Biomedical subjects

Karima Mokhtari

Publications and source records attributed to Karima Mokhtari.

13 recordsLinked to original sources

PubMed2007

MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities.

MGMT promoter methylation, which has been correlated with the response to alkylating agents, was investigated in a retrospective series of 219 glioblastomas (GBMs) treated with various modalities. MGMT methylation had no impact on survival for the whole group, but showed a significant advantage (17.1 months vs. 13.1) for patients treated with RT+ adjuvant chemotherapy (relative risk of death (RR) = 0.53; P = 0.041), particularly when patients received CT during the course of RT (MS = 19.9 months vs. 12.5 months; RR = 0.227, P = 0.001). This suggests that the prognostic impact of MGMT methylation is dependent on therapeutic modalities and schedules. MGMT methylation was not correlated with the main molecular alterations, such as 10q loss and p53 expression.

Adult↗

PubMed2006

Prognostic impact of molecular markers in a series of 220 primary glioblastomas.

BACKGROUND: In contrast to oligodendrogliomas, molecular predictors of prognosis have not been consistently found in glioblastomas. However, genetic studies show that glioblastomas consist of several genetic subtypes and raise the possibility that molecular alterations could be predictive of survival. METHODS: A search for loss of heterozygosity (LOH) on chromosome 1p, 9p, 10q, 19q, EGFR (epidermal growth factor receptor), CDK4, and MDM2 (mouse double minute) amplifications, CDKN2A (INK4A/ARF) homozygous deletions, p53 expression, was performed in a series of 220 primary glioblastomas. The molecular alterations were then correlated with each other to identify distinct molecular pathways and with clinical parameters and the course of the disease to identify prognostic markers. RESULTS: Nonrandom associations were found between EGFR amplification and LOH10q, LOH9p, and INK4A/ARF deletion, LOH1p and LOH19q, and MDM2 and CDK4 amplification, whereas mutual exclusions were found between p53 expression and EGFR amplification, LOH 9p/INK4A/ARF homozygous deletion, and MDM2 and CDK4 amplification. Age (P = 4.10(-5)) and performance status (P = .003) were the main predictors of outcome. In contrast, molecular markers were of limited impact: MDM2 amplification correlated with poor outcome on both univariate and multivariate analysis (P = .01) and EGFR amplification with good prognosis on multivariate analysis (P = .02). CONCLUSION: Despite their limited prognostic impact, the genetic markers investigated here outline distinct molecular pathways involved in glioblastoma tumorigenesis and warrant broader molecular screening.

Adolescent↗

PubMed2006

MGMT methylation: a marker of response to temozolomide in low-grade gliomas.

The methylation status of the O6-methylguanine-methyltransferase promoter (MGMTP) was evaluated in 68 low-grade gliomas treated by neoadjuvant temozolomide. Methylated MGMTP was detected in 63 of 68 (92.6 %) patients and was a favorable predictor of progression-free survival as compared with unmethylated MGMTP tumors (p < 0.0001). Assessment of MGMTP status could help identifying low-grade gliomas patients more likely to respond to chemotherapy or to benefit from MGMT depletion strategies.

Adult↗

PubMed2006

Loss of 22q chromosome is related to glioma progression and loss of 10q.

Loss of heterozygosity (LOH) of chromosome 22q has been investigated in 160 gliomas. LOH at one or more microsatellite increased with increasing grade of the tumor (P < 0.01). LOH22q was more frequent in astrocytic tumors (37%) compared to mixed or oligodendroglial tumors (21%) (P = 0.02). LOH22q was correlated to 10q loss but not to 1p or 9p loss. Taken together, these data suggest that LOH22q is an alteration associated with malignant progression of gliomas.

Brain Neoplasms↗

PubMed2006

Pitfalls in the diagnosis of brain tumours.

Establishing the diagnosis of a brain tumour is not always a straightforward process. Many non-neoplastic neurological diseases can mimic brain neoplasms on neuroimaging or on histological examination, including multiple sclerosis, stroke, pyogenic abscess, toxoplasmosis, tuberculosis, cysticercosis, fungal infections, syphilis, sarcoidosis, Behçet disease, radiation necrosis, venous thrombosis, and others. Conversely, several types of brain neoplasms, such as glioblastomas, low-grade gliomas, CNS lymphomas, and brain metastases, can present in the absence of typical tumefactive lesions, posing significant diagnostic challenges. In this Review, we discuss the process of accurately establishing the diagnosis of brain tumours, focusing on pitfalls commonly encountered in clinical practice. We also discuss the rational use and limitations of new diagnostic techniques, such as diffusion-weighted MRI, perfusion-weighted MRI, magnetic resonance spectroscopy, single-photon emission tomography, and positron emission tomography, as well as new tools for histological examination, such as immunohistochemistry and molecular genetics analysis.

Brain Diseases↗

PubMed2005

A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases.

Most primary central nervous system lymphomas (PCNSLs) in immunocompetent patients are diffuse large B-cell lymphomas (DLBCLs), characterized by poor prognosis, compared with systemic forms. A germinal center B-cell-like (GCB) origin of PCNSL was hypothesized on the basis of BCL-6 expression and ongoing mutational activity. Our goal herein was to determine, for 83 PCNSLs, the percentages of GCB and activated B-cell-like (ABC) phenotypes and their prognostic significance. CD10, BCL-6, MUM1, BCL-2, and CD138 antigens were immunohistochemically labeled on paraffin-embedded sections; the first 4 were positive in 2.4%, 55.5%, 92.6%, and 55.5% of the tumors, respectively. None of the 56 tested samples expressed CD138. Among the 82 patients with complete information, 79 (96.3%) were classified as ABC; 42 (51.2%) expressed BCL-6+ MUM1+, suggesting an "activated GCB" origin; 33 (40.2%) were exclusively MUM1+, and the remaining 4 (4.9%) were negative for all markers tested. These findings provide new insights into interpreting the poor PCNSL prognostic, which may, in part, be due to biologic aggressiveness associated with its activated B-cell-like pattern. We postulate assigning PCNSL a histogenetic "time-slot," overlapping late GC and early post-GC, that could explain the predominant ABC phenotype observed.

Adult↗

PubMed2005

Chromosome 1p loss: a favorable prognostic factor in low-grade gliomas.

Search for loss of heterozygosity on chromosomes 1p, 9p, 10q, and 19q, epidermal growth factor receptor (EGFR) gene amplification, and p53 expression was performed in a series of 131 low-grade gliomas. The profile of molecular changes, clinical findings, and histology were subsequently correlated with the course of the disease, mainly progression-free survival. When these parameters were considered as candidate variables in a multivariate analysis, only loss of heterozygosity on chromosome 1p was associated with increased progression-free survival (hazard ratio, 0.521), indicating a major favorable prognostic role of this genetic alteration in low-grade gliomas.

Adolescent↗

PubMed2005

Two types of chromosome 1p losses with opposite significance in gliomas.

Deletion of the short arm of chromosome 1 (1p) is considered a favorable prognostic factor in glial tumors. High-density array-comparative genomic hybridization analysis of 108 gliomas shows two distinct types of 1p deletions. Complete hemizygous losses of 1p, which are tightly associated with 19q loss and oligodendroglial phenotype, and partial 1p deletions mainly observed in astrocytic tumors and not associated with 19q loss. Whereas the first type predicts longer overall and progression-free survival (p < 0.0001), the second type has a pejorative prognostic value. Complete 1p-arm evaluation therefore is required to appreciate the real clinical significance of 1p loss in gliomas.

Adult↗

PubMed2005

Dural metastases.

Dural metastases are found at autopsy in 8-9% of patients with advanced systemic cancer. They arise either by direct extension from skull metastases or by hematogeneous spread. Dural metastases are often clinically asymptomatic but they may produce progressive neurological deficits and sometimes subdural hematomas. MRI may be misleading when the metastasis simulates a meningioma or when a subdural hematoma masks the underlying tumor. Whenever possible, surgical removal is the most appropriate treatment. The prognosis is poor because of the progressive systemic cancer but prolonged survival has been reported in operated patients, when the systemic cancer was controlled.

Dura Mater↗

PubMed2005

[Towards a molecular classification of gliomas].

Several molecular genetic alterations have been characterized in gliomas in the past years. Molecular profiles have been associated with specific histologic and prognostic tumor subgroups, contributing to improve the classification of gliomas. At least two alternative molecular pathways have been suggested in the astrocytoma progression involving TP53 inactivation (secondary glioblastomas) and EGFR amplification (de novo glioblastomas) respectively. Oligodendroglial tumors have demonstrated recurrent combined loss of chromosome 1p/19q, which represent a favorable prognosis marker and probably a predictor of a good chemosensitivity of the tumor. This review discusses recent molecular advances and clinical implications with special focus on oligodendroglial tumors.

Astrocytoma↗

PubMed2004

Analysis of the bHLH transcription factors Olig1 and Olig2 in brain tumors.

In the absence of specific markers, the histological diagnosis of oligodendroglial tumors is based on subjective qualitative criteria and remains controversial. Recently, two bHLH transcription factors involved in oligodendroglial specification, Olig1 and Olig2 have been proposed as potential markers of oligodendrogliomas. Expression of Olig1/2 was analyzed by in situ hybridization on 78 samples including 47 glial, 29 non-glial tumors, and two non-tumoral brain tissues. Both genes had a similar pattern of expression. Olig1 and Olig2 were expressed in 26/30 (87%) and 28/30 (93%) of oligodendroglial tumors respectively but in only 9% of glioblastomas (1/11). Olig genes were also expressed in the low-grade fibrillary astrocytomas (4/4) and anaplastic astrocytomas (2/2). No expression was found in non-glial tumors, except for one primary cerebral lymphoma. Double staining with PLP, NFH, GFAP showed that olig genes were expressed by mature, non-tumoral oligodendrocytes, but not by normal astrocytes or neurones. This study indicates that Olig1/2 expression clearly distinguishes pure Olig-negative glioblastomas from a wide spectrum of Olig-positive tumors including traditional oligodendrogliomas and oligoastrocytomas, glioblastomas with an oligodendroglial component (GBMO), and WHO grade 2 and 3 astrocytomas. Because Olig genes have a crucial role in oligodendroglial determination, our data could be of help in defining the real spectrum of oligodendroglial tumors.

Astrocytes↗

PubMed2004

Prognostic value of allelic losses and telomerase activity in meningiomas.

OBJECT: The goal of this study was to examine allelic losses and telomerase activity in meningiomas to determine whether they could be used to predict disease recurrence. METHODS: To identify predictive markers of recurrence, a cohort of high-grade (24 World Health Organization [WHO] Grade II and six WHO Grade III) and low-grade (21 WHO Grade I) meningiomas was investigated for losses of heterozygosity (LOHs) on chromosomes 1p, 9p, 10q, 14q, and 22q, a deletion of CDKN2A, and telomerase activity. Results of molecular analyses were compared with radiological and histological findings and progression-free survival (PFS). Losses of heterozygosity on chromosomes 22q, 1p, and 10q, as well as telomerase activity were related to the WHO histological grades of the lesions (p < 0.01, p < 10(-5), p < 10(-4), and p = 0.002, respectively). In the absence of an LOH on 22q, the other alterations were found infrequently. Overall, the number of molecular alterations was closely related to the histological grades of the lesions (p < 10(-6)). An LOH on 22q occurred much more frequently in convexity or falx (33 [87%] of 38 lesions) than in skull base or spinal meningiomas (four [31%] of 13 lesions) (p < 0.001). The histological grade; Simpson grade; an LOH on chromosome 1p, 9p, or 10q; and telomerase activity were correlated with a shorter PFS time (p < 10(-4), p = 0.02, p = 0.000365, p = 0.022, p = 0.00027, and p = 0.000512, respectively). CONCLUSIONS: On the basis of these data the authors suggest that LOH analysis and a telomerase activity assay could be useful to determine molecular predictors of outcome in patients with meningiomas.

Adult↗

PubMed2002

Analysis of loss of chromosome 10q, DMBT1 homozygous deletions, and PTEN mutations in oligodendrogliomas.

OBJECT: Chromosomal deletions of 10q and candidate genes such as PTEN and DMBT1 have been thoroughly investigated in glioblastomas but few data specifically address oligodendrogliomas. METHODS: In this study, 39 pure oligodendrogliomas were investigated for loss of heterozygosity (LOH) on 10q, PTEN mutations, and DMBT1 homozygous deletions. The LOH on 10q was found in 19 (48%) of 39 oligodendrogliomas and was closely related to anaplasia (p = 0.02), shorter time to progression (p = 0.0005), and poorer survival (p = 0.035). The DMBT1 homozygous deletions were found in 10 (26%) of 39 oligodendrogliomas but only one PTEN mutation was detected. The LOH on 10q is a strong predictor of survival and could be a valuable prognostic marker in oligodendrogliomas. CONCLUSIONS: Frequent inactivation of DMBT1 contrasting with rare mutations of PTEN may indicate that DMBT1 is preferentially involved in oligodendrogliomas. Nevertheless, the absence of a correlation with survival makes the role of DMBT1 in tumorigenesis still questionable and warrants further investigation.

Agglutinins↗