Background: Glioblastoma exhibits profound intratumoral heterogeneity, with anatomically distinct tumor zones characterized by divergent molecular programs that drive therapy resistance. Whether magnetic resonance imaging (MRI)-derived radiomic features can capture these regional transcriptomic differences remains unknown. We aimed to determine whether subcompartment-level radiomic features associate with transcriptomic pathway enrichment scores derived from biologically approximate tumor zones. Methods: We matched 28 patients (mean age 58.5 years; 13/28 MGMT methylated) across the IvyGAP RNA-seq atlas and the IVYGAP-RADIOMICS datasets. Single-sample GSEA (ssGSEA) pathway scores were computed for 24 gene sets. Radiomic features (3920 per subcompartment) were reduced to 597. Nested leave-one-patient-out cross-validation (LOPO-CV) with Elastic Net served as the primary predictive analysis; linear mixed-effects models (LMM) provided exploratory associational analysis. Analyses used a biologically motivated but spatially non-co-registered zone-to-subcompartment mapping; all reported associations are zone-approximate. Results: Twenty-one of 24 pathways showed no predictive signal (R2cv ≤ 0). Inflammatory Response (R2cv = 0.185, 95% CI [0.071, 0.355], p = 0.008) was the only pathway supported by both the nested CV (FDR = 0.096) and the exploratory LMM (FDR = 0.024, ΔR2 = 0.214 beyond subcompartment effects) analyses; the LMM association was robust to clinical covariate adjustment (likelihood ratio test p = 0.004). Angiogenesis (R2cv = 0.209, 95% CI [0.028, 0.353], p = 0.006) reached nested CV significance (FDR = 0.096) but was not corroborated by the LMM (FDR = 0.445); it is therefore reported as a tentative single-framework signal requiring independent validation. T2-derived texture features were selected in 100% of folds for both pathways. Conclusions: Inflammatory Response is the only pathway supported by both analytical frameworks; Angiogenesis is a tentative nested-CV-only signal pending independent validation. The absence of signal for 21 of 24 pathways should not be interpreted as evidence of biological inaccessibility: at N = 28 (vs. N ≈ 240 required by Riley criteria), severe underpowering, attenuation from the non-spatial zone-to-subcompartment mapping, and methodological constraints each independently suffice to suppress real associations. Five of the 24 gene sets (the IvyGAP zone modules) are non-independent from the outcome data and cannot be interpreted as discovery. All reported associations are zone-approximate and may partly reflect macro-compartment (between-subcompartment) effects; validation in larger cohorts with spatially precise co-registration is essential.

Intraoperative neurophysiological monitoring (IONM) is widely used during brainstem surgery to reduce the risk of neurological injury, although its prognostic value in adult brainstem glioma (BSG) surgery remains unclear. We retrospectively analyzed 22 consecutive adults who underwent surgery for BSGs with multimodal IONM between 2010 and 2023. Monitoring included somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), brainstem auditory evoked potentials (BAEPs), corticobulbar MEPs (CoMEPs), and cranial nerves electromyography. The primary endpoint was the association between intraoperative neurophysiological changes and postoperative neurological functional status at hospital discharge, assessed with the modified McCormick Scale (mMCS). Secondary endpoints included postoperative complications and length of hospital stay. SSEP warning criteria were met in 10 patients (45.5%), while 10 patients (45.5%) experienced a ≥50% reduction in MEP amplitude in at least one monitored muscle. Despite these findings, neither SSEP nor MEP amplitude changes were significantly associated with postoperative neurological status. Transcranial MEP stimulation thresholds increased significantly during surgery (p = 0.007), and threshold elevation was associated with postoperative complications (Kendall’s τ = 0.498, p = 0.007). BAEP recordings remained stable throughout all procedures. Conventional amplitude-based IONM changes were not associated with early neurological outcome after adult BSG resection. In contrast, increases in MEP stimulation threshold may represent a sensitive indicator of postoperative complications. Further prospective studies are warranted.

Purpose. Maas et al. recently showed that a microenvironment-determined risk continuum, driven by the shift from microglia-like to myeloid-derived macrophage-like tumor-associated macrophages (TAMs), independently predicts meningioma progression beyond WHO grade. Whether this gradient is recoverable from bulk RNA-seq has not been tested. Methods. We computed a microglia-to-macrophage ssGSEA ratio using expanded gene sets (15 microglia, 17 macrophage) anchored to Maas core markers across 968 meningiomas from 5 GEO datasets, validated it against pseudo-bulk profiles from the Maas snRNA-seq cohort (n=25), and tested recurrence-free survival (RFS) association by Cox regression in a 101-patient subset (73 events, median follow-up 110.2 months). Results. The ratio correlated with single-cell microglia proportion (overlap-controlled r=0.70, 95% CI 0.42-0.86) and discriminated WHO grades and transcriptomic clusters, confirming biological recoverability. The ratio did not predict RFS (HR 0.92, 95% CI 0.72-1.16, p=0.46). A quantitative attenuation analysis predicts the Maas IHC HR of 2.00 attenuates to HR 1.24-1.40 after proxy measurement error (r2=0.22-0.49) and NF2-wildtype dilution (30-45%), yielding only 15-40% power at 73 events. An exploratory NF2-expression proxy subgroup (uncorrected p=0.056) showed a trend in NF2-low tumors (HR 0.68, 95% CI 0.46-1.01) absent in NF2-high tumors (HR 0.98, p=0.89). The Chen 34-gene tumor-intrinsic panel also reached near-chance discrimination (C-index 0.552). Conclusion. Single-cell-anchored ssGSEA recovers the Maas gradient in bulk RNA-seq but attenuates it below detectability in moderate-sized, NF2-unselected cohorts. The prognostic component is bounded by power and NF2 stratification, not an intrinsic modality failure; NF2-annotated cohorts with approximately 480 events are required for definitive testing. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We aggregated meningioma RNA-seq data from five GEO datasets (GSE212666, GSE252291, GSE183653, GSE136661, GSE101638). For single-cell validation, the Maas et al. snRNA-seq Seurat object (44,266 nuclei, 26 samples) was obtained from their Zenodo deposit (doi:10.5281/zenodo.17296825). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Analysis code will be deposited on GitHub upon publication.

ABSTRACT Background Meningiomas exhibit well-established hormonal biology, yet no study has examined whether myeloid immune infiltration interacts with estrogen-responsive transcription in this tumor type. Methods We applied three-method consensus immune deconvolution (EPIC, MCPcounter, CIBERSORTx) to 968 harmonized meningioma RNA-seq transcriptomes from five public datasets, stratified by Thirimanne et al. (2024) transcriptomic subtypes. Competitive gene set enrichment compared macrophage-high versus macrophage-low tertiles with sex-adjusted, purity-adjusted, and method-independent sensitivity analyses. Survival modeling tested both total macrophage burden and a decomposed microglia-to-macrophage ratio validated against single-cell ground truth (pseudo-bulk r = 0.77). Results Macrophage-high tumors showed significant suppression of estrogen response gene sets (FDR = 4.9 × 10 −5 ) despite paradoxical ESR1 upregulation (log 2 FC = +0.40, FDR = 2.5 × 10 −26 ) and PGR downregulation (log 2 FC = −0.34, FDR = 2.7 × 10 −3 ), indicating post-receptor transcriptional disruption. This signal strengthened after sex adjustment (FDR = 1.9 × 10 −6 ) and was confirmed across a multi-layer sensitivity battery (eleven analyses including reference-matrix-independent, purity-adjusted, rotation-based self-contained, and empirical-null tests; all FDR < 3 × 10 −4 in the relevant convergent tests). Myeloid infiltration was strongly subtype-dependent (Kruskal–Wallis p = 7.4 × 10 −16 ) but grade-independent (p = 0.399), with CSF1R enriched in the macrophage-dominant Cluster B. Neither total macrophage score (HR = 0.90, p = 0.53; N = 102) nor a decomposed microglia/macrophage ratio (HR = 0.92, p = 0.46; N = 101) predicted recurrence-free survival. Conclusions The pre-registered primary endpoint — macrophage infiltration score predicting recurrence-free survival — was not supported; the estrogen–immune dissociation emerged from secondary exploratory gene-set analysis and requires independent validation. Macrophage-infiltrated meningiomas exhibit a previously unreported dissociation between maintained ESR1 expression and suppressed estrogen-responsive transcription, with implications for hormonal therapy stratification.

The diagnostic landscape for idiopathic normal-pressure hydrocephalus is intricate, and there is a pressing need for accurate and cost-effective methods. Because of the lack of accurate diagnostic and prognostic quantitative biomarkers, the frequent presence of comorbidities, and the limited understanding of the pathophysiology of the disorder, only a minority of patients receive disease-specific treatment. While traditional neuroimaging offers insights, its isolated diagnostic precision can be enhanced. Emerging quantitative methods analyzing cortical thickness based on standard T1-weighted brain MR images offer new diagnostic possibilities. We analyzed 294 patients referred to our clinic from January 2015 until December 2022. After the exclusion criteria, the final sample consisted of 100 possible iNPH patients. Of these, 71 underwent ventriculoperitoneal shunt surgery, while 29 did not qualify post-evaluation. Cortical thickness was assessed using an advanced deep-learning neuroimaging pipeline. For predictive modeling, we employed a comprehensive set of Machine Learning algorithms, including Distributed Random Forests, Extremely Randomized Trees, Generalized Linear Model with Regularization, Gradient Boosting Machines, Extreme Gradient Boosting machines, and a fully connected multi-layer Artificial Neural Network. These algorithms were strategically combined into a Super Learner ensemble approach to harness their collective predictive power. Among patients with negative CSFTT outcomes or subpar VPS surgery responses, distinct cortical variations emerged, particularly in the caudal middle frontal, rostral middle frontal, superior frontal, and superior parietal regions. Our Super Learner model, integrating CSF dynamics and cortical thickness data, achieved a 90% positive predictive value, signifying a tangible advancement over traditional measures. Analyzing preoperative cortical thickness emerges as a viable strategy for streamlining therapeutic decisions for potential iNPH patients. Future endeavors should focus on large-scale multicentric studies to further delineate specific cortical thickness patterns, potentially enhancing the prediction accuracy for VPS surgery outcomes.

OBJECTIVE Long-standing overt ventriculomegaly in adults (LOVA) is a chronic form of hydrocephalus that can lead to cognitive deficits. Data on the cognitive profile of patients with LOVA and cognitive outcomes of endoscopic third ventriculostomy (ETV) are, however, scarce and mostly qualitative. METHODS Twenty-three consecutive patients with LOVA hydrocephalus underwent ETV surgery, and their cognitive status was assessed before surgery, immediately after surgery, and at the 5-month follow-up. Cognitive function was assessed using a neuropsychological battery measuring 6 cognitive domains: general cognitive status, attention/executive function, language, visuospatial skills, short-term memory, and long-term memory. Cognitive reserve was also estimated through a measure of premorbid IQ to assess its potential influence together with other clinical and demographic variables. RESULTS Patients with LOVA did not experience general cognitive decline but rather selective long-term memory (p < 0.001) and visuospatial skills (p = 0.001) deficits alone. Moreover, ETV surgery led to significant immediate postoperative improvement in both domains (p = 0.002 and p < 0.001 respectively), that persisted at follow-up (p < 0.001 for both). However, improvement was observed only in patients with higher premorbid IQ (p < 0.001), while the others did not improve (p > 0.532). CONCLUSIONS These findings confirm the effectiveness of ETV surgery and highlight the role of cognitive reserve in promoting plasticity of brain and cognitive functions thus fostering and predicting cognitive recovery.

Glioblastoma (GBM) is the most common and lethal primary brain tumour. The prognosis for GBM patients remains poor due to rapid tumour recurrence and resistance to conventional treatments. Small Rho GTPase proteins, which regulate cell shape and motility, are critical for GBM aggressive growth and infiltration into the surrounding brain parenchyma. Hence, small-molecule inhibitors targeting them represent an appealing opportunity to hinder the infiltration behaviour of GBM. Here, a synergistic experimental and computational approach allowed us to identify an inhibitor that reduces migration in patient-derived GBM cell lines. Computational and in vitro functional assays reveal that this compound inhibits Rho GTPases function by targeting multiple allosteric sites thereby enhancing flexibility of key functional regions and hindering their interaction with protein regulators. Our research unveiled a novel hit molecule targeting Rho GTPases with significant potential to improve the treatment of GBM and other highly aggressive tumours.

Background/Objectives: Ventriculoperitoneal shunting is a validated procedure for the treatment of idiopathic normal-pressure hydrocephalus. To select shunt-responsive patients, infusion and tap tests can be used. Only gait is evaluated after the procedure to establish a potential improvement. In this study, we present our Hydro-Real-Time Neuropsychological Testing protocol to assess the feasibility of performing an ultra-fast assessment of patients during the infusion and tap test. Methods: We tested 57 patients during the infusion and tap test to obtain real-time feedback on their cognitive status. Data were obtained immediately before the infusion phase (T0), when the pressure plateau was reached (T1), and immediately after cerebrospinal fluid subtraction (T2). Based on cerebrospinal fluid dynamics, 63.15% of the patients presented a resistance to outflow > 12 mmHg/mL/min, while 88% had a positive tap test response. Results: Compared to T0, cerebrospinal fluid removal significantly improved performance on tasks exploring executive functions (counting backward, p < 0.001; verbal fluency, p < 0.001). Patients were significantly faster at counting backward at T2 vs. T1 (p < 0.05) and at T2 vs. T0 (p < 0.001) and were significantly faster at counting forward at T2 vs. T1 (p < 0.005), suggesting an improvement in speed at T2. There was a significantly smaller index at T1 vs. T0 (p = 0.005) and at T2 vs. T0 (p < 0.001), suggesting a more marked improvement in patients’ executive abilities at T2 and a smaller improvement at T1. Regarding verbal fluency, patients were worse at T1 vs. T0 (p < 0.001) and at T2 vs. T0 (p < 0.001). Conclusions: Patients’ performance can be monitored during the infusion and tap test as significant changes in executive functions are observable. In future, this protocol might help improve patients’ selection for surgery.

Intraoperative seizures (IOS) represent a complication during surgery of diffuse low-grade gliomas (DLGGs), particularly in cases of awake craniotomy, history of tumor-related epilepsy (TRE), and cortical mapping [...].

Intrasaccular flow diverters such as the Contour Neurovascular System represent a significant advancement in the endovascular management of intracranial aneurysms, particularly those with complex bifurcation morphology. However, complications such as incomplete occlusion or recurrence post-implantation remain prevalent challenges in clinical practice. Depending on the specific failure mode and anatomy, various bailout strategies may involve parent vessel reconstruction with flow diverters or surgical clipping.1-4This technical video (video 1) shows a novel bailout strategy that integrates adjunctive coil embolization through a pre-existing Contour device to address aneurysm recurrence. Key procedural elements are demonstrated, including microcatheter navigation into the residual aneurysm sac adjacent to the Contour, precise coil deployment into the interstice between the device and the aneurysm wall, and achieving complete angiographic occlusion while preventing any displacement or compromise of functionality of the existing intrasaccular device. This technique exemplifies a viable endovascular rescue approach for selected instances of aneurysm recurrence following Contour treatment, enhancing the therapeutic armamentarium available to clinicians.neurintsurg;jnis-2025-023473v1/V1F1V1Video 1 Endovascular coil embolization through a previously implanted Contour intrasaccular device for recurrent posterior communicating artery aneurysm.

Abstract CASE REPORT A 5-year-old girl diagnosed with a posterior fossa standard-risk medulloblastoma underwent surgery followed by proton therapy (PT) 23.4 Gy(RBE) (1.8 Gy(RBE)/fr) to the craniospinal axis plus a boost of 30.6 Gy(RBE) (1.8 Gy(RBE)/fr) to the tumor bed and maintenance chemotherapy according to HIT-SIOP PNET 4 protocol. The patient remained disease-free for 4 years after the end of treatmen. MRI showed a new left temporo-occipital lesion 8x10x10 mm which was irradiated from cranial field during the craniospinal phase but outside of the boost area, consistent with inoperable recurrence. She was then re-irradiated with a second course of PT 50.4 Gy(RBE) (1.8 Gy(RBE)/fr) and subsequently started on temozolomide. Periodic MRI scans showed progressive reduction of the lesion for 10 months, when new lesion progression occurred within the re-irradiated fieled. Considering the stable clinical conditions of the patient, the minimal size of the lesion, and the uncertain nature between actinic damage or cancer, a watchful waiting approach was adopted. Few months later, the area increased. [18F]FET-PET/CT evaluation documented an uptake of the drug compatible with metabolically active lesion. A biopsy was performed, and histology showed a CNS sarcoma. Genetical testing excluded cancer predisposition syndromes. Chemotherapy with bevacizumab and irinotecan was started, but the MRI showed significant progression of the disease and the patient died 6 months after the diagnosis. CONCLUSION MRI is the main diagnostic method in the follow up of CNS neoplasms, but it has limitations in discriminating recurrences/secondary tumours and tissue changes due to previous treatments, particularly radiotherapy. Recently, the use of [18F]FET-PET/CT is being investigated, but literature is still poor in children and most cases refer to high-grade gliomas. It is desirable to study it further, as it may play a relevant role in differentiating equivocal cases, as in our patient.

The Pediatric Central Nervous System (CNS) tumors incidence has increased in the last decades. A diagnostic delay could be related to adverse effects involving neurosurgical approach. Moreover, many studies report that Coronavirus-19 pandemic has even increased the diagnostic delay of solid tumors, in particular CNS types. We conducted a retrospective study including all pediatric patients who received a diagnosis of CNS tumor at Udine Hospital between January 2020 and December 2021. Our first aim was to assess if there has been a variation in the incidence rate and a possible diagnostic delay of CNS pediatric tumors during 2020-2021. As a secondary objective we evaluated if the Coronavirus-19 pandemic has affected our ability to identify tumor relapses caused by delays in planning follow-up exams and imaging. Data of every patient were recorded and compared with data from a historical cohort recruited between 2000 and 2011. 25 patients were enrolled in the study: 19 (11 males) were diagnosed with a primitive CNS tumor, 7 (3 males) with a secondary lesion. Incidence rate during 2020-2021 was 5.17 per 100.000 inhabitants (age 0-18 years) and median diagnostic interval was 6.7 weeks, both higher than in the historical cohort (but not statistically significant). Median age was 10 +/- 4,7 age (IQR 25°-75°5,9-13,7). No substantial variation of clinical presentation was detected, although some symptoms were found to be more frequent than in the past. A significant rise in the number of high histological grade tumors was recorded (63% vs 12%, p value < 0.001), but there was no difference in tumor relapses diagnostic delay (median 6,7 weeks compared with 5 weeks in historical cohort). Coronavirus-19 pandemic had no impact in diagnostic delay, planning and execution of follow-up exams in children with CNS tumors.

Abstract BACKGROUND Among children, bleeding from brain metastases is rare. Bleeding could be caused by: cancer, treatments and chemotherapy/other drugs such as Bevacizumab, NSAIDs and anticoagulants. We report a case of brain RT after metastases bleeding. METHODS A 14-years-old boy with a negative previous medical history presented to the Emergency Department with seizures and loss of consciousness. Full-body CT scan revealed brain and renal haemorrhages and a right testicular lesion. Serum βhCG was 223,773 mIU/mL. Neurosurgical bleeding control and right orchiectomy were performed: the histopathology revealed a metastatic mixed non-seminomatous germ cell neoplasia of the testis. First-line chemotherapy (4 cycles of Cisplatin/Etoposide/Ifosfamide) and second-line treatments (Paclitaxel/Ifosfamide/Cisplatin and Gemcitabine/Paclitaxel/Oxaliplatin) were performed. Suddenly, he presented with left-sided hyposthenia and partial left hemibody seizure. CT scan revealed 2 haemorrhagic brain lesions, one in each hemisphere. Surgery was not feasible. We started anti-oedema and anti-epileptic therapy, and whole brain RT (WBRT, 36 Gy/12 fx, BEDα/β= 10 Gy= 46.8 Gy). After 5 days from the start, RT had a 7-day stop because of acute oedema and clinical deterioration. Fourth-line chemotherapy was administered with CarboPEB (1st of further 4 cycles), and then WBRT was restarted. At the end of WBRT a stereotactic RT boost to both the haemorrhagic lesions was delivered (20 Gy/10 fx, BEDα/β= 10 Gy= 24.0 Gy). As of today, eight months after the end of therapy, the patient is free from disease and βhCG is negative. CONCLUSION Palliative RT in children is a non-conventional indication, but potentially effective at providing rapid haemostasis, especially in selected cases (surgery not feasible/contraindicated, adult-type histologies, …) and it is ensuring a good tumor control and low-grade acute toxicities. Hypofractionation is suggested to balance patient comfort and treatment effectiveness, especially when life expectancy is short. The optimal RT schedule, dose and fractionations need to be further investigated.