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Xiao-Wei Wang,
Blandine Boisselier,
Marta Rossetto,
Yannick Marie,
Ahmed Idbaih, Karima Mokhtari,
Konstantinos Gousias,
Khê Hoang-Xuan,
Jean-Yves Delattre,
Matthias Simon,
Marianne Labussière,
Marc Sanson
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ABSTRACT: BACKGROUND.: The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single-nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas. METHODS.: The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma. RESULTS.: The minor allele codon 105 glycine (GGT) SNP (IDH1(105GGT) ) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1(132) ) mutation. Patients who had GMB with the IDH1(105GGT) variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression-free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2-4 gliomas), a significant association was observed between IDH1(105GGT) and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM. CONCLUSIONS.: Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single-nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas. Cancer 2012. © 2012 American Cancer Society.
Cancer 11/2012; · 4.77 Impact Factor
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Anna Luisa Di Stefano,
Victor Enciso-Mora,
Yannick Marie,
Virginie Desestret,
Marianne Labussière,
Blandine Boisselier, Karima Mokhtari,
Ahmed Idbaih,
Khe Hoang-Xuan,
Jean-Yves Delattre,
Richard S Houlston,
Marc Sanson
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ABSTRACT: Background
Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1).Materials and methodsWe studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion.Resultsrs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P = .01), 10q loss (P = .02); rs4295627 and 1p-19q codeletion (P = .04), rs498872 and IDH (P = .02), 9p loss (P = .04), and 10q loss (P = .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P < 10(-3)) and rs2736100 and rs6010620 with IDH wild-type gliomas (P < 10(-3) and P = .03).Conclusion
The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.
Neuro-Oncology 11/2012; · 5.72 Impact Factor
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François Bertucci,
Corinne Bouvier-Labit,
Pascal Finetti,
José Adélaïde,
Philippe Metellus, Karima Mokhtari,
Anne-Valérie Decouvelaere,
Catherine Miquel,
Anne Jouvet,
Dominique Figarella-Branger,
Florence Pedeutour,
Max Chaffanet,
Daniel Birnbaum
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ABSTRACT: Solitary fibrous tumors (SFTs) are rare spindle cell tumors with limited therapeutic options. Their molecular basis is poorly known. No consistent cytogenetic abnormality has been reported. We used high-resolution whole-genome array-based comparative genomic hybridization (Agilent 244K oligonucleotide chips) to profile 47 samples, meningeal in >75% of cases. Few copy number aberrations (CNAs) were observed. Sixty-eight percent of samples did not show any gene CNA after exclusion of probes located in regions with referenced copy number variation (CNV). Only low-level CNAs were observed. The genomic profiles were very homogeneous among samples. No molecular class was revealed by clustering of DNA copy numbers. All cases displayed a "simplex" profile. No recurrent CNA was identified. Imbalances occurring in >20%, such as the gain of 8p11.23-11.22 region, contained known CNVs. The 13q14.11-13q31.1 region (lost in 4% of cases) was the largest altered region and contained the lowest percentage of genes with referenced CNVs. A total of 425 genes without CNV showed copy number transition in at least one sample, but only but only 1 in at least 10% of samples. The genomic profiles of meningeal and extra-meningeal cases did not show any differences. © 2012 Wiley Periodicals, Inc.
Genes Chromosomes and Cancer 10/2012; · 3.31 Impact Factor
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Agustí Alentorn,
Yannick Marie,
Catherine Carpentier,
Blandine Boisselier,
Marine Giry,
Marianne Labussière, Karima Mokhtari,
Khê Hoang-Xuan,
Marc Sanson,
Jean-Yves Delattre,
Ahmed Idbaih
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ABSTRACT: PDGFRA is a critical gene in glioma biology. Similar to EGFR, PDGFRA has been shown to be overexpressed, amplified, mutated, or truncated in gliomas, particularly glioblastomas. In addition, PDGFRA has been recently shown to be rearranged in glioblastoma. However, the frequency, cooccurrence, and clinical value of PDGFRA abnormalities in diffuse gliomas remain unclear. We investigated PDGFRA abnormalities and their clinical impact on 619 primary diffuse gliomas, including 167 grade II, 168 grade III, and 284 grade IV gliomas, with use of BAC-aCGH and validated our findings by quantitative polymerase chain reaction (PCR). We studied PDGFRA expression using reverse-transcription quantitative PCR in 84 gliomas and 12 non-tumor samples. In 138 samples, we also screened PDGFRA point mutations in exons 5, 7, 8, 9, 10, 11, and 23; presence of KDR-PDGFRA fusion gene; and PDGFRA truncation. PDGFRA was amplified and gained in 5.2% and 1.9% of samples, respectively. In addition PDGFRA was point-mutated, rearranged, and truncated in 2.9%, 0%, and 0.7% of cases, respectively. PDGFRA point mutations were observed exclusively in grade IV gliomas and in 12.5% of PDGFRA-amplified tumors. High-level PDGFRA amplification was associated with PDGFRA overexpression, high malignancy grade, and older patient age. Of interest, high-level PDGFRA amplification has an independent negative prognostic value for progression-free survival and overall survival among patients with grade III tumors. PDGFRA is altered through various genetic mechanisms in a subset of high-grade gliomas in patients who might be ideal candidates for PDGFRA inhibitor treatment, and PDGFRA gene amplification could be used as a prognostic biomarker in anaplastic gliomas.
Neuro-Oncology 10/2012; 14(11):1393-403. · 5.72 Impact Factor
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ABSTRACT: Adult grade II low-grade gliomas (LGG) are classified according to the WHO as astrocytomas, oligodendrogliomas or mixed gliomas. TP53 mutations and 1p19q codeletion are the main molecular abnormalities recorded, respectively, in astrocytomas and oligodendrogliomas and in mixed gliomas. Although IDH mutations (IDH1 or IDH2) are recorded in up to 85 % of low-grade gliomas, IDH negative gliomas do occur. We have searched for p53 expression, 1p19q codeletion and IDH status (immunohistochemical detection of the common R132H IDH1 mutation and IDH direct sequencing). Internexin alpha (INA) expression previously recorded to be associated with 1p19q codeletion (1p19q+) gliomas was also analysed. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. In contrast to the WHO classification, this molecular classification predicts overall survival on uni- and multivariate analysis (P = 0.001 and P = 0.007, respectively). Group 4 carries the worst prognosis and group 2 the best. Interestingly, p53 +/INA- expression predicts lack of 1p19q codeletion (specificity 100 %, VPP 100 %). The combined use of these three molecular markers allow for an accurate prediction of survival in LGG. These findings could significantly modify LGG classification and may represent a new tool to guide patient-tailored therapy. Moreover, immunohistochemical detection of p53, INA and mR132H IDH1 expression could represent an interesting prescreening test to be performed before 1p19q codeletion, IDH1 minor mutation and IDH2 mutation detection.
Journal of Neuro-Oncology 08/2012; 110(2):205-13. · 3.21 Impact Factor
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Alberto Gonzalez-Aguilar,
Ahmed Idbaih,
Blandine Boisselier,
Naïma Habbita,
Marta Rossetto,
Alice Laurenge,
Aurélie Bruno,
Anne Jouvet,
Marc Polivka,
Clovis Adam, [......],
Olivier Chinot,
Pierre Soubeyran,
Emmanuel Gyan,
Sylvain Choquet,
Caroline Houillier,
Carole Soussain,
Marie-Laure Tanguy,
Yannick Marie, Karima Mokhtari,
Khê Hoang-Xuan
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ABSTRACT: PURPOSE: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. EXPERIMENTAL DESIGN: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. RESULTS: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. CONCLUSIONS: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203-11. ©2012 AACR.
Clinical Cancer Research 07/2012; 18(19):5203-5211. · 7.74 Impact Factor
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Clinical neurology and neurosurgery 06/2012; · 1.30 Impact Factor
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Manuela Badiali,
Vincent Gleize,
Sophie Paris,
Loredana Moi,
Selma Elhouadani,
Antonietta Arcella,
Roberta Morace,
Manila Antonelli,
Francesca Romana Buttarelli,
Dominique Figarella-Branger,
Young-Ho Kim,
Hiroko Ohgaki, Karima Mokhtari,
Marc Sanson,
Felice Giangaspero
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ABSTRACT: KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAF(v600E) mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAF(v600E) in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAF(v600E) mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAF(v600E) mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss.
Brain Pathology 05/2012; 22(6):841-847. · 3.99 Impact Factor
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Virginie Desestret,
Pietro Ciccarino,
François Ducray,
Emmanuelle Crinière,
Blandine Boisselier,
Marianne Labussière,
Marc Polivka,
Ahmed Idbaih,
Gentian Kaloshi,
Andreas von Deimling,
Khe Hoang-Xuan,
Jean-Yves Delattre, Karima Mokhtari,
Marc Sanson
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ABSTRACT: Gliomatosis cerebri (GC) constitutes a heterogenous group of conditions involving diffuse neoplastic glial cell infiltration
of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression,
which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the
R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective
series of 40 GC treated with up-front chemotherapy, we analyzed IDH1R132H mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1R132H and 10/40 GC expressed INA. IDH1R132H staining was strongly related to progression-free survival (42.3 vs. 15.5months for positive IDH1R132H vs. negative tumors; P<0.0001) and overall survival (73.9 vs. 23.6months; P<0.0001). This effect was independent of grade, histologic subtype, and INA expression (P<0.001). Combined expression of IDH1R132H and INA was strongly associated with response to chemotherapy (100% vs. 36%; P=0.003). These data strongly suggest that INA and IDH1R132H mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.
KeywordsGliomatosis cerebri–IDH1–Alpha-internexin–Prognostic markers
Journal of Neuro-Oncology 04/2012; 105(2):219-224. · 3.21 Impact Factor
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Philippe Metellus,
Bema Coulibaly,
Carole Colin,
Andre Maues de Paula,
Alexandre Vasiljevic,
David Taieb,
Anne Barlier,
Blandine Boisselier, Karima Mokhtari,
Xiao Wei Wang,
Anderson Loundou,
Frederique Chapon,
Sandrine Pineau,
L’Houcine Ouafik,
Olivier Chinot,
Dominique Figarella-Branger
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ABSTRACT: The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities
in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics,
genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P=0.031) and p53 expression (P=0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P=0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate
analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio=40.9; 95% CI, 2.89–578.49, P=0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P=0.020) and that these tumors involved significantly more frequently the insula (P=0.004), were larger in size (>6cm, P=0.047), displayed an infiltrative pattern on MRI (P=0.007) and were all p53 negative with no 1p19q deletion (P<10−6). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular
alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new
tool to guide patient-tailored therapy.
Keywords
Isocitrate dehydrogenase-1(IDH1)
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IDH2
-Low-grade glioma-p53-LOH 1p19q mutation-Prognosis
Acta Neuropathologica 04/2012; 120(6):719-729. · 9.32 Impact Factor
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ABSTRACT: Primary CNS tumors (PCNSTs) encompass a broad and heterogeneous group of tumors, including gliomas, meningiomas, embryonal tumors, primary CNS lymphomas, CNS germ cell tumors and sellar region tumors. In recent decades, research has focused on understanding the clinical and biological significance of molecular abnormalities detected in PCNSTs. The emergence of genomic arrays, including comparative genomic hybridization and SNP arrays, have helped in the discovery of novel critically important genes and novel genomic biomarkers involved in PCNST oncogenesis (e.g., BRAF duplication in pilocytic astrocytoma). Since a summary of data from genomic arrays using gliomas has been described in a previous review, in this article we will focus on the insights provided by genome-wide DNA arrays in the genetics and genomics of nonglial PCNSTs in adults. The high-throughput assessment of gene copy-number abnormalities has improved our knowledge of molecular pathogenesis in nonglial PCNSTs, allowing for the identification of new candidate genomic regions and genes involved in tumorigenesis. These chromosome imbalances provide a promising insight into potential targets for innovative drugs and new interesting diagnostic and prognostic biomarkers for clinical practice.
Expert Review of Molecular Diagnostics 04/2012; 12(3):265-77. · 4.86 Impact Factor
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Hamid Mammar,
Khaldoun Kerrou,
Valérie Nataf,
Dominique Pontvert,
Stéphane Clemenceau,
Guillaume Lot,
Bernard George,
Marc Polivka, Karima Mokhtari,
Regis Ferrand,
Loïc Feuvret,
Jean-Louis Habrand,
Jacques Pouysségur,
Nathalie Mazure,
Jean-Noël Talbot
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ABSTRACT: To detect the presence of hypoxic tissue, which is known to increase the radioresistant phenotype, by its uptake of fluoromisonidazole (18F) (FMISO) using hybrid positron emission tomography/computed tomography (PET/CT) imaging, and to compare it with the glucose-avid tumor tissue imaged with fluorodeoxyglucose (18F) (FDG), in residual postsurgical skull base chordoma scheduled for radiotherapy.
Seven patients with incompletely resected skull base chordomas were planned for high-dose radiotherapy (dose ≥70 Gy). All 7 patients underwent FDG and FMISO PET/CT. Images were analyzed qualitatively by visual examination and semiquantitatively by computing the ratio of the maximal standardized uptake value (SUVmax) of the tumor and cerebellum (T/C R), with delineation of lesions on conventional imaging.
Of the eight lesion sites imaged with FDG PET/CT, only one was visible, whereas seven of nine lesions were visible on FMISO PET/CT. The median SUVmax in the tumor area was 2.8 g/mL (minimum 2.1; maximum 3.5) for FDG and 0.83 g/mL (minimum 0.3; maximum 1.2) for FMISO. The T/C R values ranged between 0.30 and 0.63 for FDG (median, 0.41) and between 0.75 and 2.20 for FMISO (median,1.59). FMISO T/C R >1 in six lesions suggested the presence of hypoxic tissue. There was no correlation between FMISO and FDG uptake in individual chordomas (r = 0.18, p = 0.7).
FMISO PET/CT enables imaging of the hypoxic component in residual chordomas. In the future, it could help to better define boosted volumes for irradiation and to overcome the radioresistance of these lesions. No relationship was founded between hypoxia and glucose metabolism in these tumors after initial surgery.
International journal of radiation oncology, biology, physics 03/2012; 84(3):681-7. · 4.59 Impact Factor
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ABSTRACT: Brainstem gliomas are uncommon in adults and account for only 1%-2% of intracranial gliomas. They represent a heterogeneous group of tumors that differ from those found in their pediatric counterparts. In adults, a low-grade phenotype predominates, which is a feature that likely explains their better prognosis compared to that in children. Because biopsies are rarely performed, classifications based on the radiological aspect of magnetic resonance imaging results have been proposed to establish treatment strategies and to determine outcomes: (a) diffuse intrinsic low-grade, (b) enhancing malignant glioma, (c) focal tectal gliomas, and (d) exophytic gliomas. Despite significant advances in neuroradiology techniques, a purely radiological classification remains imperfect in the absence of a histological diagnosis. Whereas a biopsy may often be reasonably avoided in the diffuse nonenhancing forms, obtaining histological proof seems necessary in many contrast-enhanced brainstem lesions because of the wide variety of differential diagnoses in adults. Conventional radiotherapy is the standard treatment for diffuse intrinsic low-grade brainstem gliomas in adults (the median survival is 5 years). In malignant brainstem gliomas, radiotherapy is the standard treatment. However, the possible benefit of combined radiotherapy and chemotherapy (temozolomide or other agents) has not been thoroughly evaluated in adults. The role of anti-angiogenic therapies in brainstem gliomas remains to be defined. A better understanding of the biology of these tumors is of primary importance for identifying homogeneous subgroups and for improving therapy options and outcomes.
The Oncologist 03/2012; 17(3):388-97. · 3.91 Impact Factor
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Monika E Hegi,
Robert-Charles Janzer,
Wanyu L Lambiv,
Thierry Gorlia,
Mathilde C M Kouwenhoven,
Christian Hartmann,
Andreas von Deimling,
Danielle Martinet,
Nathalie Besuchet Schmutz,
Annie-Claire Diserens,
Marie-France Hamou,
Pierre Bady,
Michael Weller,
Martin J van den Bent,
Warren P Mason,
René-Olivier Mirimanoff,
Roger Stupp, Karima Mokhtari,
Pieter Wesseling
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ABSTRACT: Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.
Acta Neuropathologica 01/2012; 123(6):841-52. · 9.32 Impact Factor
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Ahmed Idbaih,
François Ducray,
Caroline Dehais,
Célia Courdy,
Catherine Carpentier,
Simon de Bernard,
Emmanuelle Uro-Coste, Karima Mokhtari,
Anne Jouvet,
Jérôme Honnorat, [......],
Marie Janette Motsuo Fotso,
Christine Desenclos,
Pierre Verelle,
François Ghiringhelli,
Georges Noel,
François Labrousse,
Antoine Carpentier,
Frédéric Dhermain,
Jean-Yves Delattre,
Dominique Figarella-Branger
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ABSTRACT: Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.
PLoS ONE 01/2012; 7(10):e45950. · 4.09 Impact Factor
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Sophie Ng Wing Tin,
Nadine Martin-Duverneuil,
Ahmed Idbaih,
Catherine Garel,
Maria Ribeiro,
Judith Landman Parker,
Anne-Sophie Defachelles,
Anne Lambilliotte,
Mohamed Barkaoui,
Martine Munzer, [......],
Perrine Marec Berard,
Ghislain Nokam Talom,
Jean-Loup Pennaforte,
Hubert Ducou Le Pointe,
Marie-Anne Barthez,
Gérard Couillault,
Julien Haroche, Karima Mokhtari,
Jean Donadieu,
Khê Hoang-Xuan
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[hide abstract]
ABSTRACT: Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions.
A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response.
The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events.
VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.
Orphanet Journal of Rare Diseases 12/2011; 6(1):83. · 5.83 Impact Factor
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ABSTRACT: Meningeal solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) are distinct entities in the World Health Organization (WHO) classification of central nervous system (CNS) tumors while they belong to the same spectrum of tumors in other locations. Well-defined histological prognostic factors are also lacking for these tumors. In order to clarify the relationship between SFT and HPC and to find histological and immunohistochemical prognostic factors, we carried out a retrospective study in 89 patients. The following histological parameters were recorded: hypercellularity, collagenic areas, cytonuclear atypias, necrosis, mitotic count per 10 high-power fields, vasculo-nervous adherences defined by engulfment of vessel or nerve by the tumor, brain infiltration. We found overlapping histological and immunohistochemical features between SFT and HPC. The most relevant histological prognostic factors in the whole cohort for both progression-free survival (PFS) and overall survival (OS) in univariate analysis were hypercellularity, high mitotic count (>5 per 10 high-power fields) and necrosis. On the basis of these results, we propose a new grading scheme for these tumors which was of pronostic value for both PFS and OS in uni- and multivariate analysis. As extent of surgery was also a prognostic factor for both PFS and OS in univariate analysis, we propose that management of SFT/HPC might be based both on quality of removal and histological grade.
Brain Pathology 11/2011; 22(4):511-21. · 3.99 Impact Factor
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Jaime Gállego Pérez-Larraya,
François Ducray,
Olivier Chinot,
Isabelle Catry-Thomas,
Luc Taillandier,
Jean-Sébastien Guillamo,
Chantal Campello,
Annick Monjour,
Stéphanie Cartalat-Carel,
Maryline Barrie,
Aymeri Huchet,
Patrick Beauchesne,
Mona Matta, Karima Mokhtari,
Marie-Laure Tanguy,
Jérôme Honnorat,
Jean-Yves Delattre
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ABSTRACT: The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken.
Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition.
Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03).
Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.
Journal of Clinical Oncology 06/2011; 29(22):3050-5. · 18.37 Impact Factor
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Ahmed Idbaih,
Cyril Dalmasso,
Mathilde Kouwenhoven,
Judith Jeuken,
Catherine Carpentier,
Thierry Gorlia,
Johan M Kros,
Pim French,
Johannes Teepen,
Philippe Broët,
Olivier Delattre, Karima Mokhtari,
Marc Sanson,
Jean-Yves Delattre,
Martin van den Bent,
Khê Hoang-Xuan
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ABSTRACT: Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed-validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs.
Journal of Neuro-Oncology 06/2011; 103(2):221-30. · 3.21 Impact Factor
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Virginie Desestret,
Pietro Ciccarino,
François Ducray,
Emmanuelle Crinière,
Blandine Boisselier,
Marianne Labussière,
Marc Polivka,
Ahmed Idbaih,
Gentian Kaloshi,
Andreas von Deimling,
Khe Hoang-Xuan,
Jean-Yves Delattre, Karima Mokhtari,
Marc Sanson
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ABSTRACT: Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P < 0.0001) and overall survival (73.9 vs. 23.6 months; P < 0.0001). This effect was independent of grade, histologic subtype, and INA expression (P < 0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.
Journal of Neuro-Oncology 04/2011; 105(2):219-24. · 3.21 Impact Factor
