Publications by authors named "Thomas Czech"

126 Publications

Increased expression of GABA receptor subunits associated with tonic inhibition in patients with temporal lobe epilepsy.

Brain Commun 2021 12;3(4):fcab239. Epub 2021 Oct 12.

Department of Neurosurgery, Medical University Vienna, 1090 Vienna, Austria.

Epilepsy animal models indicate pronounced changes in the expression and rearrangement of GABA receptor subunits in the hippocampus and in para-hippocampal areas, including widespread downregulation of the subunits α5 and δ, and upregulation of α4, subunits that mediate tonic inhibition of GABA. In this case-control study, we investigated changes in the expression of subunits α4, α5 and δ in hippocampal specimens of drug resistant temporal lobe epilepsy patients who underwent epilepsy surgery. Using hybridization, immunohistochemistry and α5-specific receptor autoradiography, we characterized expression of the receptor subunits in specimens from patients with and without Ammon's horn sclerosis compared to post-mortem controls. Expression of the α5-subunit was abundant throughout all subfields of the hippocampus, including the dentate gyrus, sectors CA1 and CA3, the subiculum and pre- and parasubiculum. Significant but weaker expression was detected for subunits α4 and δ notably in the granule cell/molecular layer of control specimens, but was faint in the other parts of the hippocampus. Expression of all three subunits was similarly altered in sclerotic and non-sclerotic specimens. Respective mRNA levels were increased by about 50-80% in the granule cell layer compared with post-mortem controls. Subunit α5 mRNA levels and immunoreactivities were also increased in the sector CA3 and in the subiculum. Autoradiography for α5-containing receptors using [H]L-655,708 as ligand showed significantly increased binding in the molecular layer of the dentate gyrus in non-sclerotic specimens. Increased expression of the α5 and δ subunits is in contrast to the previously observed downregulation of these subunits in different epilepsy models, whereas increased expression of α4 in temporal lobe epilepsy patients is consistent with that in the rodent models. Our findings indicate increased tonic inhibition likely representing an endogenous anticonvulsive mechanism in temporal lobe epilepsy.
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http://dx.doi.org/10.1093/braincomms/fcab239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545616PMC
October 2021

Feasibility of intraoperative motor evoked potential monitoring during tethered cord surgery in infants younger than 12 months.

Childs Nerv Syst 2021 Oct 4. Epub 2021 Oct 4.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.

Purpose: Feasibility, reliability, and safety assessment of transcranial motor evoked potentials (MEPs) in infants less than 12 months of age.

Methods: A total of 22 patients with a mean age of 33 (range 13-49) weeks that underwent neurosurgery for tethered cord were investigated. Data from intraoperative MEPs, anesthesia protocols, and clinical records were reviewed. Anesthesia during surgery was maintained by total intravenous anesthesia (TIVA).

Results: MEPs were present in all patients for the upper extremities and in 21 out of 22 infants for the lower extremities. Mean baseline stimulation intensity was 101 ± 20 mA. If MEPs were present at the end of surgery, no new motor deficit occurred. In the only case of MEP loss, preoperative paresis was present, and high baseline intensity thresholds were needed. MEP monitoring did not lead to any complications. TIVA was maintained with an average propofol infusion rate of 123.5 ± 38.2 µg/kg/min and 0.46 ± 0.17 µg/kg/min for remifentanil.

Conclusion: In spinal cord release surgery, the use of intraoperative MEP monitoring is indicated regardless of the patient's age. We could demonstrate the feasibility and safety of MEP monitoring in infants if an adequate anesthetic regimen is applied. More data is needed to verify whether an irreversible loss of robust MEPs leads to motor deficits in this young age group.
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http://dx.doi.org/10.1007/s00381-021-05316-3DOI Listing
October 2021

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

Epilepsia 2021 Nov 12;62(11):2707-2718. Epub 2021 Sep 12.

Division of Neurosurgery, Department of Surgery, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom.

Methods: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method.

Results: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique.

Significance: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.
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http://dx.doi.org/10.1111/epi.17021DOI Listing
November 2021

Automated volumetry of hippocampal subfields in temporal lobe epilepsy.

Epilepsy Res 2021 Sep 24;175:106692. Epub 2021 Jun 24.

Department of Neurology, Clinic Hietzing & Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology, Vienna, Austria; Medical Faculty, Sigmund Freud Private University, Vienna, Austria.

Introduction: Hippocampal sclerosis is the most frequent pathological substrate in drug resistant temporal lobe epilepsy (TLE). Recently 4 types of hippocampal sclerosis (HS) have been defined in a task force by the International League Against Epilepsy (ILAE), based on patterns of cell loss in specific hippocampal subfields. Type 1 HS is most frequent and has the most favorable outcome after epilepsy surgery. We hypothesized that volume loss in specific hippocampal subfields determined by automated volumetry of high resolution MRI would correspond to cell loss in histological reports.

Material And Methods: In a group of well characterized patients with drug resistant TLE (N = 26 patients, 14 with right-sided focus, 12 with left-sided focus) volumes of the right and left hippocampus and the hippocampal subfields CA1, CA2 + 3, CA4 and dentate gyrus (DG) were estimated automatically using FreeSurfer version 6.0 from high-resolution cerebral MRI and compared to a large group of healthy controls (N = 121). HS subtype classification was attempted based on histological reports.

Results: Volumes of the whole hippocampus and all investigated hippocampal subfields (CA1, CA2 + 3, CA4 and DG) were significantly lower on the ipsilateral compared the contralateral side (p < 0.001) and compared to the healthy controls (p < 0.001). Conversely, whole hippocampal and hippocampal subfield volumes were not significantly different from healthy control values on the contralateral side. In 12 of 20 patients the pattern of hippocampal volume loss in specific subfields was in accordance with HS types from histology. The highest overlap between automated MRI and histology was achieved for type 1 HS (in 10 of 12 cases).

Conclusion: The automated volumetry of hippocampal subfields, based on high resolution MRI, may have the potential to predict the pattern of cell loss in hippocampal sclerosis before operation.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106692DOI Listing
September 2021

Myelomeningocele-Chiari II malformation-Neurological predictability based on fetal and postnatal magnetic resonance imaging.

Prenat Diagn 2021 Jul 19;41(8):922-932. Epub 2021 Jun 19.

Department of Radiology, Division of Neuro- and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria.

Objective: This systematic comparison between pre- and postnatal imaging findings and postnatal motor outcome assesses the reliability of MRI accuracy in the prognostication of the future long-term (mean, 11.4 years) ambulatory status in a historic group of postnatally repaired myelomeningocele (MMC) cases.

Methods: A retrospective, single-center study of 34 postnatally repaired MMC patients was performed. We used fetal and postnatal magnetic resonance imaging (MRI) to compare the fetal and postnatal radiological lesion level to each other and to the postnatal ambulatory level as a standard of reference and analyzed Chiari II malformation characteristics.

Results: In 13/15 (87%) and 29/31 (94%) cases, the functional level was equal to or better than the prenatal and postnatal radiological lesion level. A radiological lesion level agreement within two segments could be achieved in 13/15 (87%) patients. A worse than expected functional level occurred in cases with Myelocele (2/3 patients), coexistent crowding of the posterior fossa (2/3 patients) and/or abnormal white matter architecture, represented by callosal dysgenesis (1/3 patients). In all patients (2/2) with a radiological disagreement of more than two segments, segmentation disorders and scoliosis were observed.

Conclusion: Fetal and postnatal MRI are predictive of the long-term ambulatory status in postnatally repaired MMC patients.
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http://dx.doi.org/10.1002/pd.5987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361919PMC
July 2021

Targeting fibroblast growth factor receptors to combat aggressive ependymoma.

Acta Neuropathol 2021 08 27;142(2):339-360. Epub 2021 May 27.

Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.

Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.
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http://dx.doi.org/10.1007/s00401-021-02327-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270873PMC
August 2021

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

Epilepsia 2021 05 13;62(5):1064-1073. Epub 2021 Mar 13.

Department of Pediatrics, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy.

Methods: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques.

Results: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom.

Significance: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.
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http://dx.doi.org/10.1111/epi.16861DOI Listing
May 2021

Neurite Outgrowth Inhibitor (NogoA) Is Upregulated in White Matter Lesions of Complex Cortical Malformations.

J Neuropathol Exp Neurol 2021 Feb;80(3):274-282

From the Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Complex cortical malformations (CCMs), such as hemimegalencephaly and polymicrogyria, are associated with drug-resistant epilepsy and developmental impairment. They share certain neuropathological characteristics including mammalian target of rapamycin (mTOR) activation and an atypical number of white matter neurons. To get a better understanding of the pathobiology of the lesion architecture, we investigated the role of neurite outgrowth inhibitor A (NogoA), a known regulator of neuronal migration. Epilepsy surgery specimens from 16 CCM patients were analyzed and compared with sections of focal cortical dysplasia IIB (FCD IIB, n = 22), tuberous sclerosis complex (TSC, n = 8) as well as healthy controls (n = 15). Immunohistochemistry was used to characterize NogoA, myelination, and mTOR signaling. Digital slides were evaluated automatically with ImageJ. NogoA staining showed a significantly higher expression within the white matter of CCM and FCD IIB, whereas cortical tubers presented levels similar to controls. Further analysis of possible associations of NogoA with other factors revealed a positive correlation with mTOR and seizure frequency. To identify the main expressing NogoA cell type, double staining revealed dysmorphic neuronal white matter cells. Increased NogoA expression is associated with profound inhibition of neuritic sprouting and therefore contributes to a decrease in neuronal network complexity in CCM patients.
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http://dx.doi.org/10.1093/jnen/nlaa159DOI Listing
February 2021

Potential Importance of Early Focal Radiotherapy Following Gross Total Resection for Long-Term Survival in Children With Embryonal Tumors With Multilayered Rosettes.

Front Oncol 2020 17;10:584681. Epub 2020 Dec 17.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5-38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7-20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.
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http://dx.doi.org/10.3389/fonc.2020.584681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773839PMC
December 2020

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated -Fusion Positive Pediatric High-Grade Glioma.

J Pers Med 2020 Dec 18;10(4). Epub 2020 Dec 18.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated -fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with -fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of -fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
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http://dx.doi.org/10.3390/jpm10040290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766483PMC
December 2020

Infiltrative gliomas of the thalamus in children: the role of surgery in the era of H3 K27M mutant midline gliomas.

Acta Neurochir (Wien) 2021 07 22;163(7):2025-2035. Epub 2020 Oct 22.

Comprehensive Cancer Center-CCC CNS Unit, Medical University of Vienna, Vienna, Austria.

Background: The role of surgery in the management of pediatric non-pilocytic infiltrative thalamic gliomas needs to be revisited specifically with regard to molecularly defined subtypes.

Methods: A retrospective review of a consecutive series of children operated on a thalamic tumor between 1992 and May 2018 was performed. Neuroimaging data were reviewed for localization and extent of resection; pathology was re-reviewed according to the current WHO classification, including assessment of histone H3 K27 mutational status.

Results: Forty-nine patients with a thalamic tumor aged < 18 years at diagnosis were identified. Twenty-five patients (51%) had a non-pilocytic infiltrative glioma, of which the H3 K27M status was available in 22. Fourteen patients were diagnosed as diffuse midline glioma (DMG) H3 K27M mutant. There was no statistically significant difference in survival between patients harboring the H3 K27M mutation and wildtype. Resection ("any resection > 50%" vs "biopsy") and histological tumor grade ("°II" vs "°III+°IV") were statistically significant predictors of survival (univariate: p = 0.044 and p = 0.013, respectively). These results remained significant on multivariate analysis (HR 0.371/p = 0.048, HR 9.433/p = 0.035).

Conclusion: We advocate to still consider an attempt at maximal safe resection in the multidisciplinary treatment of unilateral thalamic non-pilocytic gliomas irrespective of their H3 K27-mutational status.
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http://dx.doi.org/10.1007/s00701-020-04589-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195935PMC
July 2021

Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental Trajectories in Pediatric Ependymoma.

Cancer Cell 2020 07;38(1):44-59.e9

Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
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http://dx.doi.org/10.1016/j.ccell.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479515PMC
July 2020

Language network reorganization before and after temporal lobe epilepsy surgery.

J Neurosurg 2020 07 3;134(6):1694-1702. Epub 2020 Jul 3.

Departments of1Biomedical Imaging and Image-guided Therapy.

Objective: Epilepsy surgery is the recommended treatment option for patients with drug-resistant temporal lobe epilepsy (TLE). This method offers a good chance of seizure freedom but carries a considerable risk of postoperative language impairment. The extremely variable neurocognitive profiles in surgical epilepsy patients cannot be fully explained by extent of resection, fiber integrity, or current task-based functional MRI (fMRI). In this study, the authors aimed to investigate pathology- and surgery-triggered language organization in TLE by using fMRI activation and network analysis as well as considering structural and neuropsychological measures.

Methods: Twenty-eight patients with unilateral TLE (16 right, 12 left) underwent T1-weighted imaging, diffusion tensor imaging, and task-based language fMRI pre- and postoperatively (n = 15 anterior temporal lobectomy, n = 11 selective amygdalohippocampectomy, n = 2 focal resection). Twenty-two healthy subjects served as the control cohort. Functional connectivity, activation maps, and laterality indices for language dominance were analyzed from fMRI data. Postoperative fractional anisotropy values of 7 major tracts were calculated. Naming, semantic, and phonematic verbal fluency scores before and after surgery were correlated with imaging parameters.

Results: fMRI network analysis revealed widespread, bihemispheric alterations in language architecture that were not captured by activation analysis. These network changes were found preoperatively and proceeded after surgery with characteristic patterns in the left and right TLEs. Ipsilesional fronto-temporal connectivity decreased in both left and right TLE. In left TLE specifically, preoperative atypical language dominance predicted better postoperative verbal fluency and naming function. In right TLE, left frontal language dominance correlated with good semantic verbal fluency before and after surgery, and left fronto-temporal language laterality predicted good naming outcome. Ongoing seizures after surgery (Engel classes ID-IV) were associated with naming deterioration irrespective of seizure side. Functional findings were not explained by the extent of resection or integrity of major white matter tracts.

Conclusions: Functional connectivity analysis contributes unique insight into bihemispheric remodeling processes of language networks after epilepsy surgery, with characteristic findings in left and right TLE. Presurgical contralateral language recruitment is associated with better postsurgical language outcome in left and right TLE.
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http://dx.doi.org/10.3171/2020.4.JNS193401DOI Listing
July 2020

Peri-interventional Behavior of the Neutrophil to Lymphocyte Ratio in Patients with Intracranial Aneurysms.

World Neurosurg 2020 09 17;141:e223-e230. Epub 2020 May 17.

Department of Neurosurgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: The neutrophil-to-lymphocyte ratio (NLR) has been investigated as an independent predictive marker for clinical outcomes in vascular diseases. This study aimed to investigate the peri-interventional behavior of the NLR in patients with ruptured and unruptured intracranial aneurysms (IAs).

Methods: A total of 117 patients with IAs, who were treated at our department and had available complete data, were retrospectively identified during a 10-year period. Routine laboratory parameters, including the neutrophil and lymphocytes counts, were evaluated before and after treatment.

Results: The baseline NLR showed significant differences between patients with ruptured and unruptured IAs (6.3 vs. 1.8; P < 0.001). In patients with ruptured IAs, the baseline NLR decreased significantly during the follow-up visits, whereas in unruptured IAs, the NLR remained low. Furthermore, higher baseline NLR values could also be observed in patients with ruptured IAs and fatal outcome than in surviving patients (8.0 vs. 5.4; P = 0.220). In patients with poor functional outcome, defined as modified Rankin score ≥3, the NLR was significantly higher before treatment (P = 0.047), at day 10 (P = 0.025), and 1 month after treatment (P = 0.001).

Conclusions: The peri-interventional NLR was significantly different between patients with ruptured and unruptured IAs. In patients with ruptured IAs, elevated baseline NLR levels were associated with poor postoperative functional outcomes and decreased postoperatively, implying the potential prognostic value of NLR in patients with IAs.
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http://dx.doi.org/10.1016/j.wneu.2020.05.084DOI Listing
September 2020

Learning from cases: Analysis of two cases of craniopharyngioma from the 19 to the 21 centuries.

F1000Res 2019 30;8:1544. Epub 2019 Aug 30.

Medical University Vienna, Vienna, Austria.

This manuscript describes the study of two cases of craniopharyngioma, which have been examined repeatedly over three separate centuries. This includes analysis by Josef Engel in 1839, who sought to uncover the physiological role of the pituitary gland; Jacob Erdheim in 1904, who initially described the disease we now call craniopharyngioma, and recent high resolution MRI and micro-CT imaging and attempted DNA analyses of the tumours. The cases highlight how, rightly or wrongly, our interpretation of data is shaped by the technologies, methodologies and prevailing theories of a given time.
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http://dx.doi.org/10.12688/f1000research.19626.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993819PMC
June 2020

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities.

Front Oncol 2019 10;9:1436. Epub 2020 Jan 10.

Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort ( = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.
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http://dx.doi.org/10.3389/fonc.2019.01436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965319PMC
January 2020

Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography.

EJNMMI Res 2019 Dec 12;9(1):110. Epub 2019 Dec 12.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Background: P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood-brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood-brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors.

Materials And Methods: We performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I-III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics.

Results: Brain distribution of [C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors.

Conclusions: Our data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity.

Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-004189-13.
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http://dx.doi.org/10.1186/s13550-019-0581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908538PMC
December 2019

Alterations in GABAA Receptor Subunit Expression in the Amygdala and Entorhinal Cortex in Human Temporal Lobe Epilepsy.

J Neuropathol Exp Neurol 2019 11;78(11):1022-1048

Department of Neurosurgery, Institute of Neurology, Department of Neurology, Department of Biomedical Imaging and Image Guided Therapy, Center for Brain Research, Department of Molecular Neurosciences, Medical University of Vienna, Vienna, Austria; Second Neurological Department, General Hospital Hietzing, Vienna, Austria; and Clinical Neuroanatomy, Neurology Department, Medical Faculty, Ulm University, Ulm, Germany.

The amygdala has long been implicated in the pathophysiology of human temporal lobe epilepsy (TLE). The different nuclei of this complex structure are interconnected and share reciprocal connections with the hippocampus and other brain structures, partly via the entorhinal cortex. Expression of GABAA receptor subunits α1, α2, α3, α5, β2, β2/3, and γ2 was evaluated by immunohistochemistry in amygdala specimens and the entorhinal cortex of 12 TLE patients and 12 autopsy controls. A substantial decrease in the expression of α1, α2, α3, and β2/3 subunits was found in TLE cases, accompanied by an increase of γ2 subunit expression in many nuclei. In the entorhinal cortex, the expression of all GABAA receptor subunits was decreased except for the α1 subunit, which was increased on cellular somata. The overall reduction in α subunit expression may lead to decreased sensitivity to GABA and its ligands and compromise phasic inhibition, whereas upregulation of the γ2 subunit might influence clustering and kinetics of receptors and impair tonic inhibition. The description of these alterations in the human amygdala is important for the understanding of network changes in TLE as well as the development of subunit-specific therapeutic agents for the treatment of this disease.
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http://dx.doi.org/10.1093/jnen/nlz085DOI Listing
November 2019

Cerebrospinal fluid disturbances after transcallosal surgery: incidence and predictive factors.

J Neurosurg 2019 Sep 27:1-9. Epub 2019 Sep 27.

1Department of Neurosurgery, Medical University of Vienna.

Objective: CSF dynamics after transcallosal resection of intraventricular lesions can be altered, and the need for shunt implantation complicates the management of these patients. Because the pathophysiological mechanism and contributing factors are poorly understood and the incidence has largely not been described, the authors conducted a study to elucidate these factors.

Methods: The authors retrospectively reviewed data from patients who had been operated on at their institution via a transcallosal approach between March 2002 and December 2016. They evaluated the need for a shunt implantation up to 3 months after surgery by assessing clinical variables. These variables were age at surgery, the need for perioperative external CSF drainage, histology of the lesion, and the following radiological parameters: pre- and postoperative Evans index, maximal postoperative extension of subdural effusions (SDEs) measured on axial images, and maximal interhemispheric fissure (IHF) width measured on coronal images assessed at 4 different points in time (preoperatively, day 1, days 2-4, and days 4-8 after surgery). To identify potential risk factors, univariate and multivariate regression models were constructed. Receiver operating characteristic (ROC) curves for significant predictors, as well as the area under the curve (AUC), were calculated.

Results: Seventy-four patients (40 female and 34 male) were identified; their median age at surgery was 17.6 years (range 4 months to 76 years). Shunt implantation was necessary in 13 patients (ventriculoperitoneal [VP] shunt, n = 7; subdural peritoneal [SDP] shunt, n = 6) after a median interval of 24 days (range 10 days to 3 months). Univariate logistic regression models revealed a significant effect of IHF width on days 4-8 (OR 1.31, 95% CI 1.03-1.66; p = 0.027), extension of SDE on days 2-4 (OR 1.33, 95% CI 1.11-1 0.60; p = 0.003), and age (OR 0.932, 95% CI 0.88-0.99; p = 0.02). In the multiple regression model, the effect of the independent variable extension of the SDE remained significant. ROC curves for the predictors IHF width on days 4-8 and extension of SDE on days 2-4 revealed an AUC equal to 0.732 and 0.752, respectively. Before shunt implantation, the ventricles were smaller compared to the preoperative size in 9 of the 13 patients (SDP shunt, n = 5; VP shunt, n = 4).

Conclusions: The rate of shunt-dependent hydrocephalus 3 months after surgery in this heterogeneous group of patients was 17.6% (95% CI 9.7%-28.2%). The authors identified as predictive factors the variables extension of the convexity space, IHF 1 week after surgery, and younger age.
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http://dx.doi.org/10.3171/2019.6.JNS19290DOI Listing
September 2019

High impact of miRNA-4521 on FOXM1 expression in medulloblastoma.

Cell Death Dis 2019 09 20;10(10):696. Epub 2019 Sep 20.

Department of Pediatrics and Adolescent Medicine, Molecular Neuro-Oncology, Medical University of Vienna, Vienna, Austria.

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although genetic variants are increasingly used in treatment stratification, survival of high-risk patients, characterized by leptomeningeal dissemination, TP53 mutation or MYC amplification, is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is deregulated in various solid tumors, including medulloblastoma, and triggers cellular proliferation, migration and genomic instability. In tissue samples obtained from medulloblastoma patients, the significant upregulation of FOXM1 was associated with a loss of its putative regulating microRNA, miR-4521. To understand the underlying mechanism, we investigated the effect of miR-4521 on the expression of the transcription factor FOXM1 in medulloblastoma cell lines. Transfection of this microRNA reduced proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through activation of caspase 3/7. Further, downstream targets of FOXM1 such as PLK1 and cyclin B1 were significantly reduced thus affecting the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may selectively suppress the pathophysiological effect of aberrant FOXM1 expression and serve as a targeted approach for medulloblastoma therapy.
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http://dx.doi.org/10.1038/s41419-019-1926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754377PMC
September 2019

Surgical Anatomy of Vertical Perithalamic Hemispherotomy.

Oper Neurosurg (Hagerstown) 2020 05;18(5):511-517

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.

Background: Vertical perithalamic hemispherotomy was introduced by Olivier Delalande in 1992 as an alternative concept of functional hemispherectomy.

Objective: To provide a step-by-step illustration of the surgical anatomy of this procedure.

Methods: The descriptions in this manuscript are based on an experience of 52 hemispherotomies performed with the same technique by a single surgeon.

Results: Our illustrations of the surgical anatomy and the descriptions of the surgical nuances facilitate a deep understanding for the surgical concept of Delalande's vertical hemispherotomy technique. They highlight the advantages (ie, reduced risk of inadvertent damage to the contralateral hemisphere and a clear orientation by defined anatomical landmarks) over the recently suggested modifications to this original technique.

Conclusion: Olivier Delalande's original technique remains the most appealing concept of vertical hemispherotomy to us.
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http://dx.doi.org/10.1093/ons/opz214DOI Listing
May 2020

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAF/TERT promoter double-mutated glioma.

Acta Neuropathol Commun 2019 08 7;7(1):128. Epub 2019 Aug 7.

Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, Spitalgasse 23, BT86/E 01, 1090, Vienna, Austria.

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAF and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAF-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAF-mutated HGG as compared to BRAF-mutated LGG. In vitro, BRAF/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAF-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAF and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.
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http://dx.doi.org/10.1186/s40478-019-0775-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685154PMC
August 2019

Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis.

Cancer Discov 2019 10 25;9(10):1406-1421. Epub 2019 Jul 25.

St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795548PMC
October 2019

Resolving medulloblastoma cellular architecture by single-cell genomics.

Nature 2019 08 24;572(7767):74-79. Epub 2019 Jul 24.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, CA, USA.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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http://dx.doi.org/10.1038/s41586-019-1434-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754173PMC
August 2019

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.

Cell 2019 08 18;178(4):835-849.e21. Epub 2019 Jul 18.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, 1090, Austria.

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
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http://dx.doi.org/10.1016/j.cell.2019.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703186PMC
August 2019

SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma.

Klin Padiatr 2019 05 20;231(3):107-135. Epub 2019 May 20.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital, Heidelberg.

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.
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http://dx.doi.org/10.1055/a-0889-8256DOI Listing
May 2019

Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.

Epilepsia 2019 06 10;60(6):1091-1103. Epub 2019 May 10.

Epigenetics in Human Health and Disease, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objectives: Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation-based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes.

Methods: DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls.

Results: Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway-related genes.

Significance: Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.
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http://dx.doi.org/10.1111/epi.14934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635741PMC
June 2019

Predisposition of Wingless Subgroup Medulloblastoma for Primary Tumor Hemorrhage.

Neurosurgery 2020 04;86(4):478-484

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Primary intratumoral hemorrhage as a presenting sign is rare in children with medulloblastomas but may result in severe complications. Given the distinct properties of molecular medulloblastoma subgroups, the impact on neurosurgical practice has still to be defined.

Objective: To investigate both clinical and radiological presentation of intratumoral hemorrhage in medulloblastoma patients in the context of molecular subgroups.

Methods: Data of all consecutive medulloblastoma patients treated at our institution between 1993 and 2018 (n = 104) were retrospectively reviewed in respect of clinical and radiological presentation as well as molecular subgroups. For cases with available tumor tissue (n = 86), subgroups were assigned by either 450 K methylation array or immunohistochemistry and CTNNB1 sequencing. Available imaging at diagnosis (n = 62) was reviewed by an experienced neuroradiologist.

Results: Within the entire cohort, 4 patients (4%) presented with massive spontaneous hemorrhage. Although no patient died as a direct consequence of hemorrhage, all suffered from serious sequelae. Moreover, 3 additional patients displayed radiological evidence of significant hemorrhage. Interestingly, all 7 cases belonged to the wingless (WNT) subgroup (n = 13), resulting in intratumoral hemorrhage in 54% (7/13) of pediatric WNT medulloblastomas. In contrast, significant hemorrhage was absent in all other molecular subgroups.

Conclusion: Our results suggest that a substantial proportion of pediatric WNT medulloblastomas display significant intratumoral hemorrhage at the time of diagnosis. Consequently, the presence of significant hemorrhage in fourth ventricle childhood tumors is suggestive of WNT medulloblastoma and should lead to a less aggressive attempt for total resection in this prognostically favorable tumor type.
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http://dx.doi.org/10.1093/neuros/nyz148DOI Listing
April 2020

Management of choroid plexus tumors-an institutional experience.

Acta Neurochir (Wien) 2019 04 19;161(4):745-754. Epub 2019 Feb 19.

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Choroid plexus tumors are rare entities. Resection is the mainstay of treatment in grade I and grade II tumors and adjuvant treatment is usually reserved for the less frequent choroid plexus carcinoma (CPC). Outcome is not only related to their histological grade but also dependent on their size, location, and presence of often multifactorial disturbances of cerebrospinal fluid (CSF) circulation.

Methods: Retrospective analysis of 36 consecutive patients operated on a choroid plexus tumor at our institution in a mixed pediatric and adult population between 1991 and 2016.

Results: Twenty-one CPP, 11 atypical choroid plexus papillomas (aCPP), and four CPC were encountered in 17 children and 19 adults. Regardless of histological grading, gross-total resection (GTR) could be achieved in 91.7% of patients. Tumor recurrence (25.0%) was significantly associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and intraoperatively evident zones of tumor infiltration (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, mainly diagnosed with CPC. The 5-year overall survival rate was 95.2% for CPP and 100.0% for both aCPP and CPC. Survival was related to the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). Even after resection, either ventricular or subdural shunting was required in 25.0% of patients.

Conclusions: We could confirm that GTR is crucial for treatment of choroid plexus tumors. Parenchymal tumor infiltration as detected intraoperatively was associated with the extent of resection and not limited to CPC. CSF disturbances mandating treatment may persist after resection.
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http://dx.doi.org/10.1007/s00701-019-03832-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431303PMC
April 2019
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