Jean-Yves Delattre

Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions.

PURPOSEnTo determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response.nnnPATIENTS AND METHODSnAdult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique.nnnRESULTSnSixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004).nnnCONCLUSIONnTMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.

A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry

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.

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. Ann Neurol 2005;58:483–487

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

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.

OLIG2 as a specific marker of oligodendroglial tumour cells

OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.

BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas

The pathological classification of gliomas constitutes a critical step of the clinical management of patients, yet it is frequently challenging. To assess the relationship between genetic abnormalities and clinicopathological characteristics, we have performed a genetic and clinical analysis of a series of gliomas. A total of 112 gliomas were analyzed by comparative genomic hybridization on a BAC array with a 1 megabase resolution. Altered regions were identified and correlation analysis enabled to retrieve significant associations and exclusions. Whole chromosomes (chrs) 1p and 19q losses with centromeric breakpoints and EGFR high level amplification were found to be mutually exclusive, permitting identification of 3 distinct, nonoverlapping groups of tumors with striking clinicopathological differences. Type A tumors with chrs 1p and 19q codeletion exhibited an oligodendroglial phenotype and a longer patient survival. Type B tumors were characterized by EGFR amplification. They harbored a WHO high grade of malignancy and a short patient survival. Finally, type C tumors displayed none of the previous patterns but the presence of chr 7 gain, chr 9p deletion and/or chr 10 loss. It included astrocytic tumors in patients younger than in type B and whose prognosis was highly dependent upon the number of alterations. A multivariate analysis based on a Cox model shows that age, WHO grade and genomic type provide complementary prognostic informations. Finally, our results highlight the potential of a whole‐genome analysis as an additional diagnostic in cases of unclear conventional genetic findings.

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 (17.1xa0months vs. 13.1) for patients treated with RT+ adjuvant chemotherapy (relative risk of death (RR)xa0=xa00.53; Pxa0=xa00.041), particularly when patients received CT during the course of RT (MSxa0=xa019.9xa0months vs. 12.5xa0months; RRxa0=xa00.227, Pxa0=xa00.001). 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.

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. Ann Neurol 2005;58:322–326

FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status

FABP7 expression has been analysed in a series of 123 glioblastomas (68 pure GBM, 55 GBMO, i.e. with oligodendroglial component). FABP7, found in 91/123 samples, showed a pure cytoplasmic expression in 69 cases, and cytoplasmicxa0+xa0nuclear expression in 22 cases. FABP7 expression was associated with pure GBM histology and shorter survival (15.7 months versus 21.5xa0months). Nuclear expression of FABP7 was more specifically related to EGFR amplification and more invasive tumors. These data, although they need to be confirmed by further studies, support the relation between FABP7, astrocytic features, invasion and poor prognosis and suggests that EGFR amplification is associated with nuclear translocation of FABP7.

Genomic changes in progression of low-grade gliomas

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.