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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 Q1 CLINICAL NEUROLOGY 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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

背景:缺乏原发性中枢神经系统淋巴瘤(PCNSL)的当代预后和复发模式。我们分析了大量随访患者中与复发相关的因素:方法:我们对1983-2020年间免疫功能正常的PCNSL(弥漫大B细胞)患者的T1后对比增强疾病进行了特征性分析。根据患者对诱导和巩固治疗的反应进行分层(完全/未确诊 [CR/CRu]、部分、稳定、进展 [POD])。难治是指在诱导期间(或复发后≤3个月)出现POD。初始复发部位分为局部(累及/邻近基线)、远处实质内、脑膜外、其他。无进展生存期(PFS)和总生存期(OS)采用比例危险法进行评估。采用竞争风险累积发生率评估局部复发情况:中位随访时间为 7.4 年(N=559)。大多数患者(321例,57%)为复发分区分析2级(年龄≥50岁,KPS≥70)。大多数患者为上脑膜(420例,81%)、多灶(274例,53%)、双侧(224例,43%)和深部结构受累(314例,56%)。几乎所有患者都接受了以甲氨蝶呤为基础的诱导治疗(532例,95%)。根据诱导的初始反应(CR/CRu 与 PR),最终达到 CR/CRu 的患者在巩固治疗后的 PFS 或 OS 方面没有差异。351名获得CR/CRu并进行巩固治疗的患者1年和5年的PFS分别为80%(95%CI:76-84%)和46%(95%CI:41-53%);局部复发与非局部复发的1年累积发生率分别为1.8%和15%。在 97 例难治性患者中,局部复发与非局部复发的 1 年累计发生率分别为 57% 与 42%。深部结构受累(HR 1.89,95%CI:1.10-3.27)与难治性患者的局部复发有关:我们首次在一个大型 PCNSL 队列中报告了全面的复发模式。结论:我们首次在大型 PCNSL 队列中报告了全面的复发模式。虽然 CR 至巩固治疗后的复发通常是远处复发且不可预测,但难治性患者的局部复发率相对较高。这些发现有助于优化这一高风险人群的多模式疗法。
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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 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae134
Madhura Ketkar, Sanket Desai, Pranav Rana, Rahul Thorat, Sridhar Epari, Amit Dutt, Shilpee Dutt

Background: 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.

Methods: 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.

Results: 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.

Conclusion: We demonstrate that PERK-mediated UPR regulates senescence reversal and its inhibition can be exploited as a potential seno-therapeutic option in glioblastoma.

背景:胶质母细胞瘤因复发导致的总生存期仅为 10-15 个月,在临床上具有挑战性。此前,我们发现胶质母细胞瘤的治疗诱导衰老(TIS)可逆转导致复发。在此,我们旨在阐明TIS逆转机制,为预防GBM复发提供潜在的治疗干预:残余衰老(RS)细胞和残余衰老末期(ERS)细胞来自 GBM 患者来源的原代培养物和模拟临床情况的细胞系。进行了 RNA 测序、转录本/蛋白质验证、基因敲除/抑制剂研究、ChIP RT-PCR、生化检测和 IHC,以了解 TIS 逆转的机理。在 GBM 正位小鼠模型中进行了体内验证:转录组分析显示,ER应激-UPR和衰老相关分泌表型(SASP)与TIS诱导和逆转共同表达。RS细胞产生和分泌的大量SASP能以旁分泌方式诱导衰老、ROS、DNA损伤和ER应激,与辐射无关。中和RS分泌组中最重要的细胞因子IL1β可抑制SASP并延缓衰老逆转。从机理上讲,随着 SASP 和内质网中大量蛋白质的积累,RS 细胞显示出受压的 ER 形态、上调的 ER 应激标志物和通过 peIF2α-ATF4-CHOP 激活的 PERK 通路,而这在 ERS 中会自发地得到解决。ChIP RT-PCR 显示,CHOP 在 CXCL8/IL8、CDKN1A/p21 和 BCL2L1/BCLXL 上的占位有助于存活。用GSK2606414敲除/抑制PERK,并与辐射结合使用,可导致持续的ER应激和衰老,但无SASP。PERKi在RS中通过细胞凋亡起到了溶解衰老的作用,并在体外和体内防止了复发,改善了总生存率:我们证明了 PERK 介导的 UPR 调节衰老逆转,其抑制作用可被用作胶质母细胞瘤的潜在衰老治疗方案。
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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 Q1 CLINICAL NEUROLOGY 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

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.

脑肿瘤患者的病程和临床结果不仅取决于肿瘤的分子和组织学特征,还取决于患者的人口统计学特征和健康的社会决定因素。虽然目前神经肿瘤学的研究已广泛利用人工智能(AI)来丰富肿瘤诊断,并更准确地预测治疗反应、术后并发症和生存期,但以公平为导向的人工智能应用还很有限。然而,在更广泛的医疗领域,促进健康公平的人工智能应用有可能成为解决神经肿瘤治疗中已知差距的实用蓝图。在这篇共识综述中,我们将介绍目前人工智能在神经肿瘤学中的应用,根据更广泛的文献,针对神经肿瘤学中最紧迫的不公平问题提出可行的人工智能解决方案,提出将公平有效融入基于人工智能的神经肿瘤学研究的框架,最后指出人工智能的局限性。
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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 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae168
Christopher Alvarez-Breckenridge, Priscilla K Brastianos, Daniel P Cahill
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引用次数: 0
Raman-based machine-learning platform reveals unique metabolic differences between IDHmut and IDHwt glioma. 基于拉曼的机器学习平台揭示了 IDHmut 和 IDHwt 胶质瘤之间独特的代谢差异。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae101
Adrian Lita, Joel Sjöberg, David Păcioianu, Nicoleta Siminea, Orieta Celiku, Tyrone Dowdy, Andrei Păun, Mark R Gilbert, Houtan Noushmehr, Ion Petre, Mioara Larion

Background: Formalin-fixed, paraffin-embedded (FFPE) tissue slides are routinely used in cancer diagnosis, clinical decision-making, and stored in biobanks, but their utilization in Raman spectroscopy-based studies has been limited due to the background coming from embedding media.

Methods: Spontaneous Raman spectroscopy was used for molecular fingerprinting of FFPE tissue from 46 patient samples with known methylation subtypes. Spectra were used to construct tumor/non-tumor, IDH1WT/IDH1mut, and methylation-subtype classifiers. Support vector machine and random forest were used to identify the most discriminatory Raman frequencies. Stimulated Raman spectroscopy was used to validate the frequencies identified. Mass spectrometry of glioma cell lines and TCGA were used to validate the biological findings.

Results: Here, we develop APOLLO (rAman-based PathOLogy of maLignant gliOma)-a computational workflow that predicts different subtypes of glioma from spontaneous Raman spectra of FFPE tissue slides. Our novel APOLLO platform distinguishes tumors from nontumor tissue and identifies novel Raman peaks corresponding to DNA and proteins that are more intense in the tumor. APOLLO differentiates isocitrate dehydrogenase 1 mutant (IDH1mut) from wild-type (IDH1WT) tumors and identifies cholesterol ester levels to be highly abundant in IDHmut glioma. Moreover, APOLLO achieves high discriminative power between finer, clinically relevant glioma methylation subtypes, distinguishing between the CpG island hypermethylated phenotype (G-CIMP)-high and G-CIMP-low molecular phenotypes within the IDH1mut types.

Conclusions: Our results demonstrate the potential of label-free Raman spectroscopy to classify glioma subtypes from FFPE slides and to extract meaningful biological information thus opening the door for future applications on these archived tissues in other cancers.

背景:福尔马林固定、石蜡包埋(FFPE)组织切片通常用于癌症诊断和临床决策,并储存在生物库中,但由于包埋介质产生的背景,它们在基于拉曼光谱的研究中的应用受到了限制:方法:利用自发拉曼光谱对来自 46 个已知甲基化亚型患者样本的 FFPE 组织进行分子指纹分析。利用光谱构建肿瘤/非肿瘤、IDH1WT/IDH1mut 和甲基化亚型分类器。支持向量机和随机森林用于识别最具鉴别力的拉曼频率。受激拉曼光谱用于验证所识别的频率。胶质瘤细胞系的质谱分析和 TCGA 被用来验证生物学发现:在此,我们开发了基于拉曼光谱的恶性胶质瘤病理学(APOLLO)--一种计算工作流程,它能根据 FFPE 组织切片的自发拉曼光谱预测胶质瘤的不同亚型。我们新颖的 APOLLO 平台可区分肿瘤和非肿瘤组织,并识别出肿瘤中强度更高的 DNA 和蛋白质对应的新拉曼峰。APOLLO 能区分异柠檬酸脱氢酶 1 突变体(IDH1mut)和野生型(IDH1WT)肿瘤,并能识别 IDHmut 胶质瘤中高度丰富的胆固醇酯水平。此外,APOLLO在更精细的临床相关胶质瘤甲基化亚型之间具有很高的鉴别力,能区分IDH1mut类型中的CpG岛高甲基化表型(G-CIMP)和G-CIMP低分子表型:我们的研究结果表明,无标记拉曼光谱具有从 FFPE 切片中对胶质瘤亚型进行分类和提取有意义的生物信息的潜力,从而为今后在其他癌症的这些存档组织中的应用打开了大门。
{"title":"Raman-based machine-learning platform reveals unique metabolic differences between IDHmut and IDHwt glioma.","authors":"Adrian Lita, Joel Sjöberg, David Păcioianu, Nicoleta Siminea, Orieta Celiku, Tyrone Dowdy, Andrei Păun, Mark R Gilbert, Houtan Noushmehr, Ion Petre, Mioara Larion","doi":"10.1093/neuonc/noae101","DOIUrl":"10.1093/neuonc/noae101","url":null,"abstract":"<p><strong>Background: </strong>Formalin-fixed, paraffin-embedded (FFPE) tissue slides are routinely used in cancer diagnosis, clinical decision-making, and stored in biobanks, but their utilization in Raman spectroscopy-based studies has been limited due to the background coming from embedding media.</p><p><strong>Methods: </strong>Spontaneous Raman spectroscopy was used for molecular fingerprinting of FFPE tissue from 46 patient samples with known methylation subtypes. Spectra were used to construct tumor/non-tumor, IDH1WT/IDH1mut, and methylation-subtype classifiers. Support vector machine and random forest were used to identify the most discriminatory Raman frequencies. Stimulated Raman spectroscopy was used to validate the frequencies identified. Mass spectrometry of glioma cell lines and TCGA were used to validate the biological findings.</p><p><strong>Results: </strong>Here, we develop APOLLO (rAman-based PathOLogy of maLignant gliOma)-a computational workflow that predicts different subtypes of glioma from spontaneous Raman spectra of FFPE tissue slides. Our novel APOLLO platform distinguishes tumors from nontumor tissue and identifies novel Raman peaks corresponding to DNA and proteins that are more intense in the tumor. APOLLO differentiates isocitrate dehydrogenase 1 mutant (IDH1mut) from wild-type (IDH1WT) tumors and identifies cholesterol ester levels to be highly abundant in IDHmut glioma. Moreover, APOLLO achieves high discriminative power between finer, clinically relevant glioma methylation subtypes, distinguishing between the CpG island hypermethylated phenotype (G-CIMP)-high and G-CIMP-low molecular phenotypes within the IDH1mut types.</p><p><strong>Conclusions: </strong>Our results demonstrate the potential of label-free Raman spectroscopy to classify glioma subtypes from FFPE slides and to extract meaningful biological information thus opening the door for future applications on these archived tissues in other cancers.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1994-2009"},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200397","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
In vivo mouse models for adult brain tumors: Exploring tumorigenesis and advancing immunotherapy development. 成人脑肿瘤体内小鼠模型:探索肿瘤发生和推进免疫疗法开发。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae131
John Figg, Dongjiang Chen, Laura Falceto Font, Catherine Flores, Dan Jin

Brain tumors, particularly glioblastoma (GBM), are devastating and challenging to treat, with a low 5-year survival rate of only 6.6%. Mouse models are established to understand tumorigenesis and develop new therapeutic strategies. Large-scale genomic studies have facilitated the identification of genetic alterations driving human brain tumor development and progression. Genetically engineered mouse models (GEMMs) with clinically relevant genetic alterations are widely used to investigate tumor origin. Additionally, syngeneic implantation models, utilizing cell lines derived from GEMMs or other sources, are popular for their consistent and relatively short latency period, addressing various brain cancer research questions. In recent years, the success of immunotherapy in specific cancer types has led to a surge in cancer immunology-related research which specifically necessitates the utilization of immunocompetent mouse models. In this review, we provide a comprehensive summary of GEMMs and syngeneic mouse models for adult brain tumors, emphasizing key features such as model origin, genetic alteration background, oncogenic mechanisms, and immune-related characteristics. Our review serves as a valuable resource for the brain tumor research community, aiding in the selection of appropriate models to study cancer immunology.

脑肿瘤,尤其是胶质母细胞瘤(GBM),具有破坏性,治疗难度大,5 年生存率仅为 6.6%。建立小鼠模型是为了了解肿瘤发生过程并开发新的治疗策略。大规模基因组研究有助于确定驱动人类脑肿瘤发生和发展的基因改变。具有临床相关基因改变的基因工程小鼠模型(GEMMs)被广泛用于研究肿瘤起源。此外,利用源自基因工程小鼠或其他来源的细胞系进行的同种异体植入模型因其一致性和相对较短的潜伏期而广受欢迎,可解决各种脑癌研究问题。近年来,免疫疗法在特定癌症类型中取得了成功,导致癌症免疫学相关研究激增,这就特别需要利用免疫功能健全的小鼠模型。在这篇综述中,我们全面总结了成人脑肿瘤的 GEMMs 和合成小鼠模型,强调了模型来源、基因改变背景、致癌机制和免疫相关特征等关键特征。我们的综述是脑肿瘤研究界的宝贵资源,有助于选择合适的模型来研究癌症免疫学。
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引用次数: 0
Letter to the editor in response to Tang et al. 致编辑的信,回应 Tang 等人的文章
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae155
Austin L Brown, Mohammad H Abu-Arja, Murali M Chintagumpala, Arnold C Paulino
{"title":"Letter to the editor in response to Tang et al.","authors":"Austin L Brown, Mohammad H Abu-Arja, Murali M Chintagumpala, Arnold C Paulino","doi":"10.1093/neuonc/noae155","DOIUrl":"10.1093/neuonc/noae155","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2154"},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375767","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
Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas. Fc增强型抗CTLA-4、抗PD-1、多柔比星和超声介导的BBB开放:治疗胶质瘤的新型组合免疫疗法。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae135
Kwang-Soo Kim, Karl Habashy, Andrew Gould, Junfei Zhao, Hinda Najem, Christina Amidei, Ruth Saganty, Víctor A Arrieta, Crismita Dmello, Li Chen, Daniel Y Zhang, Brandyn Castro, Leah Billingham, Daniel Levey, Olivia Huber, Marilyn Marques, David A Savitsky, Benjamin M Morin, Miguel Muzzio, Michael Canney, Craig Horbinski, Peng Zhang, Jason Miska, Surya Padney, Bin Zhang, Raul Rabadan, Joanna J Phillips, Nicholas Butowski, Amy B Heimberger, Jian Hu, Roger Stupp, Dhan Chand, Catalina Lee-Chang, Adam M Sonabend

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers.

Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs).

Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge.

Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

背景:胶质母细胞瘤是一种侵袭性极强的脑癌,对传统的免疫疗法策略具有抗药性。Botensilimab是一种Fc增强型抗CTLA-4抗体(FcE-aCTLA-4),在 "冷 "和免疫治疗难治性癌症中显示出持久的活性:方法:我们评估了FcE-aCTLA-4小鼠类似物在治疗难治性胶质母细胞瘤临床前模型中的疗效和免疫微环境表型,既包括单药治疗,也包括与通过低强度脉冲超声和微气泡(LIPU/MB)递送的多柔比星联合治疗。此外,我们还研究了同时接受多柔比星、抗 PD-1 和 LIPU/MB 治疗的 4 例胶质母细胞瘤患者,以探讨多柔比星调节肿瘤相关巨噬细胞/小胶质细胞(TAMs)中 FcγR 表达的新作用:结果:FcE-aCTLA-4与FcγRIV(人类FcγRIIIA的小鼠直向同源物)具有高亲和性结合,FcγRIV在人类胶质母细胞瘤的TAMs中高度表达,在诊断时表达最为活跃。值得注意的是,FcE-aCTLA-4通过TAM介导的吞噬作用,有选择性地消耗瘤内调节性T细胞(Tregs),同时保留外周Tregs。多柔比星是一种具有免疫调节功能的化疗药物,研究发现,在同时接受多柔比星和抗 PD-1 以及 LIPU/MB 的胶质母细胞瘤患者中,多柔比星会上调 TAM 上的 FcγRIIIA 。在免疫治疗耐药的神经胶质瘤小鼠模型中,FcE-aCTLA-4、抗PD-1和多柔比星与LIPU/MB的组合方案达到了90%的治愈率,这与活化的CD8+ T细胞的强健浸润和免疫记忆的建立有关,肿瘤再挑战时的排斥反应证明了这一点:我们的研究结果表明,FcE-aCTLA-4对小鼠胶质瘤具有强大的免疫调节和抗肿瘤作用,当与抗PD-1、多柔比星和LIPU/MB联合使用时,免疫调节和抗肿瘤作用显著增强。我们目前正在一项临床试验(clinicaltrials.gov NCT05864534)中研究这种联合策略。
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引用次数: 0
Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study). 针对 BRAFV600 突变黑色素瘤和脑转移患者的恩科拉非尼和宾美替尼放疗(E-BRAIN/GEM1802 II 期研究)。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae116
Iván Márquez-Rodas, Ana Álvarez, Ana Arance, Izaskun Valduvieco, Miguel-Ángel Berciano-Guerrero, Raquel Delgado, Ainara Soria, Fernándo Lopez Campos, Pedro Sánchez, Jose Luis Romero, Juan Martin-Liberal, Anna Lucas, Roberto Díaz-Beveridge, Antonio-José Conde-Moreno, Maria Del Carmen Álamo de la Gala, Almudena García-Castaño, Pedro José Prada, María González Cao, Enrique Puertas, Joana Vidal, Palmira Foro, Carlos Aguado de la Rosa, Juan Antonio Corona, Pablo Cerezuela-Fuentes, Paco López, Pablo Luna, Neus Aymar, Teresa Puértolas, Pilar Sanagustín, Alfonso Berrocal

Background: Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response.

Methods: E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.

Results: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).

Conclusions: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

背景安戈非尼加比尼替尼(EB)是晚期BRAFV600突变黑色素瘤的标准治疗方法。我们评估了安戈非尼加比尼替尼治疗BRAFV600突变黑色素瘤合并脑转移(BM)患者的疗效和安全性,并探讨了放疗是否能改善反应持续时间:E-BRAIN/GEM1802是一项前瞻性、多中心、单臂II期试验,招募了BRAFV600突变黑色素瘤和脑转移瘤患者。患者接受安戈非尼450毫克,每日一次,外加替米替尼45毫克,每日一次,首次肿瘤评估时获得部分应答或病情稳定的患者可接受放疗。治疗持续至病情进展。主要终点为EB治疗2个月后的颅内反应率(icRR),无效阈值为60%:研究纳入了 25 例无 BM 症状的患者和 23 例有 BM 症状且未使用皮质类固醇激素的患者。其中,31 名患者(64.6%)接受了序贯放疗。两个月后,icRR 为 70.8%(95% CI:55.9-83.1);完全缓解率为 10.4%。中位颅内PFS和OS分别为8.5个月(95% CI:6.4-11.8)和15.9个月(95% CI:10.7-21.4)(接受RDT的患者icPFS为8.3个月,OS为13.9个月)。最常见的3-4级治疗相关不良事件是丙氨酸氨基转移酶(ALT)升高(10.4%):在BRAFV600突变黑色素瘤和BM患者(包括有症状和需要使用类固醇的患者)中,安克瑞非尼加比尼美替尼在icRR方面显示出良好的临床获益,而且安全性良好,高级别TRAE发生率较低。序贯放疗是可行的,但似乎不能延长反应时间。
{"title":"Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).","authors":"Iván Márquez-Rodas, Ana Álvarez, Ana Arance, Izaskun Valduvieco, Miguel-Ángel Berciano-Guerrero, Raquel Delgado, Ainara Soria, Fernándo Lopez Campos, Pedro Sánchez, Jose Luis Romero, Juan Martin-Liberal, Anna Lucas, Roberto Díaz-Beveridge, Antonio-José Conde-Moreno, Maria Del Carmen Álamo de la Gala, Almudena García-Castaño, Pedro José Prada, María González Cao, Enrique Puertas, Joana Vidal, Palmira Foro, Carlos Aguado de la Rosa, Juan Antonio Corona, Pablo Cerezuela-Fuentes, Paco López, Pablo Luna, Neus Aymar, Teresa Puértolas, Pilar Sanagustín, Alfonso Berrocal","doi":"10.1093/neuonc/noae116","DOIUrl":"10.1093/neuonc/noae116","url":null,"abstract":"<p><strong>Background: </strong>Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response.</p><p><strong>Methods: </strong>E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.</p><p><strong>Results: </strong>The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).</p><p><strong>Conclusions: </strong>Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2074-2083"},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469770","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
Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis. 通过抑制 Gαq/PLC/PKCγ/STAT3 轴,靶向 HTR2B 可抑制非功能性垂体腺瘤的生长,并使卡麦角林治疗敏感化。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1093/neuonc/noae130
Shaojian Lin, Liangbo Wang, Changxi Han, Yuting Dai, Changsheng Li, Yanting Liu, Bo Zhang, Ning Huang, Anke Zhang, Tao Zhang, Yu Wang, Jing Xie, Hao Tang, Yijun Cheng, Hong Yao, Meiqing Lou, Li Xue, Zhe Bao Wu

Background: Managing nonfunctioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential.

Methods: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays.

Results: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.

Conclusions: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

背景:由于药物治疗手段有限,治疗非功能性垂体腺瘤(NFPA)十分困难。卡麦角林(CAB)对无功能垂体腺瘤的疗效还存在争议。本研究探讨了 HTR2B 在 NFPA 中的作用及其治疗潜力:我们对大量 RNA 序列数据进行了筛选,以分析 HTR2B 在 NFPA 样本中的表达水平。我们进行了体外和体内实验,以评估调节 HTR2B 对肿瘤生长和细胞周期调控的影响。利用药理抑制剂和分子相互作用实验阐明了HTR2B介导的信号通路机制:结果:在 NFPA 样本中检测到 HTR2B 表达升高,这与肿瘤存活率增加有关。抑制 HTR2B 的活性可通过调节 G2M 细胞周期抑制肿瘤生长。研究发现,用 PRX-08066 抑制 HTR2B 可通过干扰 Gαq/PLC/PKC 通路阻断 STAT3 磷酸化和核转位。PKC-γ 和 STAT3 之间的直接相互作用对 STAT3 的活化至关重要。研究表明,CAB 会通过 HTR2B 激活 pSTAT3,从而降低其治疗潜力。然而,在表达 HTR2B 的垂体瘤细胞系、异种移植垂体瘤模型和患者来源样本中,HTR2B 拮抗剂与 CAB 的组合能显著抑制肿瘤细胞的增殖。对患者来源数据的分析表明,以HTR2B/PKC-γ上调和BTG2/GADD45A下调为特征的独特分子模式可能会从CAB和PRX-08066的联合治疗中获益:HTR2B是NFPA的潜在治疗靶点,抑制HTR2B可提高CAB的疗效。结论:HTR2B是NFPA的潜在治疗靶点,抑制HTR2B可提高CAB的疗效,双重治疗方法可能对HTR2B高表达的NFPA患者有益。
{"title":"Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis.","authors":"Shaojian Lin, Liangbo Wang, Changxi Han, Yuting Dai, Changsheng Li, Yanting Liu, Bo Zhang, Ning Huang, Anke Zhang, Tao Zhang, Yu Wang, Jing Xie, Hao Tang, Yijun Cheng, Hong Yao, Meiqing Lou, Li Xue, Zhe Bao Wu","doi":"10.1093/neuonc/noae130","DOIUrl":"10.1093/neuonc/noae130","url":null,"abstract":"<p><strong>Background: </strong>Managing nonfunctioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential.</p><p><strong>Methods: </strong>We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays.</p><p><strong>Results: </strong>Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.</p><p><strong>Conclusions: </strong>HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2010-2026"},"PeriodicalIF":16.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580447","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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Neuro-oncology
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