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The neuroret-ina is not only nourished by transport of glucose across the endothelial cells of the capillaries of the iBRB but also from the choroidal vessels (CV) across the retinal pigment epithelium of the outer BRB. Such a transport of glucose is facilitated by Glucose transporter 1 (Glut1), which is co-localized with these junctional pro-teins during their maturation.

Oncolytic viruses selectively lyse tumor cells, making these agents a promising treatment modality for glioma. Accumulating data suggest that the immune system plays an important role in the anti-glioma activity of oncolytic viruses. In an immune competent glioma model, the therapeutic effect of the oncolytic adenovirus Delta24-RGD was found to depend primarily on antitumor immune responses.

The value of AgNOR staining as a tumor biological marker was tested in 26 children with pilocytic astrocytomas (20) and fibrillary astrocytomas (6). All patients were surgically treated and then followed up by periodic MRI or CT scans. Follow-up ranged from 8 to 84 months, with a mean of 44 months. AgNOR expression was determined by using semi-automated computer-assisted surface area measurements. AgNOR values ranged from 1.4 to 81.4 microm(2) per cell, with a mean of 26.6 and a median of 15.2. The median value was taken as a "cut-off" score separating two groups of patients with low and high AgNOR scores. Of the 13 patients in the low scoring group, 8 had total resections without recurrence, 3 had stable residual tumors, 1 had regressing residual tumor after irradiation and 1 had a recurrence 5 years after neuroradiologically complete resection of a fibrillary astrocytoma. In the group with high AgNOR scores only 2 patients had total resections without recurrence; 5 had stable residual tumors and 6 had residual tumors that showed progression, all within 1 year after surgery. Among the patients with classic juvenile pilocytic astrocytomas of the cerebellum 7 had residual tumor, which progressed in 2 patients, both of whom had high AgNOR scores. Among 7 patients with optic/hypothalamic tumors the 3 with rapidly progressing tumors all had very high AgNOR scores. The determination of AgNOR expression might be helpful in selection of patients with residual tumor after surgery, who may benefit from additional chemotherapy or (stereotactic) radiation therapy.

In a retrospective study of 73 patients operated on for cere-bellar pilocytic astrocytomas, results of treatment, outcome and biological behaviour of residual tumour were analysed. Complete tumour resection proven by CT or MRI scans within 1 year after surgery was achieved only in 69% of cases. In 31% of cases the surgeon’s opinion on the extent of surgical resection was not borne out by the result of postoperative neuroimaging. Progression of residual tumour or tumour recurrence appeared in 19% of patients, 1 patient showed metastatic spread along the craniospinal axis, and in 1 patient malignant degeneration appeared during follow-up. Stable residual tumour or regression of residual tumour was seen in 14% of patients. Outcome after surgical treatment, which was combined with irradiation in 10 patients (14%), was favourable in 80% and unfavourable in 20% of patients. This outcome of treatment was not influenced by a second operation for progression of residual tumour or recurrent tumour. Characteristics of patients with tumour progression after the first operation did not differ from those of the whole group. There were 17 reoperations for residual or recurrent tumour, 10 of which took place within 4 years after the initial surgical treatment. Surgery-related morbidity was 15% and mortality 4%. Irradiation to residual tumour in 8 patients was followed by complete regression in 1 patient, progression in 4 patients and no changes in 1 patient. For the remaining 2 patients the effect of irradiation on the residual tumour is unknown. Factors that determine the prognosis are discussed on the basis of this retrospective analysis and the data from the literature. It is concluded that optimal treatment for a cerebellar pilocytic astrocytoma does not consist solely in surgery with the aim of total tumour removal and careful tumour handling in order to avoid spread of tumour cells and subsequent metastases and additional radiation therapy in strictly selected cases, but also in posttreatment follow-up based on direct postoperative neuroimaging, preferably by MRI. An algorithm for postoperative follow-up management is presented.

We have performed expression profiling on 276 glioma samples of all histological subtypes, which resulted in the identification of seven distinct molecular subgroups. Interestingly, pilocytic astrocytomas (PAs) (n=6; adults) were assigned to one specific molecular cluster, together with four other, more malignant, gliomas. All the non-PAs were histologically diagnosed as higher grade gliomas with pilocytic features. Interestingly, there was a dramatic difference between survival of PAs and gliomas of other histological subtypes in this molecular cluster (>10.6 years vs. 3.4 (avg.) years; p = 0.03). Validation with an external dataset containing only PAs (GSE12907) showed that PAs are virtually always assigned to this molecular cluster, confirming the stability of the cluster. However, similar to our dataset, a subset of samples of both the REMBRANDT (8%) and TCGA (1%) datasets was also assigned to this molecular cluster. To further explore the differences between PAs and non-PAs in this molecular cluster, we performed genotyping using SNP 6.0 chip arrays. As reported previously, all PAs have only one larger genetic aberration; a focal amplification on locus 7q34, which is indicative for the presence of the tandem duplication KIAA1549-BRAF. One of the four samples of other histology also had this identical genetic aberration as PAs. The other (3/4) non-PA gliomas showed more genetic aberrations than the PAs. All patients harboring the KIAA1549-BRAF duplication were still alive (“survivors”) at the moment of writing this abstract (survival 10.6-19.6 years), whereas the remaining patients (“non-survivors”) all died within 0.44-2.7 years. High copy EGFR amplification was seen in none of the survivors but all of the other tumors. None of the samples in this cluster showed an IDH1-132H mutation. Closer inspection of the SNP arrays indicated that all non-survivors are tetraploid, whilst tumors of all survivors are near diploid (except for 3n on 7q34). The ploidy of all samples is currently validated using Fluorescence In Situ Hybridization (FISH). Polyploidy was not observed in any of the other molecular clusters. Validation with the REMBRANDT and the TCGA datasets showed that non-PAs assigned to this molecular cluster had a poor survival, similar to the non-PAs in our dataset. Interestingly, tetraploidy and EGFR amplification were also seen in the GBM samples from the TCGA that were assigned to this cluster. Gliomas from other molecular subtypes did not show tetraploidy on SNP chip data. In conclusion, we have discovered and validated a glioma subtype that shares molecular (RNA expression profile) and histological features with PAs. In spite of these similarities (and in contrast to the PAs), such tumors have a relatively poor prognosis. They are characterized by EGFR amplification and a near tetraploid cytogenetic profile. Identification of this specific subtype may have important therapeutic consequences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2011-3932

2008 Background: The biology and genetics of ependymomas remain poorly understood. As opposed to other pediatric tumors, few recurrent chromosomal abnormalities or relevant pathways have been identified. Method: In order to gain new insight into the molecular mechanisms involved in ependymoma progression, we performed BAC array-based comparative genomic hybridization (aCGH) in a series of 59 tumors at diagnosis and at relapse (42 posterior fossa and 17 supratentorial). Specific chromosomal imbalances were confirmed by FISH. Expression of candidate genes was evaluated by RT-PCR and immunohistochemistry. Results: As compared to CGH (Cancer Genet Cytogenet 2002), aCGH detected more abnormalities since 18/33 samples at diagnosis and 22/26 at recurrence showed chromosomal imbalances. Three distinct patterns were observed : no imbalance (15 at diagnosis, 4 at relapse), large and numerous imbalances (7 at diagnosis, 12 at relapse) and small and rare imbalances (11 at diagnosis, 10 at relapse). At diagnosis, absence of chromosomal imbalance was correlated with young age (p=0.034) and shorter progression-free survival (p=0.014). At relapse, patients with large and numerous imbalances had a shorter survival (p=0.026). Specific chromosomal imbalances were significantly more frequent at recurrence: 9 qter gain (54% vs 21%), 1q gain (12% vs 0%) and 6q loss (27% vs 6%). Samples were available both at diagnosis and relapse for 16 patients. Whole genome changes were towards increase of genomic abnormalities (n=10) but also simplification (n=6), the former being associated with a higher risk of death from disease (Fisher exact, p=0.03). A candidate gene strategy was focussed on the frequently gained 9qter locus. Significant overexpression compared to normal brain was identified for Tenascin-C (median 35 fold, max 220 fold, p No significant financial relationships to disclose.

Survivin, a novel member of the IAP (inhibitor of apoptosis) protein family, is associated with malignant transformation and is overexpressed in human brain cancers. On this basis, we hypothesized that the human survivin promoter may be an excellent candidate for glioma gene therapy by transcriptional targeting. To that end, we compared three recombinant adenoviral vectors (reAds), reAdGL3BCox-2, reAdGL3BMidkine, and reAdGL3BSurvivin, in which the reporter gene luciferase is driven by the Cox-2, Midkine, or surivin promoter, respectively, in glioma cell lines and primary glioma cells. The data showed the survivin promoter exhibited the highest activity among the three reAd vectors in both established and primary glioma cells. We also compared the survivin promoter activity between in D65 glioma tumor cells and in normal non-transformed astrocytes. The results indicate there is 6-12 fold higher activity in tumor cells than in the astrocytes. Also, the survivin promoter is down regulated in human brain tissue compared to the cytomegalovirus promoter. Next, the conditionally replicating adenoviral vector (CRAd), CRAd-Survivin-RGD, in which the Ad E1 gene is driven by the survivin promoter, and the Ad infectivity is enhanced by capsid modification with RGD, was seen to efficiently kill the multiple established glioma tumor cells (oncolysis). These CRAd agents driven by the survivin promoter were further shown to efficiently replicate in both the glioma cells (D65) and in U118MG xenografts both in vitro and in vivo. Also we observed the anti-tumor effects of the CRAd agents in an animal model. The tumor growth was inhibited more than 60% by i.t. injection of CRAd-Survivin agents. In conclusion, the survivin promoter is a promising tumor-specific promoter for transcriptional targeting based on its activation in glioma cells, efficient reporter gene expression, adenoviral replication in gliomas and repression in normal cells. This promoter has a |[ldquo]|tumor on|[rdquo]| and |[ldquo]|normal tissue off|[rdquo]| profile, an important parameter for cancer gene therapy. To that end, therapeutic vectors based on this approach may translate into treatment of human gliomas in the clinic.

The aim of the present study is to determine and compare initial treatment costs of microsurgery, linear accelerator (LINAC) radiosurgery, and gamma knife radiosurgery in meningioma patients. Additionally, the follow-up costs in the first year after initial treatment were assessed. Cost analyses were performed at two neurosurgical departments in The Netherlands from the healthcare providers' perspective. A total of 59 patients were included, of whom 18 underwent microsurgery, 15 underwent LINAC radiosurgery, and 26 underwent gamma knife radiosurgery. A standardized microcosting methodology was employed to ensure that the identified cost differences would reflect only actual cost differences. Initial treatment costs, using equipment costs per fraction, were a,not sign12,288 for microsurgery, a,not sign1,547 for LINAC radiosurgery, and a,not sign2,412 for gamma knife radiosurgery. Higher initial treatment costs for microsurgery were predominantly due to inpatient stay (a,not sign5,321) and indirect costs (a,not sign4,350). LINAC and gamma knife radiosurgery were equally expensive when equipment was valued per treatment (a,not sign2,198 and a,not sign2,412, respectively). Follow-up costs were slightly, but not significantly, higher for microsurgery compared with LINAC and gamma knife radiosurgery. Even though initial treatment costs were over five times higher for microsurgery compared with both radiosurgical treatments, our study gives indications that the relative cost difference may decrease when follow-up costs occurring during the first year after initial treatment are incorporated. This reinforces the need to consider follow-up costs after initial treatment when examining the relative costs of alternative treatments.

Background Frameless stereotactic neuronavigation has proven to be a feasible technology to acquire brain biopsies with good accuracy and little morbidity and mortality. New systems are constantly introduced into the neurosurgical armamentarium, although few studies have actually evaluated and compared the diagnostic yield, morbidity, and mortality of various manufacturer’s frameless neuronavigation systems. The present study reports our experience with brain biopsy procedures performed using both the Medtronic Stealth TreonTM Vertek® and BrainLAB® Varioguide frameless stereotactic brain biopsy systems. Patients and methods All 247 consecutive biopsies from January 2008 until May 2013 were evaluated retrospectively. One hundred two biopsies each were performed using the Medtronic (2008–2009) and BrainLAB® system (2011–2013), respectively. The year 2010 was considered a transition year, in which 43 biopsies were performed with either system. Patient demographics, perioperative characteristics, and histological diagnosis were reviewed, and a comparison was made between the two brain biopsy systems. Results The overall diagnostic yield was 94.6 %, i.e., 11 biopsies were nondiagnostic, 5 (4.9 %) with the Medtronic and 6 (5.9 %) with the BrainLAB® system. No differences besides the operating time (108 vs 120 min) were found between the two biopsy methods. On average, 6.6 tissue samples were taken with either technique. Peri- and postoperative complications were seen in 5.3 % and 12.9 %, consisting of three symptomatic hemorrhages (1.2 %). Biopsy-related mortality occurred in 0.8 % of all biopsies. Conclusions Regarding diagnostic yield, complication rate, and biopsy-related mortality, there seems to be no difference between the frameless biopsy technique from Medtronic and BrainLAB®. In contemporary time, the neurosurgeon has many tools to choose from, all with a relatively fast learning curve and ever improving feasibility. Thus, the issue of choice involves not the results, but the familiarity, end-user friendliness, and overall comfort when operating the system.

Malignant glioma continues to be a major target for gene therapy and virotherapy due to its aggressive growth and the current lack of effective treatment. However, these approaches have been hampered by inefficient infection of glioma cells by viral vectors, particularly vectors derived from serotype 5 adenoviruses (Ad5). This results from limited cell surface expression of the primary adenovirus receptor, coxsackie-adenovirus-receptor (CAR), on tumor cells. To circumvent this problem, Ad fiber pseudotyping, the genetic replacement of either the entire fiber or fiber knob domain with its structural counterpart from another human Ad serotype that recognizes a cellular receptor other than CAR, has been shown to enhance Ad infectivity in a variety of tumor types, including human glioma. Here, we have extended the paradigm of genetic pseudotyping to include fiber domains from non-human or "xenotype" Ads for infectivity enhancement of human glioma cell populations. In this study, we evaluated the gene transfer efficiency of a panel of Ad vectors which express one of five different "xenotype" fiber knob domains, including those derived from murine, ovine, porcine and canine species, in both human glioma cell lines as well as primary glioma tumor cells from patients. Adenovirus vectors displaying either canine Ad or porcine Ad fiber elements had the highest gene transfer to both glioma cell lines and primary tumor cells. The correlation between the viral infectivity of modified adenovirus vectors and expression of human CAR and CD46 (an adenovirus type B receptor) on the surfaces of tumor cells was also analyzed. Taken together, human adenovirus vectors modified with "xenotype" fiber elements could be excellent candidates to target human glioma.