Neuro-oncology最新文献

{"title":"Do we need B7-H3 immunohistochemistry for the inclusion of children with high-grade central nervous system tumors in clinical trials targeting B7-H3?","authors":"Mariëtte E G Kranendonk, Raoull Hoogendijk, Julie A S Lammers, Jasper van der Lugt, Nelleke Tolboom, Esther van Mastrigt, Ella de Boed, Thijs J M van den Broek, Lennart A Kester, Dannis G van Vuurden, Bastiaan B J Tops, Eelco W Hoving, Pieter Wesseling, Sabine L A Plasschaert","doi":"10.1093/neuonc/noaf095","DOIUrl":"10.1093/neuonc/noaf095","url":null,"abstract":"<p><strong>Background: </strong>Pediatric high-grade central nervous system (pHG-CNS) tumors are the leading cause of childhood cancer-related deaths, partly due to poor response to standard treatments. B7-H3 is reportedly expressed in pHG-CNS tumors, making antigen-targeting therapies, including anti-B7-H3 chimeric antigen receptor T-cell (CAR-T) therapy, promising. However, given substantial inter-tumoral protein expression diversity in CNS tumors, it's unclear which patients might benefit from these treatments. Therefore, we studied B7-H3 expression in a large set of pHG-CNS tumors.</p><p><strong>Methods: </strong>We retrospectively analyzed 136 pHG-CNS tumors (embryonal tumors (n = 44), high-grade neuroepithelial tumors (n = 4), ependymomas (n = 30),high-grade gliomas (HGGs, n = 58)) from the Princess Máxima Center for Pediatric Oncology. CD276 mRNA (encoding B7-H3) and immunohistochemical (IHC) protein expression of B7-H3 was measured and correlated to clinical-molecular data.</p><p><strong>Results: </strong>Large variability of B7-H3 mRNA and protein expression was observed both between and within tumor types. Many tumors expressed B7-H3, but 30% of diffuse midline glioma H3K27-altered and ependymomas posterior fossa type A showed no or minimal expression. This variability was unrelated to patient age, tumor location, epigenetic subclass, or molecular tumor driver. B7-H3 negative cases were high in tumor cells, ruling out low tumor cell percentage as an explanation for negative staining.</p><p><strong>Conclusions: </strong>Our study of B7-H3-expression in the largest pHG-CNS tumor set to date revealed significant interpatient variability and numerous negative cases. Our results urge for tumor tissue acquisition at enrollment in B7-H3 targeting therapeutic trials (including CAR-T cells) in order to thoroughly assess the value of IHC B7-H3 expression as biomarker and, ultimately, to allow for more tailored therapy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1864-1877"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991811","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":"Postoperative fluid restriction to prevent delayed hyponatremia after endoscopic transsphenoidal surgery.","authors":"Doriann Klaassen, Shinghei Mok, Jenie Y Hwang, Sydney L Blount, Kelley J Williams, Brendan M Fong, Michael R Chicoine, Ralph G Dacey, Nyssa F Farrell, Joshua W Osbun, Keith M Rich, Lauren T Roland, John S Schneider, Gregory J Zipfel, Chongliang Luo, Albert H Kim, Julie M Silverstein","doi":"10.1093/neuonc/noaf069","DOIUrl":"10.1093/neuonc/noaf069","url":null,"abstract":"<p><strong>Background: </strong>Readmission following endoscopic endonasal transsphenoidal surgery (EETS) for pituitary neuroendocrine tumor (PitNET) and other sellar pathology is most commonly due to delayed hyponatremia. Studies suggest postoperative fluid restriction (FR) reduces delayed hyponatremia. We present a prospective randomized controlled study evaluating post-EETS FR.</p><p><strong>Methods: </strong>300 participants were scheduled for EETS (2016-2023) at a single institution. Patients with CKD, CHF, arginine vasopressin deficiency on postoperative day (POD) 3, chronic hyponatremia, and untreated adrenal insufficiency or hypothyroidism were excluded. Groups included control (ad-lib, n = 94), moderate FR (1.8 L/day or 2 L/day weight > 100 kg, n = 39), and strict FR (1 L/day or 1.2 L/day weight > 100 kg, n = 62) from POD 3-14. Incidence of overall, moderate, and severe hyponatremia (Na < 135, 125-129, and <125 mEq/L), readmission rates, fluid intake, and thirst were evaluated.</p><p><strong>Results: </strong>The incidence of overall hyponatremia was 31.9%, 28.2%, and 21.0% in control, moderate FR, and strict FR groups, and the incidence of severe hyponatremia was 7.4%, 5.1%, and 0% in control, moderate FR, and strict FR groups. Nadir Na level was higher (1.81 mEq/L; 95% CI, 0.34 to 3.27; P = .02) and severe hyponatremia occurred less frequently (95% CI, 0.00 to 1.02; P = .04) in the strict FR vs. control group. Readmission was lower in the strict FR (1.6%, n = 1) vs. control group (6.4%, n = 6).</p><p><strong>Conclusions: </strong>Postoperative FR decreases rates of delayed hyponatremia and related readmission compared to patients drinking ad-lib. Further studies are needed to assess the optimal volume and duration of FR after EETS. Trial registration number: NCT03636568.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1746-1757"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625536","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":"Multi-site retrospective analysis of diffusion and perfusion magnetic resonance imaging correlates to glioma characteristics derived from radio-pathomic maps.","authors":"Samuel A Bobholz, Daniel Aaronsen, Aleksandra Winiarz, Savannah R Duenweg, Allison K Lowman, Michael Flatley, Fitzgerald Kyereme, Jennifer Connelly, E Kelly S Mrachek, Max O Krucoff, Anjishnu Banerjee, Peter S LaViolette","doi":"10.1093/neuonc/noaf044","DOIUrl":"10.1093/neuonc/noaf044","url":null,"abstract":"<p><strong>Background: </strong>This study determines the relationship between diffusion and perfusion-based magnetic resonance imaging signatures and radio-pathomic maps of tumor pathology in a large, multi-site cohort.</p><p><strong>Methods: </strong>This study included perfusion imaging from presurgical relative cerebral blood volume (rCBV) images from the UPenn-GBM dataset and presurgical arterial spin labeling (ASL) imaging from the UCSF-PDGM dataset. Diffusion imaging included fractional anisotropy (FA) estimates derived from diffusion tensor imaging for each subject from each institution. A previously validated autopsy-based model was applied to the structural images from each patient to generate quantitative radio-pathomic maps of cell density and extracellular fluid (ECF). Mean cell density, ECF density, FA, rCBV calculated from dynamic susceptibility contrast imaging, and rCBF calculated from ASL were computed for each patient and statistically compared within contrast-enhancement (CE) and the non-enhancing peritumor FLAIR hyperintensity (FH).</p><p><strong>Results: </strong>Both rCBV and ASL showed a positive correlation with cell density within CE (rCBV: R = 0.280, P < .001; ASL: R = 0.117, P = .023). However, both perfusion metrics also showed no association with cell density within the FH region at the group level (rCBV: R = 0.0162, P = .731; ASL: R = -0.020, P = .652). Negative correlations were observed between FA and ECF density across both CE and FH in both the UPenn-GBM (CE: r = -.204, P < .001, FH: r = -.332, P < .001) and the UCSF-PDGM (CE:r = -.179, P < .001, FH:-0.355, P < .001). Additionally, a positive ASL-cell density association per subject within FH was associated with a worse survival prognosis (HR = 5.58, P = .022).</p><p><strong>Conclusions: </strong>These results suggest that radio-pathomic maps of tumor pathology provide complementary information to other MR signatures that reveal prognostically valuable signatures of the non-enhancing tumor margin.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1899-1909"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441583","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":"Advancing clinical response against glioblastoma: Evaluating SHP1705 CRY2 activator efficacy in preclinical models and safety in phase I trials.","authors":"Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A Solt, Jamie Cope, Rex A Moats, Tsuyoshi Hirota, Jeremy N Rich, Steve A Kay","doi":"10.1093/neuonc/noaf089","DOIUrl":"10.1093/neuonc/noaf089","url":null,"abstract":"<p><strong>Background: </strong>It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity.</p><p><strong>Methods: </strong>We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. We applied a novel REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells.</p><p><strong>Results: </strong>SHP1705 is the first circadian clock-modulating compound to be found safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators, making it promising for applications in GBM where CRY2 levels are found to be low. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs).</p><p><strong>Conclusions: </strong>We demonstrate the efficacy of SHP1705 against GSCs, which pose as a major source of chemoradiation resistance leading to poor GBM patient prognosis. Novel circadian clock compounds have high potential for targeting GBM as single agents or in combination with each other or current standard-of-care.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1772-1786"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764493","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":"Benchmarking the efficacy of salvage systemic therapies for recurrent meningioma: A RANO group systematic review and meta-analysis to guide clinical trial design.","authors":"Rupesh Kotecha, Eyub Y Akdemir, Tugce Kutuk, Can Ilgın, Manmeet S Ahluwalia, Wenya L Bi, Jaishri Blakeley, Karan S Dixit, Ian F Dunn, Evanthia Galanis, Norbert Galldiks, Raymond Y Huang, Derek R Johnson, Thomas J Kaley, David O Kamson, Sylvia C Kurz, Michael W McDermott, Yazmin Odia, Matthias Preusser, Jeffrey Raizer, David A Reardon, C Leland Rogers, Roberta Ruda, David Schiff, Michael A Vogelbaum, Michael Weller, Patrick Y Wen, Minesh P Mehta","doi":"10.1093/neuonc/noaf009","DOIUrl":"10.1093/neuonc/noaf009","url":null,"abstract":"<p><strong>Background: </strong>Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a \"rate of probable interest\" to inform future clinical trial design and development on behalf of the Response Assessment in Neuro-Oncology meningioma group.</p><p><strong>Methods: </strong>PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I2 indices.</p><p><strong>Results: </strong>The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2 = 80%) and 21.7% (95% CI: 6.2-53.9%, I2 = 76%), and for grades 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2 = 68%). In the targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2 = 58%) and 49.0% (I2 = 63%) for grade 1, while for grades 2-3 tumors, the PFS-6 rates with targeted therapy and immunotherapy were 42.1% (I² = 60%) and 46.0% (I² = 0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grades 2-3 tumors.</p><p><strong>Conclusions: </strong>Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1670-1685"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979465","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":"Renaming low-grade MPNST: look before we leap.","authors":"Xuan Yu, Jingxuan Huang, Zhichao Wang","doi":"10.1093/neuonc/noaf074","DOIUrl":"10.1093/neuonc/noaf074","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1923-1925"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192057","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":"High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.","authors":"Dannielle H Upton, Jie Liu, Sandra M George, Santosh Valvi, Caitlin Ung, Benjamin S Rayner, Anjana Gopalakrishnan, Ruby Pandher, Aaminah Khan, Pooja Venkat, Chelsea Mayoh, Holly Holliday, Nicole Yeung, Hieu Nguyen, Laura Franshaw, Anahid Ehteda, Han Shen, Giovanna Farruggia, Isabella Orienti, C Patrick Reynolds, Maria Tsoli, David S Ziegler","doi":"10.1093/neuonc/noaf035","DOIUrl":"10.1093/neuonc/noaf035","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline glioma, characterized by H3K27 alteration (DMG), is the predominant high-grade glioma in children. It commonly originates in the brainstem, yet effective treatments for these patients remain elusive.</p><p><strong>Methods: </strong>To identify novel therapies for DMG, we conducted high-throughput drug screens (HTS) using biologically active, clinically approved compounds against DMG neurospheres. Multiple primary DMG cultures were utilized in conjunction with in vitro cytotoxicity and clonogenic assays to validate the efficacy of top compounds. Molecularly diverse patient-derived and transgenic DMG orthotopic models were employed to assess therapeutic efficacy alongside pharmacokinetic and immunohistochemical analyses. Mechanistic studies, including RNA sequencing, western blotting, and flow cytometry, were conducted to elucidate the antitumor efficacy of the most promising compound, fenretinide, in DMG cells.</p><p><strong>Results: </strong>Through HTS, 6 compounds were identified and validated for their potent cytotoxic activity. However, most of these compounds failed to improve survival in an orthotopic Diffuse Midline Glioma (DMG) model due to limited blood-brain barrier (BBB) penetration. In contrast, fenretinide exhibited effective BBB penetration, significantly enhancing the survival of tumor-bearing animals. Mechanistic studies revealed that fenretinide increased reactive oxygen species (ROS) generation and induced apoptosis by inhibiting PDGFRα. RNA-sequencing further elucidated that fenretinide upregulates the Unfolded Protein Response (UPR) and endoplasmic reticulum (ER) stress pathways while downregulating neurogenesis. The in vivo antitumor efficacy of 2 fenretinide formulations was demonstrated in PDGFRα-amplified and transgenic DMG models.</p><p><strong>Conclusion: </strong>This comprehensive study has identified new DMG therapeutic vulnerabilities and highlights fenretinide as a brain-penetrant, anti-DMG agent.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1813-1828"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399706","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":"Co-occurrence of congenital anomalies and childhood brain tumors in 22 million live births.","authors":"Thanh T Hoang, Jeremy M Schraw, Charles Shumate, Tania A Desrosiers, Wendy N Nembhard, Mahsa Yazdy, Eirini Nestoridi, Amanda E Janitz, Russell S Kirby, Jason L Salemi, Jean Paul Tanner, Tiffany M Chambers, Michael D Taylor, Chad D Huff, Sharon E Plon, Philip J Lupo, Michael E Scheurer","doi":"10.1093/neuonc/noaf087","DOIUrl":"10.1093/neuonc/noaf087","url":null,"abstract":"<p><strong>Background: </strong>Children born with a congenital anomaly have a higher risk of developing a brain tumor during childhood or adolescence, but the co-occurrence between specific types of congenital anomalies and specific types of childhood brain tumors (CBTs) is not well described. This study characterized the associations between specific congenital anomalies and CBTs.</p><p><strong>Methods: </strong>We leveraged a population-based registry linkage study of births (1990-2018), congenital anomalies, and cancer from 9 states (n = 22,599,099 births). Congenital anomalies were classified as major structural without a known chromosomal or genetic syndrome, chromosomal, neurofibromatosis, and/or tuberous sclerosis complex. CBT classification was based on the International Classification of Childhood Cancer for children diagnosed < 20 years. Cox regression analyses were conducted separately by congenital anomaly for anomaly-CBT combinations with at least 5 co-occurring cases. We conducted analyses for any CBT and separately for astrocytoma, atypical teratoid/rhabdoid tumor, ependymoma, medulloblastoma, mixed and unspecified gliomas, and primitive neuroectodermal tumors.</p><p><strong>Results: </strong>There were 6,247 children diagnosed with a CBT. Having any major structural anomaly was associated with risk of any CBT and across all subgroups (aHR range: 1.48-3.69) except ependymoma, particularly among children diagnosed with a tumor by 1 year of age. Of the 66 anomaly-CBT combinations analyzed, 42 were significant (P < .05), including 25 in an earlier version of this study and 16 novel associations (aHR range: 1.46-525). Anomaly-CBT associations also differed by astrocytoma histology.</p><p><strong>Conclusions: </strong>We observed consistent evidence that having a structural congenital anomaly increases risk of developing a CBT, particularly in infancy, which may provide insights into etiology.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1910-1922"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730871","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":"Germline analysis of an international cohort of pediatric diffuse midline glioma patients.","authors":"Marion K Mateos, Pamela Ajuyah, Noemi Fuentes-Bolanos, Sam El-Kamand, Paulette Barahona, Ann-Kristin Altekoester, Chelsea Mayoh, Holly Holliday, Jie Liu, Louise Cui, Elke Pfaff, Alan Mackay, Adam C Resnick, Mark Pinese, Loretta M S Lau, Dong-Anh Khuong-Quang, Kimberly Dias, Catherine Goudie, Alison Salkeld, Jo Lynne Rokita, David T W Jones, Nikoleta Juretic, Elisha Hayden, Stefan M Pfister, Christof M Kramm, Mirjam Blattner-Johnson, Nada Jabado, Maria Tsoli, Orazio Vittorio, Sabine Mueller, Yiran Guo, Katherine Tucker, Sebastian M Waszak, Sebastien Perreault, Chris Jones, Marie Wong-Erasmus, Mark J Cowley, David S Ziegler","doi":"10.1093/neuonc/noaf061","DOIUrl":"10.1093/neuonc/noaf061","url":null,"abstract":"<p><strong>Background: </strong>Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG.</p><p><strong>Methods: </strong>We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n = 153), with germline whole genome or whole exome sequencing.</p><p><strong>Results: </strong>We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with the absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = .023). P/LP germline variants were recurrent in homologous recombination (n = 9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n = 4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed a near-complete radiological response to PARP and immune checkpoint inhibition.</p><p><strong>Conclusions: </strong>Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1849-1863"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605479","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":"IRS2 as a driver of brain metastasis in colorectal cancer: A potential target for novel therapeutic strategies.","authors":"Inbal Greenberg, Fayhaa Khair-Dabour, Keren Merenbakh-Lamin, Ethan S Sokol, Anat Klein Goldberg, Dor Simkin, Avishay Spitzer, Moshe Benhamou, Shai Bar-Shira, Michal Raz, Rachel Grossman, Eilam Yeini, Paula Ofek, Tomer Meirson, Ronit Satchi-Fainaro, Hadas Reuveni, Ido Wolf, Tami Rubinek","doi":"10.1093/neuonc/noaf028","DOIUrl":"10.1093/neuonc/noaf028","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) ranks as the fourth most common cause of brain metastasis (BM), with its incidence on the rise. However, the molecular mechanisms driving the formation of these lesions from CRC remain unclear.</p><p><strong>Methods: </strong>We analyzed the Foundation Medicine genomic database, which includes over 35,000 CRC samples from both local and metastatic sites. The role of insulin receptor substrate 2 (IRS2) in CRC brain tropism was investigated using various in vitro (co-culture systems and 3D sphere formation assays), in vivo (intracranial and subcutaneous mouse models), and ex vivo (CRC Patient-Derived Explants) models. The molecular and metabolic effects of IRS2 were examined through RNA sequencing and Seahorse analysis. The therapeutic potential of a combined treatment with NT219, an IRS2 inhibitor, and 5-fluorouracil (5-FU) was assessed using our CRC BM mouse model.</p><p><strong>Results: </strong>Our research reveals a distinctive genomic profile of CRC BM and highlights the role of IRS2 in promoting CRC BM. IRS2 mediates its effect by modulating the β-catenin and oxidative phosphorylation (OXPHOS) pathways. We developed a mouse model of BM from CRC and demonstrated that treatment with the IRS2 inhibitor NT219, in combination with 5-FU, significantly suppresses BM development and prolongs survival.</p><p><strong>Conclusions: </strong>Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1729-1745"},"PeriodicalIF":13.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067035","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}