Odysseas Kargiotis

Mechanisms of angiogenesis in gliomas

SummaryGliomas are the most frequent primary tumors of the central nervous system in adults. Glioblastoma multiforme, the most aggressive form of astrocytic tumors, displays a rapid progression that is accompanied by particular poor prognosis of patients. Intense angiogenesis is a distinguishing pathologic characteristic of these tumors and in fact, glioblastomas are of the most highly vascularized malignant tumors. For this reason, research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenic blood vessels in order to develop new approaches that effectively block angiogenesis and cause tumor regression. We discuss here some important features of glioma angiogenesis and we present molecules and factors and their possible functions and interactions that play a role in neovascularization. In spite of the great progress that molecular biology has achieved on investigating tumor angiogenesis, many aspects remain obscure and the complexity of the angiogenic process stands for an obstacle in identifying the exact and complete molecular pathways orchestrating new blood vessels formation, which are necessary for the survival and expansion of these tumors.

Effects of irradiation on tumor cell survival, invasion and angiogenesis.

Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.

Blood Pressure Reduction and Secondary Stroke Prevention: A Systematic Review and Metaregression Analysis of Randomized Clinical Trials.

Current recommendations do not specifically address the optimal blood pressure (BP) reduction for secondary stroke prevention in patients with previous cerebrovascular events. We conducted a systematic review and metaregression analysis on the association of BP reduction with recurrent stroke and cardiovascular events using data from randomized controlled clinical trials of secondary stroke prevention. For all reported events during each eligible study period, we calculated the corresponding risk ratios to express the comparison of event occurrence risk between patients randomized to antihypertensive treatment and those randomized to placebo. On the basis of the reported BP values, we performed univariate metaregression analyses according to the achieved BP values under the random-effects model (Method of Moments) for those adverse events reported in ≥10 total subgroups of included randomized controlled clinical trials. In pairwise meta-analyses, antihypertensive treatment lowered the risk for recurrent stroke (risk ratio, 0.73; 95% confidence interval, 0.62–0.87; P<0.001), disabling or fatal stroke (risk ratio, 0.71; 95% confidence interval, 0.59–0.85; P<0.001), and cardiovascular death (risk ratio, 0.85; 95% confidence interval, 0.75–0.96; P=0.01). In metaregression analyses, systolic BP reduction was linearly related to the lower risk of recurrent stroke (P=0.049), myocardial infarction (P=0.024), death from any cause (P=0.001), and cardiovascular death (P<0.001). Similarly, diastolic BP reduction was linearly related to a lower risk of recurrent stroke (P=0.026) and all-cause mortality (P=0.009). Funnel plot inspection and Egger statistical test revealed no evidence of publication bias. The extent of BP reduction is linearly associated with the magnitude of risk reduction in recurrent cerebrovascular and cardiovascular events. Strict and aggressive BP control seems to be essential for effective secondary stroke prevention.

Direct oral anticoagulant– vs vitamin K antagonist–related nontraumatic intracerebral hemorrhage

Objective: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). Methods: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. Results: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6–21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3–14] vs 15 [7–25] points, p = 0.003), median baseline hematoma volume (12.8 [4–40] vs 24.3 [11–58.8] cm3, p = 0.007), and median ICH score (1 [0–2] vs 2 [1–3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13–0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = −0.57, 95% CI −1.02 to −0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21–0.91, p = 0.030). Conclusions: DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis

Objective— Although statin pretreatment (SP) is associated with better outcomes in patients with acute cerebral ischemia after an ischemic stroke/transient ischemic attack, data on the underlying mechanism of this beneficial effect are limited. Approach and Results— We sought to evaluate the potential association between SP and microembolic signal (MES) burden in acute cerebral ischemia because of large artery atherosclerosis (LAA). We prospectively evaluated consecutive patients with first-ever acute cerebral ischemia because of LAA in 3 tertiary stroke centers over a 2-year period. All patients underwent continuous 1-hour transcranial Doppler monitoring of the relevant vessel at baseline (⩽24 hours). SP was recorded and dichotomized as high dose or low-to-moderate dose. SP was documented in 43 (41%) of 106 LAA patients (mean age, 65.4±10.3 years; 72% men; low-to-moderate dose, 32%; high dose, 8%). There was a significant (P=0.022) dose-dependent effect between SP and MES prevalence: no SP (37%), SP with low-to-moderate dose (18%), and SP with high dose (0%). Similarly, a significant (P=0.045) dose-dependent effect was documented between SP and MES burden: no SP (1.1±1.8), SP with low-to-moderate dose (0.7±1.6), and SP with high dose (0±0). In multivariable logistic regression analysis adjusting for demographics, vascular risk factors, location of LAA, stroke severity, and other prevention therapies, SP was associated with lower likelihood of MES presence (odds ratio, 0.29; 95% confidence interval, 0.09–0.92; P=0.036). In addition, SP was found also to be independently related to higher odds of functional improvement (common odds ratio, 3.33; 95% confidence interval, 1.07–10.0; P=0.037). Conclusions— We found that SP in patients with acute LAA is related with reduced MES presence and lower MES burden with an apparently dose-dependent association.

Subclavian Steal Syndrome with or without Arterial Stenosis: A Review

The subclavian‐vertebral artery steal syndrome (SSS) is the hemodynamic phenomenon of blood flow reversal in the vertebral artery due to significant stenosis or occlusion of the proximal subclavian artery or the innominate artery. Occasionally, SSS is diagnosed in patients not harboring arterial stenosis. With the exception of arterial congenital malformations, the limited case reports of SSS with intact subclavian artery are attributed to dialysis arteriovenous fistulas (AVFs). Interestingly, these cases are more frequently symptomatic than those with the classical atherosclerotic SSS forms. On the other hand, the disclosure of SSS due to subclavian/innominate artery atherosclerotic stenosis, even in the absence of accompanying symptoms, should prompt a thorough cardiovascular work‐up for the early detection of coexisting coronary, carotid, or peripheral artery disease. Herein, we review the incidence, clinical presentation, sonographic findings, and therapeutic interventions related to SSS with and without subclavian/innominate artery stenosis. We also review the currently available data in the literature regarding the association of SSS and dialysis AVF. In addition, we present a patient with bilateral symptomatic SSS as the result of an arteriovenous graft (AVG) that was introduced after the preexisting AVF in the contralateral arm became nonfunctional. SSS due to subclavian or innominate artery stenosis/occlusion is rarely symptomatic warranting interventional treatment. In contrast, when it is attributed to AVF, surgical correction is frequently necessary.

Intravenous thrombolysis for acute ischemic stroke: a bridge between two centuries

ABSTRACT Introduction: Intravenous tissue-plasminogen activator (tPA) remains the only approved systemic reperfusion therapy suitable for most patients presenting timely with acute ischemic stroke. Accumulating real-word experience for over 20 years regarding tPA safety and effectiveness led to re-appraisal of original contraindications for intravenous thrombolysis (IVT). Areas covered: This narrative review focuses on fast yet appropriate selection of patients for safe administration of tPA per recently expanded indications. Novel strategies for rapid patient assessment will be discussed. The potential for mobile stroke units (MSU) that shorten onset-to-needle time and increase tPA treatment rates is addressed. The use of IVT in the era of non-vitamin K antagonist oral anticoagulants (NOACs) is highlighted. The continuing role of IVT in large vessel occlusion (LVO) patients eligible for mechanical thrombectomy (MT) is discussed with regards to ‘drip and ship’ vs. ‘mothership’ treatment paradigms. Promising studies of penumbral imaging to extend IVT beyond the 4.5-hour window and in wake-up strokes are summarized. Expert commentary: This review provides an update on the role of IVT in specific conditions originally considered tPA contraindications. Novel practice challenges including NOAC’s, MSU proliferation and bridging therapy (IVT&MT) for LVO patients, and the potential extension of IVT time-window using penumbral imaging are emerging as safe and potentially effective IVT applications.

Heart failure and the risk of ischemic stroke recurrence: A systematic review and meta-analysis

Heart failure (HF) is known to be a major risk factor for first-ever ischemic stroke (IS), and is associated with greater stroke severity and higher rates of early mortality and residual disability. There are limited data regarding the association of HF with stroke recurrence. We sought to evaluate the relationship between HF and recurrent IS using a comprehensive meta-analytical approach. We performed a systematic literature review according to PRISMA guidelines to identify all prospective study protocols (randomized clinical trials or observational cohorts) that reported rates of IS recurrence in patients with concomitant HF. We pooled independently the reported corresponding risk ratios (RRs) and hazard ratios (HRs) from each study protocol using the random effects model. Heterogeneity across included studies was evaluated using Cochran Q and I(2) statistics. Our literature search identified 7 eligible studies including 9173 IS patients (18.2% with HF). The reported mean follow-up period in the included studies ranged from 7days to 5years. The pooled estimate of RRs and HRs for recurrent IS was 1.96 (95% CI: 1.49-2.60; p<0.0001) and 1.93 (95% CI: 1.47-2.53; p<0.0001). We found no evidence of heterogeneity within studies in both the RR (I(2)=13.5%, p for Cochran Q statistic: 0.325) and HR (I(2)=0%, p for Cochran Q statistic: 0.629) analyses. HF is associated with a continuous two-fold increase in the risk of IS recurrence in patients with prior history of cerebral ischemia. The benefit of anticoagulation in this high-risk group of patients may be studied along with additional risk factor modifications.

Associations of ESR2 AluI (G/A) polymorphism with ischemic stroke in Caucasians

Raising interest towards genes implicates the effect of estrogen receptor-alpha (ESR1) gene on cerebrovascular disease, but data are lacking regarding the effect of estrogen receptor-beta (ESR2) gene. We assessed the hypothesis that AluI (G/A) polymorphism of the ESR2 gene (rs 4986938) is associated with ischemic stroke in a Caucasian population. Four hundred twenty four consecutive stroke patients and 430 age and gender-matched controls were enrolled in three stroke centers in Greece over one-year period. Patients and controls were compared in regard to the prevalence of the aforementioned polymorphism. No association was found between variations in the ESR2 gene and risk of stroke or stroke subtype in men and women. Of note, a gender-specific association of G allele with the onset of stroke at a younger age in male patients was found (63.68 ± 12.687 years in G allele (GG+AG) carriers vs. 68.95 ± 10.757 years in non-carriers (AA), p=0.008). Further population independent studies are needed to establish the role of ESR2 gene polymorphisms in relation to ischemic stroke in both genders. Such studies could lead to ERβ agonists being validated in individuals with certain genotypes and/or alleles towards the development of efficient strategies to preventing ischemic stroke in both men and women.

Percutaneous transluminal angioplasty and stenting for symptomatic intracranial arterial stenosis: A systematic review and meta-analysis

Objectives: The cumulative safety and efficacy measures of percutaneous transluminal angioplasty and stenting (PTAS) for secondary stroke prevention in patients with symptomatic intracranial arterial stenosis (sICAS) have not previously been evaluated using a meta-analytical approach. Methods: We conducted a systematic review and random effects meta-analysis of all available randomized controlled trials (RCTs) evaluating the safety and efficacy of PTAS (in comparison with medical therapy) for sICAS. Results: Three RCTs (678 total patients) were included in the quantitative analysis. PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days [risk ratio (RR) = 2.21, 95% confidence interval (CI) 1.10–4.43] and 1 year (RR = 1.92, 95% CI 1.10–3.36). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08, 95% CI 1.17–3.71). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60, 95% CI 1.98–56.62) and 1 year (RR = 8.15, 95% CI 1.50–44.34). The composite outcome of any stroke or death within 1 year (RR = 2.29, 95% CI 1.13–4.66) and 2 years (RR = 1.52, 95% CI 1.04–2.21) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the sICAS subgroup located in posterior circulation (RR = 2.37, 95% CI 1.27–4.42). Conclusions: PTAS is associated with adverse early and long-term outcomes and should not be recommended in patients with sICAS. Further research to identify subgroups of patients who could also serve as candidates for future interventional trials along with efforts to reduce procedure-related complications are needed.