Kristian Aquilina

Diffuse midline gliomas (DMGs) are near-universally lethal tumours of the childhood central nervous system ^1,2 . In animal models, DMGs form brain-wide integrated networks through neuron-to-glioma synapses ^3–6 and glioma-to-glioma gap junctional coupling ³ . This extensive connectivity robustly promotes the growth and invasion of DMG ^3–9 and other glial malignancies ^10–12 through paracrine mechanisms and direct neuron-to-glioma synapses. However, the organization and clinical implications of these connections in the living human brain remain to be elucidated. Here, we develop tumour network mapping to compute the brain-wide connectivity profile of DMG, defining a conserved brain network across pontine and thalamic DMG associated with patient short-term survival (DMG network). Tumour functional connectivity with the DMG network was independently predictive of patient overall survival across two external validation cohorts. Tumour growth mapped to DMG network-specific trajectories and peak in-network neurometabolic changes across development spatiotemporally aligned with the peak age incidence of DMG. Analyses of single-nucleus RNA sequencing data confirmed diverse synaptic gene enrichment in high-connectivity DMG. Strikingly, incidental surgical resection of high-connectivity thalamic DMG tissue conferred a significant survival advantage. Collectively, these data define a conserved and prognostically important brain network in children with DMG, consistent with the hypothesis that DMGs exploit otherwise healthy brain circuits to promote tumour growth.

As the leading cause of disability and death in children, paediatric traumatic brain injury (pTBI) is a clinical concern that impacts children on a global scale [1]. The incidence of TBI varies dramatically both between and within countries, ranging between 47 and 280 per 100,000 children, and is generally more common in males [1]. All ages are affected by TBI throughout childhood, though typically two peaks during infancy (0-2 years) and adolescence (15-18 years) are the most common intervals [1]. Mild TBIs (mTBIs) are the most frequently diagnosed, accounting for between 75 and 90% of cases, with a vast majority demonstrating no pertinent radiological findings and discharged home without follow-up.

Pleomorphic Xanthoastrocytomas (PXAs) are rare pediatric brain tumors accounting for approximately 1% of primary brain neoplasms in children and young adults. Despite recent imaging and molecular advances, gaps remain in our understanding of their diverse imaging characteristics and clinical outcomes. This study provides a large international, multi-institutional analysis of pediatric PXAs focusing on neuroimaging and clinical outcomes. We conducted a retrospective international multi-center study including 63 pediatric patients with histologically confirmed PXAs. Neuroimaging data were reviewed, and molecular analyses were recorded with emphasis on BRAF V600E mutations and CDKN2A/B deletions. Treatment modalities and clinical outcomes, including progression-free and overall survival, were analyzed using statistical survival models. 73.3% of tumors were CNS WHO grade 2 and 26.7% were CNS WHO grade 3. The median age at diagnosis was 10.7 (IQR 6.9) years. CNS WHO grade 3 tumors were significantly larger at diagnosis, with a median volume of 87,920 mm³ compared with 14,925 mm³ for grade 2 tumors (p = 0.03). BRAF V600E mutations were identified in 78% of cases and CDKN2A/B deletions in 93.5%. On MRI, PXAs typically appeared well-defined, with cortical and leptomeningeal contact (86.0% and 56.4%, respectively), frequent cysts (59.6%), and intermediate diffusivity (mean ADC 1005 × 10^-6 mm²/s). CT imaging showed most tumors were isointense to gray matter (52.0%), with hydrocephalus more common in grade 3 tumors (71.4% vs. 26.3%, p = 0.07). Gross total resection was achieved in 73.7% of cases and was associated with improved progression-free survival, independent of age at diagnosis and tumor grade (HR = 0.39; 95% CI, 0.16-0.96; p = 0.041). Larger tumor volume correlated with poorer survival outcomes (HR = 3.47; 95% CI, 0.83-14.4; p = 0.087), also independent of tumor grade and age at diagnosis. Tumor recurrence occurred in 44.8% of patients at three years. The estimated three-year overall survival rate was 94.7%. Pediatric PXAs exhibit distinct neuroimaging and molecular features correlating with prognosis. Integrated evaluation of radiological and clinical features is critical to improve risk stratification and guide personalized therapeutic strategies in this rare tumor population.

Background: Optic pathway gliomas (OPG) in infants and young children (IYC) are associated with significant long-term morbidity, but visual outcomes in this high-risk group remain poorly characterized. Methods: We retrospectively reviewed clinical, ophthalmologic, and radiological data from 81 children diagnosed with OPG before age 3 and followed at a single institution between 1981 and 2020. Best-corrected visual acuity (BCVA) was assessed using age-adjusted criteria and REiNS recommendations. Survival outcomes and prognostic factors were analysed using Kaplan-Meier and regression models. Results: Thirty-one children underwent initial surgery, four of whom had no further treatment. Sixty-six were treated with chemotherapy (62) or radiotherapy (4) at diagnosis, while 11 were initially observed. At presentation, 74% had abnormal-for-age BCVA, and 33% met criteria for bilateral visual impairment. After a median 11-year follow-up, 81.5% showed abnormal vision, 45.7% were visually impaired, and 26% were bilaterally blind. Only 36% showed BCVA improvement, while 32% worsened. The 10-year visual progression-free survival was 41.3%. Post-chiasmatic tumor involvement was the only independent predictor of visual progression (HR 2.91, P = .033). Most cases of visual deterioration occurred within the first 2 years, but late events up to 16 years post-diagnosis were also observed. Conclusions: IYC with OPG suffer from substantial and often irreversible visual morbidity, frequently already present at diagnosis. Despite long-term survival, functional visual outcomes remain poor. Our findings underscore the urgent need for earlier, vision-directed interventions and long-term visual monitoring. This large single-center cohort provides a robust benchmark for future prospective studies.

Aim This study aimed to identify factors influencing brain volumes at term-equivalent age (TEA) in preterm infants with post-haemorrhagic ventricular dilatation (PHVD) and explore how these volumes, and other factors, correlate with neurodevelopmental outcome (NDO). Method A retrospective cohort study of 84 infants with PHVD managed on a standardised pathway at a single centre between 2012 and 2020. Brain volumes were measured from TEA MRI scans in 31 infants. NDO was assessed at one and two years. Primary analyses included the 31 infants with measured brain volumes. Sensitivity analysis included all 84 infants using multiple imputation for missing brain volumes. Results Sepsis (-12.75mL, 95% CI -17.89 to -7.61) was linked to smaller cerebellar volume. Intubation (-0.09mL/day, 95% CI -0.15 to -0.04) and inotropic support (-3.19mL, 95% CI -6.18 to -0.20) were associated with reduced deep grey matter (dGM) volume. Larger dGM volume predicted lower odds of poor NDO at two years (OR 0.75, 95% CI 0.60 to 0.94). Sensitivity analysis supported these findings. Interpretation dGM volume at TEA could predict NDO among infants with PHVD. Addressing modifiable factors influencing dGM volume may improve outcomes. Understanding associations of independent variables with NDO is essential to evaluate the impact of neurosurgical interventions. What this paper adds - Among infants with post-haemorrhagic ventricular dilatation: - Sepsis was associated with smaller cerebellar volumes at term-equivalent age. - Intubation and inotrope use were associated with smaller deep grey matter volumes at term-equivalent age. - Larger deep grey matter volume at term-equivalent age was associated with improved neurodevelopmental outcome at two years.

Background: Pediatric low-grade glioma (PLGG) is a generally survivable Pediatric CNS tumor, though enduring functional and quality of life (QOL) impairments often occur. To date, PLGG outcome research has relied on quantitative scales, such as PedsQl and has not included survivors’ reports of their lived experiences in years post treatment. Methods: We conducted open-ended semi-structured interviews (OESSIs) with adult long-term PLGG survivors greater than 5 years post treatment in the context of a larger study of prognostic modelling for PLGG. Interview transcripts were analysed using Framework Analysis (FA). Results from the larger study, including medical records, clinically measured functional outcomes (at last follow-up), PedsQl (QOL) score, and responses to the Physical, Educational and Social Assessment Tool (PESAT; a functional questionnaire) and FA results, were compared to assess concordance of the two approaches in assessing life in survival. Results: Ten survivors at a median age of 21 years (18-25 years); at a median duration from diagnosis of 12 years (9-18 years) completed interviews. Open-ended semi-structured interviews identified survivors’ continuing struggle with PLGGs. Even survivors with high QOL scores worked to maintain a normal life. Interviews revealed functional deficits and problems not identified from clinical follow-up, PedsQl or PESAT questionnaires, including seizures, social relationships, employment, and mental health. Conclusions: Survivors’ narratives of their lived experiences provide unique insight into the complex, long-lasting impact of PLGG post treatment. The sometimes-stark differences regarding the nature of survivorship revealed by the different approaches warrant further exploration of the value of survivors’ narrative accounts in outcome research and in informing clinical practice.

Purpose: Postoperative speech impairment (POSI) is a core symptom of cerebellar mutism syndrome (CMS) and is a common complication after the resection of paediatric posterior fossa (PF) tumours. Preoperative glucocorticoids (pGC) are considered standard treatment to reduce tumour oedema; in addition, glucocorticoids are often administered intraoperatively (iGC) to reduce both postoperative nausea and vomiting. The study aims to investigate whether the occurrence of POSI may be associated with pGC and iGC. Methods: In a prospective observational multicentre study, we included children with a PF tumour requiring either resection or open biopsy. The use of pGC and iGC, including drug type and dose, was registered. Postoperative speech status was classified as mutism, reduced speech, or habitual speech, where mutism and reduced speech were considered POSI of higher and lower severity, respectively. Proportional odds logistic regression with adjustment for tumour type, tumour location, and age was used to analyse the occurrence of POSI associated with glucocorticoids (GC). Results: From August 2014 to November 2024, we recruited 810 children, of whom 605 were included in the primary analysis. We found no association between the use of GC (pGC nor iGC) and the occurrence of POSI. The result did not change when adjusting for tumour type, tumour location, and age. The analysis included both a comparison between using and not using pGC (OR 1.06 [95% CI 0.46 –2.49], reference level: use of pGC) and/or iGC (1.28 [0.58–2.82], reference level: use of iGC), and a dose–response analysis of the occurrence of POSI in relation to doubling the dose of GC (pGC OR 1.28 [0.84–1.98]; iGC OR 1.07 [0.62–1.82]). Conclusion: Our study did not find evidence of a significant change in the occurrence of POSI with the use of pGC or iGC, but our results alone cannot rule out that the administration of pGC or iGC may have some effect. Therefore, our data do not call for a change in recommendations for the use of GC as protection against the development of POSI. Trial registration number: Clinicaltrials.gov (NCT02300766). Date of registration: November 25, 2014