Publications by authors named "Martin Ebinger"

204 Publications

Frequent FGFR1 hotspot alterations in driver-unknown low-grade glioma and mixed neuronal-glial tumors.

J Cancer Res Clin Oncol 2022 Jan 11. Epub 2022 Jan 11.

Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Calwerstr. 3, 72076, Tuebingen, Germany.

Purpose: Low-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations.

Methods: We analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases.

Results: 368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed.

Conclusion: FGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.
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http://dx.doi.org/10.1007/s00432-021-03906-xDOI Listing
January 2022

The Dynamic of Extracellular Vesicles in Patients With Subacute Stroke: Results of the "Biomarkers and Perfusion-Training-Induced Changes After Stroke" () Study.

Front Neurol 2021 8;12:731013. Epub 2021 Nov 8.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Extracellular vesicles (EV) are sub-1 μm bilayer lipid coated particles and have been shown play a role in long-term cardiovascular outcome after ischemic stroke. However, the dynamic change of EV after stroke and their implications for functional outcome have not yet been elucidated. Serial blood samples from 110 subacute ischemic stroke patients enrolled in the prospective study were analyzed. All patients participated in the trial and received 4-week aerobic training or relaxation sessions. Levels of endothelial-derived (EnV: Annexin V+, CD45-, CD41-, CD31+/CD144+/CD146+), leukocyte-derived (LV: Annexin V+, CD45+, CD41-), monocytic-derived (MoV: Annexin V+, CD41-, CD14+), neuronal-derived (NV: Annexin V+, CD41-, CD45-, CD31-, CD144-, CD146-, CD56+/CD171+/CD271+), and platelet-derived (PV: Annexin V+, CD41+) EV were assessed via fluorescence-activated cell sorting before and after the trial intervention. The levels of EV at baseline were dichotomized at the 75th percentile, with the EV levels at baseline above the 75th percentile classified as "high" otherwise as "low." The dynamic of EV was classified based on the difference between baseline and post intervention, defining increases above the 75th percentile as "high increase" otherwise as "low increase." Associations of baseline levels and change in EV concentrations with Barthel Index (BI) and cardiovascular events in the first 6 months post-stroke were analyzed using mixed model regression analyses and cox regression. Both before and after intervention PV formed the largest population of vesicles followed by NV and EnV. In mixed-model regression analyses, low NV [-8.57 (95% CI -15.53 to -1.57)] and low PV [-6.97 (95% CI -13.92 to -0.01)] at baseline were associated with lower BI in the first 6 months post-stroke. Patients with low increase in NV [8.69 (95% CI 2.08-15.34)] and LV [6.82 (95% CI 0.25-13.4)] were associated with reduced BI in the first 6 months post-stroke. Neither baseline vesicles nor their dynamic were associated with recurrent cardiovascular events. This is the first report analyzing the concentration and the dynamic of EV regarding associations with functional outcome in patients with subacute stroke. Lower levels of PV and NV at baseline were associated with a worse functional outcome in the first 6 months post-stroke. Furthermore, an increase in NV and LV over time was associated with worse BI in the first 6 months post-stroke. Further investigation of the relationship between EV and their dynamic with functional outcome post-stroke are warranted. clinicaltrials.gov/, identifier: NCT01954797.
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http://dx.doi.org/10.3389/fneur.2021.731013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606784PMC
November 2021

Shifting acute stroke management to the prehospital setting.

Curr Opin Neurol 2022 02;35(1):4-9

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin.

Purpose Of Review: The earlier the treatment, the better the outcomes after acute ischemic stroke. Optimizing prehospital care bears potential to shorten treatment times. We here review the recent literature on mothership vs. drip-and-ship as well as mobile stroke unit concepts.

Recent Findings: Mobile stroke units result in the shortest onset-to-treatment times in mostly urban settings.

Summary: Future research should focus on further streamlining processes around mobile stroke units, especially improving dispatch algorithms and improve referral for endovascular therapy.
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http://dx.doi.org/10.1097/WCO.0000000000001012DOI Listing
February 2022

Estimating nocturnal stroke onset times by magnetic resonance imaging in the WAKE-UP trial.

Int J Stroke 2021 Nov 18:17474930211059608. Epub 2021 Nov 18.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases.

Aims: Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study).

Methods: FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep.

Results: FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( = 0.001), lesion volume ( = 0.005) and FLAIR-rSI ( < 0.001) with time since symptom onset (adjusted R= 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h).

Conclusion: Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.
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http://dx.doi.org/10.1177/17474930211059608DOI Listing
November 2021

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial.

Neurology 2022 Jan 15;98(3):e302-e314. Epub 2021 Nov 15.

From the Klinik und Hochschulambulanz für Neurologie (L.S., T.B.B., M. Endres, C.H.N.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humbold-Universität zu Berlin, and Berlin Institute of Health; Center for Stroke Research Berlin (L.S., T.B.B., I.G., J. Fiebach, M. Ebinger, M. Endres, C.H.N.), Charité-Universitätsmedizin; Berlin Institute of Health (L.S., T.B.B., M. Endres, C.H.N.), Germany; Hospices Civils de Lyon (F.B.), Service de Biostatistique; Université Lyon 1 and Centre National de la Recherche Scientifique (F.B.), UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France; Department of Neurology (J.V.), University Hospital Bern, Switzerland; Klinik und Poliklinik für Neurologie (M.J., B.C., G.T., C.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology (C.Z.S.), Aarhus University Hospital, Denmark; Department of Stroke Medicine (T.-H.C.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Diagnostic and Interventional Neuroradiology (J. Fiehler), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology (J.P., S.P.), Doctor Josep Trueta University Hospital, Department of Radiology (IDI) (J.P., S.P.), Girona Biomedical Research Institute (IDIBGI), Spain; Department of Neurology (V.T.), Austin Health, Heidelberg, Australia; Institute of Neuroscience and Psychology, University of Glasgow (K.M.), UK; Department of Stroke Medicine (N.N.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Neurology (M. Ebinger), Medical Park Berlin Humboldtmühle; German Center for Cardiovascular Research (DZHK) (M. Endres, C.H.N.), Partner Site Berlin; German Center for Neurodegenerative Diseases (DZNE) (M. Endres, C.H.N.), Partner Site Berlin; ExcellenceCluster NeuroCure (M. Endres), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; Department of Neurosciences (R.L.), Experimental Neurology, KU Leuven-University of Leuven; and VIB-KU Leuven Center for Brain and Disease Research (R.L.), Laboratory of Neurobiology, Leuven, Belgium.

Background And Objectives: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.

Methods: We performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.

Results: Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, = 0.022) without evidence of heterogeneity in relation to CMB presence ( of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.

Discussion: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.

Trial Registration Information: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.

Classification Of Evidence: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.
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http://dx.doi.org/10.1212/WNL.0000000000013055DOI Listing
January 2022

Introducing isotonic fluids into pediatric oncology.

Pediatr Hematol Oncol 2021 Nov 9:1-8. Epub 2021 Nov 9.

Department of Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.

Hypotonic fluids are commonly used in pediatric oncology despite evidence that these fluids can lead to hospital-acquired hyponatremia. This practice is most likely due to lack of data evaluating risks and benefits of isotonic fluids in pediatric oncology. To address this issue, our study investigates the effects of exchanging hypotonic fluids with isotonic fluids in a large pediatric oncology unit. Prevalence of laboratory disorders before and after the change to balanced, isotonic fluids for all patients are compared in this retrospective analysis. Disturbances in electrolyte levels, fluid-, acid-base balance and kidney function were examined. The rate of hyponatremia was reduced using isotonic fluids. There were no hypernatremic events. Volume overload might increase the use of furosemide when using isotonic fluids. Potassium and bivalent cation levels increased. The risk of acidosis is greatly reduced, whereas alkalosis was more frequent due to furosemide use. The rate of acute kidney injury did not increase. Using isotonic fluids for hyper-hydration in pediatric oncology lead to a modest reduction of hospital-acquired hyponatremia without causing hypernatremia, but the effects on fluid balance need further investigation. The additional intake of bivalent cations and buffering anions in balanced fluids has measurable effects.
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http://dx.doi.org/10.1080/08880018.2021.1996494DOI Listing
November 2021

Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome.

Front Neurol 2021 20;12:730923. Epub 2021 Oct 20.

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients. This is an exploratory analysis of subacute ischemic stroke patients enrolled in the study nested within the randomized controlled trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere ("normalized CE-ROI"). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-α, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS). Ninety-three patients with a median baseline NIHSS of 9 [IQR 6-12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18-37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2-23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46-67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient -0.002, Standard Error 0.007, < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke. In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed. NCT01954797.
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http://dx.doi.org/10.3389/fneur.2021.730923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567961PMC
October 2021

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

Blood 2022 Jan;139(2):256-280

Pathology Unit, Laboratories Department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.
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http://dx.doi.org/10.1182/blood.2021013338DOI Listing
January 2022

Cost-Effectiveness of Magnetic Resonance Imaging-Guided Thrombolysis for Patients With Stroke With Unknown Time of Onset.

Value Health 2021 11 31;24(11):1620-1627. Epub 2021 Jul 31.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Patients waking up with stroke symptoms are often excluded from intravenous thrombolysis with alteplase (IV-tpa). The WAKE-UP trial, a European multicenter randomized controlled trial, proved the clinical effectiveness of magnetic resonance imaging-guided IV-tpa for these patients. This analysis aimed to assess the cost-effectiveness of the intervention compared to placebo.

Methods: A Markov model was designed to analyze the cost-effectiveness over a 25-year time horizon. The model consisted of an inpatient acute care phase and a rest-of-life phase. Health states were defined by the modified Rankin Scale (mRS). Initial transition probabilities to mRS scores were based on WAKE-UP data and health state utilities on literature search. Costs were based on data from the University Medical Center Hamburg-Eppendorf, literature, and expert opinion. Incremental costs and effects over the patients' lifetime were estimated. The analysis was conducted from a formal German healthcare perspective. Univariate and probabilistic sensitivity analyses were performed.

Results: Treatment with IV-tpa resulted in cost savings of €51 009 and 1.30 incremental gains in quality-adjusted life-years at a 5% discount rate. Univariate sensitivity analysis revealed incremental cost-effectiveness ratio being sensitive to the relative risk of favorable outcome on mRS for placebo patients after stroke, the costs of long-term care for patients with mRS 4, and patient age at initial stroke event. In all cases, IV-tpa remained cost-effective. Probabilistic sensitivity analysis proved IV-tpa cost-effective in >95% of the simulations results.

Conclusions: Magnetic resonance imaging-guided IV-tpa compared to placebo is cost-effective in patients with ischemic stroke with unknown time of onset.
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http://dx.doi.org/10.1016/j.jval.2021.05.005DOI Listing
November 2021

Comparing efficacy and side effects of two systemic chemotherapy regimens for eye-preserving therapy in children with retinoblastoma.

Pediatr Blood Cancer 2022 Feb 4;69(2):e29362. Epub 2021 Oct 4.

Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany.

Background: Eye-preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce.

Methods: The efficacy and side effects of two different eye-preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non-interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event-free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated.

Results: The EFES after VEC (2-year EFES 72.3%) was higher than after CyVEC (2-year EFES 50.4%) (p  < .001). The OES did not differ significantly between the two treatment groups (p = .77; 2-year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES (p  < .0001; 2-year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES (p  < .0001; 2-year OES ICRB A/B/C 93.1% vs. ICRB D/E 61.5%). The multivariate analysis showed that age at diagnosis older than 12 months and ICRB A/B/C were associated with better EFES. No second malignancies or ototoxicities were reported after a follow-up of median 3.1 years after diagnosis of retinoblastoma (range 0.1-6.9 years).

Conclusions: Despite omitting cyclophosphamide, the EFES was higher after VEC chemotherapy that contains higher doses of carboplatin compared to CyVEC. The major risk factor for enucleation was advanced ICRB tumor grouping. Randomized clinical trials on efficacy and side effects of eye-preserving chemotherapy are required to tailor treatment protocols for retinoblastoma patients.
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http://dx.doi.org/10.1002/pbc.29362DOI Listing
February 2022

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

J Immunother Cancer 2021 10;9(10)

University Children's Hospital, University Medical Center Würzburg, Würzburg, Germany

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.

Methods: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.

Results: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8 T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.

Conclusions: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
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http://dx.doi.org/10.1136/jitc-2021-003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488729PMC
October 2021

Game-theoretical mapping of fundamental brain functions based on lesion deficits in acute stroke.

Brain Commun 2021 2;3(3):fcab204. Epub 2021 Sep 2.

Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks.
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http://dx.doi.org/10.1093/braincomms/fcab204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473841PMC
September 2021

Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B.

Nat Commun 2021 09 20;12(1):5530. Epub 2021 Sep 20.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Resarch Center (DKFZ), Heidelberg, Germany.

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.
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http://dx.doi.org/10.1038/s41467-021-25708-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452680PMC
September 2021

Elevated Serum Inflammatory Markers in Subacute Stroke Are Associated With Clinical Outcome but Not Modified by Aerobic Fitness Training: Results of the Randomized Controlled Trial.

Front Neurol 2021 26;12:713018. Epub 2021 Aug 26.

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Inflammatory markers, such as C-reactive Protein (CRP), Interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha and fibrinogen, are upregulated following acute stroke. Studies have shown associations of these biomarkers with increased mortality, recurrent vascular risk, and poor functional outcome. It is suggested that physical fitness training may play a role in decreasing long-term inflammatory activity and supports tissue recovery. We investigated the dynamics of selected inflammatory markers in the subacute phase following stroke and determined if fluctuations are associated with functional recovery up to 6 months. Further, we examined whether exposure to aerobic physical fitness training in the subacute phase influenced serum inflammatory markers over time. This is an exploratory analysis of patients enrolled in the multicenter randomized-controlled trial. Patients within 45 days of stroke onset were randomized to receive either four weeks of aerobic physical fitness training or relaxation sessions. Generalized estimating equation models were used to investigate the dynamics of inflammatory markers and the associations of exposure to fitness training with serum inflammatory markers over time. Multiple logistic regression models were used to explore associations between inflammatory marker levels at baseline and three months after stroke and outcome at 3- or 6-months. Irrespective of the intervention group, high sensitive CRP (hs-CRP), IL-6, and fibrinogen (but not TNF-alpha) were significantly lower at follow-up visits when compared to baseline ( all ≤ 0.01). In our cohort, exposure to aerobic physical fitness training did not influence levels of inflammatory markers over time. In multivariate logistic regression analyses, increased baseline IL-6 and fibrinogen levels were inversely associated with worse outcome at 3 and 6 months. Increased levels of hs-CRP at 3 months after stroke were associated with impaired outcome at 6 months. We found no independent associations of TNF-alpha levels with investigated outcome parameters. Serum markers of inflammation were elevated after stroke and decreased within 6 months. In our cohort, exposure to aerobic physical fitness training did not modify the dynamics of inflammatory markers over time. Elevated IL-6 and fibrinogen levels in early subacute stroke were associated with worse outcome up to 6-months after stroke. ClinicalTrials.gov, NCT01953549.
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http://dx.doi.org/10.3389/fneur.2021.713018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426903PMC
August 2021

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.

Stroke 2021 12 26;52(12):3768-3776. Epub 2021 Aug 26.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (I.L., M.J., E.S., F.Q., B.C., C.G., G.T.).

Background And Purpose: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke).

Methods: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE.

Results: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], <0.001). Higher age (=0.04) and male sex (=0.01) were predictors for the occurrence of SAE.

Conclusions: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.
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http://dx.doi.org/10.1161/STROKEAHA.120.033425DOI Listing
December 2021

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke.

Eur Stroke J 2021 Jun 18;6(2):168-175. Epub 2021 Jun 18.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke.

Patients And Methods: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke.

Results: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile.

Conclusions: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.
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http://dx.doi.org/10.1177/23969873211014758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370068PMC
June 2021

Hyperintense acute reperfusion marker associated with hemorrhagic transformation in the WAKE-UP trial.

Eur Stroke J 2021 Jun 12;6(2):128-133. Epub 2021 Jun 12.

Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

Introduction: Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome.

Patients And Methods: We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3-6 at 90 days.

Results: HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72-26.58) and any PH (OR 6.92; 95%CI 1.34-29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90).

Conclusion: In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.
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http://dx.doi.org/10.1177/23969873211007686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370087PMC
June 2021

Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors.

Pediatr Blood Cancer 2021 Dec 4;68(12):e29267. Epub 2021 Aug 4.

University Medical Center Augsburg, Paediatric and Adolescent Medicine, Swabian Children's Cancer Center, Augsburg, Germany.

Background: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly.

Materials And Methods: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available.

Results: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders.

Conclusions: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.
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http://dx.doi.org/10.1002/pbc.29267DOI Listing
December 2021

Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review).

J Clin Med 2021 Jun 8;10(12). Epub 2021 Jun 8.

Department I-General Pediatrics, Hematology/Oncology, Children's Hospital, University Hospital Tübingen, 72076 Tübingen, Germany.

Acute lymphoblastic leukemia is by far the most common malignancy in children, and new immunotherapeutic approaches will clearly change the way we treat our patients in future years. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R-ALL). The use of blinatumomab in R/R ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. For heavily pretreated patients, the response to one or two cycles of blinatumomab ranges from 34% to 66%. Two randomized controlled trials have very recently demonstrated an improved reduction in minimal residual disease as well as an increased survival for patients treated with blinatumomab compared to standard consolidation treatment in first relapse. Current trials using blinatumomab frontline for high-risk patients or as a consolidation treatment post-transplant will show whether efficacy is even higher in less heavily pretreated patients. Due to the distinct pattern of adverse events compared to high-dose conventional chemotherapy, blinatumomab could play an important role for patients with a risk for severe chemotherapy-associated toxicities. This systematic review discusses all published results for blinatumomab in children as well as all ongoing clinical trials.
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http://dx.doi.org/10.3390/jcm10122544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230017PMC
June 2021

Influence of stroke infarct location on quality of life assessed in a multivariate lesion-symptom mapping study.

Sci Rep 2021 06 29;11(1):13490. Epub 2021 Jun 29.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22-36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4-9; median EQ-5D score 90 days after stroke 1, IQR 0-4, median lesion volume 3.3 ml, IQR 1.1-16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.
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http://dx.doi.org/10.1038/s41598-021-92865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241844PMC
June 2021

is frequently expressed in ependymal tumours and associated with prognostic relevant subgroups.

J Clin Pathol 2021 Jun 28. Epub 2021 Jun 28.

Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany

Aims: An ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 () transcription factor is a putative tumour suppressor and drives cancer cells towards a stem cell-like state. A transcriptome study reported high expression in ependymal tumours, but data on protein expression are lacking.

Methods: We, therefore, analysed expression by immunohistochemistry in 172 ependymoma samples and correlated its expression to histology, WHO grade, anatomical location and molecular subgroups.

Results: Mean nuclear expression in ependymoma was 27.5% (95% CI 23.3 to 31.7). expression in subependymoma (mean: 5%) was significantly lower compared with myxopapillary (30%), WHO grade II (26%) and anaplastic ependymoma (35%). Supratentorial ependymomas also displayed significant lower levels (15%) compared with spinal cord tumours (30%). Expression levels in YAP1-fused ependymoma (41%) were higher compared with REL-associated protein (RELA)-fusion positive tumours (17%), while expression was similar in posterior fossa group A (33%) and B (29%) ependymomas. Kaplan-Meier analysis in RELA-fusion positive ependymomas and posterior fossa group B showed a significant better outcome for at or above the cut-off of 19.45% compared with tumours with below the cut-off.

Conclusions: We demonstrate that is frequently expressed in human ependymal tumours and immunohistochemistry may be helpful in determining prognostic relevant subgroups.
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http://dx.doi.org/10.1136/jclinpath-2021-207526DOI Listing
June 2021

The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy-VISTA-Endovascular.

PLoS One 2021 20;16(5):e0251888. Epub 2021 May 20.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis.

Methods: The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database.

Results: Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]).

Conclusions: Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251888PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136663PMC
October 2021

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Stroke 2021 07 13;52(7):2338-2346. Epub 2021 May 13.

Department of Neurology, University Hospitals Leuven, Belgium (L.S., A.W., R. Lemmens).

Background And Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra.

Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function.

Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26).

Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days.

Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.
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http://dx.doi.org/10.1161/STROKEAHA.120.033071DOI Listing
July 2021

Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke.

Nat Commun 2021 05 10;12(1):2590. Epub 2021 May 10.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.
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http://dx.doi.org/10.1038/s41467-021-22786-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110812PMC
May 2021

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Institute of Human Genetics, Medical Faculty, University Duisburg-Essen, 45122 Essen, Germany.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.
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http://dx.doi.org/10.3390/cancers13081876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070790PMC
April 2021

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

J Cereb Blood Flow Metab 2021 10 17;41(10):2617-2627. Epub 2021 Apr 17.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Stroke Research Berlin, Berlin, Germany.

MRI-based vessel size imaging (VSI) allows for assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort ('Biomarkers And Perfusion--Training-Induced changes after Stroke') nested within a randomized controlled trial (intervention: 4-week training relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.
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http://dx.doi.org/10.1177/0271678X211010071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504415PMC
October 2021

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): Safety analyses of a randomized clinical trial.

Int J Stroke 2022 Jan 7;17(1):93-100. Epub 2021 Apr 7.

Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background And Aim: To report the six-month safety analyses among patients enrolled in the "Physical Fitness Training in Subacute Stroke-PHYS-STROKE" trial and identify underlying risk factors associated with serious adverse events.

Methods: We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5-45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training.

Results: Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81).

Conclusions: Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials.

Data Access Statement: The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.
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http://dx.doi.org/10.1177/17474930211006286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739607PMC
January 2022

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Pediatr Blood Cancer 2021 06 15;68(6):e28963. Epub 2021 Mar 15.

The Goldschleger eye institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment.

Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication.

Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy.

Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.
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http://dx.doi.org/10.1002/pbc.28963DOI Listing
June 2021

Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial.

Eur J Neurol 2021 06 22;28(6):2017-2025. Epub 2021 Mar 22.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background And Purpose: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD.

Methods: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale.

Results: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS.

Conclusions: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.
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http://dx.doi.org/10.1111/ene.14797DOI Listing
June 2021
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