Impact of dexamethasone in patients with aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: The role of corticosteroids in the treatment of patients with aneurysmal subarachnoid haemorrhage (SAH) has remained controversial for decades. Recent studies have suggested that the administration of corticosteroids in SAH patients is associated with favourable outcomes. Given their significant adverse effects, it is essential to identify those patients who will benefit from treatment with corticosteroids. METHODS: A retrospective analysis of a prospectively collected cohort (n = 306) with SAH who were treated by microsurgical clipping or endovascular intervention was performed. The role of dexamethasone administration was analysed with regard to clinical conditions and SAH-related complications. Outcome was assessed at discharge and during follow-up using the Glasgow Outcome Scale (GOS). RESULTS: Patients treated with dexamethasone presented with more episodes of hyperglycaemia (P < 0.001), more overall infections (P < 0.001) and more ventriculostomy-related infections (P = 0.004). Multivariate analysis demonstrated that treatment with dexamethasone was associated with an unfavourable outcome at discharge (GOS 1-3) [odds ratio (OR) 2.814, 95% confidence interval (CI) 1.440-5.497, P = 0.002]. In the subgroup of microsurgically treated patients, dexamethasone administration was associated with a favourable outcome at follow-up (OR 0.193, 95% CI 0.06-0.621, P = 0.006). A higher risk for unfavourable outcome (OR 3.382, 95% CI 1.67-6.849, P = 0.001) at discharge was observed in endovascularly treated patients who received dexamethasone but this had no impact on the outcome at follow-up. CONCLUSIONS: Treatment with dexamethasone seems to be associated with a risk reduction for an unfavourable outcome in those patients who underwent microsurgical clipping. Despite an increased frequency of adverse effects, glucocorticoids may have a potential benefit in this specific surgical subgroup compared to endovascularly treated SAH patients.

Surgical management of pituitary metastases.

BACKGROUND: Pituitary metastases are rare and commonly described in case reports or small case series. Due to its rarity this entity is not subject to standardized treatment guidelines, there is debate about typical initial symptoms that may lead to finding the correct diagnosis and information about the clinical course is also sparse. METHODS: We have conducted a retrospective analysis of patients with pituitary metastases who were surgically treated via a transsphenoidal procedure at our institution between 2006 and 2014. Underlying primary disease, clinical and surgical course as well as adjuvant radiotherapy and follow-up data are presented. RESULTS: 14 patients met the inclusion criteria (8 female, 6 male). Mean age was 61.5 years. Most patients became symptomatic with visual symptoms--both visual deterioration and/or diplopia (n = 13)--and anterior lobe insufficiency (n = 8). Surprisingly diabetes insipidus was only seen in three patients. All patients underwent transsphenoidal surgery initially, four patients had to undergo surgery for residual tumor or recurrence, two of them via a transcranial route. Breast cancer was the most common entity (n = 6), followed by prostate cancer (n = 3), nsclc (n = 2) and melanoma, thyroid cancer and renal cancer in one case each. Postoperative MRI showed gross total resection in four cases and residual disease in eight cases (subtotal resection, partial resection and biopsy), two patients files were incomplete regarding MRI-results. All patients underwent adjuvant radiotherapy. Survival after the initial diagnosis of cancer was 36 and 16 months after diagnosis of pituitary metastases. CONCLUSION: Our results indicate that transsphenoidal surgery is a safe method to resect pituitary metastases and that the extend of resection does not have an influence on survival time. Our results also indicate that diabetes insipidus may not be the most common initial symptom of pituitary metastases and lack thereof should not lead to making a wrong diagnosis and delaying appropriate therapy.

DHEA(S)--a novel marker in Cushing's disease.

INTRODUCTION: Dehydroepiandrosterone sulfate (DHEA(S)) is a multi-functional steroid implicated in a broad range of biological effects, including obesity, diabetes, bone metabolism, neuroprotection, and anti-tumorigenesis. It has not yet undergone wider research in the context of Cushing's disease. The objective of this study was to determine if perioperative blood levels of DHEA(S) correlate with levels of ACTH and cortisol, and therefore may be useful as a new, additional marker for the early definition of cure in patients suffering from Cushing's disease. METHODS: Forty-two consecutive patients undergoing transsphenoidal surgery for Cushing's disease from September 2009 to September 2010 were perioperatively monitored for ACTH, cortisol, and DHEA(S). RESULTS: Pre-operative blood samples revealed ACTH levels of median 65 ng/l (range 11-1,183 ng/l, standard deviation 183.76), cortisol of median 257 µg/l (range 93-803 µg/l, standard deviation 140.88), and DHEA(S) of median 2.22 mg/l (range 0.44-7.79 mg/l, standard deviation 1.82) according to the pathology of Cushing's disease. Postoperative blood samples drawn over a 7-day time span showed a drop in median ACTH to just 14.5 % (median: 9 ng/l, range 2-44, standard deviation 12.75) of its median preoperative figure. Median cortisol levels were reduced to 6.9 % (median: 18 µg/l, range 10-190 µg/l, standard deviation 38.04) of their preoperative values and DHEA(S) levels decreased to 17 % (median: 0.38 mg/l, range 0.05-2.29, standard deviation 0.51). In persistent disease, no patient showed a drop in DHEA(S) below 38 % of its preoperative figures. CONCLUSIONS: DHEA(S) shows the potential to become an additional marker in the diagnosis and follow-up of patients. However, it needs to be examined further, including whether DHEA(S) may also be a useful predictor of recovery of the HPA-axis after successful surgery.

How to deal with incompletely treated AVMs: experience of 67 cases and review of the literature.

INTRODUCTION: Despite the availability of multimodal treatment options, some arteriovenous malformations remain difficult to treat, either for intrinsic reasons at initial presentation or for reasons evolving during the course of treatment. Frequently, such cases can be easily resolved with further therapy, but some become a continuously growing treatment dilemma while exhausting dwindling therapeutic options. PATIENTS AND METHODS: A retrospective analysis was performed to identify patients with cerebral AVM who were treated unsuccessfully. Treatment was termed "not successful" if (1) postoperative angiography showed a residual AVM or missing flow reduction after palliative embolization, (2) therapy was associated with a substantial deterioration of existing neurological deficits or death, or (3) rebleeding from residual AVM occurred after therapy. Special interest was focused on the angiographic appearance of residual AVMs, their characteristic features, and their follow-up regarding second and third therapies. RESULTS: According to these criteria we identified 46 internal patients from our own series of 474 patients and 21 external patients who were referred from other institutions or sought a second opinion after incomplete treatment elsewhere. Out of those 67 cases, 50 patients (74.6%) were diagnosed with a residual AVM. Eleven patients (16.4%) experienced a deterioration of their clinical condition under therapy. Six patients did not show a flow reduction after palliative embolization. Twenty-five of the 67 patients were readmitted because of an ICH, either originating from an AVM residual or under palliative embolization. Thus, an increased risk of re-hemorrhage was found for palliative embolization (n = 16) in partially treated lesions (n = 10) and in patients with AVM grade IV and V located in eloquent regions (n = 22). In dealing with residual AVMs, microsurgical resection alone or in combination was found to be the most efficient therapeutic option, being successful in 58.9% of cases. CONCLUSION: An estimated 10% of AVM treatments may fail because of inadequate selection of either patients or management. Besides, for thorough decision-making, angiographic follow-up in all AVM patients is mandatory to allow an early identification of patients with an incompletely treated AVM requiring a second attempt. Major attention should be focused especially on high-risk subgroups with complex AVMs, partially treated AVMs, or those treated by only a palliative regimen.

Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy.

OBJECTIVE: Angiogenesis is mediated by a number of different growth factors and appears vital for tumor growth. The understanding of angiogenic mechanisms could offer new therapeutic perspectives; in this context, the role of four potentially angiogenic growth factors was analyzed in a large series of meningiomas of different grades. METHODS: Vascular endothelial growth factor (VEGF), placenta growth factor, hepatocyte growth factor/scatter factor, and basic fibroblast growth factor were quantified in 69 tumors by enzyme-linked immunosorbent assay. Microvessel density and proliferative activity were determined on paraffin sections, and clinical tumor invasiveness was rated. Induction of endothelial chemotaxis and capillary-like tube formation were studied in vitro using modified Boyden chamber assays and three-dimensional collagen gel assays, respectively. RESULTS: Tumors included 40 benign (World Health Organization [WHO] Grade I), 21 atypical (WHO Grade II), and 8 anaplastic/malignant (WHO Grade III) meningiomas. We found a correlation between meningioma grade and VEGF content (r = 0.37, P = 0.002), which was 2-fold higher in atypical than in benign meningiomas (P = 0.022) and 10-fold higher in malignant than in benign meningiomas (P = 0.025). Among different subtypes of Grade I meningiomas, VEGF levels were 10-fold higher in meningothelial than in fibrous meningiomas (P = 0.015). None of the other three factors investigated showed any association with tumor grade, microvessel density, or invasiveness, and VEGF also did not correlate with vascularity or invasiveness. Moreover, vascularity did not increase with malignancy grade. Endothelial chemotaxis and capillary-like tube formation in vitro were induced by meningioma extracts and were most effectively blocked by co-addition of antibodies against basic fibroblast growth factor, followed by anti-VEGF, whereas anti-hepatocyte growth factor/scatter factor was not effective. The chemotactic activity of meningioma extracts on endothelial cells correlated with their VEGF content (r = 0.6, P = 0.003). CONCLUSION: Meningiomas do not show an angiogenic switch involving VEGF and/or hepatocyte growth factor/scatter factor, as has previously been found in gliomas. Nevertheless, the biological activity of VEGF and basic fibroblast growth factor in meningiomas suggests that both are potential targets for antiangiogenic therapy in meningiomas of all WHO grades.

Application of a novel metal artifact correction algorithm in flat-panel CT after coil embolization of brain aneurysms: intraindividual comparison.

PURPOSE: To evaluate a novel algorithm for correcting beam hardening artifacts caused by metal implants in computed tomography performed on a C-arm angiography system equipped with a flat panel (FP-CT). MATERIALS AND METHODS: 16 datasets of cerebral FP-CT acquisitions after coil embolization of brain aneurysms in the context of acute subarachnoid hemorrhage have been reconstructed by applying a soft tissue kernel with and without a novel reconstruction filter for metal artifact correction. Image reading was performed in multiplanar reformations (MPR) in average mode on a dedicated radiological workplace in comparison to the preinterventional native multisection CT (MS-CT) scan serving as the anatomic gold standard. Two independent radiologists performed image scoring following a defined scale in direct comparison of the image data with and without artifact correction. For statistical analysis, a random intercept model was calculated. RESULTS: The inter-rater agreement was very high (ICC = 86.3 %). The soft tissue image quality and visualization of the CSF spaces at the level of the implants was substantially improved. The additional metal artifact correction algorithm did not induce impairment of the subjective image quality in any other brain regions. CONCLUSION: Adding metal artifact correction to FP-CT in an acute postinterventional setting helps to visualize the close vicinity of the aneurysm at a generally consistent image quality.

Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria.

Tumor cells with stem cell-like properties can be cultured from human glioblastomas by using conditions that select for the expansion of neural stem cells. We generated cell lines from glioblastoma specimens with the goal to obtain model systems for glioma stem cell biology. Unsupervised analysis of the expression profiles of nine cell lines established under neural stem cell conditions yielded two distinct clusters. Four cell lines were characterized by the expression of neurodevelopmental genes. They showed a multipotent differentiation profile along neuronal, astroglial and oligodendroglial lineages, grew spherically in vitro, expressed CD133 and formed highly invasive tumors in vivo. The other five cell lines shared expression signatures enriched for extracellular matrix-related genes, had a more restricted differentiation capacity, contained no or fewer CD133+ cells, grew semiadherent or adherent in vitro and displayed reduced tumorigenicity and invasion in vivo. Our findings show that stable, multipotent glioblastoma cell lines with a full stem-like phenotype express neurodevelopmental genes as a distinctive feature, which may offer therapeutic targeting opportunities. The generation of another distinct cluster of cell lines showing similarly homogeneous profiling but restricted stem cell properties suggests that different phenotypes exist, each of which may lead to the typical appearance of glioblastoma.

Isolation and culture of human neuromicrovascular endothelial cells for the study of angiogenesis in vitro.

Neovascularization in the adult central nervous system occurs as a response to several pathophysiological conditions such as ischemia, wound repair, or neoplasia. Endothelial cells from different blood vessel types, different organs, and different species are heterogeneous; therefore, the appropriate cell type should be used to study specific aspects of vascular pathology. We have developed a method to isolate human cerebral microvascular endothelial cells (CMECs) from small, freshly obtained specimens of normal brain adherent to human arteriovenous malformations (AVMs). The isolation procedure involves enzymatic digestions and gradient centrifugations, yielding over 95% pure primary cultures. Alternative isolation methods using magnetic beads, panning, or cloning were not superior with regard to cell purity or yield. CMECs were identified by their immunoreactivity for vWF, CD34, EN4, binding of Ulex europeus lectin, and uptake of DiI-Ac-LDL. They displayed ultrastructural features characteristic of blood-brain barrier endothelial cells and expressed GLUT-1. CMECs were subcultured; however, prolonged culture led to reduced culture purity. Vascular endothelial growth factor, basic fibroblast growth factor and hepatocyte growth factor/scatter factor stimulated the directional motility of CMECs, with dose-response profiles similar to human umbilical vein endothelial cells (HUVECs). In contrast, to stimulate proliferation, lower concentrations of growth factors tended to be necessary for CMECs than for the large vessel endothelial cells. CMECs formed capillary tube-like structures in an in vitro angiogenesis assay using matrigel. This study expands the spectrum of available tissue sources for the isolation of human neuromicrovascular endothelial cells, which are essential for the in vitro study of blood-brain barrier function and cerebral angiogenesis.

Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis.

Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme-linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11-fold higher in high-grade tumors and those of HGF/SF 7-fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII-related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high-grade tumors were significantly more potent in the tube formation assay than the low-grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low-grade tumors. Upon induction of angiogenesis in high-grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor.

Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells.

Malignant gliomas are characterized by rapid growth, infiltration of normal brain tissue, and high levels of tumor-associated angiogenesis. The genetic and local environmental tissue factors responsible for the malignant progression from low to high grade gliomas and the highly malignant behavior of glioblastomas are not well understood. In a study of 77 human brain tissue extracts, high grade (III-IV) tumors had significantly greater scatter factor (SF) content than did low grade tumors or non-neoplastic tissue. To investigate the potential significance of SF accumulation in gliomas, we measured the effects of SF on DNA synthesis and motility of cultured human glioma cell lines. SF stimulated DNA synthesis in 7/10 glioma cell lines and in 3/3 neuromicrovascular endothelial cell (NMVEC) lines, consistent with our previous report that SF stimulated cell proliferation of a few human glioma cell lines. SF markedly stimulated the chemotactic migration of 10/10 glioma cell lines as well as 3/3 NMVEC lines. In addition, SF stimulated the 2-dimensional migration of glioma cells on culture surfaces coated with specific extracellular matrix molecules (collagen i.v., laminin, and fibronection). As expected based on these biologic responses to SF, 10/10 glioma lines and 4/4 NMVEC lines expressed mRNA for c-met, the SF receptor. To assess the possible in vivo significance of these migration assays, we compared the chemotactic response of a glioma cell line to human brain cyst fluids and tumor extracts that contained high or low SF concentrations. Fluids and extracts with high SF content tended to induce higher levels of chemotactic migration than did fluids and extracts with low SF content. Addition of anti-SF monoclonal antibody (MAb) inhibited migration induced by fluids and extracts with high SF content by about 30-50%.