Neuro-oncology最新文献

{"title":"Diffusion and contrast-enhancement MRI phenotypes associated with immune checkpoint inhibitor exposure and with immune cell infiltration in brain metastases.","authors":"Francesco Sanvito, Gianluca Nocera, Zexi Wang, Eileen Shiuan, Lu Sun, Sonoko Oshima, Asher Kim, Irina Kryukov, Guowen Shao, Nicholas S Cho, Noriko Salamon, Benjamin M Ellingson, Robert Prins, Won Kim, Jingwen Yao","doi":"10.1093/neuonc/noaf084","DOIUrl":"10.1093/neuonc/noaf084","url":null,"abstract":"<p><strong>Background: </strong>MRI-derived apparent diffusion coefficient (ADC) and contrast-enhancement (CE) may represent noninvasive biomarkers to evaluate microstructural tissue changes and histopathological immune cell infiltration induced by immune checkpoint inhibitors (ICI).</p><p><strong>Methods: </strong>One hundred and twenty-five lesions across 93 patients were analyzed. ADC (reflecting water diffusivity) and CE T1-subtraction maps (reflecting blood-brain barrier permeability) tumor values were used for bivariate histograms of ADC and CE, and to quantify voxel fractions belonging to highADC-highCE and lowADC-lowCE quadrants. The association between ICI exposure and voxel frequency in ADC-CE quadrants was evaluated with multivariate mixed-effects models accounting for corticosteroid exposure and other variables. In a subset of patients (n = 23), the association between immune cell counts (CD45 + cell density) from tissue samples and ADC-CE phenotypes was tested.</p><p><strong>Results: </strong>ICI and corticosteroid exposure were associated with distinct ADC-CE phenotypes on bivariate histograms. ICI-exposed lesions showed significantly higher voxel frequency in the highADC-highCE quadrant (P < .001) and lower voxel frequency in the lowADC-lowCE quadrant (P < .01), compared to ICI-naïve lesions. Multivariate analyses confirmed that ICI exposure was an independent determinant of higher voxel frequency in the highADC-highCE quadrant (P = .001) and lower voxel frequency in the lowADC-lowCE quadrant (P = .01) in the absence of corticosteroid treatment. Corticosteroid usage significantly influenced the relationship between ADC-CE phenotypes and ICI exposure. Voxel frequency in ADC-CE quadrants was correlated with CD45 + cell density in histopathology (partial ρ = 0.56 P = .01 for highADC-highCE, partial ρ = -0.64 P < .01 for lowADC-lowCE).</p><p><strong>Conclusions: </strong>ADC-CE phenotypes are associated with ICI exposure and immune cell infiltration in BM, representing potential noninvasive markers to monitor ICI-induced pathophysiological changes.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2194-2205"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677092","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}

{"title":"Transcriptomics-Guided High-Throughput Drug Screening Identifies Potent Therapies for P53 Pathway Alterated DIPG/DMG.","authors":"Zhuang Jiang, Luyang Xie, Hang Zhou, Yibo Geng, Xiong Xiao, Tian Li, Yuxuan Deng, Mingxin Zhang, Shaobo Shan, Cheng Xu, Liwei Zhang","doi":"10.1093/neuonc/noaf216","DOIUrl":"https://doi.org/10.1093/neuonc/noaf216","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline gliomas (DMGs), particularly diffuse intrinsic pontine gliomas (DIPGs), are aggressive pediatric brain tumors with a median survival of less than 12 months. Notably, approximately 70% of these tumors harbor P53 pathway alterations, including TP53 or PPM1D mutations. Identifying precision therapies for this subset is crucial. This study aims to employ transcriptomics-guided high-throughput drug screening to identify effective treatments for DIPG/DMG with P53 pathway alterations.</p><p><strong>Methods: </strong>Transcriptomic profiling of 98 patient samples containing 31 DIPGs revealed key activated pathways. Patient-derived cell lines were subjected to high-throughput screening using a cell cycle-targeting drug library. Lead candidates were validated both in vitro and in orthotopic xenograft models, while combination therapies were assessed for their ability to overcome TP53-mutant resistance.</p><p><strong>Results: </strong>Transcriptomic analysis revealed activation of P53 and cell cycle pathways in DIPGs. High-throughput drug screening identified SN-38, a topoisomerase I inhibitor, as selectively targeting TP53 wild-type tumor cells by inducing G2 arrest and apoptosis. TP53 knockdown abolished SN-38's efficacy, while PPM1D knockdown enhanced sensitivity, confirming a TP53-dependent mechanism. Conversely, TP53-mutated cells exhibited SN-38 resistance via ATR pathway activation. Combining SN-38 with the ATR inhibitor AZ20 restored apoptosis and suppressed TP53-mutant tumor growth in vitro and in vivo.</p><p><strong>Conclusions: </strong>Guided by transcriptomic profiling, this study utilized high-throughput drug screening to identify SN-38 as a potential therapy for TP53 wild-type DIPG/DMG, while the SN-38 and AZ20 combination was effective against TP53-mutant tumors. This approach provides a promising treatment strategy for this malignancy and establishes a novel paradigm for drug screening in DIPG/DMG.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091562","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}

{"title":"A molecular array for 10-second diagnosis of common spinal tumor types with picosecond infrared laser mass spectrometry.","authors":"Alexa Fiorante, Michael Woolman, David G Munoz, Taira Kiyota, Lan Anna Ye, Yasmine Farahmand, Darah Vlaminck, Francis O Talbot, Sunit Das, Sorcha Kellett, Christine Giuffrida, Gelareh Zadeh, Howard J Ginsberg, Ahmed Aman, Arash Zarrine-Afsar","doi":"10.1093/neuonc/noaf047","DOIUrl":"10.1093/neuonc/noaf047","url":null,"abstract":"<p><strong>Background: </strong>Improving the surgical outcomes for commonly occurring spinal neoplasms of extradural and intradural extramedullary origins requires precise intraoperative diagnosis provided by highly trained neuropathologists.</p><p><strong>Methods: </strong>Through a retrospective study of n = 319 patient specimens, verified where appropriate by learning curve analysis to be sufficient for statistically significant observations, we aimed to assess the utility of 10-second picosecond infrared laser mass spectrometry (MS; PIRL-MS) for non-subjective diagnosis of major spinal tumor types of metastatic carcinoma, schwannoma, and meningiomas.</p><p><strong>Results: </strong>The sensitivity and specificity values of spinal tumor-type diagnosis (based on n = 182 independent specimens) were (93% ± 1)% and (97% ± 2)%, respectively. This classification utilizes n = 41 cellular lipids including phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, and ceramides whose identities were established using high-resolution tandem MS. Furthermore, the accuracy of diagnosis of a model that contained n = 97 meningioma and n = 106 schwannoma was not drastically influenced by the presence of n = 54 additional intradural extramedullary spinal neoplasms of myxopapillary ependymoma, neurofibroma, paraganglioma, and solitary fibrous tumor types in the differential diagnosis, confirming the generalizability and robustness of the identified molecular array in rendering correct classification even in the presence of data not seen previously by the model.</p><p><strong>Conclusions: </strong>The identified lipids form a \"molecular array\" for robust diagnosis of meningioma and schwannoma tumors by non-pathologists in a manner similar to genomic, transcriptomic, or methylomic arrays used to diagnose brain cancer types, albeit on a much faster timescale of seconds as opposed to hours.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2060-2072"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468623","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}

{"title":"ROBIN: A unified nanopore-based assay integrating intraoperative methylome classification and next-day comprehensive profiling for ultra-rapid tumor diagnosis.","authors":"Simon Deacon, Inswasti Cahyani, Nadine Holmes, Graeme Fox, Rory Munro, Satrio Wibowo, Thomas Murray, Hannah Mason, Mark Housley, Daniel Martin, Abdi Sharif, Areeba Patel, Robert Goldspring, Sebastian Brandner, Felix Sahm, Stuart Smith, Simon Paine, Matthew Loose","doi":"10.1093/neuonc/noaf103","DOIUrl":"10.1093/neuonc/noaf103","url":null,"abstract":"<p><strong>Background: </strong>Advances in our technological capacity to interrogate CNS tumor biology have led to the ever increasing use of genomic sequencing in diagnostic decision making. Presently, CNS tumors are classified based on their epigenetic signatures, leading to a paradigm shift in diagnostic pathways. Such testing can be performed so rapidly using nanopore sequencing that results can be provided intraoperatively. This information greatly improves the fidelity of smear diagnosis and can help surgeons tailor their approach, balancing the risks of surgery with the likely benefit. Nevertheless, full integrated diagnosis may require subsequent additional assays to detect pathognomonic somatic mutations and structural variants, thereby delaying the time to final diagnosis.</p><p><strong>Methods: </strong>Here, we present ROBIN, a tool based on PromethION nanopore sequencing technology that can provide both real-time, intraoperative methylome classification and next-day comprehensive molecular profiling within a single assay. ROBIN utilizes 3 methylation classifiers to improve diagnostic performance in the intraoperative setting.</p><p><strong>Results: </strong>We demonstrate classifier performance on 50 prospective intraoperative cases, achieving a diagnostic turnaround time under 2 hours and generating robust tumor classifications within minutes of sequencing. Furthermore, ROBIN can detect single nucleotide variants, copy number variants, and structural variants in real time, and is able to inform a complete integrated diagnosis within 24 hours. Classifier performance demonstrated concordance with final integrated diagnosis in 90% of prospective cases.</p><p><strong>Conclusion: </strong>Nanopore sequencing can greatly improve turnaround times for standard-of-care diagnostic testing and is furthermore able to reliably provide clinically actionable intraoperative tumor classification.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2035-2046"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110110","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}

{"title":"Automated longitudinal treatment response assessment of brain tumors: A systematic review.","authors":"Tangqi Shi, Aaron Kujawa, Christian Linares, Tom Vercauteren, Thomas C Booth","doi":"10.1093/neuonc/noaf037","DOIUrl":"10.1093/neuonc/noaf037","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal assessment of tumor burden using imaging helps to determine whether there has been a response to treatment both in trial and real-world settings. From a patient and clinical trial perspective alike, the time to develop disease progression, or progression-free survival, is an important endpoint. However, manual longitudinal response assessment is time-consuming and subject to interobserver variability. Automated response assessment techniques based on machine learning (ML) promise to enhance accuracy and reduce reliance on manual measurement. This paper evaluates the quality and performance accuracy of recently published studies.</p><p><strong>Methods: </strong>Following PRISMA guidelines and the CLAIM checklist, we searched PUBMED, EMBASE, and Web of Science for articles (January 2010-November 2024). Our PROSPERO-registered study (CRD42024496126) focused on adult brain tumor automated treatment response assessment studies using ML methodologies. We determined the extent of development and validation of the tools and employed QUADAS-2 for study appraisal.</p><p><strong>Results: </strong>Twenty (including 17 retrospective and 3 prospective) studies were included. Data extracted included information on the dataset, automated response assessment including pertinent steps within the pipeline (index tests), and reference standards. Only limited conclusions are appropriate given the high bias risk and applicability concerns (particularly regarding reference standards and patient selection), and the low-level evidence. There was insufficient homogenous data for meta-analysis.</p><p><strong>Conclusions: </strong>The study highlights the potential of ML to improve brain tumor longitudinal treatment response assessment. Interpretation is limited due to study bias and limited evidence of generalizability. Prospective studies with external datasets validating the latest neuro-oncology criteria are now required.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1946-1971"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399703","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}

{"title":"CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.","authors":"Xiaoming Zhang, Mengyuan Jiang, Wanxiang Niu, Ben Xu, Ce Zhang, Minglong Yang, Shanshan Hu, Chaoshi Niu","doi":"10.1093/neuonc/noaf019","DOIUrl":"10.1093/neuonc/noaf019","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma stem cells and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in the glioma microenvironment.</p><p><strong>Methods: </strong>GDE-circPRKD3 was screened out through high-throughput sequencing and verified by RT-PCR, sanger sequencing, and RNase R assays. A series of in vitro and in vivo experiments were performed to investigate the function of GDE-circPRKD3. RNA-seq, RNA immunoprecipitation, multicolor flow cytometry, and western blotting were used to explore the regulation of GDE-circPRKD3 on STAT3 signaling-mediated TME remodeling.</p><p><strong>Results: </strong>We have characterized a circRNA PRKD3 in GSC exosomes, and lower circPRKD3 expression predicts a worse prognosis for glioblastoma patients. Overexpression of GDE-circPRKD3 significantly impairs the biological competence of glioma and prolongs the survival of xenograft mice. GDE-circPRKD3 binds to HNRNPC in an m6A-dependent manner, accelerates mRNA decay of IL6ST, and inhibits downstream target STAT3. Notably, GDE-circPRKD3 promotes CXCL10 secretion by reprogramming tumor-associated macrophages, which in turn recruits CD8+ tumor-infiltrating lymphocytes against GBM. Moreover, brain-targeted lipid nanoparticle delivery of circPRKD3 combined with immune checkpoint blockade therapy achieves significant combinatorial benefits.</p><p><strong>Conclusions: </strong>This study provides a novel mechanism by which GDE-circPRKD3 relies on STAT3 signaling to remodel immunosuppressive TME and offers a potential RNA immunotherapy strategy for GBM treatment.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1987-2005"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047421","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}

{"title":"Phase 1 dose-escalation trial using convection-enhanced delivery of radio-immunotheranostic 124I-Omburtamab for diffuse intrinsic pontine glioma.","authors":"Mark M Souweidane, Evan D Bander, Pat Zanzonico, Anne S Reiner, Nicole Manino, Sofia Haque, Jorge A Carrasquillo, Serge K Lyashchenko, Sunitha B Thakur, Jason S Lewis, Maria Donzelli, Nai-Kong V Cheung, Steven M Larson, Kim Kramer, Neeta Pandit-Taskar, Ira J Dunkel","doi":"10.1093/neuonc/noaf039","DOIUrl":"10.1093/neuonc/noaf039","url":null,"abstract":"<p><strong>Background: </strong>Median survival for patients with Diffuse Intrinsic Pontine Glioma (DIPG) is 8-12 months.</p><p><strong>Methods: </strong>A phase 1, open label, 3 + 3 dose-escalation trial delivered radiolabeled 124I-Omburtamab, targeting B7-H3, using MR-guided stereotactic convection-enhanced delivery (CED) into the brainstem of pediatric DIPG patients. CED was performed after completion of standard-of-care external-beam radiation therapy (EBRT). Fifty children were treated and evaluable. 124I-Omburtamab activity was escalated from 0.25 to 10.0 mCi (9.25-370 MBq) and volume escalated from 0.25 mL to 10.0 mL with serial PET/MRI post administration. Safety was the primary outcome. National Cancer Institute Common Terminology Criteria for Adverse Events were assessed for 30 days following CED of 124I-Omburtamab. Secondary outcomes included overall survival and lesion-to-whole-body absorbed dose ratio.</p><p><strong>Results: </strong>The maximum tolerated activity per study protocol was determined to be 6mCi (222 MBq). The overall mean (±SD) total absorbed dose in the lesion per unit injected activity was 35.2 ± 18 cGy/MBq with a high lesion-to-whole-body absorbed dose ratio averaging 816, across all activity levels. Eleven patients had treatment-related grade 3 CNS toxicities with no grade-4 or -5 CNS toxicities. Five dose-limiting toxicity events occurred. Median survival was 15.29 months from diagnosis (95% CI: 12.20-16.83 months). Survival rate estimates at 1, 2, and 3 years were 65.4% (CI 53.3-80.1%), 18.4% (CI: 10.2-33.2%), and 11.7% (CI: 5.3-25.7%), respectively.</p><p><strong>Conclusions: </strong>Administration of 124I-Omburtamab via CED is a safe treatment option for DIPG, with a maximum tolerated activity level identified. This study represents the first-in-human theranostic use of a 124I radiopharmaceutical, simultaneously, as an imaging and therapeutic agent.</p><p><strong>Trial registration: </strong>NCT01502917; https://clinicaltrials.gov/study/NCT01502917.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2117-2126"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449609","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}

{"title":"H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.","authors":"Yupei Guo, Zian Li, Leslie A Parsels, Zhuwen Wang, Joshua D Parsels, Anushka Dalvi, Stephanie The, Nan Hu, Victoria M Valvo, Robert Doherty, Erik Peterson, Xinjun Wang, Sujatha Venkataraman, Sameer Agnihotri, Sriram Venneti, Daniel R Wahl, Michael D Green, Theodore S Lawrence, Carl Koschmann, Meredith A Morgan, Qiang Zhang","doi":"10.1093/neuonc/noaf097","DOIUrl":"10.1093/neuonc/noaf097","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy (RT) is the primary treatment for diffuse midline glioma (DMG), a lethal pediatric malignancy defined by histone H3 lysine 27-to-methionine (H3K27M) mutation. Based on the loss of H3K27 trimethylation producing broad epigenomic alterations, we hypothesized that H3K27M causes a functional double-strand break (DSB) repair defect that could be leveraged therapeutically with PARP inhibitor and RT for selective radiosensitization and antitumor immune response.</p><p><strong>Methods: </strong>H3K27M isogenic DMG cells and orthotopic brainstem DMG tumors in immune deficient and syngeneic, immune competent mice were used to evaluate the efficacy and mechanisms of PARP1/2 inhibition by olaparib or PARP1-selective inhibition by AZD9574 with concurrent RT.</p><p><strong>Results: </strong>H3K27M mutation caused a homologous recombination repair (HRR) defect characterized by impaired RT-induced K63-linked polyubiquitination of histone H1 and inhibition of HRR protein recruitment. H3K27M DMG cells were selectively radiosensitized by olaparib in comparison to isogenic controls, and this effect translated to efficacy in H3K27M orthotopic brainstem tumors. Olaparib and RT induced an innate immune response and induction of NK cell (NKG2D) activating ligands leading to increased NK cell-mediated lysis of DMG cells. In immunocompetent syngeneic orthotopic DMG tumors, either olaparib or AZD9574 in combination with RT enhanced intratumoral NK cell infiltration and activity in association with NK cell-mediated therapeutic responses and favorable activity of AZD9574.</p><p><strong>Conclusions: </strong>The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of PARP1 inhibitors with RT in DMG patients.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2129-2146"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015055","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}

{"title":"Phase Ib study with expansion of ibrutinib, lenalidomide, and rituximab in patients with relapsed/refractory central nervous system lymphoma.","authors":"Lauren R Schaff, Anna F Piotrowski, Elena Pentsova, Igor T Gavrilovic, Andrew Lin, Thomas J Kaley, Venissala Wongchai, Laleh Emadi-Paramkouhi, Juli Madzsar, Lillian Quinn, Ashley Gonzalez, Laura Breakey, Sarah S Tang, Joe S Mendez, Rachna Malani, Craig Nolan, Vaios Hatzoglou, Robert J Young, Lisa M DeAngelis, Anne S Reiner, Katherine S Panageas, Jasmine H Francis, Ingo K Mellinghoff, Christian Grommes","doi":"10.1093/neuonc/noaf104","DOIUrl":"10.1093/neuonc/noaf104","url":null,"abstract":"<p><strong>Background: </strong>Treatment options for recurrent/refractory central nervous system (CNS) lymphoma are limited but Bruton's tyrosine kinase inhibitor ibrutinib has shown promise. To increase efficacy and reduce resistance, ibrutinib was combined with lenalidomide in a preclinical study and rituximab (R2I) in a phase Ib trial with expansion.</p><p><strong>Methods: </strong>Ibrutinib 560 mg (dose level 1) or 840 mg (levels 2-4) was administered daily; lenalidomide was dosed on days 1-21 at 10 mg (level 1 + 2), 15 mg (level 3), or 20 mg (level 4) daily; rituximab 500 mg/m2 was administered every 28 days. Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing.</p><p><strong>Results: </strong>25 patients were enrolled (3 each into dose levels 1-3; 6 into level 4; and 10 into the expansion cohort at level 4). The median age was 67 years (range 41-85) and the median Eastern Cooperative Oncology Group 1 (range 0-2). Patients had a median of 2 prior regimens (range 1-5). Common adverse events were thrombocytopenia, rash, and lymphopenia. No aspergillosis or grade 5 toxicities were observed. After 12.8 months of median follow-up, 20/25 (80%) showed a response with a median time to best response of 60 days (range, 25-615). Median progression-free survival (PFS) was 4.3 months (95% CI: 2.4-not reached) with a PFS12m of 37% (95% CI: 22%-63%). Median overall survival has not been reached. Patients with rash during treatment had improved PFS (HR: 0.17, 95% CI: 0.05-0.55, P-value = .003).</p><p><strong>Conclusions: </strong>R2I was tolerated well with high response rates and a short time to best respond. Median PFS was limited but 1/3 of patients had durable responses >12 months. This trial was registered at www.clinicaltrials.gov (NCT03703167).</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2107-2116"},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023919","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}

{"title":"Extracellular Matrix Stiffness Conditions Glioblastoma Cells for Long-term Migration: Mechanical Memory as a Driver of Invasion and Recurrence in Glioblastoma.","authors":"Paola Suarez-Meade, Rachel Whitehead, Steve Rosenfeld, Paula Schiapparelli, Konstantinos Konstantopoulos, Alfredo Quinones-Hinojosa","doi":"10.1093/neuonc/noaf205","DOIUrl":"https://doi.org/10.1093/neuonc/noaf205","url":null,"abstract":"<p><p>Extracellular matrix (ECM) stiffening correlates with tumor invasion in various cancer types, including glioblastoma (GBM). Increased matrix stiffness promotes a migratory phenotype through dysregulation of cell-ECM bidirectional communication. Exposure to stiffer environments is sensed by cells, which then adapt in ways that promote invasive behavior. These adaptive changes are imprinted onto the cells and persist even after they are placed in new, softer microenvironments via a process known as \"mechanical memory\". Mechanical memory is believed to be driven by mechanosensitive transcription factor activity and epigenetic remodeling. Glioblastoma (GBM) recurrence is linked to the ability of cells to disperse and infiltrate the surrounding healthy tissue. ECM stiffness in GBM is heterogeneous; it starts with a softer tumor core and becomes progressively stiffer towards the tumor's edges, potentially promoting sustained tumor invasion through mechanical memory. This review discusses the role of ECM stiffness in cancer cell behavior and the implications of ECM stiffening in GBM. We then describe the findings associated with mechanical memory and relay underlying mechanisms currently understood to drive the preservation of mechanically primed phenotypes. Lastly, we discuss how matrix stiffness can drive migratory phenotypes in GBM cells and the potential role that progressive ECM dysregulation at the tumor periphery can link the formation of invasive tumor niches to the aggressive, resistant, and mesenchymal-like phenotypes present in GBM recurrent tumors.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092274","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}