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Sandra-Nadia Ngwabyt Bikeye,
Carole Colin,
Yannick Marie,
Raphaël Vampouille,
Philippe Ravassard, Audrey Rousseau,
Blandine Boisselier,
Ahmed Idbaih,
Charles Félix Calvo,
Pascal Leuraud,
Myriam Lassalle,
Soufiane El Hallani,
Jean-Yves Delattre,
Marc Sanson
Cancer Cell International 01/2011; 11:10. · 1.97 Impact Factor
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Soufiane El Hallani,
Blandine Boisselier,
Florent Peglion, Audrey Rousseau,
Carole Colin,
Ahmed Idbaih,
Yannick Marie,
Karima Mokhtari,
Jean-Léon Thomas,
Anne Eichmann,
Jean-Yves Delattre,
Andrew J Maniotis,
Marc Sanson
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ABSTRACT: Glioblastoma is one of the most angiogenic human tumours and endothelial proliferation is a hallmark of the disease. A better understanding of glioblastoma vasculature is needed to optimize anti-angiogenic therapy that has shown a high but transient efficacy. We analysed human glioblastoma tissues and found non-endothelial cell-lined blood vessels that were formed by tumour cells (vasculogenic mimicry of the tubular type). We hypothesized that CD133+ glioblastoma cells presenting stem-cell properties may express pro-vascular molecules allowing them to form blood vessels de novo. We demonstrated in vitro that glioblastoma stem-like cells were capable of vasculogenesis and endothelium-associated genes expression. Moreover, a fraction of these glioblastoma stem-like cells could transdifferentiate into vascular smooth muscle-like cells. We describe here a new mechanism of alternative glioblastoma vascularization and open a new perspective for the antivascular treatment strategy.
Brain 04/2010; 133(Pt 4):973-82. · 9.46 Impact Factor
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ABSTRACT: To study the neuroimaging features of intracranial solitary fibrous tumors (ISFTs).
Retrospective study of neuroimaging features of 9 consecutive histopathologically proven ISFT cases. Location, size, shape, density, signal intensity and gadolinium uptake were studied at CT and MRI. Data collected from diffusion-weighted imaging (DWI) (3 patients), perfusion imaging and MR spectroscopy (2 patients), and DSA (4 patients) were also analyzed.
The tumors most frequently arose from the intracranial meninges (7/9), while the other lesions were intraventricular. Tumor size ranged from 2.5 to 10 cm (mean=6.6 cm). They presented multilobular shape in 6/9 patients. Most ISFTs were heterogeneous (7/9) with areas of low T2 signal intensity that strongly enhanced after gadolinium administration (6/8). Erosion of the skull was present in about half of the cases (4/9). Components with decreased apparent diffusion coefficient were seen in 2/3 ISFTs on DWI. Spectroscopy revealed elevated peaks of choline and myo-inositol. MR perfusion showed features of hyperperfusion.
ISFT should be considered in cases of extra-axial, supratentorial, heterogeneous, hypervascular tumor. Areas of low T2 signal intensity that strongly enhance after gadolinium injection are suggestive of this diagnosis. Restricted diffusion and elevated peak of myo-inositol may be additional valuable features.
European journal of radiology 03/2010; 80(2):387-94. · 2.65 Impact Factor
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Sandra-Nadia Ngwabyt Bikeye,
Carole Colin,
Yannick Marie,
Raphaël Vampouille,
Philippe Ravassard, Audrey Rousseau,
Blandine Boisselier,
Ahmed Idbaih,
Charles Félix Calvo,
Pascal Leuraud,
Myriam Lassalle,
Soufiane El Hallani,
Jean-Yves Delattre,
Marc Sanson
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ABSTRACT: ASPM (Abnormal Spindle-like Microcephaly associated) over-expression was recently implicated in the development of malignant gliomas.
To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. Aspm expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres in vitro and in mouse xenografts in vivo. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.
These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.
Cancer Cell International 01/2010; 10:1. · 1.97 Impact Factor
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Caroline Houillier,
Karima Mokhtari,
Catherine Carpentier,
Emmanuelle Crinière,
Yannick Marie, Audrey Rousseau,
Gentian Kaloshi,
Caroline Dehais,
Julien Laffaire,
Florence Laigle-Donadey,
Khê Hoang-Xuan,
Marc Sanson,
Jean-Yves Delattre
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ABSTRACT: The loss of chromosomes 1p-19q is the only prognostic molecular alteration identified in low-grade gliomas (LGGs) to date. Search for loss of heterozygosity (LOH) on chromosomes 1p, 9p, 10q, and 19q was performed in a series of 231 LGGs. Loss of chromosomes 1p-19q was strongly correlated with prolonged progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. LOH on 9p and 10q were associated with shortened PFS (P = .01 and .03, respectively) on univariate analysis. On multivariate analysis, LOH on 9p remained significant for PFS (P = .05), whereas LOH on 10q had a significant effect on OS (P = .02). Search for LOH 9p and 10q appears to be a useful complement to analysis of chromosomes 1p-19q in LGGs.
Neuro-Oncology 01/2010; 12(1):2-6. · 5.72 Impact Factor
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ABSTRACT: Ependymomas are glial neoplasms originating from the wall of the ventricles or from the spinal canal. The significance of histopathological features in accurately predicting biological behavior is still debated. Moreover, key molecular events in the pathogenesis of ependymoma are yet to be defined. The main objective of the present study was to identify specific patterns of chromosomal aberrations that correlate with tumor location, histological subtype and grade. Forty-five ependymoma samples were analyzed by 1-megabase resolution array comparative genomic hybridization (CGH). Association between clinical or histopathological parameters and the genomic alterations identified was evaluated. The most frequently detected chromosome (chr) abnormalities were gain of chr 7, 9, 12 and 15 and loss of chr 22. Co-occurrence of those five alterations characterized spinal ependymomas (P = 0.01). Myxopapillary ependymomas displayed a specific genomic profile defined by concurrent gain of chr 5, 7, 9, 16 and 18 (P = 0.0007). Overall, the number of chromosomal abnormalities detected was inversely correlated with the malignancy grade. Gain of chr 1q correlated with intracranial high-grade tumors (P = 0.002). Loss of chr 6q was mainly observed in infratentorial (P = 0.02) and World Health Organization (WHO) grade III (P = 0.04) lesions. Chr 10q loss was associated with high-grade ependymomas (P = 0.01). The +7/+9/+12/+15/-22 genomic profile is significantly associated with WHO grade II spinal ependymomas, whereas the +5/+7/+9/+16/+18 genomic pattern is specific of myxopapillary ependymomas. Identification of specific genomic imbalances at a given tumor location suggests that ependymomas from different central nervous system (CNS) regions represent genetically distinct diseases. Detecting genomic alterations associated with aggressive biological behavior may help stratify patients in high- and low-risk disease.
Journal of Neuro-Oncology 10/2009; 97(3):353-64. · 3.21 Impact Factor
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ABSTRACT: Adult leukodystrophies with neuroaxonal spheroids (LNS) constitute a heterogeneous group of genetic diseases. Herein, we report on two unrelated patients with LNS characterized by rapid onset, predominant involvement of the frontal white matter, and areas of decreased apparent diffusion coefficient on diffusion-weighted imaging. We found similar cases in the literature and propose that they represent a distinct entity within the group of LNS. Further studies will be required to identify its molecular basis.
Journal of Neurology 06/2009; 256(10):1649-54. · 3.47 Impact Factor
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ABSTRACT: Primary central nervous system lymphoma (PCNSL) constitutes a rare group of extranodal non-Hodgkin's lymphomas (NHLs), primarily of B cell origin, whose incidence has markedly increased in the last three decades. Immunodeficiency is the main risk factor, but the large majority of patients are immunocompetent. Recent evidence suggests a specific tumorigenesis that may explain their particular clinical behavior compared with systemic NHL. The addition of i.v. high-dose methotrexate (MTX) chemotherapy to whole-brain radiotherapy (WBRT) has considerably improved the prognosis, leading to a threefold longer median survival time compared with WBRT alone and represents the current standard of care. However, this combined treatment exposes the patient, especially the elderly, to a high risk for delayed neurotoxicity. In the older population (>60 years), there is growing evidence that MTX-based chemotherapy alone as initial treatment is the best approach to achieve effective tumor control without compromising patient quality of life. In the younger population, the risk for neurotoxicity is much lower, and this strategy is controversial because it may be associated with higher relapse rates. Future efforts should focus on the development of new polychemotherapy regimens allowing the reduction or deferral of WBRT in order to minimize the risk for delayed neurotoxicity. In this setting, intensive chemotherapy with autologous blood stem cell transplantation was recently demonstrated to be feasible and efficient as salvage therapy and is currently being evaluated as part of primary treatment. This review highlights the recent advances in the pathogenesis and treatment of PCNSL in the immunocompetent population.
The Oncologist 05/2009; 14(5):526-39. · 3.91 Impact Factor
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ABSTRACT: As progress is being made in understanding the biology of cancer, revision to any current tumor classification is needed every 5 years or so. Technology of genomic analysis, among others, is evolving rapidly and new information has to be integrated to update any such classification. The fourth edition of the WHO classification of tumors of the central nervous system was published in 2007 and aims at establishing a nomenclature that is used and accepted worldwide, and at incorporating the latest advances in the field.
The 2007 WHO classification is focused on neoplasms of the central nervous system. Several newly recognized entities, which have become established since the previous, 2000 classification have been included. A wealth of genomic data has been added and distinct genetic alterations represent criteria to define tumor subsets, such 1p/19q codeletion in oligodendrogliomas. Yet, morphology is still the gold standard of the WHO classification.
Other novel clinically relevant and carefully defined entities are expected to join the growing list of brain tumors in the near future. New tools in cytogenetics and molecular genetics are rapidly changing the field of central nervous system neoplasms. Integrating genetic data in clinical routine practice is essential. A true histogenetic nomenclature may be the next step for the WHO classification of central nervous system neoplasms.
Current Opinion in Neurology 01/2009; 21(6):720-7. · 4.94 Impact Factor
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Mathieu Rodero,
Yannick Marie,
Mathieu Coudert,
Emmeline Blondet,
Karima Mokhtari, Audrey Rousseau,
William Raoul,
Catherine Carpentier,
Florian Sennlaub,
Philippe Deterre,
Jean-Yves Delattre,
Patrice Debré,
Marc Sanson,
Christophe Combadière
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ABSTRACT: Few reliable prognostic molecular markers have been characterized for glioblastoma multiforme (GBM), considered the deadliest of human cancers. We hypothesized that genetic polymorphisms in chemokines and their receptors, which together control microglial cell mobilization, may influence survival.
Distributions of one polymorphism of the chemokine CCL2 (-2518A<G) and two polymorphisms of the chemokine receptor CX3CR1 (termed V249I and T280M) were determined in a prospective series of 230 patients with GBM and correlated with overall survival. The replication study used data from a retrospective series of 106 additional patients with GBM. The extent of microglial cell infiltration was assessed by immunochemistry in 102 tumor specimens.
Survival analysis showed that the common CX3CR1-I249 allele was an independent favorable prognostic factor in both groups, prospective and retrospective, with hazard ratios of 0.619 (95% CI, 0.451 to 0.850; P = .0031) and 0.354 (95% CI, 0.217 to 0.580; P < .0001), respectively. This beneficial effect was observed only in patients who underwent surgery. Patients with only this CX3CR1-I249 allele had a substantially longer mean survival (23.5 v 14.1 months; P < .0001). The CCL2-2518G allele was not associated with patient survival. Immunohistochemical analysis of primary tumor biopsies showed that the common CX3CR1 variant allele was associated with reduced microglial cell infiltration.
The common CX3CR1 allelic variant was associated with increased GBM survival and with reduced tumor infiltration by microglia. The CX3CR1 polymorphism does not seem to be a risk factor for GBM but may prove useful in predicting survival.
Journal of Clinical Oncology 11/2008; 26(36):5957-64. · 18.37 Impact Factor
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Ahmed Idbaih,
Rosana Carvalho Silva,
Emmanuelle Crinière,
Yannick Marie,
Catherine Carpentier,
Blandine Boisselier,
Sophie Taillibert, Audrey Rousseau,
Karima Mokhtari,
François Ducray,
Joelle Thillet,
Marc Sanson,
Khê Hoang-Xuan,
Jean-Yves Delattre
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ABSTRACT: Using a one-megabase BAC-based array comparative genomic hybridization technique (aCGH), we have investigated a series of 16 low-grade gliomas (LGGs) and their subsequent progression to higher-grade malignancies. The most frequent chromosome imbalances in primary tumors were gains of chromosomes 7q, 8q, and 22q, and losses of chromosomes 1p, 13q, and 19q. In tumor progression, gains of chromosomes 11q, 7q, 20q, and 21q, and losses of chromosomes 9p, including CDKN2A locus, 19q, 14q, 1p, and 6q were the most frequent genomic disequilibria. Progressive tumors were more imbalanced than primary tumors in terms of altered chromosomal arms (3.8 vs. 6.6 in mean abnormal chromosomal arm) and altered BACs (17 vs. 21%). Interestingly, putative novel candidate genes associated with glioma progression were identified, in particular DOCK8, PTPRD, CER1, TPHO, DHFR, MSH3, ETS1, ACACA, and CSE1L.
Journal of Neuro-Oncology 08/2008; 90(2):133-40. · 3.21 Impact Factor
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Ahmed Idbaih,
Emmanuelle Crinière,
Yannick Marie, Audrey Rousseau,
Karima Mokhtari,
Michèle Kujas,
Younas El Houfi,
Catherine Carpentier,
Sophie Paris,
Blandine Boisselier,
Florence Laigle-Donadey,
Joëlle Thillet,
Marc Sanson,
Khê Hoang-Xuan,
Jean-Yves Delattre
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ABSTRACT: Various gene amplifications have been observed in gliomas. Prognostic-genomic correlations testing simultaneously all these amplified genes have never been conducted in anaplastic oligodendrogliomas. A set of 38 genes that have been reported to be amplified in gliomas and investigated as the main targets of amplicons were studied in a series of 52 anaplastic oligodendrogliomas using bacterial artificial chromosome-array based comparative genomic hybridization and quantitative polymerase chain reaction. Among the 38 target genes, 15 were found to be amplified in at least one tumor. Overall, 27% of anaplastic oligodendrogliomas exhibited at least one gene amplification. The most frequently amplified genes were epidermal growth factor receptor (EGFR) and cyclin-dependent kinase 4/sarcoma amplified sequence (CDK4/SAS) in 17% and 8% of anaplastic oligodendrogliomas, respectively. Gene amplification and codeletion of chromosome arms 1p/19q were perfectly exclusive (p = 0.005). In uni- and multivariate analyses, gene amplification was a negative prognostic factor for progression-free survival and overall survival in anaplastic oligodendrogliomas, providing complementary information to the classic prognostic factors identified in anaplastic oligodendrogliomas (extent of surgery, KPS, and chromosome arms 1p/19q status).
Neuro-Oncology 07/2008; 10(4):540-7. · 5.72 Impact Factor
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ABSTRACT: There is no standard of care for elderly patients with glioblastoma (GBM) and poor performance status. A 79-year-old woman with GBM, aphasia, and hemiplegia achieved a complete response after only one cycle of temozolomide (TMZ) (150mg/m2/day over 5 days). Genomic profiling of the tumor demonstrated loss of chromosome 10 and MDM2 amplification, which are predictive of poor outcome. The MGMT promoter was methylated, and it is likely that this at least partially explains the exquisite chemosensitivity in our patient. This unusual case report suggests that TMZ warrants further investigation in elderly patients with poor performance status.
Journal of Neuro-Oncology 04/2008; 88(2):185-8. · 3.21 Impact Factor
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Ahmed Idbaih,
Blandine Boisselier,
Yannick Marie,
Marc Sanson,
Soufiane El Hallani,
Emmanuelle Crinière,
Maryam Fourtassi,
Sophie Paris,
Catherine Carpentier, Audrey Rousseau,
Karima Mokhtari,
Christophe Combadière,
Florence Laigle-Donadey,
Khê Hoang-Xuan,
Jean-Yves Delattre
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ABSTRACT: The transcription factor p53 and its negative regulator MDM2 are pivotal in normal and cancer cells biology. Recently, a functional single-nucleotide polymorphism in the promoter region of MDM2 (MDM2 SNP309), alone or in combination with TP53 R72P, was shown to be associated with the risk, prognosis, age at onset, molecular markers, and response to chemotherapy of various cancers. This SNP has never been specifically investigated in a large series of oligodendroglial tumors. In a comparison with 232 healthy controls, we retrospectively analyzed blood samples of 293 oligodendroglial tumor patients for MDM2 SNP309. In addition, the TP53 R72P polymorphism and chromosome 1p/19q status, a major biomarker in oligodendroglial tumors, were investigated. The frequencies of T/T, T/G, and G/G genotypes in patients and controls did not suggest an increased risk of oligodendroglial tumor formation correlating with MDM2 SNP309. A borderline association was found between MDM2 SNP309 and overall survival (p=0.05), but in multivariate analysis, MDM2 SNP309 did not provide prognostic information complementary to age, tumor phenotype, grade, and 1p/19q status in oligodendroglial tumors. Finally, MDM2 SNP309, alone or in combination with TP53 R72P, was not associated with oligodendroglial tumors.
Brain Research 04/2008; 1198:16-20. · 2.73 Impact Factor
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ABSTRACT: Gangliogliomas are unusual central nervous system (CNS) neoplasms occurring mainly in children and young adults and inducing chronic pharmacoresistant epilepsy. These are usually well differentiated neuroepithelial tumors composed of neurons in association with neoplastic glial cells. Gangliogliomas present with favorable outcome. However, some may recur and/or progress to anaplasia and be associated with a dismal prognosis. Since histopathological features do not consistently correlate with clinical outcome, reliable prognostic factors have yet to be defined in gangliogliomas. Survivin is an anti-apoptotic protein whose expression has been found to be of prognostic significance in many human cancers, including gliomas. The objective of this study was to assess survivin expression using immunohistochemistry in 15 gangliogliomas. Ten lesions were low-grade neoplasms whereas 5 were high-grade tumors. Survivin expression appeared restricted to the neoplastic glial component and was detected in 6/15 gangliogliomas. Two additional tumors expressed survivin upon relapse. Half survivin expressing lesions displayed less than 1% immunoreactive cells. Survivin expression in more than 5% neoplastic glial cells was detected only in malignant and/or recurrent gangliogliomas. Extended lifespan in survivin expressing cells might enhance aggressive behavior in these tumors through accumulation of mutations, thereby allowing progression to malignant phenotypes. Survivin expression may carry a negative prognostic value in gangliogliomas.
Journal of Neuro-Oncology 05/2006; 77(2):153-9. · 3.21 Impact Factor
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ABSTRACT: Primary intracranial melanocytic tumors are rare lesions, sellar ones being even more exceptional. So far, six melanomas and two melanocytomas have been described in an intrasellar and/or suprasellar location.
We report on the case of a 25-year-old Caucasian woman presenting with a 4-year history of amenorrhea and an intrasellar mass with suprasellar extension suggestive of a pituitary macroadenoma.
A gross subtotal resection of a hemorrhagic tumor was performed. Histological examination revealed melanin-laden pleomorphic tumor cells that tested positive for HMB-45 and S-100 and negative for cytokeratins, thus demonstrating that the tumor was a melanocytic neoplasm. An extensive workup failed to find evidence of any other primary site. The patient received no further treatment and is alive and well after 24 months of follow-up.
Primary sellar melanocytic neoplasms are extremely rare lesions and present with few differential diagnoses. Deciding whether the tumor is best classified as a melanocytoma or a melanoma may prove difficult. Wide histological variations in both melanocytomas and melanomas render careful consideration of the clinical, radiological, and gross features essential in distinguishing one from the other.
Neurosurgery 09/2005; 57(2):E369; discussion E369. · 2.79 Impact Factor
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ABSTRACT: We conducted the current review of the paraneoplastic neurologic syndromes (PNSs) associated with gynecologic and breast carcinomas to describe their clinical and immunologic characteristics and their relative frequency. We retrospectively reviewed 92 patients whose serum was sent to our laboratories to detect onconeural antibodies and who were diagnosed as having PNSs associated with breast or gynecologic tumors. PNSs were defined as "definitive" and "possible" (atypical PNS, no onconeural antibodies, and no improvement after tumor treatment). Forty-nine patients had breast and 43 had gynecologic cancer. Sixty-three patients had onconeural antibodies (50 Yo-ab, 5 Hu-ab, 5 Ri-ab, and 3 amphiphysin-ab). Cerebellar ataxia represented 57 (62%) of all PNSs and was associated with anti-Yo in 88%. All Yo-abnegative patients had breast cancer; 4 of them had a mild cerebellar syndrome that improved after tumor treatment. Sensorypredominant neuropathies were present in 17 (18%) patients. Seven of them had Hu-ab (5) or amphiphysin-ab (2). Other PNSs were opsoclonus-myoclonus syndrome (4 cases, Ri-ab in 2), sensorimotor neuropathy (4 cases), paraneoplastic encephalomyelitis (4 cases, Ri-ab in 3), paraneoplastic retinopathy (2 cases), amyotrophic lateral sclerosis (2 cases), stiff-person syndrome (1 with amphiphysin-ab), and limbic encephalitis (1 case). All patients with gynecologic cancer presented definitive PNS, and onconeural antibodies were diagnosed in 93% of them. In contrast, 20% of PNSs associated with breast cancer were defined as possible and the incidence of onconeural antibodies was 51%, excluding the 2 patients with paraneoplastic retinopathy in whom antiretinal antibodies were not analyzed. In patients with possible PNS, a coincidental association between the tumor and the neurologic disorder cannot be excluded.
Medicine 06/2003; 82(3):216-23. · 4.35 Impact Factor
