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Jean-Yves Delattre

Publications and source records attributed to Jean-Yves Delattre.

At least 19 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↗
PubMed2007

The 61 A/G EGF polymorphism is functional but is neither a prognostic marker nor a risk factor for glioblastoma.

The A/G61 polymorphism located in the 5'UTR of the EGF gene has been found to be both a risk factor and a prognostic factor in glioblastoma (GBM), but the functional consequences have not been investigated. Here we show, in vitro, that this polymorphism is functional, in that the G allele promoter is 40% more active than the A variant (P < 0.001). However, analysis of a large series of 209 GBM patients and 214 control subjects did not confirm that A/G61 polymorphism is a significant risk factor for GBM, despite a trend for higher GG frequency in these patients. Furthermore, A/G61 polymorphism was not a prognostic factor for survival in GBM patients, although it does appear to affect progression-free survival.

5' Untranslated Regions↗
PubMed2006

Prognostic stratification of patients with anaplastic gliomas according to genetic profile.

BACKGROUND: There is a need to improve the current, controversial, and poorly reproducible classification of anaplastic gliomas, which represent a highly heterogeneous entity in terms of survival. METHODS: The impact of the most common genetic alterations on survival was investigated based on 156 anaplastic gliomas: Among the patients who were included, the gender ratio was 1.32, the median age was 45.5 years (range, 20-83 years), and the median Karnofsky performance status was 70 (range, 40-100). Genetic analysis included a search for loss of heterozygosity (LOH) on chromosomes 1p and 19q; amplification of chromosomes 9p and 10q and of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4) and mouse double-minute (MDM2) genes; and p53 expression. RESULTS: The median survival was 33.5 months, and the median progression-free survival was 15.8 months. In a univariate analysis, LOH on 1p and 19q was correlated with longer survival, whereas p53 expression, LOH on 9p, LOH on 10q, amplified EGFR, and deleted CDKN2A were correlated with shorter survival. LOH on 1p and 19q were associated with oligodendrogliomas, LOH on 10q was related to EGFR amplification, and LOH on 1p and 19q was mutually exclusive with EGFR amplification and LOH on 10q. In a multivariate analysis, the significant prognostic factors were age, histology, LOH on 1p and 19q, and P16/CDKN2A deletion. Recursive partitioning analysis (RPA) divided the whole group hierarchically into 3 distinct prognostic subgroups: Group A with 1p19q codeletion (median survival, 98 months), Group B with EGFR amplification (median survival, 17 months), and Group CC (median survival, 31 months), providing a basis for a genetically based prognostic subclassification for patients with Grade III gliomas. CONCLUSIONS: The search for 1p19q codeletion and EGFR receptor amplification provides a simple, clinically relevant prognostic subclassification of grade III gliomas.

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

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↗
PubMed2006

Glioma in the elderly.

PURPOSE OF REVIEW: This review updates available data on the management of gliomas in the elderly. RECENT FINDINGS: Prospective randomized studies have recently established the benefit of radiotherapy and the validity of an accelerated course of irradiation in older patients with malignant gliomas. SUMMARY: The incidence of gliomas is increasing in the elderly population. Unfortunately, increasing age is one of the most consistent negative prognostic factors in gliomas and the optimal management of this population remains unsettled since patients aged 65 years or more are usually excluded from clinical trials. The previous nihilistic approach is progressively changing towards more active strategies with recent evidence that older patients (70-80 years) may benefit from surgery, radiotherapy, or chemotherapy. Initial performance status, quality of life, and concomitant pathologies are important factors to consider before treatment onset. In the future, it will be necessary to design specific schedules of treatment in this population.

Aged↗
PubMed2006

Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma.

Oligodeoxynucleotides containing CpG motifs (CpG ODNs) display a strong immunostimulating activity and drive the immune response toward the Th1 (T helper type 1) phenotype. These ODNs have shown promising efficacy in preclinical studies when injected locally in several cancer models. We conducted a phase 1 trial to define the safety profile of CpG-28, a phosphorothioate CpG ODN, administered intratumorally by convection-enhanced delivery in patients with recurrent glioblastoma. Cohorts of three to six patients were treated with escalating doses of CpG-28 (0.5-20 mg), and patients were observed for at least four months. Twenty-four patients entered the trial. All patients had previously been treated with radiotherapy, and most patients had received one or several types of chemotherapy. Median age was 58 years (range, 25-73) and median KPS was 80% (range, 60%-100%). Adverse effects possibly or probably related to the studied drug were moderate and consisted mainly in worsening of neurological conditions (four patients), fever above 38 degrees C that disappeared within a few days (five patients), and reversible grade 3 lymphopenia (seven patients). Only one patient experienced a dose-limiting toxicity. Preliminary evidence of activity was suggested by a minor response observed in two patients and an overall median survival of 7.2 months. In conclusion, CpG-28 was well tolerated at doses up to 20 mg per injection in patients with recurrent glioblastoma. Main side effects were limited to transient worsening of neurological condition and fever.

Adjuvants, Immunologic↗
PubMed2006

Role of ABC transporters in the chemoresistance of human gliomas.

Malignant gliomas are frequently chemoresistant and this resistance seems to depend on at least two mechanisms. First, the poor penetration of many anticancer drugs across the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB) and blood-tumor barrier (BTB), due to their interaction with several ATP-binding cassette (ABC) drug efflux transporters that are overexpressed by the endothelial or epithelial cells of these barriers. Second, resistance may involve the tumor cells themselves. Although ABC drug efflux transporters in tumor cells confer multidrug resistance (MDR) on several other solid tumors, their role in gliomas is unclear. This review focuses on astrocytes and summarizes the current state of knowledge about the expression, distribution and function of ABC transporters in normal and tumor astroglial cells. The recognition of anticancer drugs by ABC transporters in astroglial cells and their participation in the multidrug resistance phenotype of human gliomas is discussed.

ATP-Binding Cassette Transporters↗
PubMed2006

[Update on cerebral tumors].

This review aims to discuss the main advances in gliomas, primary cerebral lymphomas and cerebral metastasis. The recent development of molecular biology and cerebral imaging allows a better understanding and management of gliomas and phase III studies have concluded to the benefit of adjuvant temozolomide administered during and after radiotherapy for glioblastomas: this strategy is yet to become a standard. Optimal treatment for primary central nervous system lymphoma remains to be defined, and several studies aims to precise the value of radiotherapy as consolidation treatment. Several trials reviewing the current treatment options for brain metastasis (whole brain radiation therapy, surgical resection stereotactic radiosurgery and chemotherapy) are highlighted.

Antineoplastic Agents↗
PubMed2005

Successful combination of local CpG-ODN and radiotherapy in malignant glioma.

Oligodeoxynucleotides containing CpG motifs (CpG-ODN) display broad immunostimulating activity and are currently under clinical trial in various malignancies, including recurrent glioblastomas. Combining CpG-ODN with another therapy that could induce antigen release might enhance tumor-specific immune response. We investigated whether radiotherapy (RT) could be associated advantageously to intratumoral injections of CpG-ODN. Fisher rats bearing 9L glioma were treated with various combinations of RT and CpG-28, an oligonucleotide with good immunostimulating activity. RT and CpG-28 induced complete tumor remission in one-third of the animals. When both treatments were combined, complete tumor remission was achieved in two-thirds of the animals (p < 0.001 when compared to non-treated rats, p < 0.03 when compared to CpG-28 alone). Such efficacy was not observed in nude mice, underlying the role of T cells in antitumor effects. The combination of both treatments appeared optimal when the delay between RT and CpG-28 administration was <3 days (from 100% survival for a 3 days delay, to 57% survival for a 21 days delay, p < 0.05). Tumor infiltration by immune cells and expression within tumors of the CpG receptor, TLR9, were not modified by irradiation. These results support an attractive strategy of sequential radiotherapy and immunotherapy by CpG-ODN and have potential implications for future clinical trials with CpG-ODN.

Animals↗
PubMed2005

Epileptic seizures during follow-up of patients treated for primary brain tumors.

OBJECTIVE: To determine the presentation, incidence, and severity of seizures in follow-up of patients treated for primary brain tumors. METHODS: A total of 234 consecutive patients attending an outpatient clinic for chemotherapy of a supratentorial brain tumor were examined. RESULTS: Seizures occurred in 183 patients. All patients with epilepsy were on antiepileptic drugs (AEDs). Compared with patients without epilepsy, patients with epilepsy had a higher proportion of low-grade gliomas (p < 0.001) and cortical tumor location (p < 0.001). In 158 (86.4%) patients, seizures were an early manifestation of the disease, and epilepsy developed in only 25 (13.6%) individuals in the course of the malignant disease. Generalization occurred in 50% of early seizures, but in only 19.1% of patients with seizures persisting after the initiation of AEDs and specific antitumor therapies. The reduction in seizure generalization was significant (p = 0.001). Despite AED and various antitumor treatments, one-half of the patients had a seizure within 1 month and two-thirds within 3 months before the last evaluation. CONCLUSIONS: Most tumor-related seizures first appear early in the course of disease, usually as a presenting manifestation. Antiepileptic drugs combined with specific antitumor treatments significantly reduce the rate of seizure generalization. However, most patients continue to have focal epilepsy during follow-up.

Adult↗
PubMed2005

Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases.

PURPOSE: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older. PATIENTS AND METHODS: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively. RESULTS: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum doses were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% +/- 5% and 13% +/- 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% +/- 6% and 40% +/- 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% +/- 2% and 91% +/- 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis. Seven cases of radionecrosis were described and were related to the margin dose (p = 0.03). CONCLUSION: Radiosurgery for elderly patients was effective and safe. Age alone should not be a criterion for denying radiosurgery to any patient with brain metastases.

Aged↗
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

Clinical relevance of non-neuronal auto-antibodies in patients with anti-Hu or anti-Yo paraneoplastic diseases.

About half of the patients with paraneoplastic diseases develop an immune response against neuronal antigens expressed by both the tumor and the nervous system. In 31 patients with anti-Hu antibodies and 19 patients with anti-Yo antibodies, we searched for the presence of additional non-neuronal auto-antibodies and further studied whether the presence of such auto-antibodies was correlated with a specific oncological or neurological presentation. Positive antinuclear antibodies (ANA) were found at a titer of 1:40 or above in 48% patients with anti-Hu antibodies, and in 37% patients with anti-Yo antibodies. Anti-cytoplasmic antibodies were also detected in 42% patients with anti-Yo antibodies. No specific correlation between the presence of non-neuronal auto-antibodies and clinical characteristics of the patients could be identified. In particular, neither the type of underlying cancer, the overall survival, the tumor response to treatment, nor the neurological presentation were related to the serological status.

Aged↗
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↗