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Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC50) values varied significantly (10 nM &lt, IC50 &lt, 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.

Background The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria of grade 2 versus 3 have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a cut-off of mitoses separating grade 2 and grade 3 tumors. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival. Material and Methods Maximal mitotic activity on consecutive high power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytoma IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumor volume, plurilobar involvement, post-surgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation. Results Among the 75 (64%) of tumors which had gone through observational follow-up after resection, the maximal mitotic activity, the post-surgical residual volume and the plurilobar involvement were independent prognostic factors of TTT (p < 0.0001). A threshold of mitotic activity for grade 2 was fitted on TTT and OS prognosis. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p = 0.0057) and a median OS of 102 months versus 73 months respectively (p = 0.001). Residual volume < 1 cm3 was associated with longer OS (113 months versus 88 months, p = 0.0021). Conclusion Mitotic activity and post-surgical residual volume can be combined to evaluate prognosis in resected astrocytoma IDH-mutant and could select the best candidates for observational follow-up.

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity.In BriefA combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors.Highlights•Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data•Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers•AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection•AID mutational load predicts response and is associated with favorable outcome in ICI treated patients

Meningiomas are the most frequent among intracranial tumors, and represent more than 30% of primitive central nervous system neoplasms. Arising from the meninges, they are generally benign lesions and can be treated by either radio-clinical follow-up or surgical resection with excellent outcome. However, more than 20% of meningiomas harbor atypical or malignant features and represent challenges for both prognostic evaluation and therapeutic strategy. The discovery of the genetic and epigenetic landscapes of meningiomas enabled the identification of new prognostic markers and potential therapeutic targets for refractory meningiomas. This review summarizes current epidemiology, histological and molecular characteristics, diagnosis and treatments for meningiomas, and highlights the close relationship between the development of meningiomas and hormonal intake, as illustrated by recent recommendations of the "Agence Nationale de Securité du Medicament", the French national drug safety agency.

Purpose Strategies to modulate the tumor microenvironment (TME), including the vascular and immune components, have opened new therapeutic avenues with dramatic yet heterogeneous intertumor efficacy in multiple cancers, including brain malignancies. Therefore, investigating molecular actors of TME may help understand the interactions between tumor cells and TME. Immune checkpoint proteins such as a Cluster of Differentiation 80 (CD80) and CD86 are expressed on the surface of tumor cells and infiltrative tumor lymphocytes. However, their expression and prognostic value in glioblastoma (GBM) is still unclear. Methods In this study, we have investigated, in a retrospective local discovery cohort and a validation TCGA dataset, expression of CD80 and CD86 at mRNA level and their prognostic significance in response to standard of care. CD80 and CD86 at the protein level were also investigated in the discovery cohort. Results Both CD80 and CD86 are expressed heterogeneously in GBM at mRNA and protein levels. In a univariate analysis, the mRNA expression of CD80 and CD86 was not significantly correlated with OS in both ONT and TCGA datasets. On the other hand, CD80 and CD86 mRNA high expression was significantly associated with shorter PFS (p

BackgroundGlioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.MethodsWe performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.ResultsWe retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.ConclusionAs the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies.Implications for PracticeThis review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.

Autotrophic microorganisms catalyze the entry of dissolved inorganic carbon (DIC; = CO2 + HCO3− + CO32−) into the biological component of the global carbon cycle, despite dramatic differences in DIC abundance and composition in their sometimes extreme environments. “Cyanobacteria” are known to have CO2 concentrating mechanisms (CCMs) to facilitate growth under low CO2 conditions. These CCMs consist of carboxysomes, containing enzymes ribulose 1,5-bisphosphate oxygenase and carbonic anhydrase, partnered to DIC transporters. CCMs and their DIC transporters have been studied in a handful of other prokaryotes, but it was not known how common CCMs were beyond “Cyanobacteria”. Since it had previously been noted that genes encoding potential transporters were found neighboring carboxysome loci, α-carboxysome loci were gathered from bacterial genomes, and potential transporter genes neighboring these loci are described here. Members of transporter families whose members all transport DIC (CHC, MDT and Sbt) were common in these neighborhoods, as were members of the SulP transporter family, many of which transport DIC. 109 of 115 taxa with carboxysome loci have some form of DIC transporter encoded in their genomes, suggesting that CCMs consisting of carboxysomes and DIC transporters are widespread not only among “Cyanobacteria”, but also among members of “Proteobacteria” and “Actinobacteria”.

BACKGROUND There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. METHODS Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. RESULTS 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1–22 years), median time since radiotherapy was 2.8 years (0.6–18 years), median number of previous chemotherapy lines was 2 (1–5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4–18+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. CONCLUSIONS In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.

BACKGROUND About 10% of IDH-mutant gliomas harbor non-canonical IDH mutations (non-R132H IDH1 and IDH2 mutations). The aim of the present study was to analyze the characteristics of these gliomas in comparison to those of IDH1 R132H mutant gliomas. MATERIAL AND METHODS We retrospectively analyzed the characteristics of a multicentric series of 161 gliomas with non-canonical IDH mutations and compared them to those of consecutive series of 109 IDH1 R132H mutant gliomas. Medical, radiological and pathological were reviewed. RESULTS Median age at diagnosis was 35 years in gliomas with a non-canonical IDH1 mutation, 42 years in those with an IDH2 mutation and 44 years in those with an IDH1R132H mutation. A familial history of cancer was more frequent in gliomas with a non-canonical IDH mutation than in those with an IDH1 R132H mutation (22,3% vs 5,5%, p CONCLUSION Gliomas with non-canonical IDH mutations are associated with distinct clinical, radiological and histological characteristics. Their prognosis, however, is similar to that of gliomas with canonical IDH mutations.

BACKGROUND Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade. MATERIAL AND METHODS We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies. RESULTS Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSION This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.

PURPOSE Actionable oncogenic fusion FGFR3-TACC3 (F3T3) is found in 3% of gliomas. Our goal was to characterize the clinical, radiological and molecular features of patients with F3T3-positive glioma. PATIENTS AND METHODS Overall, we screened 1112 gliomas by RT-PCR (861 WHO grade IV, 140 grade III and 111 grade II) and identified 50 F3T3-positive cases. We performed a radiological and radiomic case control study. RESULTS F3T3 fusion was exclusively found in IDH wild-type gliomas. F3T3 was mutually exclusive with the EGFR amplification (0/38 versus 143/336 of F3T3-negative cases, P=0.01), whereas it was associated with CDK4 amplification (7/33 versus 22/321 of F3T3-negative cases, P=0.04) and MDM2 amplification (6/33 versus 15/354 of F3T3-negative cases, P=0.03). F3T3-positive gliomas showed a longer overall survival than F3T3-negative gliomas (median OS 40.1 and 20.0 months, P=0.02), particularly in the grade IV subgroup (40.1 versus 19.0 months, P=0.006). Multivariate analysis showed that F3T3 fusion is an independent predictor of favorable outcome for glioblastoma patients. F3T-positive gliomas were associated with involvement in non-eloquent areas (r=0.31 P=0.007), cortico-subcortical regions and insula involvement (adjusted p CONCLUSION Gliomas harboring F3T3 gene fusions show specific molecular features, distinct radiological and radiomic features and a less aggressive clinical evolution.

BACKGROUND Meningioma therapy efficiency is used to being assessed by 6 months progression survival rate (PFS6), which remains the most consensual criterion. Nevertheless, different patterns of meningiomas intrinsic aggressiveness and growth rates directly impact the PFS6 leading to unreliability of drug effect assessment. Moreover, therapeutic response remains rare in meningiomas. These points lead to consider classical and updated RANO criteria as not fully adapted to meningiomas. Based on phase II CEVOREM trial experience, we aim to improve the assessment of drugs efficiency in meningiomas via the determination of growth rate before and under treatment. MATERIAL AND METHODS Twenty patients were included in Cevorem trial which tested the combination of octreotide and everolimus as previously described. MRI assessment was performed in the 3 to 6 preinclusion months, at inclusion then every 3 months. Progression was assessed by investigators according to RANO criteria. An independent central review was performed with 2 reviewers and 1 adjudicator: largest diameter, 2D maximal area as 3D volume were assessed by autosegmentation software (Brainlab). Results from central review were correlated to investigators assessment. 3D volume growth rate (3DVGR) was calculated using 2 different processes (one simple and one complex). Comparison of 3DVGR before vs. under treatment was performed. Meningioma growth under treatment was compared to theoretical meningioma growth based on preinclusion data using a model of meningioma growth. RESULTS PFS6 assessed via the independent central review was in accordance with PFS6 assessed by investigators following RANO criteria. Then, we analyzed 3DVGR before and during therapy. Standard deviation was higher using the complex 3DVGR calculation process. A decrease of more than 50% of the 3DVGR was observed in 30/36 tumors at 3 months with the both calculation modes and could be considered as a threshold of drugs activity. Median volume growth rate decreased from 88.3 or 17.2%/3 months before inclusion to -2.2 or à -0.6 %/3mo at 3 months depending of the calculation mode (p CONCLUSION 3DVGR measurement during versus before seems as a sensitive and reliable tool which provides valuable comparison in a phase 2 study to assess drugs activity in meningioma in complement to PFS6. 3DVGR assessment should be considered in future clinical trials.

Introduction Adenoviral infection is a classic cause of lymphohistiocytic hemophagocytosis (LH) in bone marrow transplantation but is rare outside this setting. Case report A 31-year-old female, with a history of treated mesencephalic astrocytoma, was hospitalized for fever, pancytopenia, elevated liver enzymes, hyperferritinemia and hypertriglyceridemia. Adenovirus viral load in blood was 7.3 × 10 9 copies/mL. Bone marrow aspirate examination confirmed LH. The patient recovered without specific LH or adenovirus-directed treatment. Conclusion Adenovirus-related LH, common in bone marrow transplant recipients, should also be considered in patients with chemotherapy in solid tumors.

BACKGROUND Participation of glioma patients in early phase clinical trials has recently shown to be safe, although clinical benefits reported in this population were marginal. We aimed to evaluate whether an enrichment strategy based on molecular profiling associates with improved outcome in gliomas patients participating in early phase trials. MATERIAL AND METHODS Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2017 were analyzed for clinicopathological characteristics, toxicity, response, median progression-free survival (PFS) and overall survival (OS). The primary objective was to evaluate the feasibility and benefit of using molecular profiling to guide enrollment. RESULTS Ninety-one patients were enrolled, of whom 47/91 (51.6%) were molecularly oriented. Molecular targets included IDH1/2 (n=15) and BRAF (11) mutations, FGFR1-3 fusions (n= 10) and mutations (n = 4), mismatch repair deficiency (8), and MDM2 amplification (1). Grade 3/4 adverse events were reported in 9/91 (9.9%) patients. In patients with IDH1/2-wild-type high-grade glioma (n=45), the overall response rate (24.0% [95% CI 11.5–43.4] vs 0.0% [95% CI 0.0–16.1], P=0.027) was significantly higher in molecularly-oriented vs non-molecularly-oriented patients. Updated outcome results, and clinical and molecular factors associated with response, PFS and OS in multivariate analyses will be presented at the conference. CONCLUSION Using molecular profiling to guide enrollment in early phase trials is feasible and offers potential benefit to gliomas patients. Further studies are warranted to identify the population most likely to benefit from this approach.

A. Pierre-Justin a M. Yger a A. Bertrand b S. Crozier a J. Savatovsky c C. Rosso a M. Sanson d Y. Samson a Service des urgences cerebrovasculaires, groupe hospitalier Pitie-Salpetriere, 47-83, boulevard de l'Hopital, 75013 Paris, France Service de neuroradiologie diagnostique et fonctionnelle, groupe hospitalier Pitie-Salpetriere, 47-83, boulevard de l'Hopital, 75013 Paris, France Service de neuroradiologie, fondation ophtalmologique Adolphe-de-Rothschild, 29, rue Manin, 75019 Paris, France Service de neuro-oncologie, groupe hospitalier Pitie-Salpetriere, 47-83, boulevard de l'Hopital, 75013 Paris, France

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p

Objectif de l’etude Le traitement de reference des glioblastomes comporte apres la chirurgie une radiotherapie associee a du temozolomide en concomitance suivie par du temozolomide adjuvant. Les patients atteints de glioblastome multifocal sont souvent traites par du temozolomide seul sans irradiation cerebrale. A notre connaissance, aucune etude n’a evalue le role de l’irradiation encephalique in toto associee au temozolomide concomitant et adjuvant chez des patients atteints d’un glioblastome multifocal. Nous rapportons retrospectivement les resultats de l’irradiation encephalique in toto associee au temozolomide concomitant et adjuvant. Materiel et methode Entre avril 2009 et septembre 2017, 11 patients atteint d’un glioblastome multifocal (plus de trois lobes) ont ete pris en charge par chimioradiotherapie premiere. L’âge median etait de 50 ans [34–74]. La dose mediane de radiotherapie etait de 45 Gy en 25 fractions de 1,8 Gy avec un etalement de 37 jours [29–41]. Le temozolomide etait administre concomitamment a la radiotherapie a une dose de 75 mg/m2/j, puis en situation adjuvante a la dose de 150–200 mg/m2 (j1–j5) tous les mois. L’evaluation de l’etat general au moyen de l’indice de Karnofsky etait au moment du diagnostic de 80 % [30–90]. Resultats Les durees medianes de survie globale et la survie sans progression etaient respectivement de 10 mois [4–25] et 5 mois [3–21]. L’indice de Karnofsky etait stable un mois apres la fin de la radiotherapie. Pendant la chimioradiotherapie, la dose de corticotherapie etait stable ou en diminution chez cinq patients. En dehors de l’alopecie, aucune toxicite de grade 3–4 liee a la radiotherapie n’a ete notifiee. Le temozolomide a ete arrete chez un patient durant la chimioradiotherapie pour une thrombopenie de grade 4. Pour les autres cas de toxicite de grade 3–4 liee au temozolomide, deux lymphopenies de grade 3 ont ete rapportees. Le temozolomide adjuvant a ete administre chez neuf patients avec un nombre median de cycles de cinq [2–12]. Conclusion Notre etude est en faveur de l’efficacite et de la bonne tolerance immediate de l’irradiation encephalique in toto avec du temozolomide concomitant et adjuvant pour les patients atteints d’un glioblastome multifocal nouvellement diagnostique.

Low-grade gliomas (LGG) are thought to be very rare in elderly patients (60 years) and have not been thoroughly studied.A series of 62 elderly (or=60 years of age) LGG patients were identified in a department database collecting information on pathologically identified adult supratentorial LGG. The clinical, radiologic, pathologic, and therapeutic data of these patients were analyzed and compared to those of 704 younger LGG patients (60 years).Comparisons between older and younger groups showed that elderly patients more often presented with a clinical deficit (p0.0001), a lower Karnofsky performance status (p = 0.0002), a larger tumor on MRI (p = 0.03), and a lower rate of tumor resection (p0.0001). Chemotherapy was more often used as first line treatment (p = 0.001). Among the patients who died of progressive disease, 55% of the elderly patients had not received radiotherapy compared to 11% in the younger group (p0.0001). Survival was shorter in older patients (p0.0001), with a 5-year survival rate of 40%. An astrocytic phenotype (p = 0.0097), increasing age (p = 0.0049), and a tumor crossing the midline (p = 0.028) were negative prognostic factors in the older group.We found that 8% of low-grade gliomas (LGG) occur in older patients (or=60 years of age). The clinical-radiologic picture of LGG in the elderly population differs from younger patients. Although long-term survival occurs, the course is generally more severe because elderly patients accumulate negative prognostic factors and because they are probably undertreated.

Background: Treatment with a regimen of bevacizumab–irinotecan has been shown to be effective in recurrent grade 3 and 4 gliomas, but the effect of this regimen against recurrent oligodendroglial tumors has not been specifically studied. Methods: The bevacizumab–irinotecan regimen was retrospectively evaluated in a consecutive series of 25 patients with recurrent oligodendroglial tumors. All patients had not responded to previous treatment with radiation therapy and at least one line of temozolomide chemotherapy. Bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m 2 according to the antiepileptic regimen) were administered every 14 days. Response was measured clinically and on monthly MRI. Results: The objective response rate was 72% (20% complete response, 52% partial response). After a median follow up of 202 days, the median progression-free survival was 140 days (95% confidence interval [CI] 116–∞), and overall survival had not been reached. The 6-month progression-free survival was 42% (95% CI 26%–67%). Among the 17 patients in whom the status of the main molecular alterations of gliomas could be evaluated (search for deletions of chromosomes 1p, 19q, 9p, and 10q and amplification of epidermal growth factor receptor, mouse double-minute gene, and cyclin-dependent kinase 4 gene), no relation could be found between the response rate and the type of genetic change (including 1p-19q codeletion). The profile of tolerance was fair, with treatment discontinuation in 20% of patients. Intratumoral hemorrhages occurred in 6 patients (24%), but the treatment had to be discontinued because of symptomatic bleeding in only 1 patient (4%). Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable.

Background: Up-front temozolomide (TMZ) has been recently proposed as a treatment for gliomatosis cerebri (GC), but no predictive or prognostic markers have been identified so far. Because 1p19q codeletion and methylguanine methyl transferase promoter (MGMTP) methylation have been correlated with chemosensitivity of gliomas, their value was investigated in a cohort of patients with GC treated with TMZ. Methods: A cohort of 25 GC patients who were treated with TMZ was investigated for 1p19q codeletion and O6-methylguanine DNA. Results: Patients with a 1p/19q codeletion had a higher response rate (88% [8/9] vs 25% [4/16], p = 0.002), higher progression-free survival (24.5 vs 13.7 months, p = 0.017), and higher overall survival (66.8 vs 15.2 months, p = 0.011) than patients without 1p/19q codeletion. Fourteen of 19 evaluable tumors for MGMTP status were methylated. MGMTP methylation was associated with 1p/19q codeletion ( p = 0.045). Patients with unmethylated MGMTP tended to have a shorter progression-free survival and a higher rate of progressive disease. Conclusion: Response rate to temozolomide and prognosis seem tightly correlated to 1p19q loss. The impact of methylguanine methyl transferase promoter methylation status on gliomatosis cerebri is still unsettled in this population.

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Resume L’oncogenese est determinee par la survenue d’alterations genetiques specifiques, aboutissant soit a la surexpression d’oncogenes, soit a l’inactivation de genes suppresseurs de tumeur. L’accumulation de ces alterations genetiques survenant dans un ordre defini determine la progression tumorale et permet d’etablir une classification moleculaire des tumeurs. Celle-ci peut permettre de distinguer des profils genetiques de pronostics differents (notamment la perte des chromosomes 1p et 19q associee a un pronostic favorable dans les oligodendrogliomes). Le role des alterations non genetiques (reactivation de l’activite telomerase qui permet l’immortalisation de la cellule, activation de boucles auto- ou paracrines) est discute, de meme que les mecanismes de l’oncogenese des meningiomes et schwannomes (inactivation du gene NF2 ), ependymomes et medulloblastomes.

Seizures are common in low-grade gliomas (LGGs) and are highly correlated with the presence of the isocitrate-dehydrogenase 1 mutation (IDH1m). We aimed to explore the correlation between the IDH1m in LGGs and the presence of epilepsy as initial symptom. METHODS: Observational retrospective study on 164 patients with LGGs (86 oligodendrogliomas, 41 astro-oligodendroglial tumors and 37 astrocytomas) of whom 71% had seizures as initial symptom, analyzed according to Fisher's exact and Mann Whitney test. RESULTS. There was no difference in age or brain tumor location in patient with or without seizures. Seizures were more frequent in the group of IDH1m (92/117; 78 %) vs. (27/47; 57.4%), p = 0.01. Fronto-insular location was more frequent in the group of IDH1m (75/117; 65%) vs (13/47; 27%), p = 0.01. There was no difference if analyzed by histological type of low-grade gliomas, except for oligodendrogliomas, in which seizures were more frequent with IDH1m 52/65 (80,0 %) p = 0.02. The average age of the IDH1m with seizures was not significantly higher: 41.5 yrs vs. 39.5 yrs without seizures, p = 0.27. The type of seizures simple/complex partial (64/117; 55%) vs. generalized (53/117; 45%) is similar regardless of the presence of IDH1m, p = 0.8 CONCLUSION. Epilepsy as initial symptom in oligodendrogliomas is associated with the presence of IDH1 mutation. Fronto-insular location is more frequent among IDH1 mutated LGGs. There is no difference in type of seizures among IDH1 mutated LGGs.

Novel chromosomal rearrangements involving tyrosine-kinase receptors FGFR3 and EGFR and resulting in actionable fusion proteins with strong oncogenic activity have been recently described in glioblastoma (GBM). 602 gliomas [380 grade IV (GBM), 116 grade III, 106 grade II] from the Pitie-Salpetriere brain tumor bank “Onconeurotheque” were analyzed for the presence of FGFR3-TACC3 and EGFR-SEPT14 by RT-PCR and sequencing . We identified 30 patients with fusion transcripts: 11 (8 GBM, one grade III, two grade II) with FGFR3-TACC3 and 19 (18 GBM and one grade III) with EGFR-SEPT14 fusion, including a GBM patient recurring after standard treatment. None of the 144 IDH1 mutated and 12 IDH2 mutated gliomas (including 28 GBM) had FGFR3-TACC3 or EGFR-SEPT14 fusions (P < 0.0002). EGFR-SEPT14 was associated with EGFR amplification 13/16 cases (81%) (12/14 in GBM EGFR-SEPT14+ vs 79/207 in GBM EGFR-SEPT14-, P = 0.001) and with EGFR vIII variant in 8/15 (53%), whereas none of the FGFR3-TACC3 fusions had EGFR abnormalities (0/8 in GBM FGFR3-TACC3+ vs 79/207 in GBM FGFR3-TACC3-, P = 0.027). Of particular interest, FGFR3-TACC3 positive tumors showed a very strong, diffuse and homogeneous FGFR3 expression by immunostaining, in contrast to fusion negative tumors, suggesting that FGFR3-TACC3 protein is expressed in nearly all tumor cells. In GBM patients, median overall survival was 32.80 months for FGFR3-TACC3+ patients, 25.50 months for EGFR-SEPT14+ patients compared to 17.20 for the other GBM patients (P = 0.60; NS). In conclusion we found that these gene fusions are not restricted to GBM but involve also grade II and III IDH wild-type tumors. Due to their oncogenic activity these genes fusions define a subset of patients that could benefit from specific molecular targeting at recurrence. We are now planning anti-FGFR and anti-EGFR treatment in this preselected population.

Resume Objectif Evaluer les effets du Temozolomide sur la fertilite feminine et la pertinence de notre prise en charge en preservation de la fertilite. Patientes et methodes De 2005 a 2009, 24 patientes traitees par temozolomide pour un gliome de bas grade ont ete inclues dans l’etude (12 femmes ayant eu une consultation de preservation de fertilite et 12 femmes sans consultation de preservation de fertilite). Une etude retrospective de leurs dossiers et l’envoi d’un questionnaire ont ete entrepris pour apprecier leur fertilite apres traitement. Resultats Parmi les 24 patientes, 15 patientes n’ont pas eu de preservation de fertilite et les 9 restantes ont eu une cryoconservation d’embryons associee ou non a une cryoconservation ovocytaire. Quatre patientes sont ou ont ete enceintes (un accouchement, une fausse couche spontanee, une grossesse en cours dans le groupe preservation de fertilite et une grossesse en cours dans le groupe ou aucune preservation de la fertilite n’a ete realisee). Discussion Premiere etude sur l’effet du temozolomide sur la fertilite feminine. Conclusion Le temozolomide n’est pas totalement gonadotoxique.

The objective of the study was to assess the efficacy of docetaxel in recurrent supratentorial malignant gliomas. The sample size of the study was determined by the Gehan's method for a response rate of 20% and a β error of 5%. In the first step 14 patients (age 27–69, median 50; Karnofsky index 50–90, median 75) with recurrent malignant glioma after surgery, radiotherapy and nitrosourea, were enrolled (12 glioblastomas, 2 anaplastic astrocytomas). Docetaxel at the initial dose of 80 mg/m2 was administered every 3 weeks until progression or unacceptable toxicity. A total of 41 cycles was administered. Patients received a median of two cycles (range 1–6). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was terminated. Two stabilizations were observed (14 and 15 weeks). Median TTP was 7 weeks (44 days). Median overall survival from recurrence was 26.5 weeks (6.4 months). Grade 3–4 neutropenia was observed in 8 patients (57%) but no life-threatening toxicity was observed. Other toxicities were uncommon and mild. Dose reduction was performed in 5 patients. This study suggests that docetaxel displayed no significant activity in patients with malignant recurrent gliomas.

We investigated two polymorphisms of the epidermal growth factor receptor promoter as potential risk factors and prognostic markers for glioblastoma. The -216T allele (which results in a 30% higher activity) was more frequent in the patients compared with the control population (224/376 = 59.6% vs 165/352 = 46.8%; p = 0.0006) corresponding to an odd ratio of 1.67 (1.24; 2.25). A modest difference in median survival was also associated with the TT genotype.