Background and Purpose: The pathophysiology of development, growth, and rupture of intracranial aneurysms (IAs) is only partly understood. Cyclooxygenase 2 (COX-2) converts arachidonic acid to prostaglandin H ₂ , which, in turn, is isomerized to prostaglandin E ₂ . In the human body, COX-2 plays an essential role in inflammatory pathways. This explorative study aimed to investigate COX-2 expression in the wall of IAs and its correlation to image features in clinical (1.0T, 1.5T, and 3.0T) magnetic resonance imaging (MRI) and ultra-high-field 7T MRI. Methods: The study group comprised 40 patients with partly thrombosed saccular IAs. The cohort included 17 ruptured- and 24 unruptured IAs, which had all been treated microsurgically. Formaldehyde-fixed paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 (Dako, Santa Clara, CA; Clone: CX-294). We correlated Perls Prussian blue staining, MRI, and clinical data with immunohistochemistry, analyzed using the Trainable Weka Segmentation algorithm. Results: Aneurysm dome size ranged between 2 and 67 mm. The proportion of COX-2 positive cells ranged between 3.54% to 85.09%. An upregulated COX-2 expression correlated with increasing IA dome size ( P =0.047). Furthermore, there was a tendency of higher COX-2 expression in most ruptured IAs ( P =0.064). At all field strengths, MRI shows wall hypointensities due to iron deposition correlating with COX-2 expression ( P =0.022). Conclusions: Iron deposition and COX-2 expression in IAs walls correlate with signal hypointensity in MRI, which might, therefore, serve as a biomarker for IA instability. Furthermore, as COX-2 was also expressed in small unruptured IAs, it could be a potential target for specific medical treatment.

Background and purpose: Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high morbidity and mortality proceeding from the initial severity and following complications of aSAH. Various scores have been developed to predict these risks. We aimed to analyze the clinical value of different radiographic scores for prognostication of aSAH outcome.Methods: Initial computed tomography scans (≤48 h after ictus) of 745 aSAH cases treated between January 2003 and June 2016 were reviewed with regard to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and Claassen, Barrow Neurological Institute (BNI), Hijdra, original Graeb and Fisher scale scores. The primary endpoints were development of delayed cerebral ischemia (DCI), in‐hospital mortality and unfavorable outcome (modified Rankin Scale score >3) at 6 months after subarachnoid hemorrhage. Secondary endpoints included the different complications that can occur during aSAH. Clinically relevant cutoffs were defined using receiver‐operating characteristic curves. The radiographic scores with the highest values for area under the curve (AUC) were included in the final multivariate analysis.Results: The Hijdra sum score had the most accurate predictive value and independent associations with all primary endpoints: DCI (AUC 0.678, adjusted odds ratio [aOR] 2.83; p < 0.0001); in‐hospital mortality (AUC 0.704, aOR 2.83; p < 0.0001) and unfavorable outcome (AUC 0.726, aOR 2.91; p < 0.0001). Multivariate analyses confirmed the independent predictive value of the radiographic scales for risk of decompressive craniectomy (SEBES and Fisher score), cerebral vasospasm (SEBES, BNI score and Fisher score) and shunt dependency (Hijdra ventricle score and Fisher score) after aSAH.Conclusions: Initial radiographic severity of aSAH was independently associated with occurrence of different complications during aSAH and the final outcome. The Hijdra sum score showed the highest diagnostic accuracy and robust predictive value for early detection of risk of DCI, in‐hospital mortality and unfavorable outcome after aSAH.

Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines received two cycles of TMZ (150 µM) treatment for 72 h each. Regrown cells (RG2) were defined as TMZ resistant cells. MTT assay revealed significantly less susceptibility and sustained growth of RG2 compared with parental cells after TMZ challenge. TMZ-induced DNA damage significantly decreased in 53BP1-foci reporter transduced-RG2 cells compared with parental cells, associated with downregulation of MSH2 and MSH6. Flow cytometry revealed reduced G2/M arrest, increased EdU incorporation and suppressed apoptosis in RG2 cells after TMZ treatment. Colony formation and neurosphere assay demonstrated enhanced clonogenicity and neurosphere formation capacity in RG2 cells, accompanied by upregulation of stem markers. Collectively, we established an acute TMZ resistance model that recapitulated key features of TMZ resistance involving impaired mismatch repair, redistribution of cell cycle phases, increased DNA replication, reduced apoptosis and enhanced self-renewal. Therefore, this model may serve as a promising research tool for studying mechanisms of TMZ resistance and for defining therapeutic approaches to GBM in the future.

Background: Previous medical history strongly contributes to the genesis of intracranial aneurysms (IA). A possible impact of regular medication on the occurrence of abdominal aortic aneurysms has been reported. Aim: To evaluate the value of regular medication on the risk of development and rupture of IA. Methods: Data on medication use and related comorbidities were obtained from the institutional IA registry. A 1:1 age- and sex-matched patient sample was collected from the population-based Heinz Nixdorf Recall Study with individuals from the same area. Results: In the analysis comparing IA cohort (n = 1960) with the matched normal population (n = 1960), the use of statins (adjusted odds ratio, 1.34 [95% confidence interval 1.02–1.78]), antidiabetics (1.46 [1.08–1.99]), and calcium channel blockers (1.49 [1.11–2.00]) was independently associated with higher risk of IA, whereas uricostatics (0.23 [0.14–0.38]), aspirin (0.23 [0.13–0.43]), beta-blockers (0.51 [0.40–0.66]), and angiotensin-converting enzyme inhibitors (0.38 [0.27–0.53]) were related to lower risk of IA. In the multivariable analysis within the IA cohort (n = 2446), SAH patients showed higher drug exposure with thiazide diuretics (2.11 [1.59–2.80]), but lower prevalence of remaining antihypertensive medication—beta-blockers (0.38 [0.30–0.48]), calcium channel blockers (0.63 [0.48–0.83]), angiotensin-converting enzyme inhibitors (0.56 [0.44–0.72]), and angiotensin-1 receptor blockers (0.33 [0.24–0.45]). Patients with ruptured IA were less likely to be treated with statins (0.62 [0.47–0.81]), thyroid hormones (0.62 [0.48–0.79]), and aspirin (0.55 [0.41–0.75]). Conclusions: Regular medication might impact the risks related to the development and rupture of IA. Further clinical trials are required to clarify the effect of regular medication on IA genesis.

Objective: Despite recent advances in neuro-intensive care, there is still considerable mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). In this long-term monocentric observational cohort study, we aimed to analyze the rates, timing, and predictors of mortality after SAH. Methods: All consecutive SAH cases treated between January 2003 and June 2016 were included. Patients' demographic characteristics, previous medical history, SAH-related parameters, and available post-treatment follow-up data were collected and evaluated as potential mortality predictors in univariate and multivariate analyses. Results: Of 992 patients, 179 died during the initial treatment and 33 during the follow-up time reaching an overall mortality rate of 21.4%. Of over 119 tested variables, we identified the following independent predictors in the final multivariate Cox regression analysis: age >55 years (p= 15 points (p=0.003); intracranial pressure (ICP) increase (p<0.0001); and delayed cerebral ischemia (DCI) (p<0.0001). Being exposed to all five risk factors resulted in the case fatality rate of 75 % within a median survival of 14 days, compared to 2.5 % within a median of 1525 days when none of these features were present. Conclusions: The initial impact of aneurysmal bleeding is amongst the major mortality causes after SAH. Of potentially preventable adverse events, ICP increase and DCI occurring during initial treatment also present eminent clinical relevance for patients' survival in the long-term follow-up. Further ICP and DCI management optimization might help to decrease the mortality rate after SAH.