Catherine Gozé

Imaging growth and isocitrate dehydrogenase 1 mutation are independent predictors for diffuse low-grade gliomas

BACKGROUND We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults. METHODS One hundred thirty-one adult patients with newly diagnosed supratentorial diffuse low-grade gliomas were retrospectively studied. RESULTS Isocitrate dehydrogenase 1 mutations were present in 107 patients. The mean spontaneous velocity of diametric expansion was 5.40 ± 5.46 mm/y. During follow-up (mean, 70 ± 54.7 mo), 56 patients presented a malignant transformation and 23 died. The median malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (149 and 198 mo, respectively) than in cases of fast velocity of diametric expansion (46 and 82 mo; P < .001 and P < .001, respectively) and in cases with IDH1 mutation (100 and 198 mo, respectively) than in cases without IDH1 mutation (72 mo and not reached; P = .028 and P = .001, respectively). In multivariate analyses, spontaneous velocity of diametric expansion and IDH1 mutation were independent prognostic factors for malignant progression-free survival (P < .001; hazard ratio, 4.23; 95% CI, 1.81-9.40 and P = .019; hazard ratio, 2.39; 95% CI, 1.19-4.66, respectively) and for overall survival (P < .001; hazard ratio, 26.3; 95% CI, 5.42-185.2 and P = .007; hazard ratio, 17.89; 95% CI, 2.15-200.1, respectively). CONCLUSIONS The spontaneous velocity of diametric expansion and IDH1 mutation status are 2 independent prognostic values that should be obtained at the beginning of the management of diffuse low-grade gliomas in adults.

Microfoci of malignant progression in diffuse low-grade gliomas: towards the creation of an intermediate grade in glioma classification?

Low-grade gliomas (GII) inescapably progress to high-grade gliomas (GIII). The duration of this transition is highly variable between patients and reliable predictive markers do not exist. We noticed in a subset of cases of GII, obtained by awake neurosurgery, the presence of microfoci with high cellular density, high vascular density, or minimal endothelial proliferation, which we called GII+. Our aim was to investigate whether these foci display immunohistochemical and molecular characteristics similar to GIII and whether their presence is correlated to poor prognosis. We analyzed cell proliferation, hypoxia, vascularization, and alterations of tumorigenic pathways by immunohistochemistry (Ki-67, CD31, HIF-1-alpha, EGFR, P-AKT, P53, MDM2) and fluorescence in situ hybridization (EGFR, MDM2, PDGFRA) in the hypercellular foci of 16 GII+ cases. We compared overall survival between GII, GII+, and GIII. Ki-67, and CD31 expression was higher in the foci than in the tumor background in all cases. Aberrant expression of protein markers and genomic aberrations were also observed in some foci, distinct from the tumor background. Survival was shorter in GII+ than in GII cases. Our results suggest that these foci are the early histological hallmark of anaplastic transformation, which is supported by molecular aberrations. Our study is the first to demonstrate intratumoral morphological, immunohistochemical, and molecular heterogeneity in resection specimens of GII, the presence of which is correlated to shorter survival. Our findings question the discriminative capacity of the current glioma classification and provide arguments in favor of the creation of a grade intermediate between GII and GIII, to optimize the treatment strategy of GII.

World Health Organization Grade II Gliomas and Subventricular Zone: Anatomic, Genetic, and Clinical Considerations

BACKGROUND:Recent studies suggest a possible origin of human gliomas from subventricular zone (SVZ) stem cells. OBJECTIVE:To evaluate the relationship of World Health Organization grade II gliomas (GIIGs) with the SVZ and to investigate the presence of different genetic patterns, depending on their relationship with the SVZ. METHODS:Forty-three consecutive patients were operated on for GIIG. Preoperative fluid-attenuated inversion recovery-weighted magnetic resonance images were reviewed to assess the presence of cortical involvement and the relationship between gliomas and the SVZ. Patients were divided into 2 groups: group 1, tumors in contact with the SVZ; and group 2, tumors not in contact with the SVZ. Preoperative and postoperative tumor volumes were calculated. Genetic analysis was performed to study 1p19q allelic loss. RESULTS:Twenty-four patients were in group 1 and 19 in group 2. All tumors were in contact with the cortex. Preoperative volume was significantly larger in group 1 than in group 2 (P = .003). The proportion of total and subtotal resections was higher in group 2 (P = .01). Insular tumors never showed 1p19q codeletions. Noninsular tumors exhibited a significantly different incidence of complete 1p19q codeletion, with allelic loss more common in group 1 (P = .03). CONCLUSION:GIIGs showed a constant relationship with the cortex and a larger volume when they came in contact with the ventricles. A distinct genetic pattern was found in noninsular SVZ GIIGs. This parameter can be considered for therapeutic management.

IDH mutation and 1p19q codeletion distinguish two radiological patterns of diffuse low-grade gliomas

Diffuse low-grade gliomas (DLGG) prognosis is variable, depending on several factors, including the isocitrate dehydrogenase (IDH) mutation and the 1p19q codeletion. A few studies suggested associations between these parameters and tumor radiological characteristics including topography. Our aim was analyzing the correlations between the IDH and 1p19q statuses and the tumor intracerebral distribution (at the lobar and voxel levels), volume, and borders. We conducted a retrospective, monocentric study on a consecutive series of 198 DLGG patients. The IDH and 1p19q statuses were recorded. The pre-treatment magnetic resonance FLAIR imagings were reviewed for determination of lobar topography, tumor volume, and characterisation of tumor borders (sharp or indistinct). We conducted a voxel-based lesion-symptom mapping analysis to investigate the correlations between the IDH and 1p19q statuses and topography at the voxel level. The IDH mutation and 1p19q statuses were correlated with the tumor topography defined using lobar anatomy (p < 0.001 and p = 0.004, respectively). Frontal tumors were more frequently IDH-mutant (87.1 vs. 57.4%) and 1p19q codeleted (45.2 vs. 17.0%) than temporo-insular lesions. At the voxel level, these associations were not found. Tumors with sharp borders were more frequently IDH-mutant (p = 0.001) while tumors with indistinct borders were more frequently IDH wild-type and 1p19q non-codeleted (p < 0.001). Larger tumors at diagnosis (possibly linked to a slower growth rate) were more frequently IDH-mutant (p < 0.001). IDH wild-type, 1p19q non-codeleted temporo-insular tumors are distinct from IDH-mutant, 1p19q codeleted frontal tumors. Further studies are needed to determine whether the therapeutic strategy should be adapted to each pattern.

Synthesis of a large peptide mimicking the DNA binding properties of the sex determining protein, SRY

The sex determining protein, SRY, has been recently described as containing a DNA binding motif, also called the SRY box. This 80 amino acid box was synthesized using the continuous flow solid‐phase technique. The product was then purified and tested according to such diverse criteria as its intrinsic structure or its biological activity (DNA binding capacity), and compared to the full‐length protein. The data indicate that the peptide is relevant for the properties described so far for the protein.

Gene SRY et anomalies de la determination genetique du sexe chez l’homme

Normal sexual development in man is the consequence of a complex process. This review focuses on the translation of genedal sex (XX or XY karyotype) into gonadal sex (testis or ovary). During the last three years attempts to identify and clone the testis determining factor (TDF) have exploited detailed maps of the Y chromosome established by geneticists over the last decade. A candidate gene, named SRY (sex determining region, Y) located at the tip of the short arm of the Y chromosome, shows many characteristics in common with TDF in that it is the sole element of the Y chromosome required for male development. The discovery of TDF led us to analyse sex-reversed individuals, i.e. XX males and XY females, with the aim of constructing a model for the processes regulating the development of an organ as complex as the testis. This SRY gene is now the subject of intense molecular biological effort by various groups, effort which we hope will elucidate the mechanism(s) of sex determination.ResumeLa compréhension des mécanismes de détermination du sexe chez l’homme a franchi une étape importante ces trois dernières années. Le gène SRY, localisé sur le chromosome Y, et seul élément nécessaire de ce chromosome au développement mâle, a ainsi pu être isolé. De nombreux critères permettent aujour ’hui de l’assimiler au facteur TDF (ou „testis determining factor”). Par l’étude des propriétés de la protéine SRY et par l’étude d’autres formes d’ambiguités sexuelles, on espère aujourd’hui pouvoir progresser dans la reconstitution de la cascade conduisant à la formation d’un organe aussi complexe que le testicule. On conçoit le formidable challenge que cette recherche constitue dans le domaine de la biologie du développement