Publications by authors named "Christian Hartmann"

237 Publications

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours.

Neuropathol Appl Neurobiol 2021 Jun 5. Epub 2021 Jun 5.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, 10117, Berlin, Germany.

Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours.

Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.

Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic and one VHL-disease-related ELSTs (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs, but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).

Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.
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http://dx.doi.org/10.1111/nan.12741DOI Listing
June 2021

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

Neuromodulation 2021 May 27. Epub 2021 May 27.

Department of Neurosurgery, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

Objective: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.

Materials And Methods: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs. omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.

Results: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs. 21.2% (41/193) who preferred the omnidirectional period.

Conclusion: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.
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http://dx.doi.org/10.1111/ner.13407DOI Listing
May 2021

Within- and across-network alterations of the sensorimotor network in Parkinson's disease.

Neuroradiology 2021 May 21. Epub 2021 May 21.

Department of Diagnostic and Interventional Radiology, University Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany.

Purpose: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks.

Methods: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters.

Results: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON.

Conclusion: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy.
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http://dx.doi.org/10.1007/s00234-021-02731-wDOI Listing
May 2021

Inadvertent hypothermia after endovascular therapy is not associated with improved outcome in stroke due to anterior circulation large vessel occlusion.

Eur J Neurol 2021 May 11. Epub 2021 May 11.

Department of Neurology, Dresden Neurovascular Center, Technische Universität Dresden, Dresden, Germany.

Background And Purpose: Hypothermia may be neuroprotective in acute ischemic stroke. Patients with anterior circulation large vessel occlusion (acLVO) are frequently hypothermic after endovascular therapy (EVT). We sought to determine whether this inadvertent hypothermia is associated with improved outcome.

Methods: We extracted data of consecutive patients (January 2016 to May 2019) who received EVT for acLVO from our prospective EVT register of all patients screened for EVT at our tertiary stroke center. We assessed functional outcome at 3 months and performed multivariate analysis to calculate adjusted risk ratios (aRRs) for favorable outcome (modified Rankin Scale scores = 0-2) and mortality across patients who were hypothermic (<36°C) and patients who were normothermic (≥36°C to <37.6°C) after EVT. Moreover, we compared the frequency of complications between these groups.

Results: Among 837 patients screened, 416 patients received EVT for acLVO and fulfilled inclusion criteria (200 [48.1%] male, mean age = 76 ± 16 years, median National Institutes of Health Stroke Scale score = 16, interquartile range [IQR] = 12-20). Of these, 209 patients (50.2%) were hypothermic (median temperature = 35.2°C, IQR = 34.7-35.7) and 207 patients were normothermic (median temperature = 36.4°C, IQR = 36.1-36.7) after EVT. In multivariate analysis, hypothermia was not associated with favorable outcome (aRR = 0.99, 95% confidence interval [CI] = 0.75-1.31) and mortality (aRR = 1.18, 95% CI = 0.84-1.66). More hypothermic patients suffered from pneumonia (36.4% vs. 25.6%, p = 0.02) and bradyarrhythmia (52.6% vs. 16.4%, p < 0.001), whereas thromboembolic events were distributed evenly (5.7% vs. 6.8%, not significant).

Conclusions: Inadvertent hypothermia after EVT for acLVO is not associated with improved functional outcome or reduced mortality but is associated with an increased rate of pneumonia and bradyarrhythmia in patients with acute ischemic stroke.
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http://dx.doi.org/10.1111/ene.14906DOI Listing
May 2021

Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin.

Acta Neuropathol 2021 Apr 30. Epub 2021 Apr 30.

Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced β-catenin binding resulting in increased cytosolic and nuclear β-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/β-catenin signaling.
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http://dx.doi.org/10.1007/s00401-021-02307-1DOI Listing
April 2021

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1.

Acta Neuropathol 2021 Apr 19. Epub 2021 Apr 19.

Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
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http://dx.doi.org/10.1007/s00401-021-02302-6DOI Listing
April 2021

Motor Evoked Potentials Improve Targeting in Deep Brain Stimulation Surgery.

Neuromodulation 2021 Mar 28. Epub 2021 Mar 28.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Objectives: One of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects.

Materials And Methods: Motor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated.

Results: Intraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects.

Conclusions: Intraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.
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http://dx.doi.org/10.1111/ner.13386DOI Listing
March 2021

Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.

Am J Surg Pathol 2021 Feb 24. Epub 2021 Feb 24.

*Institute of Neuropathology **Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster †Hopp Children's Cancer Center (KiTZ) ‡Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg §Institute of Human Genetics, University of Ulm & Ulm University Hospital, Ulm ∥Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg ¶Swabian Childrens' Cancer Center, University Childrens' Hospital Augsburg and EU-RHAB Registry, Augsburg #Department of Neuropathology, Institute of Pathology, Hannover Medical School ‡‡Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany ††Department of Pediatric Hematology and Oncology, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic §§Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
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http://dx.doi.org/10.1097/PAS.0000000000001694DOI Listing
February 2021

Clinical Improvement After Treatment With IncobotulinumtoxinA (XEOMIN®) in Patients With Cervical Dystonia Resistant to Botulinum Toxin Preparations Containing Complexing Proteins.

Front Neurol 2021 9;12:636590. Epub 2021 Feb 9.

Department of Neurology, University of Düsseldorf, Düsseldorf, Germany.

This study investigated the clinical long-term effect of incobotulinumtoxinA (incoBoNT/A) in 33 cervical dystonia (CD) patients who had developed partial secondary therapy failure (PSTF) under previous long-term botulinum toxin (BoNT) treatment. Patients were treated four times every 12 weeks with incoBoNT/A injections. Physicians assessed treatment efficacy using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the baseline visit, week 12 and 48. Patients rated quality of life of CD with the Craniocervical Dystonia Questionnaire (CDQ-24). Titres of neutralizing antibodies(NAB) were determined at start of the study and after 48 weeks. All patients had experienced significant and progressive worsening of symptoms in the last 6 months of previous BoNT treatment. Repeated incoBoNT/A injections resulted in a significant reduction in mean TWSTRS at week 12 and 48. Patients' rating of quality of life was highly correlated with TWSTRS but did not change significantly over 48 weeks. During the 48 weeks -period of incoBoNT/A treatment NAB titres decreased in 32.2%, did not change in 45.2%, and only increased in 22.6% of the patients. Thus, repeated treatment with the low dose of 200 MU incoBoNT/A over 48 weeks provided a beneficial clinical long-term effect in PSTF and did not booster titres of NAB.
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http://dx.doi.org/10.3389/fneur.2021.636590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900567PMC
February 2021

Primary and secondary gliosarcoma: differences in treatment and outcome.

Br J Neurosurg 2021 Feb 4:1-8. Epub 2021 Feb 4.

Department of Neurosurgery, Hannover Medical School, Hannover, Germany.

Introduction: There are only few studies comparing differences in the outcome of primary versus secondary gliosarcoma. This study aimed to review the outcome and survival of patients with primary or secondary gliosarcoma following surgical resection and adjuvant treatment. The data were also matched with data of patients with primary and secondary glioblastoma (GBM).

Patients And Methods: Treatment histories of 10 patients with primary gliosarcoma and 10 patients with secondary gliosarcoma were analysed and compared. Additionally, data of 20 patients with primary and 20 patients with secondary GBM were analysed and compared. All patients underwent surgical resection of the tumour in our department. Follow-up data, progression-free survival (PFS), and median overall survival (mOS) were evaluated.

Results: The median PFS in patients with primary gliosarcoma was significantly higher than in patients with secondary gliosarcoma ( = 0.037). The 6-month PFS rates were 80.0% in patients with primary and 30.0% in patients with secondary gliosarcoma. Upon recurrence, five patients with primary gliosarcoma and four patients with secondary gliosarcoma underwent repeat surgical resection. The mOS of patients with primary gliosarcoma was significantly higher than that of patients with secondary gliosarcoma ( = 0.031). The percentage of patients surviving at 1-year/2-year follow-up in primary gliosarcoma was 70%/20%, while it was only 10%/10% in secondary gliosarcoma. When PFS and mOS of primary gliosarcoma was compared to primary GBM, there were no statistically differences ( = 0.509;  = 0.435). The PFS and mOS of secondary gliosarcoma and secondary GBM were also comparable ( = 0.290 and  = 0.390).

Conclusion: Patients with primary gliosarcoma have a higher PFS and mOS compared to those with secondary gliosarcoma. In the case of tumour recurrence, patients with secondary gliosarcoma harbour an unfavourable prognosis with limited further options. The outcome of patients with primary or secondary gliosarcoma is comparable to that of patients with primary or secondary GBM.
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http://dx.doi.org/10.1080/02688697.2021.1872773DOI Listing
February 2021

The prognostic significance of clinicopathological features in meningiomas: Microscopic brain invasion can predict patient outcome in otherwise benign meningiomas.

Neuropathol Appl Neurobiol 2021 Jan 28. Epub 2021 Jan 28.

Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.

Aims: Brain invasion (BI) was firstly defined as a single criterion of atypia in otherwise benign meningiomas in the revised fourth edition of 2016 WHO classification of brain tumours after being previously inconsistently addressed. However, recent studies have raised doubts about the prognostic significance of BI in otherwise benign meningiomas. In our study, we investigate the reproducibility of such a prognostic effect.

Methods: We identified two cohorts one consisting of 483 patients with meningioma WHO grade I (M°I) or atypical meningioma WHO grade II (M°II) from Hannover Medical School and the other including atypical meningiomas defined according to the classical WHO criteria (M°IIb) from the University Hospital Heidelberg. Follow-up data with a median observation time of 38.2 months were available from 308 cases. These included 243 M°I and 65 M°II patients with the latter group consisting of 25 patients with otherwise benign meningiomas with BI (M°IIa) and 40 with M°IIb.

Results: A significant difference of progression-free interval (PFI) was found between patients with M°I and M°II, M°I and M°IIa and those with M°I and M°IIb of both cohorts and each separately. However, PFI of M°IIa and M°IIb patients showed no significant difference. In the multivariate regression analysis adjusted for M°I/M°IIa versus M°IIb, sex, age, extent of resection and tumour location, BI exhibited the strongest risk of relapse (Hazard ratio: 4.95) serving as an independent predictor of PFI (p = 0.002).

Conclusions: Our results clearly support the definition of BI as a single criterion of atypia in WHO classification of 2016.
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http://dx.doi.org/10.1111/nan.12700DOI Listing
January 2021

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1.

Acta Neuropathol 2021 02 14;141(2):281-290. Epub 2020 Dec 14.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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http://dx.doi.org/10.1007/s00401-020-02247-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847462PMC
February 2021

Investigating the 1-year decline in midbrain-to-pons ratio in the differential diagnosis of PSP and IPD.

J Neurol 2021 Apr 4;268(4):1526-1532. Epub 2020 Dec 4.

Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.

Background: A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt_MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC).

Methods: Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses.

Results: PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p < 0.001), with an overall predictive accuracy of 95.6% for an MTPR ≤ 0.54. PSP-patients also presented a significantly stronger 1-year decline in MTPR compared to IPD (p < 0.001). Though predictive accuracy of relΔ_MTPR for PSP (M = - 4.74% ± 4.48) from IPD (M =  + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔ_MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500).

Conclusion: The present results indicate that the relΔ_MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.
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http://dx.doi.org/10.1007/s00415-020-10327-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990839PMC
April 2021

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis.

Acta Neuropathol 2021 01 20;141(1):85-100. Epub 2020 Nov 20.

Department of Paediatrics, University of Otago, Christchurch, New Zealand.

Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.
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http://dx.doi.org/10.1007/s00401-020-02243-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785563PMC
January 2021

Strategy for Deployment of Integrated Healthy Aging Regions Based Upon an Evidence-Based Regional Ecosystem-The Styria Model.

Front Med (Lausanne) 2020 29;7:510475. Epub 2020 Sep 29.

Department of Internal Medicine, Medical University Graz, Graz, Austria.

In 2013, the European Commission founded the platform European Innovation Partnership on Active and Healthy Aging as a communication and innovation network in this domain. The goal of the current study was the development of an integrated regional ecosystem for active and healthy aging for the region of Styria via a step-by-step co-creation process. A mixed model approach was used to establish an ecosystem for active and healthy aging, which includes macro-, meso- and micro-level stakeholders in the province of Styria, Austria. Based on the results, eight recommendations for the deployment of a healthy aging region were developed. The visibility and accessibility of healthy aging products and services were evaluated as key factors for innovation in active and healthy aging in the region. Health professionals were identified as major drivers of innovation related to active and healthy aging in Styria. The study presented in this article assessed the capacities for healthy aging in the Styria region and identified the need to improve communication pathways between all levels of the public health system and market.
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http://dx.doi.org/10.3389/fmed.2020.510475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550727PMC
September 2020

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity.

Acta Neuropathol 2020 12 14;140(6):893-906. Epub 2020 Sep 14.

Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas-including the prognostically relevant SDH mutations-are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.
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http://dx.doi.org/10.1007/s00401-020-02218-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666289PMC
December 2020

Infratentorial IDH-mutant astrocytoma is a distinct subtype.

Acta Neuropathol 2020 10 10;140(4):569-581. Epub 2020 Aug 10.

Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.
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http://dx.doi.org/10.1007/s00401-020-02194-yDOI Listing
October 2020

Interplay between Extracellular Matrix Stiffness and JAM-A Regulates Mechanical Load on ZO-1 and Tight Junction Assembly.

Cell Rep 2020 07;32(3):107924

UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK. Electronic address:

Tight-junction-regulated actomyosin activity determines epithelial and endothelial tension on adherens junctions and drives morphogenetic processes; however, whether or not tight junctions themselves are under tensile stress is not clear. Here, we use a tension sensor based on ZO-1, a scaffolding protein that links the junctional membrane to the cytoskeleton, to determine if tight junctions carry a mechanical load. Our data indicate that ZO-1 is under mechanical tension and that forces acting on ZO-1 are regulated by extracellular matrix (ECM) stiffness and the junctional adhesion molecule JAM-A. JAM-A depletion stimulates junctional recruitment of p114RhoGEF/ARHGEF18, mechanical tension on ZO-1, and traction forces at focal adhesions. p114RhoGEF is required for activation of junctional actomyosin activity and tight junction integrity on stiff but not soft ECM. Thus, junctional ZO-1 bears a mechanical load, and junction assembly is regulated by interplay between the physical properties of the ECM and adhesion-regulated signaling at tight junctions.
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http://dx.doi.org/10.1016/j.celrep.2020.107924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383227PMC
July 2020

Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window.

Neuromodulation 2021 Feb 15;24(2):343-352. Epub 2020 Jul 15.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Objectives: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS?

Materials And Methods: Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms.

Results: For best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS.

Conclusions: dDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.
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http://dx.doi.org/10.1111/ner.13234DOI Listing
February 2021

Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus.

Neuromodulation 2021 Feb 13;24(2):279-285. Epub 2020 Jul 13.

Department of Neurology & Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Objective: The effect of anesthesia type in terms of asleep vs. awake deep brain stimulation (DBS) surgery on therapeutic window (TW) has not been investigated so far. The objective of the study was to investigate whether asleep DBS surgery of the subthalamic nucleus (STN) improves TW for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population.

Materials And Methods: A total of 104 consecutive patients with Parkinson's disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction.

Results: Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups.

Conclusions: Our study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials.
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http://dx.doi.org/10.1111/ner.13237DOI Listing
February 2021

Somatosensory area 3b is selectively unaffected in corticobasal syndrome: combining MRI and histology.

Neurobiol Aging 2020 10 21;94:89-100. Epub 2020 May 21.

Institute for Anatomy I, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Research Centre Jülich, Jülich, Germany. Electronic address:

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.009DOI Listing
October 2020

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.

J Clin Oncol 2020 06 24;38(18):2028-2040. Epub 2020 Apr 24.

Department of Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany.

Purpose: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy.

Patients And Methods: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia.

Results: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, iSHH-II, 83%; = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], 74 [CSI]; = .012).

Conclusion: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
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http://dx.doi.org/10.1200/JCO.19.03057DOI Listing
June 2020

The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria.

BMC Mol Cell Biol 2020 Apr 17;21(1):30. Epub 2020 Apr 17.

Institute-Associated Research Group "Cell adhesion and cell polarity", University of Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany.

Background: Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a recently identified cell adhesion molecule which is predominantly expressed by epithelial cells of the intestine and the kidney. Its expression is downregulated in both colon and renal cancer suggesting a tumor suppressive activity. The function of TMIGD1 at the cellular level is largely unclear. Published work suggests a protective role of TMIGD1 during oxidative stress in kidney epithelial cells, but the underlying molecular mechanisms are unknown.

Results: In this study, we address the subcellular localization of TMIGD1 in renal epithelial cells and identify a cytoplasmic scaffold protein as interaction partner of TMIGD1. We find that TMIGD1 localizes to different compartments in renal epithelial cells and that this localization is regulated by cell confluency. Whereas it localizes to mitochondria in subconfluent cells it is localized at cell-cell contacts in confluent cells. We find that cell-cell contact localization is regulated by N-glycosylation and that both the extracellular and the cytoplasmic domain contribute to this localization. We identify Synaptojanin 2-binding protein (SYNJ2BP), a PDZ domain-containing cytoplasmic protein, which localizes to both mitochondria and the plasma membrane, as interaction partner of TMIGD1. The interaction of TMIGD1 and SYNJ2BP is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1. We also find that SYNJ2BP can actively recruit TMIGD1 to mitochondria providing a potential mechanism for the localization of TMIGD1 at mitochondria.

Conclusions: This study describes TMIGD1 as an adhesion receptor that can localize to both mitochondria and cell-cell junctions in renal epithelial cells. It identifies SYNJ2BP as an interaction partner of TMIGD1 providing a potential mechanism underlying the localization of TMIGD1 at mitochondria. The study thus lays the basis for a better understanding of the molecular function of TMIGD1 during oxidative stress regulation.
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http://dx.doi.org/10.1186/s12860-020-00274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164261PMC
April 2020

Physiological functions of junctional adhesion molecules (JAMs) in tight junctions.

Biochim Biophys Acta Biomembr 2020 09 2;1862(9):183299. Epub 2020 Apr 2.

Institute-associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Germany; Cells-In-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Germany. Electronic address:

Junctional adhesion molecules (JAMs) comprise a small subfamily of the immunoglobulin superfamily of adhesion receptors with a multitude of physiological functions in vertebrate development and homeostasis. Several members of the JAM family localize at tight junctions of epithelial and endothelial cells where they interact with PDZ domain-containing scaffolding proteins. For some JAM family members, molecular mechanisms have been elaborated through which they regulate cell-cell contact maturation and tight junction formation. For other members of this family our knowledge on their role in barrier-forming epithelia is still fragmentary. Here, we review our current understanding of the contribution of JAM family proteins to the barrier function of epithelial and endothelial cells with a major focus on epithelial tight junctions.
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http://dx.doi.org/10.1016/j.bbamem.2020.183299DOI Listing
September 2020

Pediatric rosette-forming glioneuronal tumor of the septum pellucidum.

Childs Nerv Syst 2020 11 26;36(11):2867-2870. Epub 2020 Mar 26.

Department of Neurosurgery, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.

Rosette-forming glioneuronal tumor (RGNT) is a rare tumor entity which has been reported mainly occurring in the fourth ventricle. It has been described as a benign lesion with limited extension into surrounding structures, including the cerebellar vermis, midbrain, and cerebral aqueduct. More recently, few cases involving also other midline structures have been documented as well. Here, we report about diagnosis and treatment of RGNT in the septum pellucidum in a pediatric patient which has not been described previously. A 7-year-old boy had a 3-week history of headache. Magnetic resonance imaging showed a solid mass in the septum pellucidum accompanied by hydrocephalus. The tumor was resected via a transcortical approach. Histological examination revealed the typical findings of a RGNT. At 2-year follow-up, there was no tumor recurrence, and clinical outcome was unremarkable. RGNT has to be considered in the differential diagnosis of pediatric midline tumors also outside of the fourth ventricle. Surgical resection is the first-line therapy which may result in beneficial outcome in the long term. The role of adjuvant therapy needs further definition since due to the rarity of this tumor entity, available data is very limited.
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http://dx.doi.org/10.1007/s00381-020-04575-wDOI Listing
November 2020

Expression of Olig2, Nestin, NogoA and AQP4 have no impact on overall survival in IDH-wildtype glioblastoma.

PLoS One 2020 11;15(3):e0229274. Epub 2020 Mar 11.

Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065747PMC
July 2020

Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma.

Cancers (Basel) 2020 Feb 24;12(2). Epub 2020 Feb 24.

Institute of Personalized Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia.

Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. : This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. : Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. : Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens.
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http://dx.doi.org/10.3390/cancers12020520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072286PMC
February 2020

Meningitis gone viral: description of the echovirus wave 2013 in Germany.

BMC Infect Dis 2019 Nov 29;19(1):1010. Epub 2019 Nov 29.

Department of Neurology, University Hospital, Medical Faculty Heinrich-Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.

Background: Aseptic meningitis epidemics may pose various health care challenges.

Methods: We describe the German enterovirus meningitis epidemics in the university hospital centers of Düsseldorf, Cologne and Berlin between January 1st and December 31st, 2013 in order to scrutinize clinical differences from other aseptic meningitis cases.

Results: A total of 72 enterovirus (EV-positive) meningitis cases were detected in our multicenter cohort, corresponding to 5.8% of all EV-positive cases which were voluntarily reported within the National Enterovirus surveillance (EVSurv, based on investigation of patients with suspected aseptic meningitis/encephalitis and/or acute flaccid paralysis) by physicians within this period of time. Among these 72 patients, 38 (52.8%) were enterovirus positive and typed as echovirus (18 pediatric and 20 adult cases, median age 18.5 years; echovirus 18 (1), echovirus 2 (1), echovirus 30 (31), echovirus 33 (1), echovirus 9 (4)). At the same time, 45 aseptic meningitis cases in our cohort were excluded to be due to enteroviral infection (EV-negative). Three EV-negative patients were tested positive for varicella zoster virus (VZV) and 1 EV-negative patient for herpes simplex virus 2. Hospitalization was significantly longer in EV-negative cases. Cerebrospinal fluid analysis did not reveal significant differences between the two groups. After discharge, EV-meningitis resulted in significant burden of sick leave in our pediatric cohort as parents had to care for the children at home.

Conclusions: Voluntary syndromic surveillance, such as provided by the EVSurv in our study may be a valuable tool for epidemiological research. Our analyses suggest that EV-positive meningitis predominantly affects younger patients and may be associated with a rather benign clinical course, compared to EV-negative cases.
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http://dx.doi.org/10.1186/s12879-019-4635-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883514PMC
November 2019