Background Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. Methods The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. Discussion Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. Trial registration NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Introduction Preoperative language mapping using functional magnetic resonance imaging (fMRI) aims to identify eloquent areas in the vicinity of surgically resectable brain lesions. fMRI methodology relies on the blood‐oxygen‐level‐dependent (BOLD) analysis to identify brain language areas. Task‐based fMRI studies the BOLD signal increase in brain areas during a language task to identify brain language areas, which requires patients' cooperation, whereas resting‐state fMRI (rsfMRI) allows identification of functional networks without performing any explicit task through the analysis of the synchronicity of spontaneous BOLD signal oscillation between brain areas. The aim of this study was to compare preoperative language mapping using rsfMRI and task fMRI to cortical mapping (CM) during awake craniotomies. Methods Fifty adult patients surgically treated for a brain lesion were enrolled. All patients had a presurgical language mapping with both task fMRI and rsfMRI. Identified language networks were compared to perioperative language mapping using electric cortical stimulation. Results Resting‐state fMRI was able to detect brain language areas during CM with a sensitivity of 100% compared to 65.6% with task fMRI. However, we were not able to perform a specificity analysis and compare task‐based and rest fMRI with our perioperative setting in the current study. In second‐order analysis, task fMRI imaging included main nodes of the SN and main areas involved in semantics were identified in rsfMRI. Conclusion Resting‐state fMRI for presurgical language mapping is easy to implement, allowing the identification of functional brain language network with a greater sensitivity than task‐based fMRI, at the cost of some precautions and a lower specificity. Further study is required to compare both the sensitivity and the specificity of the two methods and to evaluate the clinical value of rsfMRI as an alternative tool for the presurgical identification of brain language areas.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Twenty-three GBM patients were assessed byF-fluoromisonidazole (F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: = 0.61, = 0.002) and their volumes (hypoxia vs. hypervascularization: = 0.91, < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.

OBJECTIVEMiddle cerebral artery (MCA) aneurysms are a particular subset of intracranial aneurysms that can be excluded by clipping or coiling. A comparison of the results between these two methods is often limited by a selection bias in which wide-neck and large aneurysms are frequently treated with surgery. Here, the authors report the results of two centers using opposing policies in the management of MCA aneurysms: one center used a clip-first policy while the other used a coil-first policy, which limited the selection bias and ensured a good comparison of these two treatment modalities.METHODSAll patients treated for either ruptured or unruptured MCA aneurysms at one of two institutions between January 2012 and December 2015 were eligible for inclusion in this study. At one center a clip-first policy was applied, whereas the other applied a coil-first policy. The authors retrospectively reviewed the medical records of these patients and compared their clinical and radiological outcomes.RESULTSA total of 187 aneurysms were treated during the inclusion period; 88 aneurysms were treated by coiling and 99 aneurysms by clipping. The baseline patient and radiological characteristics were similar between the two groups, but the clinical presentation of the ruptured aneurysm cohort differed slightly. In the ruptured cohort (n = 90), although patients in the coiling group had a higher rate of additional surgery, the complication rate, functional outcome, and risk of death were similar between the two treatment groups. In the unruptured cohort (n = 97), the complication rate, functional outcome, and risk of death were also similar between the two treatment groups, although the risk of discomfort related to the temporal muscle atrophy was higher in the surgical group. Overall, the rate of complete occlusion was higher in the clipping group (84.2%) than in the coiling group (31%), which led to a higher risk in the coiling group of aneurysm retreatment within the first 2 years (p = 0.04).CONCLUSIONSClipping and coiling for MCA aneurysm treatment provide the same clinical outcome for ruptured and unruptured aneurysms. However, clipping provides higher short- and long-term rates of complete exclusion, which in turn decreases the risk of aneurysm retreatment. Whether this lower occlusion rate can have a clinical impact in the long-term must be further evaluated.

To avoid motion artifacts, almost all speech-related functional magnetic resonance imagings (fMRIs) are performed covertly to detect language activations. This method may be difficult to execute, especially by patients with brain tumors, and does not allow the identification of phonological areas. Here, we aimed to evaluate overt task feasibility. Thirty-three volunteers participated in this study. They performed two functional sessions of covert and overt generation of a short sentence semantically linked with a word. Three main contrasts were performed: Covert and Overt for the isolation of language-activated areas, and Overt > Covert for the isolation of the motor cortical activation of speech. fMRI data preprocessing was performed with and without unwarping, and with and without regression of movement parameters as confounding variables. All types of results were compared to each other. For the Overt contrast, Dice coefficients showed strong overlap between each pair of types of results: 0.98 for the pair with and without unwarping, and 0.9 for the pair with and without movement parameter regression. The Overt > Covert contrast allowed isolation of motor laryngeal activations with high statistical reliability and revealed the right-lateralized temporal activity related to acoustic feedback. Overt speaking during magnetic resonance imaging induced few artifacts and did not significantly affect the results, allowing the identification of areas involved in primary motor control and prosodic regulation of speech. Unwarping and motion artifact regression in the postprocessing step, seem to not be necessary. Changes in lateralization of cortical activity by overt speech shall be explored before using these tasks for presurgical mapping.

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Conventional MRI plays a key role in the management of patients with high grade glioma but multiparametric MRI and PET tracers could provide further information to better characterize the tumor metabolism and heterogeneity, by identifying the regions having a high risk of recurrence.In this study, we focused on the proliferation, hypervascularization and hypoxia, all factors considered as factors of poor prognosis. They were assessed by measuring the uptake of 18 F-FLT, the rCBV maps and the uptake of 18 F-FMISO, respectively. For each modality, the volumes and high uptake sub-volumes (hotspots) were semi-automatically segmented and compared to contrast enhancement (CE) volume on T1w-Gd images, commonly used in the management of patient with glioblastoma. Methods: DSC MRI (31 patients), 18 F-FLT PET (20 patients) and/or 18 F-FMISO PET (20 patients), for a total of 31 patients, were performed on pre-operative glioblastoma patients.Volumes and hotspots were segmented on SUV maps for 18 F-FLT (using FLAB) and 18 F-FMISO (using mean contralateral + 3.3 SD) PET and on rCBV maps (using mean contralateral + 1.96 SD) for DSC MRI and overlaid on T1w-Gd images. For each modality, the percentage of peripheral volumes and the peripheral hotspot outside the CE volume were calculated. Results: All tumors showed high proliferation, hypervascularization and hypoxic regions. Images also showed pronounced heterogeneity of both tracers uptake and rCBV maps, within each individual case. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularization and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were [1.6% -155.5 %], [1.5% -89.5%] and [3.1% -78.0%] for 18 F-FLT, rCBV and 18 F-FMISO respectively. All patients had hyperproliferative hotspots outside CE volume, whereas hotspots of hypervasculature and hypoxia were mainly 4 detected within the enhancing region. Conclusion: The spatial analysis of the multiparametric maps with the segmented volumes and hotspots provides valuable information to optimize the management and treatment of the patients with glioblastoma.

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