Andreas Unterberg

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (nxa0= 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage

Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9–12, and avoidance of corticosteroids. Conclusion These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (pxa0<xa00.0001). Highest mutation frequencies were detected in gliosarcomas (81xa0%), oligodendrogliomas (78xa0%), oligoastrocytomas (58xa0%), primary glioblastomas (54xa0%), and solitary fibrous tumors (50xa0%). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (pxa0<xa00.0001), but inversely associated with loss of ATRX expression (pxa0<xa00.0001) and IDH1/IDH2 mutations (pxa0<xa00.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.

Motor cortex stimulation for long-term relief of chronic neuropathic pain: A 10 year experience

Abstract Chronic subthreshold stimulation of the contralateral precentral gyrus is used in patients with intractable neuropathic pain for more than 15 years. The aim of this study was to analyse retrospectively our own patient group with long term follow‐up of 10 years. Seventeen patients with chronic neuropathic pain were treated with contralateral epidural stimulation electrodes. In 10 cases, trigeminal neuropathic pain (TNP) and in seven cases post‐stroke pain (PSP) were diagnosed. The placement of the electrodes was performed in local anaesthesia using neuronavigation and intraoperative neuromonitoring. A test trial of minimum one week including double‐blind testing was conducted and pain intensity was measured using a visual analogue scale (VAS). Correct placement of the electrode was achieved in all patients using intraoperative neurophysiological monitoring. Double‐blind testing was able to identify 6 (35%) non‐responders. In 5 of 10 (50%) with TNP and 3 of 7 (43%) with PSP a positive effect with pain reduction ≥50% was observed. The mean follow‐up period was 3.6 years (range 1–10 years) and includes a patient with 10 years of positive stimulation effect. Stimulation of the motor cortex is a treatment option for patients with chronic neuropathic pain localized in the face or upper extremity. Double‐blind testing can identify non‐responders. Patients with TNP profit more than patients with PSP. The positive effect can last for ten years in long‐term follow‐up.

DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

BACKGROUNDnThe WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups.nnnMETHODSnIn this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip.nnnFINDINGSnWe retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma.nnnINTERPRETATIONnDNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma.nnnFUNDINGnGerman Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry

The activating E17K mutation in the AKT1 gene has been detected in several tumor entities. Currently several clinical studies with specific AKT1 inhibitors are under way. To determine whether AKT1 mutations are involved in human tumors of the nervous system, we examined a series of 1,437 tumors including 391 primary intracranial brain tumors and 1,046 tumors of the coverings of the central and peripheral nervous system. AKT1E17K mutations were exclusively seen in meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance was seen in the variant of meningothelial meningioma WHO grade I of basal and spinal localization. In contrast, AKT1E17K mutations were rare in WHO grade II and absent in WHO grade III meningiomas. In order to more effectively detect this mutation, we tested for immunohistochemical markers associated with this alteration. We observed strong up-regulation of SFRP1 expression in all meningiomas with AKT1E17K mutation and in HEK293 cells after transfection with mutant AKT1E17K, but not in meningiomas and HEK293 cells lacking this mutation.

Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain

OBJECTIVESnThe detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS).nnnMETHODSnThe convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 μl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD.nnnRESULTSnOf 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves.nnnCONCLUSIONnThe gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

MRI of the Perihemorrhagic Zone in a Rat ICH Model: Effect of Hematoma Evacuation

BackgroundPerihemorrhagic pathophysiology of spontaneous intracerebral hemorrhages (ICH) remains unclear. Recently, ischemic changes in the perihemorrhagic zone (PHZ) have been discussed as a potential source of secondary damage. In this study, we focussed on diffusion and perfusion characteristics of experimental ICH.MethodsExperimental ICH was induced with a double injection model in rats. In total, 49 animals were examined at three timepoints within 3.5xa0h after ICH with a 2.35T animal scanner. We investigated perihemorrhagic relative apparent diffusion coefficients (rADC) and relative mean transit time (rMTT). Animals were divided into 2 groups; controls (gr1, nxa0=xa027) and facilitated hematoma evacuation with recombinant tissue plasminogen activator (rt-PA) after the first of 3 imaging time points (gr2, nxa0=xa022). Diffusion (rADC) and perfusion (rMTT) characteristics were analyzed in 3 regions of interest surrounding the hematoma (ROI1–3).ResultsOverall rADC and rMTT values in ROI3 (normal tissue) did not show any changes. There was mild edema—not ischemia—in ROIs1 and 2 at TP1 with rADC of 1.05–1.18 in both groups indicating vasogenic edema (not ischemia). This did not change with hematoma evacuation. There was mild (non-critical) perfusion reduction in ROIs1 and 2 at TP1, which disappeared after clot evacuation in group 2 (Pxa0<xa00.05 for TP3). Multifactorial ANOVA showed a solid trend (0.06xa0<xa0Pxa0<xa00.1) for clot evacuation associated normalization of perfusion in ROIs 1 and 2 within and in between groups 1 and 2.ConclusionsWe demonstrated vasogenic edema and mild perfusion reduction in the PHZ above the ischemic threshold. The existence of a perihemorrhagic “penumbra” indicating critically ischemic tissue analogous to ischemic stroke is unlikely.

‘Long’ pressure reactivity index (L-PRx) as a measure of autoregulation correlates with outcome in traumatic brain injury patients

BackgroundCerebral autoregulation and, consequently, cerebrovascular pressure reactivity, can be disturbed after traumatic brain injury (TBI). Continuous monitoring of autoregulation has shown its clinical importance as an independent predictor of neurological outcome. The cerebral pressure reactivity index (PRx) reflects that changes in seconds of cerebrovascular reactivity have prognostic significance. Using an alternative algorithm similar to PRx, we investigate whether the utilization of lower-frequency changes of the order of minutes of mean arterial blood pressure (MAP) and intracranial pressure (ICP) could have a prognostic value in TBI patients.Materials and methodsHead-injured patients requiring continued advanced multimodal monitoring, including hemodynamic, ICP and microdialysis (MD) monitoring, were analyzed retrospectively. A low-frequency sample pressure reactivity index (L-PRx) was calculated, using 20-min averages of MAP and ICP data as a linear Pearsons correlation. The mean values per patient were correlated to outcome at 6xa0months after injury. Differences of monitoring parameters between non-survivors and survivors were compared.ResultsA total of 29 patients (mean age 37.2xa0years, 26 males) suffering from TBI were monitored for a mean of 109.6xa0h (16–236xa0h, SDu2009±u200960.4). Mean L-PRx was found to be of 0.1 (−0.2 to 0.6, SDu2009±u20090.20), six patients presented impaired (>0.2) values. The averaged L-PRx correlated significantly with ICP (ru2009=u20090.467, pu2009=u20090.011) and 6-month outcome (ru2009=u2009−0.556, pu2009=u20090.002). Significant statistical differences were found in L-PRx, cerebral perfusion pressure (CPP), lactate, and lactate-pyruvate ratio when comparing patients who died (nu2009=u20095) and patients who survived.ConclusionsL-PRx correlates with the 6-month outcome in TBI patients. Very slow changes of MAP and ICP may contain important autoregulation information. L-PRx may be an alternative algorithm for the estimation of cerebral autoregulation and clinical prognosis.

Comparative study of application accuracy of two frameless neuronavigation systems: experimental error assessment quantifying registration methods and clinically influencing factors

This study aimed at comparing the accuracy of two commercial neuronavigation systems. Error assessment and quantification of clinical factors and surface registration, often resulting in decreased accuracy, were intended. Active (Stryker Navigation) and passive (VectorVision Sky, BrainLAB) neuronavigation systems were tested with an anthropomorphic phantom with a deformable layer, simulating skin and soft tissue. True coordinates measured by computer numerical control were compared with coordinates on image data and during navigation, to calculate software and system accuracy respectively. Comparison of image and navigation coordinates was used to evaluate navigation accuracy. Both systems achieved an overall accuracy of <1.5xa0mm. Stryker achieved better software accuracy, whereas BrainLAB better system and navigation accuracy. Factors with conspicuous influence (Pu2009<u20090.01) were imaging, instrument replacement, sterile cover drape and geometry of instruments. Precision data indicated by the systems did not reflect measured accuracy in general. Surface matching resulted in no improvement of accuracy, confirming former studies. Laser registration showed no differences compared to conventional pointers. Differences between the two systems were limited. Surface registration may improve inaccurate point-based registrations but does not in general affect overall accuracy. Accuracy feedback by the systems does not always match with true target accuracy and requires critical evaluation from the surgeon.