Sandro Manuel Krieg

Background: Supramaximal resection beyond the contrast-enhancing margin is associated with prolonged survival in IDH-wild type glioblastoma, but whether this benefit is uniform is unknown, and no biomarker identifies responders. We tested whether on a neural methylation-based signature (neural-high vs neural-low) determines benefit and can be obtained intraoperatively by nanopore sequencing for surgical stratification.Methods:In discovery and validation cohorts of newly diagnosed IDH-wildtype glioblastoma treated with chemoradiotherapy, Cox models tested the interaction between RANO class 1 vs 2-3 resection and neural-high vs neural-low tumours for overall survival (primary) and progression-free survival (secondary); sensitivity analyses included residual-volume modelling. In the prospective EpiGuide study, patients undergoing glioblastoma surgery had intraoperative nanopore sequencing with real-time neural-class prediction compared with matched EPIC array classification; the primary endpoint was a valid neural class within a prespecified 30-min on-flow-cell window.Findings: The retrospective analysis included 247 (discovery) and 303 (validation) patients. RANO class interacted with neural score in both cohorts (p=0·02 discovery, p=0·20 validation): supramaximal resection benefited neural-high tumours (adjusted HR 0·35 [95% CI 0·18-0·67] discovery; 0·46 [0·29-0·74] validation) but had an inconsistent effect in neural-low tumours (1·22 [0·53-2·82]; 0·75 [0·46-1·21]); sensitivity analyses were consistent. In EpiGuide, 47 of 67 enrolled had paired nanopore and array data; intraoperative classification agreed with the array in 39 (83·0%) of 47 (AUC 0·89; sensitivity 79·3%, specificity 88·9%). Presequencing took 42·4 min (SD 12·43); median on-flow-cell time to a confident, correct call was 11 min (IQR 6-20), and 34 (72·3%) reached this within the window.Interpretation. The neural signature identified IDH-wildtype glioblastomas in which RANO class 1 resection was associated with longer survival, with no reproducible benefit in neural-low tumours. Intraoperative nanopore sequencing enabled neural-class prediction within a feasible surgical timeframe, concordant with the methylation-array reference. These findings support prospective evaluation of biomarker-stratified extent-of-resection strategies but do not yet establish clinical utility for routine surgery.Funding. German Research Foundation (DFG), Else-Kröner-Frisenius Foundation, Illumina, Fördergemeinschaft Kinderkrebszentrum Hamburg, TRANSCAN (BMBF).Registration.This prospective, non-interventional, blinded intraoperative feasibility and concordance study did not require registration.

Purpose: Between lumbar decompression and the first follow-up visit (~ 6 weeks post-op), the day-to-day course of recovery is not routinely captured in detail. We tested whether a single-item, smartphone well-being ePROM (“How are you today?”, 0–100 VAS; higher = better), sent every 2–3 days, could be deployed in routine care, what level of endpoint completion was achieved, whether it showed preliminary convergent validity when measured at the same visit as clinic PROMs (ODI, PHQ-9), and whether serial responses could illustrate postoperative recovery trajectories. Methods: Consecutive patients with degenerative lumbar disease completed a digital baseline survey (Feb 1–Aug 31, 2025; n = 429). Patients with an operative indication for lumbar disc herniation or spinal canal stenosis who underwent lumbar decompression entered postoperative high-frequency well-being monitoring for 6 weeks. Patients were not included in the digital follow-up pathway when web-based participation was not feasible in routine care. The pathway generated electronic health record-accessible submissions but did not include automated alert thresholds or a mandated alert-to-action protocol. Results: Of 183 operated patients invited to postoperative monitoring, 70/183 (38.3%) contributed an evaluable clinic ODI at ~ 6 weeks, 68/183 (37.2%) had a same-day PHQ-9, and 48/183 (26.2%) were endpoint-complete for both visit-day measures; this low endpoint-completion rate represents a major implementation barrier. In the pair-level timing dataset, same-day well-being versus reverse-coded ODI (100 − ODI; higher = less disability) showed moderate concordance (ρ = 0.54, 95% CI 0.37–0.68; n = 107 pairs), with similar moderate estimates at short lags (≤ 2 days ρ ≈ 0.46; ≤4 days ρ ≈ 0.42), while longer-lag estimates were exploratory and non-monotonic. On the visit day, well-being related inversely to depressive burden (PHQ-9 ρ = −0.25; n = 68). In a joint model using raw ODI and PHQ-9, higher disability and higher depressive burden were associated with lower concurrent well-being (standardized β: −0.35 for ODI; −0.20 for PHQ-9), although explained variance was limited (adjusted R² = 0.151). Conclusion: Routine-care deployment was technically possible, and time-aligned measures showed preliminary convergent validity, but endpoint completion was low (26.2%) and prevents any claim of broad feasibility or universal scalability. The ePROM should be considered a hypothesis-generating trajectory signal that requires equity safeguards and prospective closed-loop alert-to-action testing before implementation as a clinical decision tool.

Meningiomas in pediatric and adolescent/young adult patients are poorly characterized biologically and clinically, and risk stratification is largely extrapolated from adult tumors. We analyze 293 tumors from patients aged 0-39 years using integrated histopathological and molecular profiling. Youth-onset meningiomas are enriched for NF2 and SMARCE1 alterations and exhibit a gain-dominated copy-number landscape, including recurrent chr17q gain, whereas canonical adult high-risk features, such as chr1p loss, lack prognostic significance. Adult-derived prognostic frameworks, including WHO grade, methylation-based stratification and integrated risk scores, fail to predict progression in patients ≤21 years of age. Tumors segregate into age-enriched epigenetic clusters defined by SMARCE1, NF2 and BAP1 alterations. Among NF2-altered tumors, patterns of Merlin inactivation, shaped by germline status and co-occurring copy-number variations, delineate biologically divergent subsets. In patients ≤21 years, extent of resection is the dominant predictor of outcome, while molecular features further refine risk assessment. These findings define pediatric and young adult meningiomas as a distinct molecular entity and support age-adapted risk refinement that integrates molecular features with strong clinical determinants.

Molecular testing is essential for classifying central nervous system (CNS) tumors, with methylation profiling providing the highest diagnostic granularity. However, this requires more resources and time than conventional hematoxylin and eosin (H&E) histopathology, which is widely available globally. Here we propose Hetairos, an artificial intelligence algorithm that predicts 102 methylation-based CNS tumor subtypes from digital H&E slides. Built and validated on 9,606 patients and over 11,000 slides from 11 centers across four continents, Hetairos identified 50–70% of cases with high confidence, achieving an accuracy of 0.87 for its highest-rated predictions. Hetairos outperformed five board-certified neuropathologists in a direct histology-only comparison (0.68 versus 0.30). Prospective evaluation in routine diagnostics confirmed its performance, reducing turnaround time from 12 days (molecular testing) to 12 min. Hetairos supports diagnostic decision-making across the full spectrum of pediatric and adult CNS tumors by narrowing differential diagnoses and guiding efficient testing.

Tumours historically classified as extraventricular neurocytoma (EVN), initially in comparison with central neurocytoma, are defined by location and morphology; however, emerging molecular data demonstrate that this term is outdated. We report 14 previously unpublished tumours with a robust EVN DNA methylation profile, independent of original histopathologic diagnosis or anatomic location. Integrated molecular analyses identified FGFR1 alterations, particularly FGFR1::TACC1 fusions, as the predominant molecular driver of this tumour class. A smaller number of tumours harboured FGFR1 hotspot mutations (p.N546K and p.K656E). Among these, two cases additionally showed NF1 variants, and one tumour carried a PIK3CA mutation (p.H1047L). In addition, a single case exhibited an NTRK2 fusion. Histologically, tumours exhibited neurocytic differentiation with neuropil islands and a minor glial component, while immunohistochemistry showed frequent OLIG2 expression, contrasting with the typical immunophenotype of central neurocytoma. Notably, tumours with an EVN DNA methylation profile were identified in both extraventricular and intraventricular locations, demonstrating that anatomy‐based definitions are inadequate for this tumour type. Clinical follow‐up (median 33.2 months) showed predominantly lower grade behaviour, with occasional recurrence. Collectively, these findings support the view that tumours previously labelled as EVN do not represent a direct counterpart of central neurocytoma but instead constitute a molecularly and epigenetically distinct glioneuronal tumour type. We propose the designation glioneuronal tumour with neurocytic differentiation (GNTN) to reflect its biological identity and to align the terminology with contemporary molecular neuropathology, and recommend DNA methylation profiling as an essential diagnostic criterion.

Objective: Rapid-sequence magnetic resonance imaging (rMRI) has emerged as a radiation-free alternative to computed tomography (CT) in pediatric neuroimaging. This study aimed to evaluate the diagnostic utility, clinical consequences, and subgroup-specific differences in pediatric patients undergoing rMRI for emergency neurosurgical indications. Methods: We conducted a retrospective, single-center study of 158 rMRIs in 73 pediatric patients who underwent rMRI between January 2017 and December 2023 due to suspected complications of hydrocephalus and brain tumors. A short MRI protocol (195 s) including FLAIR BLADE and T2 HATSE sequences was employed. Patients were categorized into tumor non-related and tumor-related hydrocephalus groups. Results: A total of 158 rMRIs in 73 pediatric patients were included. The mean age was 7.09 ± 4.63 years, with 69.6% male patients. Ventricular size monitoring was the most common rMRI indication (96.2%). Clinical consequences followed in 52.5% of cases, including surgical interventions (21.5%) and shunt valve adjustments (37.3%). Sedation was required in only 5.1% of patients. Only 1.9% required follow-up CT. Statistically significant intergroup differences were found in drainage type (p < 0.001), diagnosis (p < 0.001), and need for follow-up MRI (17.4% in the tumor-related hydrocephalus group vs. 4.5% in the tumor non-related hydrocephalus group; p = 0.014). Conclusions: rMRI is a safe, efficient, and effective alternative to CT for emergency neuroimaging in pediatric patients with hydrocephalus, tumors, or shunts. It facilitates timely clinical decision-making while avoiding radiation exposure. Our findings support broader implementation of rMRI protocols, particularly for patients requiring ongoing tumor surveillance.