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Magnetic resonance spectroscopy (MRS), that may be added to conventional magnetic resonance imaging (MRI) exam exhibit an increasing role in the management of brain tumors. These technique allow quantitative analysis of metabolites, either cell specific, either reflecting physiological and/or pathological process. With a rigorous approach, MRS explore brain metabolism that may improve MRI data in clinical practice in neuro-oncology. Positive diagnosis of brain tumor, differential diagnosis between infiltrative glioma (grade II) and gliomatosis, determination of the limits of tumor infiltration, and distinction between tumor and post-therapeutic images are some of the potential applications of MRS. Ongoing and future studies may also precise the place of MRS in the differential diagnosis between high grade glioma, metastasis and CNS lymphoma, as well as in monitoring therapy in glioma.

Announcement of cancer diagnosis and first contact with medical team in charge of treatment is critical for the patient as well as for the quality of care. The French Cancer Plan include a special focus on these announcement which should be performed in adequate conditions and which should include the presentation of a personalised treatment plan, that reflect multidisciplinary discussion and decision performed before. In order to generalized a formal announcement consultation all over the country in 2005, an experimentation has been performed in 58 centers grouped in 37 projects. Neuro-Oncology Unit of the Assistance Publique-Hopitaux de Marseille did participate to that experimentation. Evaluation of these experiment focus on physician, nurse, and patient perception as well as cost impact and exploration of language during that particular time. Implication of a referent nurse in that time was a strong option of our center. We analyzed the result in 80 patients referred in our center for initial diagnosis (78%) or announcement of recurrence (14%) in a 5 months time. Implication of the nurse appear to be critical for patient confidence and accessibility to information for the all medical team. Organization of a particular time devoted to cancer announcement appear to have a favourable impact on quality of care and patient perception, and constitute a first step to a personalized management of patients with cancer.

Background: Management of unresectable progressive meningioma remains controversial and constitutes a major challenge since therapeutic options including chemotherapy and hormone modulation are limited. Recent data have suggested that hydroxyurea treatment may have an antitumoral effect. The purpose of this prospective phase II study was to evaluate the efficacy of hydroxyurea treatment for unresectable progressive meningioma., Methods: From 1997 to 1999, consecutive patients presenting unresectable meningioma with clinically and/or neuroradiologically documented progression were considered for entry into this protocol. Previous radiotherapy was not a mandatory inclusion criteria. Treatment consisted of continuous oral administration of hydroxyurea at a dose of 20 mg/kg per day. Follow-up assessment included physical examination, computed tomography (CT), and magnetic resonance imaging (MRI) performed every three months, as well as regular blood testing. The primary endpoint was documentation of objective response by MRI or CT., Results: The intent-to-treat population was 43 patients with at least 18 months follow-up. Median age was 60.4 years. Twenty-eight patients had undergone surgery following initial diagnosis. The meningioma was located in the skull base in 67% of patients. Histology was benign in 18 and atypical in 10. The eligible population included 36 patients with documented progressive disease at the time of inclusion; with progression documented clinically in 29 (67.5%) and/or radiologically in 20 (46%). In 7 patients, clinical or radiological progression could not be confirmed. The intent-to-treat analysis at median 26 months follow-up revealed objective response to hydroxyurea in only 3 patients (7%) including one on the basis of improvement in visual symptoms and two on MRI analysis. Progressive disease was observed clinically or radiologically in 26 patients (60.5%). Of the eligible population (n=36), 2 achieved an objective response and 13 (36%) exhibited stabilization under hydroxyurea therapy, while 21 (58%) progressed under treatment. Overall tolerance was good but anemia (grade I-II) and asthenia (grade I-II) were observed in 28% and 23.5% respectively. Treatment was discontinued in 3 patients because of chronic skin toxicity in one and anemia and asthenia in two., Conclusion: Hydroxyurea treatment is of marginal efficacy for meningioma and must not be considered as an alternative if radiotherapy or surgery is feasible. New efficient medical treatments are still required for progressive meningiomas.

Among diffuse gliomas, oligodendrogliomas may account for 25% of cases. They have a better prognosis and chemosensitivity as compared to astrocytomas. Genetic studies have shown a correlation between oligodendrocyte phenotype and presence of 1p/19q deletions. In addition, these deletions are of prognostic value. The aim of the present study was to describe a new method to detect 1p/19q deletions when little tumoral material is available (stereotactic biopsies (SBs)). Since smears (cytological preparations) are routinely done for intraoperative diagnosis of gliomas, we have searched for 1p/19q deletions by FISH in a series of 30 patients with a glioma. In 14 cases, loss of heterozygosity (LOH) analysis was also performed in order to validate our method. We found that FISH analysis on frozen smears was a simple, rapid and reliable method to detect 1p/19q deletions and a good concordance was found with LOH data (85%). The main advantages of FISH analysis on frozen smears are the following. First, it requires little material and can be easily done in the case of SBs. Second, it has a higher sensitivity than LOH especially in infiltrative areas of gliomas. Third, it allows detection of a codeletion 1p/19q in a single tumor cell. In contrast, LOH analysis is easier to interpret and can detect smaller and partial deletion whose pronostic significance remains to be defined. In conclusion, these two techniques can be used to investigate 1p/19q status in gliomas. The appropriate choice of one or other of these two techniques will depend on the specific questions that need to be answered.

Recently, we demonstrated that U87 glioblastoma xenograft tumors treated with anti-adrenomedullin (AM) antibody were less vascularized than control tumors, suggesting that AM might be involved in neovascularization and/or vessel stabilization. Angiogenesis, the sprouting of new capillaries from preexisting blood vessels, is a multistep process that involves migration and proliferation of endothelial cells, remodeling of the extracellular matrix and functional maturation of the newly assembled vessels. In our study, we analyzed the role of AM on human umbilical vein endothelial cell (HUVEC) phenotype related to different stages of angiogenesis. Here we report evidence that AM promoted HUVEC migration and invasion in a dose-dependent manner. The action of AM is specific and is mediated by the calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) receptors. Furthermore, AM was able to induce HUVEC differentiation into cord-like structures on Matrigel. Suboptimal concentrations of vascular endothelial growth factor (VEGF) and AM acted synergistically to induce angiogenic-related effects on endothelial cells in vitro. Blocking antibodies to VEGF did not significantly inhibit AM-induced capillary tube formation by human endothelial cells, indicating that AM does not function indirectly through upregulation of VEGF. These findings suggest that the proangiogenic action of AM on cultured endothelial cells via CRLR/RAMP2 and CRLR/RAMP3 receptors may translate in vivo into enhanced neovascularization and therefore identify AM and its receptors acting as potential new targets for antiangiogenic therapies., (Copyright 2003 Wiley-Liss, Inc.)

Context: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objective: To define clinical practice guidelines for the management of adult patients with intracranial glioma in collaboration with the Association of French-speaking Neuro-oncologists (Anocef) and the French society of neurosurgeons (SNCLF). These recommendations cover diagnosis, classification, treatment and follow-up of patients with these tumors., Method: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers., Results: This article is a summary version of the full document presenting the clinical practice guidelines with algorithms. The main recommendations concern the place of the surgery, radiotherapy, chemiotherapy, imagery and concomitant medical treatments in the specific treatment strategy of grade III and IV glioma, grade II glioma, gliomatosis cerebri, pilocytic astrocytoma, subependymoma, xanthoastrocytoma, intracranial ependymoma and brain stem glioma.

Purpose: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma., Patients and Methods: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years., Results: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively., Conclusion: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.

Purpose: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy., Patients and Methods: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed., Results: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression., Conclusion: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

Background: Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy., Patients and Methods: In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed., Results: Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression., Conclusions: TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.

Object: Gliomatosis cerebri (GC), a rare entity characterized by a widespread infiltration of brain by tumor, lacks objective and quantitative diagnostic criteria. Single-voxel spectroscopy and chemical shift imaging (two-dimensional proton magnetic resonance [MR] spectroscopy) were performed using both short (20- or 22-msec) and long (135-msec) echo times in nine patients suffering from GC, nine patients with low-grade gliomas (LGGs), and 25 healthy volunteers to establish the precise metabolic pattern of this uncommon brain neoplasm., Methods: The gliomatosis infiltration was characterized by markedly elevated levels of creatine-phosphocreatine (Cr) and mvo-inositol (Ins), a reduced level of N-acetyl aspartate (NAA), and a moderately elevated level of choline-containing compounds (Cho). This pattern differs strikingly from LGGs, which are characterized by elevated levels of Cho and Ins, markedly reduced levels of NAA, and low-to-normal Cr concentrations. Although the distinction between GC and LGG, based on histological and MR imaging criteria, is a matter of debate, MR spectroscopy produces valuable information for the differentiation between these two entities and, hence, the choice of therapeutic strategy. It also provides new insight into the pathophysiology of GC because elevated Cr and Ins levels may be related to proliferation of glial elements or, more probably, activation of normal glia. Elevated levels of Cho reflect cellular proliferation and reduced NAA corresponds to reversible neuronal injury and/or focal invasion by the tumor process., Conclusions: Owing to the unfavorable clinical outcome associated with GC compared with that associated with LGG, the findings of this study illustrate the diagnostic and prognostic value of proton MR spectroscopy in the characterization of infiltrating gliomas.

The diagnosis of Gliomatosis cerebri (GC) is known to be difficult and is still a matter of debate. In order to better define this entity, we studied clinical, neuroradiological, pathological and follow-up data of 9 patients affected with GC. MRI were done with T1 before and after gadolinium injection, and with T2-weighted images and Flair in 3 cases. Histological confirmation of glial proliferation was obtained in all patients by craniotomy or stereotactic biopsies. Patients were treated and followed-up in our center. The histological analyses highlighted a heterogeneous glial proliferation with various degrees of anaplasia in all the cases including 2 cases of oligodendroglioma, 1 case of anaplastic oligodendroglioma, 2 cases of anaplastic mixed oligoastrocytoma, 1 case of anaplastic astrocytoma, 2 cases of glioblastoma and 1 case of astrocytic proliferation typical of GC. The topography of the tumoral infiltration was characteristic involving mainly the white matter, basal ganglia and thalamus, brainstem and less often hypothalamus. More than two cerebral lobes were involved. Contrast enhancement, mass effect and necrosis were minimal compared to the extent of tumoral infiltration. Patients were treated with various schemes of treatment all including nitrosourea. Survival from diagnosis was under one year except for 2 patients (17 and 14 months). This study shows that the diagnosis of GC needs to be based not on pathological data alone, but on pathological, clinical and, above all, on radiological criteria. Response to therapy could not clearly be observed in GC, despite oligodendroglial component in 6/9 cases. Prognosis of GC was constantly poor.

Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Peptidylglycine alpha-amidating monooxygenase is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. The high expression of peptidylglycine alpha-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of alpha-amidated peptides in tumorigenic growth processes in the brain. After screening of amidated peptides, it was found that human glioblastoma cell lines express high levels of adrenomedullin (AM) mRNA, and that immunoreactive AM is released into the culture medium. AM is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analyzed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendrogliomas. In the present study we also demonstrate the presence of mRNA encoding the putative AM receptors, calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both glioma tissues and glioblastoma cell lines and further show that exogenously added AM can stimulate the growth of these glioblastoma cells in vitro. These findings suggest that AM may function as an autocrine growth factor for glioblastoma cells. One way to test the autocrine hypothesis is to interrupt the function of the endogenously produced AM. Herein, we demonstrate that a polyclonal antibody specific to AM, blocks the binding of the hormone to its cellular receptors and decreases by 33% (P < 0.001) the growth of U87 glioblastoma cells in vitro. Intratumoral administration of the anti-AM antibody resulted in a 70% (P < 0.001) reduction in subcutaneous U87 xenograft weight 21 days after treatment. Furthermore, the density of vessels was decreased in the antibody-treated tumors. These findings support that AM may function as a potent autocrine/paracrine growth factor for human glioblastomas and demonstrate that inhibition of the action of AM (produced by tumor cells) may suppress tumor growth in vivo.

Cavernous sinus lymphoma is a rare occurrence. We report a case of a 37-year-old woman who was admitted for an oculo-motor paresis and retro-orbital pain. CT scan and MRI disclosed a cavernous sinus tumor. A surgical biopsy was performed through a pterional approach and the histological diagnosis was a solitary primary Burkitt's lymphoma. Aggressive chemotherapy led to a complete and asymptomatic remission after a follow-up of 9 years. The mechanism of the primary localization in the cavernous sinus is discussed.

Purpose: Most primary oligodendrogliomas and mixed gliomas (oligoastrocytoma) respond to treatment with procarbazine, lomustine, and vincristine (PCV), with response rates of approximately 80%. However, limited data on second-line treatments are available in patients with recurrent tumors. A novel second-generation alkylating agent, temozolomide, has recently demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme and anaplastic astrocytoma. This study describes the effects of temozolomide in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic mixed oligoastrocytoma (AOA)., Patients and Methods: Forty-eight patients with histologically confirmed AO or AOA who had received previous PCV chemotherapy were treated with temozolomide (150 to 200 mg/m2/d for 5 days per 28-day cycle). The primary end point was objective response. Secondary end points included progression-free survival (PFS), time to progression, overall survival (OS), safety, and tolerability., Results: Eight patients (16.7%) experienced a complete response, 13 patients (27.1%) experienced a partial response (objective response rate, 43.8%), and 19 patients (39.6%) experienced stable disease. For the entire treatment group, median PFS was 6.7 months and median OS was 10 months. For objective responders, median PFS was 13.1 months and median OS was 16 months. For complete responders, PFS was more than 11. 8 months and OS was more than 26 months. Response correlated with improved survival. Temozolomide was safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia., Conclusion: Temozolomide is safe and effective in the treatment of recurrent AO and AOA.

Objective: We report the long-term follow-up of 31 patients with cavernous sinus meningiomas who were treated either with surgery and radiotherapy (RT) or with RT alone. This retrospective review was undertaken to compare long-term efficacy and morbidity of RT with or without previous surgery versus complete, aggressive surgical removal., Methods: Between 1980 and 1997, we performed a retrospective study of 31 patients harboring cavernous sinus meningiomas. The patient group comprised 25 women and 6 men. Patients were divided into two therapeutic categories: patients treated with surgery and RT (Group I, 17 patients) and patients treated with RT alone (Group II, 14 patients). Twenty-five patients (14 in Group I and 11 in Group II) were treated for primary tumors, and 6 patients (3 in Group I and 3 in Group II) were treated for recurrent disease. All three patients who were treated by RT alone at the time of recurrent disease had had previous surgery as initial treatment. Tumor control, treatment morbidity, and functional outcomes were evaluated for all patients. Twenty-eight patients were alive at the time of analysis, with a median follow-up period of 6.1 years., Results: The progression-free survival rate was 92.8% at 10-year follow-up. Only two patients exhibited tumor progression after initial treatment. One of the patients who experienced tumor regrowth 4 years after surgery and RT benefited from additional conventional external beam radiation, and this patient exhibited no evidence of tumor progression at the last follow-up examination 6 years later. Two patients experienced cranial nerve impairment after surgery, and no patients developed late radiation toxicity. Follow-up status as measured by the Karnofsky Performance Scale deteriorated in 7% of patients and was the same or improved in 93% of patients., Conclusion: The results of combined surgery and RT or RT alone indicated a high rate of tumor control and a low risk of complications. Complete aggressive surgical removal of cavernous sinus meningiomas is associated with an increased incidence of morbidity and mortality and does not demonstrate a better rate of tumor control. Conventional external beam radiation seems to be an efficient and safe initial or adjuvant treatment of these lesions, and these findings should serve as a basis for evaluating new alternatives such as radiosurgery or stereotactic RT.

Since glioblastomas in adults are uniformly fatal, evaluation of easily reproducible prognostic criteria which would attempt to define groups of patients is required. However, there is lack of a clear consensus regarding the expression of some markers in the literature. Therefore, an immunohistochemical study was performed to determine the prognostic significance of Ki67, p53, and epidermal growth factor receptor (EGFR) in a retrospective series of 63 glioblastomas. Image analysis was carried out in positive specimens to quantify the immunoprecipitates. p53 and EGFR expression were specifically addressed in the 36 primary glioblastomas reported in this series. In all cases, clinical data (age, Karnofsky performance scale index [KPS] before surgery, extent of surgery) and immunohistochemical features were analysed using univariate and multivariate analysis to ascertain whether any significant correlation exists between [1] EGFR expression [2], p53 accumulation [3], Ki67 labelling index and prognosis (survival time and disease-free survival time, DFST). The results showed that in this series of glioblastomas, none of these markers had any prognostic value. Among the clinical parameters, a high KPS before surgery was found to be indicative of a shorter DFST and survival time (P < 0.05), whereas a younger age at onset and total or subtotal surgical excision were associated with a longer survival (P < 0.001 and 0.05, respectively). EGFR protein accumulation was inversely correlated with p53 accumulation (P = 0.01). The percentage of the primary glioblastomas expressing EGFR was much lower in our study (33%) than in the literature suggesting that the molecular distinction between primary and secondary glioblastomas is not so clear-cut.

Plasminogen activators (PAs) play a key role in malignant transformation. PA secretion by tumoral cells is strongly correlated with their aggressive phenotype. Regulation of invasive potential by growth factors has been also demonstrated. This study was designed to investigate the effects of 5alpha-dihydrotestosterone (DHT), epidermal growth factor (EGF), transforming growth factor beta1 (TGFbeta1), retinoic acid and basic fibroblastic growth factor (bFGF) on cell growth and PA expression and secretion in DU145 and PC3 cells, 2 human prostatic-cancer cell lines. The proliferation of 2 cell lines was significantly increased only by EGF (about 30%), but decreased by TGFbeta1 (40% inhibition). However, EGF-treated cells showed significant enhancement (about 400%) of u-PA secretion. A similar effect was observed when cells were cultured with DHT (200%) and with TGFbeta1 (300%). Nevertheless, u-PA mRNA level in EGF-, TGFbeta1 - or DHT-treated cells was amplified only between 110 and 180% of control, suggesting that growth factors differently controlled the steps of PA expression. Furthermore, our results clearly showed the divergent effect of TGFbeta1, i.e., an inhibition of prostatic-cell-line growth accompanied by an increase in proteolytic activity.

Thymidine kinase (TK) is involved in DNA synthesis by the salvage pathway. In this study, thymidine kinase (TK) was determined in routinely prepared cytosols of primary tumors from 290 breast-cancer patients. Enzyme activity was measured using a radioenzymatic method optimized for detection of the fetal isoenzyme. High levels of TK (> or = 126 mU/mg protein) were positively associated with histological grade in both pre/peri-and post-menopausal patients. In pre/peri-menopausal patients, high concentrations of TK were also found more frequently in progesterone receptor (PgR)-negative tumors than in PgR-positive samples. In post-menopausal patients, high levels of TK were associated with large tumor size, estrogen receptor (ER) negativity and PgR negativity. In univariate analysis, high levels of TK were strongly associated with shorter overall survival in both pre/peri- (p = 0.001) and post-menopausal patients (p = 0.02). Pre/peri-menopausal patients whose tumors had high levels of TK also had an increased risk of relapse (p = 0.001). In multivariate analysis (including treatment protocol, patient age, lymph-node involvement, tumor size, histological grade, ER and PgR status), TK status was found to be an independent prognostic factor for recurrence-free survival in pre/peri-menopausal patients with a weight similar to that of PgR status. In post-menopausal patients, TK was the only factor selected for overall survival.

Specific and recurring chromosomal and genetic alterations have been identified in gliomas and could described a model of tumoral progression from benin glioma to glioblastoma multiforme. However, the heterogeneity of profiles of molecular alterations that have been observed in gliomas seems to reflect the variety of clinical evolutions which characterise those tumors. Loss of genetic material on chromosomes 17, 9 and 19, then of chromosome 10 have been associated to pathogenesis of glioma and a pejorative prognostic value have been attributed to the alteration of chromosome 10. Gliomas also express growth factors and growth factors receptors that may be important in promoting tumor growth, like Epidermal growth factor (EGF), fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF). Tumoral invasion which characterise also gliomas, may involve proteases like plasminogen activators (PA) and metalloproteases, under the regulation of specific receptors and inhibitors. PA inhibitor type 1 (PAI1), associated to the most aggressive form of gliomas, may also participate to tumoral neoangiogenesis. Description and understanding of these alterations may contribute to develop new treatment modalities in gliomas.

In the natural history of post-menopausal patients with primary breast cancer, high estrogen receptor levels (ER) have been associated with a poor recurrence-free survival. The purpose of this study was to investigate whether there are any biological intratumoral characteristics to support this puzzling clinical observation. In a population of 542 post-menopausal, primary-breast-cancer patients, 3 normal distributions fitted into the frequency distribution curve of the logarithmically transformed ER-EIA values. The biological profiles of the low ER group, and of the intermediate and high ER groups identified in the ER-positive population were compared. Parameters correlated with ER functional aspect (progesterone receptors and PS2), receptors of epidermal growth factor (EGFR), protease cathepsin D and tumor proliferation (deduced from thymidine kinase activity) were analyzed. As previously reported, the levels of progesterone receptors and PS2 increased significantly from the low to the high ER groups. The highest levels of cathepsin D and thymidine kinase which have been previously related to a poor prognosis in breast cancer were found in the low ER group, but high levels were, surprisingly, also found in the high ER group. This study indicates that the ER-positive post-menopausal population is biologically heterogeneous. The high levels of thymidine kinase found in the high ER group suggest that overexpression of ER may be associated with proliferation enhancement, partly explaining the poor spontaneous prognosis related to this subset.