Abstract Purpose Comprehensive data on frequency, clinical characteristics and outcomes of primary metastatic ependymoma in children are limited. Methods Children with intracranial or spinal ependymoma registered between 2000 and 2025 in the “HIT-2000 trial, HIT-2000 interim-registry, I-HIT-MED-registry and SIOP-Ependymoma II study were analysed according to initial staging (postoperative residual tumor, metastases), tumour biology, treatment and outcome based on central neuropathological/-radiological review. Results Among 822 patients, lumbar cerebrospinal fluid (CSF) analysis was available in 763 patients, MRI in all. Metastatic disease was identified in 36 patients (4.4%; 22 males/14 females; median age 11.3 years (range, 0.4–17.1)). Primary tumor site was intracranial (20/766, 2.6%) in 20 patients (PF-EPN-A, n = 10; PF-EPN-B, n = 2; PF-EPN-NOS, n = 1; ZFTA–RELA, n = 3; not classifiable/unknown, n = 4) and spinal (16/56, 28.6%) in 16 (MPE, n = 13; SP-EPN, n = 3). Six intracranial cases showed microscopic CSF positivity only (M1; 0.8% of CSF-staged patients), five relapsed and one died. Intracranial metastases (M2) occurred in 13 patients (intracranial, n = 11; spinal, n = 2), and spinal metastases (M3) in 28 (intracranial, n = 12; spinal, n = 16). Median follow-up time was 5.9 years (SD ± 1.12). Residual tumor after initial surgery persisted in 18 patients (11≥1 re-surgery). First-line radiotherapy was administered to 16 patients (44.4%), most receiving craniospinal irradiation (CSI, n = 13; local radiotherapy only, n = 3). Chemotherapy was applied in 18 patients (50.0%; SKK/mSKK n = 13; high-dose chemotherapy n = 1; others n = 4) with measurable response in 16 patients (CR, n = 3, PR, n = 2, SD, n = 5, and PD, n = 6). Twenty-two tumors relapsed (intracranial, n = 17; spinal, n = 5) and 8 patients died (intracranial, n = 7, including 4 PF-EPN-A; spinal, n = 1). Intracranial primaries had inferior 5-year progression-free and overall survival vs. spinal (PFS, 14.4%±9.2% vs. 63.0%±17.7%, OS, 60.4%±11.7% vs. 100%, pPFS/pOS=0.02/0.12). Conclusion Primary metastatic pediatric ependymoma is rare and differs by primary site. Metastatic intracranial ependymoma is associated with a significantly worse progression-free survival and overall unfavourable outcome compared with metastatic spinal disease.

Abstract Purpose Contemporary therapy protocols suggest to delay or avoid craniospinal irradiation (CSI) by applying intensive chemotherapy in children with medulloblastoma up to the age of three to five years due to the high long-term toxicity of CSI in very young children. The optimal age for switching to a CSI-containing strategy needs to be evaluated. Methods This is a retrospective analysis of a German patient cohort. Patients were eligible if diagnosed with non-WNT/non-SHH medulloblastoma under 7 years of age and DNA- methylation-based classification profiling was available. Treatment was classified as “infant-type”, if CSI was not planned upfront, planned in the case of incomplete response or progression, or was delivered as an individual decision after “infant-type” chemotherapy [max dose 24 Gy] and as “childhood/adult-type” if CSI in standard doses (max dose 24 Gy in standard risk or 35.2/36 Gy for high-risk disease] was delivered first-line treatment. Results 372 patients (263 M/109 F) were eligible. The median age at diagnosis was 4.2±1.5 years. With a median follow-up of 5.7 years in surviving patients, 156 patients relapsed, and 129 died. Overall, 194 patients (52.2%, median age: 3.5, range 0.9-7.0) received “infant-type” treatment and 130 patients (34.9%, median age: 5.1, range 2.6-7.0) were treated according to “childhood/adult-type” strategy. The “infant type” approach was associated with significant inferior progression-free survival (PFS) (5-yearPFS: “infant-type” 38.6%±4.1% vs. “childhood/adult-type” 56.3%±5.0%; pPFS=0.001), and overall-survival (OS) (5-yearOS: “infant-type” 55.0%±4.1% vs. “childhood/adult-type” 68.3%±4.8% pOS = 0.01). This was retained when restricting the analysis to patients between three and five years (n = 163): 5-yearPFS: “infant-type” 42.6%±6.0% vs. “childhood/adult type” 56.0%±7.7%; pPFS=0.03; 5-yearOS: “infant-type” 57.4±6.0% vs. “childhood/adult-type” 69.9%±7.5% pOS = 0.05. Outcome according to molecular classification and neurocognitive testing will be presented at the meeting. Conclusion “Infant-type” CSI-sparing approaches were associated with less favourable PFS and OS compared with “childhood/adult-type” strategies including upfront craniospinal irradiation.

Abstract:With the advent of multi-omic molecular profiling techniques, central nervous system tumor types previously not recognized by conventional neuropathological assessment have emerged, particularly among tumors formerly termed as "CNS- primitive neuroectodermal tumors." Given the diverse histopathological, molecular, radiological, and clinical characteristics of these tumors, diagnostic approaches and treatment strategies need to be adapted to our increasing knowledge. The small number of patients per year for individual tumor types precludes large cohort studies and mandates international cooperation and harmonization. To this end, the SIOPE Brain Tumor Group together with the European Reference Network for Pediatric Cancers has published the European Standards of Clinical Practice guidelines for rare embryonal and sarcomatous tumors.

Standard assessment of treatment response in craniopharyngioma (CP) includes volumetric measurement of solid and cystic tumour components on contrast-enhanced MRI. This study compared the detection of tumour progression using MRI with and without contrast administration. Progressive disease (PD) was assessed based on the measurement of tumour volume change using MRI without contrast. Contrast-enhanced MRI served as the reference standard. In most patients, non-contrast T1- and T2-weighted sequences were sufficient to assess PD. Non-contrast MRI showed a sensitivity of 89.9

Abstract Children, adolescent and young adults (CAYA) with relapsed high-grade gliomas (rHGG) share a dismal prognosis. Singular immunotherapeutic interventions like therapeutic vaccines have shown safety and immunogenicity, yet limited clinical efficacy. In the HIT-HGG Rez Immunovac phase I/II study (Eudra-CT 2013-000419-26) we optimzed induction and persistance of immune responses by combining upfront Treg-depletion using metronomic cyclophosphamide followed by therapeutic dendritic cell-based vaccines and subsequent checkpoint inibitor blockade (4x Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg q3wk followed by Nivo mono 6 mg/kg q4wk for up to one year). Primary efficacy endpoint was to reach a 6-month post-relapse overall survival (prOS) of at least 82%. Twenty-five CAYAs with a mean age of 13.8 years [4.3-19.5] were enrolled between 2018-2024. Five patients were excluded due to progression before vaccine start or insufficient tumor material, 20 patients received therapy as per protocol. Fifteen SAEs were noted with no unexpected toxicities. The primary end point was confirmed with a 6-month prOS of 84% and one patient being alive after 31.2 months follow-up. PrOS was significantly improved over a historical control group (HCG, n = 87) from the HIT-HGG database (median OS 9.0 months, range 3.3-31.2 vs. 4.98 months, range 0.26-47.77 in Immunovac vs. HCG patients respectively, p=0.0003). Patients with stable disease at the end of vaccination had a better prOS than those relapsing during the vaccine schedule. Immunomonitoring demonstrated a decline in Tregs and a shift from naïve to memory T-cell subsets under treatment. Vaccine-specific CD4+ and CD8+ T-cell responses were observed in almost all patients, including responses against tumor-specific HLA-class I/II epitopes from the respective immunopeptidomes. Furthermore, spatial omics using cyclic immunofluorescence imaging technology at baseline revealed an immune-cold tumor microenvironment (TME) dominated by myeloid cells (∼50%), predominantly M2-polarized macrophages. T- and NK-cells contributed ∼10% and 15%, respectively. Immune effector cells were spatially dispersed, displayed an exhausted phenotype and were typically embedded within immunosuppressive glial niches or stromal compartments. The tumor compartment exhibited aggressive features, including high Ki67, strong GFAP expression, and frequent p53 alterations, but showed robust HLA-class II expression, revealing potential vulnerability to CD4+ T-cell-mediated responses. In conclusion, our data demonstrate safety and clinical efficacy of an optimized immunotherpeutic regime in CAYA with rHGG. Our immunomonitoring data show substantial T-cell responses and changes in the peripheral immune compartments. Together with insights from the TME these results will shape the design of future immunotherapy trials in HGG.

ABSTRACT:BackgroundCurrent treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model. METHODS:Patients aged 0-21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries. RESULTS:For 291 trial patients, the 5-year progression-free survival (PFS) and overall survival (OS) were 62 ± 3% and 81 ± 2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: posterior-fossa group A ependymoma (EPN-PFA) (n = 146): 45 ± 4%/77 ± 4%; posterior-fossa group B ependymoma (EPN-PFB) (n = 19): 90 ± 7%/100%; supratentorial ependymoma, ZFTA fusion-positive (EPN-ZFTA) (n = 59): 64 ± 7%/86 ± 5%; supratentorial ependymoma, YAP1 fusion-positive (EPN-YAP1) (n = 4): 50 ± 25%/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and/or subtype EPN-PFA1c/d/e, 2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS/OS 75 ± 10%/92 ± 7%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS/OS: 33 ± 6%/64 ± 6%). Among EPN-ZFTA, 11/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS/OS: 36 ± 15%/91 ± 9%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS/OS: 19 ± 16%/57 ± 18% vs. 79 ± 7%/97 ± 3%, P = .0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (P < .0001 for PFS and OS). CONCLUSIONS:These results strongly suggest the inclusion of molecular parameters into stratification and the use of distinct treatment strategies within future ependymoma trials.

OBJECTIVE:The purpose of this study was to review the assessment of residual tumor, analyze surgical factors associated with incomplete resection, determine the risk of neurological sequelae for reoperation, and assess the impact of second surgeries on survival. METHODS:Patients 0-21 years old with nonmetastatic intracranial ependymoma treated within the prospective multicenter E-HIT2000 trial were included. Prospective central neuroradiological review of pre- and postoperative imaging was performed. RESULTS:The 291 patients included in the E-HIT2000 trial underwent surgery at 71 centers in Germany, Austria, and Switzerland. Timely central review of postoperative imaging of sufficient quality was performed in 206 patients, and extent of resection was classified as gross-total resection (GTR) in 137 (67%) patients and incomplete with residual disease (RD) in 69 (33%) patients. Surgeons erroneously reported GTR in 11/40 patients with RD and available surgical reports; adhesions in the rhomboid fossa and/or brainstem were the most common reasons for intentional RD. Twenty-three of the 69 patients with RD underwent a second surgery as part of their primary treatment, 11 before and 12 after the start of adjuvant therapy; in 11/23 patients, GTR was achieved after a maximum of 3 procedures. The frequency of postoperative neurological deficits in the patients with second surgery did not differ from that in patients with primary GTR. Ten-year overall survival with GTR was 69.8% ± 4.4% versus 51.2% ± 7.1% with RD (p = 0.002). A second surgery significantly improved progression-free survival (42.4% ± 11.5% vs 22.2% ± 6.5% without second surgery, p = 0.004). CONCLUSIONS:Second surgery was not associated with an increased frequency of neurological sequelae and conferred an advantage in survival overall. The authors strongly recommend early central neuroradiological review to evaluate postoperative residual tumor and discuss reoperation. Further studies are needed to outline a tailored risk assessment for each patient based on molecular and clinical aspects.

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

BACKGROUND:The HIT network was established in 2000 to create a population-based structure aiming to improve survival rates and reduce late effects for children with central nervous system (CNS) tumors by conducting comprehensive clinical trials. METHODS:The HIT network currently consists of 10 coordinating trial centers mandated by the German Society for Pediatric Oncology and Hematology (GPOH) to conduct clinical trials and research projects, and to provide counseling to local centers for individual patients. The network is complemented by 11 reference centers (neuropathology, tumor biology, neuroradiology, pediatric neurosurgery, cerebrospinal fluid [CSF], assessments, radiotherapy, genetics), biostatistical support, and currently 72 local treatment sites. RESULTS:Numbers of children and adolescents with newly diagnosed CNS tumors registered to trials and registries increased from approximately 500 to more than 600 per year, corresponding to >95% of affected HIT-eligible children and adolescents in Germany. Clinical counseling and upfront reference assessments ensure homogeneous clinical standards and avoid inadequate treatment of individual patients. Since 2007, the established reference services have been partially re-funded by German health insurances. DISCUSSION:The HIT network provides a unique structure for population-based state-of-the-art diagnostic assessments, treatment recommendations and counseling. It increases the "a priori" accuracy of stratification parameters, and the timely inclusion into clinical trials and tumor-specific registries. Favorable outcomes are achieved within the trials and registry landscape, for example, through consistent reference assessments, reducing the gap to real world data. Resulting data facilitate representative, unbiased high-quality research projects across all CNS tumor entities. Interdisciplinary cooperation and competitive scientific output are enhanced.

BACKGROUND:For localized germinoma, whole-ventricular radiotherapy (WVRT) is standard-of-care in Europe; 24 Gray (Gy) with 16 Gy boost following chemotherapy. The SIOP-CNS-GCT-II trial aimed to examine the effect of response-adapted radiotherapy on patient outcome. METHODS:Patients with localized germinoma received 4 courses of "carboPEI" chemotherapy, then 24 Gy WVRT if in complete remission (CR), with an additional 16 Gy tumor boost if residual disease was present. Metastatic cases received 24 Gy craniospinal radiotherapy (CSRT) with 16 Gy boost to all sites. RESULTS:Between 2012 and 2018, 227 fully-staged germinoma patients were treated according to protocol. Five-year event-free (EFS) and overall survival (OS) for 166 localized germinoma were 0.94 ± 0.02 and 0.98 ± 0.01, respectively. Sixty-five of 166 (39.2%) were in CR after chemotherapy, of whom 64/65 received 24 Gy WVRT, only 2 of whom (2/64; 3.1%) relapsed. Of 90/166 patients in partial remission (PR) after chemotherapy, 88/90 received 24 Gy WVRT + 16 Gy; 2 relapsed (2/88; 2.3%). Of the 11 remaining patients, 8 had stable disease (SD) after chemotherapy; 7/8 received 24 Gy WVRT + 16 Gy boost and 1 received 24 Gy WVRT + 30 Gy boost because of a teratoma component; none relapsed. Three remaining patients with progressive disease (PD) during chemotherapy had variable treatments, due to differing histologies and disease spread; 1 relapsed. Five-year EFS and OS for 61 metastatic germinoma were 0.98 ± 0.02 and 1.00 ± 0.00, respectively, with 55/61 (90.2%) in CR and 5/61 (11.5%) in PR after 24 Gy CSRT + 16 Gy; 1 relapsed. CONCLUSIONS:Response-adapted radiotherapy for localized germinoma led to excellent survival outcomes. Further treatment de-escalation should be considered in future strategies to reduce treatment burden and late effects.

Background:Diffuse intrinsic pontine glioma (DIPG) remains uniformly lethal. Stereotactic biopsy confirms the diagnosis and enables molecular profiling. Metastasis along the biopsy track (BTM) has been reported only anecdotally; its prevalence, clinical relevance, and implications for treatment remain unclear. Methods:A multicenter retrospective study in patients with confirmed DIPG and BTM was conducted based on central neuroradiologic review. Radiotherapy schedules were re-assessed to evaluate the feasibility of upfront biopsy track irradiation. Results:Ten children met inclusion criteria (median age 6.8 years). Biopsy route was supratentorial in six and infratentorial in four children, and side-cutting needles were used predominantly. H3F3A mutations were most frequent (n = 8); TP53 alterations were common in tumors with extended molecular profiling available. Median PFS was 8.1 months. Five patients each developed BTM prior to (median 2.7 months) or concurrently with progression of primary tumor. There was no difference in overall survival (median OS 12.0 months) compared with the reference cohort. Estimated BTM prevalence among biopsied DIPG from additional registry data was between 6.9% and 13.0%. Primary biopsy track irradiation proved to be feasible, and comparing the surgical access routes, the infratentorial biopsy track hardly increased radiation exposure of the whole brain. Conclusions:Needle track metastasis is a rare progression pattern in stereotactic biopsied DIPG. Upfront irradiation of the biopsy track may represent a strategy to mitigate the potential risk of BTM. From a dosimetric perspective, an infratentorial approach may therefore be considered, as it was associated with only marginally increased radiation exposure.

Background:Despite hypothalamus-sparing surgical techniques, hypothalamic obesity remains common in childhood craniopharyngioma (cCP) survivors. Emerging evidence suggests a role for hypothalamic inflammation (HI) in obesity development. This study aimed to quantitatively assess post-operative T2 signal intensity (SI) changes, suggestive of inflammation and edema, using MRI and investigate its association with clinical outcomes, including BMI changes, over a 1-year period. Methods:We retrospectively analyzed 2 cCP cohorts. Diagnostic and post-operative MRIs were evaluated for changes in hypothalamic T2 SI on FLAIR. We assessed clinical and radiological predictors of post-operative T2 SI and examined correlations between ΔT2SI and ΔBMI z-score from pre-operative to 3 months after surgery. A multivariable model was used to evaluate factors influencing BMI z-score change. In a subgroup (n = 40), we compared post-operative T2 SI between patients with and without hypothalamic syndrome at 6 months. Results:Both left (P < .001) and right (P < .05) hypothalamic T2 SI increased post-operatively. Higher post-operative T2 SI was associated with increased pre-operative T2 SI, age, less cystic tumors, and higher post-operative Müller grades. ΔT2SI correlated with ΔBMI z-score at 3 months (r = 0.56, 95% CI: 0.29-0.74). ΔT2SI (left) was significantly associated with ΔBMI z-score (β = 1.02, SE = 0.35) after adjusting for baseline variables. Patients with hypothalamic syndrome (n = 17) had higher post-operative T2 SI than those without (n = 23, P < .01). Conclusion:Our data suggest that hypothalamic T2 SI increase is associated with the BMI increase and hypothalamic dysfunction after cCP surgery. These insights enhance our understanding of the pathophysiology underlying post-operative hypothalamic obesity and may inform future preventive and therapeutic strategies.

Abstract Background Posterior Fossa Syndrome/Cerebellar Mutism Syndrome (PFS/CMS) is a serious surgical complication that causes severely debilitating long-term deficits in communication, motor function and cognition in affected children. Despite emerging evidence that injury to efferent cerebellar pathways may account for the wide variety of symptoms observed in PFS/CMS, the underlying pathophysiology remains poorly understood. Here, we aim to identify critical structures that are frequently affected in PFS/CMS using multivariate lesion symptom mapping. Methods Early postoperative cerebellar lesions were analyzed in 154 children with midline intraventricular medulloblastoma from a German medulloblastoma series. 52 children developed postoperative PFS/CMS (34%) defined as complete mutism (PFS1, 41/52) or the inability to string 3-word sentences (PFS2, 11/52). Lesions were manually segmented and defined as new T2-FLAIR hyperintensities surrounding the surgical cavity, reflecting surgery-related tissue damage. Lesion maps were transformed into MNI-152 space using a customized pipeline. Sparse canonical correlation analysis for neuroimaging (SCCAN) was conducted to identify patterns of surgical damage associated with PFS/CMS. 47/154 patients underwent follow-up neuropsychological testing. The surgical approach to tumor resection was evaluated from surgical reports. Results SCCAN identified a pattern of surgical damage significantly associated with PFS/CMS (r=.35, p<.001) with peak voxel weights in the right superior cerebellar peduncle, vermal lobule VI and left lobule IX. PFS/CMS was associated with reduced processing speed (β = −.42, p=.006) and fine motor skills (Purdue Pegboard dominant hand: β = −.42, p=.011; non-dominant hand: β = −.48, p=.004). Vermian incision was not associated with an increased risk for PFS/CMS (OR = 1.78, p=.204). Conclusion Our findings suggest that surgical damage to the cerebellar outflow pathways and superior vermis is associated with PFS/CMS, potentially implicating disrupted cerebello-cortical communication. Surgical techniques that minimize damage to these structures may reduce the incidence and severity of PFS/CMS in the future.

Choroid plexus papilloma (CPP) and atypical choroid plexus papilloma (aCPP) have excellent outcomes. However, some CPP/aCPP relapse and may qualify for postoperative adjuvant treatment. German patients from the International CPT-SIOP Registry diagnosed with CPP/aCPP between 2011 and 2023 were included and analysed according to initial staging (postoperative residual tumor [R+], metastases [M+]), biology, postoperative treatment strategy and outcome. Additionally, patients from the published CPT-SIOP-2000 trial (PMID34997889) were combined with the registry cohort for validation purpose. Ninety-three patients were identified (male: n = 53, female: n = 40). Median age at diagnosis was 1.9 (0.1–17.6) years. Initial staging was R0/M0 in n = 61, R+/M0 in n = 24, R0/M + in n = 5 and R+/M + in n = 3. aCPP was diagnosed in n = 38 patients. Molecular subgroup was available for n = 36: ”adult” n = 3, “pediatric A” n = 21 and “pediatric B” n = 12 (6/12 aCPP). Median follow-up was 5.5 (± 0.99) years. Twelve tumors relapsed: R0/M0 n = 4, R+/M0 n = 7, R+/M + n = 1. One patient with relapse died. Most patients did not receive postoperative treatment (n = 88). Five patients (R0/M + n = 2; R+/M + n = 1; R0/M0 n = 2) received postoperative chemotherapy. None was irradiated during first-line treatment. In the enlarged cohort (n = 197), histological diagnosis had a significant impact on PFS (5y-PFS: CPP 90 ± 3.1, aCPP 78.6 ± 4.6, PFS = 0.01). Both, R+ (5y-PFS: R0 90.6 ± 2.6, R + 69.1 ± 7.0, PFS = 0.01) as well as molecular subgroup “pediatric B” (5y-PFS: pediatric A 95.2

BACKGROUND:Malignant rhabdoid tumors occasionally develop along cranial nerves, but clinical, histopathological, and molecular features have not been examined in larger series. PROCEDURE:We retrospectively interrogated data from the European Rhabdoid Registry, EU-RHAB, to identify malignant rhabdoid tumors affecting cranial nerves. We retrieved clinical information and reviewed magnetic resonance imaging (MRI) data. Furthermore, histopathological review and molecular profiling were performed. RESULTS:Among 425 patients, we identified a total of 14 harboring malignant rhabdoid tumors with cranial nerve involvement. Median age at diagnosis was 28 months (range: 0-13 years). Various cranial nerves were affected, the trigeminal nerve (n = 4) and the facial and/or vestibulocochlear nerve (n = 5) being most frequently involved. In most cases, the initial clinical and neuroradiological suspicion was schwannoma. Neuroradiology review of magnetic resonance imaging studies confirmed a tumor along the cranial nerve, but signal characteristics with restricted diffusion were rather suggestive of a malignant tumor of high cellularity. Histopathological examination, using among others neurofilament staining confirmed the diagnosis and infiltration of nerve fascicles. DNA methylation profiles demonstrated high similarity with ATRT-MYC as well as extracranial malignant rhabdoid tumors (median calibrated scores: 1.00). CONCLUSIONS:Malignant rhabdoid tumors of the cranial nerves represent a small but clinically distinct group, which initially is often not included in the differential diagnoses of pediatric cranial nerve tumors. Restricted diffusion on MRI may provide an early diagnostic clue. Histopathology and molecular signature are characteristic, but the developmental origin of malignant rhabdoid tumors of the cranial nerves remains to be determined.

PURPOSE:European Reference Networks (ERN) are collaborative networks connecting healthcare professionals across Europe. A virtual multidisciplinary tumor board (VMTB) for children with central nervous system (CNS) tumors was established within the ERN for pediatric oncology (ERN PaedCan) in 2022. We report the experience with this new format. METHODS:A web-based questionnaire was distributed to physicians for cases presented between November 2022 and November 2023, addressing the implementation of provided recommendations, satisfaction and basic data about the local institution. Baseline information of the presented cases was taken from anonymized VMTB protocols. RESULTS:In the first year, 19 patients from 11 institutions located in nine European countries were discussed in 21 VMTB. The German national reference center for neuroradiology demonstrated MRI findings in 19/21 (91%) conferences. 19 questionnaires were answered by physicians from all participating countries. Main reason for VMTB presentation were questions about therapy (79%). Presenting institutions treated a median of 10 (5-150) neuro-oncological pediatric patients per year. All hospitals conducted own institutional tumor boards. National central review was available in 3/9 countries (33%). Recommendations were followed, at least partly, in all except one patient experiencing unexpected clinical deterioration. Recommendations were considered helpful in 90%. All participants would recommend the VMTB to colleagues. Technical issues regarding data provision were reported as the main obstacle in 56%. CONCLUSION:A European VMTB for pediatric patients with CNS tumors is feasible and perceived as useful by the participants. Recommendations were followed frequently. Optimization of privacy-compliant data exchange is crucial for continuance of the format.

To evaluate MRI changes in T2-weighted imaging (T2WI) signal intensity (T2SI) as a potential imaging marker for assessing response to radiotherapy (RT) in pediatric low-grade glioma (pLGG). This retrospective study analyzed imaging data of 56 pLGG patients (mean age, 12.4 ± 3.5 years; 33/56 [58.9

DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.