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Development of a highly differentiated rat brain organoid model for exploring glioblastoma invasion dynamics and therapy. 高分化大鼠脑类器官模型的建立探讨胶质母细胞瘤的侵袭动力学和治疗。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-24 DOI: 10.1093/neuonc/noaf271
Wenjing Zhou, Elena Martinez-Garcia, Katharina Sarnow, Georgia Kanli, Petr V Nazarov, Yaquan Li, Stephanie Schwab, Johannes Meiser, Christian Jaeger, Jakub Mieczkowski, Agnieszka Misztak, Frits A Thorsen, Konrad Grützmann, Boris Mihaljevic, Barbara van Loon, Jubayer A Hossain, Yan Zhang, Zhiyi Xue, Wenjie Li, Shannon S Moreino, Anna Golebiewska, Simone P Niclou, Magnar Bjørås, Saverio Tardito, Justin V Joesph, Taral R Lunavat, Halala S Saed, Marzieh Bahador, Mingzhi Han, Carina Fabian, Hrvoje Miletic, Xingang Li, Gunnar Dittmar, Olivier Keunen, Barbara Klink, Jian Wang, Rolf Bjerkvig

Background: Human brain organoids (BOs) are important models for studying early brain development and neurological disorders. While techniques for creating BOs are advancing, they remain developmental structures. Therefore, when human BOs are used to studying glioma-host interactions, the tumor behavior may be influenced by the BO-developmental microenvironment. Here, we describe the maturation of rat brain organoids (rBOs) into fully differentiated BOs and demonstrate their value as a model for studying glioblastoma (GB)-host interactions and their use in testing therapeutic interventions.

Materials and methods: rBOs were obtained from fetal cortical brains on the 18th day of gestation. Transcriptomic, proteomic, and metabolomic analyses determined their differentiation into maturity. Their developmental trajectory was compared to human BOs derived from induced pluripotent stem cells as well as to rat brain development. Tumor-rBO interactions, including invasion parameters and therapeutic interactions, were studied using five human GB models.

Results: The rBOs develop into organized structures with myelinated neurons, oligodendrocytes, synapses, and glial cells, mirroring the rat brain development. GB invasion in rBOs matched those observed in orthotopic xenografts, enabling real-time assessment of invasion metrics: cellular heterogeneity, single-cell invasion speed, and tumor progression. The BOs had a strong impact on GB transcriptional activity and can be used to study therapeutic interventions. The rBO differentiation status influenced GB invasion capacity.

Conclusions: The rBOs serve as an effective target brain structure for studying GB invasion parameters and for evaluating therapeutic interventions. Their rapid development into mature brain tissue makes rBOs a valuable brain avatar system for studying tumor-host interactions.

背景:人脑类器官(BOs)是研究早期大脑发育和神经系统疾病的重要模型。虽然创建bo的技术正在进步,但它们仍然是发展中的结构。因此,当将人bo用于研究胶质瘤与宿主的相互作用时,肿瘤行为可能会受到bo发育微环境的影响。在这里,我们描述了大鼠脑类器官(rBOs)成熟为完全分化的BOs,并证明了它们作为研究胶质母细胞瘤(GB)-宿主相互作用模型的价值,以及它们在测试治疗干预措施中的应用。材料和方法:在妊娠第18天从胎儿皮质脑中获得rbo。转录组学、蛋白质组学和代谢组学分析确定了它们向成熟期的分化。将它们的发育轨迹与诱导多能干细胞衍生的人类BOs以及大鼠脑发育进行了比较。采用五种人体GB模型研究肿瘤与rbo的相互作用,包括侵袭参数和治疗相互作用。结果:rBOs发育成有髓鞘神经元、少突胶质细胞、突触和胶质细胞的有组织结构,反映了大鼠大脑发育。rbo中的GB侵袭与原位异种移植物中观察到的相同,能够实时评估侵袭指标:细胞异质性、单细胞侵袭速度和肿瘤进展。BOs对GB转录活性有强烈影响,可用于研究治疗干预措施。rBO分化状态影响GB的入侵能力。结论:rbo是研究GB侵袭参数和评价治疗干预措施的有效靶脑结构。它们在成熟脑组织中的快速发育使rbo成为研究肿瘤-宿主相互作用的有价值的脑化身系统。
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引用次数: 0
A framework for using DNA methylation-based modelling for the clinical management of cranial meningioma. 颅脑膜瘤临床管理中使用DNA甲基化模型的框架。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-19 DOI: 10.1093/neuonc/noaf237
Alexander P Landry, Justin Z Wang, Vikas Patil, Andrew Ajisebutu, Chloe Gui, Leeor S Yefet, Yosef Ellenbogen, Jeff Liu, Yasin Mamatjan, Qingxia Wei, Olivia Singh, Sheila Mansouri, Felix Ehret, David Capper, Aaron A Cohen-Gadol, Ghazaleh Tabatabai, Marcos Tatagiba, Felix Behling, Jill S Barnholtz-Sloan, Andrew E Sloan, Lola B Chambless, Alireza Mansouri, Serge Makarenko, Stephen Yip, Derek S Tsang, Andrew Gao, Kenneth Aldape, Farshad Nassiri, Gelareh Zadeh

Background: DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed.

Methods: We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade.

Results: We first demonstrated that all risk groups benefit from gross total resection. All "high-risk, RT sensitive" tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (p = 0.003); after STR, from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (p = 0.004). "Low-risk, RT sensitive cases" (n = 1207, 61.8%) also benefitted from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, p = 0.03), suggesting that RT be considered in these patients. Neither "low-risk RT resistant" (n = 84, 4.3%) nor "high-risk RT resistant" (n = 356, 18.2%) cases benefitted from RT, and the latter group was associated with universally poor outcomes.

Conclusions: We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

背景:DNA甲基化分析可用于预测脑膜瘤患者的术后预后和放疗反应(RT)。为了将这些互补模型无缝整合到临床实践中,需要一个实用的框架。方法:我们利用近2000例手术治疗脑膜瘤的DNA甲基化分析和临床结果数据。现有的基于甲基化的预测模型被分为四个风险组:低复发风险和高复发风险,每个风险组都有RT敏感和耐药亚组。在现有生物标志物(包括切除程度和WHO分级)的背景下,风险组与无进展生存期相关。结果:我们首先证明了所有风险组都受益于全切除。所有“高风险,RT敏感”肿瘤(n = 306, 15.7%)也受益于辅助RT: GTR后,中位PFS从4.68(4.13-9.48)年增加到未达到(p = 0.003);STR后,从2.12(1.59-3.02)年到4.09(3.41-未达)年(p = 0.004)。“低风险、对放疗敏感的病例”(n = 1207, 61.8%)也受益于STR后的放疗(中位PFS为7.39(6.66-12.8)年vs. 16.53(10.35-未达到)年,p = 0.03),表明这些患者可以考虑接受放疗。“低风险RT抵抗”(n = 84, 4.3%)和“高风险RT抵抗”(n = 3556, 18.2%)病例均未从RT治疗中获益,后者与普遍较差的预后相关。结论:我们确定了甲基化定义的脑膜瘤风险群体,辅助放疗可以获得额外的益处,从而形成了一个临床决策框架,将分子模型直接整合到临床实践中。
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引用次数: 0
Opposing Functions of White Matter in Glioblastoma. 胶质母细胞瘤中白质的相反功能。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-14 DOI: 10.1093/neuonc/noaf266
Daniel J Silver, Gunnar H D Poplawski, Justin D Lathia
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引用次数: 0
"TREAT"ing Seizures as an Important Endpoint. “治疗”癫痫发作作为一个重要的终点。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-14 DOI: 10.1093/neuonc/noaf268
Mei-Yin Polley, David Schiff
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引用次数: 0
Amide proton transfer-weighted (APTw) CEST MRI in clinical routine for single time point diagnosis of pseudoprogression in IDH-wildtype glioblastoma. 酰胺质子转移加权(APTw) CEST MRI在单时间点诊断idh野生型胶质母细胞瘤假进展的临床常规。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-13 DOI: 10.1093/neuonc/noaf261
Thomas Zeyen, Inga Krause, Andreas Decker, Florian Kroh, Sebastian Regnery, Johannes Weller, Niklas Schaefer, Mousa Zidan, Anna-Laura Potthoff, Matthias Schneider, Lea L Friker, Jochen Keupp, Christoph Katemann, Julian P Layer, Christina Schaub, Eleni Gkika, Hartmut Vatter, Torsten Pietsch, Alexander Radbruch, Ulrich Herrlinger, Daniel Paech

Background: Differentiating progressive disease (PD) from treatment-related effects (TRE) in glioblastoma remains challenging, particularly at single time point evaluations. TRE can occur at any disease stage, and its underlying biology is poorly understood. This study evaluates the clinical feasibility and diagnostic performance of amide proton transfer-weighted (APTw) MRI in this challenge.

Methods: Following the integration of APTw MRI into the routine clinical workflow for brain tumor imaging, we screened a total of 870 scans from 626 patients. APTw signal (voxel-based measurement) was automatically quantified in gadolinium-enhanced T1w and FLAIR regions of interest using a deep learning-based approach for 3D tumor segmentations. PD and TRE were compared using unpaired t-tests, and diagnostic accuracy was assessed via ROC- and logistic regression analysis.

Results: Among 256 MRI scans of 143 patients with glioblastoma, 65 scans showed PD (n = 42) or TRE (n = 23). The median APTw signal was higher in PD (2.23%) vs TRE (1.76%; p = 0.001). ROC analysis showed an area under the curve (AUC) of 0.82. In patients with early PD or TRE (<6 months post-radiotherapy), the AUC increased to 0.93. Anti-angiogenic therapy decreased APTw signal (p < 0.01). Combining APTw MRI with DWI and PWI improved diagnostic accuracy (AUC = 0.90).

Conclusions: APTw MRI is a non-invasive imaging tool that is feasible for clinical routine and aids in differentiation of early progression from pseudoprogression in glioblastoma. Its diagnostic accuracy decreases with application of anti-angiogenic treatment and at later follow-up time points. Highest diagnostic accuracy was found in a multimodal approach combining APTw MRI, PWI and DWI.

背景:区分胶质母细胞瘤的进展性疾病(PD)和治疗相关效应(TRE)仍然具有挑战性,特别是在单时间点评估中。TRE可发生在任何疾病阶段,其潜在的生物学机制尚不清楚。本研究评估了酰胺质子转移加权(APTw) MRI在这一挑战中的临床可行性和诊断性能。方法:将APTw MRI纳入脑肿瘤成像的常规临床工作流程,共筛选626例患者的870张扫描图。使用基于深度学习的3D肿瘤分割方法,在钆增强的T1w和FLAIR感兴趣区域自动量化APTw信号(基于体素的测量)。PD和TRE采用非配对t检验进行比较,并通过ROC和logistic回归分析评估诊断准确性。结果:143例胶质母细胞瘤患者的256次MRI扫描中,65次扫描显示PD (n = 42)或TRE (n = 23)。PD患者APTw信号中位数(2.23%)高于TRE患者(1.76%,p = 0.001)。ROC分析显示曲线下面积(AUC)为0.82。结论:APTw MRI是一种无创成像工具,可用于临床常规,有助于区分胶质母细胞瘤的早期进展和假进展。其诊断准确性随着抗血管生成治疗的应用和后期随访时间点而降低。结合APTw MRI、PWI和DWI的多模态方法诊断准确率最高。
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引用次数: 0
Mounting evidence implicates medroxyprogesterone acetate in meningioma risk, but mechanisms require further investigation. 越来越多的证据表明醋酸甲孕酮与脑膜瘤风险有关,但机制有待进一步研究。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-12 DOI: 10.1093/neuonc/noaf267
Brooke C Braman, David R Raleigh
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引用次数: 0
Cysteine addiction in drug resistant glioblastoma and therapeutic targeting with designer selenium compounds. 半胱氨酸成瘾在耐药胶质母细胞瘤中的作用及设计硒化合物的靶向治疗。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-10 DOI: 10.1093/neuonc/noaf265
Deanna Tiek, Xiao Song, Runxin Wu, Xiaozhou Yu, Maya Walker, Yingyu Mao, Derek Sisbarro, Qiu He, Assa Magassa, Amandeep Singh, Junxuan Lu, Arun K Sharma, Jason Miska, Bo Hu, Marcelo G Bonini, Xiaoyu Zhang, Shi-Yuan Cheng

Background: Cysteine is a multifunctional amino acid that can be oxidized affecting disulfide bond formation, redox signaling, and protein function. Reactive oxygen species (ROS) and the metabolic environment dictate cysteine uptake and oxidation status - especially in redox sensitive pathways. As many chemotherapeutic agents increase ROS, including the standard for glioblastoma (GBM), temozolomide (TMZ), we hypothesized that TMZ-resistant (TMZ-R) GBM would have increased ROS affecting cysteine reactivity that could be therapeutically targeted.

Methods: Here, to study the metabolic state within drug sensitive and resistant GBM, we used metabolite tracing with 13C-Cyst(e)ine, specialized cysteine reactivity proteomics and CRISPR screening with drug treatments to determine the efficacy of targeting cysteine metabolic pathways with our designer selenium drug in both patient derived cell lines and patient derived xenograft GBM orthotopic models.

Results: We show that TMZ-R have increased cyst(e)ine uptake, cysteine reactivity, and sensitivity to selenium (Se)-containing compounds - which can bind cysteine - in vitro and in vivo. We show that in TMZ-R models selenium compound treatment increases the need for thioredoxin reductases where co-treatment of Se compounds and the thioredoxin inhibitor auranofin significantly improves overall survival in mouse models.

Conclusions: Overall, our findings show a unique metabolic environment in TMZ-R models where designer brain penetrant Se-containing compounds target cysteine reactivity within proteins necessary for cancer cell survival and hold therapeutic potential.

背景:半胱氨酸是一种多功能氨基酸,可以被氧化,影响二硫键的形成、氧化还原信号和蛋白质功能。活性氧(ROS)和代谢环境决定了半胱氨酸的摄取和氧化状态-特别是在氧化还原敏感途径中。由于许多化疗药物会增加ROS,包括治疗胶质母细胞瘤(GBM)的标准药物替莫唑胺(TMZ),我们假设TMZ耐药(TMZ- r) GBM会增加ROS,影响半胱氨酸反应性,从而成为治疗靶向。方法:为了研究药物敏感和耐药GBM内的代谢状态,我们使用13c -囊肿(e)线代谢物示踪,专门的半胱氨酸反应性蛋白质组学和药物治疗的CRISPR筛选来确定我们的设计药物硒靶向半胱氨酸代谢途径在患者来源的细胞系和患者来源的异种移植GBM原位模型中的疗效。结果:我们发现TMZ-R在体外和体内均增加了囊氨酸的摄取、半胱氨酸的反应性以及对含硒化合物(可以结合半胱氨酸)的敏感性。我们发现,在TMZ-R模型中,硒化合物处理增加了对硫氧还蛋白还原酶的需求,其中硒化合物和硫氧还蛋白抑制剂金糠蛋白的共同处理显著提高了小鼠模型的总体存活率。结论:总的来说,我们的研究结果显示了TMZ-R模型中独特的代谢环境,其中设计的脑渗透含硒化合物靶向癌细胞生存所需蛋白质中的半胱氨酸反应性,并具有治疗潜力。
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引用次数: 0
Bayesian Adaptive Randomized Trial of Blended Cognitive Behavioral Therapy for Severe Fatigue in Stable Diffuse Glioma. 混合认知行为疗法治疗稳定弥漫性胶质瘤严重疲劳的贝叶斯自适应随机试验。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-09 DOI: 10.1093/neuonc/noaf256
Maxine Gorter, Jantine G Röttgering, Vera Belgers, Marieke E C Blom, Brigit Thomassen, Philip C De Witt Hamer, Johanna M Niers, Mathilde C M Kouwenhoven, Henri P Bienfait, Celine S Gathier, Annette Compter, Marjolein Geurts, Tom J Snijders, Peter M Van De Ven, Linda Douw, Hans Knoop, Martin Klein

Background: While severe fatigue is common in patients with diffuse glioma, no evidence-based treatment is currently available. The objective of this RCT was to evaluate efficacy of blended cognitive behavioral therapy (bCBT) for severe fatigue.

Methods: Severely fatigued patients (Checklist Individual Strength, fatigue-severity subscale [CIS-fatigue] ≥ 35) with diffuse glioma and stable disease were randomized to 12 weeks of bCBT or a waiting list condition (WLC). The primary endpoint was fatigue severity 2 weeks after intervention. This Bayesian adaptive trial included prespecified interim analyses for efficacy at n = 40, 50, 60, 70, and 80. Secondary outcomes-health-related quality of life (HRQoL), anxiety, future uncertainty and depression-were assessed at 2 and 12 weeks after intervention.

Results: The trial was stopped for efficacy at the first interim analysis. Of 47 patients randomized, 40 patients reached primary endpoint (mean age 53 years, 47% female). The posterior probability that CIS-fatigue scores were lower with bCBT than with WLC was 99.94%, with a large standardized effect size (Cohen's d) of 1.12 [95% CI: 0.43-1.81]. At 2 weeks after intervention, 68% of patients were no longer severely fatigued after bCBT, compared to 24% in WLC. At 12 weeks follow-up, fatigue was still significantly lower in the bCBT group compared to WLC (d = 1.22). bCBT also demonstrated beneficial effects (d = 0.42-1.19) on anxiety, HRQoL, and future uncertainty.

Conclusions: bCBT significantly reduces fatigue and improves anxiety and HRQoL in patients with diffuse glioma. These findings enable evidence-based supportive care strategies for reducing fatigue and enhancing HRQoL in this population.

背景:虽然严重疲劳在弥漫性胶质瘤患者中很常见,但目前尚无循证治疗方法。本随机对照试验的目的是评估混合认知行为疗法(bbct)治疗严重疲劳的疗效。方法:弥漫性胶质瘤且病情稳定的严重疲劳患者(检查表个人力量,疲劳-严重程度亚量表[cis -疲劳]≥ 35)随机分为12周bbct组或等待名单组(WLC)。主要终点是干预后2周的疲劳严重程度。该贝叶斯适应性试验包括预先指定的中期疗效分析,在n = 40、50、60、70和80时。次要结局-健康相关生活质量(HRQoL)、焦虑、未来不确定性和抑郁-在干预后2周和12周进行评估。结果:在第一次中期分析时因疗效而终止试验。在47例随机患者中,40例患者达到主要终点(平均年龄53岁,47%为女性)。bbct组cis -疲劳评分低于WLC组的后验概率为99.94%,标准化效应量(Cohen’s d)较大,为1.12 [95% CI: 0.43-1.81]。干预后2周,68%的患者在bbcbt后不再严重疲劳,而WLC的这一比例为24%。在12周的随访中,与WLC相比,bbct组的疲劳程度仍显着降低(d = 1.22)。bCBT对焦虑、HRQoL和未来不确定性也有有益的影响(d = 0.42-1.19)。结论:bbct可显著减轻弥漫性胶质瘤患者的疲劳,改善焦虑和HRQoL。这些发现使循证支持性护理策略能够在该人群中减少疲劳并提高HRQoL。
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引用次数: 0
Reliable cognitive changes the first year following guideline-based treatment of IDH mutated gliomas: a longitudinal multicenter study. 基于指南的IDH突变胶质瘤治疗后第一年的可靠认知变化:一项纵向多中心研究
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-09 DOI: 10.1093/neuonc/noaf263
Isabelle Rydén, Francesco Latini, Åsa Alberius Munkhammar, Per Hellström, Alice Neimantaite, Andrew Lycett, Dima Harba, Louise Carstam, Malin Blomstrand, Maria Zetterling, Anja Smits, Asgeir S Jakola

Background: Management of isocitrate dehydrogenase (IDH) mutated gliomas is multidisciplinary and current guidelines support early multimodal treatment. The effects of this treatment approach on cognition are less studied. We aimed to study changes in cognitive functioning the first year following treatment in these patients and explore predictors of cognitive deterioration.

Methods: Patients with a first-time diagnosis of IDH mutated glioma were neuropsychologically assessed before and one year after surgery. Results were compared to published norms, and impairment defined as z <-1.645. Matched controls were assessed at corresponding times, and reliable change indices (RCIs) were calculated to account for practice effects. Logistic regression models investigated predictors for cognitive declines. Tumor locations for declined versus non-declined patients were visualized using heatmaps.

Results: Of the 127 included patients, 104 underwent multi-modal treatment. Pre-operative impairments ranged from 3% to 24 %, depending on the specific test. Cognitive declines according to RCI domains were largest in tests of executive functioning (24%), learning/memory (23%) and language (21%). Tests of inhibition/flexibility (32%), naming speed (29%), verbal memory (28%), object naming (28%) and verbal fluency (22%) showed the largest proportions of declines. Regression models revealed that older age and chemoradiotherapy predicted declines in specific domains as well as in individual tests (P<0.05).

Conclusions: Significant changes occurred in several cognitive domains after guideline-based treatment. Older age and chemoradiotherapy increased the risk of cognitive declines one year after surgery, but to which extent the deficits are persistent or progressing remains unknown.

背景:异柠檬酸脱氢酶(IDH)突变胶质瘤的管理是多学科的,目前的指南支持早期多模式治疗。这种治疗方法对认知的影响研究较少。我们的目的是研究这些患者治疗后第一年认知功能的变化,并探索认知功能恶化的预测因素。方法:首次诊断为IDH突变胶质瘤的患者术前和术后1年进行神经心理评估。结果与已发表的规范进行比较,损伤定义为z。结果:在纳入的127例患者中,104例接受了多模式治疗。术前损伤从3%到24%不等,取决于具体的测试。在执行功能(24%)、学习/记忆(23%)和语言(21%)测试中,RCI域的认知能力下降幅度最大。抑制/灵活性(32%)、命名速度(29%)、言语记忆(28%)、物体命名(28%)和言语流畅性(22%)的测试显示出最大比例的下降。回归模型显示,年龄越大和放化疗可以预测特定领域以及个体测试的下降(结论:在基于指南的治疗后,几个认知领域发生了显著变化。年龄较大和放化疗增加了术后一年认知能力下降的风险,但这种缺陷在多大程度上是持续的或进展的尚不清楚。
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引用次数: 0
Seeing the Whole Picture: AI Aids Integrative Diagnosis of Gliomas from Histopathology. 全局观:人工智能辅助胶质瘤的组织病理学综合诊断。
IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-11-09 DOI: 10.1093/neuonc/noaf262
Xiufang Ren, Wen Cheng, Anhua Wu
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引用次数: 0
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Neuro-oncology
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