Incidence and Mortality of Spontaneous Subarachnoid Hemorrhage in Martinique.

BACKGROUND: Incidence of spontaneous subarachnoid hemorrhages (SAH) varies wildly across the world and seems to be low in Central and South America (4.2 per 100 000 person-years; CI 95%; 3.1-5.7). The objective of our study was to describe the characteristics of SAH and to estimate its incidence and severity in Martinique, a small French island located in the Caribbean Sea. METHODS: Due to its insular nature and small captive population, Martinique is ideal for the setting up of population-based epidemiological studies with good exhaustiveness. Our study, spanning a 7 year period (2007-2013), consisted of retrospective case ascertainment with multiple overlapping methods. Crude incidence and 30 day case-fatality rates for SAH among the Martinican population were computed for the study period. Incidence and disease severity was also analyzed according to age, gender and aneurysm presence. World age-standardized incidence rates were also calculated. RESULTS: A total of 121 patients had a SAH during the study period, with a higher frequency of female cases (71.1% versus 28.9%, p<0.001). Patient mean age was 57.1 years (median = 55 [46-66]). An aneurysmal origin was found in 96 SAH cases (79.3%). Crude annual incidence was 4.36 per 100 000 person-years (CI 95% 2.30-6.42). World age-standardized incidence was 3.29 per 100 000 person-years (CI 95% 1.74-4.84). During the 30 days following SAH diagnosis, 29 patients died (case fatality rate: 24% (CI 95% 16.4-31.6)). CONCLUSIONS: The incidence of spontaneous subarachnoid hemorrhage in Martinique is much lower than in other parts of the world and similar to countries in Central and South America. These results are possibly related to environmental factors and most particularly to a low rate of smoking in the Martinican population. Thirty-day case-fatality rate is similar to what is observed in developed countries.

Proteomic analysis underlines the usefulness of both primary adherent and stem-like cell lines for studying proteins involved in human glioblastoma.

Primary cell lines derived as neurospheres, enriched in cancer stem cells, are currently the focus of interest in glioblastoma to test new drugs, because of their tumor initiating abilities and resistance to conventional therapies. However, not all glioblastoma samples are propagatable under neurosphere culture and not all neurosphere cell lines are tumorigenic. These cells therefore cannot recapitulate the heterogeneity of glioblastoma samples. We have conducted a proteomic analysis of primary glioblastoma cell lines derived either as adherent cells in the presence of serum (n=11) or as neurospheres (n=12). A total of 963 proteins were identified by nano-LC/Q-TOF MS: 342 proteins were found only in neurosphere lines and were mostly implicated in various metabolic and cellular processes, while 112 proteins were found only in adherent cells and mostly linked to cell adhesion. A protein signature of 10 proteins, 9 of them involved in a cell adhesion pathway, characterized adherent lines. Neurospheres were characterized by 73 proteins mostly linked to DNA metabolic processes associated to cell cycle and protein metabolism. In the Repository of Molecular Brain Neoplasia Data, expression of genes coding for several proteins related to adherent cells or neurospheres were of prognostic relevance for glioblastoma. BIOLOGICAL SIGNIFICANCE: Primary cell lines enriched in cancer stem cells (CSC) have become popular models for testing new drugs for glioblastoma. In this proteomic study on an important number of cell lines obtained either as adherent cells in the presence of serum (a classic way to derive cell lines) or as neurospheres (enriched in CSC), we show that each type of cell line displays different GBM-specific features, highlighting that these two culture types are complementary tools for drug screening.

Immune genes are associated with human glioblastoma pathology and patient survival.

BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Several recent transcriptomic studies in GBM have identified different signatures involving immune genes associated with GBM pathology, overall survival (OS) or response to treatment. METHODS: In order to clarify the immune signatures found in GBM, we performed a co-expression network analysis that grouped 791 immune-associated genes (IA genes) in large clusters using a combined dataset of 161 GBM specimens from published databases. We next studied IA genes associated with patient survival using 3 different statistical methods. We then developed a 6-IA gene risk predictor which stratified patients into two groups with statistically significantly different survivals. We validated this risk predictor on two other Affymetrix data series, on a local Agilent data series, and using RT-Q-PCR on a local series of GBM patients treated by standard chemo-radiation therapy. RESULTS: The co-expression network analysis of the immune genes disclosed 6 powerful modules identifying innate immune system and natural killer cells, myeloid cells and cytokine signatures. Two of these modules were significantly enriched in genes associated with OS. We also found 108 IA genes linked to the immune system significantly associated with OS in GBM patients. The 6-IA gene risk predictor successfully distinguished two groups of GBM patients with significantly different survival (OS low risk: 22.3 months versus high risk: 7.3 months; p < 0.001). Patients with significantly different OS could even be identified among those with known good prognosis (methylated MGMT promoter-bearing tumor) using Agilent (OS 25 versus 8.1 months; p < 0.01) and RT-PCR (OS 21.8 versus 13.9 months; p < 0.05) technologies. Interestingly, the 6-IA gene risk could also distinguish proneural GBM subtypes. CONCLUSIONS: This study demonstrates the immune signatures found in previous GBM genomic analyses and suggests the involvement of immune cells in GBM biology. The robust 6-IA gene risk predictor should be helpful in establishing prognosis in GBM patients, in particular in those with a proneural GBM subtype, and even in the well-known good prognosis group of patients with methylated MGMT promoter-bearing tumors.

[Retrospective analysis of 24 recurrent glioblastoma after chemoradiation and treated with nitrosoureas or irinotecan and bevacizumab]. / Analyse rétrospective de 24 glioblastomes récidivant après radiochimiothérapie concomitante et traités par nitrosourées ou par l'association irinotécan et bévacizumab.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

Spinal epidural hematoma: not always an obvious diagnosis.

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency. SEH is characterized by an archetypal clinical presentation including abrupt spinal pain followed more or less rapidly by various degrees of neurological deficit. The diagnosis of SEH, often based on a clinical presumption, represents a clinical challenge. Several reports have outlined missed or delayed diagnosis due to unusual and confusing onsets or unawareness of this diagnosis by physicians. Therefore, physicians should keep in mind the possibility of SEH in their differential diagnosis when confronted with patients complaining of sudden onset of acute spinal pain with or without neurological sign, because the impact of a delayed diagnosis can be disabling catastrophic neurological sequelae. We suggest that SEH is a dynamic disease, which occurs in patients with an abnormal vasculature structural degenerative change. The bleeding is probably of multifactorial origin incriminating veins as well as arteries. Therefore, we proposed a classification of SEH, according to the most probable etiology whatever the associated factors, in six groups: spontaneous, secondary, iatrogenic, traumatic, recurrent, and idiopathic SEH.

Human glioblastoma stem-like cells are more sensitive to allogeneic NK and T cell-mediated killing compared with serum-cultured glioblastoma cells.

Glioblastoma multiforme (GBM) is the most dramatic primary brain cancer with a very poor prognosis because of inevitable disease recurrence. The median overall survival is less than 1 year after diagnosis. Cancer stem cells have recently been disclosed in GBM. GBM stem-like cells (GSCs) exhibit resistance to radio/chemotherapeutic treatments and are therefore considered to play an important role in disease recurrence. GSCs are thus appealing targets for new treatments for GBM patients. In this study, we show that GBM cells with stem cell characteristics are resistant to lysis mediated by resting natural killer (NK) cells because of the expression of MHC class I molecules. However, GSCs are killed by lectin-activated NK cells. Furthermore, in experiments using the therapeutic antibody CetuximAb, we show that GSCs are sensitive to antibody-mediated cytotoxicity. We confirm the sensitivity of GSC to cytotoxicity carried out by IL2-activated NK cells and tumor-specific T cells. More importantly, we show that GSCs are more sensitive to NK and T cell-mediated lysis relatively to their corresponding serum-cultured GBM cells obtained from the same initial tumor specimen. Altogether, these results demonstrate the sensitivity of GSC to immune cell cytotoxicity and, therefore, strongly suggest that GSCs are suitable target cells for immunotherapy of GBM patients.

Surgical treatment of rare cauda equina tumours.

BACKGROUND: Cauda equina tumours (CET) are rare and usually benign. Treatment of schwannomas and benign ependymomas, which are the most frequent histopathological types of CET, is now well established. However, management of other presumed histopathological types of CET is still a matter of debate. The aim of this study was to assess the incidence and the surgical treatment of rare CET. METHOD: A retrospective study was carried out on 176 adult patients surgically treated for CET in our two departments from 1994 to 2010. We reviewed pre- and postoperative symptoms, magnetic resonance imaging aspects, surgical findings, outcome including operative neurological morbidity, local recurrence rate and operative mortality, and incidence of rare CET. FINDINGS: Seventeen percent (30 patients) of CETs operated on were neither schwannomas nor benign ependymomas. Half of these cases were benign tumours, with paragangliomas being the most common. Two patients were in poorer clinical condition after surgery, one patient experienced a local recurrence, and one died following surgery, from the progress of his disease (Von Hippel-Lindau disease). The other half were malignant tumours, with metastases being the most common. One third of the patients were worsened by surgery, and the mortality rate was 1/3 at 8 months (1-27 months). CONCLUSIONS: Roughly one in six CET were neither schwannomas nor benign ependymomas. This study demonstrated the efficiency of surgery for rare benign CET with a low local recurrence rate. Surgical treatment of rare malignant CET led to a high rate of increased postoperative neurological deficit in patients with a reduced life expectancy.

[MGMT analysis in gliomas]. / Intérêt de la MGMT dans les gliomes.

MGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose.

Intradural extramedullary spinal inflammatory myofibroblastic tumor: case report and literature review.

The authors present the case of an inflammatory myofibroblastic tumor that involves the cervical spinal cord meninges, presenting in a manner mimicking en plaque meningioma, which has never been previously reported. During the first surgical procedure, which did not involve exploration of the intradural space, inflammatory epidural tissue was found. We performed a second operation to remove the tumor that was finally intradural, dural-based and very tough. Imaging studies, surgical findings, and histopathological examinations were used to support the diagnosis. Intradural extramedullary inflammatory myofibroblastic tumor is a rare entity that has only been described nine times in the literature. Surgery remains the treatment of choice. Although histologically benign, spinal inflammatory myofibroblastic tumor can be aggressive and requires a large resection and long-term follow-up of the entire central nervous system with magnetic resonance imaging.

Differential analysis of glioblastoma multiforme proteome by a 2D-DIGE approach.

BACKGROUND: Genomics, transcriptomics and proteomics of glioblastoma multiforme (GBM) have recently emerged as possible tools to discover therapeutic targets and biomarkers for new therapies including immunotherapy. It is well known that macroscopically complete surgical excision, radiotherapy and chemotherapy have therapeutic limitations to improve survival in these patients. In this study, we used a differential proteomic-based technique (2D-Difference Gel Electrophoresis) coupled with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to identify proteins that may serve as brain tumor antigens in new therapeutic assays. Five samples of patients presenting a GBM and five samples of microscopically normal brain tissues derived from brain epileptic surgery specimen were labeled and run in 2D-PAGE (Two-Dimensional Polyacrylamide Gel Electrophoresis) with an internal pool sample on each gel. Five gels were matched and compared with DIA (Difference In-gel Analysis) software. Differential spots were picked, in-gel digested and peptide mass fingerprints were obtained. RESULTS: From 51 protein-spots significantly up-regulated in GBM samples, mass spectrometry (MS) identified twenty-two proteins. The differential expression of a selected protein set was first validated by western-blotting, then tested on large cohorts of GBM specimens and non-tumor tissues, using immunohistochemistry and real-time RT-PCR. CONCLUSIONS: Our results confirmed the importance of previously described proteins in glioma pathology and their potential usefulness as biological markers but also revealed some new interesting targets for future therapies.

A 4-gene signature associated with clinical outcome in high-grade gliomas.

PURPOSE: Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors. EXPERIMENTAL DESIGN: We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status. RESULTS: This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P < 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26-0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P < 0.001). CONCLUSION: The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas.

DNA methylation in glioblastoma: impact on gene expression and clinical outcome.

BACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.

Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions.

Immunotherapy is a promising new treatment for patients suffering from glioma, in particular glioblastoma multiforme (GBM). However, tumour cells use different mechanisms to escape the immune responses induced by the treatment. As many other tumours, gliomas express or secrete several immunosuppressive molecules that regulate immune cell functions. In this study, we first analysed FasL, HLA-G, IDO, PDL-1 and TGF-beta1, -beta2 and -beta3 expression by transcriptomic microarray analysis in a series of 20 GBM samples and found respectively 15%, 60%, 85%, 30%, 70%, 80% and 35% of positive specimens. mRNA expression was then confirmed in 10 GBM primary cell lines and 2 immortalised cell lines U251 and U87MG. Furthermore, the protein expression of PDL-1, IDO activity and TGF-beta2 secretion were found on most of the untreated GBM primary cell lines. Remarkably, treatment with IFN-gamma increased the PDL-1 cell surface expression and the IDO activity, but reduced the TGF-beta2 secretion of GBM cell lines. We finally analysed the immunosuppressive effects of IDO, PDL-1 and TGF-beta1-3 by measuring IFN-gamma production and cell cytotoxicity activity of tumour antigen-specific T cells. PDL-1 partially affected the IFN-gamma production of antigen-specific T cells in response to GBM primary cell lines, and IDO inhibited lymphocyte proliferation induced by lectins. None of these molecules directly affected the T cell cytotoxicity function. Due to the functional role of PDL-1 and IDO molecules expressed by GBM cells, one could expect that blocking these molecules in the immunotherapy strategies would reinforce the efficiency of these treatments of GBM patients.

Olfactory ensheathing cell tumour: case report and literature review.

Olfactory ensheathing cell tumour (OECT) and olfactory groove schwannoma (OGS) are among the rarest intracranial tumour types that develop within anterior cranial fossa. These tumours share several similarities, including radiological and histological aspects, and only immunohistochemical staining can differentiate between them. We report a case of OECT occurring in a 28-year-old woman with a history of complex partial seizures, emotional lability and anosmia. Radiological features showed a predominantly left subfrontal extra-axial mass. Total excision of the tumour, connected to the cribriform plate and contiguous to the left olfactory bulb, was performed. Histological examination suggested an atypical schwannoma; however, immunohistochemical staining was strongly positive for S-100 protein but negative for both epithelial membrane antigen (EMA) and CD 57 (Leu-7). The final diagnosis was olfactory ensheathing cell tumour. We describe the third case of OECT and emphasize the important role of immunohistochemical staining in diagnosis: awareness of this entity, and use of immunohistochemistry help to distinguish it from OGS.

Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods.

This multicenter study assesses the value of O(6)-methylguanine-DNA methyltransferase (MGMT) status for predicting overall survival in glioblastoma patients. Five methods are used, to identify the approach with the best prognostic value. Eighty-one tumors were obtained from patients with glioblastomas treated by surgery and radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ. MGMT promoter methylation was assessed by qualitative methyl-specific polymerase chain reaction (MSP), semiquantitative methyl-specific polymerase chain reaction (SQ-MSP), and pyrosequencing, while MGMT expression was measured at the RNA level by quantitative real-time PCR (Q-RT-PCR) and at the protein level by immunohistochemistry (IHC). MGMT promoter methylation as evaluated by MSP, SQ-MSP, and pyrosequencing was significantly correlated with overall survival. The best predictive value was obtained by pyrosequencing of one specific CpG position. Overall survival was 14 and 25 months for patients with percentages of methylation below and above the median, respectively. In contrast, MGMT status determined by Q-RT-PCR and IHC showed little or no correlation with overall survival, respectively. These results confirm the prognostic value of MGMT promoter methylation in glioblastoma patients initially treated with TMZ. SQ-MSP allowed better discrimination than classical MSP, and pyrosequencing represented a good option.

Hearing loss attributable to a cerebellopontine-angle arachnoid cyst in a child.

Although hearing loss in newborns and infants is predominantly due to malformations and infections, there are other situations which may compromise hearing quality in later stages, including posterior-fossa arachnoid cysts (ACs). We report the case of an 8-year-old girl who presented with hearing loss linked to a pontocerebellar-angle AC which had been diagnosed and treated when she was 14 months old. The pathophysiology of this late AC complication is discussed. This case reminds us that a close follow-up with audiologic monitoring and/or brain stem auditory evoked response is necessary in children with posterior-fossa AC because modern neuroradiological imaging methods do not inform about cerebral and nerve functions, although they provide excellent morphological details of ACs and have improved the ease and accuracy of their early diagnosis. Therefore, surgery should be performed before complete hearing loss occurs; however, in hearing-impaired patients, it remains unclear which surgical treatment is most appropriate.

Survival and prognostic factors in a series of adults with medulloblastomas.

OBJECT: In this article, the authors report their experience in the management of adult patients with medulloblastoma at their institution to identify prognostic factors important for survival and disease control. METHODS: Between 1977 and 2005, 27 patients who were >or=16 years old and had medulloblastoma were treated consecutively. There were 16 women and 11 men with a median age of 21 years (range 16-54 years). Gross-total resection was performed in 21 patients, subtotal (>or=90%) in 2, incomplete in 1, and biopsy in 3 patients. Six patients had the desmoplastic variant, and 21 patients presented with classic medulloblastoma. Staging according to the Chang classification showed 4 patients with tumors invading the brainstem (2 with Stage T3b and 2 with Stage T4), 3 patients with metastases (2 with Stage M2 and 1 with Stage M3), and 1 patient in whom the stage was unknown (Stage MX) who died 10 days postoperatively. Twenty patients were assigned to the standard-risk group and 7 to the high-risk group. All patients except the one whose status was classified as Stage MX underwent craniospinal radiotherapy at our institution. Seven patients received chemotherapy before radiotherapy. RESULTS: The 5- and 10-year overall survival rates for the present study were 81 and 62%, respectively. The median overall survival time was 17.7 years. The 5- and 10-year event-free survival rates were 72 and 57%, respectively. The median event-free survival time was 17.9 years. Univariate analysis showed that survival was significantly correlated with sex (women had a better prognosis than men) and M stage (patients without metastases had a better outcome). Patient age, duration of symptoms, Karnofsky Performance Scale score at presentation, hydrocephalus, tumor location, brainstem invasion, extent of resection, histological subtype, preradiotherapy chemotherapy, risk group, and period of presentation were not significant variables. Multivariate analysis identified sex and M stage as well as the period of presentation as independent prognostic factors for overall and event-free survival times. Eleven patients suffered tumor recurrence within a median time of 4.2 years. The posterior fossa was not the most common site of recurrence, and delayed recurrence was not rare. All patients in whom the tumor recurred have died despite aggressive treatments. The median survival time after diagnosis of recurrence was 2.5 years. Questionnaires on quality of life and cognition showed high scores in favor of limited negative effects in the perception of mental and physical health after treatment. The authors observed 1 supposed second malignancy (thyroid carcinoma) and no evidence of pituitary dysfunction. CONCLUSIONS: Long-term survival is possible in adults treated for medulloblastoma. Although rare, metastasis seeding at presentation is a poor prognostic factor. The possibility of delayed recurrence necessitates close follow-up of all patients. Tumor recurrences should be treated with aggressive therapies as some patients may have sustained response. Adjuvant chemotherapy should be given to high-risk patients, but its role in reducing recurrences, particularly distant ones, remains unclear in the standard-risk group.

Topotecan in combination with radiotherapy in unresectable glioblastoma: a phase 2 study.

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression.

Glioblastoma multiforme shows multiple chromosomal aberrations, the impact of which on gene expression remains unclear. To investigate this relationship and to identify putative initiating genomic events, we integrated a paired copy number and gene expression survey in glioblastoma using whole human genome arrays. Loci of recurrent copy number alterations were combined with gene expression profiles obtained on the same tumor samples. We identified a set of 406 "cis-acting DNA targeted genes" corresponding to genomic aberrations with direct copy-number-driving changes in gene expression, defined as genes with either significantly concordant or correlated changes in DNA copy number and expression. Functional annotation revealed that these genes participate in key processes of cancer cell biology, providing insights into the genetic mechanisms driving glioblastoma. The robustness of the gene selection was validated on an external microarray data set including 81 glioblastomas and 23 non-neoplastic brain samples. The integration of array CGH and gene expression data highlights a robust cis-acting DNA targeted genes signature that may be critical for glioblastoma progression, with two tumor suppressor genes PCDH9 and STARD13 that could be involved in tumor invasiveness and resistance to etoposide.

Diagnosis of childhood astrocytomas.

BACKGROUND: Astrocytomas are the most common brain tumours, accounting for 28 - 50% of all primary CNS tumours. Diagnosis of CNS tumours remains difficult because the varied and nonspecific presentations of CNS tumours in childhood. Objectives/method: The clinical presentations of CNS astrocytomas vary with their sites of location; therefore, a period of uncertainty often precedes diagnosis, and approximately 42% of patients with an intracranial process make several visits to various physicians between the onset and diagnosis. However, on clinical suspicion of a brain tumour, a wide range of neuroimaging techniques may be used to assess the diagnosis of paediatric brain lesions. In this review the authors, for ease of presentation, describe the clinical presentations of supratentorial, infratentorial and spinal cord astrocytomas as well as their radiological and pathological features, and discuss their differential diagnoses. RESULTS/CONCLUSIONS: Understanding and mastering the numerous imaging features of several subtypes of primary brain tumours affecting children, in addition to radiological features of non-tumoural disorders, remains a significant challenge and demands increased awareness of the paediatric brain diseases.