Monitoring the Antiplatelet Therapy Efficacy in Patients with Acute Ischemic Stroke.

BACKGROUND: Stroke is one of the leading causes of morbidity and mortality in populations of developed countries. Ischemic strokes account for 85 - 90% of all strokes, with the majority of strokes of non-cardioembolic pathogenesis. Platelet aggregation plays a key role in arterial thrombus formation. Therefore, effective antiplatelet therapy plays a key role in secondary prevention. Acetylsalicylic acid (ASA) is the main drug of choice, and clopidogrel therapy is another recommended treatment option. Monitoring of the efficacy of antiplatelet therapy has been intensively studied in patients with coronary artery disease in the context of coronary stent implantation. It is not yet part of the routine procedure in patients with stroke [1-3]. METHODS: This study investigated the efficacy of antiplatelet therapy with ASA and clopidogrel using optical and impedance aggregometry in 42 consecutive patients with acute ischemic stroke. Patients were treated with throm-bolysis at baseline and platelet function was examined 24 hours after administration, focusing on the occurrence of platelet hyperaggregability and assessing the efficacy of any chronically administered antiplatelet therapy. Subsequently, patients were administered a loading dose of ASA or clopidogrel followed by a check of its efficacy 24 hours after administration. In the following days, the maintenance dose of the drug was continued and regular laboratory monitoring of treatment efficacy was performed every 24 hours. RESULTS: In patients with atherothrombotic stroke indicated for antiplatelet therapy, monitoring of residual platelet activity allowed for detection of potentially atrisk patients. These were 35% (9% borderline ineffective) of patients taking ASA and 55% (18% borderline ineffective) of patients treated with clopidogrel. The dose was adjusted, increased the administered treatment and no recurrence of stroke was observed in this study group at 1-year follow-up. CONCLUSIONS: Personalized antiplatelet therapy based on platelet function tests appears to be a useful method to reduce the risk of recurrent vascular events.

Mechanical Thrombectomy Quality Indicators Study in Czech Stroke Centers: Results of the METRICS Study.

BACKGROUND AND PURPOSE: Rigorous and regular evaluation of defined quality indicators is crucial for further improvement of both technical and clinical results after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Following the recent international multi-society consensus quality indicators, we aimed to assess trend in these indicators on national level. MATERIAL AND METHODS: The prospective multicenter study (METRICS) was conducted in Czech Republic (CR) in year 2019. All participating centers collected technical and clinical data including defined quality indicators and results were subsequently compared with those from year 2016. RESULTS: In the 2019, 1375 MT were performed in the CR and 1178 (86%) patients (50.3% males, mean age 70.5 ± 13.0 years) were analyzed. Recanalization (TICI 2b-3) was achieved in 83.7% of patients and 46.2% of patients had good 3-month clinical outcome. Following time intervals were shortened in comparison to 2016: "hospital arrival - GP" (77 vs. 53 min; p<0.0001), "hospital arrival - maximal achieved recanalization" (122 vs. 93 min; p<0.0001), and "stroke onset - maximal achieved recanalization" (240 vs. 229 min; p p<0.0001). More patients with tandem occlusion were treated in 2019 (7.8 vs. 16.5%; p<0.0001) and more secondary transports were in 2019 (31.3 vs. 37.8%; p=0.002). No difference was found in 3-month clinical outcome and in the rate of periprocedural complications. Results of the METRICS study met all criteria of multi-society consensus quality indicators. CONCLUSION: Nationwide comparison between 2016 and 2019 showed improvement in the key time intervals, but without better overall clinical outcomes after MT.

Intravenous Thrombolysis in Patients with Acute Ischemic Stroke after a Reversal of Dabigatran Anticoagulation with Idarucizumab: A Real-World Clinical Experience.

BACKGROUND: Intravenous thrombolysis (IVT) is contraindicated in patients with acute ischemic stroke (AIS) using oral anticoagulants. A specific human monoclonal antibody was introduced to reverse immediately the anticoagulation effect of the direct inhibitor of thrombin, dabigatran. Until now, mostly individual cases presenting with successful IVT after a reversal of dabigatran anticoagulation in patients with AIS were published. Thus, we aimed to report real-world data from clinical practice. METHODS: Patients with AIS on dabigatran treated with IVT after antidote reversal were enrolled in the retrospective nationwide study. Neurological deficit was scored using the National Institutes of Health Stroke Scale (NIHSS) and 90-day clinical outcome using modified Rankin scale (mRS) with a score 0-2 for a good outcome. Intracerebral hemorrhage (ICH) was defined as a presence of any sign of bleeding on control imaging after IVT, and symptomatic intracerebral hemorrhage (SICH) was assessed according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria. RESULTS: In total, 13 patients (7 men, mean age 70.0 ± 9.1 years) with a median NIHSS admission score of 7 points were analyzed. Of these patients, 61.5% used 2 × 150 mg of dabigatran daily. Antidote was administrated 427 ± 235 minutes after the last intake of dabigatran, with a mean activated prothrombin time of 38.1 ± 27.8 seconds and a mean thrombin time of 72.2 ± 56.1 seconds. Of the 13 patients, 2 had ICH and 1 had SICH, and no other bleeding complications were observed after IVT. Of the total number of patients, 76.9% had a good 3-month clinical outcome and 3 patients (23.1%) died. Recurrent ischemic stroke occurred in 2 patients (15.4%). CONCLUSION: The data presented in the study support the safety and efficacy of IVT after the reversal of the anticoagulation effect of dabigatran with antidote in a real-world clinical practice.

Prolonged Corrected QT Interval as a Predictor of Clinical Outcome in Acute Ischemic Stroke.

BACKGROUND: This study aimed to investigate changes of corrected QT (QTc) interval during acute ischemic stroke and its correlation with high-sensitivity troponin I (hsTnI), brain natriuretic peptide (BNP), neurological outcome, and 1-year mortality. METHODS: We registered electrocardiogram in 69 patients immediately after admission to the intensive care unit and then after 24 and 48 hours. Computed tomography was performed on admission to determine brain infarct size and localization. Neurological outcome was assessed by modified Rankin scale (mRS) at discharge. RESULTS: Forty-five (65.2%) patients had prolonged QTc at baseline; only 18 (26.1%) patients had prolonged QTc after 48 hours. Baseline QTc was not associated with neurological outcome (P = .27). However, prolonged QTc after 48 hours was associated with worse mRS at discharge (4.5 [4.0-6.0] versus 2.0 [1.0-3.0]; P < .0001). Patients who deceased during hospitalization (n = 7 [10.1%]) as compared with survivors had more frequently prolonged QTc after 48 hours (38.9 versus 0%; P < .0001), higher level of hsTnI (48.4 [36.1-75.0] versus 8.6 [3.4-26.5]; P = .003), and BNP (334 [224-866] versus 109 [30-190]; P = .014). In univariate analysis, 1-year mortality was associated with prolonged QTc after 48 hours, hsTnI, and BNP. In multivariate analysis, only BNP remained to be associated with 1-year mortality (odds ratio 3.41, 95% confidence interval 1.06-11.03). CONCLUSIONS: QTc interval in patients with acute ischemic stroke is a dynamic parameter. Prolonged QTc after 48 hours, but not baseline QTc, correlated with neurological outcome and 1-year mortality. Patients with prolonged QTc had higher level of hsTnI.

Length of occlusion predicts recanalization and outcome after intravenous thrombolysis in middle cerebral artery stroke.

BACKGROUND AND PURPOSE: The length of large vessel occlusion is considered a major factor for therapy in patients with ischemic stroke. We used 4D-CT angiography evaluation of middle cerebral artery occlusion in prediction of recanalization and favorable clinical outcome and after intravenous thrombolysis (IV-tPA). METHODS: In 80 patients treated with IV-tPA for acute complete middle cerebral artery/M1 occlusion determined using CT angiography and temporal maximum intensity projection, calculated from 4D-CT angiography, the length of middle cerebral artery proximal stump, occlusion in M1 or M1 and M2 segment were measured. Univariate and multivariate analyses were performed to define independent predictors of successful recanalization after 24 hours and favorable outcome after 3 months. RESULTS: The length of occlusion was measureable in all patients using temporal maximum intensity projection. Recanalization thrombolysis in myocardial infarction 2 to 3 was achieved in 37 individuals (46%). The extension to M2 segment as a category (odds ratio, 4.58; 95% confidence interval, 1.39-15.05; P=0.012) and the length of M1 segment occlusion (odds ratio, 0.82; 95% confidence interval, 0.73-0.92; P=0.0007) with an optimal cutoff value of 12 mm (sensitivity 0.67; specificity 0.71) were significant independent predictors of recanalization. Favorable outcome (modified Rankin scale 0-2) was achieved in 25 patients (31%), baseline National Institutes of Health Stroke Scale (odds ratio, 0.82; 95% confidence interval, 0.72-0.93; P=0.003) and the length of occlusion M1 in segment (odds ratio, 0.79; 95% confidence interval, 0.69-0.91; P=0.0008) with an optimal cutoff value of 11 mm (sensitivity 0.74; specificity 0.76) were significant independent predictors of favorable outcome. CONCLUSIONS: The length of middle cerebral artery occlusion is an independent predictor of successful IV-tPA treatment.

Endovascular treatment for acute ischemic stroke in patients with tandem lesion in the anterior circulation: analysis from the METRICS study.

BACKGROUND: Acute ischemic stroke (AIS) due to anterior circulation tandem lesion (TL) remains a technical and clinical challenge for endovascular treatment (EVT). Conflicting results from observational studies and missing evidence from the randomized trials led us to report a recent real-world multicenter clinical experience and evaluate possible predictors of good outcome after EVT. METHODS: We analyzed all AIS patients with TL enrolled in the prospective national study METRICS (Mechanical Thrombectomy Quality Indicators Study in Czech Stroke Centers). A good 3-month clinical outcome was scored as 0-2 points in modified Rankin Scale (mRS), achieved recanalization using the Thrombolysis In Cerebral Infarction (TICI) scale and symptomatic intracerebral hemorrhage (sICH) according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria. RESULTS: Of 1178 patients enrolled in METRICS, 194 (19.2%) (59.8% males, mean age 68.7±11.5 years) were treated for TL. They did not differ in mRS 0-2 (48.7% vs 46.7%; p=0.616), mortality (17.3% vs 22.7%; p=0.103) and sICH (4.7% vs 5.1%; p=0.809) from those with single occlusion (SO). More TL patients with prior intravenous thrombolysis (IVT) reached TICI 3 (70.3% vs 50.8%; p=0.012) and mRS 0-2 (55.4% vs 34.4%; p=0.007) than those without IVT. No difference was found in the rate of sICH (6.2% vs 1.6%; p=0.276). Multivariate logistic regression analysis showed prior IVT as a predictor of mRS 0-2 after adjustment for potential confounders (OR 3.818, 95% CI 1.614 to 9.030, p=0.002). CONCLUSION: Patients with TL did not differ from those with SO in outcomes after EVT. TL patients with prior IVT had more complete recanalization and mRS 0-2 and IVT was found to be a predictor of good outcome after EVT.

Thrombectomy vs medical management in low NIHSS acute anterior circulation stroke.

OBJECTIVE: To undertake an effectiveness and safety analysis of EVT in patients with LVO and NIH Stroke Scale (NIHSS) score ≤6 using datasets of multicenter and multinational nature. METHODS: We pooled patients with anterior circulation occlusion from 3 prospective international cohorts. Patients were eligible if presentation occurred within 12 hours from last known well and baseline NIHSS ≤6. Primary outcome was modified Rankin Scale (mRS) score 0-1 at 90 days. Secondary outcomes included neurologic deterioration at 24 hours (change in NIHSS of ≥2 points), mRS 0-2 at 90 days, and 90-day all-cause mortality. We used propensity score matching to adjust for nonrandomized treatment allocation. RESULTS: Among 236 patients who fit inclusion criteria, 139 received EVT and 97 received medical management. Compared to medical management, the EVT group was younger (65 vs 72 years; p < 0.001), had more proximal occlusions (p < 0.001), and less frequently received concurrent IV thrombolysis (57.7% vs 71.2%; p = 0.04). After propensity score matching, clinical outcomes between the 2 groups were not significantly different. EVT patients had an 8.6% (95% confidence interval [CI] -8.8% to 26.1%) higher rate of excellent 90-day outcome, despite a 22.3% (95% CI, 3.0%-41.6%) higher risk of neurologic deterioration at 24 hours. CONCLUSIONS: EVT for LVO in patients with low NIHSS score was associated with increased risk of neurologic deterioration at 24 hours. However, both EVT and medical management resulted in similar proportions of excellent clinical outcomes at 90 days. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with acute anterior circulation ischemic strokes and LVO with NIHSS < 6, EVT and medical management result in similar outcomes at 90 days.

Risks associated with the stroke predisposition at young age: facts and hypotheses in light of individualized predictive and preventive approach.

Stroke is one of the most devastating pathologies of the early twenty-first century demonstrating 1-month case-fatality rates ranging from 13 to 35% worldwide. Though the majority of cases do occur in individuals at an advanced age, a persistently increasing portion of the patient cohorts is affected early in life. Current studies provide alarming statistics for the incidence of "young" strokes including adolescents. Young stroke is a multifactorial disease involving genetic predisposition but also a number of modifiable factors, the synergic combination of which potentiates the risks. The article analyzes the prevalence and impacts of "traditional" risk factors such as sedentary lifestyle, smoking, abnormal alcohol consumption, drug abuse, overweight, hypertension, abnormal sleep patterns, and usage of hormonal contraceptives, among others. Further, less explored risks such as primary vascular dysregulation and associated symptoms characteristic for Flammer syndrome (FS) are considered, and the relevance of the FS phenotype for the stroke predisposition at young age is hypothesized. Considering the high prevalence of known genetic and modifiable risk factors in the overall predisposition to the young stroke, the risk mitigating measures are recommended including innovative screening programs by application of specialized questionnaires and biomarker panels as well as educational programs adapted to the target audiences such as children, adolescents, and young adults.

Predictive and individualized management of stroke-success story in Czech Republic.

The model of centralized stroke care in the Czech Republic was created in 2010-2012 by Ministry of Health (MH) in cooperation with professional organization-Cerebrovascular Section of the Czech Neurological Society (CSCNS). It defines priorities of stroke care, stroke centers, triage of suspected stroke patients, stroke care quality indicators, their monitoring, and reporting. Thirteen complex cerebrovascular centers (CCC) provide sophisticated stroke care, including intravenous thrombolysis (IVT), mechanical thrombectomy (MTE), as well as other endovascular (stenting, coiling) and neurosurgical procedures. Thirty-two stroke centers (SC) provide stroke care except endovascular procedures and neurosurgery. The triage is managed by emergency medical service (EMS). The most important quality indicators of stroke care are number of hospitalized stroke patients, number of IVT, number of MTE, stenting and coiling, number of neurosurgical procedures, and percentage of deaths within 30 days. Indicators provided into the register of stroke care quality (RES-Q) managed by CSCNS are time from stroke onset to hospital admission, door-to-needle time, door-to-groin time, type of ischemic stroke, and others. Data from RES-Q are shared to all centers. Within the last 5 years, the Czech Republic becomes one of the leading countries in acute stroke care. The model of centralized stroke care is highly beneficial and effective. The quality indicators serve as tool of control of stroke centers activities. The sharing of quality indicators is useful tool for mutual competition and feedback control in each center. This comprehensive system ensures high standard of stroke care. This system respects the substantial principles of personalized medicine-individualized treatment of acute stroke and other comorbidities at the acute disease stage; optimal prevention, diagnosis and treatment of possible complications; prediction of further treatment and outcome; individualized secondary prevention, exactly according to the stroke etiology. The described model of stroke care optimally meets criteria of predictive, preventive, and personalized medicine (PPPM), and could be used in other countries as well with the aim of improving stroke care quality in general.

Mechanical Thrombectomy for Acute Ischemic Stroke in Czech Republic: Technical Results from the Year 2016.

BACKGROUND AND PURPOSE: Experienced multidisciplinary stroke team and well-organized hospital management are considered necessary to achieve good results after mechanical thrombectomy (MT) in acute ischemic stroke patients. We analyzed the technical results of MT performed in the Czech Republic in the year 2016 to provide relevant data for further quality improvement. MATERIAL AND METHODS: All centers performing MT in the CR were called for detailed technical and clinical data from year 2016, which were anonymously analyzed and relevant technical key time intervals were compared. Clinical outcomes were assessed according to the HERMES meta-analysis. RESULTS: In the 2016, 1053 MTs were performed in the CR. Of 15 dedicated centers, the data from 12 centers and from 886 (84%) patients (49.2% males, mean age 69.8 ± 12.3 years) were analyzed. The overall median of time from hospital arrival to groin puncture (GP) was 77 min with a range from 40 to 109 min among individual hospitals, from GP to first passage of stent retriever 20 (15-40) min and from GP to maximal reached recanalization 42 (33-80) min. The median of recanalization time was 240 (219-320) min. The recanalization (TICI 2b-3) was achieved in 81.7% of patients, 44.1% of patients had a good 3-month clinical outcome and 6.3% suffered from symptomatic intracerebral hemorrhage. Peri-procedural complications were recorded in 89 (10%) patients. CONCLUSION: Despite achieved good overall results, a great variability in some of the analyzed key time intervals among individual centers performing MT warrants further quality improvement.

Mechanical thrombectomy performs similarly in real world practice: a 2016 nationwide study from the Czech Republic.

BACKGROUND: Randomized clinical trials have proven mechanical thrombectomy (MT) to be a highly effective and safe treatment in acute stroke. The purpose of this study was to compare neurothrombectomy data from the Czech Republic (CR) with data from the HERMES meta-analysis. METHODS: Available nationwide data for the CR from 2016 from the Safe Implementation of Treatments in Stroke-Thrombectomy (SITS-TBY) registry for patients with terminal internal carotid artery (ICA) and/or middle cerebral artery (MCA) occlusions were compared with data from HERMES. CR and HERMES patients were comparable in age, sex, and baseline National Institutes of Health Stroke Scale scores. RESULTS: From a total of 1053 MTs performed in the CR, 845 (80%) were reported in the SITS-TBY. From these, 604 (72%) were included in this study. Occlusion locations were as follows (CR vs HERMES): ICA 22% versus 21% (P=0.16), M1 MCA 62% versus 69% (P=0.004), and M2 MCA 16% versus 8% (P<0.0001). Intravenous thrombolysis was given to 76% versus 83% of patients, respectively (P=0.003). Median onset to reperfusion times were comparable: 232 versus 285 min, respectively (P=0.66). A modified Thrombolysis in Cerebral Infarction score of 2b/3 was achieved in 74% (433/584) versus 71% (390/549) of patients, respectively (OR 1.17, 95% CI 0.90-1.5, P=0.24). There was no statistically significant difference in the percentage of parenchymalhematoma type 2 (OR 1.12, 95% CI 0.66-1.90, P=0.68). A modified Rankin Scale score of 0-2 at 3 months was achieved in 48% (184/268) versus 46% (291/633) of patients, respectively (OR 0.92, 95% CI 0.71-1.18, P=0.48). CONCLUSIONS: Data on efficacy, safety, and logistics of MT from the CR were similar to data from the HERMES collaboration.

Co-deletion of 1p/19q as Prognostic and Predictive Biomarker for Patients in West Bohemia with Anaplastic Oligodendroglioma.

BACKGROUND: Anaplastic oligodendrogliomas (AO) are rare tumors. Two phase III clinical trials (RTOG 9402 and EORTC 26951) proved favorable effects of radiotherapy (RT) with chemotherapy (procarbazine, lomustine and vincristine; PCV) in patients with AO carrying chromosomal mutation of co-deletion1p/19q even if it was not the primary endpoint of these studies. We assessed 1p/19q co-deletion as a prognostic and predictive biomarker for our patients with AO. MATERIALS AND METHODS: 1p/19q co-deletion was assessed by fluorescence in situ hybridization in tumor samples from 23 patients and correlated with progression-free (PFS) and overall (OS) survival for the entire cohort and for the subgroups of patients with different treatment (neurosurgery plus RT alone vs. RT plus PCV). RESULTS: 1p/19q co-deletion was identified in 12 out of 23 tumors (52.2%). Patients with co-deletion had longer OS (587 vs. 132 weeks, p=0.012) and a trend for longer PFS (321 vs. 43 weeks, p=0.075). Patients with co-deletion treated with neurosurgery and RT plus PCV vs. neurosurgery and RT alone also had longer OS (706 vs. 423 weeks, p=0.008). There was no survival difference for patients without 1p/19q co-deletion in relation to treatment. CONCLUSION: The prognostic value of 1p/19q co-deletion in our patients with AO was verified. The strong positive predictive value of this biomarker for OS was also shown for patients with co-deletion treated with neurosurgery and RT plus PCV vs. neurosurgery and RT alone.

New treatment paradigm for patients with anaplastic oligodendroglial tumors.

Oligodendrogliomas are uncommon tumors in neurooncology that represent about 5% of primary brain malignancies. Their high sensitivity to radiotherapy and chemotherapy was observed a long time ago. Nonetheless, the evidence-based proof of the significantly longer survival in patients with oligodendrogliomas treated with combined chemotherapy and radiotherapy in comparison to radiotherapy-alone did not exist. The long-term follow-up of two landmark phase III clinical trials: RTOG 9402 and EORTC 26951, recently demonstrated favorable effects of combined radiotherapy and chemotherapy (procarbazine, lomustine and vincristine) in patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas carrying the chromosomal mutation of co-deletion of 1p/19q. There is also an increasing role of other molecular biomarkers, such as mutations in the metabolic enzyme isocitrate dehydrogenase 1/2, O6-methylguanine DNA methyltransferase gene promoter methylation, or glioma genome cytosine-phosphate-guanine islands methylator phenotype. The analysis of molecular genetics in oligodendrogliomas is now recommended as an important part of the management of these tumors and together with the novel chemotherapeutic regimens means a paradigm shift in current clinical practice in neurooncology.

Personalized approach to primary and secondary prevention of ischemic stroke.

Primary and secondary prevention of ischemic stroke represents a significant part of stroke management and health care. Although there are official guidelines concerning stroke management, new knowledge are introduced to them with a slight delay. This article provides an overview of current information on primary and secondary prevention of ischemic stroke. It summarizes information especially in the field of cardioembolic stroke, the use of new anticoagulants and the management of carotid stenosis based on the results of recent clinical studies. The optimal approach in stroke management is to follow these recommendations, to know new strategies and to apply an individual personalized approach in our clinical decisions.

Automated infarction core delineation using cerebral and perfused blood volume maps.

PURPOSE: Thrombolytic therapy in patients with acute ischemic stroke is contraindicated when the infarction core exceeds a given threshold. To date, there are no standardized guidelines for computed tomography infarction core assessment. Current practice involves use of thresholding methods, where the results are further adjusted by an experienced physician. An automated method for infarction core delineation and volume measurement was developed and tested. MATERIALS AND METHODS: CT postprocessing software was developed for analysis of whole brain perfused blood volume (PBV) and cerebral blood volume (CBV) maps. The program was designed for potential use with mean transit time (MTT) or cerebral blood flow (CBF) maps. The proposed method was tested on a set of 12 patients on both PBV and CBV maps with whole brain coverage by comparison with the results of a simple thresholding method and with manually marked findings provided by two independent physicians. RESULTS: The proposed method produced a marked infarct core volume corresponding to 53 % of the manually delineated volumes. The simple thresholding method with the optimal threshold, using the same dataset, marked 15[Formula: see text] larger volume compared to the volume delineated by physicians. CONCLUSION: An automated infarction core segmentation method based on local neighborhood features was developed and tested, demonstrating its utility in distinguishing between infarcted and non-infarcted areas, as well as reduction in the number of false positives and volume error.

New molecularly targeted therapies for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults, exhibiting high mortality. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has only limited effectiveness. The progress in genomics regarding GBM, in the detection of new markers of oncogenesis, abnormalities in signalling pathways, tumor microenvironment, and pathological angiogenesis over the past decade are briefly discussed. The role of novel prognostic in this review biomarkers [isocitrate dehydrogenases 1 and 2, CpG island methylator phenotype, promoter methylation status of the MGMT (O-6-methylguanine-methyltransferase) gene] is also discussed. New targeted therapeutic approaches are classified into several functional subgroups, such as inhibitors of growth factors and their receptors, inhibitors of proteins of intracellular signaling pathways, epigenetic gene-expressing mechanisms, inhibitors of tumor angiogenesis, tumor imunotherapy and vaccines. Finally novel possibilities for GBM treatment are summarized in this review.