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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.)

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: 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.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.)

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.

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.

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.)

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.

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.)

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.)

Software-based manual segmentation is critical to the supervision of diffuse low-grade glioma patients and to the optimal treatment's choice. However, manual segmentation being time-consuming, it is difficult to include it in the clinical routine. An alternative to circumvent the time cost of manual segmentation could be to share the task among different practitioners, providing it can be reproduced. The goal of our work is to assess diffuse low-grade gliomas' manual segmentation's reproducibility on MRI scans, with regard to practitioners, their experience and field of expertise. A panel of 13 experts manually segmented 12 diffuse low-grade glioma clinical MRI datasets using the OSIRIX software. A statistical analysis gave promising results, as the practitioner factor, the medical specialty and the years of experience seem to have no significant impact on the average values of the tumor volume variable.

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.

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.

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.)

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: 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.)

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.

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.

Supratentorial hemispheric diffuse low-grade gliomas (LGGs), i.e., World Health Organization grade II gliomas, are a heterogeneous group of tumors. During their natural course, LGGs tend to progress to a higher grade of malignancy, leading to neurological disability and ultimately to death. In this review, we will show, that during their low-grade period, these tumors exhibit systematically a spontaneous and continuous radiological growth, whatever their histological subtypes. The radiological tumor growth is easily quantified by measuring the evolution of the equivalent tumor diameter (calculated from the tumor volume), obtaining the velocity of diametric expansion (VDE). The spontaneous VDE of LGGs varies markedly with an average VDE of about 4 mm/year. It depends on intrinsic factors (1p19q codeletion status, P53 overexpression status) and can be modified by extrinsic factors (pregnancy). The spontaneous VDE carries a strong prognostic significance regarding progression-free and overall survivals. As a consequence, VDE should be integrated along with the other "static" parameters (multimodal imaging, histological and molecular analyses) in the initial investigations. In addition, the assessment of VDE obtained before, during, and after a particular oncological treatment helps in analyzing their effects on LGGs on an individual basis, helping to guide the decision making.

Bevacizumab is one of the rare drugs that could improve high-grade glioma outcome after failure of chemoradiotherapy. However, to date, there is no biomarker predictive for efficacy of bevacizumab therapy in terms of survival improvement for patients with high-grade glioma. We performed a retrospective analysis of clinical factors associated with patient survival using a training cohort of 110 consecutive patients treated with bevacizumab for recurrent high-grade glioma and an independent validation cohort of 109 patients. In the training cohort, 110 consecutive patients received bevacizumab-based therapy. The number of chemotherapy cycles delivered was 1,411. Median follow-up was 12 months. Thirty-four patients (31%) had objective partial response and 24% had stable disease on magnetic resonance imaging evaluation. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 9.2 months, respectively. On univariate analysis, among classical prognosis factors, only Karnofsky status ≥70% was associated with improved outcome. Surprisingly, patients with low bevacizumab dose intensity (<5 mg/kg/week) had better PFS (12 vs. 2 months, P < 0.0001) and OS (16 vs. 6 months, P = 0.0002). On multivariate analysis, low bevacizumab dose intensity was the most significant independent prognostic factor of survival. Analysis of the validation cohort yielded similar results, externally validating this observation. This large retrospective study using two independent cohorts of high-grade glioma suggests that the currently recommended dosage of bevacizumab (5 mg/kg/week) is not optimal. Further prospective randomized trials using lower dosages are warranted.

Objectives: Here we present a model aiming to provide an estimate of time from tumour genesis, for grade II gliomas. The model is based on a differential equation describing the diffusion-proliferation process. We have applied our model to situations where tumour diameter was shown to increase linearly with time, with characteristic diametric velocity., Materials and Methods: We have performed numerical simulations to analyse data, on patients with grade II gliomas and to extract information concerning time of tumour biological onset, as well as radiology and distribution of model parameters., Results and Conclusions: We show that the estimate of tumour onset obtained from extrapolation using a constant velocity assumption, always underestimates biological tumour age, and that the correction one should add to this estimate is given roughly by 20/v (year), where v is the diametric velocity of expansion of the tumour (expressed in mm/year). Within the assumptions of the model, we have identified two types of tumour: the first corresponds to very slowly growing tumours that appear during adolescence, and the second type corresponds to slowly growing tumours that appear later, during early adulthood. That all these tumours become detectable around a mean patient age of 30 years could be interesting for formulation of strategies for early detection of tumours., (© 2011 Blackwell Publishing Ltd.)

Diffuse WHO grade II (GIIG) may be unresectable when involving critical structures. To assess the feasibility and functional tolerance (cognition and quality of life) of an original therapeutic strategy combining neoadjuvant chemotherapy followed by surgical resection for initially inoperable GIIG. Ten patients underwent Temozolomide for unresectable GIIG, as initial treatment or at recurrence after previous partial resection, due to invasion of eloquent areas or bi-hemispheric diffusion preventing a total/subtotal removal. Functional outcome after both treatments was assessed, with evaluation of seven cognitive domains. Chemotherapy induced tumor shrinkage (median volume decrease 38.9%) in ipsilateral functional areas in six patients and in the contralateral hemisphere in four. Only four patients had a 1p19q codeletion. The tumor shrinkage made possible the resection (mean extent of resection 93.3%, 9 total or subtotal removals) of initially inoperable tumors. Postoperatively, three patients had no deficits, while verbal episodic memory and executive functions were slightly impaired in seven patients. However, global quality of life was roughly preserved on the EORTC QLQ C30 + BN 20 (median score: 66.7%). Role functioning score was relatively reduced (median score: 66.7%) whereas KPS was preserved (median score: 90, range 80-100). Seven patients became seizure-free while three improved. This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances). Cognitive deficits seem mostly related to tumor location. Because KPS is not reliable enough, a detailed neuropsychological assessment should be systematically performed in GIIG.

Recent advances in the treatment of malignant gliomas have highlighted the fact that the appearance of new contrast-enhancing lesions on magnetic resonance imaging (MRI) is not always indicative of tumor recurrence. It has been suggested that transient seizure-related MRI changes could mimic disease progression (peri-ictal pseudoprogression [PIPG]). However, the clinical and MRI features associated with this situation have not been well described. Here, we consulted the databases of 6 institutions to identify patients with brain tumor who presented during the follow-up period transient MRI lesions wrongly suggesting tumor progression in a context of epileptic seizures. Ten patients were identified. All patients but 1 were long-term survivors who had initially been treated with radiotherapy. The PIPG episode occurred after a median interval of 11 years after radiotherapy. MRI features were highly similar across patients and consisted of transient focal cortical and/or leptomeningeal enhancing lesions that erroneously suggested tumor progression. All patients improved after adjustment of their antiepileptic drugs and transient oral corticosteroids, and MRI findings were normalized 3 months after the PIPG episode. Two patients demonstrated several seizure relapses with the same clinicoradiological pattern. After a median follow-up period of 3.5 years after the initial PIPG episode, only 1 patient presented with a tumor recurrence. In conclusion, in patients with brain tumor, especially in long-term survivors of radiotherapy, the appearance of new cortical and/or leptomeningeal contrast-enhancing lesions in a context of frequent seizures should raise the suspicion of PIPG. This phenomenon is important to recognize in order to avoid futile therapeutic escalation.

Objective: Seizure is the presenting symptom in most of World Health Organization grade II gliomas (GIIGs). Rarely, a GIIG is discovered incidentally on imaging. Little is known about the natural course and prognosis of incidental GIIGs. The aim of the present study is to characterize their natural history and to investigate whether their clinical and radiological behaviors differ from those of symptomatic GIIGs., Methods: The clinical and radiological findings, treatments, and outcomes of 47 histologically-proven incidental GIIGs were compared with those of 1249 symptomatic GIIGs., Results: Incidental GIIGs differ significantly from symptomatic GIIGs: they have a female predominance (p = 0.05), smaller initial tumor volumes (p < 0.001), lower incidence of contrast enhancement (p = 0.009), and are more likely to undergo gross total surgical removal (p < 0.001). Proliferation rates were similar to that observed among symptomatic GIIGs. Younger age at the time of discovery, frontal lobes, and noneloquent brain regions were associated with incidental GIIGs, as compared to their symptomatic counterparts. When not treated, incidental GIIGs demonstrated radiological growth (median velocity of diametric expansion at 3.5 mm/year), and became symptomatic at a median interval of 48 months after radiological discovery. Overall, incidental discovery was associated with a significant survival benefit (p = 0.04)., Interpretation: Incidental GIIGs are progressive tumors leading to clinical transformation toward symptomatic GIIGs. They may represent an earlier step in the natural history of a glioma than the symptomatic GIIGs.

Twelve pregnancies in 11 adult women harboring World Health Organization (WHO) grade II gliomas (GIIGs) prior to pregnancy were reviewed to address whether pregnancy affects tumor growth using a quantitative approach of the radiological velocity of diametric expansion (VDE) on successive magnetic resonance images. VDE was significantly increased during pregnancy as compared to prepregnancy (p < 0.001) and to postdelivery (p = 0.012) periods. Pregnancy increases the radiological growth rates of GIIGs. An increase in seizure frequency was observed concomitantly in 40% of cases and further oncological treatment was started after delivery in 25% of cases.

Grade II gliomas grow slowly and linearly (at rates about 4 mm/year) before undergoing anaplastic transformation. In order to analyze how surgery may affect radiological grade II glioma kinetics, we restrospectively reviewed our national database searching for patients operated on for a supratentorial grade II glioma between 1997 and 2007. We selected patients with at least two postoperative MRI with a minimal delay of 6 months. For each patient, postoperative residues were segmented on successive MRIs. Velocities of diameter expansion were estimated by linear regression of mean diameter evolution for each patient. Fifty-four patients fulfilled inclusion criteria. Median postoperative follow-up was 1.6 years with, on average, 3.4 MRI examinations per patient. Postoperative growth rates of mean diameter were normally distributed, around a mean value of 4.3 mm/year (SD = 3.2 mm/year). Statistical analysis showed no difference between this distribution and the distribution of preoperative growth rates in a previous series of 143 grade II gliomas. For a subset of 23 patients, delay between first MRI and surgery made it possible to estimate also preoperative growth rates. Intrapatient comparison revealed that growth rates were grossly unchanged for 80% of cases. In summary, inter- and intrapatient comparison of pre- and postoperative growth rates proves that surgery does not change grade II glioma dynamics, thus, acting as a cytoreduction.

Advances in the understanding of the natural history of diffuse low-grade gliomas and the optimization of their therapeutic management have allowed an improvement of their prognosis. Therefore, more and more young women harboring such gliomas now envision a pregnancy. However, relationships between gliomas and pregnancy are poorly known. We performed a retrospective review of all observed pregnancies in the adult female population of supra-tentorial hemispheric gliomas followed by a French glioma study group. Clinical, imaging and pathological findings were reviewed. In the present case studies, eight pregnancies in eight females were observed in a total of 443 adult females diagnosed between 1992 and 2007. Glioma was diagnosed before pregnancy in five patients and during pregnancy in three patients. In six cases, pregnancy appears as having possible negative interaction with the tumor, such as clinical worsening, tumor changes in imaging and histological findings. In two cases, pregnancy appears as having no effect in the natural history of the tumor. The present results suggest a possible negative interaction between pregnancy and diffuse gliomas. We thus propose informing the patient about the possible risks of tumor growth increase and of malignant transformation during pregnancy. In the presence of such a tumor, a pregnancy may reasonably be envisioned, but the benefit-to-risk ratio should be carefully weighed and discussed. If a pregnancy is decided, we thus advise performing a very close neurological follow-up with repeated control MRIs in addition to rigorous obstetrical monitoring.

Object: There are few data in the literature concerning a multimodal approach to insular WHO Grade II gliomas (GIIGs) and the control of epilepsy after treatment. In this paper, the authors describe a monocentric series of 46 cases in which patients underwent various sequential treatments for insular GIIGs. On the basis of global results with regard to epilepsy, the respective interests in the various treatments are discussed., Methods: Available data on 46 patients harboring insular GIIGs were extracted from a local database of 288 GIIGs. The various therapeutic sequences were analyzed in parallel with the course of seizure frequency., Results: Despite the usual difficulties with seizure quantification in retrospective studies, the authors showed that 1) the negative course of seizure frequency was mostly connected to tumor progression, 2) surgery almost always had a favorable effect on epilepsy, and 3) chemotherapy had a mostly favorable effect with acceptable tolerance. The authors were unable to draw conclusions about the role of radiotherapy given the too few cases., Conclusions: This extensive experience with insular GIIGs tends to confirm interest in their surgical removal and supports interest in chemotherapy from an epileptological point of view.

Purpose: Fotemustine is a nitrosourea compound used for the treatment of malignant gliomas, especially in France. Recently, an EORTC-NCIC study has shown that a concomitant combination of radiotherapy plus temozolomide (an oral cytotoxic drug) improved survival in glioblastoma patients. We set out to test a concurrent combination of radiotherapy and fotemustine for newly malignant gliomas., Methods: A prospective single-center phase II study opened for accrual in September 2004. Patients over 18 years of age able to give informed consent and with histologically proven, newly diagnosed supratentorial malignant gliomas were eligible. All patients were treated by a standard cranial irradiation (conformal irradiation, tumor bulk plus a margin of 2.5 cm) and concomitant daily administration of 10 mg/m(2) of fotemustine (5 days per week, 6 weeks, 1 h 30 min before radiation therapy). Adjuvant chemotherapy, fotemustine, was administered at tumor progression as standard and classic regimen., Results: Twenty-two patients were enrolled, 16 men and 6 women, median age 56 years (range 32-74), median Karnofsky performance status 70 (range 60-90). Histology included 16 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 1 mixed glioma. Eight patients underwent surgery (three total resections). Fourteen patients had a stereotactic biopsy. The concurrent radiotherapy-fotemustine combination was well tolerated: toxicity was mild and three hematologic toxicities grade 3-4 were observed. Median survival from the initial diagnosis was 9.9 months, two patients are currently alive. Median survival was 11 months for surgery and 9 months for stereotactic biopsy., Conclusions: Concomitant radiotherapy-fotemustine combination is safe and well tolerated. Overall survival of over 10 months for the whole population compares favorably with other reports.

Background: To analyze the functional and oncological results after re-operation for recurrent WHO grade II Glioma located in eloquent regions., Method: We reviewed a consecutive series of 19 patients with GIIG within functional areas who underwent two operations separated by at least 1 year. Intraoperative electrical stimulation mapping was used in all operations for recurrence and in 14 of the initial procedures. A specific rehabilitation was provided., Findings: At the first operation, we performed 14 subtotal and 5 partial resections. Eighteen patients returned to a normal socio-professional life. Nine patients received adjuvant treatment. At the second operation, we performed 1 total, 13 subtotal and 5 partial resections. Three patients with a preoperative neurological deficit improved, 13 remained unchanged, and 3 slight new deficits appeared. In 14 of the 17 patients with preoperative chronic epilepsy, the seizures were reduced or disappeared. Sixteen patients returned to a normal socio-professional life. Pathohistological examination showed that 11 tumours had progressed to high-grade glioma. The median time between the two operations was 4.1 years (range 1 to 7.8 years) and the median follow-up from initial diagnosis was 6.6 years (range 2.3 to 14.3 years). No deaths occurred during the follow-up period., Conclusions: Repeat operations guided by intra-operative electrical stimulation is an efficacious treatment for recurrent grade II glioma in an eloquent area.

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.

In this study, we investigated the prognostic value of MRI contrast enhancement (CE) at the time of histological diagnosis specifically in a selected population of WHO grade II gliomas. We reviewed 927 histologically proven WHO grade II gliomas for which contrast-enhanced MR images were available at the time of histological diagnosis. CE patterns were classified into three categories: "patchy and faint," "nodular-like," and "ring-like." CE progression over time was recorded before oncological treatment on successive MR images, when available. CE was present in 143 cases (15.9%), with 93 patchy and faint, 50 nodular-like, and no ring-like patterns. CE areas were time progressive before oncological treatment in 35 of the 56 available cases (62.5%). Regardless of its pattern, the presence of CE was not significantly associated with a worsened prognosis (p = 0.415) by univariate analysis. Only the nodular-like pattern of CE (p < 0.01) and the time-progressive CE (p < 0.001) in the available subgroup proved to be statistically associated with survival since first oncological treatment. The present results show the necessity, in cases of WHO grade II gliomas, to study CE at the time of histological diagnosis and, whenever possible, to follow its progression over time before oncological treatment. Nodular-like CE and time-progressive CE are associated with a worsened prognosis, both suggesting malignant transformation, even though histopathological examination cannot initially disclose signs of malignancy in those areas.

Malignant glioma patients have a life expectancy reduced to about 15 months despite aggressive surgery, radiotherapy (RT), and chemotherapy. Doxorubicin has shown a marked cytotoxic effect against malignant glioma cells in vitro. The brain exposure to this drug is, however, hindered by the blood-brain barrier. Encapsulation of doxorubicin in liposomal carriers has been shown to reduce toxicities and to improve brain tumors exposure to doxorubicin. In this study, we evaluated the radiosensitizing properties of a nonpegylated liposomal doxorubicin (Myocet, MYO) on two subcutaneous (U87 and TCG4) and one intracranial (U87) malignant glioma models xenografted on nude mice. Doxorubicin biodistribution was assessed by a high-performance liquid chromatography method. Antitumor efficacy was investigated by tumor volume measurements and mice survival determination. We showed that (i) encapsulation of doxorubicin ensured a preferential deposition of doxorubicin in tumoral tissue in comparison with free doxorubicin; (ii) doxorubicin accumulated in both subcutaneous and intracranial tumors during repeated injections of MYO and this accumulation was linked to the potentiation of RT efficacy on two subcutaneous models; (iii) MYO was unable to improve the antitumoral efficacy of RT on an intracranial glioma model. Finally, this study emphasizes the importance of performing preclinical studies on models closer as possible of human tumors and localization to be more predictive of therapeutic effects observed in humans.

Object: Despite better knowledge of cortical language organization, its subcortical anatomofunctional connectivity remains poorly understood. The authors used intraoperative subcortical stimulation in awake patients undergoing operation for a glioma in the left dominant hemisphere to map the language pathways and to determine the contribution of such a method to surgical results., Methods: One hundred fifteen patients harboring a World Health Organization Grade II glioma within language areas underwent operation after induction of local anesthesia, using direct electrical stimulation to perform online cortical and subcortical language mapping throughout the resection., Results: After detection of cortical language sites, the authors identified 1 or several of the following subcortical language pathways in all patients: 1) arcuate fasciculus, eliciting phonemic paraphasia when stimulated; 2) inferior frontooccipital fasciculus, generating semantic paraphasia when stimulated; 3) subcallosal fasciculus, inducing transcortical motor aphasia during stimulation; 4) frontoparietal phonological loop, eliciting speech apraxia during stimulation; and 5) fibers coming from the ventral premotor cortex, inducing anarthria when stimulated. These structures were preserved, representing the limits of the resection. Despite a transient immediate postoperative worsening, all but 2 patients (98%) returned to baseline or better. On control MR imaging, 83% of resections were total or subtotal., Conclusions: These results represent the largest experience with human subcortical language mapping ever reported. The use of intraoperative cortical and subcortical stimulation gives a unique opportunity to perform an accurate and reliable real-time anatomofunctional study of language connectivity. Such knowledge of the individual organization of language networks enables practitioners to optimize the benefit-to-risk ratio of surgery for Grade II glioma within the left dominant hemisphere.

The advent of magnetic resonance imaging (MRI) has allowed the follow-up of tumor growth by precise volumetric measurements. Such information about tumor dynamics is, however, usually not fully integrated in the therapeutic management, and the assessment of tumor evolution is still limited to qualitative description. In parallel, computational models have been developed to simulate in silico tumor growth and treatment efficacy. Nevertheless, direct clinical interest of these models remains questionable, and there is a gap between scientific advances and clinical practice. In this paper, WHO grade II glioma will serve as a paradigmatic example to illustrate that computational models allow characterizing tumor dynamics from serial MRIs. The role of these dynamics for both therapeutic management and biological research will be discussed.

Rationale: 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., Objective: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas., Methods: 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., Results: 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)., Conclusion: 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.

Despite the lack of class I evidence, it is widely agreed that surgery can improve the functional and vital prognosis for WHO grade II gliomas when the resection is at least subtotal radiologically, that is, leaving less than 10 cm(3) of visible residual tumor. Because these tumors frequently invade functional areas, the preoperative estimation of the probable residual volume remains challenging. This article presents a probabilistic map of postoperative residues, with the aim of predicting before the decision for surgical intervention whether the resection could be subtotal. We selected 65 patients who underwent surgery with intraoperative functional mapping between 1999 and 2004 for a WHO grade II glioma located in a sensorimotor and/or language area. For each case, the postoperative image was normalized on a standard atlas, and the residual tumor was segmented. A probabilistic map of residues was then computed. The fusion between the map and a preoperative image allowed a preoperative estimation of the expected extent of resection. The map enhances the regions where grade II glioma cannot be resected. The success rate for the preoperative classification of partial versus subtotal resection is 82%. Although both its reliability and accuracy have to be improved, this probabilistic map gives preoperatively an objective estimation of the expected extent of resection for grade II glioma resected under intraoperative functional mapping. This rationale will assist in decisions regarding surgical resection and may thus contribute to the elaboration of a therapeutic consensus for WHO grade II glioma.

While surgery is proned in low-grade glioma (LGG), the invasion of functional areas frequently prevents a complete resection. We report the first case of a patient operated on for a left frontal LGG, diagnosed because of seizures, with partial resection due to an invasion of the controlateral hemisphere. Chemotherapy enabled a regression of this controlateral extension. Postchemotherapy surgery performed with intraoperative functional mapping then allowed a complete resection, without sequelae. The patient has a normal socio-professional life, with no seizure. No other treatment was given. There was no recurrence, with a follow-up of 2 years since the second surgery (3.5 years since the first symptom). We propose a new therapeutic strategy in unresectable LGG, with preoperative chemotherapy, to make a radical surgery possible in a second step, while preserving the quality of life.