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Purpose: This study aimed to evaluate the prognostic performance of amino-acid PET in high-grade gliomas (HGG) patients at the time of temozolomide (TMZ) treatment discontinuation, after the Stupp protocol., Methods: The analysis included consecutive HGG patients with dynamic [18F]FDOPA PET imaging within 3 months of the end of TMZ therapy, post-Stupp protocol. Static and dynamic PET parameters, responses to RANO criteria for MRI and clinical and histo-molecular factors were correlated to progression-free (PFS)., Results: Thirty-two patients (59.4 [54.0;67.6] years old, 13 (41%) women) were included. Static PET parameters peak tumor-to-background ratio and metabolic tumor volume (respective thresholds of 1.9 and 1.5 mL) showed the best 84% accuracies for predicting PFS at 6 months (p = 0.02). These static PET parameters were also independent predictor of PFS in multivariate analysis (p ≤ 0.05)., Conclusion: In HGG patients having undergone a Stupp protocol, the absence of significant PET uptake after TMZ constitutes a favorable prognostic factor., (© 2024. The Author(s).)

Background: Amino acid PET is recommended for the initial diagnosis of brain lesions, but its value for identifying aggressive lesions remains to be established. The current study therefore evaluates the added-value of dynamic [18 F]FDOPA PET as an adjunct to conventional MRI for determining the aggressiveness of presumed glial lesions at diagnosis., Methods: Consecutive patients, with a minimal 1 year-follow-up, underwent contrast-enhanced MRI (CE MRI) and dynamic [18 F]FDOPA PET to characterize their suspected glial lesion. Lesions were classified semi-automatically by their CE MRI (MRI-/+), and PET parameters (static tumor-to-background ratio, TBR; dynamic time-to-peak ratio, TTP ratio ). Diagnostic accuracies of MRI and PET parameters for the differentiation of tumor aggressiveness were evaluated by chi-square test or receiver operating characteristic analyses. Aggressive lesions were either defined as lesions with dismal molecular characteristics based on the WHO 2021 classification of brain tumors or with compatible clinico-radiological profiles. Time-to-treatment failure (TTF) and overall survival (OS) were evaluated., Results: Of the 109 patients included, 46 had aggressive lesions (45 confirmed by histo-molecular analyses). CE MRI identified aggressive lesions with an accuracy of 73%. TBR max (threshold of 3.2), and TTP ratio (threshold of 5.4 min) respectively identified aggressive lesions with an accuracy of 83% and 76% and were independent of CE MRI and clinical factors in the multivariate analysis. Among the MRI-lesions, 11/56 (20%) were aggressive and respectively 55% and 50% of these aggressive lesions showed high TBR max and short TTP ratio in PET. High TBR max and short TTP ratio in PET were significantly associated to poorer survivals (p ≤ 0.009)., Conclusion: Dynamic [18 F]FDOPA PET provides a similar diagnostic accuracy as contrast enhancement in MRI to identify the aggressiveness of suspected glial lesions at diagnosis. Both methods, however, are complementary and [18 F]FDOPA PET may be a useful additional tool in equivocal cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Diagnostic value of 3,4-dihydroxy-6-[ 18 F]fluoro-L-phenylalanine ([ 18 F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG)., Methods: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [ 18 F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [ 18 F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured., Results: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively., Conclusion: [ 18 F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Diagnostic accuracy of amino-acid PET for distinguishing progression from treatment-related changes (TRC) is currently based on single-center non-homogeneous glioma populations. Our study assesses the diagnostic value of static and dynamic [ 18 F]FDOPA PET acquisitions to differentiate between high-grade glioma (HGG) recurrence and TRC in a large cohort sourced from two independent nuclear medicine centers., Methods: We retrospectively identified 106 patients with suspected glioma recurrences (WHO GIII, n = 38; GIV, n = 68; IDH-mutant, n = 35, IDH-wildtype, n = 71). Patients underwent dynamic [ 18 F]FDOPA PET/CT (n = 83) or PET/MRI (n = 23), and static tumor-to-background ratios (TBRs), metabolic tumor volumes and dynamic parameters (time to peak and slope) were determined. The final diagnosis was either defined by histopathology or a clinical-radiological follow-up at 6 months. Optimal [ 18 F]FDOPA PET parameter cut-offs were obtained by receiver operating characteristic analysis. Predictive factors and clinical parameters were assessed using univariate and multivariate Cox regression survival analyses., Results: Surgery or the clinical-radiological 6-month follow-up identified 71 progressions and 35 treatment-related changes. TBR mean , with a threshold of 1.8, best-differentiated glioma recurrence/progression from post-treatment changes in the whole population (sensitivity 82%, specificity 71%, p < 0.0001) whereas curve slope was only significantly different in IDH-mutant HGGs (n = 25). In survival analyses, MTV was a clinical independent predictor of progression-free and overall survival on the multivariate analysis (p ≤ 0.01). A curve slope > -0.12/h was an independent predictor for longer PFS in IDH-mutant HGGs CONCLUSION: Our multicentric study confirms the high accuracy of [ 18 F]FDOPA PET to differentiate recurrent malignant gliomas from TRC and emphasizes the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant HGGs., Key Points: • The diagnostic accuracy of dynamic amino-acid PET, for distinguishing progression from treatment-related changes, is currently based on single-center non-homogeneous glioma populations. • This multicentric study confirms the high accuracy of static [ 18 F]FDOPA PET images for differentiating progression from treatment-related changes in a homogeneous population of high-grade gliomas and highlights the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant high-grade gliomas. • Dynamic acquisitions should be performed in IDH-mutant glioma patients to provide valuable information for the differential diagnosis of recurrence and treatment-related changes., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics., Methods: We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network., Results: Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival., Conclusion: The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population., (© The Author(s) 2022. Published by Oxford University Press.)

The assessment of gliomas by 18 F-FDOPA PET imaging as an adjunct to MRI showed high performance by combining static and dynamic features to noninvasively predict the isocitrate dehydrogenase (IDH) mutations and the 1p/19q codeletion, which the World Health Organization classified as significant parameters in 2016. The current study evaluated whether other 18 F-FDOPA PET radiomics features further improve performance and the contributions of each of these features to performance. Methods: Our study included 72 retrospectively selected, newly diagnosed glioma patients with 18 F-FDOPA PET dynamic acquisitions. A set of 114 features, including conventional static features and dynamic features, as well as other radiomics features, were extracted and machine-learning models trained to predict IDH mutations and the 1p/19q codeletion. Models were based on a machine-learning algorithm built from stable, relevant, and uncorrelated features selected by hierarchic clustering followed by a bootstrapped feature selection process. Models were assessed by comparing area under the curve using a nested cross-validation approach. Feature importance was assessed using Shapley additive explanations values. Results: The best models were able to predict IDH mutations (logistic regression with L2 regularization) and the 1p/19q codeletion (support vector machine with radial basis function kernel) with an area under the curve of 0.831 (95% CI, 0.790-0.873) and 0.724 (95% CI, 0.669-0.782), respectively. For the prediction of IDH mutations, dynamic features were the most important features in the model (time to peak, 35.5%). In contrast, other radiomics features were the most useful for predicting the 1p/19q codeletion (up to 14.5% of importance for the small-zone low-gray-level emphasis). Conclusion: 18 F-FDOPA PET is an effective tool for the noninvasive prediction of glioma molecular parameters using a full set of amino-acid PET radiomics features. The contribution of each feature set shows the importance of systematically integrating dynamic acquisition for prediction of the IDH mutations as well as developing the use of radiomics features in routine practice for prediction of the 1p/19q codeletion., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Immunohistochemistry and recent molecular technologies progressively guided access to personalized anti-tumoral therapies. We explored the feasibility, efficacy, and the impact of molecular profiling in patients with advanced brain tumors. This multicentric prospective trial ProfiLER enrolled patients with primary brain tumors, who have been pre-treated with at least one line of anti-cancer treatment, and for whom molecular profiles had been achieved using next-generation sequencing and/or comparative genomic hybridization on fresh or archived samples from tumor, relapse, or biopsies. A molecular tumor board weekly analyzed results and proposed molecular-based recommended therapy (MBRT). From February 2013 to December 2015, we enrolled 141 patients with primary brain tumor and analyzed 105 patients for whom tumor genomic profiles had been achieved. Histology mainly identified glioblastoma (N = 46, 44%), low-grade glioma (N = 26, 25%), high-grade glioma (N = 12, 11%), and atypical and anaplastic meningioma (N = 8, 8%). Forty-three (41%) patients presented at least one actionable molecular alteration. Out of 61 alterations identified, the most frequent alterations occurred in CDKN2A (N = 18), EGFR (N = 12), PDGFRa (N = 8), PTEN (N = 8), CDK4 (N = 7), KIT (N = 6), PIK3CA (N = 5), and MDM2 (N = 3). Sixteen (15%) patients could not be proposed for a MBRT due to early death (N = 5), lack of available clinical trials (N = 9), or inappropriate results (N = 2). Only six (6%) of the 27 (26%) patients for whom a MBRT had been proposed finally initiated MBRT (everolimus (N = 3), erlotinib (N = 1), ruxolitinib (N = 1), and sorafenib (N = 1)), but discontinued treatment for toxicity (N = 4) or clinical progression (N = 2). High-throughput sequencing in patients with brain tumors may be routinely performed, especially when macroscopic surgery samples are available; nevertheless delays should be reduced. Criteria for clinical trial enrollment should be reconsidered in patients with brain tumors, and a panel of genes specifically dedicated to neurologic tumors should be developed to help decision-making in clinical practice., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Lessons Learned: Treatment with temozolomide and BCNU was associated with substantial response and survival rates for patients with unresectable anaplastic glioma, suggesting potential therapeutic alternative for these patients. The optimal treatment for unresectable large anaplastic gliomas remains debated., Background: The optimal treatment for unresectable large anaplastic gliomas remains debated., Methods: Adult patients with histologically proven unresectable anaplastic oligodendroglioma or mixed gliomas (World Health Organization [WHO] 2007) were eligible. Treatment consisted of BCNU (150 mg/m 2 ) and temozolomide (110 mg/m 2 for 5 days) every 6 weeks for six cycles before radiotherapy., Results: Between December 2005 and December 2009, 55 patients (median age of 53.1 years; range, 20.5-70.2) were included. Forty percent of patients presented with wild-type IDH1 gliomas, and 30% presented with methylated MGMT promoter. Median progression-free survival (PFS), centralized PFS, and overall survival (OS) were 16.6 (95% confidence interval [CI], 12.8-20.3), 15.4 (95% CI, 10.0-20.8), and 25.4 (95% CI, 17.5-33.2) months, respectively. Complete and partial responses under chemotherapy were observed for 28.3% and 17% of patients, respectively. Radiotherapy completion was achieved for 75% of patients. Preservation of functional status and self-care capability (Karnofsky performance status [KPS] ≥70) were preserved until disease progression for 69% of patients. Grade ≥ 3 toxicities were reported for 52% of patients, and three deaths were related to treatment. By multivariate analyses including age and KPS, IDH mutation was associated with better prognostic for both PFS and OS, whereas MGMT promoter methylation was associated with better OS., Conclusion: The association of BCNU and temozolomide upfront is active for patients with unresectable anaplastic gliomas, but toxicity limits its use., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose: 18 F-FDopa PET imaging of gliomas is routinely interpreted with standardized uptake value (SUV)-derived indices. This study aimed to determine the added value of dynamic 18 F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas., Methods: We retrospectively included 58 patients having undergone an 18 F-FDopa PET for establishing the initial diagnosis of gliomas, whose molecular features were additionally characterized according to the WHO 2016 classification. Dynamic parameters, involving time-to-peak (TTP) values and curve slopes, were tested for the prediction of glioma types in addition to current static parameters, i.e., tumor-to-normal brain or tumor-to-striatum SUV ratios and metabolic tumor volume (MTV)., Results: There were 21 IDH mutant without 1p/19q co-deletion (IDH+/1p19q-) gliomas, 16 IDH mutants with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 IDH wildtype (IDH-) gliomas. Dynamic parameters enabled differentiating the gliomas according to these molecular features, whereas static parameters did not. In particular, a longer TTP was the single best independent predictor for identifying (1) IDH mutation status (area under the curve (AUC) of 0.789, global accuracy of 74% for the criterion of a TTP ≥ 5.4 min) and (2) 1p/19q co-deletion status (AUC of 0.679, global accuracy of 69% for the criterion of a TTP ≥ 6.9 min). Moreover, the TTP from IDH- gliomas was significantly shorter than those from both IDH+/1p19q- and IDH+/1p19q+ (p ≤ 0.007)., Conclusion: Prediction of the molecular features of newly diagnosed gliomas with 18 F-FDopa PET and especially of the presence or not of an IDH mutation, may be obtained with dynamic but not with current static uptake parameters.

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 labeling 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., (© 2019 International Society of Neuropathology.)

Background: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined., Materials and Methods: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM., Results: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival ( p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma., Conclusion: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway., Implications for Practice: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Purpose: Complementary and alternative medicine (CAM) use increases in cancer patients, including adult patients with diffuse gliomas., Methods: Questionnaires addressing CAM use were distributed to adult patients with gliomas of WHO grades II-IV and ECOG performance score of 0-2 during hospital visits and filled in anonymously. The study was conducted in nine centers in France from May 2017 to May 2018. Descriptive cohort analyses and comparative analyses according to gender, age, WHO grade, and recurrent versus newly diagnosed disease were conducted., Results: Two hundred twenty-seven questionnaires were collected; 135 patients (59%) were male. Median age was 48 years, 105 patients (46%) declared having glioblastoma, 99 patients (43%) declared having recurrent disease. Hundred-three patients (45%) had modified their alimentary habits after the glioma diagnosis. At the time of the questionnaire, 100 patients (44%) were on complementary treatment, mainly vitamins and food supplements, and 73 patients (32%) used alternative medicine approaches, mainly magnetism and acupuncture. In total, 154 patients (68%) declared using at least one of these approaches. Expenditures exceeding 100 € per month were reported by users in 14% for modification of alimentary habits, in 25% for complementary treatment, and in 18% for alternative medicines. All approaches were commonly considered as improving quality of life and experienced as efficient, notably those associated with more expenditures., Conclusions: CAM are frequently used by glioma patients in France. Underlying needs and expectations, as well as potential interactions with tumor-specific treatments, and financial and quality of life burden, should be discussed with patients and caregivers.

Purpose: Recurrence of glioblastoma (GB) occurs in most patients after standard concomitant temozolomide-based radiochemotherapy (CTRC). Bevacizumab (BV), an anti-VEGF antibody, has an effect on progression-free survival (PFS) but not on overall survival (OS). However, a small part of the patients experience a survival, longer than expected. This retrospective study aims to characterize long responder (LR) patients treated with BV for a first or second GBM recurrence., Methods: Medical records from patients (814) who received BV for a first or second recurrence of primary glioblastoma between September 2010 and September 2015, and initially treated by CTRC were analyzed. Patients, who had at least a stable disease according to RANO criteria at 12 months from the start of BV, were included. Patients who had, a secondary GB, or received BV in neoadjuvant or adjuvant setting were excluded., Results: We focused on 65 LR patients without progression 12 months after the first injection of BV (8%). Median PFS was 21.7 months [95% CI (19.3; 27.2)] and median OS was 31.1 months [95% CI (24.3; 37.5)] from the start of BV. No prognostic factor was associated with OS in multivariate analysis. Karnofsky performance status, neurological status and corticosteroid dose were stable at 12 months., Conclusions: Our results highlight that among patients receiving bevacizumab in first or second recurrence, one patient out of twelve could be classified as LR. A median OS of 31.1 months from the start of BV could be expected in this subpopulation. These findings reinforce the potential benefit of the use of BV in the situation of recurrence. 256 words.

Background: Epileptic seizures impair quality of life in diffuse low-grade glioma (DLGG) patients. Tumor resection significantly impacts postoperative seizure control, but the precise extent of resection (EOR) required for optimal seizure control is not clear yet., Objective: To identify the EOR and residual tumor volume that correlated to postoperative seizure control, defined as a total seizure freedom (Class 1A in reference to Engel classification system) with and without antiepileptic drugs in patients undergoing surgical resection of supratentorial DLGG., Methods: A retrospective review was conducted of all patients who underwent first-line surgical resection of supratentorial DLGG who presented with preoperative seizures without adjuvant oncological treatment. EOR and residual tumor volume were quantified from pre- and post-operative magnetic resonance imagings. Receiver operating characteristic curves were plotted to determine the EOR and residual tumor volume that corresponded to optimal postoperative seizure control., Results: Of the 346 included patients, 65.5% had controlled seizures postoperatively, with higher age at resection (adjusted OR per unit, 1.03 [95% confidence interval:1.01-1.06], P = .043) and higher percentage of resection (adjusted OR per unit, 1.02 [95% confidence interval:1.00-1.03], P < .001) found as independent predictors of postoperative seizure control. Optimal EOR was ≥91% and optimal residual tumor volume was ≤19 cc to improve postoperative seizure control., Conclusion: Postoperative seizure control is more likely when EOR is ≥91% and/or when residual tumor volume is ≤19 cc in supratentorial DLGG gliomas who present with seizures. Resected peritumoral cortex should, however, be taken into account in future studies., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: Glioblastoma is the most frequent primary malignant brain tumor. In daily practice and at whole country level, oncological care management for glioblastoma patients is not completely known., Objectives: To describe oncological patterns of care, prognostic factors, and survival for all patients in France with newly-diagnosed and histologically confirmed glioblastoma, and evaluate the impact of extended temozolomide use at the population level., Methods: Nationwide population-based cohort study including all patients with newly-diagnosed and histologically confirmed glioblastoma in France in 2008 and followed until 2015., Results: Data from 2053 glioblastoma patients were analyzed (male/female ratio 1.5, median age 64 years). Median overall survival (OS) was 11.2 [95% confidence interval (CI) 10.7-11.9] months. The first-line therapy and corresponding median survival (MS, in months) were: 13% did not receive any oncological treatment (biopsy only) (MS = 1.8, 95% CI 1.6-2.1), 27% received treatment without the combination of radiotherapy (RT)-temozolomide (MS = 5.9, 95% CI 5.5-6.6), 60% received treatment including the initiation of the concomitant phase of RT-temozolomide (MS = 16.4, 95% CI 15.2-17.4) whom 44% of patients initiated the temozolomide adjuvant phase (MS = 18.9, 95% CI 18.0-19.8). Only 22% patients received 6 cycles or more of adjuvant temozolomide (MS = 25.5, 95% CI 24.0-28.3). The multivariate analysis showed that the risk of mortality was significantly higher for the non-progressive patients who stopped at 6 cycles (standard protocol) than those who continued the treatment, hazard ratio = 1.5 (95% CI 1.2-1.9)., Conclusion: In non-progressive patients, prolonging the adjuvant temozolomide beyond 6 cycles may improve OS.

Diffuse low-grade gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training data set of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter.

Objective: In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-( 18 F)-fluoro-L-phenylalanine ( 18 F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUV max )/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18 F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year., Methods: 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18 F-FDOPA PET, quantified with SUV max ratio, along with a serial MRI enabling VDE determination., Results: SUV max ratio was above 1.8 in 5 patients (25%) all of whom had a VDE <4 mm/year (100%) and IDH mutation (100%). Moreover, a SUV max ratio above 1.8 was associated with higher rates of VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10)., Conclusion: This pilot study shows that in diffuse Grade II-III gliomas, a high 18 F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18 F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas.

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Purpose: To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife ® , according to the association or not with an additional whole brain irradiation., Patients and Methods: Institutional retrospective study of 102 patients treated for one to three brain metastasis: 76 with exclusive hypofractionated stereotactic radiotherapy and 26 with hypofractionated stereotactic radiotherapy and whole brain irradiation. Objectives were assessed and compared between these two groups according to the Kaplan-Meier method and Cox model., Results: Median follow-up was 18.8 months. There were no difference between exclusive hypofractionated stereotactic radiotherapy and hypofractionated stereotactic radiotherapy with whole brain irradiation for overall survival (respective median 21.5 and 20.1 months), risk of neurological death (respectively 9.2% and 15.4% at one year). At one year: the risk of cerebral progressive disease was greater in the group receiving exclusive hypofractionated stereotactic radiotherapy (respectively 43.4% vs. 26.2%, P=0.043), the risk of local recurrence was 25% versus 17.6% (P=0.28) and the development of new brain metastasis was 23.7% versus 11.5% (P=0.27). After salvage treatments, crude local control was similar in the two groups, respectively 78.6% and 73.5%. Whole brain irradiation has been avoided for 72.4% of patients in the group receving exclusive hypofractionated stereotactic radiotherapy., Conclusion: Whole brain irradiation improves local control of brain metastatic disease in addition to hypofractionated stereotactic radiotherapy. Sparing whole brain irradiation for salvage treatments only does not affect overall survival or risk of neurological death in selected patients with favourable prognosis., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Diffuse low-grade gliomas (DLGG) are cerebral tumors occurring in young adults, with an inescapable progression to higher grade of malignancy, resulting in functional impairment and death. DLGG evolve in several phases: an asymptomatic period despite a slow radiological growth; a period in which inaugural symptoms occur, usually epilepsy with possible mild cognitive disorders; then a phase with malignant transformation generating disabling neurological deficits; and ultimately the terminal stage. Early maximal surgical resection significantly increases overall survival while preserving quality of life. Surgeries are conducted under local anesthesia in order to map neural networks crucial for brain functions, and with the goal to use neuroplasticity mechanisms by sparing cerebral connectivity. Adjuvant oncological treatments such as chemotherapy and/or radiotherapy are kept for partial resection or non-operable recurrences. Because of an increase of incidentally discovered DLGG, explained by a facilitated access to brain imaging, awake surgery has been proposed in asymptomatic patients, with the aim of maximizing the rate of total or even "supratotal" resection in smaller tumors. Outcomes have been optimized, both regarding oncological results thanks to minimization of malignant transformation, as well as regarding functional results, with neither neurological deficit nor epilepsy in this sub-group of incidental DLGG. Thus, it seems legitimate to set up a screening by cerebral MRI in the population from 20 to 40years, to propose adapted therapeutic strategies based upon an upfront radical surgery, and so to create the foundations of a prophylactic and personalized functional neuro-oncologie., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Requests of organs to be transplanted increase. As a matter of urgency, it is not always easy to decide if a patient carrier of a brain tumor can be candidate in the donation. After a review of the literature, the members of the Association of the Neuro-oncologists of French Expression (ANOCEF) and the Club of Neuro-oncology of the French Society of Neurosurgery propose consensual recommendations in case of donor carrier of primitive tumor intra-cranial or intra-medullary. A contact with the neuro-oncologist/neurosurgeon will allow to discuss the indication in case of glioma of grade I/II/III, according to the grade, the current status (absence of progressive disease), the number of surgeries and of lines of treatment. The taking is disadvised in case of glioma of grade IV (glioblastoma), of lymphoma or meningioma of grade III. No contraindication for the meningiomas of grade I, and individual discussion for the meningiomas of grade II. It is advisable to remain careful in case of hemangiopericytoma and of meningeal solitary fibrous tumor. The patients in first complete remission of a medulloblastoma or intra-cranial primitive germinoma seem good candidates for the taking of organ if the follow-up is of at least 10 years (3 years for non germinomas). In every case, a multidisciplinary discussion is desirable when it is materially possible., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Primary central nervous system tumors (PCNST) are rare tumors responsible for high mortality and morbidity. Their epidemiology is poorly known, and clinical data are scarcely analyzed at a national level. In this study, we aimed at providing descriptive epidemiological data and incidence rates for all histological subtypes of PCNST according to the WHO classification. We conducted a nationwide population-based study of all newly diagnosed and histologically confirmed PCNST in France, between 2006 and 2011. A total of 57,816 patients were included: male 46.4%, median age at diagnosis 56 years old (range 0-99). For all newly diagnosed PCNST with histological confirmation the crude incidence rate was 15.5/10 5 per 100,000 person-years. To enable international comparisons, standardized rates were calculated: 14.1/10 5 (population of reference: USA), 14.5/10 5 (population of reference: Europe), and 12.0/10 5 (population of reference: world). 23.4% of samples were cryopreserved. Resection was performed in 79.1% of cases. Results are detailed (incidence rate, sex ratio, median age at diagnosis, number of cryopreserved samples, and type of surgery) for each of the 143 histological subtypes of PCNST, including all rare tumors. For example, incidence rates (population of reference: USA) were 0.018/10 5 for anaplastic gangliogliomas, 0.054/10 5 for malignant meningiomas, and 0.036/10 5 for hemangiopericytomas. Our study is the first to describe incidence rates and epidemiological data for all histological subtypes of PCNST, including rare tumors, at a national level. Its methodology ensures the exhaustiveness of the data collection for histologically-proven cases. Histological population-based studies have many perspectives in the field of clinical epidemiology and research.

The origins of diffuse low-grade gliomas (DLGG) are unknown. Beyond some limited data on their temporal and cellular origins, the mechanisms and risk factors involved are poorly known. First, based on strong relationships between DLGG development and the eloquence of brain regions frequently invaded by these tumors, we propose a "functional theory" to explain the origin of DLGG. Second, the biological pathways involved in DLGG genesis may differ according to tumor location (anatomo-molecular correlations). The cellular and molecular mechanisms of such "molecular theory" will be reviewed. Third, the geographical distribution of diffuse WHO grade II-III gliomas within populations is heterogeneous, suggesting possible environmental risk factors. We will discuss this "environmental theory". Finally, we will summarize the current knowledge on genetic susceptibility in gliomas ("genetic predisposition theory"). These crucial issues illustrate the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and personalized management of DLGG patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Diffuse low-grade gliomas are rare primitive cerebral tumours of adults. These tumors progress continuously over time and then turn to a higher grade of malignancy associated with neurological disability, leading ultimately to death. Tumour size is one of the most important prognostic factors. Thus, it is of great importance to be able to assess the volume of the tumor during the patients' monitoring. MRI is nowadays the recommended modality to achieve this. Furthermore, if surgery remains the first option for diffuse low-grade gliomas, chemotherapy is increasingly used (before or after a possible surgery). However, crucial and difficult questions remain to be answered: identifying subgroups of patients who could benefit from chemotherapy, determining the best time to initiate chemotherapy, defining the duration of chemotherapy and evaluating the optimal time to perform surgery, or otherwise radiotherapy. In this study, we propose to help clinicians in decision-making, by designing new predictive models dedicated to the evolution of the diameter of the tumor. Two proposed statistical models (linear and exponential) have been validated on a database of 16 patients whose temozolomide-based chemotherapy lasted between 14 and 32 months, with an average duration of 22.8 months. The selection of the most appropriate model has been achieved with the corrected Akaike's Information Criterion. The results are very promising, with coefficients of determination varying from 0.79 to 0.97 with an average value of 0.90 for the linear model. This shows it is possible to alert the clinician to a change in the tumor diameter's dynamics.

Glioblastoma is the most common malignant brain tumor in adults. Baseline health-related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty-four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ-C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C-index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Although a large amount of data supports early surgical resection for symptomatic diffuse low-grade glioma, the therapeutic strategy is still a matter of debate regarding incidentally discovered diffuse low-grade glioma. Indeed, early and "preventive" surgery has recently been proposed in asymptomatic patients with silent diffuse low-grade glioma with better outcomes. The present review discusses the importance of an early diagnosis and of a preventive surgical treatment to improve the outcomes of incidental diffuse low-grade glioma and suggests the possible relevance of a tailored screening policy.

Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient's age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one-out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results.

Purpose of Review: High-grade glioma (HGG) patients are at particularly high risk of venous thromboembolism (VTE) occurrence and recurrence. VTE is associated with worsened survival in these patients. At present, the main challenge when prescribing anticoagulants in HGG patients is to address the risk of intracranial hemorrhage and provide the optimal treatment., Recent Findings: Here, we discuss the latest biological findings and their potential implications for better classification in daily practice and stratification of patients in future trials according to their risk of developing a VTE., Summary: To help clinicians, international guidelines have been provided for cancer patients, but their implementation remains suboptimal. We report here the specificities of VTE management in HGG patients relative to other cancer patients. Particular aspects such as anticoagulation under targeted therapies, primary and secondary prophylaxis, and the role of new oral anticoagulants are discussed as well.

Purpose: Glioma grading is necessary for prognostic evaluation and optimal treatment decisions. The aims of this study were to establish whether a correlation between F-FDOPA uptake with tumor grade was observed and to determine which of the SUV-derived indices was the best correlated., Patients and Methods: Thirty-one patients were retrospectively included (mean [SD] age, 36.8 [12.1] years) including 21 proven low-grade tumors due to histology, imaging, and clinical follow-up and 10 histologically proven high-grade tumors. Static PET acquisitions were postreconstructed between the 10th and 30th minute after injection of F-FDOPA. Regions of interest of 20 mm were applied to tumors, and isocontoured volumes were defined at levels of 50% and 80% of the peak intensity voxel. Background was quantified with 30-mm-diameter regions of interest on contralateral striatum and centrum semioval. Tumoral uptake was evaluated with the following SUV-derived indices: SUVmax, SUVmean, SUVmax, and SUVmean of isocontoured volume, tumor/striatum ratio (T/S), and tumor/normal brain ratio (T/N)., Results: All the SUV-derived indices tested were significantly correlated with tumor grade, considering low-grade and high-grade groups (P < 0.05), except for the SUVmean 50%. The 2 best-correlated indices were SUVmean T/N and SUVmean T/S, with correlation coefficients of 0.561 and 0.522, respectively. Receiver operating characteristic analysis defined optimal thresholds of 1.33 and 1 for sensitivity and specificity of 71% and 100% and 67% and 100%, respectively., Conclusions: F-FDOPA PET SUV-derived indices are routinely available information that enables accurate discrimination of low-grade and high-grade gliomas. The best-correlated indices were SUVmean T/N and SUVmean T/S with thresholds of 1.33 and 1.

Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event.

Diffuse low-grade glioma grows, migrates along white matter tracts, and progresses to high-grade glioma. Rather than a "wait and see" policy, an aggressive attitude is now recommended, with early surgery as the first therapy. Intraoperative mapping, with maximal resection according to functional boundaries, is associated with a longer overall survival (OS) while minimizing morbidity. However, most studies have investigated the role of only one specific treatment (surgery, radiotherapy, chemotherapy) without taking a global view of managing the cumulative time while preserving quality of life (QoL) versus time to anaplastic transformation. Our aim is to switch towards a more holistic concept based upon the anticipation of a personalized and long-term multistage therapeutic approach, with online adaptation of the strategy over the years using feedback from clinical, radiological, and histomolecular monitoring. This dynamic strategy challenges the traditional approach by proposing earlier therapy, by repeating treatments, and by reversing the classical order of therapies (eg, neoadjuvant chemotherapy when maximal resection is impossible, no early radiotherapy) to improve OS and QoL. New individualized management strategies should deal with the interactions between the course of this chronic disease, reaction brain remapping, and oncofunctional modulation elicited by serial treatments. This philosophy supports a personalized, functional, and preventive neuro-oncology., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper., (Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors, with few specific epidemiological studies. We aimed at describing the geographical distribution of a homogeneous series of histologically confirmed DGII/IIIG, over a four-year period (2006-2009), at a national level. The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase and data collected directly from every neuropathology department. Personal home addresses were collected for confirmed cases. For each region, the incidence of DGII/IIIG was analyzed and standardized on the age and sex distribution of the French population. The number of patients with newly diagnosed, histologically confirmed DGII/IIIG was 4,790. The overall crude rate was 19.4/10(6). To enable international comparisons, standardized rates were calculated as follows: 19.8/10(6), 18.8/10(6) and 16.0/10(6) (reference population, Europe, US and world, respectively). The geographical distribution by region showed significant differences, with higher incidence rates in Northeast and central parts of France. This work is the first studying the geographical distribution of a pure series of DGII/IIIG at a national level. It demonstrates significant heterogeneity in the distribution, and raises the question of the role of environmental and/or genetic risk(s) factor(s) for DGII/IIIG.

Background: Secondary gliosarcomas are rare tumors, especially those arising from a World Health Organization (WHO) grade II glioma not irradiated. We report a case with subtotal resection for a WHO grade II oligoastrocytoma, without adjuvant treatment, whose metaplastic transformation into gliosarcoma suddenly occurred 4 years later with meningeal dissemination. We show a favorable outcome after therapeutic management of this rare entity., Patient: A 46 year-old woman underwent surgery for a right premotor WHO grade II oligoastrocytoma discovered incidentally. Because of a subtotal resection with only 1 cc of residue, no complementary therapy was given, and the patient enjoyed a normal life for 4 years. In the meantime, the magnetic resonance images performed every 6 months showed a very low growth rate. Suddenly, the tumor switched toward a gliosarcoma profile with meningeal dissemination., Results: Reoperation, radiotherapy, and chemotherapy were performed, enabling a control of the disease with 15 months of follow-up (i.e., with radiologic shrinkage of the multiple lesions and preservation of quality of life)., Conclusion: A delayed sarcomatous transformation can acutely occur with a low proliferation index in a nonirradiated WHO grade II oligoastrocytoma. Furthermore, an aggressive therapeutic strategy can allow control of secondary gliosarcomas, even in cases of leptomeningeal spreading., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults., Methods: One hundred thirty-one adult patients with newly diagnosed supratentorial diffuse low-grade gliomas were retrospectively studied., Results: Isocitrate dehydrogenase 1 mutations were present in 107 patients. The mean spontaneous velocity of diametric expansion was 5.40 ± 5.46 mm/y. During follow-up (mean, 70 ± 54.7 mo), 56 patients presented a malignant transformation and 23 died. The median malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (149 and 198 mo, respectively) than in cases of fast velocity of diametric expansion (46 and 82 mo; P < .001 and P < .001, respectively) and in cases with IDH1 mutation (100 and 198 mo, respectively) than in cases without IDH1 mutation (72 mo and not reached; P = .028 and P = .001, respectively). In multivariate analyses, spontaneous velocity of diametric expansion and IDH1 mutation were independent prognostic factors for malignant progression-free survival (P < .001; hazard ratio, 4.23; 95% CI, 1.81-9.40 and P = .019; hazard ratio, 2.39; 95% CI, 1.19-4.66, respectively) and for overall survival (P < .001; hazard ratio, 26.3; 95% CI, 5.42-185.2 and P = .007; hazard ratio, 17.89; 95% CI, 2.15-200.1, respectively)., Conclusions: The spontaneous velocity of diametric expansion and IDH1 mutation status are 2 independent prognostic values that should be obtained at the beginning of the management of diffuse low-grade gliomas in adults., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB., Patients and Methods: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm., Results: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm., Conclusions: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB., Clinical Trial Registration: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918)., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The incidence of glioblastoma (GBM) has increased in patients aged 70 years or older, and will continue to grow. Elderly GBM patients have been excluded from most clinical trials; furthermore, optimal care management as well as benefit/risk ratio of GBM treatments are still being debated. This study describes oncological patterns of care, prognostic factors, and survival for patients ≥ 70 years in France. We identified patients over 70 with newly diagnosed and histologically confirmed GBM on data previously published by the French Brain Tumor DataBase. We included 265 patients. Neurological deficits and mental status disorders were the most frequent symptoms. The surgery consisted of resection (RS n = 95) or biopsy (B n = 170); 98 patients did not have subsequent oncological treatment. After surgery, first-line treatment consisted of radiotherapy (RT n = 76), chemotherapy (CT n = 52), and concomitant radiochemotherapy (CRC n = 39). The median age at diagnosis was 76, 74, and 73 years, respectively, for the untreated, B + RT and/or CT, RS ± RT and/or CT groups. Median survival (in days, 95 % CI) with these main strategies, when analyzed according to surgical groups, was: B-CT n = 41, 199[155-280]; B-CRC n = 21, 318[166-480]; B-RT n = 37, 149[130-214]; RS-CT n = 11, 245[211-na]; RS-CRC n = 18, 372[349-593]; RS-RT n = 39, 269[218-343]. This population study for elderly GBM patients is one of the most important in Europe, and could be considered as a historical cohort to compare future treatments. Moreover, we can hypothesize that elderly patients (versus patients <70 years) are undertreated. Karnofsky performance status seems to be the most relevant clinical predictive factor, and RS and CRC have a positive impact on survival for elderly GBM patients in the general population, at least when feasible.

Object: Diffuse WHO Grade II glioma (diffuse low-grade glioma [DLGG]) is an infiltrative brain tumor that usually migrates along the white matter fibers. The delayed CSF dissemination of supratentorial DLGGs is an exceptional complication and is rarely described in adults. Here, the authors report outcomes in a surgical series of 9 patients with DLGGs with subsequent leptomeningeal and/or subependymal seeding (LMSS) following multiple incomplete resections., Methods: The authors performed a retrospective review of patients who underwent surgery for histopathologically confirmed WHO Grade II gliomas between 1998 and 2012 and experienced a secondary CSF spread. Information regarding clinical features, surgical procedures, histopathological results, adjuvant treatment, and clinical outcomes was collected and analyzed., Results: Nine consecutive patients were included in this study. There were 6 men and 3 women whose mean age was 35.5 years (range 22-59 years) at the time of initial symptom onset. All patients underwent surgery with the aid of intraoperative mapping, with incomplete tumor removal because of invasion of eloquent structures. The neuropathological examination diagnosed a DLGG in all cases (7 oligodendrogliomas, 1 astrocytoma, and 1 oligoastrocytoma). Five patients had a 1p19q codeletion. Because of tumor regrowth, the 9 patients underwent reoperation (2 surgeries in 6 cases and 3 surgeries in 3 cases), again with incomplete resection. There were no surgical complications. Adjuvant therapy (radiotherapy and chemotherapy) was administered in all patients because of progression to a higher grade of malignancy that was histopathologically confirmed in all tumors. The patients suddenly worsened, and the diagnosis of LMSS was made with a mean delay of 77 months (range 27-140 months) after the initial symptom onset. Six patients benefited from salvage chemotherapy while palliative care was chosen in 3 cases. The median survival in the 6 patients who underwent LMSS treatment was significantly longer than that in the 3 patients who did not receive salvage chemotherapy (p = 0.03). Indeed, all patients died, with a mean delay between the diagnosis of LMSS and death of 11 months (range 2-38 months) and with a mean delay between the initial symptom onset and death of 88 months (range 34-144 months)., Conclusions: Cerebrospinal fluid dissemination of DLGG is a rare but possible event. It can occur throughout the progression of WHO Grade II oligodendrogliomas, oligoastrocytomas, and astrocytomas, regardless of 1p19q status. This complication seems to appear in patients who have undergone multiple incomplete resections. Salvage therapy can be considered in patients with good neurological status. However, LMSS is associated with a decreased overall survival. Therefore, this rare entity deserves further multicenter studies to better understand its pathophysiology and to adapt therapeutic strategies.

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

Background: It is commonly believed that, before being diagnosed after onset of symptoms, diffuse low-grade glioma evolve silently for a long time. The present study aimed to estimate for the first time the exact duration of this silent phase, during which the glioma is radiologically visible but undiscovered., Methods: We retrospectively reviewed our French national database of diffuse low-grade glioma, searching for patients with an MRI-based assessment of their velocity of diameter growth at diagnosis and before any treatment (at least three MRIs over more than 6 months). For each patient, the duration of the silent phase was estimated by the formula: duration = initial diameter / initial velocity of growth., Results: A total of 148 patients were included in the study. The mean lead-time duration (i.e., duration of the silent phase) was 14.0 ± 7.8 years (median, 11.6 ; range, 1.6-39.4). The lead-time is statistically not correlated to the tumor volume. It is markedly decreasing with the velocity of diameter expansion., Conclusions: Diffuse low-grade glioma are radiologically detectable but clinically silent for more than a decade. Such a long period of silent evolution could explain our current failure to cure these tumors. It can also be viewed as a window of opportunity to detect these tumors earlier, suggesting the need to set up a screening program.

Background: Radiotherapy with concomitant and adjuvant temozolomide (six cycles) is the standard treatment after surgery in glioblastoma patients. Few studies have assessed the impact of additional cycles of temozolomide on survival., Patients and Methods: We conducted a bi-centric retrospective study comparing survival and toxicity according to the number of cycles of adjuvant temozolomide., Results: Fifty-eight patients were included. All patients received radiotherapy with concomitant temozolomide. Thirty-eight patients received six cycles, while 20 received nine or more (median=14) cycles. The risk of recurrence was significantly higher in the group receiving six cycles compared to the other group. Prolonged treatment improved progression-free survival (p=0.03) and overall survival (p=0.01) in multivariate analysis without a significant increase in toxicity., Conclusion: Prolonged administration of temozolomide seems to improve progression-free and overall survival, without increased toxicity. Prospective studies in larger populations are needed to better-define the population to whom it can be proposed and its optimal duration.

The involvement of eloquent brain areas may preclude the total/subtotal surgical resection of diffuse low-grade gliomas (DLGGs). The feasibility and functional tolerance of neoadjuvant chemotherapy have been demonstrated in such cases. The present study assesses the clinical and radiological impact of neoadjuvant chemotherapy on the natural course of DLGG. Seventeen patients without feasible surgical resection (infiltration of functional areas and/or large contralateral extension) were retrospectively selected. Temozolomide based neoadjuvant chemotherapy was initiated, inducing a tumor volume decrease and allowing a functional based maximal surgical resection. The median follow-up since initial radiological diagnosis was 5.9 years (range, 1.4-11). The median time to malignant transformation was 5.9 years. Six patients (35 %) had 1p19q codeletion, 12 patients (70 %) with IDH mutation and MGMT promoter methylation, and eight patients (47 %) had p53 overexpression. Chemotherapy reduced tumor volume (median -35.6 %, range -61.6 to -5.1 %) in contralateral hemisphere through the corpus callosum in seven cases (41 %) and in ipsi-lesional functional areas in ten cases (59 %). Chemotherapy significantly decreased the imaging tumor growth (measured by the velocity of diametric expansion VDE) with a median of -3.2 mm/year (range, -29.8 to -0.9 mm/year) (p < 0.001). A tumor volume decrease of more than 20 % was correlated with a lower postoperative residual tumor (median 2 cc, p = 0.04), a greater extent of resection (93.1 vs. 89.5 %), a higher probability of total/subtotal removal. Neoadjuvant chemotherapy with Temozolomide could optimize the surgical resection of DLGGs and could impact their natural history. Further large prospective studies with long-term follow-up are needed.

Object: The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed., Methods: Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age ≥ 18 years at diagnosis, histological diagnosis of WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value ≤ 0.1) were included in the multivariate Cox proportional hazard regression model analysis., Results: At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were an age ≥ 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a greater extent of resection., Conclusions: This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.

Background: Supratentorial diffuse low-grade gliomas present a slow macroscopic tumor growth that can be quantified through the measurement of their velocity of diametric expansion. We assessed whether spontaneous velocity of diametric expansion can predict long-term outcomes as a categorical variable and as a continuous predictor., Methods: A total of 407 adult patients with newly diagnosed supratentorial diffuse low-grade gliomas in adults were studied., Results: The mean spontaneous velocity of diametric expansion before first-line treatment was 5.8 ± 6.3 mm/year. During the follow-up (mean, 86.5 ± 59.4 months), 209 patients presented a malignant transformation, and 87 died. The malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (median, 103 and 249 months, respectively) than in cases of fast velocity of diametric expansion (median, 35 and 91 months, respectively; P < .001). In multivariate analyses, spontaneous velocity of diametric expansion as a categorical variable (<4, ≥4 and <8, ≥8 and <12, ≥12 mm/year) was an independent prognostic factor for malignant progression-free survival (P < .001; hazard ratio, 3.87; 95% confidence interval [CI], 2.67-5.52) and for overall survival (P < .001; hazard ratio, 4.62; 95% CI, 2.58-7.97). Velocity of diametric expansion was also an independent prognostic factor for overall survival as a continuous predictor, showing a linear relationship between overall survival and spontaneous velocity of diametric expansion (hazard ratio, 1.09 per one unit increase; 95% CI, 1.06-1.12; P < .001)., Conclusions: Independent of the molecular status, the spontaneous velocity of diametric expansion allows the identification of rapidly growing diffuse low-grade gliomas (at higher risk of worsened evolution) during the pretherapeutic period and without delaying treatment.

Indications and choice of antiepileptic drugs (AED), treatments for cerebral edema and prophylactic and curative treatments of thromboembolic complications of brain metastasis are discussed.

Background: The most-used prognostic scheme for malignant gliomas included only patients aged 18 to 70 years. The purpose of this study was to develop a prognostic model for patients ≥70 years of age with newly diagnosed glioblastoma., Methods: A total of 437 patients ≥70 years of age with newly diagnosed glioblastoma, pooled from 2 tertiary academic institutions, was identified for recursive partitioning analysis (RPA). The resulting prognostic model, based on the final pruned RPA tree, was validated using 265 glioblastoma patients ≥70 years of age from a data set independently compiled by a French consortium., Results: RPA produced 9 terminal nodes, which were pruned to 4 prognostic subgroups with markedly different median survivals: subgroup I = patients <75.5 years of age who underwent surgical resection (9.3 months); subgroup II = patients ≥75.5 years of age who underwent surgical resection (6.4 months); subgroup III = patients with Karnofsky performance status of 70 to 100 who underwent biopsy only (4.6 months); and subgroup IV = patients with Karnofsky performance status <70 who underwent biopsy only (2.3 months). Application of this prognostic model to the French cohort also resulted in significantly different (P < .0001) median survivals for subgroups I (8.5 months), II (7.7 months), III (4.3 months), and IV (3.1 months)., Conclusions: This model divides elderly glioblastoma patients into prognostic subgroups that can be easily implemented in both the patient care and the clinical trial settings. This purely clinical prognostic model serves as a backbone for the future incorporation of the increasing number of potential molecular prognostic markers., (Copyright © 2012 American Cancer Society.)

Purpose of this study was to determine the effect of waiting time for radiotherapy on overall survival of patients with glioblastoma treated in the EORTC-NCIC trial at 18 centers in France. A total of 400 adult patients with glioblastoma who were treated between January 1, 2006 and December 31, 2006 were included. There were 282 patients with "minimum criteria" according to the EORTC-NCIC trial: (i) concurrent chemotherapy with temozolomide; and (ii) age between 18 and 70 years old. Among these patients, 229 were treated with adjuvant temozolomide and were classified as "maximal criteria". One-hundred and eighteen patients were in the "without minimal criteria" group. Waiting time from the first symptom (FS-RT), pathology diagnosis (P-RT), multidisciplinary meeting (MM-RT), surgery (S-RT), and CT scan for delineation (CT-RT) until the start of radiotherapy were recorded. Median follow-up for all patients was 327 days. Overall, median FS-RT, P-RT, MM-RT, CT-RT, and S-RT times were 77, 36, 32, 12, and 41 days, respectively. Median, and 12 and 24-month overall survival were 409 days, and 56.3 ± 2.1 % and 27.6 ± 2.6 %, respectively. Univariate analysis failed to reveal a difference in survival, irrespective of the delay. In multivariate analysis, independent favorable prognostic factors for overall survival were age (p ≤ 0.0001) and type of surgery (p = 0.0006). In this large series treated during the EORTC-NCIC protocol period, waiting time until radiotherapy did not seem to affect patient outcome.