Jan Jakob A. Mooij

Intracranial Aneurysms in Patients with Subarachnoid Hemorrhage: CT Angiography as a Primary Examination Tool for Diagnosis—Systematic Review and Meta-Analysis

PURPOSEnTo calculate the sensitivity and specificity of computed tomographic (CT) angiography in the diagnosis of cerebral aneurysms in patients with acute subarachnoid hemorrhage (SAH) at presentation.nnnMATERIALS AND METHODSnA systematic search for relevant studies was performed of the PubMed/MEDLINE and EMBASE databases. Two reviewers independently assessed the methodologic quality of each study by using the Quality Assessment of Diagnostic Accuracy Studies tool. The inclusion criteria were met by 50 studies. Heterogeneity was tested, and the presence of publication bias was visually assessed (by using a funnel plot). A meta-analysis of the reported sensitivity and specificity of each study with 95% confidence intervals (CIs) was performed on a per-patient level.nnnRESULTSnConcerning sensitivity, the selected studies showed moderate heterogeneity. For specificity, low heterogeneity was observed. Moderate-heterogeneity studies that investigated only sensitivity or specificity were excluded from the pooled analyses by using a bivariate random effects model. The majority of the studies (n = 30) used a four-detector row CT scanner. The studies had good methodologic quality. Pooled sensitivity was 98% (95% CI: 97%, 99%), and pooled specificity was 100% (95% CI: 97%, 100%). Potential sources of variability among the studies were variations in the methodologic features (quality score), CT examination procedure (number of rows on the multidetector CT scanner), the standard of reference used, and the prevalence of ruptured intracranial aneurysms. There was evidence for publication bias, which may have led to overestimation of the diagnostic accuracy of CT angiography.nnnCONCLUSIONnMultidetector CT angiography can be used as a primary examination tool in the diagnostic work-up of patients with SAH.

International subarachnoid aneurysm trial 2009: endovascular coiling of ruptured intracranial aneurysms has no significant advantage over neurosurgical clipping.

In the May 2009 issue of The Lancet Neurology, the 5-year follow-up results of the International Subarachnoid Aneurysm Trial (ISAT) were published. The authors concluded that, although the significant difference between coiling and neurosurgical clipping of ruptured intracranial aneurysms in terms of death and severe disability after 1 year has vanished (primary endpoint), coiling should still be favored over neurosurgical clipping because mortality rates significantly favored coiling. In this commentary, it is this particular conclusion that is challenged by combining data from previous ISAT publications with the current 5-year follow-up results. This modified intent-to-treat analysis clearly demonstrates that the significant advantage in terms of mortality in favor of the endovascularly treated patients is no longer present, with a hazard ratio of 0.80 in favor of endovascular treatment (95% confidence interval: 0.60-1.05; P = .10). Therefore, for everyday clinical practice and decision making, coiling and clipping are to be considered equivalent in the long term.

SOMATOSENSORY EVOKED-POTENTIAL MONITORING OF TEMPORARY MIDDLE CEREBRAL-ARTERY OCCLUSION DURING ANEURYSM OPERATION

Somatosensory evoked potentials (SEPs) in response to median nerve stimulation were used as a guide to cortical function during temporary occlusion of the distal M1 segment of the middle cerebral artery (MCA) in the surgical treatment of five large aneurysms of the MCA bifurcation. MCA occlusion times ranged from 8 to 19 minutes under moderate hypothermia at 28.8 degrees to 30.3 degrees C. SEPs were preserved for variable times during MCA occlusion, ranging from no increase in latency after 13 minutes of occlusion to severe deterioration after 6 minutes. In no case was MCA occlusion maintained for longer than 3 minutes in the presence of a severely disturbed SEP. Recovery of the SEP to its preoperative relationship with that of the nonoperated hemisphere was seen in all cases before the end of operation. All patients were awake after rewarming at the end of operation without any neurological deficit. Monitoring the SEP pertaining to the territory of a cerebral artery during its temporary occlusion can help avoid ischemic damage and will allow the surgeon to take advantage of the several benefits of this technique in aneurysm surgery.

TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme.

SummaryPurposeIn order to improve the survival of patients with a glioblastoma multiforme tumor (GBM), new therapeutic strategies must be developed. The use of a death inducing ligand such as TRAIL (TNF Related Apoptosis Inducing Ligand) seems a promising innovative therapy. The aim of this study was to quantify the expression of the death regulating receptors TRAIL-R1, TRAIL-R2 and TRAIL on primary GBM specimens and to correlate this expression with survival.Experimental designExpression of TRAIL and TRAIL-receptors was assessed by immunohistochemistry, both quantitatively (% of positive tumor cells) and semi-quantitatively (staining intensity) within both the perinecrotic and intermediate tumor zones of primary GBM specimens. RT-PCR of GBM tissue was performed to show expression of TRAIL receptor mRNA.ResultsImmunohistochemistry showed a slight diffuse intracytoplasmic and a stronger membranous staining for TRAIL and TRAIL receptors in tumor cells. Semi-quantitative expression of TRAIL showed a significantly higher expression of TRAIL in the perinecrotic zone than in the intermediate zone of the tumor (P=0.0001). TRAIL-R2 expression was significantly higher expressed than TRAIL-R1 (P=0.005). The antigenic load of TRAIL-R2 was positively correlated with survival (P=0.02). Multivariate analysis of TRAIL-R1 within the study group (n=62) showed that age, gender, staining intensity, antigenic load, % of TRAIL-R1 expression, were not statistically correlated with survival however radiotherapy was significantly correlated (multivariate analysis: age: P=0.15; gender: P=0.64; staining intensity: P=0.17; antigenic load: P=0.056; % of TRAIL-R1 expression: P=0.058; radiotherapy: P=0.0001). Subgroup analysis of patients who had received radiotherapy (n=47) showed a significant association of % of TRAIL-R1 expression and the antigenic load of TRAIL-R1 with survival (multivariate analysis: P=0.036, respectively, P=0.023).Multivariate analysis of TRAIL-R2 staining intensity and antigenic load, within the study group (P=0.004, respectively, P=0.03) and the subgroup (P=0.002, respectively, P=0.004), showed a significant association with survival. RT-PCR analysis detected a negative relation between the amount of TRAIL-R1 mRNA and the WHO grade of astrocytic tumors (P=0.03).ConclusionsTRAIL-R1 and TRAIL-R2 expression on tumor cells are independent prognostic factors for survival in patients with a glioblastoma multiforme. Both receptors could be targets for TRAIL therapy. As TRAIL-R2 is more expressed, in comparison with TRAIL-R1, on GBM tumor cells, TRAIL-R2 seems to be of more importance as a target for future TRAIL therapy than TRAIL-R1.

Review: On TRAIL for malignant glioma therapy?

J. M. A. Kuijlen, E. Bremer, J. J. A. Mooij, W. F. A. den Dunnen and W. Helfrich (2010) Neuropathology and Applied Neurobiology36, 168–182u2028On TRAIL for malignant glioma therapy?

The proliferative potential of the pilocytic astrocytoma : The relation between MIB-1 labeling and clinical and neuro-radiological follow-up

The proliferative potential of 39 pilocytic and 5 low grade astrocytomas was studied in relation to the Ki-67 activity as measured by the MIB-1 Labelings Index. The results were correlated to the biological behaviour of the tumor as measured by clinical and neuro-radiological (CT- or MRI-scans) follow-up of the patient. This study was undertaken to answer the question whether MIB-1 expression reflects differences in biological behaviour of these tumors, such as rapid progression of residual tumor or stable remaining tumor. MIB-1 LI values ranged from 0 to 19% in the group of pilocytic astrocytomas (mean 4,2%) and from 0 to 15% in the 5 low grade astrocytomas (mean 4,2%). All patients were operated and 23 of them had incomplete tumor resection as proven on postoperative neuro-imaging studies. Those 23 patients could be subdivided into two groups; one without progression of residual tumor during follow-up (n=12) and the other with tumor progression (n=11). mean MIB-1 LI in the group with ‘quiescent’ tumor tended to be lower than in the group with progressive tumor: 3,3% vs. 6,6%. Residual tumors which were negative for MIB-1 staining showed fewer progressions of residual tumor compared to those being positive for MIB-1 staining, however this difference was not significant (p=0, 15, Fisher exact test). Tumor samples of a second operation of the same patient had lower MIB-1 LI values than those of the samples taken at first operation. The proliferating potential seemed to be decreased after part of the tumor was resected. Pilocytic astrocytomas with a negative MIB-1 LI are unlikely to show progression of residual tumor after partial resection. MIB-1 staining might be an additional tool in determining the frequency and duration of follow-up and in making decisions regarding further treatment of a patient operated for a pilocytic astrocytoma with residual tumor.

The angiopoietin 1/angiopoietin 2 balance as a prognostic marker in primary glioblastoma multiforme.

OBJECTnIn the present study, the authors analyzed the ANGPT1/ANGPT2 balance in the context of therapeutic outcome in 62 patients with primary glioblastomas multiforme (GBMs).nnnMETHODSnThe tumor tissue used was obtained in adult patients who underwent neurosurgical debulking. Microvessel density was assessed by morphometric analysis. Double immunostaining for Ki 67/CD34 and cleaved caspase-3/CD34 was used to investigate the proliferation and apoptotic fraction of both endothelial and tumor cells. The expression of VEGFs (A-D) was evaluated on immunohistochemistry. To measure tumor vascular stabilization, the ANGPT1/ANGPT2 mRNA balance was determined using real-time reverse transcriptase polymerase chain reaction.nnnRESULTSnWithin the hypoxic perinecrotic tumor area, the apoptotic fraction of endothelial cells was positively correlated with VEGFA expression (p < 0.001). Higher levels of VEGFA correlated with greater proliferation of endothelial cells in the intermediate tumor area (p = 0.031). Vascular endothelial growth factor D was significantly more highly expressed within the perinecrotic tumor area compared with the intermediate tumor area (p < 0.001). Multivariate analysis showed a significant association between the ANGPT1/ANGPT2 balance and the survival time of patients with GBMs (p = 0.035).nnnCONCLUSIONSnThe results of the present study suggest that the ANGPT1/ANGPT2 balance has prognostic value in patients with primary GBMs. The authors findings support the need for further studies of the feasibility of antiangiogenic therapy in primary GBMs, with a special focus on the normalization of tumor vasculature.

Feasibility of magnetic resonance angiography (MRA) follow-up as the primary imaging modality after coiling of intracranial aneurysms.

Background: Digital subtraction angiography (DSA) is still regarded as the gold standard for detecting residual flow in treated aneurysms. Recent reports have also shown excellent results from magnetic resonance angiography (MRA) imaging. This is an important observation, since DSA is associated with a risk of medical complications, is time consuming, and is more expensive. Purpose: To determine whether MRA could replace conventional DSA and serve as the primary postinterventional imaging modality in patients with coiled intracranial aneurysms. Material and Methods: We studied a prospectively enrolled cohort of 190 patients treated endovascularly for a first-ruptured and/or unruptured intracranial aneurysm between January 2004 and December 2008. The imaging protocol included a 1.5T time-of-flight (TOF) MRA and a DSA at 3 months (on the same day) and, depending on comparability, a 1.5T TOF-MRA or DSA 1 year after treatment. All images were evaluated by a multidisciplinary panel. Results: In 141/190 patients, both an MRA and DSA were performed after 3-month follow-up. In 2/141 patients (1.4%), (small) neck remnants gave false-negative MRA results. In one patient (0.7%), this led to additional neurosurgical clipping of the aneurysm. In 25/141 patients, future follow-up (>3 months) consisted of DSA because of various reasons. In 24/25 of these patients, primary MRA images alone would invariably have led to additional DSA imaging. Conclusion: The present study shows that 1.5T TOF-MRA is a feasible primary follow-up modality after coiling of intracranial aneurysms. Given our data, we now suggest that, in every patient with a coiled intracranial aneurysm, the first follow-up, 3 months after coiling, should be an MRA study. Only when this MRA is inconclusive (e.g., because of coil artifacts), or in the case of suspicion of recanalization, should DSA be performed additionally.

The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour

Aims: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved in the migration of immune cells in the injured brain, they may also be involved in chemoattraction of NSCs towards a brain tumour. Methods: The expression profile of various chemokine receptors in NSCs, harvested from the subventricular zone of adult mice, was investigated by reverse transcriptase‐ polymerase chain reaction analysis. Furthermore, the functionality of the chemokine receptors was assessed in in vitro chemotaxis assays and calcium signalling experiments. To test the in vivo migration of NSCs, a syngeneic mouse model was developed, whereby a B16F10 melanoma cell line was grafted into one hemisphere and later NSCs were grafted in the contralateral hemisphere. Furthermore, the expression of chemokines in this melanoma cell line was investigated. Results and conclusions: Adult mouse NSCs functionally express various chemokine receptors of which CXC chemokine receptor (CXCR)4 shows the highest mRNA levels and most pronounced functional responses in vitro. CXC chemokine ligand (CXCL)12, the ligand for CXCR4, is expressed by the melanoma cell line. In this mouse model for metastatic brain tumours, it is shown that NSCs express CXCR4 at their cell membranes while they migrate towards the tumour, which produces CXCL12. It is therefore suggested that the CXCR4/CXCL12 pathway plays a role in the mechanism underlying tumour‐mediated attraction of NSCs.

Cranialization of the frontal sinus—the final remedy for refractory chronic frontal sinusitis

OBJECTnChronic sinusitis can be a debilitating disease with significant impact on quality of life. Frontal sinusitis has a relatively low prevalence, but complications can be severe due to its anatomical location. After failure of conservative measures, typically endoscopic procedures are performed to improve the drainage of the frontal sinus. The cranialization of the frontal sinus is the final surgical measure, in which the affected frontal sinus is truly removed. In this study the authors describe the surgical technique of cranialization of the frontal sinus for refractory chronic frontal sinusitis, systematically search the literature for its application, and assess patient satisfaction in a cohort of consecutively treated patients after long-term follow-up.nnnMETHODSnA consecutive cohort of 15 patients with refractory chronic frontal sinusitis was treated by cranialization of the frontal sinus and followed over a 20-year period (1989-2008) for the direct results and complications of the surgery. Long-term follow-up (mean 6.5 years) was obtained to assess the long-term effects of the cranialization.nnnRESULTSnIn all patients the signs and symptoms of chronic frontal sinusitis responded very well to the cranialization. Five patients had surgical complications, of which 2 were serious. One patient died of an unrelated cause and 1 patient was lost to follow-up. The remaining 13 patients had a long-term follow-up, which revealed that 12 of them thought that their life was better after the surgical procedure.nnnCONCLUSIONSnCranialization of the frontal sinus deserves consideration as the final remedy for refractory chronic frontal sinusitis after definite failure of other options.