Abstract Background and aims Despite advances in molecular characterization, CNS tumours remain the leading cause of cancer-related mortality in children, underscoring the need for more clinical research. This study analyses the current clinical trial landscape for the two most common paediatric CNS tumour entities: gliomas and embryonal tumours. Methods A comprehensive analysis was conducted using ClinicalTrials.gov dataset with the following keywords: high-grade glioma, low-grade glioma, diffuse midline glioma, diffuse intrinsic pontine glioma, CNS embryonal tumors, medulloblastoma, and atypical teratoid/rhabdoid tumor. All trials involving these tumor entities and initiated since January 1, 2010, were included. Trial characteristics were extracted and analyzed using descriptive statistics. Results As of the data cutoff point on January 1, 2026, 379 clinical trials were identified, including 238 glioma, 71 CNS embryonal tumor, and 70 multi-entity trials. Most trials were interventional (89.5%) and treatment-oriented (85.8%). Among these trials 283 were early phase with only 18 phase 3 trials. Trials were evenly distributed between multicenter (53.9%) and single-center designs (46.1%). At the time of analysis, 181 trials were active, 118 had been completed, and 53 were terminated, with slow recruitment accounting for 19.61% of terminations. Randomization was applied in only 48 trials. Outcome reporting was limited, with results available for 70 trials. All studies reporting outcomes were interventional, while no observational studies reported results (20.64% vs 0%, p = 0.001). Multicenter trials demonstrated higher rates of result reporting compared with single-center trials (25.87% vs 9.88%, p = 0.001). Importantly, only 39 trials exclusively enrolled pediatric patients (ages 0–17). Conclusions Despite the biological distinctiveness of pediatric CNS tumors, most trials enroll both pediatric and adult populations. Even among pediatric studies, few are tumor-specific, complicating result interpretation. The predominance of early-phase, non-randomized designs, along with slow recruitment and limited reporting, underscores the urgent need for multicenter, pediatric-focused, disease-specific trials to improve outcomes in pediatric CNS tumors.

BACKGROUND:Exercise-associated cardiac arrhythmias may contribute to poor performance and sudden cardiac death in horses. Widespread monitoring is limited by device availability and suitability for field use. OBJECTIVES:To (1) compare electrocardiographic (ECG) quality from a smart textile system (Myant Skiin Equine) with a reference device (Televet II) during exercise, and (2) evaluate whether arrhythmia detection with Myant Skiin Equine is comparable to the Televet II. STUDY DESIGN:Prospective blinded clinical study. METHODS:Fifty racehorses (25 Thoroughbreds, 25 Standardbreds) underwent up to three high-speed exercise sessions, with simultaneous ECG recordings from both devices. Recordings were assessed for diagnostic quality and arrythmia detection. RESULTS:Simultaneous ECGs were recorded with both systems across 123 exercise sessions. Median (IQR) peak speed during exercise was 14.7 m/s (13.5-16.2). Twenty-nine (12%) recordings were non-diagnostic due to ≥10% artefact throughout the session (10 Myant; 19 Televet). The Myant Skiin Equine produced more artefact-free recordings (94/123; 76%) than the Televet II (45/123; 37%) (95% CI 28-46%; p < 0.001). Mean maximum heart rate (217.8 ± 10.1 bpm Myant; 217.6 ± 9.9 bpm Televet) showed strong agreement between devices (ICC = 0.995, mean bias = -0.153 bpm). In 79 paired diagnostic recordings assessed for arrhythmia detection, arrhythmias were detected in 85% of recordings, and in 43/50 horses (86%; 95% CI 73-94%). Agreement for arrhythmia classification was 97.5% (k = 0.96), with all discrepancies occurring because of artefact. MAIN LIMITATIONS:Modest sample size and exclusion of some recordings due to artefact and horse withdrawal. Only the best-quality lead per recording was analysed, limiting multi-lead assessment and arrhythmia characterisation. Differences in device software and data handling may have influenced signal interpretation. CONCLUSION:The Myant smart textile system provides ECG recordings of comparable quality and arrhythmia detection to Televet II during high-speed exercise in racehorses. This technology offers a practical and alternative tool for field-based cardiac monitoring and may facilitate broader adoption.

BACKGROUND:Infant medulloblastoma (age <3-5 years at diagnosis) is a major challenge in paediatric oncology. Clinical studies of molecularly defined non-WNT/non-SHH infant medulloblastoma (~60% of cases) have not been done, and this group is currently considered to have uniformly high risk. Understanding the potential for its biological subclassification and clinical stratification is an essential goal towards improved outcomes. This study therefore aimed to directly compare different therapeutic approaches in non-WNT/non-SHH infant medulloblastoma and assess the relationships between outcomes and clinicomolecular features. METHODS:We assembled an international cohort of infants with non-WNT/non-SHH medulloblastoma identified from non-trial cohorts in nine countries. Inclusion criteria were age 0-5 years and a principal non-WNT/non-SHH medulloblastoma classification (group 3 [MBGroup3] or group 4 [MBGroup4]; confidence score >0·8) using DNA methylation array-based classification. Patient clinical and molecular data were collected from contributing institutions and centrally reviewed using standardised annotation protocols. A survival cohort was defined by the availability of complete progression-free and overall survival data, and grouped by whether principal upfront therapy included craniospinal irradiation or consisted of chemotherapy only. Chemotherapy was subclassified into high-dose, intraventricular methotrexate-based, and standard-dose regimens. We assessed the relationships between tumour molecular pathology, treatments received, and outcomes (progression-free and overall survival) using Kaplan-Meier plots, univariable log-rank tests, and Cox regression. FINDINGS:The total collected cohort (n=375) comprised 262 males and 110 females (three patients had missing sex data), with a median age of 3·0 years (IQR 2·5-4·0). MBGroup3 tumours predominated (246 [66%] of 375 patients), among which molecular subgroups 4 (98 [40%]), 2 (75 [30%]), and 3 (46 [19%]) were most common. The remaining 129 (34%) of 375 patients had MBGroup4 tumours. 313 patients were included in the survival cohort. Upfront craniospinal irradiation was associated with significantly better 5-year progression-free survival (62% [95% CI 55-70]) than non-craniospinal irradiation approaches (including focal radiotherapy or chemotherapy-only strategies; 33% [23-44]; p<0·0001). When upfront chemotherapy-only approaches were used, high-dose chemotherapy produced better survival rates (5-year overall survival 60% [95% CI 42-87]) than standard-dose chemotherapy (27% [13-57]). Patients with MBGroup3 subgroup 4 represented a novel chemosensitive group, with 5-year progression-free survival of 64% (95% CI 44-95) when treated upfront with high-dose chemotherapy only (n=14). Patients with MBGroup3 subgroup 2 or 3 with MYC amplification (n=10) had 5-year progression-free and overall survival rates of 0% when treated with chemotherapy only. Patients with MBGroup3 subgroup 2 or 3 without MYC amplification who were treated upfront with chemotherapy only (n=10) had 5-year progression-free survival of 30% (12-77) and 5-year overall survival of 58% (34-100). INTERPRETATION:Non-WNT/non-SHH infant medulloblastoma outcomes are associated with specific biomarkers and type of therapy received. This real-world experience identifies a favourable-risk group (MBGroup3 subgroup 4) with good prognosis and a very-high-risk group (MBGroup3 subgroup 2 or 3 with MYC amplification) with poor prognosis, providing a foundation for biomarker-driven MBGroup3 clinical trials. FUNDING:Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero, and Blue Skye Thinking.

Importance:Understanding the reasons for variations in population-level survival differences in childhood cancer is important to guide improvement efforts. Collaboration between population-based cancer registries (CRs) to apply the international consensus Toronto guidelines to record tumor stage at diagnosis is a key first step. Objective:To test whether survival probabilities by tumor stage vary internationally, using 6 childhood solid tumors as exemplars. Design, Setting, and Participants:The International Benchmarking of Childhood Cancer Survival by Stage (BENCHISTA) population-based retrospective cohort study included all incident cases of neuroblastoma, Wilms tumor, medulloblastoma, osteosarcoma, Ewing sarcoma of bone, and rhabdomyosarcoma diagnosed between January 1, 2014, and December 31, 2017, with 3-year follow-up for survival. A total of 73 CRs from 27 countries (23 European as well as Australia, Brazil, Canada, and Japan) constituted the dataset. Analyses were conducted from June 2023 to December 2024. Main Outcomes and Measures:Three-year overall survival (OS) by stage for each tumor type, with comparisons between countries grouped into 5 predefined European areas. Multivariable Cox and logistic models estimated each area's hazard or odds ratio of death compared with Central Europe (Austria, Belgium, France, Germany, Switzerland, and the Netherlands), adjusted by age group and stage. Results:A total of 9883 cases were included; 4452 (45%) were girls and overall median (IQR) age was 54 (22-122) months; stage completeness was 93% (9199 of 9883). Three-year OS rates were as follows: Wilms tumor, 95% (95% CI, 94%-96%); neuroblastoma, 83% (95% CI, 81%-84%); medulloblastoma, 79% (95% CI, 77%-81%); Ewing sarcoma, 78% (95% CI, 75%-80%); rhabdomyosarcoma, 77% (95% CI, 74%-79%); and osteosarcoma, 75% (95% CI, 73%-77%). Geographical variations in age-adjusted OS were found for neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdomyosarcoma. Following additional adjustment for stage, differences were no longer significant for neuroblastoma (in the UK and Ireland) and rhabdomyosarcoma (in Eastern Europe) while becoming significant for neuroblastoma in Eastern Europe (hazard ratio, 1.36; 95% CI, 1.05-1.76) and medulloblastoma in Southern Europe (hazard ratio, 1.42; 95% CI, 1.03-1.94). However, no mitigation of survival variation was observed for Ewing sarcoma in the UK and Ireland (hazard ratio, 2.06; 95% CI, 1.39-3.04) and Eastern Europe (hazard ratio, 1.87; 95% CI, 1.22-2.86) as well as for medulloblastoma in Eastern Europe (hazard ratio, 1.68; 95% CI, 1.13-2.49). Conclusions and Relevance:In this BENCHISTA cohort study of 6 solid tumors, international variation in population-level OS was associated with differences in tumor stage distribution for some cancer types and regions. Additional factors are suggested for further investigation. The results have important implications for national health systems for monitoring early diagnosis efforts and supporting collaboration between CRs and clinicians to sustain standardized use of Toronto guidelines to improve understanding of survival variation in childhood cancer.

Abstract Introduction Medulloblastoma (MB) is the most common malignant paediatric brain tumour with standard-risk five-year survival approaching 75%[1][2] . Multimodal therapy imposes substantial neurocognitive burden and diminished health-related quality of life in long-term survivors[1][3]. Identifying biological determinants of survivorship outcomes represents a priority for risk-stratified intervention[3][4][5][6][7][8][9][10]. Methods We undertook an integrated clinico-molecular analysis of patients from the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Quality of survival was assessed in 218 patients using the Health Utilities Index (HUI3), Strength and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). Neuropsychometric assessment employed Wechsler Intelligence Scale (WISC IV) in 140 patients. Patients were classified into molecular groups (WNT, SHH, MBGrp3, MBGrp4)[11][12]. In HIT-SIOP-PNET4 patients (n = 74), 39 single nucleotide polymorphisms with reported neurocognitive-modifying effects were genotyped by Agena MassARRAY. Results SIOP-UKCCSG-PNET3 patients receiving chemotherapy prior to craniospinal irradiation demonstrated significantly reduced health status (p = 0.019) and increased behavioural difficulties (p < 0.001) compared to both conventional and hyperfractionated radiotherapy arms in HIT-SIOP-PNET4. SHH patients demonstrated superior quality of life relative to WNT and MBgrp4 (p < 0.0191). Neuropsychometric performance showed no association with molecular group or clinico-demographic variables. However, 7 SNPs (rs1050450, rs11611788, rs1695, rs1801131, rs4708867, rs4880, and rs9476886) were significantly associated with WISC domains, with five showing associations across multiple cognitive domains. Conclusion This integrated analysis identifies distinct clinical and molecular determinants of survivorship outcomes. Germline genetic modifiers of neurocognitive function provide potential targets for risk stratification and targeted therapeutic development. These findings support integrating biological determinants, patient-reported outcomes, and direct neuropsychometric assessments into clinical trial design to inform risk-adapted therapeutic strategies and precision approaches to counselling, surveillance, intervention and rehabilitation. 1. S. Bailey, S. Jacobs, M. Kourti, M. Massimino, N. Andre, F. Doz, C. Dufour, S. Vennarini, L. Padovani, K. Aquilina, U. Thomale, A. Joshi, T. Pietsch, S. Avula, G. Morana, S. Rutkowski, B. Pizer, SC Clifford, Medulloblastoma therapy: Consensus treatment recommendations from SIOP-Europe and the European Reference Network, EJC Paediatric Oncology, Volume 5, 2025, 100205, ISSN 2772-610X, https://doi.org/10.1016/j.ejcped.2024.100205. 2. Mani S, Chatterjee A, Dasgupta A, Shirsat N, Epari S, Chinnaswamy G, Gupta T. WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go? Oncotarget. 2023 Feb 7;14:105-110. doi: 10.18632/oncotarget.28360. PMID: 36749287; PMCID: PMC9904321. 3. Chevignard M, Câmara-Costa H, Doz F, Dellatolas G. Core deficits and quality of survival after childhood medulloblastoma: a review. Neurooncol Pract. 2017 Jun;4(2):82-97. doi: 10.1093/nop/npw013. Epub 2016 Aug 26. PMID: 31385962; PMCID: PMC6655396. 4. Frič, R., Due-Tønnessen, B.J., Lundar, T. et al. Long-term outcome of posterior fossa medulloblastoma in patients surviving more than 20 years following primary treatment in childhood. Sci Rep 10, 9371 (2020). https://doi.org/10.1038/s41598-020-66328-8 5. Aktekin, E.H., Kütük, M.Ö., Sangün, Ö. et al. Late effects of medulloblastoma treatment: multidisciplinary approach of survivors. Childs Nerv Syst 40, 417–425 (2024). https://doi.org/10.1007/s00381-023-06146-1 6. Hugo Câmara-Costa, Kim S Bull, Colin Kennedy, Andreas Wiener, Gabriele Calaminus, Anika Resch, Virginie Kieffer, Clémence Lalande, Geraldina Poggi, Katja von Hoff, Jacques Grill, François Doz, Stefan Rutkowski, Maura Massimino, Rolf-Dieter Kortmann, Birgitta Lannering, Georges Dellatolas, Mathilde Chevignard, on behalf of the Quality of Survival working group of the Brain Tumour Group of SIOP-Europe, Quality of survival and cognitive performance in children treated for medulloblastoma in the PNET 4 randomized controlled trial, Neuro-Oncology Practice, Volume 4, Issue 3, September 2017, Pages 161–170, https://doi.org/10.1093/nop/npw028 7. Bull, K.S., Kennedy, C.R., Bailey, S. et al. Improved health-related quality of life outcomes associated with SHH subgroup medulloblastoma in SIOP-UKCCSG PNET3 trial survivors. Acta Neuropathol 128, 151–153 (2014). https://doi.org/10.1007/s00401-014-1300-4 8. Kim S. Bull et al. Reduction of Health Status 7 Years After Addition of Chemotherapy to Craniospinal Irradiation for Medulloblastoma: A Follow-Up Study in PNET 3 Trial Survivors—on Behalf of the CCLG (formerly UKCCSG). JCO 25, 4239-4245(2007). DOI:10.1200/JCO.2006.08.7684 9. Colin Kennedy, Kim Bull, Mathilde Chevignard, David Culliford, Helmuth G. Dörr, François Doz, Rolf-Dieter Kortmann, Birgitta Lannering, Maura Massimino, Aurora Navajas Gutiérrez, Stefan Rutkowski, Helen A. Spoudeas, Gabriele Calaminus, Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma, International Journal of Radiation Oncology*Biology*Physics, Volume 88, Issue 2, 2014, Pages 292-300, ISSN 0360-3016, https://doi.org/10.1016/j.ijrobp.2013.09.046. 10. Hugo Câmara-Costa, Anika Resch, Virginie Kieffer, Clémence Lalande, Geraldina Poggi, Colin Kennedy, Kim Bull, Gabriele Calaminus, Jacques Grill, François Doz, Stefan Rutkowski, Maura Massimino, Rolf-Dieter Kortmann, Birgitta Lannering, Georges Dellatolas, Mathilde Chevignard, Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy, International Journal of Radiation Oncology*Biology*Physics, Volume 92, Issue 5, 2015, Pages 978-985, ISSN 0360-3016, https://doi.org/10.1016/j.ijrobp.2015.04.023. 11. Goschzik T, Schwalbe EC, Hicks D, Smith A, Zur Muehlen A, Figarella-Branger D, Doz F, Rutkowski S, Lannering B, Pietsch T, Clifford SC. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 2018 Dec;19(12):1602-1616. doi: 10.1016/S1470-2045(18)30532-1. Epub 2018 Nov 1. PMID: 30392813; PMCID: PMC6262170. 12. Schwalbe EC, Williamson D, Lindsey JC, Hamilton D, Ryan SL, Megahed H, Garami M, Hauser P, Dembowska-Baginska B, Perek D, Northcott PA, Taylor MD, Taylor RE, Ellison DW, Bailey S, Clifford SC. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013 Mar;125(3):359-71. doi: 10.1007/s00401-012-1077-2. Epub 2013 Jan 5. PMID: 23291781; PMCID: PMC4313078.

Background: We present three patients who developed symptomatic hypercalcaemia following discontinuation of the Type II RAF inhibitor, Tovorafenib. Methods: We report three paediatric cases who had been enrolled in the phase 2 FIREFLY-1 (PNOC026; NCT04775485) Kilburn et al. (2024), which was investigating the safety and efficacy of Tovorafenib monotherapy in patients with relapsed or refractory paediatric low-grade glioma (pLGG) harbouring a KIAA-BRAFfusion or BRAF V600E mutation. Hypercalcaemia was detected within weeks after discontinuation of Tovorafenib. Results: Adjusted serum calcium concentrations at first presentation were 2.91 mmol/L at 21 days (Patient 1), 3.06 mmol/L at 14 days (Patient 2), and 3.58 mmol/L at 26 days (Patient 3) following cessation of Tovorafenib. Calcium concentrations normalised following treatment with additional fluid and, in two of the patients, a single dose of bisphosphonate. Conclusion: We suspect that the hypercalcaemia reflects a rebound increase in bone turnover following Tovorafenib discontinuation and recommend that monitoring bone biochemistry after treatment cessation be considered as part of management protocols.

Lay Summary Paediatric Low-Grade Glioma (PLGG) is the commonest brain tumour of childhood. Most children and young adults under eighteen years old with PLGG will survive long-term, but many will face functional or quality of life consequences from the tumour and its required treatment. Accordingly, research efforts have focused on developing new treatments which are more effective and less toxic which target the underlying genetic changes within the MAPK pathway known to cause PLGG growth. Over the last few years, these new and targeted therapies are increasingly being used in PLGG but outside of more standardised and monitored clinical trials, without consistency regarding when to start the new therapies or the required supportive care that patients receive alongside these new drugs. We provide the first national real-world efficacy and toxicity data from a large PLGG cohort receiving MAPKi outside of clinical trials in the UK. We collected data from 50 patients treated with MAPK inhibitor therapy (MAPKi) between 2016 and 2024 across 7 UK Paediatric Brain Tumour centres. We collected standardised assessments of tumour response to treatment on MRI scan (Radiological response), visual responses in those with tumours involving the optic pathway, and survival outcomes (overall survival and progression of tumours; progression-free survival). We also collected and analysed data on treatment side effects, need for dose reductions or stopping of therapy earlier than 2 years. We calculated the ratio of duration of response on MAPKi compared to prior chemotherapy which is a recognised measure of MAPKi treatment benefit. At a median period of 3.5 years from starting MAPKi therapy, 96% of patients remained alive but 38% had tumour progression. Seventy-four percent of patients had a radiological benefit from MAPKi therapy observed on MRI imaging (stable disease 54%, partial response 20%). Of 35 patients with optic pathway tumours, 72% had visual benefit from MAPKi therapy (63% stable, 9% improved). Seventy-seven patients had a prolonged MAPKi: prior chemotherapy ratio of > 1.3: 1 demonstrating superior benefit from MAPKi therapy compared to prior chemotherapy. We conclude that MAPKi therapies provide safe and effective treatment for PLGG, with significantly prolonged periods without tumour progression compared to prior chemotherapy.

Radiographic morphometry provides a quantitative means to evaluate bone conformation in horses, yet validation of these parameters in foals has not previously been undertaken. This study aimed to determine the intra- and inter-rater repeatability and reproducibility of established carpal and third metacarpal (MC3) radiographic parameters in Thoroughbred foals and to establish baseline conformational data. Twenty Thoroughbred foals were radiographed without sedation from birth to 14 months of age at two-month intervals. Dorsopalmar carpal and lateromedial MC3 radiographs were obtained using standardised protocols. Fifteen individual and eleven relative angular carpal parameters, along with three MC3 cortical dimensions, were measured three times by two evaluators. Intra-class correlation coefficients (ICC) and Bland-Altman analyses were used to assess reliability. All parameters were measurable in vivo, and intra-rater repeatability was excellent (ICC > 0.9) for 6 of 15 (40%) individual angular carpal and all MC3 variables. Inter-rater repeatability was excellent for eight individual and six relative carpal parameters. MC3 cortical dimensions demonstrated excellent agreement between and within raters (ICC > 0.9; bias ≤ 0.09 mm). These findings indicate that standardised radiographic methods can be reliably applied to foals to quantify carpal and metacarpal conformation. The validated parameters and baseline data established here provide a foundation for future investigations of skeletal growth, conformation, and injury risk in young Thoroughbred horses.

Background The carpal and third metacarpal (MC3) bones of the equine forelimb undergo morphological adaptation during early growth, influenced by developmental and mechanical factors. However, the longitudinal interactions between dorsal carpal morphology and MC3 structural characteristics have not been fully characterized. Improved understanding of these relationships may help identify morphological indicators associated with bone injury risk before training. Objectives To examine the longitudinal associations between dorsal carpal angular morphology and MC3 diaphyseal parameters in growing Thoroughbred foals. Methods Twenty Thoroughbred foals were followed from within two weeks after birth to 14 months of age. Dorsopalmar carpal and lateromedial MC3 radiographs were obtained at two-month intervals. Two dorsal carpal angular parameters and three MC3 parameters (dorsal cortical width, total bone length, and a radiographic index representing relative dorsal cortical thickening and structural adaptation previously associated with peak strain at the dorsal midshaft) were measured using ImageJ software. Linear mixed-effects models were applied, with foal identity as a random effect and age and limb side as fixed effects. Results Both dorsal carpal parameters were positively associated with MC3 length, dorsal cortical width, and radiographic index. The strongest association was observed between proximal dorsocranial inclination and the radiographic index (2.55 ± 0.25° per unit increase; p < 0.001). Conclusions These findings demonstrate significant longitudinal associations between dorsal carpal angulation and MC3 structural parameters during early limb development. While this pattern is consistent with mechanical adaptation, the observational study design does not permit direct causal inference or differentiation between growth-related and exercise-related loading effects.

Background:Pediatric central nervous system (CNS) tumors are the leading cause of cancer-related death among children and adolescents globally. Despite the complex and multidisciplinary care needed, there is limited evidence on standardized quality indicators (QIs) for pediatric neuro-oncology (PNO). Methods:A modified Delphi process was conducted to develop consensus-based QIs for PNO. Candidate indicators were identified through a systematic review of published literature. After expert screening, indicators were evaluated by a multidisciplinary panel through 2 rounds of Delphi surveys. Consensus was defined as ≥75% agreement. A subsequent consensus meeting and tiering process were conducted to categorize the selected indicators. Results:The systematic review identified 35 studies containing 124 relevant indicators; these were subsequently refined to 63 candidate indicators for evaluation in 2 Delphi surveys. Thirty-two experts from 5 specialties and 15 countries participated in the consensus process. A consensus was established that included that indicators would have the following 3 characteristics: reflect the continuum of PNO care, be continuous variables, and be feasible to measure across diverse resource settings. Through 2 rounds of Delphi surveys, a total of 48 indicators met the consensus threshold. Indicators were subsequently consolidated to 31, following discussion and merging of overlapping items. Final indicators were categorized into 2 sets: 19 core indicators and 12 extended indicators. Conclusions:By providing a framework for evaluating quality across the continuum of PNO care, these indicators can aid benchmarking and guide quality improvement interventions. Prospective validation and assessment of their impact on patient outcomes are still needed.

Background Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMBSHH). Comparison of these therapies in large molecularly defined iMBSHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies. Methods In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMBSHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMBSHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS). Findings Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMBSHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMBSHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-naïve iMBSHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMBSHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MBSHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-naïve PFS findings were validated in a re-evaluation of smaller historical trials cohorts. Interpretation Our findings show that iMBSHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMBSHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Funding Cancer Research UK, Children with Cancer UK, Children’s Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.

Rare paediatric central nervous system (CNS) tumours comprise a biologically-heterogeneous group of low-incidence diseases that present significant challenges to both therapeutic development and clinical research, limiting the availability of high-quality evidence to guide clinical care. The UK3CR Children’s Cancer Research Group (CRG) CNS Tumours Subgroup convened a multidisciplinary workshop to identify research priorities and establish a strategic framework for advancing clinical trials in this setting. Four high-priority tumour groups—craniopharyngioma, choroid plexus carcinoma (CPC), very high-risk medulloblastoma (VHR-MB), and rare embryonal and sarcomatous tumours (REST), including embryonal tumour with multilayered rosettes (ETMR)—were evaluated. Key outcomes included the feasibility of a UK-led craniopharyngioma trial, the need for enhanced national CPC data collection, and support for European early-phase platform trials in VHR-MB. REST highlighted transnational regulatory complexity requiring coordinated registries and parallel trial models. Cross-cutting barriers included regulatory discordance, contracting delays, fragmented funding, pharmacovigilance differences, data-sharing constraints, and interoperable infrastructures. The workshop emphasised innovative methodologies, including Bayesian/adaptive designs, platform trials, and external control arms, to maximise efficiency in small populations, alongside strengthened patient involvement and international collaboration. Collectively, these findings define a collaborative and internationally-aligned strategic roadmap to accelerate clinical research and improve outcomes in rare paediatric CNS tumours.

Abstract Background The type II RAF inhibitor tovorafenib is US FDA-approved for patients ≥6 months of age with BRAF-altered, relapsed/refractory, pediatric low-grade glioma (pLGG). It is hypothesized that tovorafenib may inhibit CRAF within growth plate chondrocytes, slowing growth plate maturation and linear growth. This analysis investigated growth recovery after treatment with tovorafenib and factors that may impact growth recovery trajectories. Methods This was a retrospective pooled analysis of on- and off-treatment growth in children with BRAF-altered relapsed/refractory pLGG treated with tovorafenib for ≥6 months in two clinical trials and an expanded access program. Patients had to have at least one height measurement recorded >90 days post-treatment as of December 16, 2024. Growth suppression, recovery, and catch-up growth were derived from annualized growth velocity on and off treatment. Exposure–growth models explored growth patterns on and off treatment. Results Sixty-eight patients were included with median (range) baseline age of nine (2-16) years and median follow up 10 months post-treatment. Ninety percent of patients exhibited growth suppression during treatment, of whom 93% showed early post-treatment growth recovery and 77% showed catch-up growth. Reversible growth suppression was observed in both sexes across ages. Of 26 patients with on-treatment bone age, there was no abnormal advancement of bone age on or off treatment. Exposure–growth models suggest that younger baseline age may be associated with faster growth recovery off treatment. Conclusions Growth suppression observed with tovorafenib was reversible, with evidence of post-treatment growth recovery and catch-up growth in most patients. Clinical trials NCT04775485 (FIREFLY-1); NCT03429803 (PNOC014); NCT05760586 (Expanded Access Program).

BACKGROUND:Due to the novelty and rarity of infant-type hemispheric glioma (IHG), optimal treatment and factors determining clinical outcomes are yet to be established. METHODS:We curated a series of 164 patients with IHG; 155 identified by methodical literature search and nine additional patients contributed by collaborators. RESULTS:All tumors were hemispheric, diagnosed at a median age of 3.4 (0-52) months, and frequently (95%) non-metastatic. One hundred forty-two (86.5%) tumors harbored fusions involving receptor tyrosine kinase (RTK) genes (ALK [67/142, 47%], NTRK1/2/3 [32/142, 22.5%], ROS1 [29/142, 20.4%], MET [13/142, 9.2%], and ABL2 [1/142, 0.7%]). Sixty-four percentage, 20%, and 8% of patients were treated with surgery and adjuvant chemotherapy, surgery-only, and surgery plus targeted therapy, respectively. Five patients received radiation. Three-year event-free survival (EFS) and overall survival (OS) was 49.5% [40.7-60.2] and 79.6% [72.1-87.9], respectively. Twenty-two patients succumbed to disease, of which tumor progression (8/22, 36%) and intra-cranial hemorrhage (5/22, 23%) were the most common causes. Multivariate analysis showed that the factors most associated with an increased risk of death were no treatment except for surgery and presence of residual tumor after definitive surgery. These findings present a challenging dichotomy where surgery is both a serious risk factor for early death and, when successful, a benefit. CONCLUSIONS:Together, these findings show that IHG is a fusion driven tumor of the very young that is survivable even after progression. While optimal primary therapy for patients with IHG has yet to be established, the findings of this meta-analysis suggest treatment should focus on lowering surgical morbidity and improving its success.

Abstract Background Infant MB (iMB) treatment strategies may include adjuvant focal RT (fRT) for local control, to minimize neurocognitive side-effect of craniospinal irradiation (CSI). From a large international cohort of 380 relapsed iMB, we previously described fRT was associated with worse post relapse survival (PRS) compared to chemotherapy alone, in univariate analysis. Methods We performed a sub-analysis of patients initially treated with adjuvant fRT, to describe their pattern of relapse and salvage practices. Results The cohort included 51 patients who relapsed after initial fRT (median dose: 54 Gy) along with conventional in 47 patients or high-dose chemotherapy (HDC) in 4 patients. Median age at diagnosis was 34.2 months (range 11-55). At initial diagnosis, 42(85.7%) achieved gross total resection and 46(90.2%) were localized. Maintenance therapy or intrathecal/intraventricular chemotherapy were added in 14 patients. Molecular subgrouping was available in 31 patients (8 SHH, 17 group 3, 6 group 4). Median time of relapse was 13 months from diagnosis (5-51.9). Relapse was disseminated or combined (local and distant) in 96% of the cases. Twelve patients (24%) underwent palliative management. Thirty-nine (76%) patients received curative intent salvage therapy, of which 31 (79%) received CSI (median dose of 36 Gy, range 18-39.6). CSI was administered alone in 22% or with conventional chemotherapy or HDC in 65% and 13% . The 5 years PRS was 20.8% (±9%). Female sex, age <24 months at diagnosis, late relapse ≥12 months from diagnosis, asymptomatic relapse, salvage CSI, CR post-salvage therapy were associated with better PRS. Patients salvaged with CSI had a 5-year PRS of 26.5% vs 0% without. Conclusion Following adjuvant fRT, almost all patients who relapsed presented with dissemination, despite initial localized disease, and dismal PRS. Focal RT in combination with upfront therapy is ineffective to prevent leptomeningeal relapses and the success of salvage CSI is limited.

10029 Background: Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor that targets BRAF and CRAF. Based on preclinical data, CRAF plays an essential role in chondrocyte maturation, a required step in linear bone growth. Children treated with tovorafenib in early phase studies demonstrate a reversible decrease in growth velocity consistent with CRAF inhibition with no signs of premature closure of growth plates or adverse effects on bone such as fractures or treatment emergent osteopenia. Here we report a combined analysis of off-treatment growth recovery in patients treated with tovorafenib in 3 clinical studies. Methods: Patients aged < 18 years with BRAF altered relapsed/refractory LGG treated with tovorafenib in the Phase 1 PNOC014 study (NCT03429803), Phase 2 FIREFLY-1 study (NCT04775485), or Expanded Access Program (EAP) for patients (NCT05760586) were included. Relevant medical history, neuroendocrine medications, growth parameters, and tovorafenib dosing were collected. Pre- and post-treatment annualized growth velocity (AGV) was calculated for all patients with growth data available ≥90 days post-discontinuation of tovorafenib. Results: As of 17-Jan-2025,38 / 167 (23%) patients were evaluable for growth recovery. Among these evaluable patients, median age at start of treatment was 9.5 yrs (range 3.5 -16.5). Eighteen (47%) patients had a tumor associated endocrinopathy or comorbidity that may affect growth including growth hormone deficiency (8), thyroid disease (8), precocious puberty (6) and panhypopituitarism (4) at baseline. Four (11%) were receiving a gonadotropin-releasing hormone analogue for precocious puberty and 2 (5%) were receiving growth hormone replacement concurrent with tovorafenib. Median baseline height Z-score was -0.13 (range -2.57, 2.64) with 4 patients having Z-score > 2 or < -2. Median on-treatment AGV was 1.7 cm/yr [n = 36, interquartile range (IQR) 0.4 - 2.2] at 12 mo and 2.3 cm/yr (n = 25, IQR 0 - 3.3) at 24 mo. Median age at end of treatment was 11 yrs (range 4.4 - 17.5), and median off-treatment follow up was 10.3 mo (range 3.2 - 37.2). Median off-treatment AGV was 4.3 cm/yr (n = 38; IQR 1.8 - 7.6) at 3 mo, 10.2 cm/yr (n = 26, IQR 2.3 - 13.8) at 6 mo and 7.7cm/yr (n = 5, IQR 4.1 - 13.9) at 12 mo. Thirty-four (89%) patients had recovery of AGV, and 28 (74%) had an increase in Z-score towards baseline indicating catch-up growth. Patients with slow AGV recovery tended to be > 15 years, younger females with precocious puberty/Tanner stage 4, or have only 3 months of off-treatment follow up. Conclusions: Decreases in growth velocity were common during tovorafenib treatment. Majority of patients to date demonstrate AGV recovery as early as 3 months with signs of catchup within 6-12 months after stopping tovorafenib. Preliminary findings indicate tumor-associated precocious puberty/Tanner stage 4 in females may be a risk factor for slow AGV recovery.

Background: Due to the high frequency of laminitis reported for both conditions, the relationship between pituitary pars intermedia dysfunction (PPID) and insulin dysregulation (ID), and the potential role of dopamine in modifying insulin secretion, requires further investigation. Objectives: To evaluate the effect of pergolide mesylate on insulin sensitivity and postprandial insulin and glucose responses in horses and ponies with ID, both with or without concurrent PPID. Study design: Randomised crossover study. Methods: Sixteen horses and ponies, comprising eight matched pairs (PPID+ID or ID-only), were given pergolide mesylate at a dose of 2 mu g/kg bwt orally once daily for 4 weeks (plus a 4-week non-treatment control period, with a 4-week washout between phases). A combined glucose and insulin tolerance test (CGIT) and a standard meal test (SMT; containing 1.1 g/kg bwt of starch and 0.1 g/kg bwt of free sugars), were performed before and after each treatment period to determine insulin sensitivity and postprandial insulin and glucose responses, respectively. Variables derived from the CGIT and SMT were analysed using linear mixed models. Results: Pergolide treatment did not alter any of the variables derived from the CGIT in either the PPID+ID or ID-only groups (all p > 0.05). For the SMT, insulin responses were reduced by pergolide treatment for the PPID+ID group, with Delta change values for the total area under the curve for insulin over 300 mins (estimated marginal mean [95% confidence interval]) being -25.4 (-39.9 to -7.3) min center dot mIU/mL (p = 0.03) and Delta change values for peak insulin concentration being -100 (-167 to -29) mu IU/mL (p = 0.04). No effect of pergolide treatment was detected for the ID-only group. Main limitationsNumber of animals and heterogeneity among groups. Conclusions: Pergolide had no effect on tissue insulin sensitivity. However, the results suggest that postprandial hyperinsulinaemia may be limited by this dopamine receptor agonist in animals with PPID plus ID.