Background and Purpose— Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods— Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0–2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results— Median age was 75 years (interquartile range, 64–82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10–19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions ( P =0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05–1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03–1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08–1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15–1.39), alteplase use (OR, 1.49; 95% CI, 1.08–2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45–1.96). Conclusions— High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03356392.

Epidermal growth factor receptor (EGFR) and its mutant form EGFRvIII are overexpressed in a large proportion of glioblastomas (GBM). Immunotherapy with an EGFRvIII-specific vaccine has shown efficacy against GBM in clinical studies. However, immune escape by antigen-loss variants and lack of control of EGFR wild-type positive clones limit the usefulness of this approach. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells may represent an alternative immunotherapeutic strategy. For targeting to GBM, we generated variants of the clinically applicable human NK cell line NK-92 that express CARs carrying a composite CD28-CD3ζ domain for signaling, and scFv antibody fragments for cell binding either recognizing EGFR, EGFRvIII, or an epitope common to both antigens. analysis revealed high and specific cytotoxicity of EGFR-targeted NK-92 against established and primary human GBM cells, which was dependent on EGFR expression and CAR signaling. EGFRvIII-targeted NK-92 only lysed EGFRvIII-positive GBM cells, while dual-specific NK cells expressing a cetuximab-based CAR were active against both types of tumor cells. In immunodeficient mice carrying intracranial GBM xenografts either expressing EGFR, EGFRvIII or both receptors, local treatment with dual-specific NK cells was superior to treatment with the corresponding monospecific CAR NK cells. This resulted in a marked extension of survival without inducing rapid immune escape as observed upon therapy with monospecific effectors. Our results demonstrate that dual targeting of CAR NK cells reduces the risk of immune escape and suggest that EGFR/EGFRvIII-targeted dual-specific CAR NK cells may have potential for adoptive immunotherapy of glioblastoma.

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02056-2) contains supplementary material, which is available to authorized users.

Background: Endovascular treatment has become standard of care for the treatment of acute ischemic stroke with large vessel occlusion. However, patients treated in clinical practice differ from the selected populations randomized in clinical trials. Aims: The German Stroke Registry Endovascular Treatment (GSR-ET) aims at a systematic evaluation of outcome, safety, and process parameters of endovascular stroke treatment in standard of care in Germany. Methods: The GSR-ET is an academic, independent, prospective, multicenter, observational registry study. Participating stroke centers from all over of Germany consecutively enroll patients transferred to the angiography suite with an intention to be treated with endovascular stroke treatment. Patients receive regular care. Data are collected as part of clinical routine. Baseline clinical and procedural information and clinical follow-up information after 90 days are recorded. Here, we present an analysis of baseline data of the first 1662 patients included in the GSR-ET. Results: The registry was established in June 2015. By 31 December 2017, 1662 patients were enrolled in 23 active sites. Mean age was 72 AE 13 years, 50% were female, and median National Institutes of Health Stroke Scale on admission was 15 (IQR 10-19), 88% had anterior circulation occlusion. Median ASPECT score was 8 (IQR 7-10) prior to intervention. Fifty-nine percent of patients received intravenous thrombolysis prior to thrombectomy. Mean ''onset-to-groin'' time was 224 AE 176 min. Conclusions: Baseline characteristics of stroke patients undergoing thrombectomy in clinical practice differ from those in the randomized trials. The GSR-ET will provide valuable insights into practices of endovascular treatment in routine care of acute ischemic stroke. (GSR-ET ClinicalTrials.gov Identifier: NCT03356392.