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Ventriculoperitoneal shunt (VPS) with adjustable differential pressure valves are commonly used to treat infants with hydrocephalus avoiding shunt related under- or overdrainage. The aim of this study was to analyse the influence of VPS adjustable differential pressure valve on the head circumference (HC) and ventricular size (VS) stabilization in infants with post intraventricular haemorrhage, acquired and congenital hydrocephali. Forty-three hydrocephalic infants under 6 months old were prospectively included between 2014 and 2018. All patients were treated using a VPS with adjustable differential pressure valve. HC and transfontanelle ultrasonographic VS measurements were regularly performed and pressure valve modifications were done aiming HC and VS percentiles between the 25th and 75th. The patients were divided into two groups: infants with hydrocephalus due to an intraventricular haemorrhage (IVH-H), and infants with hydrocephalus due to other aetiologies (OAE-H). The mean of pressure valve modification was 3.7 per patient in the IVH-H group, versus 2.95 in the OAE-H group. The median of last pressure valve value was higher at 8.5 cm H2O in the IVH-H group comparing to 5 cm H2O in the OAE-H group (p = 0.013). Optimal VPS pressure valve values could be extremely difficult to settle in order to gain normalisation of the HC and VS in infants. However, after long term follow up (mean of 18 months) and several pressure valve modifications, this normalisation is possible and shows that infants with IVH-H need a higher pressure valve value comparing to infants with OAE-H.

Current guidelines suggest surgical decompression for ischemic cerebellar stroke in case of significant mass effect. Recent research has aimed to identify a possible threshold for mass effect. However, a computer-assisted volumetry in acute setting is time consuming and impracticable, wherefore the aim of this study was to assess the accuracy and clinical applicability of the ABC/2 method in case of ischemic cerebellar stroke. Imaging data of 125 patients, including preoperative CT or MRI scans were used for volumetric analysis. The ABC/2 formula using scans in axial and coronal planes. BrainLab® Elements software was used for computer assisted volumetry by defining the region of interest allowing automated volumetric calculation. Measurements were conducted independently by blinded clinicians. Pearson correlation and Bland-Altmann test were used for statistical analysis. Among the 125 cerebellar infarctions analyzed, there was no statistical difference of mean infarct volume measurement between the ABC/2 formula and computer-assisted volumetry (16.6mL vs. 15.91mL; range 0.8-67.7mL; p = 0.76). The Spearman correlation test indicated a strong correlation between the two methods (r = 0.985, 95% CI: 0.979-0.990, p < 0.0001). Discrepancies were most notable in smaller infarction volumes (<10 mL), prompting a subgroup analysis. For infarct volume less than 10mL, the ratio of volumetric differences ranged from 47% to 60%, with absolute volume differences from -3-3 mL whereas the ratio ranged from -20% to 29%, with absolute volume differences from -6-8 mL in cases with infarct volume greater equal 10mL. ABC/2 formula shows a good correlation with computer-assisted volumetry. Consequently, it could serve as a fast and practical tool for estimating cerebellar infarct volume and aiding decision-making in clinical practice. However, the limitations and variability of the ABC/2 method, particularly for smaller infarcts, must be considered.

Background: Inhibitors of cyclin-dependent kinases (CDKs) and epigenetic modifier enhancer of zeste homolog 2 (EZH2) have emerged as promising options in the pharmacotherapy of malignant tumors. Recently, we demonstrated synergistic antitumor effects of the CDK4/6 inhibitor abemaciclib and the EZH2 inhibitors GSK126 or tazemetostat in patient-derived glioblastoma (GBM) models. Importantly, all three drugs are substrates of the two most important plasma membrane multidrug transporters ABCB1 and ABCG2, with abemaciclib and tazemetostat also being inhibitors of these proteins. Methods: To investigate whether increased intracellular accumulation of either of the two drugs used in combination could have contributed to corresponding synergisms, we developed a simple LC-MS/MS method for simultaneous detection of the three substances in cell culture lysates. The method was validated in accordance with the current International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline M10 on bioanalytical method validation and study sample analysis. Results: All acceptance criteria were met. Subsequent analysis of intracellular drug concentrations confirmed increased cellular uptake of tazemetostat in the presence of abemaciclib in both GBM cell lines studied compared to single agent treatment. A comparable pattern was also observed for GSK126, but in only one of the two cell lines used. Conclusions: In conclusion, the observed synergistic antitumor effect could be partly due to increased intracellular accumulation, although this alone is certainly not sufficient to explain it. Overall, the developed method provides a valuable approach for characterizing interactions at the transport level and for predicting the efficiency of both anticancer substance classes in different cell lines.

Astrocytes contribute to many higher brain functions. A key mechanism in glia-to-neuron signalling is vesicular exocytosis; however, the identity of exocytosis organelles remains a matter of debate. Since vesicles derived from the trans-Golgi network (TGN) are not considered in this context, we studied the astrocyte TGN by immunocytochemistry applying anti-Rab6A. In mouse brain, Rab6A immunostaining is found to be unexpectedly massive, diffuse in all regions, and is detected preferentially and abundantly in the peripheral astrocyte processes, which is hardly evident without glial fibrillary acid protein (GFAP) co-staining. All cells positive for the astrocytic markers glutamine synthetase (GS), GFAP, aldehyde dehydrogenase 1 family member L1 (Aldh1L1), or SRY (sex determining region Y)-box 9 (SOX9) were Rab6A+. Rab6A is excluded from microglia, oligodendrocytes, and NG2 cells using cell type-specific markers. In human cortex, Rab6A labelling is very similar and associated with GFAP+ astrocytes. The mouse data also confirm the specific astrocytic labelling by Aldh1L1 or SOX9; the astrocyte-specific labelling by GS sometimes debated is replicated again. In mouse and human brain, individual astrocytes display high variability in Rab6A+ structures, suggesting dynamic regulation of the glial TGN. In summary, Rab6A expression is an additional, global descriptor of astrocyte identity. Rab6A might constitute an organelle system with a potential role of Rab6A in neuropathological and physiological processes.

Background: Hydrogen peroxide (H2O2) is a well-known hemostatic and antiseptic agent in neurosurgical practice. While there are concerns regarding the use of H2O2 due to its potential for neuronal damage, the pathophysiological effect on neuronal cells is not clearly understood. Methods: An online survey concerning the use of H2O2 was conducted in a board-certified platform, and an experimental study was designed to investigate the effect of H2O2 on neuronal and tumor cells. Brain tissues of mice and brain/tumor tissues of humans were irrigated with H2O2 3%, H2O2 1.5%, and NaCl 0.9%, and processed by bipolar coagulation. Tissue sections were obtained and stained with H&E and analyzed by the depth and degree of neuronal damage measured from the cortical surface (μm). Results: In total, 242 neurosurgeons participated in the survey, and 81% of neurosurgeons reported use of H2O2 in neurosurgical practice. however only 5% of the participants had a literature-based knowledge of the pathophysiological mechanism of H2O2. In total, eight mouse brain tissues, 21 human brain tissues, and seven human tumor tissues were processed and analyzed. The experimental study found that H2O2 caused vacuolization of neuronal tissue in mouse brain tissues, with a mean depth of damage of 343.7 ± 39.7 μm after 2 min and 460.1 ± 36.4 μm after 10 min exposure to H2O2 3% (p < 0.001). In human brain tissues, vacuolization was detected in sections exposed to H2O2 1.5% and 3%, with a mean depth of damage of 543.8 ± 304.5 μm and 859.0 ± 379 μm (p = 0.003). In the bipolar coagulation group, the mean depth of neuronal damage, of 2504 ± 1490 μm, was nearly three times greater than that in the H2O2 group (p < 0.001). Similar results were observed in human tumor tissues as well. Conclusions: H2O2 seems to cause less local damage on neuronal and tumor cells than conventional bipolar cauterization, suggesting it as a good alternative to be used for hemostasis and marginal tumor cell treatment. However, due to its potential risk for embolism, H2O2 should be used with caution.

The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival. A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the Brainlab® software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myelocytic (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records. The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myelocytic tumor infiltration (p=0.78, p=0.74) between these groups. In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.

Here, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo , and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly ( Rb, PLK1, RRM2, PRC1, CENPF, TPX2 ), histone modification ( HIST1H1B, HIST1H3G ), DNA damage/replication stress events ( TOP2A, ATF4 ), immuno-oncology ( DEPDC1 ), EMT-counterregulation ( PCDH1 ) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.

Background The development of robotic systems has provided an alternative to frame-based stereotactic procedures. The aim of this experimental phantom study was to compare the mechanical accuracy of the Robotic Surgery Assistant (ROSA) and the Leksell stereotactic frame by reducing clinical and procedural factors to a minimum. Methods To precisely compare mechanical accuracy, a stereotactic system was chosen as reference for both methods. A thin layer CT scan with an acrylic phantom fixed to the frame and a localizer enabling the software to recognize the coordinate system was performed. For each of the five phantom targets, two different trajectories were planned, resulting in 10 trajectories. A series of five repetitions was performed, each time based on a new CT scan. Hence, 50 trajectories were analysed for each method. X-rays of the final cannula position were fused with the planning data. The coordinates of the target point and the endpoint of the robot- or frame-guided probe were visually determined using the robotic software. The target point error (TPE) was calculated applying the Euclidian distance. The depth deviation along the trajectory and the lateral deviation were separately calculated. Results Robotics was significantly more accurate, with an arithmetic TPE mean of 0.53 mm (95% CI 0.41 – 0.55 mm) compared to 0.72 mm (95% CI 0.63 – 0.8 mm) in stereotaxy (p < 0.05). In robotics, the mean depth deviation along the trajectory was -0.22 mm (95% CI -0.25 – -0.14 mm). The mean lateral deviation was 0.43 mm (95% CI 0.32 – 0.49 mm). In frame-based stereotaxy, the mean depth deviation amounted to -0.20 mm (95% CI -0.26 – -0.14 mm), the mean lateral deviation to 0.65 mm (95% CI 0.55 – 0.74 mm). Conclusion Both the robotic and frame-based approach proved accurate. The robotic procedure showed significantly higher accuracy. For both methods, procedural factors occurring during surgery might have a more relevant impact on overall accuracy.

Background: Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy, often associated with hippocampal sclerosis (HS), which involves selective neuronal loss in the Cornu Ammonis subregion 1 CA1 and CA4 regions of the hippocampus. Granule cells show migration and mossy fiber sprouting, though the mechanisms remain unclear. Microglia play a role in neurogenesis and synaptic modulation, suggesting they may contribute to epilepsy. This study examines the role of microglia and axonal guidance molecules in neuronal reorganization in TLE. Methods: Nineteen hippocampal samples from patients with TLE undergoing epilepsy surgery were analyzed. Microglial activity (M1/M2-like microglia) and neuronal guidance molecules were assessed using microscopy and semi-automated techniques. Gene expression was evaluated using the nCounter Expression Profiling method. Results: Neuronal cell loss was correlated with decreased activity of the M1 microglial phenotype. In the CA2 region, neuronal preservation was linked to increased mossy fiber sprouting and microglial presence. Neuronal markers such as Deleted in Colorectal Cancer (DCC) and Synaptopodin were reduced in areas of cell death, while Netrin-1 was elevated in the granule cell layer, potentially influencing mossy fiber sprouting. The nCounter analysis revealed downregulation of genes involved in neuronal activity (e.g., NPAS4, BCL-2, GRIA1) and upregulation of IκB, indicating reduced neuroinflammation. Conclusions: This study suggests reduced neuroinflammation in areas of neuronal loss, while regions with preserved neurons showed mossy fiber sprouting associated with microglia, Netrin-1, and DCC.