Search

Objective: To evaluate the natural progression and the impact of temozolomide in low-grade gliomas and to correlate these changes with the profile of genetic alterations.Methods: The mean tumor diameter (MTD) of low-grade gliomas was evaluated on serial magnetic resonance images before (n = 39), during, and after (n = 107) treatment with neoadjuvant temozolomide. MTD growth curves were correlated with chromosomes 1p-19q loss and p53 overexpression in the tumors.Results: Before temozolomide onset, MTD increased linearly over time, indicating a continuous growth that was significantly slower in 1p-19q deleted tumors (3.4 vs 5.9mm/year; p = 0.0016) and in tumors that did not overexpress p53 (4.2 vs 6.3mm/year; p = 0.05). During temozolomide treatment, almost all patients (92%) experienced initial decrease of MTD. Subsequently, some tumors started to resume growth despite continuous administration of temozolomide, with a lower rate of relapse in 1p-19q deleted tumors (16.6 vs 58%; p = 0.0004) and in tumors that did not overexpress p53 (26 vs 68%; p = 0.003). When temozolomide was discontinued in the absence of tumor progression, a majority of tumors resumed their progressive growth within a year.Interpretation: Untreated low-grade gliomas grow continuously at a rate that is influenced by the genetic alterations of the tumors. Temozolomide reverses this pattern at the onset, but this effect is often brief in patients whose tumors overexpress p53 and do not harbor the 1p-19q codeletion, suggesting acquired chemoresistance. A majority of tumors will resume their growth when treatment is discontinued, raising the issue of the optimal duration of treatment in continuously responding patients. [ABSTRACT FROM AUTHOR]

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.

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.

Serial magnetic resonance images of 27 patients with untreated World Health Organization grade II oligodendrogliomas or mixed gliomas were reviewed retrospectively to study the kinetics of tumor growth before anaplastic transformation. Analysis of the mean tumor diameters over time showed constant growth. Linear regression, using a mixed model, found an average slope of 4.1mm per year (95% confidence interval, 3.8-4.4mm/year). Untreated low-grade oligodendrogliomas or mixed gliomas grow continuously during their premalignant phase, and their pattern of growth can be predicted within a relatively narrow range. These findings could be of interest to optimize patients management and follow-up.

Portions of chromosomes 1p and 19q, which are frequently deleted in oligodendrogliomas, are subject to genomic imprinting, suggesting that the putative tumor suppressor genes could be monoallelically expressed. The parental origins of 1p and 19q allele losses were determined in 6 cases of pure oligodendroglioma. An equilibrated parental loss (3 maternal and 3 paternal) was found for 1p deletions. In contrast, 19q deletions always occurred on the paternal copy (p = 0.015). In this setting, a cloning strategy based on a search for homozygous deletion or mutation of the remaining allele would be appropriate for identifying the tumor suppressor gene located on 1p but inappropriate for identifying the presumably monoallelically expressed tumor suppressor gene located on 19q.

Constitutional DNA from 44 selected patients suspected of being genetically predisposed to develop astrocytic tumors was analyzed for germline mutations of the p53, p16, and PTEN genes. Six constitutional missense mutations of the p53 gene were identified (13.6%), but no mutations of the p16 and PTEN genes were found, suggesting that (1) germline p53 mutations contribute to a small portion of astrocytic tumors, (2) inherited mutations of the p16 and PTEN gene do not predispose to the development of gliomas, and (3) other genes are involved in glioma predisposition.

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associated with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies, also called the "anti-Hu syndrome," is believed to result from an immune response triggered by tumor antigens and misdirected to the neurons. To further assess the issue of cell-mediated immunity in this disease, the peripheral blood lymphocyte surface phenotype was studied in 15 patients suffering from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein was used to stimulate in vitro peripheral blood mononuclear cells of 10 seropositive patients and of 10 patients from each control group. Phenotypic analysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO+CD4+) T cells in the seropositive group in comparison with the two control groups. Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [3H]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells revealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant increase of the interferon-gamma/interleukin-4 ratio was found in culture supernatants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protein is an antigenic target for autoreactive CD4+ T cells, presumably of the Th1 subtype, which could therefore be directly involved in cell-mediated injury of the nervous system as well as in antitumoral immunity.