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Background Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL–PCNSL. Patients and methods Patients with refractory/relapsed (R/R) DLBCL–PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20mg/day, D1-21 for cycle 1; and 25mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0=10%; P1=30%). Results Fifty patients were included. Forty-five patients (PCNSL, N=34; PVRL, N=11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9–51.2) in assessable patients and 32.0% (95% CI 21.9–51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2months (range 1.5–31), the median progression-free survival (PFS) and overall survival (OS) were 7.8months (95% CI 3.9–11.3) and 17.7months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS=9.5months (95% CI, 8.1–14.8] for CD4/CD8≥1.6; median PFS=2.8months, [95% CI, 1.1–7.8) for CD4/CD8 Conclusions The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. Clinical trials number NCT01956695.

Background Vascular endothelial growth factor receptor (VEGFR)2 overexpression on glioblastoma endothelia serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed a positive correlation of of VEGFR2 specific T cells as well as altered intra-tumoral immunity with prolonged overall survival. One partial response was reported with VXM01 alone. The current trial aimed at intensifying the efficacy signal and testing the co-administration of a checkpoint inhibitor. Material and Methods A multicentre, open-label phase I/II study (EudraCT 2017 003076 31) included 28 patients (25 non-resectable, 3 resectable) with progressive glioblastoma after standard chemoradiotherapy. VXM01 was administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab (800 mg) was given intravenously q2w. Treatment continued up to week 96 followed by a 2-year observation period. Endpoints included safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, and tumor immune biomarkers. Results Treatment with VXM01 106 or 107 CFU plus avelumab was completed in all patients. No treatment-related toxicities were observed. Three partial responses (according to iRANO) with tumor reductions of 58, 81 and 95% to baseline, respectively, were reported in the non-resectable patients (Objective response rate (ORR) was 12% (3/25)). Two of these patients were progression-free > 12 months. Best response in 3 additional non-resectable patients was SD including one patient progression-free > 6 months. In one resected patient, tumor shrinkage of 30% each was observed after initial treatment before resection as well as subsequent to incomplete resection, associated with survival > 18 months, and accompanied by an increase of intratumoral CD8+ T-cells. Conclusion VXM01 in combination with avelumab was safe and produced detectable peripheral VEGFR-2-specific immune responses. Three non-resected patients had an objective response, three more patients experienced best response stable disease. For future studies a patient enrichment strategy based on immune biomarkers might be envisaged.

Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Patients and Methods In a retrospective analysis of individual patient data using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, p Conclusion Any association of psychiatric adverse events with LEV did not persist beyond the concomitant treatment phase. Antiemetic properties of LEV may be beneficial during the maintenance temozolomide.

Background Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. Material and Methods The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium ( Results Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented. Conclusion These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.

BACKGROUND Maintenance of functioning and wellbeing during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. MATERIAL AND METHODS We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. RESULTS 5539 patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9%-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8–5.4 months, and median time-to-deterioration between 8.2–11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. CONCLUSION HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients’ functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signalled.

International audience; 18F-FDOPA PET has demonstrated its additional value during the clinical course of glioma, at initial diagnosis, for treatment planning or follow-up. The aim of the current review was to summarize current applications of 18F-FDOPA PET in gliomas and constitute, as a perspective, a first step in harmonizing clinical practices in French centers. In France, the indication for 18F-FDOPA PET is restricted to the assessment of primary brain tumor recurrence. According to the literature, this indication could be expanded to primary diagnosis and, to a lesser extent, treatment monitoring. There is a real need to harmonize standard procedures among French centers. The objective is to increase the availability of data for this rare entity of glioma and to develop multi-parametric PET analyses (static, dynamic and textural), also known as radiomics, by using artificial intelligence algorithms. For this purpose, kinetics analysis with dynamic PET acquisition should be implemented in routine practice because it has demonstrated its additional value for initial diagnosis in gliomas. Therefore, this review proposes a workflow based on acquisition and reconstruction parameters that can be implemented in each center to increase the amount of standardized 18F-FDOPA PET data in neuro-oncology imaging in France. This would help in creating a national database and developing national multi-center studies that can respond to the challenge of using multi-parametric PET in glioma.

BACKGROUND Improvement or maintenance of autonomy is a crucial and understudied issue for glioblastoma (GBM) patients whose outcome is poor. Biopsy-only GBM (BO-GBM) is a situation where survival is short and independence is of particular importance. Our objective was to explore functional outcome in biopsy-only patients. MATERIAL AND METHODS A regional glioma SIRIC cohort was conducted at CHU Timone in 2014–2017 and we retrospectively reviewed the BO-GBM subgroup. We prospectively collected age, corticosteroid dose, tumoral surface, treatment allocated and completed, and survival outcome. Functional independence was analyzed as a cumulative time of Karnofsky performance status (KPS) ≥70 from the date of diagnosis until death. We analyzed potential factors associated to time with KPS ≥70. RESULTS Among 535 patients enrolled in the cohort, surgery was restricted to biopsy in 139 patients (BO-GBM). Mean tumoral surface measured on gadolinium-enhanced T1-weighted MRI was 1198mm2 (min: 65; max: 4515mm2). Mean steroid dose at diagnosis was 50mg prednisolone per day. Corticosteroid dose was ≥50mg prednisolone per day for 77 patients and CONCLUSION Patients with inoperable GBM referred to radiotherapy-temozolomide present a valuable duration of functional independence, although shorter in patients not referred to RT. Duration of functional independence could be considered in addition to PFS and OS for treatment evaluation in patients with GBM.

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 “Biopsy-only” glioblastoma is associated with a heterogeneous functional and survival outcome. BO-GBM patients is an understudied group of patients associated to a poor outcome, which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) standard regimen completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients. Our objective was to explore pattern of care and prognosis associated to BO-GBM in our center. MATERIAL AND METHODS Patients with BO-GBM included in a prospective regional glioma SIRIC cohort initiated in 2014 and closed in 2017 were retrospectively reviewed for patients characteristics, MRI finding, treatment allocation and delivery. PFS and OS were analyzed. RESULTS Of 535 patients included in the cohort, 86 patients were referred > 3 months post-surgery and were excluded from this analysis while 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. Of 158 patients, 18 patients were excluded for missing data leaving 139 patients for the present analysis. Fifty-four (39%) were referred to RT-TMZ (50 patients completed concomitant treatment), 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF) (of which 4 were subsequently referred to RT), 17 (12%) were referred to palliative care only (PC). Groups differed at baseline for age (mean 60, 68, and 69 years, for RT-TMZ, CT-UF, and PC respectively); for KPS (70, 60, and 50 for RT-TMZ, CT-UF, and PC respectively); for mean tumor surface measured on gadolinium-enhanced T1-weighted (793, 1420, 1412 mm2 for RT-TMZ, CT-UF, PC); for tumor extension (bilateral in 6.4% and 29.3% for RT-TMZ and CT-UF respectively); for mean steroid intake (45, 60, 100 mg daily respectively). Median OS was 14 months (95% CI, 9.65–18.71), 8 months (95% CI, 4.62–7.67), and 2 months (95% CI, 0.67–3.33) for RT-TMZ, CT-UF, and PC respectively. CONCLUSION Inoperable GBM constitute a large and heterogeneous population in which one third of patients are amenable to standard of care, with survival outcome close to the one of patients who underwent surgery. Patients considered unfit for RT-TMZ at diagnosis fail to be referred subsequently to RT after CT and exhibit a poor survival outcome. Thus, reliable criteria are needed to help selecting patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.

BACKGROUND The role of surgery for the treatment of malignant gliomas in patients 70 years of age or older is unsettled. We conducted a randomized trial that compared surgical resection of the tumor and biopsy only, both followed by standard therapy, in such patients. MATERIAL AND METHODS Patients aged 70 years and older, with a KPS of at least 50, presenting with a radiological suspicion of an operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008–2017), with the adjunction of concomitant and adjuvant temozolomide when this regimen became standard (2017–2019). The primary end point was survival; secondary endpoints were progression free survival (PFS), cognitive status (MMS), autonomy (KPS), quality of life (EORTC QLQ C30 and BN20), and perioperative morbidity/ mortality. RESULTS From 2008 to 2019, 107 patients from 9 centers were enrolled in the study, of whom 101 were evaluable for analysis because the diagnosis of GBM was histologically confirmed (50 patients in the “surgery” arm and 51 patients in the “biopsy” arm). There was no statistically significant difference of median survival between the “surgery” arm (9.37 mo) and the “biopsy” arms (8.96 mo, p=0.36). However, the surgery group had increased PFS (5.06 mo vs 4.02 mo; p=0.034; p=0.002 on multivariate analysis) and better QOL (e.g. physical and cognitive functioning, motor dysfunction, fatigue) and KPS score evolution as compared to the “biopsy” group. Surgery was not associated with increased mortality or morbidity. CONCLUSION This study suggests that optimal debulking surgery does not provide a significant survival benefit in elderly patients suffering from newly diagnosed malignant glioma, but resection improves QOL and autonomy with a significant though modest improvement of PFS.

International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.

BACKGROUND GB are highly aggressive tumors which systematically relapse. Our objective was to identify disease progression mechanisms and genomic drivers of GB treatment resistance. MATERIAL AND METHODS Ten paired frozen tumors from initial and recurrent surgery after RTCT were screened by CGH Array. Next, NGS of the selected genes was performed on 19 paired tumors (38 samples). Molecular alterations were correlated with patient data. TCGA was used to characterize the molecular profile of MPDZ. RESULTS Nineteen IDHwt GB patients with a median age of 54.5 years (37.2–72.8) were included. Using CGH array, unsupervised analysis clustered the whole samples by paired of initial and recurrent tumors. However only 44% of CGH Array alterations were shared between initial and recurrent tumors (amplifications: 55%; deletions: 30%). The new alterations detected at relapse were amplifications in 25% and deletions in 23% of tumors. Two regions corresponding to 171 genes were lost at relapse (p=0.03): 19q13.33 and 19q13.41. Using DAVID genome, 3/171 genes (related to neutrophil chemotactic factors) were identified: FPR1, FPR2, FPR3. Moreover, 24 genes were lost (including MPDZ) and 2 genes were gained in 20% of recurrent tumors. Totally, 29 genes were analyzed by NGS and 4 genes showed pathogenic mutations shared by initial and recurrent tumors: FPR2, REL, TYRP1 and MPDZ. Only MPDZ showed, at relapse, an increasing rate of mutated variants and a new mutation affecting the splicing site. These alterations were independent from classical prognostic factors (age, sexe, karnofsky performans status, MMS and MGMT status) and from patient survivals. To explore MPDZ expression, we used TCGA initial dataset and observed that a lower RNA expression of MPDZ was associated with IDHwt (p CONCLUSION Our results suggest that MPDZ is frequently altered at initial diagnosis with increased alterations in recurrent IDHwt GB after RTCT, suggesting that MPDZ impairment could contribute to the resistance/relapse mechanisms. Further investigations are needed to validate these results. Our results suggest that MPDZ is frequently altered at initial diagnosis with increased alterations in recurrent IDHwt GB after RTCT, suggesting that MPDZ impairment could contribute to the resistance/relapse mechanisms. Further investigations are needed to validate these results.

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.

BACKGROUND: To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. MATERIAL AND METHODS: We assessed survival associations of anticoagulant use from baseline up to start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomized clinical trials in newly diagnosed glioblastoma including 1,273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with: anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents, versus neither nor. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. RESULTS: Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS compared to no use on multivariate analysis (p=0.001, HR=1.52, 95% CI: 1.18–1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. CONCLUSION: Anticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumor properties in glioblastoma.

BACKGROUND: Thrombocytopenia is a major adverse event of temozolomide (TMZ) chemotherapy. It may lead to dose reduction/interruption or bleeding. Platum (NCT02227576) was a phase II open label, multicenter single arm trial evaluating the thrombopoetin receptor agonist, romiplostim, for secondary prevention of TMZ-induced thrombocytopenia in patients with newly diagnosed glioblastoma. MATERIAL AND METHODS: Patients diagnosed with CTCAE grade 3/4 thrombocytopenia during standard treatment of glioblastoma received weekly subcutaneous injections of romiplostim at a starting dose of 750 µg. Dose adjustments were based on weekly platelets counts. The study aimed at demonstrating that the percentage of thrombopenic patients treated with romiplostim able to complete 6 cycles of maintenance TMZ chemotherapy exceeded 10% (p0=0.10; pA=0.35) (Gerber et al., 2007). Using type I error equal to 0.05 and 95% power, 31 patients had to be recruited. According to a Fleming’s two step design, an interim analysis was planned after recruitment of 20 evaluable patients. Three scenarios were pre-defined: (1) 2 patients or less meeting the endpoint: termination for futility (pP0), (3) 3 to 5 patients meeting the endpoint: enrollment of 11 more evaluable patients. RESULTS: Twenty patients (13 females) were enrolled in step 1 between July 2014 and December 2016. Median age was 60.5 (range: 33–72 years). Surgery included biopsy (n=7), partial (n=5), subtotal (n=2) or gross total resection (n=6). Isocitrate dehydrogenase 1(R132H) mutations were noted in 2 cases. The median lowest count of platelets at screening was 25,500/mm(3) (range 9,000–59,000). Sixteen patients were enrolled after radiotherapy and before maintenance initiation, 4 were enrolled after maintenance TMZ initiation. Twelve patients enrolled in step 1 received the 6 planned maintenance TMZ cycles, corresponding to a success rate of 60% (95% confidence interval 36–81). Four of 8 patients discontinued TMZ because they did not respond to romiplostim, 2 for progression and 1 for clinical deterioration prior to completion of six cycles, 1 due to an adverse event. Eighteen severe adverse events were observed, none was judged to be related to romiplostim. The trial was terminated early for success. CONCLUSION: Thrombopoetin receptor agonists such as romiplostin allow to assure adequate exposure to chemotherapy in glioblastoma patients experiencing early, severe chemotherapy-induced thrombocytopenia.

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5–82.5) and median Karnofsky performance status (KPS) was 60 (range, 40–80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2–6.2), and median overall survival was 8.2 months (95%CI: 0.6–15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL.

Background To define a core set of geriatric data to be methodically collected in clinical cancer trials of older adults, enabling comparison across trials. Patients and methods Following a consensus approach, a panel of 14 geriatricians from oncology clinics identified seven domains of importance in geriatric assessment. Based on the international recommendations, geriatricians selected the mostly commonly used tools/items for geriatric assessment by domain (January–October 2015). The Geriatric Core Dataset (G-CODE) was progressively developed according to RAND appropriateness ratings and feedback during three successive Delphi rounds (July–September 2016). The face validity of the G-CODE was assessed with two large panels of health professionals (55 national and 42 international experts) involved both in clinical practice and cancer trials (March–September 2017). Results and discussion After the last Delphi round, the tools/items proposed for the G-CODE were the following: (1) social assessment: living alone or support requested to stay at home; (2) functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire; (3) mobility: Timed Up and Go test; (4) nutrition: weight loss during the past 6 months and body mass index; (5) cognition: Mini-Cog test; (6) mood: mini-Geriatric Depression Scale and (7) comorbidity: updated Charlson Comorbidity Index. More than 70% of national experts (42 from 20 cities) and international experts (31 from 13 countries) participated. National and international surveys showed good acceptability of the G-CODE. Specific points discussed included age-year cut-off, threshold of each tool/item and information about social support, but no additional item was proposed. Conclusion We achieved formal consensus on a set of geriatric data to be collected in cancer trials of older patients. The dissemination and prospective use of the G-CODE is needed to assess its utility.

BACKGROUND: Glioblastomas, the most common primary central nervous system tumors, induce a peritumoral vasogenic edema impairing functional status and quality of life. Steroids reduce brain tumor-related edema, but are associated with numerous side effects. It was reported in a retrospective series that angiotensin receptor blockers (ARBs) might be associated with reduced peritumoral edema. The ASTER study is a randomized, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care can reduce steroid requirement during radiotherapy in patients with newly diagnosed glioblastoma. MATERIAL AND METHODS: Patients with a histologically confirmed newly diagnosed glioblastoma after biopsy or partial surgical resection were randomized between Losartan or placebo in addition to standard of care (SOC) with radiotherapy (RT) and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain edema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral edema on MRI, tolerance, and survival. RESULTS: Seventy five (75) patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain edema on the last day of radiotherapy, or one month after completion of RT, was seen between both arms. A trend towards reduction of peritumoral edema over time was seen on MRI, but this reduction did not reach statistical significance. Median OS was similar in both arms. CONCLUSION: Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant radiotherapy and temozolomide.

Background The characteristics of elderly patients with IDH-mutant (IDHm) high-grade gliomas (HGG) remain to be described. This study aims to describe characteristics and patterns of care of elderly patients with IDHm HGG included in the French POLA network dedicated to HGG. Methods The characteristics and patterns of care of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients ( Results Out of the 1433 HGG patients included, 119 (8.3%) occurred in elderly patients. Histology consisted of 1p/19q codeleted anaplastic oligodendroglioma (71.8%), anaplastic IDHm astrocytomas (12.8%) and IDHm glioblastoma (15.4%). Median age at diagnosis was 74 years (70.2-87.1), median Karnofsky Performans Status (KPS) was 80 (50-100). Treatments consisted of a wait and scan policy (7.7%), radiotherapy (RT) alone (7.7%), chemotherapy (CT) alone (41%), RT-CT (RT-TMZ: 25.6%, RT-PCV: 15.4%) or palliative care (2.6%). The clinical, radiological and histological presentations of elderly patients IDHm HGG were different from those of elderly patients IDHwt HGG. Compared to elderly patients IDHwt HGG, elderly patients IDHm were less frequently associated with cognitive impairment (p = 0.045), contrast enhancement (p = 0.01) and had a lower proliferative index (Ki67) (p = 0.005). In contrast, there was no difference regarding clinical, radiological and histological presentations of elderly and younger patients IDHm HGG but their management was different. Elderly patients IDHm less frequently underwent gross total resection (p = 0.002) and radiotherapy (p Conclusions IDHm HGG in elderly show prolonged survival. However, their poorer outcome compared to younger IDHm gliomas may results from patient or tumor characteristics or from under-treatment, suggesting a role for geriatric assessment. Legal entity responsible for the study French POLA network. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

BACKGROUND The brainstem is the second location of brain tumors after optic pathways in NF1. In NF1 children, brainstem gliomas are usually indolent and have a better prognosis than their counterparts in non NF1 children. In contrast, the natural history and prognosis of adult brainstem gliomas in NF1 are nearly unknown. MATERIAL AND METHODS We conducted a retrospective analysis of medical records and MRI of adult NF1 patients followed for a brainstem glioma in 8 centers over a 17 years period (2000–2017). Clinical and imaging characteristics, management and outcome were analyzed. RESULTS Twenty five patients were included in the study (13 males and 12 females) with a median age of 32 (range 17–58). The epicenter of the tumor was located into the pons n=13 (52%), the mesencephalon n=7 (28%), the medulla oblongata n=5 (20%). On MRI, contrast enhancement was seen in 19 tumors (76%). Pathological examination was available in 13 tumors (52%) and showed a high grade astrocytoma (III or IV) in 9 tumors. Five patients were asymptomatic, 3 remained asymptomatic during the follow-up (median follow-up: 86 months, range 22–124). Twenty patients were symptomatic with a median duration of symptom of 2.5 months (range 1–10) before diagnosis. Among these symptomatic patients, 15 died from tumor progression despite treatment with radiation therapy and or chemotherapy. The median overall survival of symptomatic patients was 36 months. CONCLUSION Brainstem gliomas are rare tumors in adults with NF1. Unlike children, adult brainstem gliomas seem to have an unexpected poor prognosis, suggesting the disease may be different in adulthood.

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.

Les glioblastomes (GB) sont les gliomes les plus frequents et les plus graves de l’adulte. Au plan moleculaire, ils se caracterisent par une activation de la voie des recepteurs tyrosine-kinase (RTK) aux facteurs de croissance et par une inhibition de la voie des genes suppresseurs de tumeurs p53 et RB1. L’etat de methylation du gene de la MGMT est le facteur pronostique moleculaire le plus important et semble predire la chimiosensibilite aux alkylants. Comme dans d’autres cancers, des cellules souches cancereuses ont ete identifiees et pourraient constituer une cible therapeutique privilegiee. La prise en charge des GB repose actuellement sur la chirurgie, la radiotherapie et la chimiotherapie. La radiochimiotherapie concomitante (RTCT), selon le protocole de Stupp applicable a la majorite des patients atteints de GB, constitue le progres therapeutique recent le plus important. La place de la chimiotherapie dans les formes inoperables et chez les sujets âges reste a preciser. L’impact des therapies ciblees en premiere ligne de traitement constitue un enjeu majeur des essais en developpement.

BACKGROUND: Predictive marker of bevacizumab activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high grade glioma (HGG) treated with bevacizumab. METHODS: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline and 2 weeks apart from bevacizumab initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective cohort (Cohort2;n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort3;n = 34). Dosages were correlated to objective response (OR), Progression-free survival (PFS), and overall survival (OS). In cohort 1, multiple time points were performed up to progression. Additionally MMP2 and MMP9 plasma levels were analyzed in patients with newly diagnosed GB, after surgery. Finally, MMP2 and 9 RNA were assessed in tumor tissue of a separated group of paired newly diagnosed and recurrent GB (n = 29). RESULTS: In cohort1, high MMP2 baseline level was associated to a probability of OR of 83.3% versus 15.4% in case of low MMP2 level (p = 0.001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard-ratio(HR), 3.92; 95% confidence-interval(CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as decrease of VEGF (p = 0.038 for PFS and p = 0.013 for OS) and MMP9 (p = 0.016 for PFS and p= 0.025 for OS). In cohort2, MMP2, but not MMP9, confirmed its predictive significance. In cohort3, no association was found between MMP2, MMP9 and outcome. In cohort 1, significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0.031). No significant difference was observed both for plasma level and tissue RNA expression between newly diagnosed and recurrent GB. CONCLUSIONS: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival, while changes over time may reflect tumor control. Comparison of MMP2/MMP9 levels between initial diagnosis and recurrence may suggest that bevacizumab could be similarly effective in this two setting. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed. SECONDARY CATEGORY: Clinical Neuro-Oncology.

Glutamate synthase (NADH-GOGAT) is one of several proteins whose expression is either enhanced in, or specific to developing legume root nodules induced by (Brady)Rhizobium infection. This enzyme catalyzes the second committed step in the assimilation of symbiotically fixed nitrogen; the transamidation of 2-oxoglutarate by glutamine to yield two moles of glutamate. We have previously purifed alfalfa root nodule NADH-GOGAT and raised antibodies against this protein. To investigate the regulation of the gene encoding this enzyme, we have isolated a full length cDNA clone for NADH-GOGAT from an alfalfa nodule cDNA library. This 7.5 kb cDNA includes the sequence encoding the mature 210 kd protein (the amino terminus of which has been sequenced), as well as an apparent transit peptide. Northern blots indicate that mRNA levels are developmentally regulated in the nodule, showing a similar pattern to that of previously characterized genes encoding aspartate aminotransferase and phosphoenoylpyruvate carboxylase.

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.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.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.

Malignant gliomas are the most frequent primary brain tumors in adults. Temozolomide is an oral alkylating cytotoxic agent of second generation, used in the treatment of high-grade gliomas. It is indicated in newly diagnosed glioblastoma multiform as well as in recurrent or progressive malignant gliomas, such as glioblastoma multiform or anaplastic astrocytoma. However, temozolomide is also used, off label, in other clinical situations and the main objective of this study was to establish recommendations and guidelines for relevant prescriptions of temozolomide in primary brain tumors and brain metastasis in adults. The literature review was analysed by experts who determined the evidence level (A to E) according to the scale of recommendations adopted by the "Haute Autorité de santé--HAS--(French National Authority for Health)". For high-grade and low-grade gliomas, based on the level of evidence from the literature, the use of temozolomide can be justified, with a B2 score attributed to these indications. In contrast, for the others indications, the use of temozolomide appeared to be more controversial or even not recommended (score C to E). Regarding the dosing schedule and administration scheme, as well as the co-administration with other anticancer drugs, a C score was attributed for the off label situations.

Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan.To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas.Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated.From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1).This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

The recurrence and progression of treated intracranial meningiomas highlights the problem of the type of follow-up that should be used and whether early complementary treatment is indicated. The aim of this study was to evaluate different biochemical markers involved in cell proliferation and transformation to identify new prognostic factors in intracranial meningiomas. Between 1989 and 2003, 120 intracranial meningiomas were studied biochemically. The levels of estrogen receptors (RE), progesterone receptors (RP), cathepsin B (CB), cathepsin L (CL), stefin A (ATA), stefin B (STB), cystatin C (CYSC), urokinase (u-PA), type 1 plasminogen activator inhibitors (PAI-1), cathepsin D (CD) and thymidine kinase activity (TK) were measured in tumor extracts using biochemical assays.Out of 120 meningiomas, 73 were grade I, 39 grade II and eight grade III according to the WHO classification. Of these patients, 17 showed recurrence. The mean follow-up was 47 months. Monofactorial analysis showed that expression of progesterone receptors (RP) had an inverse correlation with recurrence (p=0.0025 %) and that thymidine kinase activity (TK), cathepsin L (CL), the WHO grade and the degree of tumor resection correlated with recurrence (p0.05). Principal component analysis and linear discriminant analysis confirmed these results. The results of this study confirm the importance of biological parameters (PR, CL, TK) as prognostic factors for the risk of recurrence in intracranial meningiomas.

Neoangiogenesis is a critical feature that can differentiate high-grade from low-grade glioma. Conventional MR imaging does not assess this histological feature accurately. The goal of this study was to evaluate the gain in relative cerebral blood volume measurement using perfusion MRI in the management of cerebral gliomas.Between 1998 and 2001, 32 histologically proven glial tumors were assessed by perfusion MRI using echoplanar imaging (EPI) and gradient-echo techniques. Relative cerebral blood volume (rCBV) was measured in all patients and compared to histological data.rCBV values were significantly correlated to histological grading in all 32 patients (P0.001). Mean rCBV values were 8.74 (+/-3.79) for glioblastomas, 7.37 (+/-2.83) for anaplastic gliomas and 0.84 (+/-0.61) for low-grade gliomas. Mean rCBV values were significantly different between low- and high-grade gliomas, making it possible to determine a threshold (2.5-3) that can separate these two types of lesion. In determining the histological grading, rCBV was shown to be significantly more accurate than conventional MRI (P0.005).Perfusion MRI using the EPI technique reliably assesses tumoral neoangiogenesis in gliomas preoperatively. The specificity and sensitivity of this technique make this radiological modality a valuable tool in the assessment of cerebral gliomas.

Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined.A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology.Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper).Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index.Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

Ependymomas are rare intracranial tumors observed in adults. Prognostic factors as well as proper therapeutic management remain controversial. We report a retrospective study of 121 cases intracranial ependymomas diagnosed between 1990 and 2004 in adult patients. Mean age was 46 years with a 1/1 sex-ratio. Supratentorial and infratentorial localization was noted for 41 (33.9%) and 80 (66.1%) patients respectively. Total gross resection was achieved for 62.8% of tumors. WHO staging was grade II for 72.7% and III for 27.3%. Recurrence developed in 41 (33.9%) patients. Median follow-up was 70 months. The 5-year and 10-year overall survivals were 85 and 76% respectively; the respective progression-free survivals were 64 and 43%. At univariate analysis, age, KPS, localization, extent of surgery and histological grade were correlated with overall survival. At multivariate analysis age, location, histological grade and extent of surgery contributed most to prediction of overall survival. Concerning progression-free survival, univariate analysis found age, KPS, localization, extent of surgery, complementary treatment and histological grade to be correlated with recurrence. Multivariate analysis retained extent of surgery, histological grade and complementary treatment as the most important predictors of progression-free survival. This study demonstrated that extent of surgery and tumor grade are the two main prognostic factors in adult intracranial ependymomas with respect to overall and progression-free survival. Furthermore, our data suggest that postoperative radiotherapy significantly increases progression-free survival in patients with incompletely resected grade II tumors.

Twenty years ago, the discovery of the chemosensitivity of anaplastic oligodendrogliomas considerably boosted interest for these tumors. In spite of difficulties for histological diagnosis, numerous studies on radiotherapy and chemotherapy for oligodendrogliomas appeared these last years. They allowed to detail the appropriate role for these therapeutics. For low grade oligodendrogliomas, radiotherapy delays the anaplastic transformation, but does not modify the overall survival; its indication has to be discussed particularly in the absence of clinical symptoms. Chemotherapy seems to be effective for low grade oligodendrogliomas as well as anaplastic tumors. However, phase III studies are necessary to clarify the contribution of chemotherapy for the treatment of low grade oligodendrogliomas, mainly in relation to radiotherapy. In anaplastic oligodendrogliomas, in spite of the lack of phase III studies, radiotherapy seems to be effective. Chemotherapy is clearly effective, but the most appropriate timing (neoadjuvant, adjuvant, at recurrence) is unknown. Results of current prospective studies are awaited. Recently, molecular genetic analysis, particularly the loss of 1p and 19q chromosomes appears to demonstrate a genetic influence on both prognosis and response to treatment.

BACKGROUND Currently, the survival of patients age > 70 years with glioblastoma multiforme (GBM) ranges from 4 months to 6 months, although radiotherapy and/or chemotherapy may prolong survival in certain subgroups. Temozolomide is an oral chemotherapeutic agent with efficacy against malignant gliomas and a favorable safety profile. This open-label, single-center, Phase II study was designed to evaluate the efficacy and safety of temozolomide as first-line chemotherapy and exclusive treatment in elderly patients with newly diagnosed GBM. METHODS Chemotherapy-naive patients (age > 70 years) were treated with temozolomide at a dose of 150–200 mg/m2 per day for 5 consecutive days of a 28-day cycle until they developed disease progression. No radiation therapy was administered. The primary endpoint was median overall survival (OS); secondary endpoints included progression-free survival (PFS) and toxicity. RESULTS Thirty-two patients (median age, 75 years; median Karnofsky performance status, 70) experienced a median OS of 6.4 months and a median PFS of 5.0 months. Of 29 patients who were assessed for response, 9 patients (31%) achieved a partial response, 12 patients (41%) maintained stable disease, and 8 patients (28%) developed progressive disease. Adverse events primarily were mild, with NCI CTC Grade 3–4 thrombocytopenia and neutropenia reported to occur in 6% and 9% of patients, respectively. No neurotoxicity was observed. Treatment delays and dose reductions occurred in 13% and 14% of cycles, respectively. CONCLUSIONS Temozolomide represents a safe, easily administered, and effective therapeutic approach for elderly patients with newly diagnosed GBM. Cancer 2004. © 2004 American Cancer Society.

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.

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.

Background Predictive marker of bevacizumab activity is an unmet medical need, while activity of this anti-VEGF Mab is reported to be heterogeneous, particularly in glioblastoma. Objective To identify circulating biomarker that predicts response to bevacizumab and outcome in recurrent high grade glioma (HGG). Methods Eleven angiogenic makers were analyzed, using ELISA, at baseline and one month apart from bevacizumab initiation in a first cohort of 26 HGG patients of our institution (cohort 1); Plasma marker dosages were correlated to objective response (RANO criterias), Progression-free survival (PFS), and overall survival (OS). Correlations were validated in a separate cohort of 50 patients (Cohort 2). Markers analyses were performed in two other cohorts treated with cytotoxic agents up front (cohort 3 n = 20) or concomitant to radiotherapy (cohort 4 n = 24). Results In cohort 1, high MMP2 baseline level was associated to a probability of response of 83.3% versus 15.4% in case of low MMP2 level (p = 0.001). By univariate analyses, confirmed by multivariate analysis, MMP2 correlated with PFS (p = 0.007) and OS (p = 0.001), as decrease of plasmatic VEGF level (p = 0.038 for PFS and p = 0.013 for OS) and MMP9 level (PFS p = 0.016, OS p = 0.025). These results were confirmed with a similar magnitude in cohort 2 for MMP2 only (p Conclusions Among patients with recurrent HGG treated with bevacizumab, but apparently not with cytotoxic agent, higher plasma MMP2 levels were associated with objective response, prolonged tumor control and survival. Further studies are needed to validate the predictive value of these/this biomarker(s) both with glioma and other cancers. Disclosure O. Chinot: Roche consultant. All other authors have declared no conflicts of interest.

Disclosure A. Barlier: the research prgramm was partially supported by Novartis. All other authors have declared no conflicts of interest. Meningiomas are the most frequent brain tumors after 35 years-old. When total surgical removal is not possible, radiotherapy and radiosurgery are able to control tumoral growth in some cases. But no chemotherapy has ever been demonstrated to be really efficient. Then, in cases of recurrence (particularly in WHO grade 2 and 3 meningiomas), no therapeutic exist at present, leading to fatal issue. Pi3Kinase-Akt-mTor pathway is activated in meningiomas, due to Merlin protein (encoded by NF2 gene) inactivation. SST2 somatostatin receptors are strongly expressed in meningiomas. These receptors are targeted by somatostatin agonists (octreotide and a new “pan-sst” agonist, pasireotide) which antiproliferative effect is known in other types of tumors. The aim of our study is to test in vitro effects of m-Tor inhibitor (Everolimus) and/or somatostatin agonists Octreotide or pasireotide, on human meningiomas in primary culture. By real time PCR, we found that sst2 was expressed in all meningiomas. The expression level of Merlin was highly variable between tumors and was inversely correlated with mTor pathway activation (p