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Abstract In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system 1 – 4 . These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies. Analyses at single-cell resolution show that diverse subtypes of microglia exist during development and homeostasis of the central nervous system, and identify specific subsets of microglia associated with demyelination and neurodegenerative disease in mice and humans.

ObjectivesThe introduction of the 2016 WHO classification of CNS tumors has made the combined molecular and histopathological characterization of tumors a pivotal part of glioma patient management. Recent publications on radiogenomics-based prediction of the mutational status have demonstrated the predictive potential of imaging-based, non-invasive tissue characterization algorithms. Hence, the aim of this study was to assess the potential of multiparametric 18F-FET PET-MRI including MR fingerprinting accelerated with machine learning and radiomic algorithms to predict tumor grading and mutational status of patients with cerebral gliomas.Materials and methods42 patients with suspected primary brain tumor without prior surgical or systemic treatment or biopsy underwent an 18F-FET PET-MRI examination. To differentiate the mutational status and the WHO grade of the cerebral tumors, support vector machine and random forest were trained with the radiomics signature of the multiparametric PET-MRI data including MR fingerprinting. Surgical sampling served as a gold standard for histopathological reference and assessment of mutational status.ResultsThe 5-fold cross-validated area under the curve in predicting the ATRX mutation was 85.1%, MGMT mutation was 75.7%, IDH1 was 88.7%, and 1p19q was 97.8%. The area under the curve of differentiating low-grade glioma vs. high-grade glioma was 85.2%.Conclusion18F-FET PET-MRI and MR fingerprinting enable high-quality imaging-based tumor decoding and phenotyping for differentiation of low-grade vs. high-grade gliomas and for prediction of the mutational status of ATRX, IDH1, and 1p19q. These initial results underline the potential of 18F-FET PET-MRI to serve as an alternative to invasive tissue characterization.

Brain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies. A deeper knowledge of the immune cell profile within the brain cancer tumor microenvironment (TM) could identify targets to improve immunotherapy efficacy. Here, in glioblastoma, the authors find haematopoietic stem and progenitor cells in the TM, which are associated with poor prognosis and increased immunosuppression.

ABSTRACT BACKGROUND Delayed cerebral ischemia (DCI) has a strong impact on outcome of patients with aneurysmal subarachnoid hemorrhage (SAH). Positive effect of antiplatelet therapy on DCI rates has been supposed upon smaller SAH series. OBJECTIVE To analyze the benefit/risk profile of antiplatelet use in SAH patients. METHODS This retrospective case–control study was based on institutional observational cohort with 994 SAH patients treated between January 2003 and June 2016. The individuals with postcoiling antiplatelet therapy (aspirin with/without clopidogrel) were compared to a control group without antiplatelet therapy. Occurrence of DCI, major/minor bleeding events in the follow-up computed tomography scans, and favorable outcome at 6 mo after SAH (modified Rankin scale < 3) were compared in both groups. RESULTS Of 580 patients in the final analysis, 329 patients received post-treatment antiplatelet medication. There were no significant differences between the compared groups with regard to basic outcome confounders. Aspirin use was independently associated with reduced DCI risk (P < .001, adjusted odds ratio = 0.41, 95% confidence interval 0.24-0.65) and favorable outcome (P = .02, adjusted odds ratio = 1.78, 95% confidence interval 1.06-2.98). Regarding bleeding complications, aspirin was associated only with minor bleeding events (P = .02 vs P = .51 for major bleeding events). CONCLUSION Regular administration of aspirin might have a positive impact on DCI risk and outcome of SAH patients, without increasing the risk for clinically relevant bleeding events. In our SAH cohort, dual antiplatelet therapy showed no additional benefit on DCI risk, but increased the likelihood of major bleeding events.

Blood pressure management is crucial in the treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Possible association between the blood pressure increase and the risk of delayed cerebral ischemia (DCI) and different systemic complications after aSAH is still a matter of debate. This study aims to elucidate the influence of blood pressure levels on the outcome of aSAH. All consecutive aSAH patients (n = 690) treated between 01/2003 and 06/2016 were included. The mean value of the mean arterial pressure (MAP) during 14 days after ictus was calculated for each individual. According to the institutional standards of vasospasm management, the mean 14 days MAP ≥ 95 mmHg was referred as increased (IMAP) and the patients with and without vasospasm were analyzed separately. Study endpoints were the occurrence of DCI on computed tomography scans, development of cardiac and nephrological complications, and poor outcome 6 months after aSAH (mRS > 2). Associations were tested in univariable/multivariable binary logistic regression analysis. IMAP was documented in 474 (68.7%) cases and was more common in individuals with poor neurological conditions at admission (p < 0.001), severe amount of intracranial blood (p = 0.001) and premorbid hypertension (p < 0.001). IMAP was independently associated with the occurrence of DCI (p = 0.014; aOR = 2.97; 95% CI 1.25–7.09) and poor functional outcome (p = 0.020; aOR = 3.14; 95% CI 1.20–8.22) in patients with vasospasm, but not in counterparts without vasospasm (p = 0.113/p = 0.086). IMAP had no influence on cardiac or nephrological complications. In aSAH individuals with cerebral vasospasm, sustained increase of blood pressure exceeding the therapeutic targets is strongly associated with the risk of DCI and poor outcome. Therefore, such an intrinsic increase of blood pressure might reflect the autoregulatory mechanisms against the impending cerebral ischemia in patients with cerebral vasospasm. Trial registration number: German clinical trial registry (DRKS, Unique identifier: DRKS00008749, 06/09/2015).

The partial pressure of carbon dioxide (PaCO2) in the arterial blood is a strong vasomodulator affecting cerebral blood flow and the risk of cerebral edema and ischemia after acute brain injury. In turn, both complications are related to poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to analyze the effect of PaCO2 levels on the course and outcome of aSAH. All patients of a single institution treated for aSAH over 13.5 years were included (n = 633). Daily PaCO2 values from arterial blood gas measurements were recorded for up to 2 weeks after ictus. The study endpoints were: delayed cerebral ischemia (DCI), need for decompressive craniectomy due to increased intracranial pressure > 20 mmHg refractory to conservative treatment and poor outcome at 6-months follow-up (modified Rankin scale > 2). By correlations with the study endpoints, clinically relevant cutoffs for the 14-days mean values for the lowest and highest daily PaCO2 levels were defined by receiver operating characteristic curve analysis. Association with the study endpoints for the identifies subgroups was analyzed using multivariate analysis. The optimal range for PaCO2 values was identified between 30 and 38 mmHg. ASAH patients with poor initial condition (WFNS 4/5) were less likely to show PaCO2 values within the range of 30–38 mmHg ( p  < 0.001, OR = 0.44). In the multivariate analysis, PaCO2 values between 30 and 38 mmHg were associated with a lower risk for decompressive craniectomy ( p  = 0.042, aOR = 0.27), DCI occurrence ( p  = 0.035; aOR = 0.50), and poor patient outcome ( p  = 0.004; aOR = 0.42). The data from this study shows an independent positive association between low normal mean PaCO2 values during the acute phase of aSAH and patients’ outcome. This effect might be attributed to the reduction of intracranial hypertension and alterations in the cerebral blood flow.

Background ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters. Methods Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT 2 -PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed. Results ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3β and p-STAT3β. Conclusions Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM.

Animal models are still indispensable for understanding the basic principles of glioma development and invasion. Preclinical approaches aim to analyze the treatment efficacy of new drugs before translation into clinical trials is possible. Various animal disease models are available, but not every approach is useful for addressing specific questions. In recent years, it has become increasingly evident that the tumor microenvironment plays a key role in the nature of glioma. In addition to providing an overview, this review evaluates available rodent models in terms of usability for research on the glioma microenvironment.

Patient expectations and satisfaction are critical outcomes in cranial and spinal neurosurgery, yet discrepancies between anticipated and actual results can hinder postoperative adjustment. This prospective longitudinal study investigated how coping strategies and preoperative patient education influence satisfaction with surgical outcomes. Two self-developed questionnaires assessed expectations, perceived illness burden, patient education quality, hospital experience, postoperative recovery, and overall satisfaction after surgery. Coping strategies were evaluated using the validated Essen Coping Questionnaire . Data from 277 patients were analyzed, stratified by surgical complexity. No significant difference in patient education quality was found between complexity groups (mean difference 0.62, 95% CI [–1.65, 0.41];  t (221) = –1.19,  p  = .237). Patients undergoing less complex procedures reported higher preoperative burden (mean difference 1.72, 95% CI [–3.33, –0.10];  t (231) = –2.09,  p  = .038). Linear regression revealed that the quality of preoperative education, postoperative burden, and coping strategies  trust in medical art  and  willingness to accept help significantly predicted satisfaction ( F (10,79) = 3.41,  p  < .001). These findings highlight the importance of patient-doctor communication, tailored education, and psychological preparedness in shaping patient-reported outcomes. Enhancing preoperative support and fostering adaptive coping may improve satisfaction and postoperative adjustment, advocating for a more personalized approach to neurosurgical care.