared with the ones of the parental tumor by using histology, methylome profiling, pTERT mutations and multiplexed spatial immunofluorescences. Their cellular stability overtime was validated by flow cytometry. Therapeutic sensitivity was evaluated and predictive factors of tumoroid generation were analyzed. Results All the tumoroids analyzed had similar histological (N=21) and molecular features (N=7) than the parental tumor. Median generation time was 5 days. Success rate was 65 %: it was higher for high grade gliomas and brain metastases versus IDH mutated low grade gliomas. For high-grade gliomas, neither other clinical, neuro-imaging, histological nor molecular factors were predictive of tumoroid generation success. The cellular organization inside tumoroids analyzed by MACSima revealed territories dedicated to specific cell subtypes. Finally, we showed the correlation between tumoroid and patient treatment responses to radio-chemotherapy and their ability to respond to immunotherapy thanks to a dedicated and reproducible 3D analysis workflow. Conclusion patient-derived tumoroid model that we developed offers a robust, user-friendly, low-cost and reproducible preclinical model valuable for therapeutic development of all type of primary or metastatic brain tumors, allowing their integration into forthcoming early-phase clinical trials.
在神经肿瘤学中,急需生成患者化身背景,以便进行治疗预测和临床前治疗开发。我们的目标是开发一种快速、可重复、低成本且易于使用的肿瘤标本生成和分析方法,该方法适用于所有类型的原发性和转移性脑肿瘤。方法从 89 名患者中生成肿瘤组织:包括 77 个胶质瘤在内的 81 个原发性肿瘤和 8 个脑转移瘤。通过组织学、甲基组分析、pTERT 基因突变和多重空间免疫荧光,将瘤体的形态、细胞和分子特征与原发肿瘤进行比较。流式细胞术验证了它们的细胞稳定性超时。对治疗敏感性进行了评估,并分析了类肿瘤生成的预测因素。结果 分析的所有瘤样都具有与原代肿瘤相似的组织学特征(21 个)和分子特征(7 个)。中位生成时间为 5 天。成功率为 65%:高级别胶质瘤和脑转移瘤的成功率高于 IDH 突变的低级别胶质瘤。对于高级别胶质瘤,其他临床、神经影像学、组织学或分子因素都不能预测瘤体生成的成功率。通过 MACSima 分析肿瘤内部的细胞组织,发现了特定细胞亚型的专用区域。最后,我们展示了类肿瘤和患者对放射化疗的治疗反应之间的相关性,以及他们对免疫疗法的反应能力,这要归功于专用的、可重复的三维分析工作流程。结论 我们开发的病人衍生肿瘤模型提供了一个强大、用户友好、低成本和可重现的临床前模型,对所有类型的原发性或转移性脑肿瘤的治疗开发都很有价值,可将其纳入即将进行的早期临床试验。
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引用次数: 0
EGFR and EGFRvIII coopt host defense pathways, promoting progression in glioblastoma. 表皮生长因子受体和表皮生长因子受体vIII协同宿主防御途径,促进胶质母细胞瘤的进展。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-09 DOI: 10.1093/neuonc/noae182
Zhenyi An, Qi-Wen Fan, Linyu Wang, Hiroyuki Yoda, Megumi J Barata, David Jimenez-Morales, Joanna J Phillips, Danielle L Swaney, Erica Stevenson, Ethan Lee, Nevan Krogan, William A Weiss

Background: Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.

Methods: We used phospho-proteomics, RNA-sequencing, TCGA data and glioblastoma cell culture and mouse models to study the signal transduction mediated by EGFR and EGFRvIII.

Results: We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment.

Conclusion: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.

背景:表皮生长因子受体和表皮生长因子受体vIII(表皮生长因子受体的一种肿瘤特异性截短突变体)的共扩增是胶质母细胞瘤的标志性遗传病变:我们利用磷酸蛋白组学、RNA测序、TCGA数据以及胶质母细胞瘤细胞培养和小鼠模型研究了表皮生长因子受体和表皮生长因子受体vIII介导的信号转导:结果:我们发现表皮生长因子受体(EGFR)和表皮生长因子受体vIII能刺激先天性免疫防御受体Toll样受体2(TLR2);敲除TLR2能显著提高正位胶质母细胞瘤异种移植物的存活率。表皮生长因子受体和表皮生长因子受体vIII以配体无关的方式激活TLR2,促进肿瘤生长和免疫逃避。我们的研究表明,表皮生长因子受体和表皮生长因子受体vIII合作激活了Rho相关蛋白激酶ROCK2,ROCK2通过激活TLR2和WNT信号以及重塑肿瘤微环境调节恶性进展:总之,我们的研究结果表明,表皮生长因子受体和表皮生长因子受体vIII通过ROCK2和下游WNT-β-catenin/TLR2信号通路合作驱动肿瘤进展。
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引用次数: 0
Cognitive phenotypes: Unraveling the heterogeneity in cognitive dysfunction among patients with primary brain tumors receiving radiotherapy. 认知表型:揭示接受放疗的原发性脑肿瘤患者认知功能障碍的异质性。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-09 DOI: 10.1093/neuonc/noae183
Anny Reyes, Alena Stasenko, Austin Hopper, Jiwandeep S Kohli, Jonathan L Helm, Mia Salans, Divya Prabhakaran, Lily Kamalyan, Molly Wilkinson, Soumya Unnikrishnan, Roshan Karunamuni, Jona Hattangadi-Gluth, Carrie R McDonald

Background: Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis (LPA) to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT).

Methods: Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, 12-months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated.

Results: The optimal model identified three unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (p=.007) and a greater proportion of males (p<.001); the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (p-values<.05); and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory the most vulnerable. Patients that declined reported greater symptoms of depression (p=.007) and poorer quality of life (p=.025).

Conclusions: We identified three distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (e.g., IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.

背景:原发性脑肿瘤患者表现出不同的认知功能障碍模式,我们利用潜在特征分析(LPA)来确定接受放疗(RT)患者的认知表型及其轨迹:在一项前瞻性纵向试验中,96名患者在放疗前和放疗后(3、6、12个月)完成了神经心理学测试,包括处理速度、执行功能、语言、言语和视觉记忆的测量。对 2-4 个等级的模型进行了研究。对不同表型的人口统计学和临床数据进行了研究,并对 RT 后的认知变化进行了评估:结果:最佳模型确定了三种独特的认知表型,包括一组有全身障碍的患者(11.5%)、一组有孤立言语记忆障碍的患者(21.9%)和一组有轻微障碍的患者(66.7%)。言语记忆表型患者受教育年限较少(p=.007),男性比例较高(p结论:我们在接受RT治疗的原发性脑肿瘤患者中发现了三种不同的认知表型,每种表型都与独特的人口统计学和临床(如IDH突变状态)特征相关,情绪症状与晚期认知能力下降相关。这种以患者为中心的方法增强了我们对认知功能障碍和治疗相关神经毒性相关临床特征的了解。
{"title":"Cognitive phenotypes: Unraveling the heterogeneity in cognitive dysfunction among patients with primary brain tumors receiving radiotherapy.","authors":"Anny Reyes, Alena Stasenko, Austin Hopper, Jiwandeep S Kohli, Jonathan L Helm, Mia Salans, Divya Prabhakaran, Lily Kamalyan, Molly Wilkinson, Soumya Unnikrishnan, Roshan Karunamuni, Jona Hattangadi-Gluth, Carrie R McDonald","doi":"10.1093/neuonc/noae183","DOIUrl":"https://doi.org/10.1093/neuonc/noae183","url":null,"abstract":"<p><strong>Background: </strong>Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis (LPA) to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT).</p><p><strong>Methods: </strong>Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, 12-months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated.</p><p><strong>Results: </strong>The optimal model identified three unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (p=.007) and a greater proportion of males (p<.001); the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (p-values<.05); and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory the most vulnerable. Patients that declined reported greater symptoms of depression (p=.007) and poorer quality of life (p=.025).</p><p><strong>Conclusions: </strong>We identified three distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (e.g., IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154718","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
Towards consistency in pediatric brain tumor measurements: Challenges, solutions, and the role of artificial intelligence-based segmentation. 实现小儿脑肿瘤测量的一致性:挑战、解决方案和基于人工智能的分割的作用。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1093/neuonc/noae093
Ariana M Familiar, Anahita Fathi Kazerooni, Arastoo Vossough, Jeffrey B Ware, Sina Bagheri, Nastaran Khalili, Hannah Anderson, Debanjan Haldar, Phillip B Storm, Adam C Resnick, Benjamin H Kann, Mariam Aboian, Cassie Kline, Michael Weller, Raymond Y Huang, Susan M Chang, Jason R Fangusaro, Lindsey M Hoffman, Sabine Mueller, Michael Prados, Ali Nabavizadeh

MR imaging is central to the assessment of tumor burden and changes over time in neuro-oncology. Several response assessment guidelines have been set forth by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working groups in different tumor histologies; however, the visual delineation of tumor components using MRIs is not always straightforward, and complexities not currently addressed by these criteria can introduce inter- and intra-observer variability in manual assessments. Differentiation of non-enhancing tumors from peritumoral edema, mild enhancement from absence of enhancement, and various cystic components can be challenging; particularly given a lack of sufficient and uniform imaging protocols in clinical practice. Automated tumor segmentation with artificial intelligence (AI) may be able to provide more objective delineations, but rely on accurate and consistent training data created manually (ground truth). Herein, this paper reviews existing challenges and potential solutions to identifying and defining subregions of pediatric brain tumors (PBTs) that are not explicitly addressed by current guidelines. The goal is to assert the importance of defining and adopting criteria for addressing these challenges, as it will be critical to achieving standardized tumor measurements and reproducible response assessment in PBTs, ultimately leading to more precise outcome metrics and accurate comparisons among clinical studies.

磁共振成像是评估神经肿瘤学中肿瘤负荷和随时间变化的核心。儿科神经肿瘤学反应评估(RAPNO)工作组针对不同的肿瘤组织学制定了多项反应评估指南;然而,使用核磁共振成像直观地划分肿瘤成分并不总是那么简单,而且这些标准目前尚未解决的复杂性会导致人工评估中观察者之间和观察者内部的差异。区分无增强肿瘤和瘤周水肿、轻度增强和无增强以及各种囊性成分可能具有挑战性;特别是考虑到临床实践中缺乏足够和统一的成像方案。利用人工智能(AI)进行自动肿瘤分割或许能提供更客观的划分,但这依赖于人工创建的准确一致的训练数据(地面实况)。本文回顾了识别和定义小儿脑肿瘤(PBT)亚区域的现有挑战和潜在解决方案,这些挑战和解决方案在现行指南中并未明确涉及。本文旨在强调定义和采用标准以应对这些挑战的重要性,因为这对实现标准化肿瘤测量和可重复的 PBT 反应评估至关重要,最终将带来更精确的结果指标和临床研究间的准确比较。
{"title":"Towards consistency in pediatric brain tumor measurements: Challenges, solutions, and the role of artificial intelligence-based segmentation.","authors":"Ariana M Familiar, Anahita Fathi Kazerooni, Arastoo Vossough, Jeffrey B Ware, Sina Bagheri, Nastaran Khalili, Hannah Anderson, Debanjan Haldar, Phillip B Storm, Adam C Resnick, Benjamin H Kann, Mariam Aboian, Cassie Kline, Michael Weller, Raymond Y Huang, Susan M Chang, Jason R Fangusaro, Lindsey M Hoffman, Sabine Mueller, Michael Prados, Ali Nabavizadeh","doi":"10.1093/neuonc/noae093","DOIUrl":"10.1093/neuonc/noae093","url":null,"abstract":"<p><p>MR imaging is central to the assessment of tumor burden and changes over time in neuro-oncology. Several response assessment guidelines have been set forth by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working groups in different tumor histologies; however, the visual delineation of tumor components using MRIs is not always straightforward, and complexities not currently addressed by these criteria can introduce inter- and intra-observer variability in manual assessments. Differentiation of non-enhancing tumors from peritumoral edema, mild enhancement from absence of enhancement, and various cystic components can be challenging; particularly given a lack of sufficient and uniform imaging protocols in clinical practice. Automated tumor segmentation with artificial intelligence (AI) may be able to provide more objective delineations, but rely on accurate and consistent training data created manually (ground truth). Herein, this paper reviews existing challenges and potential solutions to identifying and defining subregions of pediatric brain tumors (PBTs) that are not explicitly addressed by current guidelines. The goal is to assert the importance of defining and adopting criteria for addressing these challenges, as it will be critical to achieving standardized tumor measurements and reproducible response assessment in PBTs, ultimately leading to more precise outcome metrics and accurate comparisons among clinical studies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071450","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
Radiomics-based prediction of local control in patients with brain metastases following postoperative stereotactic radiotherapy. 基于放射组学预测脑转移瘤患者术后立体定向放射治疗的局部控制情况。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1093/neuonc/noae098
Josef A Buchner, Florian Kofler, Michael Mayinger, Sebastian M Christ, Thomas B Brunner, Andrea Wittig, Bjoern Menze, Claus Zimmer, Bernhard Meyer, Matthias Guckenberger, Nicolaus Andratschke, Rami A El Shafie, Jürgen Debus, Susanne Rogers, Oliver Riesterer, Katrin Schulze, Horst J Feldmann, Oliver Blanck, Constantinos Zamboglou, Konstantinos Ferentinos, Angelika Bilger-Zähringer, Anca L Grosu, Robert Wolff, Marie Piraud, Kerstin A Eitz, Stephanie E Combs, Denise Bernhardt, Daniel Rueckert, Benedikt Wiestler, Jan C Peeken

Background: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk.

Methods: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of BMs (AURORA) retrospective study (training cohort: 253 patients from 2 centers; external test cohort: 99 patients from 5 centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (T2-FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set.

Results: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (P < .001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively.

Conclusions: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy.

背景:手术切除是治疗巨大或无症状脑转移瘤(BMs)患者的标准方法。尽管辅助立体定向放疗后局部控制有所改善,但局部失败(LF)的风险依然存在。因此,我们旨在开发并从外部验证一种基于治疗前放射组学的预测工具,以识别局部放疗失败高风险患者:数据来自脑转移灶切除腔立体定向放射治疗多中心分析(AURORA)回顾性研究(训练队列:来自两个中心的253名患者;外部测试队列:来自五个中心的99名患者)。从对比度增强的BM(T1-CE MRI序列)和周围水肿(FLAIR序列)中提取放射学特征。对放射学特征和临床特征的不同组合进行了比较。最终的模型在整个训练队列中进行训练,并使用之前通过内部 5 倍交叉验证确定的最佳参数集,然后在外部测试集上进行测试:外部测试中表现最好的是结合放射学和临床特征训练的弹性网回归模型,其一致性指数(CI)为 0.77,优于任何临床模型(最佳 CI:0.70)。在 Kaplan-Meier 分析中,该模型有效地根据 LF 风险对患者进行了分层(p < 0.001),并显示出增量净临床获益。24个月时,我们发现低风险组和高风险组分别有9%和74%的患者出现LF:结合临床和放射学特征预测 LF 的发生率要优于单独使用任何一组临床特征。LF高风险患者可能会从更严格的随访程序或强化治疗中获益。
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引用次数: 0
NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma. NRG-BN002:Ipilimumab、Nivolumab 及联合疗法在新诊断的 GBM 患者中的 I 期研究。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1093/neuonc/noae058
Andrew E Sloan, Kathryn Winter, Mark R Gilbert, Kenneth Aldape, Serah Choi, Patrick Y Wen, Nicholas Butowski, Fabio M Iwamoto, Raju R Raval, Alfredo D Voloschin, Carlos Kamiya-Matsuoka, Minhee Won, Minesh P Mehta

Background: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting.

Methods: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results.

Results: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively.

Conclusions: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM.

Clinicaltrials.gov registration: NCT02311920.

背景:免疫检查点抑制剂(ICIs)对多种实体瘤有疗效,但对胶质母细胞瘤(GBM)的疗效有限。这项研究评估了抗CTLA-4和抗PD-1 ICIs单药或联合用药在完成标准放化疗后新诊断的GBM中的安全性,随后打算在这种情况下测试联合ICIs:主要终点是切除和化疗后新诊断为单灶、胸骨上GBM的成人患者的剂量限制性毒性(DLT)。对伊匹单抗和尼伐单抗进行了单独和联合试验,并根据DLT结果计划扩大队列:9家机构共招募了32名患者;每组DLT评估队列中有6名患者,扩增队列中有14名患者。中位年龄:55 岁,67.7% 为男性,83.9% 为白人。治疗耐受性良好,4级事件占16%;联合用药的毒性没有意外增加,没有5级事件。每种单药治疗中都出现了一次 DLT,而联合治疗中未出现任何 DLT,因此扩大了联合治疗的应计范围。中位随访时间为 19.6 个月。所有接受联合治疗的患者的中位总生存期(OS)和无进展生存期(PFS)分别为20.7个月和16.1个月:IPI和NIVO联合TMZ辅助治疗新诊断的GBM是安全和可耐受的,其毒性与其他癌症相似。IPI+NIVO联合用药的毒性并不比单一用药大。这些结果支持进行后续疗效试验,在 II/III 期试验中对新诊断的 GBM 患者进行 ICIs 联合用药试验。
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引用次数: 0
Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy. 以 IGF2-IGF1R 信号为靶点,重编程肿瘤微环境以增强病毒-免疫疗法。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1093/neuonc/noae105
Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Background: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

Methods: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

Results: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice.

Conclusions: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

背景:美国食品和药物管理局(FDA)批准了溶解性单纯疱疹-1病毒(oHSV)疗法,这凸显了它作为癌症免疫疗法的治疗前景和安全性。尽管有此前景,但目前 oHSV 的疗效明显局限于一小部分患者,这主要是由于肿瘤和肿瘤微环境(TME)的抗药性:方法:利用 RNA 测序(RNA-Seq)来确定 oHSV 耐药性的分子靶点。采用颅内人类和鼠类胶质瘤或乳腺癌脑转移(BCBM)肿瘤小鼠模型来阐明oHSV治疗诱导耐药的机制:结果:转录组分析发现 IGF2 是 oHSV 治疗后的主要分泌蛋白之一。此外,在使用 oHSV、rQNestin34.5v.2(71.4%)(p=0.0020)(ClinicalTrials.gov,NCT03152318)治疗后,14 名复发性 GBM 患者中有 10 人的 IGF2 表达明显上调。IGF2 的消耗大大增强了体外 oHSV 介导的肿瘤细胞杀伤力,并提高了体内 BCBM 肿瘤小鼠的存活率。为了减轻oHSV在TME中诱导的IGF2,我们构建了一种新型oHSV,即oHSV-D11mt,它能分泌修饰的IGF2R结构域11(IGF2RD11mt),作为IGF2诱饵受体。通过IGF2RD11mt选择性阻断IGF2可显著提高细胞毒性,减少oHSV诱导的中性粒细胞/PMN-MDSCs浸润,减少免疫抑制/血管生成细胞因子的分泌,同时增加CD8+细胞毒性T淋巴细胞(CTLs)浸润,从而提高GBM或BCBM肿瘤小鼠的生存率:这是首次报道 oHSV 诱导的分泌型 IGF2 在 oHSV 治疗耐药性中发挥关键作用的研究。
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Neuro-oncology
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