Karima Mokhtari

Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix"), Lutetia Parisorum, Île-de-France, France

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Publications (156)828.08 Total impact

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    ABSTRACT: To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs).
    Neurology 08/2014; · 8.25 Impact Factor
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    ABSTRACT: Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile.
    Cancer 08/2014; · 5.20 Impact Factor
  • Presse medicale (Paris, France : 1983). 07/2014;
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    ABSTRACT: boulevard de l'Hô pital, 75651 Paris cedex 13, France k Fédération de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, INSERM-UPMC UMRS 975-CRICM, 47-83, boulevard de l'Hô pital, 75651 Paris cedex 13, France r e v u e n e u r o l o g i q u e x x x (2 0 1 4) x x x – x x x * Corresponding author. Service de Neurologie, Bâ timent Mazarin, Groupe Hospitalier Pitié -Salpê triè re, 47-83 Boulevard de l'Hô pital, Available online xxx a b s t r a c t A solitary tuberculous brain lesion (STBL) can be difficult to distinguish from a glioma, metastasis or other infectious disease, especially from a pyogenic brain abscess. We analyzed the clinical characteristics, diagnostic procedures and outcomes of 24 patients with STBL diagnosed in three centers from France, India and Mexico. We also reviewed 92 STBL cases previously reported in the literature. General symptoms were found in 54% of our patients, including enlarged lymph nodes in 20%. Cerebrospinal fluid was typically abnormal, with NEUROL-1302; No. of Pages 10 Please cite this article in press as: Psimaras D, et al. Solitary tuberculous brain lesions: 24 new cases and a review of the literature. Revue neurologique (2014),
    Revue Neurologique 06/2014; 170(6-7):454-463. · 0.51 Impact Factor
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    ABSTRACT: Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.
    Oncotarget 06/2014; · 6.64 Impact Factor
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    ABSTRACT: Mutations in isocitrate dehydrogenase genes IDH1 or IDH2 are frequent in glioma, and IDH mutation status is a strong diagnostic and prognostic marker. Current IDH mutation screening is performed with an immunohistochemistry (IHC) assay specific for IDH1 R132H, the most common mutation. Sequencing is recommended as a second-step test for IHC-negative or -equivocal cases. We developed and validated a new real-time quantitative polymerase chain reaction (PCR) assay for single-step detection of IDH1 R132H and 11 rare IDH1/2 mutations in formalin-fixed paraffin-embedded (FFPE) glioma samples. Performance of the IDH1/2 PCR assay was compared to IHC and Sanger sequencing.
    Acta neuropathologica communications. 06/2014; 2(1):58.
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    ABSTRACT: A solitary tuberculous brain lesion (STBL) can be difficult to distinguish from a glioma, metastasis or other infectious disease, especially from a pyogenic brain abscess. We analyzed the clinical characteristics, diagnostic procedures and outcomes of 24 patients with STBL diagnosed in three centers from France, India and Mexico. We also reviewed 92 STBL cases previously reported in the literature. General symptoms were found in 54% of our patients, including enlarged lymph nodes in 20%. Cerebrospinal fluid was typically abnormal, with lymphocytic pleocytosis and a high protein level. The lung CT scan was abnormal in 56% of patients, showing lymphadenopathy or pachipleuritis. Brain MRI or CT was always abnormal, showing contrast-enhanced lesions. Typically, MRI abnormalities were hypointense on T1-weighted sequences, while T2-weighted sequences showed both a peripheral hypersignal and a central hyposignal. The diagnosis was documented microbiologically or supported histologically in 71% of cases. Clinical outcome was good in 83% of cases.
    Revue Neurologique 04/2014; · 0.51 Impact Factor
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    ABSTRACT: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs). The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. 1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10(-4)), IDH1/2 mutation (P < 10(-4)), chromosome 4 loss (P < 10(-3)), and better overall survival (P < 10(-4)). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023). The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations.
    Neuro-Oncology 04/2014; · 6.18 Impact Factor
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    ABSTRACT: Central neurocytoma is a rare primary central nervous system tumour of young adults with good prognosis. Typical and atypical forms are described according to various histologic and histopathologic parameters. Central neurocytoma develops in the periventricular areas and is revealed by increased intracranial pressure. The tumour exhibits typical characteristics on CT scan and MRI and a characteristic peak of glycine on spectroscopy-MRI. The main treatment is total resection, which is achievable only in half of the cases. External beam therapy improves local control of partially resected and/or atypical central neurocytoma. Many studies show that stereotactic radiotherapy can be used in the therapeutic management as exclusive treatment, in postoperatives residues and in case of distant recurrence. Chemotherapy is the last line of treatment in refractory forms, especially in the forms with extracranial and/or neuromeningeal spread and in recurrent forms after treatment with surgery and/or radiotherapy.
    Cancer/Radiothérapie 04/2014; · 1.48 Impact Factor
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    ABSTRACT: TP53 is a pivotal gene frequently mutated in diffuse gliomas and particularly in astrocytic tumors. The majority of studies dedicated to TP53 in gliomas were focused on mutational hotspots located in exons 5-8. Recent studies have suggested that TP53 is also mutated outside the classic mutational hotspots reported in gliomas. Therefore, we have sequenced all TP53 coding exons in a retrospective series of 61 low grade gliomas (LGG) using high throughput sequencing technology. In addition, TP53 mutational status was correlated with: (i) p53 expression, (ii) tumor type, (iii) chromosome arms 1p/19q status and (iv) clinical features of patients. The cohort included 32 oligodendrogliomas (O), 21 oligoastrocytomas (M) and 8 astrocytomas (A). TP53 mutation was detected in 52.4 % (32/61) of tumors (34 % of O, 71.4 % of M and 75 % of A). All mutations (38 mutations in 32 samples) were detected in exons 4, 5, 6, 7, 8 and 10. Missense and non-missense mutations, including seven novel mutations, were detected in 42.6 and 9.8 % of tumors respectively. TP53 mutations were almost mutually exclusive with 1p/19q co-deletion and were associated with: (i) astrocytic phenotype, (ii) younger age, (iii) p53 expression. Using a threshold of 10 % p53-positive tumor cells, p53 expression is an interesting surrogate marker for missense TP53 mutations (Se = 92 %; Sp = 79.4 %) but not for non-missense mutation (18.4 % of mutations). TP53 and p53 statuses were not prognostic in LGG. In conclusion, we have identified novel TP53 mutations in LGG. TP53 mutations outside exons 4-8 are rare. Although it remains imperfect, p53 expression with a threshold of 10 % is a good surrogate marker for missense TP53 mutations and appears helpful in the setting of LGG phenotype diagnosis.
    Journal of Neuro-Oncology 03/2014; · 3.12 Impact Factor
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    ABSTRACT: Une lésion cérébrale tuberculeuse solitaire (STBL) peut être difficile de distinguer d’une tumeur gliale ou métastatique ou d’autres maladies infectieuses, particulièrement l’abcès cérébral à pyogène. Nous avons analysé les caractéristiques et l’évolution clinique ainsi que les explorations à visée diagnostique chez 24 patients avec STBL diagnostiqués dans trois centres en France, en Inde et au Mexique. Nous avons aussi analysé 92 cas de STBL précédemment rapportés dans la littérature. Des signes généraux ont été trouvés chez 54 % de nos patients, notamment des adénopathies dans 20 % des cas. Typiquement le liquide céphalorachidien était anormal, avec une pleiocytose lymphocytaire et une hyperprotéinorachie. Le scanner pulmonaire était anormal dans 56 % de patients, montrant des adénopathies ou des anomalies parenchymateuses. L’IRM ou scanner cérébral étaient toujours anormaux, retrouvant des lésions prenant le contraste. Typiquement l’IRM montrait des anomalies hypointenses sur les séquences T1; sur les séquences T2 la lésion apparaissait hyperintense en périphérie et hypointense au centre. Le diagnostic a été affirmé sur le plan microbiologique ou histologique dans 71 % de cas. L’évolution clinique était bonne dans 83 % des cas.
    Revue Neurologique 01/2014; · 0.51 Impact Factor
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    ABSTRACT: IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated-which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.
    BioMed Research International 01/2014; 2014:540236. · 2.88 Impact Factor
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    ABSTRACT: Central neurocytoma is a rare primary central nervous system tumour of young adults with good prognosis. Typical and atypical forms are described according to various histologic and histopathologic parameters. Central neurocytoma develops in the periventricular areas and is revealed by increased intracranial pressure. The tumour exhibits typical characteristics on CT scan and MRI and a characteristic peak of glycine on spectroscopy-MRI. The main treatment is total resection, which is achievable only in half of the cases. External beam therapy improves local control of partially resected and/or atypical central neurocytoma. Many studies show that stereotactic radiotherapy can be used in the therapeutic management as exclusive treatment, in postoperatives residues and in case of distant recurrence. Chemotherapy is the last line of treatment in refractory forms, especially in the forms with extracranial and/or neuromeningeal spread and in recurrent forms after treatment with surgery and/or radiotherapy.
    Cancer/Radiothérapie 01/2014; · 1.48 Impact Factor
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    ABSTRACT: Background. Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. Materials and Methods. We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. Results. In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. Conclusion. A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.
    BioMed Research International 01/2014; 2014:827327. · 2.88 Impact Factor
  • La Presse Médicale. 01/2014;
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    ABSTRACT: Background Diffuse low-grade gliomas (LGGs) form a heterogeneous subgroup of gliomas in adults. Chromosome (chr) arms 1p/19q codeletion and IDH mutation have been shown to be closely associated with oligodendroglial phenotype and better prognosis. We sought to identify relevant biomarkers in non 1p/19q codeleted LGGs.Methods We characterized a retrospective series of 126 LGGs using genomic arrays, microsatellite analysis, IDH sequencing, MGMT promoter methylation assay, and p53 expression analysis.ResultsOur study confirms that 1p/19q codeletion, mutually exclusive with p53 overexpression, was associated with: (i) better prognosis, (ii) oligodendroglial phenotype, (iii) MGMT promoter methylation, and (iv) IDH mutation. Interestingly, 1p/19q codeleted tumors occur in older patients at diagnosis. Our study shows that non 1p/19q codeleted LGGs can be divided in 5 main genomic subgroups: (i) 11p loss, (ii) 19q loss (iii) 7 gain, (iv) 19 gain, and (v) unclassified. In non 1p/19q codeleted LGGs, we demonstrated that (i) 11p loss is associated with astrocytoma phenotype and has an independent negative prognostic value, and (ii) 19q loss diminished the favorable prognostic value of IDH mutation. Our findings were validated in an independent cohort of 98 LGGs.Conclusion Novel genomic entities and biomarkers have been identified in non 1p/19q codeleted LGGs. Our findings may help to stratify non 1p/19q codeleted LGGs, facilitating future individualization of treatment. Further prospective studies are warranted to support our findings.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare.
    Journal of Neuro-Oncology 11/2013; · 3.12 Impact Factor
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    ABSTRACT: A 59-year-old woman with no history of trauma presented with severe headaches and right-sided weakness. A CT scan showed a left hemispheric isodense subdural collection thought consistent with a subacute subdural hematoma (figure 1A). The patient underwent a single parietal burr hole for evacuation, but the neurosurgeon found subdural fleshy tissue and performed a biopsy. Immediate postoperative MRI showed a homogeneous hypercellular subdural mass (figure 1, B-F).(1) Pathology was consistent with Burkitt lymphoma (figure 2). Retrospectively, the homogeneous density of the collection argued against hematoma. In nonemergent situations, an atypical radiologic appearance of a subdural hematoma may suggest the need for further radiologic investigations before surgical evacuation.(2.)
    Neurology 10/2013; 81(17):e128-9. · 8.25 Impact Factor
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    ABSTRACT: Central nervous system (CNS) angiitis is a rare inflammatory disorder. To date, clinical data are lacking and treatment remains a matter of debate. The aim of this study is to analyse the main characteristics, response to therapy and outcome of 32 patients with CNS angiitis. Single-centre retrospective study in a tertiary centre was made. Diagnosis of CNS angiitis was made by cerebral angiography and/or magnetic resonance angiography and/or CNS biopsy. The main features and outcomes of primary and secondary CNS angiitis were compared and predictive factors of a favourable outcome were searched. Thirty-one patients (median age 45 Q1-Q3 37-54) sex ratio F/M 2.1) were included. Main clinical features were hemiparesis (35.5 %) and headache (29 %). The median CSF protein level was 0.64(0.52-0.81) g/L and was superior to 1 g/L in six cases. CNS magnetic resonance (MR) imaging findings were most frequently ischemic (96.8 %), bilateral (83.9 %), multiple (87.1 %) and supratentorial (96.8 %). The MR angiography was abnormal in all cases. Among the 31 patients in the study, 19 (61.3 %) were diagnosed with primary CNS angiitis. Systemic lupus erythematosus (n = 6) and vasculitis (n = 4) were the most frequent aetiologies of secondary CNS angiitis. No difference was evidenced between primary and secondary CNS angiitis. Steroids were administered in 79.2 % of treated patients and combined with immunosuppressants in 79.2 % of cases. Eight cases of CNS angiitis relapse were noted. CNS angiitis remains a severe illness. Treatment often associated steroids and immunosuppressants, and diagnosis delay is significantly associated with a poorer prognosis.
    Clinical Rheumatology 10/2013; · 2.04 Impact Factor
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    ABSTRACT: The aim of the present study was to evaluate the impact of first-line radiotherapy on low-grade gliomas (LGGs) growth kinetics. The mean tumor diameter (MTD) of 39 LGGs was retrospectively measured on serial magnetic resonance images before (n = 16) and after radiotherapy onset (n = 39). After radiotherapy, a decrease of the MTD was observed in 37 patients. Median duration of the MTD decrease was 1.9 years (range 0-8.1 years). According to RANO criteria, the rates of partial and minor responses were 15 and 28 % at the first evaluation after radiotherapy and 36 and 34 % at the time of maximal MTD decrease. The presence of a 1p19q codeletion and the absence of p53 expression were associated with longer durations of MTD decrease (5.3 vs 1 years, p = 0.02 and 2.4 vs 1.8 years, p = 0.05, respectively) while no association was observed between IDH1-R132H expression and duration of MTD decrease. In most patients, MTD decrease after radiotherapy occurred in two phases: an initial phase of rapid MTD decrease followed by a second phase of slower MTD decrease. Patients with a high rate of MTD decrease during the initial phase (>7 mm/year) had both a shorter duration of response (1.9 vs 5.3 years, p = 0.003) and a shorter overall survival (5.5 vs 11.6 years, p = 0.0004). LGGs commonly display a prolonged and ongoing volume decrease after radiotherapy. However, patients who respond rapidly should be carefully monitored because they are at a higher risk of rapid progression.
    Journal of Neuro-Oncology 08/2013; · 3.12 Impact Factor

Publication Stats

5k Citations
828.08 Total Impact Points

Institutions

  • 1998–2014
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • • Département de Neuropathologie
      • • Service de Neurochirurgie
      Lutetia Parisorum, Île-de-France, France
  • 1996–2014
    • Pierre and Marie Curie University - Paris 6
      • Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 2007–2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Institut de Recherche sur les Phénomènes Hors Equilibre
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2006–2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • Assistance Publique Hôpitaux de Marseille
      • Service de neurochirurgie infantile
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
    • University of Bonn
      • Neurochirurgische Klinik
      Bonn, North Rhine-Westphalia, Germany
  • 2000–2009
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2005
    • Institut Curie
      • Service de Radiothérapie
      Lutetia Parisorum, Île-de-France, France