Neuro-oncology pediatrics最新文献

{"title":"The DIPG/DMG National Tumor Board: The power of advocacy.","authors":"Rebecca Ronsley, Greta Peng, Eileen Gutierrez, Patricia Baxter, Jason Fangusaro, Adam L Green, Lindsay B Kilburn, Carl Koschmann, Jasia Mahdi, Michelle Monje, Ashley S Plant-Fox, Nicholas A Vitanza, Sebastian M Waszak, Cheng-Chia Fred Wu, Matthew J Barkovich, David Mirsky, Sabine Mueller","doi":"10.1093/neuped/wuaf009","DOIUrl":"10.1093/neuped/wuaf009","url":null,"abstract":"<p><strong>Background: </strong>Diffuse intrinsic pontine gliomas (DIPG) and diffuse midline gliomas (DMG) are fatal brain tumors and clinical trial enrollment remains a cornerstone of treatment; however, barriers to trial identification, access and enrollment persist. The DIPG/DMG National Brain Tumor Board (DMG NTB) was created based on family foundation advocacy to address these challenges by providing centralized, multidisciplinary guidance to improve access to expertise and facilitate clinical trial awareness and enrollment.</p><p><strong>Methods: </strong>We conducted a retrospective descriptive analysis of cases presented to the DMG NTB between November 2022 and December 2024. Data were extracted from standardized intake forms, meeting records and chart reviews, including patient demographics, disease characteristics, molecular findings, referring institution type, trial recommendations, and radiologic evaluations. Geographic reach and provider participation were also analyzed.</p><p><strong>Results: </strong>A total of 349 presentations representing 279 unique patients were reviewed. Referrals came from 93 institutions across 35 states, including 48% from treating physicians, 34% via self-referral, and 18% from My DIPG Navigator. The median age was 9 years (range: 1-52), and 83% of patients had undergone tumor biopsy, with molecular profiling available in 81% of those cases. The DMG NTB provided a median of six clinical trial options. Imaging review resulted in additional findings, recommendations, or both in over half of cases. Participation grew by 89.5% over the evaluated time period.</p><p><strong>Conclusions: </strong>The DMG NTB has established a scalable, patient-centered system that enhances trial awareness, eligibility screening, care coordination, and multidisciplinary learning for patients with DIPG/DMG. This parent-driven initiative addresses longstanding gaps in access to expertise. Ongoing integration with research networks will be critical to maximizing its impact on outcomes for children and young adults.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXR2-activated CNS neuroblastoma: Characterized by variable structural disruption of the <i>FOXR2</i> regulatory region, recurrent copy number alterations, and elevated <i>FOXR2</i> expression.","authors":"Jianling Ji, Venkata Yellapantula, Dong Xu, Dolores Estrine, Alexander Markowitz, Jennifer Han, Katherine Ma, Cindy Fong, Debra Hawes, Ashley Margol, Katrina O'Halloran, Nathan J Robison, Jaclyn A Biegel, Jennifer A Cotter, Gordana Raca, Jessica W Tsai","doi":"10.1093/neuped/wuag014","DOIUrl":"10.1093/neuped/wuag014","url":null,"abstract":"<p><strong>Background: </strong>FOXR2 is a forkhead box transcription factor implicated in central nervous system neuroblastoma (CNS-NB FOXR2). The underlying genetic mechanisms and clinical features of CNS-NB FOXR2 have yet to be elucidated.</p><p><strong>Methods: </strong>Six CNS-NB FOXR2 cases were identified through DNA methylation profiling. Optical genome mapping, chromosomal microarray, whole genome sequencing, OncoKids panel, RNA sequencing (RNA-seq), and clinical data were analyzed.</p><p><strong>Results: </strong>Case 1 demonstrated a 13-kb insertion approximately 25 kb upstream of <i>FOXR2</i>. Case 2 showed 2 non-contiguous focal gains in Xp11.21 (encompassing <i>FOXR2</i>) and Xp22.2p22.13, approximately 37 Mb apart, resulting from a complex rearrangement disrupting the <i>FOXR2</i> regulatory region. Case 3 harbored a pericentric inversion between <i>RLIM</i> and a site 17.98 kb upstream of <i>FOXR2</i>. Recurrent copy number alterations included 1q gain (100%), 16q loss (80%), distal 11q loss (60%), and gain of chromosomes 8 and 17q (40% each). All three female patients showed X chromosome loss. <i>FOXR2</i> expression was elevated in both cases with available RNA-seq data.Overall survival ranged from 1.81-15.62 years. Clinical treatment was highly variable, and molecular testing was unavailable at diagnosis for 4 of 5 patients.</p><p><strong>Conclusions: </strong>Structural disruption of the <i>FOXR2</i> regulatory region, recurrent copy number alterations, and elevated <i>FOXR2</i> expression are features of CNS-NB FOXR2. These rearrangements do not alter the coding region and may not be detected by routine testing. Initial pathology may suggest other entities, highlighting the importance of molecular testing at diagnosis. Favorable clinical outcomes require accurate initial diagnosis as evidenced by our clinical cohort.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"2 2","pages":"wuag014"},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13070476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative splicing in pediatric central nervous system tumors highlights oncofetal candidate <i>CLK1</i> exon 4.","authors":"Ammar S Naqvi, Patricia J Sullivan, Ryan J Corbett, Priyanka Sehgal, Karina L Conkrite, Komal S Rathi, Brian M Ennis, Katharina E Hayer, Bo Zhang, Miguel A Brown, Daniel P Miller, Alex Sickler, Adam A Kraya, Kaleem L Coleman, Joseph M Dybas, Zhuangzhuang Geng, Christopher Blackden, Shehbeel Arif, Antonia Chroni, Aditya Lahiri, Madison L Hollawell, Phillip B Storm, Dalia Haydar, Jessica B Foster, Mateusz Koptyra, Peter J Madsen, Sharon J Diskin, Andrei Thomas-Tikhonenko, Adam C Resnick, Jo Lynne Rokita","doi":"10.1093/neuped/wuag009","DOIUrl":"10.1093/neuped/wuag009","url":null,"abstract":"<p><strong>Background: </strong>Pediatric brain tumors are the leading cause of disease-related mortality in children, yet many aggressive tumors lack effective therapies. RNA splicing is a hallmark of cancer, but it has not yet been systematically studied in pediatric brain tumors.</p><p><strong>Methods: </strong>We analyzed 729 pediatric brain tumors spanning histologies and molecular subtypes to quantify differential tumor splicing. We developed the <i>Splicing Burden Index (SBI)</i> to enable cross-sample comparisons and performed hierarchical clustering of highly variable splice events to define splicing-informed tumor groups. These were integrated with clinical outcomes, pathway activity, and proteogenomic data. Recurrent splice events were prioritized for predicted functional impact, and <i>in vitro</i> perturbation studies were performed targeting the splicing kinase <i>CDC-like kinase 1 (CLK1)</i>.</p><p><strong>Results: </strong>SBI revealed substantial interhistology and intrahistology heterogeneity. Clusters were enriched for histologies and molecular subtypes, several of which were independently associated with survival beyond histology and clinical covariates. Spliceosome pathway activity varied across clusters and was associated with worse survival, yet was not correlated with SBI, indicating distinct dimensions of splicing dysregulation. Functional prioritization identified a recurrent in <i>CLK1</i> exon 4, required for canonical kinase activity. <i>CLK1</i> exon 4 inclusion followed an oncofetal pattern and showed context-dependent associations with outcome distinct from total <i>CLK1</i> expression. Pharmacologic inhibition and exon 4-specific perturbation of <i>CLK1</i> reduced tumor cell viability and disrupted cancer-relevant splicing and transcriptional programs.</p><p><strong>Conclusions: </strong>This study systematically characterizes splicing in pediatric brain tumors, identifies splicing-informed subgroups, and prioritizes <i>CLK1</i> exon 4 as an oncofetal tumor-specific event, motivating further preclinical exploration.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"2 1","pages":"wuag009"},"PeriodicalIF":0.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes following radiotherapy for atypical teratoid/rhabdoid tumor in combination with surgery and intensive chemotherapy: A report from Children's Oncology Group study ACNS0333.","authors":"Paul Aridgides, Anita Mahajan, Thomas E Merchant, Mark Krailo, Allen Buxton, Jared Deck, Douglas Strother, Annie Huang, Jaclyn A Biegel, Ben Ho, Claire Mazewski, Victor Lewis, Ian F Pollack, Sarah E S Leary, Maryam Fouladi, Alyssa T Reddy","doi":"10.1093/neuped/wuaf015","DOIUrl":"10.1093/neuped/wuaf015","url":null,"abstract":"<p><strong>Background: </strong>Children's Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI).</p><p><strong>Methods: </strong>Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression.</p><p><strong>Results: </strong>Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (<i>P</i> = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (<i>P</i> = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (<i>P</i> = .031) and RT-OS (<i>P</i> = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, <i>P</i> = .38) or gross total resection (<i>P</i> = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (<i>P</i> = .22). M+ had CSI (<i>n</i> = 6) or focal RT (<i>n</i> = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment).</p><p><strong>Conclusions: </strong>RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the p53 pathway to treat atypical teratoid rhabdoid tumors.","authors":"Alaa Refaat, Hyekyung P Cho, Justin S Williams, Jennifer Stripay, Kaley Blankenship, Kimberly S Mercer, Rebekah De Vries, Michele Connelly, Debolina Ganguly, Sarah Robinson, Evan Savage, Nathaniel R Twarog, Ayush Attery, Dipranjan Laha, Kaiwen Yu, Suresh Poudel, Sandeep K Dhanda, Clinton F Stewart, Burgess B Freeman, Charles W M Roberts, Christopher Tinkle, Elizabeth A Stewart, Santhosh A Upadhyaya, Anang A Shelat, Martine F Roussel","doi":"10.1093/neuped/wuaf018","DOIUrl":"10.1093/neuped/wuaf018","url":null,"abstract":"<p><strong>Background: </strong>Rhabdoid tumors (RTs) are rare aggressive pediatric cancers that can arise throughout the body, including in the central nervous system (CNS), where they are called atypical teratoid rhabdoid tumors (ATRTs), and in extra-CNS locations such as kidneys and other soft tissues, where they are designated as malignant rhabdoid tumors (MRTs). We previously identified MDM2 as a therapeutic vulnerability in RTs and showed that treatment with the MDM2 inhibitor idasanutlin (IDA) increased survival in mice bearing MRT xenografts. However, the therapeutic potential of IDA in ATRTs, where the blood-brain barrier limits drug access, was unknown. We hypothesized that combining IDA with selinexor (SEL), a CNS penetrant XPO1 inhibitor, would potentiate p53-mediated activation and increase therapeutic response in vivo.</p><p><strong>Methods: </strong>We characterized XPO1 and the p53 pathway in RT cell lines and patient samples using whole genome sequencing, evaluated the pharmacodynamic consequence of treatment with IDA and/or SEL using immunoblot and quantitative proteomics, and assessed the effect of each agent and the combination on cell viability in vitro and in orthotopic xenograft models in vivo. Mechanisms of therapeutic resistance were identified in ATRT cells subject to long-term cell culture experiments under escalating drug pressure.</p><p><strong>Results: </strong>Selinexor potentiated IDA-induced p53 pathway activation but also caused p53-independent cytotoxicity in ATRT cells. In vivo combination therapy was well-tolerated, reduced tumor burden, and increased survival. The BCL-2 family of proteins was identified as key modulators of intrinsic and acquired resistance.</p><p><strong>Conclusions: </strong>Combining MDM2 inhibitors and XPO1 inhibitors is a promising therapeutic strategy for treating children with ATRT.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"2 1","pages":"wuaf018"},"PeriodicalIF":0.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147523864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential and risks of FLASH radiotherapy in pediatric patients.","authors":"Jan Schuemann, Bethany Rothwell, Anthony Mascia, Yi Fan, Billy W Loo, Torunn Yock, Kevin X Liu, John Perentesis, Daphne A Haas-Kogan","doi":"10.1093/neuped/wuaf014","DOIUrl":"10.1093/neuped/wuaf014","url":null,"abstract":"<p><p>Irradiation at ultra-high dose rates, also termed as 'FLASH' radiotherapy, has generated great interest in radiation oncology due to its potential to preferentially spare healthy tissue without compromising tumor control. Over the past decade, studies on the potential benefits of FLASH radiotherapy (FLASH-RT) have grown rapidly, yet the underlying mechanisms of this differential effect remain poorly understood. Nonetheless, compelling preclinical data, particularly the preservation of cognitive function after whole-brain irradiation, suggest that FLASH-RT may significantly improve quality of life, especially for pediatric patients. Early preclinical (large animal) and adult clinical trials are underway, prompting consideration of how and when to translate this modality to pediatric populations. This review summarizes the current state of FLASH-RT, with a special focus on pediatric CNS applications. We discuss disease-specific opportunities and limitations, how biological and clinical differences between adults and children may influence the FLASH effect, and key factors that must be evaluated before safe and effective pediatric translation.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"2 1","pages":"wuaf014"},"PeriodicalIF":0.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147523882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ten years of pediatric low-grade glioma care in Kenya: Outcomes, progress, and gaps toward achieving global childhood cancer equity.","authors":"Philip Maseghe Mwachaka, Minda Okemwa, Cyrus Mugo, Scott Coven, Richard Ellenbogen, Dalton Wamalwa, Sarah Leary","doi":"10.1093/neuped/wuaf008","DOIUrl":"10.1093/neuped/wuaf008","url":null,"abstract":"<p><strong>Background: </strong>Pediatric low-grade gliomas (pLGGs) are the most common childhood central nervous system tumors and one of the six index cancers prioritized by the WHO Global Initiative for Childhood Cancer because their treatment success depends on strong health system integration, including timely diagnosis, referral to specialist centers, and multidisciplinary care. In low-and middle-income countries like Kenya, these systems are often under-resourced, and outcomes remain poorly described. This study assessed clinical characteristics, care timelines, treatment outcomes, and survival of with pLGGs treated at Kenya's largest referral and teaching hospital.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of pediatric patients (<19 years) who underwent surgery for low-grade gliomas from January 2014 to December 2023. Data was extracted from clinical, imaging, and pathology records. Descriptive statistics, Kaplan-Meier survival analysis, and Cox regression were performed.</p><p><strong>Results: </strong>The cohort consisted of 84 patients (52 males; median age of 8 years). Headache (76.2%), vomiting (41.7%), seizures (28.6%), and limb weakness (27.4%) were the most frequent presenting symptoms. The median time from symptom onset to imaging was 61 days, and to surgery was 97 days. Gross total resection was achieved in 58.3% of cases, and 76.2% had good immediate postoperative function (Glasgow Outcome Score 5). The most common histology was pilocytic astrocytoma (<i>n</i> = 55, 65.5%). Median overall survival was 1408 days with 1-, 3-, and 5-year survival probabilities of 67%, 56%, and 46%, respectively. Extent of resection and postoperative functional status were key predictors of survival.</p><p><strong>Conclusions: </strong>While surgical care provided favorable short-term functional outcomes, long-term survival for children with pLGGs in Kenya remains substantially low. These findings call for urgent development of robust pediatric neuro-oncology multidisciplinary care and structured long-term follow-up pathways.</p>","PeriodicalId":521114,"journal":{"name":"Neuro-oncology pediatrics","volume":"1 1","pages":"wuaf008"},"PeriodicalIF":0.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12642936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}