Daniele Piccolo

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.

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.

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 (R²_cv ≤ 0). Inflammatory Response (R²_cv = 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 (R²_cv = 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.

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.

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. Video 1 Endovascular coil embolization through a previously implanted Contour intrasaccular device for recurrent posterior communicating artery aneurysm.:

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.

Purpose To determine the relationship between intravoxel incoherent motion (IVIM) MRI parameters and clinical changes post-tap test (TT) in idiopathic normal-pressure hydrocephalus (iNPH) patients. Methods Forty-four probable iNPH patients underwent 3 T MRI before and after TT. IVIM parameters were calculated from eight different bilateral regions of interest in basal ganglia, centrum semiovale, and corona radiata. Patients were categorized based on TT response into positive (group 1) and negative (group 2) groups. A Welch two-sample t-test was used to compare differences in D, D*, f, and ADC between the two groups, while a paired t-test was employed to assess the changes within each group before and after TT. These parameters were then correlated with clinical results. Results In the lenticular and thalamic nuclei, D value was significantly lower in the group 1 compared to group 2 both pre- and post-TT (p = 0.002 and p = 0.007 respectively). Post-TT, the positive response group exhibited a notably reduced D* value (p = 0.012) and significantly higher f values (p = 0.028). In the corona radiata and centrum semiovale, a significant post-TT reduction in D* was observed in the positive response group (p = 0.017). Within groups, the positive response cohort showed a significant post-TT increase in ADC (p < 0.001) and a decrease in D* (p = 0.007). Conclusion IVIM permits the acquisition of important non-invasive information about tissue and vascularization in iNPH patients. Enhanced perfusion in the lenticular and thalamic nuclei may suggest the role of re-established microvascular and glymphatic pathways, potentially elucidating the functional improvement in motor function after TT in iNPH patients.

Background: Few cases of adult idiopathic occlusion of the foramen of Monro (AIOFM) are described in the literature. The diagnosis of AIOFM after an endoscopic procedure is even more infrequent. Case Description: We described the case of a 50-year-old woman who developed bilateral membranous occlusion of both Monro foramina 20 years after an endoscopic third ventriculostomy (ETV) for triventricular hydrocephalus due to an aqueductal stenosis. The patient underwent an endoscopic treatment (left foraminoplasty and septostomy) to check the patency of the stoma on the floor of the third ventricle. After the endoscopic procedure, the symptoms improved and the postoperative magnetic resonance imaging (MRI) demonstrated the resolution of the biventricular hydrocephalus. Conclusion: Bilateral occlusion of both FM with consequent bilateral lateral ventricles enlargement is an extremely rare condition, especially if we consider the cases of biventricular hydrocephalus after endoscopic procedures. In our opinion, an endoscopic approach should be attempted as first choice procedure, avoiding any intraventricular stent or shunt placement.