No Harmful Effect of Endovascular Treatment before Decompressive Surgery-Implications for Handling Patients with Space-Occupying Brain Infarction.

This study explored short- and mid-term functional outcomes in patients undergoing decompressive hemicraniectomy (DHC) due to space-occupying cerebral infarction and asked whether there is a potentially harmful effect of a priorly performed endovascular treatment (EVT). Medical records were screened for patients requiring DHC due to space-occupying cerebral infarction between January 2016 and July 2021. Functional outcomes at hospital discharge and at 3 months were assessed by the modified Rankin Scale (mRS). Out of 65 patients with DHC, 39 underwent EVT before DHC. Both groups, i.e., EVT + DHC and DHC alone, had similar volumes (280 ± 90 mL vs. 269 ± 73 mL, t-test, p = 0.633) and proportions of edema and infarction (22.1 ± 6.5% vs. 22.1 ± 6.1%, t-test, p = 0.989) before the surgical intervention. Patients undergoing EVT + DHC tended to have a better functional outcome at hospital discharge compared to DHC alone (mRS 4.8 ± 0.8 vs. 5.2 ± 0.7, Mann-Whitney-U, p = 0.061), while the functional outcome after 3 months was similar (mRS 4.6 ± 1.1 vs. 4.8 ± 0.9, Mann-Whitney-U, p = 0.352). In patients initially presenting with a relevant infarct demarcation (Alberta Stroke Program Early CT Score ≤ 5), the outcome was similar at hospital discharge and after 3 months between patients with EVT + DHC and DHC alone. This study provided no evidence for a harmful effect of EVT before DHC in patients with space-occupying brain infarction.

Non-ischemic cerebral enhancing (NICE) lesions after flow diversion for intracranial aneurysms: a multicenter study.

BACKGROUND: Non-ischemic cerebral enhancing (NICE) lesions have been reported as a rare complication of various neuroendovascular procedures, but information on their incidence after flow diversion is scant. It is unclear if specific devices or novel coating technologies may impact their occurrence. METHODS: We conducted a multicenter study on the incidence of NICE lesions after flow diverter (FD) implantation for cerebral aneurysm treatment. RESULTS: Eight centers identified 15 patients and provided detailed data. The clinical presentation ranged from asymptomatic to hemiplegia and cognitive impairment. The mean time to diagnosis after treatment was 65.1±101.5 days. Five centers disclosed information on all of their 1201 FD procedures during the inclusion period (2015-2022), during which 12 patients were diagnosed with NICE lesions in these institutions-that is, an incidence of 1%. FD coatings did not increase the incidence (6/591 patients (1%) treated with surface-modified FD vs 6/610 patients (1%) treated with bare FD; P=1.00). Significantly increased rates of 3.7% (6 cases in 161 procedures; P<0.01) and 3.3% (5 cases in 153 procedures; P<0.01) were found with stents of two specific product lines. The use of one product line was associated with a significantly lower incidence (0 cases in 499 procedures (0%); P<0.01). CONCLUSIONS: Novel stent coatings are not associated with an increased incidence of NICE lesions. The incidence rate of 1% suggests that these lesions may occur more often after flow diversion than after other endovascular treatments. We found a concerning accumulation of NICE lesion cases when FDs from two product families were used.

Preserved White Matter Integrity and Recovery After Brain Tumor Surgery: A Prospective Pilot Study on the Frontal Aslant Tract.

Introduction: Damage to white matter tracts can cause severe neurological deficits, which are often hardly predictable before brain tumor surgery. To explore the possibility of assessing white matter integrity and its preservation, we chose the frontal aslant tract (FAT) due to its involvement in multiple neurological functions such as speech and movement initiation. Methods: Right-handed patients with left hemispheric intracerebral tumors underwent FAT tractography within 7 days before and 3 days after surgery. Neurological performance score and aphasia score were assessed within 7 days before and after surgery, as well as at follow-up 3 months postoperatively. Results: Fifteen patients were prospectively analyzed. After multivariate analysis and receiver operating characteristic analysis, we found that preoperative fractional anisotropy (FA) of the left FAT indicated the preoperative aphasia score (cutoff 0.40, p = 0.015). Aphasia scores 3 months postoperatively were predicted by both postoperative FA of the left FAT (cutoff 0.35, p = 0.005) and postoperatively preserved FA of the left FAT (cutoff 95.8%, p = 0.017). Postoperatively preserved right FAT FA inversely predicted postoperative aphasia score (cutoff 95.1%, p = 0.016). Discussion: Assessment of white matter integrity preservation is possible and correlates with outcome after brain tumor surgery. It may be useful for patient counseling and assessment of rehabilitation potential, as well as to investigate relevant brain networks in the future. Clinical Trial Registration: The trial was prospectively registered at ClinicalTrials.gov (NCT04302857).

Case report: Treatment of advanced CSF1-receptor associated leukoencephalopathy with hematopoietic stem cell transplant.

CSF1 receptor-related leukoencephalopathy is a rare genetic disorder presenting with severe, adult-onset white matter dementia as one of the leading symptoms. Within the central nervous system, the affected CSF1-receptor is expressed exclusively in microglia cells. Growing evidence implicates that replacing the defective microglia with healthy donor cells through hematopoietic stem cell transplant might halt disease progression. Early initiation of that treatment is crucial to limit persistent disability. However, which patients are suitable for this treatment is not clear, and imaging biomarkers that specifically depict lasting structural damage are lacking. In this study, we report on two patients with CSF1R-related leukoencephalopathy in whom allogenic hematopoietic stem cell transplant at advanced disease stages led to clinical stabilization. We compare their disease course with that of two patients admitted in the same timeframe to our hospital, considered too late for treatment, and place our cases in context with the respective literature. We propose that the rate of clinical progression might be a suitable stratification measure for treatment amenability in patients. Furthermore, for the first time we evaluate [18F] florbetaben, a PET tracer known to bind to intact myelin, as a novel MRI-adjunct tool to image white matter damage in CSF1R-related leukoencephalopathy. In conclusion, our data add evidence for allogenic hematopoietic stem cell transplant as a promising treatment in CSF1R-related leukoencephalopathy patients with slow to moderate disease progression.

Preoperative language tract integrity is a limiting factor in recovery from aphasia after glioma surgery.

Aphasia can occur in a broad range of pathological conditions that affect cortical or subcortical structures. Here we test the hypothesis that white matter integrity of language pathways assessed by preoperative diffusion tensor imaging (DTI) is associated with language performance and its recovery after glioma resection. 27 patients with preoperative DTI were included. Segmentation of the arcuate fascicle (AF), the inferior fronto-occipital fascicle (IFOF), the inferior longitudinal fascicle (ILF), the superior longitudinal fascicle (SLF), and the uncinate fascicle (UF) was performed with a fully-connected neural network (FCNN, TractSeg). Median fractional anisotropy (FA) was extracted from the resulting volumes as surrogate marker for white matter integrity and tested for correlation with clinical parameters. After correction for demographic data and multiple testing, preoperative white matter integrity of the IFOF, the ILF, and the UF in the left hemisphere were independently and significantly associated with aphasia three months after surgery. Comparison between patients with and without aphasia three months after surgery revealed significant differences in preoperative white matter integrity of the left AF (p = 0.021), left IFOF (p = 0.015), left ILF (p = 0.003), left SLF (p = 0.001, p = 0.021, p = 0.043 for respective sub-bundles 1-3), left UF (p = 0.041) and the right AF (p = 0.027). Preoperative assessment of white matter integrity of the language network by time-efficient MRI protocols and FCNN-driven segmentation may assist in the evaluation of postoperative rehabilitation potential in glioma patients.

White Matter Integrity of the Corticospinal Tract for Estimation of Individual Patient Risk for Postoperative Neurological Deterioration after Glioma Surgery.

BACKGROUND: Tractography has become a standard tool for planning neurosurgical operations and has been proven to be useful for risk stratification. In various conditions, tractography-derived white matter integrity has been shown to be associated with neurological outcome. Postoperative performance has been shown to be a prognostic marker in glioma. We aimed to assess the relation of preoperative corticospinal tract (CST) integrity with postoperative neurological deterioration in patients with malignant glioma. METHODS: We retrospectively analyzed a cohort of 24 right-handed patients (41.7% female) for perioperative neurological performance score (NPS) and applied our anatomical tractography workflow to extract the median fractional anisotropy (FA) of the CST in preoperative magnetic resonance imaging (MRI). RESULTS: Median FA of the CST ipsilateral to the tumor correlated significantly with preoperative NPS (p = 0.025). After rank order correlation and multivariate linear regression, we found that the preoperative median FA of the right CST correlates with preoperative NPS, independently from epidemiological data (p = 0.019). In patients with lesions of the right hemisphere, median FA of the right CST was associated with a declining NPS in multivariate linear regression (p = 0.024). Receiver operating characteristic (ROC) analysis revealed an optimal FA cutoff at 0.3946 in this subgroup (area under the curve 0.83). Patients below that cutoff suffered from a decline in neurological performance significantly more often (p = 0.020). CONCLUSIONS: Assessment of preoperative white matter integrity may be a promising biomarker for risk estimation of patients undergoing craniotomy for resection of malignant glioma.

Treatment Effect of CT-Guided Periradicular Injections in Context of Different Contrast Agent Distribution Patterns.

Acutely manifesting radicular pain syndromes associated with degenerations of the lower spine are frequent ailments with a high rate of recurrence. Part of the conservative management are periradicular infiltrations of analgesics and steroids. The purpose of this study is to evaluate the dependence of the clinical efficacy of CT-guided periradicular injections on the pattern of contrast distribution and to identify the best distribution pattern that is associated with the most effective pain relief. Using a prospective study design, 161 patients were included in this study, ensuring ethical standards. Statistical analysis was performed, with the level of statistical significance set at p = 0.05. A total of 37.9% of patients experienced significant but not long-lasting (four weeks on average) complete pain relief. A total of 44.1% of patients experienced prolonged, subjectively satisfying pain relief of more than four weeks to three months. A total of 18% of patients had complete and sustained relief for more than six months. A significant correlation exists between circumferential, large area contrast distribution including the zone of action between the disc and affected nerve root contrast distribution pattern with excellent pain relief. Our results support the value of CT-guided contrast injection for achieving a good efficacy, and, if necessary, indicative repositioning of the needle to ensure a circumferential distribution pattern of corticosteroids for the sufficient treatment of radicular pain in degenerative spine disease.

18F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18F-labeled tau PET tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine (18F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18F-PI-2620 PET. The gain of sensitivity by adding 18F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363.

AIMS: Meningiomas are the most frequent primary brain tumours. Recently, knowledge about the molecular drivers underlying aggressive meningiomas has been expanded. A hotspot mutation in the AKT1 gene (AKT1E17K ), which is found in meningiomas at the convexity and especially at the skull base, has been associated with earlier tumour recurrence. METHODS: Here, we analysed the effects of the AKT1E17K mutation and treatment response to the Akt inhibitor AZD5363 in transgenic meningioma cell clones and mouse xenografts modelling convexity or skull base meningiomas. RESULTS: We show that the AKTE17K mutation significantly enhances meningioma cell proliferation and colony size in vitro, resulting in significantly shortened survival times of mice carrying convexity or skull base AKT1E17K xenografts. Treatment of mutant cells or xenografts (150 mg/kg/d) with AZD5363 revealed a significant decrease in cell proliferation and colony size and a prolongation of mouse survival. Western blots revealed activation of AKT1 kinase (phosphorylation at Ser273 and Thr308) by the E17K mutation in human meningioma samples and in our in vitro and in vivo models. CONCLUSIONS: Our data suggest that AKT1E17K mutated meningiomas are a promising selective target for AZD5363.

First Experience of Three Neurovascular Centers With the p64MW-HPC, a Low-Profile Flow Diverter Designed for Proximal Cerebral Vessels With Antithrombotic Coating.

Background: In the last decade, flow diversion (FD) has been established as hemodynamic treatment for cerebral aneurysms arising from proximal and distal cerebral arteries. However, two significant limitations remain-the need for 0.027" microcatheters required for delivery of most flow diverting stents (FDS), and long-term dual anti-platelet therapy (DAPT) in order to prevent FDS-associated thromboembolism, at the cost of increasing the risk for hemorrhage. This study reports the experience of three neurovascular centers with the p64MW-HPC, a FDS with anti-thrombotic coating that is implantable via a 0.021" microcatheter. Materials and methods: Three neurovascular centers contributed to this retrospective analysis of patients that had been treated with the p64MW-HPC between March 2020 and March 2021. Clinical data, aneurysm characteristics, and follow-up results, including procedural and post-procedural complications, were recorded. The hemodynamic effect was assessed using the O'Kelly-Marotta Scale (OKM). Results: Thirty-two patients (22 female, mean age 57.1 years) with 33 aneurysms (27 anterior circulation and six posterior circulation) were successfully treated with the p64MW-HPC. In 30/32 patients (93.75%), aneurysmal perfusion was significantly reduced immediately post implantation. Follow-up imaging was available for 23 aneurysms. Delayed aneurysm perfusion (OKM A3: 8.7%), reduction in aneurysm size (OKM B1-3: 26.1%), or sufficient separation from the parent vessel (OKM C1-3 and D1: 65.2%) was demonstrated at the last available follow-up after a mean of 5.9 months. In two cases, device thrombosis after early discontinuation of DAPT occurred. One delayed rupture caused a caroticocavernous fistula. The complications were treated sufficiently and all patients recovered without permanent significant morbidity. Conclusion: Treatment with the p64MW-HPC is safe and feasible and achieves good early aneurysm occlusion rates in the proximal intracranial circulation, which are comparable to those of well-established FDS. Sudden interruption of DAPT in the early post-interventional phase can cause in-stent thrombosis despite the HPC surface modification. Deliverability via the 0.021" microcatheter facilitates treatment in challenging vascular anatomies.

Assessment of a Reliable Fractional Anisotropy Cutoff in Tractography of the Corticospinal Tract for Neurosurgical Patients.

BACKGROUND: Tractography has become a standard technique for planning neurosurgical operations in the past decades. This technique relies on diffusion magnetic resonance imaging. The cutoff value for the fractional anisotropy (FA) has an important role in avoiding false-positive and false-negative results. However, there is a wide variation in FA cutoff values. METHODS: We analyzed a prospective cohort of 14 patients (six males and eight females, 50.1 ± 4.0 years old) with intracerebral tumors that were mostly gliomas. Magnetic resonance imaging (MRI) was obtained within 7 days before and within 7 days after surgery with T1 and diffusion tensor image (DTI) sequences. We, then, reconstructed the corticospinal tract (CST) in all patients and extracted the FA values within the resulting volume. RESULTS: The mean FA in all CSTs was 0.4406 ± 0.0003 with the fifth percentile at 0.1454. FA values in right-hemispheric CSTs were lower (p < 0.0001). Postoperatively, the FA values were more condensed around their mean (p < 0.0001). The analysis of infiltrated or compressed CSTs revealed a lower fifth percentile (0.1407 ± 0.0109 versus 0.1763 ± 0.0040, p = 0.0036). CONCLUSION: An FA cutoff value of 0.15 appears to be reasonable for neurosurgical patients and may shorten the tractography workflow. However, infiltrated fiber bundles must trigger vigilance and may require lower cutoffs.

Endovascular Treatment of Intracranial Aneurysms in Small Peripheral Vessel Segments-Efficacy and Intermediate Follow-Up Results of Flow Diversion With the Silk Vista Baby Low-Profile Flow Diverter.

Background and Purpose: Low-profile flow diverter stents (FDS) quite recently amended peripheral segments as targets for hemodynamic aneurysm treatment; however, reports on outcomes, especially later than 3 months, are scarce. This study therefore reports our experience with the novel silk vista baby (SVB) FDS and respective outcomes after 8 and 11 months with special respect to specific adverse events. Materials and Methods: Forty-four patients (mean age, 53 years) harboring 47 aneurysms treated with the SVB between June 2018 and December 2019 were included in our study. Clinical, procedural, and angiographic data were collected. Follow-ups were performed on average after 3, 8, and 11 months, respectively. Treatment effect was assessed using the O'Kelly Marotta (OKM) grading system. Results: Overall, angiographic follow-ups were available for 41 patients/45 aneurysms. Occlusion or significant reduction in aneurysmal perfusion (OKM: D1, B1-B3 and A2-A3) was observed in 98% of all aneurysms after 8 months. Only 2% of the treated aneurysms remained morphologically unaltered and without an apparent change in perfusion (OKM A1). Adverse events in the early post-interventional course occurred in seven patients; out of them, mRS-relevant morbidity at 90 days related to FDS treatment was observable in two patients. One death occurred in the context of severe SAH related to an acutely ruptured dissecting aneurysm of the vertebral artery. Conclusion: The SVB achieves sufficient occlusion rates of intracranial aneurysms originating from peripheral segments, which are comparable to prior established conventional FDS with acceptably low complication rates. However, alteration of a hemodynamic equilibrium in distal localizations requires special attention to prevent ischemic events.

Diffusion weighted imaging in high-grade gliomas: A histogram-based analysis of apparent diffusion coefficient profile.

PURPOSE: Glioblastoma and anaplastic astrocytoma represent the most commonly encountered high-grade-glioma (HGG) in adults. Although both neoplasms are very distinct entities in context of epidemiology, clinical course and prognosis, their appearance in conventional magnetic resonance imaging (MRI) is very similar. In search for additional information aiding the distinction of potentially confusable neoplasms, histogram analysis of apparent diffusion coefficient (ADC) maps recently proved to be auxiliary in a number of entities. Therefore, our present exploratory retrospective study investigated whether ADC histogram profile parameters differ significantly between anaplastic astrocytoma and glioblastoma, reflect the proliferation index Ki-67, or are associated with the prognostic relevant MGMT (methylguanine-DNA methyl-transferase) promotor methylation status. METHODS: Pre-surgical ADC volumes of 56 HGG patients were analyzed by histogram-profiling. Association between extracted histogram parameters and neuropathology including WHO-grade, Ki-67 expression and MGMT promotor methylation status was investigated due to comparative and correlative statistics. RESULTS: Grade IV gliomas were more heterogeneous than grade III tumors. More specifically, ADCmin and the lowest percentile ADCp10 were significantly lower, whereas ADCmax, ADC standard deviation and Skewness were significantly higher in the glioblastoma group. ADCmin, ADCmax, ADC standard deviation, Kurtosis and Entropy of ADC histogram were significantly correlated with Ki-67 expression. No significant difference could be revealed by comparison of ADC histogram parameters between MGMT promotor methylated and unmethylated HGG. CONCLUSIONS: ADC histogram parameters differ significantly between glioblastoma and anaplastic astrocytoma and show distinct associations with the proliferative activity in both HGG. Our results suggest ADC histogram profiling as promising biomarker for differentiation of both, however, further studies with prospective multicenter design are wanted to confirm and further elaborate this hypothesis.

PET/MRI Delivers Multimodal Brain Signature in Alzheimer's Disease with De Novo PSEN1 Mutation.

BACKGROUND: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer's disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap. MATERIAL AND METHODS: We presented a 31-year-old male patient without a family history of dementia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [18F]Florbetaben and the secondgeneration tau tracer [18F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls. RESULTS: Widespread ß-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disruption of default mode and sensory-motor network functional connectivity. Molecular genetic analysis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val). CONCLUSION: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an array of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating anti- amyloid/tau therapeutic approaches.

Single-Center Experience With the Bare p48MW Low-Profile Flow Diverter and Its Hydrophilically Covered Version for Treatment of Bifurcation Aneurysms in Distal Segments of the Anterior and Posterior Circulation.

Background and Purpose: Flow diversion has profoundly changed the way aneurysms are treated. However, it conventionally requires dual antiplatelet medication and has yet been considered off-label use in the posterior circulation or within peripheral vessels of the anterior circulation. Here, we report our experience with the p48MW/p48MW hydrophilic coating (HPC) in the anterior and posterior circulation. This novel low-profile flow diverter is specifically designed for treatment of small peripheral vessels, and the p48MW HPC has an anti-thrombotic polymer coating, which allows application of a single antiplatelet function medication in conditions that expectably require further surgery. Materials and Methods: Thirty-two patients were prospectively included. Twenty-six treatments were performed with one flow diverter, four required two overlapping flow diverters, one case demanded three overlapping flow diverters, and in one case, extensive dissecting aneurysm telescoping with eight flow diverters was necessary. Twenty-two complex bifurcation aneurysms were treated. Three months' follow-up was available for 14 patients. Results: Deployment was uneventful in all cases. In four cases, undersizing was unavoidable and resulted in significant shortening of the flow diverter, which demanded implantation of further flow diverters to sufficiently treat the target aneurysm. Three flow diverters required balloon angioplasty for optimal wall approximation. All parent vessels remained patent. Available 3-month follow-up studies showed decreased influx or delayed washout in all aneurysms; none was occluded completely. There were no device-related clinical complications. Conclusions: Implantation of the p48MW/p48MW HPC is safe and effective for treatment of distally located cerebral aneurysms. Considering the reported rates of ischemic complications associated with flow diversion of complex bifurcation aneurysms, the p48MW/p48MW HPC potentially provides increased safety for complex bifurcation aneurysms in the anterior and posterior circulation.

KLF4K409Q-mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment.

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

Flow diversion in challenging vascular anatomies: the use of low profile stent retrievers for safe and accurate positioning of the microcatheter.

BACKGROUND: Hemodynamic therapy with Flow-Diverters has become a fundamental option for treatment of cerebral aneurysms. A major obstacle of Flow-Diverters is the comparatively stiff microcatheter required for implantation. Consequentially, maneuverability is limited and primary catheterization of peripheral targets may be difficult or even futile in challenging vascular anatomies. To overcome this, a highly navigable microcatheter must be used to attain the desired vascular segment, followed by a hardly controllable exchange-maneuver via a long microwire, involving a high risk for wire-perforation. Our study aimed to investigate the value of low-profile stent-retrievers as a railway for introduction of the required microcatheter, which allows to maintain a stable endovascular position and reduce the risk for procedural vessel injury. METHODS: 14cases (8females, mean-age 59y) of Flow-Diverter-Implantation requiring the use of a low-profile stent-retriever were reviewed. All cases featured a challenging vascular anatomy. After micro-catheterization of the desired segment, the stent-retriever was carefully deployed as an anchor in a secure, distal location. In all cases a pREset/LITE-stent-retriever was used for introduction of the equipment required for implantation. RESULTS: In all cases the anchoring-maneuver was performed without technical complications. The stent-retrievers maintained a stable position after deployment in all situations. No potential traumatic sudden movements of the microcatheter occurred. No procedure-related perforations, dissections or vasospasms were observable during the interventions or their aftermath. CONCLUSIONS: In our experience the stent-retriever-anchoring-maneuver represents a potentially essential and safe amendment for flow diverter treatment in technically challenging situations.

Histogram Analysis of Diffusion Weighted Imaging in Low-Grade Gliomas: in vivo Characterization of Tumor Architecture and Corresponding Neuropathology.

Background: Low-grade gliomas (LGG) in adults are usually slow growing and frequently asymptomatic brain tumors, originating from glial cells of the central nervous system (CNS). Although regarded formally as "benign" neoplasms, they harbor the potential of malignant transformation associated with high morbidity and mortality. Their complex and unpredictable tumor biology requires a reliable and conclusive presurgical magnetic resonance imaging (MRI). A promising and emerging MRI approach in this context is histogram based apparent diffusion coefficient (ADC) profiling, which recently proofed to be capable of providing prognostic relevant information in different tumor entities. Therefore, our study investigated whether histogram profiling of ADC distinguishes grade I from grade II glioma, reflects the proliferation index Ki-67, as well as the IDH (isocitrate dehydrogenase) mutation and MGMT (methylguanine-DNA methyl-transferase) promotor methylation status. Material and Methods: Pre-treatment ADC volumes of 26 LGG patients were used for histogram-profiling. WHO-grade, Ki-67 expression, IDH mutation, and MGMT promotor methylation status were evaluated. Comparative and correlative statistics investigating the association between histogram-profiling and neuropathology were performed. Results: Almost the entire ADC profile (p25, p75, p90, mean, median) was significantly lower in grade II vs. grade I gliomas. Entropy, as second order histogram parameter of ADC volumes, was significantly higher in grade II gliomas compared with grade I gliomas. Mean, maximum value (ADCmax) and the percentiles p10, p75, and p90 of ADC histogram were significantly correlated with Ki-67 expression. Furthermore, minimum ADC value (ADCmin) was significantly associated with MGMT promotor methylation status as well as ADC entropy with IDH-1 mutation status. Conclusions: ADC histogram-profiling is a valuable radiomic approach, which helps differentiating tumor grade, estimating growth kinetics and probably prognostic relevant genetic as well as epigenetic alterations in LGG.

Delayed Stroke after Aneurysm Treatment with Flow Diverters in Small Cerebral Vessels: A Potentially Critical Complication Caused by Subacute Vasospasm.

Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.