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Some cancers are involved in inherited genetic syndromes. These genetic diseases are suspected of being involved in approximately 1% of gliomas. Few data are available on glioblastomas and their characteristics among these diseases. Familial syndromes known to predispose individuals to glioblastoma are neurofibromatosis type 1, Li-Fraumeni's syndrome, tuberous sclerosis, and Turcot's syndrome. This review discusses glioblastomas related to these diseases and the current knowledge on the statistical, clinical, and molecular biology data. Non-syndromic glioma families are discussed: a better understanding of molecular abnormalities in these groups should help understand the mechanisms of gliomagenesis. A case of malignant glioma requires the physician to actively search for the possibility of inherited factors and eventually suggest genetic counseling.

Background and purpose We review the indications and limitations of chemotherapy in glioblastoma multiform (GBM), including the role played by alkylating and other cytotoxic agents and the increased input of clinical research on targeted agents in GBM management. Methods In 2005, a phase III study clearly concluded in the benefit of adding temozolomide during and after radiotherapy treatment in GBM and thus defined the new standard of treatment in this devastating disease. This schedule increased the median survival from 12.1 to 14 months and the two- and five-year survival rates from 8 to 26%, and 3 to 10%, respectively, with a good tolerance profile. Moreover, methylation of the promoter of the O6 methylguanine DNA transferase (MGMT) gene exhibits a prognostic impact independently of therapeutic schedule but may also predict the benefit of adding temozolomide to radiotherapy. However, pitfalls in MGMT determination and lack of prospective validation have to be solved before considering MGMT as a decisional marker. More recently, antiangiogenic agents including enzastaurin, cediranib, bevacizumab, and others that target mainly the VEGF pathway, have been evaluated in this highly angiogenic disease. Among them, only bevacizumab has been associated with clear anti-tumor activity, although the lack of control studies limits the impact of the results to date. Conclusions Recent studies conducted in GBM, both in the adjuvant and recurrent setting, have changed the natural course of the disease and opened a new area of clinical research, including imaging and response evaluation, predictive markers, and other targeted therapies.

Resume Les gliomes malins demeurent le probleme majeur de la neuro-oncologie, par leur frequence, leur gravite et les difficultes de traitement qu’ils posent. Les etapes de diagnostic clinique et neuroradiologique sont bien etablies et performantes ; la stabilite de ces acquis contraste avec le paradoxe des avancees de la recherche biologique qui demeurent sans consequence pratique, sinon de susciter une multitude de protocoles de recherche clinique. En neuropathologie des gliomes malins, les nouvelles methodes d’immunohistochimie et de genetique moleculaire font entrevoir les insuffisances des seuls aspects morphologiques au profit de criteres d’ontogenese cellulaire auquel le neuropathologue n’avait pas acces anterieurement. Ces donnees de biologie moleculaire et de genetique tumorale sont attendues en routine pour etablir des diagnostics precis guidant les strategies de traitement specifique de chaque type tumoral. En neurochirurgie, le lien entre l’etendue des exereses et la duree de survie a ete etabli et la chirurgie « optimale » aidee par les nouvelles technologies peroperatoires est devenu le temps essentiel du traitement initial et parfois de la recidive des gliomes. Surtout, le developpement des methodes de nanoneurochirurgie, d’implantation in situ d’agents cytotoxiques ou immunomodulateurs et les reponses obtenues par ces depots ouvrent un champ d’actions therapeutiques imaginees de longue date, mais demeurees virtuelles faute de disposer des technologies adequates de mise en œuvre. En radiotherapie, les methodes d’imagerie, les algorithmes de recalage conformationnel et de dosimetrie ont permis la reduction considerable des effets iatrogenes mais les resultats obtenus sont encore modestes et surtout transitoires. En chimiotherapie, les obstacles pharmacocinetiques, le faible nombre de molecules disponibles et les capacites innees ou acquises des systemes de chimioresistance et de reparation des lesions alkylantes sont retenus pour rendre compte de la mediocrite de l’apport objectif pour les patients, mais il y a espoir : des sous-groupes chimiosensibles peuvent etre identifies, de nouvelles molecules (fotemustine, temozolomide) et surtout les antagonistes des boucles de proliferation cellulaire, autocrines et paracrines, font envisager la mise a disposition des cliniciens de nouvelles associations et esperer des complementarites d’action. Enfin, les multiples possibilites de l’immunotherapie et des therapies geniques sont en exploration dans des etudes de phase I et II ; elles tentent de combler cette distance entre les connaissances acquises par la recherche fondamentale et les resultats obtenus en clinique. Au total, les gliomes malins demeurent d’un pronostic tres defavorable, mais les avancees des methodes diagnostiques et therapeutiques sont certaines ; des a present, quelques types tumoraux relevent de traitements specifiques qui montrent que ces nouvelles approches derivees des recherches en oncogenese sont possibles et valident les theories biologiques qui les sous-tendent.

Resume L’imagerie est actuellement la plaque tournante du diagnostic des tumeurs intracrâniennes. Ces dernieres annees, l’apparition de nouvelles techniques d’imagerie par resonance magnetique (IRM) a permis d’en affiner encore l’exploration et de parvenir a approcher le diagnostic de nature dans un nombre croissant de cas. La presence d’une tumeur intracrânienne peut etre evoquee devant des tableaux neurologiques varies ou etre de decouverte fortuite. Les techniques d’imagerie utilisees comprennent la tomodensitometrie, l’IRM et exceptionnellement l’angiographie. Les techniques d’IRM de diffusion, d’IRM de perfusion et de spectro-IRM sont deja d’un apport considerable dans certaines histologies, mais leur place reste a definir. Le diagnostic neuroradiologique de tumeur s’appuie sur des criteres precis qui peuvent tous etre pris en defaut. Le diagnostic de nature repose sur un faisceau d’arguments parmi lesquels l’âge du patient et la localisation de la tumeur jouent un role essentiel.

Resume Introduction Les complications neurologiques des traitements chimiotherapiques varient selon la nature des produits utilises dans leur topographie, leur intensite et leur evolution. Actualites et points forts Les progres dans la strategie therapeutique en oncologie se sont accompagnes de nouvelles toxicites, limitant les doses et les voies d'administration. Leur augmentation actuelle est proportionnelle aux effets additifs ou synergiques des traitements administres de facon concomitante ou sequentielle. Les symptomes dependent des voies d'administration utilisees, des doses et de la pharmacodynamique du medicament. Perspectives et projets La neurotoxicite exige une surveillance constante des symptomes; elle peut etre le facteur limitant du traitement oncologique avec un impact immediat sur la qualite de vie. Les diagnostics differentiels sont nombreux. Detectees au stade d'etat, les manifestati neurotoxiques ne sont pas toujours reversibles. L'utilisation de neuroprotecteurs est a l'etude.

In this paper, the on-line coupling of solid-phase extraction, based on a restricted-access support with liquid chromatography-mass spectrometry (LC-MS), for the analysis of biological samples is described. The system was tested with cortisol and prednisolone for plasma analysis and arachidonic acid for urine analysis. A precolumn packed with a 25-micron C18 alkyl-diol support is used for direct plasma or urine injection. Using column-switching techniques, the analytes enriched on the precolumn are eluted to the analytical column without transfer loss. An on-line heart-cut technique was employed and only the analyte-containing fraction eluting from the LC column is directed to the MS to protect the LC-MS interface and ion-source from contamination. The whole system is operated in a parallel mode, that is, sample pre-treatment and LC-MS analysis are performed simultaneously to provide the shortest possible analysis time. The only off-line sample pre-treatment step required was centrifugation to remove particulate matter. With the fully automated system, total analysis times of 5 and 9.5 min were achieved for cortisol in serum and arachidonic acid in urine, respectively. Cortisol and related compounds were quantitatively recovered from plasma with a detection limit for prednisolone (direct injection of 100 microliters on restricted-access precolumn) of 2 ng/ml.

Systemic metastases from ovarian carcinoma are frequent, but they seldom affect the central nervous system. We present here the case of a patient treated for an ovarian cancer by surgery and chemotherapy. Three months after the end of chemotherapy, the patient developed cerebral metastases from ovarian carcinoma (CMOC) treated by iterative surgery and and whole brain irradiation. As the frequency of solitary cerebral metastasis of ovarian cancer is higher than with other cancers, it is likely that they behave slightly differently. Literature analysis reveals an increase in the incidence of CMOC since the middle of the nineties. CMOC can occur during or after adjuvant chemotherapy and the best management strategies to better define determinants of survival for patients are not well known. It appears that a better outcome of CMOC may be obtained by an aggressive treatment, if possible, including surgery, radiotherapy, and chemotherapy. Taking into account the increase in the incidence of the CMOC and their early occurrence, some authors have proposed a prophylactic brain radiotherapy in patients who receive adjuvant chemotherapy.

38 adults with recurrent supratentorial malignant gliomas, including glioblastoma multiforme (21), anaplastic astrocytomas (9), probably transformed low-grade astrocytomas (6), pinealoblastoma (1) and non-metastatic tumour of unknown histology (1), were treated with fotemustine 100 mg/m2 intravenously every week for 3 consecutive weeks followed by a 5-week rest period. Maintenance treatment consisted of one infusion every 3 weeks. Patients were divided into three groups according to treatment effect. 10 objective responses (26%) with a median time without progression of 32.7 weeks, 18 stabilisations (47%) and 10 failures (26%) were observed. Pathological findings of the initial primary tumour and neurological functional status were unequally distributed in these groups. Haematological and liver toxicities were mild, delayed, transient and reversible. Thrombocytopenia and leukopenia were more frequent (30%) in patients treated with prior chemotherapy. Fotemustine is a well tolerated active drug in recurrent malignant gliomas with an original and short treatment schedule.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

Objectifs Connaitre les modifications de l’aspect IRM des gliomes sous traitement anti-angiogenique. Savoir eviter le piege des sequences avec injection de Gadolinium. Connaitre les sequences IRM indispensables pour le suivi et celles a ne pas faire. Points cles La reponse d’un gliome sous Bevacizumab est souvent mixte. Elle depend de l’aspect necrotique ou tissulaire de la tumeur. La sequence cle est le T2. La sequence T1 injectee et la perfusion doivent etre evitees car elle sont faussees.

Neutron captures on 10 B may be a neat way to provide some selectivity in a fast neutron beam: when the neutrons are thermalized in the tissue, they produce nuclear reaction with 10 B nuclei, releasing energetic α particles and Li ions. Provided that a sufficient amount of 10 B may be carried with a specific molecule inside tumoral cells, a very efficient component of irradiation can be added. Tumors like glioblastomas, soft tissues sarcomas or melanomas, which are highly radioresistant, may benefit of this potentiation to obtain better local control, while sparing more the normal tissues. Results of tumor targeting with boronated compounds, of dosimetry and radiobiology in our fast neutron beam will be presented.