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1.
J Clin Invest ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32603315

RESUMO

Immunotherapeutic strategies are increasingly important in neuro-oncology and the elucidation of escape mechanisms which lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing wildtype and Pd-1-/- mice survived significantly longer than immunodeficient Pfp-/- Rag2-/- mice. While tumors in Pfp-/- Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and Pd-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in wildtype mice were distinguished by an interferon-γ-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even stronger to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.

3.
J Neurol ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367296

RESUMO

OBJECTIVE: Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH. METHODS: We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives. RESULTS: We identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified. CONCLUSIONS: Our data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.

4.
Sci Rep ; 10(1): 4764, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179801

RESUMO

Prognosis of patients with high-grade aneurysmal subarachnoid hemorrhage (aSAH) is only insufficiently displayed by current standard prognostic scores. This study aims to evaluate the role of pupil status for mortality prediction and provide improved prognostic models. Anonymized data of 477 aSAH patients admitted to our medical center from November 2010 to August 2018 were retrospectively analyzed. Identification of variables independently predicting in-hospital mortality was performed by multivariable logistic regression analysis. Final regression models included Hunt & Hess scale (H&H), pupil status and age or in a simplified variation only H&H and pupil status, leading to the design of novel H&H-Pupil-Age score (HHPA) and simplified H&H-Pupil score (sHHP), respectively. In an external validation cohort of 402 patients, areas under the receiver operating characteristic curves (AUROC) of HHPA (0.841) and sHHP (0.821) were significantly higher than areas of H&H (0.794; p < 0.001) or World Federation of Neurosurgical Societies (WFNS) scale (0.775; p < 0.01). Accordingly, including information about pupil status improves the predictive performance of prognostic scores for in-hospital mortality in patients with aSAH. HHPA and sHHP allow simple, early and detailed prognosis assessment while predictive performance remained strong in an external validation cohort suggesting adequate generalizability and low interrater variability.

5.
Scand J Trauma Resusc Emerg Med ; 28(1): 15, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122368

RESUMO

BACKGROUND: To determine the prevalence and characteristics of prechiasmatic visual system injuries (VSI) among seriously injured patients with concomitant head trauma in Europe by means of a multinational trauma registry. METHODS: The TraumaRegister DGU® was searched for patients suffering from serious trauma with a Maximum Abbreviated Injury Scale (AIS) ≥ 3 between 2002 and 2015 in Europe. After excluding cases without significant head injury defined by an AIS ≥ 2, groups were built regarding the existence of a concomitant damage to the prechiasmatic optic system comprising globe and optic nerve. Group comparisons were performed with respect to demographic, etiological, clinical and outcome characteristics. RESULTS: 2.2% (1901/84,627) of seriously injured patients with concomitant head trauma presented with additional VSI. These subjects tended to be younger (mean age 44.7 versus 50.9 years) and were more likely of male gender (74.8% versus 70.0%) compared to their counterparts without VSI. The most frequent trauma etiologies were car accidents in VSI patients (28.5%) and falls in the control group (43.2%). VSI cases were prone to additional soft tissue trauma of the head, skull and orbit fractures as well as pneumocephalus. Primary treatment duration was significantly longer in the VSI cohort (mean 23.3 versus 20.5 days) along with higher treatment costs and a larger proportion of patients with moderate or severe impairment at hospital discharge despite there being a similar average injury severity at admission in both groups. CONCLUSIONS: A substantial proportion of patients with head injury suffers from additional VSI. The correlation between VSI and prolonged hospitalization, increased direct treatment expenditures, and having a higher probability of posttraumatic impairment demonstrates the substantial socioeconomic relevance of these types of injuries.

6.
Int J Mol Sci ; 21(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178271

RESUMO

Extracellular vesicles (EVs) are known for their important role in cancer progression and hold considerable potential as a source for tumor biomarkers. However, purification of tumor-specific EVs from patient plasma is still an urgent unmet need due to contamination by normal host cell-derived EVs, that results in compromised analytical sensitivity. Here we identified fatty acid synthase (FASN), a key lipogenic enzyme which is highly expressed in malignant glioma cells, to be elevated in CD63- and CD81-positive EVs in glioma patient plasma samples, opening vital opportunities to sort brain tumor-specific EVs.

7.
Acta Neuropathol Commun ; 8(1): 28, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32151286

RESUMO

Peripheral metastases of glioblastoma (GBM) are very rare despite the ability of GBM cells to pass through the blood-brain barrier and be disseminated through the peripheral blood. Here, we describe a detailed genetic and immunological characterization of a GBM metastasis in the skeleton, which occurred during anti-PD-1 immune checkpoint therapy. We performed whole genome sequencing (WGS) and 850 K methylation profiling of the primary and recurrent intracranial GBM as well as one of the bone metastases. Copy number alterations (CNA) and mutational profiles were compared to known genomic alterations in the TCGA data base. In addition, immunophenotyping of the peripheral blood was performed. The patient who was primarily diagnosed with IDH-wildtype GBM. After the resection of the first recurrence, progressive intracranial re-growth was again detected, and chemotherapy was replaced by PD-1 checkpoint inhibition, which led to a complete intracranial remission. Two months later MR-imaging revealed multiple osseous lesions. Biopsy confirmed the GBM origin of the skeleton metastases. Immunophenotyping reflected the effective activation of a peripheral T-cell response, with, however, increase of regulatory T cells during disease progression. WGS sequencing demonstrated distinct genomic alterations of the GBM metastasis, with gains along chromosomes 3 and 9 and losses along chromosome 4, 10, and 11. Mutational analysis showed mutations in potentially immunologically relevant regions. Additionally, we correlated tumour-infiltrating lymphocyte and microglia presence to the occurrence of circulating tumour cells (CTCs) in a larger cohort and found a decreased infiltration of cytotoxic T cells in patients positive for CTCs. This study exemplifies that the tumour microenvironment may dictate the response to immune checkpoint therapy. In addition, our study highlights the fact that despite an effective control of intracranial GBM, certain tumour clones have the ability to evade the tumour-specific T-cell response and cause progression even outside of the CNS.

9.
J Neurol ; 267(6): 1663-1671, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32067124

RESUMO

BACKGROUND: Deep brain stimulation (DBS) within the pallidum represents an effective and well-established treatment for isolated dystonia. However, clinical outcome after surgery may be variable with limited response in 10-25% of patients. The effect of lead location on clinical improvement is still under debate. OBJECTIVE: To identify stimulated brain regions associated with the most beneficial clinical outcome in dystonia patients. METHODS: 18 patients with cervical and generalized dystonia with chronic DBS of the internal pallidum were investigated. Patients were grouped according to their clinical improvement into responders, intermediate responders and non-responders. Magnetic resonance and computed tomography images were co-registered, and the volume of tissue activated (VTA) with respect to the pallidum of individual patients was analysed. RESULTS: VTAs in responders (n = 11), intermediate responders (n = 3) and non-responders (n = 4) intersected with the posterior internal (GPi) and external (GPe) pallidum and the subpallidal area. VTA heat maps showed an almost complete overlap of VTAs of responders, intermediate and non-responders. VTA coverage of the GPi was not higher in responders. In contrast, VTAs of intermediate and non-responders covered the GPi to a significantly larger extent in the left hemisphere (p < 0.01). CONCLUSIONS: DBS of ventral parts of the posterior GPi, GPe and the adjacent subpallidal area containing pallidothalamic output projections resulted in favourable clinical effects. Of note, non-responders were also stimulated within the same area. This suggests that factors other than mere lead location (e.g., clinical phenotype, genetic background) have determined clinical outcome in the present cohort.

10.
Acta Neurochir (Wien) ; 162(4): 893-903, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016589

RESUMO

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) as a serious type of stroke is frequently accompanied by a so-called initial thunderclap headache. However, the occurrence of burdensome long-term headache following SAH has never been studied in detail so far. The aim of this study was to determine the prevalence and characteristics of long-term burdensome headache in good-grade SAH patients as well as its relation to health-related quality of life (HR-QOL). METHODS: All SAH cases treated between January 2014 and December 2016 with preserved consciousness at hospital discharge were prospectively interviewed regarding burdensome headache in 2018. Study participants were subsequently scrutinized by means of a standardized postal survey comprising validated pain and HR-QOL questionnaires. A retrospective chart review provided data on the initial treatment. RESULTS: A total of 93 out of 145 eligible SAH patients participated in the study (62 females). A total of 41% (38/93) of subjects indicated burdensome headache at follow-up (mean 32.6 ± 9.3 months). Comparison between patients with (HA+) and without long-term headache (HA-) revealed significantly younger mean age (47.9 ± 11.8 vs. 55.6 ± 10.3 years; p < .01) as well as more favorable neurological conditions (WFNS I/II: 95% vs. 75%; p = .03) in HA+ cases. The mean average headache of the HA+ group was 3.7 ± 2.3 (10-point numeric rating scale), and the mean maximum headache intensity was 5.7 ± 2.9. Pain and HR-QOL scores demonstrated profound alterations in HA+ compared to HA- patients. CONCLUSIONS: Our results suggest that a considerable proportion of SAH patients suffers from burdensome headache even years after the hemorrhage. Moreover, long-term headache is associated with reduced HR-QOL in these cases.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31962356

RESUMO

BACKGROUND AND OBJECTIVE: Microsurgical vascular nerve decompression and percutaneous ablative interventions aiming at the Gasserian ganglion are promising treatment modalities for patients with medical refractory trigeminal neuralgia (TN). Apart from clinical reports on a variable manifestation of facial hypoesthesia, the long-term impact of trigeminal ganglion radiofrequency thermocoagulation (RFT) on sensory characteristics has not yet been determined using quantitative methods. MATERIAL AND METHODS: We performed standardized quantitative sensory testing according to the established protocol of the German Research Network on Neuropathic Pain in a cohort of patients with classical (n = 5) and secondary (n = 11) TN before and after percutaneous Gasserian ganglion RFT (mean follow-up: 6 months). The test battery included thermal detection and thermal pain thresholds as well as mechanical detection and mechanical pain sensitivity measures. Clinical improvement was also assessed by means of renowned pain intensity and impairment questionnaires (Short-Form McGill Pain Questionnaire, Pain Disability Index, and Pain Catastrophizing Scale), pain numeric rating scale, and anti-neuropathic medication reduction at follow-up. RESULTS: All clinical parameters developed favorably following percutaneous thermocoagulation. Only mechanical and vibration detection thresholds of the affected side of the face were located below the reference frame of the norm population before and after the procedure. Statistically significant persistent changes in quantitative sensory variables caused by the intervention could not be detected in our patient sample. CONCLUSION: Our data suggest that TN patients improving considerably after RFT do not undergo substantial long-term alterations regarding quantitative sensory perception.

12.
Clin Cancer Res ; 26(11): 2626-2639, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31988196

RESUMO

PURPOSE: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. EXPERIMENTAL DESIGN: We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing. RESULTS: Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell-mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. CONCLUSIONS: Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.

13.
Acta Neuropathol ; 139(1): 175-192, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473790

RESUMO

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.

14.
J Neurol Surg A Cent Eur Neurosurg ; 81(3): 227-232, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31777050

RESUMO

BACKGROUND AND STUDY AIMS/OBJECTIVE: Cranioplasty, a common neurosurgical intervention following decompressive craniectomy (DC), is associated with high complication rates. Bone flap resorption in particular leads to a considerable number of patients requiring further surgery. The aim of this study was to investigate the frequency and time of occurrence of complications following cranioplastic procedures in children and adults. MATERIAL AND METHODS: Data of children and adults who underwent cranioplasty between July 2010 and March 2018 were analyzed retrospectively. Clinical data, complications, and risk factors regarding aseptic bone resorption (ABR) were evaluated including patient age, occurrence of shunt-dependent hydrocephalus, and number of fragments in autologous bone flaps. RESULTS: Severe traumatic brain injury (TBI) was the leading cause for DC among children (66.7%), associated with a significantly higher number of fragments (p = 0.002). In the adult population, the most common cause was malignant infarction (55.9%) followed by TBI (24.6%). Pediatric patients in our institution received autologous bone flaps less frequently than adult patients (61.1% and 83.1%, respectively). Young age and a higher number of fragments in autologous bone flaps were associated with the occurrence of ABR. Children and adolescents showed significantly higher rates of aseptic bone necrosis (p = 0.007) and revision cranioplasty (p = 0.036). Kaplan-Meier estimates were used to further analyze bone flap resorption in children and adults, showing that revision surgery due to ABR was performed earlier in children (p = 0.001, log-rank test). CONCLUSION: Pediatric patients demand specific care when cranioplasty is performed following DC. We identified age as an independent risk factor. The higher number of fragments appears to be a correlation due to the higher number of TBIs in children. Our data indicate that young age is the most important risk factor for the development of ABR as a frequent and early complication with a shorter revision-free time interval in children. Consequently, the uncritical use of cryopreserved autologous bone flaps should be questioned in this population.

15.
J Cancer Res Clin Oncol ; 146(3): 659-670, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754832

RESUMO

BACKGROUND: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. METHODS: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. RESULTS: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). CONCLUSIONS: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-31879817

RESUMO

BACKGROUND: Mechanical thrombectomies (MT) in stroke have changed the standard treatment regimen with a continuous increase of MTs during the last years. A subsequent reduction in the rates of decompressive craniectomies (DC) as well as a change in clinical characteristics of patients undergoing an additional DC after MT may be assumed. Therefore, objective of this study was to investigate the influence of nowadays regularly performed MT on patients undergoing DC. METHODS: Patients with DC due to cerebral infarctions between January 2009 and January 2018 were included. Patients' clinical presentation and surgical parameters were collected retrospectively. Initial GCS and NIHSS, extent of the stroke, time interval from symptom onset to DC, and neurological outcome were compared between patients with and without thrombectomy. RESULTS: A total of 5469 ischemic strokes were treated in the investigated period, leading to DC in 119 cases (2.2%). A decrease in the rate of performed DCs was recorded: in 2009, 2.8% of ischemic stroke patients underwent surgery compared to 1.9% in 2017. In the meantime, the number of MTs in our center has increased from 84 in 2014 to 160 in 2017. MT was performed in 32 patients prior to DC. No significant differences could be seen between the groups regarding age, initial NIHSS (median 18 in both groups, p = 0.81), extent of the infarctions prior to DC (median ASPECTS 0 in both groups, p = 0.87), time interval from symptom onset to DC, and neurological outcome. CONCLUSIONS: The introduction of routinely performed MT as part of the standard treatment regimen for ischemic stroke has led to a decrease in DCs. However, DC patients with and without MT showed no differences regarding their initial clinical criteria and outcome. These results suggest that earlier DC studies in patients with MCA infarction also apply for the collective of thrombectomized patients.

17.
Transl Stroke Res ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858408

RESUMO

The pathophysiology of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) is incompletely understood. Intrathecal activation of inflammatory immune cells is suspected to play a major role for the induction of DCI. The aim of this study is to identify immune cell subsets and mediators involved in the pathogenesis of DCI. We prospectively collected blood and CSF from 25 patients with aSAH at early and late time points. We performed multicolor flow cytometry of peripheral blood and CSF, analyzing immune cell activation and pro-inflammatory cyto- and chemokines. In addition to the primary immune analysis, we retrospectively analyzed immune cell dynamics in the CSF of all our SAH patients. Our results show an increased monocyte infiltration secondary to aneurysm rupture in patients with DCI. Infiltrating monocytes are defined by a non-classical (CD14dim CD16+) phenotype at early stages. The infiltration is most likely triggered by the intrathecal immune activation. Here, high levels of pro-inflammatory chemokines, such as CXCL1, CXCL9, CXCL10, and CXCL11, are detected. The intrathecal cellular activation profile of monocytes was defined by upregulation of CD163 and CD86 on monocytes and a presumable later differentiation into antigen-presenting plasmacytoid dendritic cells (pDCs) and hemosiderophages. Peripheral immune activation was reflected by CD69 upregulation on T cells. Analysis of DCI prevalence, Hunt and Hess grade, and clinical outcome correlated with the degree of immune activation. We demonstrate that monocytes and T cells are activated intrathecally after aSAH and mediate a local inflammatory response which is presumably driven by chemokines. Our data shows that the distinct pattern of immune activation correlates with the prevalence of DCI, indicating a pathophysiological connection to the incidence of vasospasm.

18.
Oncotarget ; 10(58): 6049-6061, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31692882

RESUMO

Glioblastoma are highly invasive and associated with limited therapeutic options and a grim prognosis. Using stem cells to extend current therapeutic strategies by targeted drug delivery to infiltrated tumors cells is highly attractive. This study analyzes the tumor homing and therapeutic abilities of clinical grade human mesenchymal stem cells (MSCs) in an orthotopic glioblastoma mouse model. Our time course analysis demonstrated that MSCs display a rapid targeted migration to intracerebral U87 glioma xenografts growing in the contralateral hemisphere within the first 48h hours after application as assessed by histology and 7T magnetic resonance imaging. MSCs accumulated predominantly peritumorally but also infiltrated the main tumor mass and targeted distant tumor satellites while no MSCs were found in other regions of the brain. Intratumoral application of MSCs expressing herpes simplex virus thymidine kinase followed by systemic prodrug application of ganciclovir led to a significant tumor growth inhibition of 86% versus the control groups (p<0.05), which translated in a significant prolonged survival time (p<0.05). This study demonstrates that human MSCs generated according to apceth's GMP process from healthy donors are able to target and provide a significant growth inhibition in a glioblastoma model supporting a potential clinical translation.

19.
Breast Cancer Res ; 21(1): 101, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481116

RESUMO

BACKGROUND: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. METHODS: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). RESULTS: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. CONCLUSION: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.


Assuntos
Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/secundário , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Contagem de Células , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Mutação , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Análise de Sobrevida
20.
Neurosurg Rev ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414197

RESUMO

Traumatic brain injury (TBI) in older adults is an increasing issue in modern medicine. Nevertheless, it remains unclear which patients presenting with TBI and 80 years of age or older benefit from an operative treatment. The aim of this study was to explore the effect of an operative treatment in isolated TBI patients ≥ 80 years of age. Data were derived from the TraumaRegister DGU® from 2002 to 2016. Inclusion criteria were ≥ 80 years of age, an Abbreviated Injury ScaleHead (AIS) ≥ 3, and an AISNon-Head ≤ 1. The cohort was split in operatively and non-operatively treated patients, and outcome was assessed at discharge using the Glasgow Outcome Scale (GOS). A favorable outcome was defined as a GOS of 4 or 5. A total of 1.693 patients (431 operatively and 1.262 non-operatively treated patients) were analyzed. Mortality rate was 54.4% (687 patients) in the non-operative group and 49.4% in the operative group. Simultaneously, there were more patients discharged with a GOS 2 (persistent vegetative state) in the operative group (7.9%, 34 patients) than in the non-operative group (1.0%, 13 patients). An analysis of the operatively treated patients showed an association between a higher mortality risk and brainstem hemorrhage (p = 0.04), fixed pupils (p = 0.001), initial intubation (p = 0.03), and an AISHead of 5/6 (p = 0.03). Patients 80 years of age or older seem to benefit from an operative treatment regarding mortality rate. However, there has been a higher rate of a poor neurological outcome particularly with regard to persistent vegetative state in the operative treatment group at discharge.

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