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Visualization of fiber tracts around the tumor is critical for neurosurgical planning and preservation of crucial structural connectivity during tumor resection. Biophysical modeling approaches estimate fiber tract orientations from differential water diffusivity information of diffusion MRI. However, the presence of edema and tumor infiltration presents a challenge to visualize crossing fiber tracts in the peritumoral region. Previous approaches proposed free water modeling to compensate for the effect of water diffusivity in edema, but those methods were limited in estimating complex crossing fiber tracts. We propose a new cascaded multi-compartment model to estimate tissue microstructure in the presence of edema and pathological contaminants in the area surrounding brain tumors. In our model (COMPARI), the isotropic components of diffusion signal, including free water and hindered water, were eliminated, and the fiber orientation distribution (FOD) of the remaining signal was estimated. In simulated data, COMPARI accurately recovered fiber orientations in the presence of extracellular water. In a dataset of 23 patients with highly edematous brain tumors, the amplitudes of FOD and anisotropic index distribution within the peritumoral region were higher with COMPARI than with a recently proposed multi-compartment constrained deconvolution model. In a selected patient with metastatic brain tumor, we demonstrated COMPARI’s ability to effectively model and eliminate water from the peritumoral region. The white matter bundles reconstructed with our model were qualitatively improved compared to those of other models, and allowed the identification of crossing fibers. In conclusion, the removal of isotropic components as proposed with COMPARI improved the bio-physical modeling of dMRI in edema, thus providing information on crossing fibers, thereby enabling improved tractography in a highly edematous brain tumor. This model may improve surgical planning tools to help achieve maximal safe resection of brain tumors.

There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells.Significance:This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.See related commentary by Koncar and Agnihotri, p. 3195

this text corresponds to the legends of supplemental tables 1 to 3 and supplemental figures 1 to 14

The supplemental figure 12 describes EGR1 expression during cell dedifferentiation. The supplemental figure 13 descries miR-199a-3p conserved sites in EGR1 3'UTR. The supplemental figure 14 describes the effects of shEGR1 and synthetic miR-199a-3p on EGR1 and miR-199a-3p expression and the consequence on NANOG expression.

tables describing OCT4 and NANOG positive cells (sup table S1); tables describing gene clustering and GEO (sup tables S2 and S3)

In most cases, vestibular schwannomas with papilledema are associated with intracranial hypertension secondary to hydrocephalus (obstructive or communicating). We describe the atypical case of a 39-years-old man who presented with bilateral papilledema revealing a vestibular schwannoma, but without hydrocephalus and with normal intracranial pressure. Ophtalmologic signs were completely resolved after tumor removal. The pathophysiological mechanism generally described to explain bilateral papilledema in such cases is tumor-induced hyperproteinorachia. However, in the absence of hydrocephalus or intracranial hypertension, this case raises the question of the mechanisms involved in the visual impairment related to vestibular schwannoma., Les schwannomes vestibulaires avec œdème papillaire sont en général associés à une hypertension intracrânienne secondaire à une hydrocéphalie (communicante ou obstructive). Nous décrivons ici le cas atypique d’un homme de 39 ans ayant présenté un œdème papillaire révélateur d’un schwannome vestibulaire, mais sans hydrocéphalie et avec une pression intracrânienne normale. L’exérèse tumorale a permis une régression complète des signes ophtalmologiques. En l’absence d’obstruction ventriculaire, le mécanisme physiopathologique généralement décrit pour expliquer l’atteinte visuelle est l’hydrocéphalie secondaire à une hyperprotéinorachie. Cependant, en l’absence d’hydrocéphalie ou d’hypertension intracrânienne, ce cas soulève la question des mécanismes impliqués dans l’atteinte visuelle secondaire à la présence d’un schwannome vestibulaire

Background. Diagnostic value of 18F-fluoro-L-dihydrophenylalanine (18F-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 was made only based on the clinical and the MRI data. For step 2, the same process was repeated considering the 18F-FDOPA PET results. A level of confidence of the decisions was assigned to each step. Changes in diagnosis and management induced by 18F-FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions was assessed. The diagnostic performances of each step was 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. In case of equivocal MR findings, 18F-FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice.

Purpose: Lower eyelid management is challenging. The conchal cartilage is often considered a spacer of choice for treating lower eyelid retraction. However, dermis graft has also recently been shown to be a viable spacer. The aim of this study was to compare the efficacy of dermis graft to that of conchal cartilage graft in this indication. Methods: A retrospective comparative study was conducted in patients who underwent lower eyelid lengthening with autologous dermis graft (group 1) or autologous conchal cartilage graft (group 2). The main outcome measure was the reduction in inferior scleral show (ISS) assessed by three independent masked surgeons. Secondary outcome measures was the assessment of lagophthalmos and corneal keratitis. Complications were also recorded. Results: Twenty-five eyelids of 23 patients were included: 11 and 14 eyelids, respectively in group 1 (dermis graft) and group 2 (conchal cartilage graft). Patient mean follow-up was 12.3 (±12.5) and 7.1 (±7.7) months, respectively. No statistical differences in postoperative ISS reduction, lagophthalmos and exposure keratitis was observed ( p = 0.540, p = 0.946, p = 0.934, respectively). Three patients experienced a grade I Clavien–Dindo complication in group 1 and one patient experienced a grade II complication in group 2 ( p = 0.540). Conclusion: Autologous dermis grafts and conchal cartilage grafts provide favorable outcomes without major complications.

PURPOSE To assess the efficacy and safety of bone-anchored dental implant placement at the same time as orbital exenteration compared with delayed implant placement. MATERIALS AND METHODS A retrospective comparative study was conducted in a single tertiary care center between December 2003 and December 2017. Patients who underwent bone-anchored implant placement at the same time as orbital exenteration were included (group 1) and compared with patients who underwent delayed implant placement (group 2). The main outcome was the 1-year success rate of implant osseointegration. The secondary outcomes were the 5-year success rate of osseointegration, postoperative complications, and time between orbital exenteration and prosthesis placement. RESULTS Ten and 11 patients (21 and 22 implants) with a mean follow-up of 50.2 and 48.5 months were included in groups 1 and 2, respectively. Patients in group 1 were significantly older (69.7 vs 61.2 years, P = .026). No significant differences were found between both groups regarding tumor type and location, prior treatments, smoking status, and postoperative radiation beam radiotherapy. The 1- and 5-year success rates of osseointegration were 95.5% and 93.3% in group 1, and 100% and 100% in group 2, respectively (P = .488 and P = .450 between both groups). One implant did not osseointegrate in group 1 due to osteitis. Ethmoidal fistula was the most common postoperative complication found in both groups (P = .670). The mean time between orbital exenteration and episthesis placement was 8 (3 to 14) vs 11 (3 to 15) months in groups 1 and 2, respectively (P = .467). CONCLUSION Placing implants at the same time as orbital exenteration is a viable procedure. It reduces surgical morbidity and allows placement of implants in a nonirradiated area.

Although frame-based stereotactic biopsy is still considered the gold standard for brain biopsies, frameless robot-assisted stereotactic systems are now able to provide an equal level of safety and accuracy. However, both systems suffer from a lack of efficiency of the operative workflow.To describe the technique of a new frameless and noninvasive registration tool Neurolocate (Renishaw). This tool, combined with an intraoperative cone-beam computed tomography imaging system like O-ARM (Medtronic), might facilitate the achievement and workflow of robot-assisted stereotactic intracranial biopsies.Neurolocate is a 3-dimensional fiducial tool fixed directly on the Neuromate (Renishaw) robot arm. It consists of 5 radio-opaque spherical fiducials, whose geometry is constant. This tool made it possible to carry out the coregistration then the biopsy in the same operating time, following a five-step procedure described here. We retrospectively extracted selected preliminary results from our initial experience.Over 1 year, 23 consecutive adult patients were biopsied with Neurolocate in our center. The mean overall operative time, from patient's installation to skin closure, was 97 minutes ± 27 (SD). The entire procedure took place in a single location unit (operating room), which facilitated workflow and surgical planning. No invasive gesture was performed outside of the operating time.Neurolocate is a new frameless and noninvasive registration tool that could improve workflow and flexibility for operating room management and surgical planning. It may also increase the comfort of patients undergoing robot-assisted intracranial stereotactic biopsies. The accuracy and safety profile should be addressed in specific studies.

Cancer cells in similar functional states are found in all glioblastoma, despite the genomic heterogeneity observed between and within these brain tumors. Metabolism being downstream of all signaling pathways regulating cell behaviors, we looked for metabolic weaknesses in link with motility, a key functional state for glioblastoma aggressiveness. A signature-driven data reduction approach highlighted motile cells present in thirty tumors from four independent single-cell transcriptomic datasets. Analyses integrating trajectory modeling disclosed, as characteristic of motile cells, enhanced oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). The soundness of this prediction was verified using migration and invasion assays with patient-derived cells and tissue organoids. Pharmacological and genetic manipulations showed that enhanced ROS production and MPST activity are required for the cells’ motility. Biochemical assays indicated that MPST acts by protecting protein cysteine residues from dismal hyperoxidation. In vivo, MPST knockdown translated in reduced tumor burden, and a robust increase in mice survival. These results show that enhanced oxidative stress coupled with MPST mobilization plays a key role in glioblastoma cell motility.

International audience; To ensure appropriate blood supply through the brain, the cerebral blood vessels, neurons, and as-trocyte glial cells must interact according to complex mechanisms. This interaction, named "neurovascular coupling" (NVC), describes the link between neuronal activity and cerebral blood flow (CBF) changes. 25 Several methods have been developed to assess the NVC in humans by exploring either cerebral tissue oxygenation using functional MRI, near-infrared spectrosco-py, or positron emission tomography, or CBF changes using transcranial Doppler (TCD) ultrasonography. 9,21 TCD ultrasonography is the ultrasound (US) imaging technique mostly used in the clinic to explore CBF because of its high temporal resolution and noninvasive nature. For example, sensorimotor or cognitive stimulatory effects on cerebral blood velocity have been studied using low-frequency (≤ 2-MHz) transducers. 4 In healthy individuals, this response leads to an average 10%-20% increase in CBF in the posterior cerebral artery during visual stimulation, 1 and a 5%-8% increase in the middle cerebral artery during a cognitive task. 22 However, despite good spatiotemporal resolution, TCD US imaging is limited to the exploration of large cerebral vessels and is not able to detect subtle changes of low blood flow in cortical vessels that may occur during a task. Recently, very high frame rate US imaging (> 10,000 frames per second) was shown to enable high-resolution and high-sensitivity power Doppler imaging, 2,29 allowing ABBREVIATIONS BOLD = blood oxygen level-dependent; CBF = cerebral blood flow; DES = direct electrostimulation; fUS = functional US; mSA = median surface area; NVC = neurovascular coupling; TCD = transcranial Doppler; UHF-US = ultra-high-frequency US; US = ultrasound. OBJECTIVE : Neurovascular coupling reflects the link between neural activity and changes in cerebral blood flow. Despite many technical advances in functional exploration of the brain, including functional MRI, there are only a few reports of direct evidence of neurovascular coupling in humans. The authors aimed to explore, for the first time in humans, the local cerebral blood flow of the primary motor cortex using ultra-high-frequency ultrasound (UHF-US) Doppler imaging to detect low blood flow velocity (1 mm/sec).METHODS : Four consecutive patients underwent awake craniotomy for glioma resection using cortical direct electro-stimulation for brain mapping. The primary motor cortical area eliciting flexion of the contralateral forearm was identified. UHF-US color Doppler imaging of this cortical area was acquired at rest, during repeated spontaneous forearm flexion, and immediately after the movement's termination. In each condition, the surface areas of the detectable vessels were measured after extraction of non-zero-velocity colored pixels and summed. RESULTS : During movement, local cerebral blood flow increased significantly by 14.4% (range 5%-30%) compared with baseline. Immediately after the termination of movements, the local hyperemia decreased significantly by 8.6% (range 1.9%-15.7%). CONCLUSIONS : To the authors' knowledge, this study is the first to provide a real-time demonstration of the neurovas-cular coupling in the human cortex by ultrasound imaging. They assume that UHF-US may be used to gather original and advanced data on brain functioning, which could be used to help in the identification of functional cortical areas during brain surgery. Clinical trial registration no.: NCT03179176 (clinicaltrials.gov) https://thejns.org/doi/abs/10.3171/2018.5.JNS18754

Summary Introduction Based on the radiological responses obtained with a schedule of ten mg/kg every two weeks bevacizumab was approved by the FDA for recurrent glioblastomas. Due to the negative results concerning overall survival of patients receiving bevacizumab, the European application was rejected. Despite this, many centers apply an off-label prescription. Our aim was to evaluate the safety and efficacy of schedules of low doses of bevacizumab. Methods From September 2013 to August 2016, we recruited patients with progressive glioblastoma, whatever the previous treatments. We compared a routine control group (CG) of ten mg/kg, to a low dose group (LDG) composed of 5 subgroups: G5: five mg/kg, G4: four mg/kg, G3: three mg/kg, G2: two mg/kg, G1: one mg/kg; each patient was treated with the same dose every two weeks. Results Fifty-three patients were treated: 20 women and 33 men, 24 in the CG and 29 in the LDG. The median age at diagnosis was 62 years [35.0–77.0]. No statistical difference was found in overall survival either for the CG or the LDG (P = 0.086) or among groups (P = 0.251), with even a trend toward improvement for LDG: 62 weeks [20–145] versus 73 weeks [18–178]. The median progression free survival was comparable: 19.5 weeks [6.0–54.0] for the CG and 15.0 weeks [0.0–134.0] for the LDG (P = 0.221). Bevacizumab was stopped either due to progression (45.1%) or toxicity (52.9%), without significant differences between doses but maybe less toxicities in the LDG (16.7% for toxicity in G1). Discussion Use of bevacizumab at progression at lower than usual doses seems to give the same results as the standard dose without giving additional toxicity.

Background Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.

AimPhantom eye syndrome is a poorly understood and underestimated complication of eye removal (ER). Seeing with the amputated eye, referred to as phantom vision (PV), is undoubtedly the most intriguing and confusing complication experienced by anophthalmic patients. The aim of the study was to assess PV prevalence, clinical features and risk factors after ER.MethodsA multicentric questionnaire-based study was conducted between April 2016 and July 2017. Patients >18 years who underwent ER >3 months ago had a socket examination before inclusion. Data recorded included patients’ demographics, and preoperative, surgical and postoperative features.ResultsOne hundred patients (53 men) with a mean age of 65.1 years (29–92; SD=13.0) were included. ER indications were: uveal melanoma (n=24, 24%), trauma (n=20, 20%), retinal detachment (n=20, 20%), glaucoma (n=14, 14%) and endophthalmitis (n=12, 12%). Thirty (30%) patients experienced PV. Elementary and complex visual hallucinations were experienced by 80% and 20% of patients, respectively. PV usually appeared within the first postoperative month and tended to decrease over time. Risk factors for PV were the preoperative use of proton beam therapy (p=0.006), uveal melanoma (p=0.014), enucleation (p=0.015), anxiety with a Hospital and Anxiety Depression (HAD) score ≥8 (p=0.042), depression with a HAD score ≥8 (p=0.030), phantom eye pain (p=0.044) and phantom eye sensations (p=0.002).ConclusionPV was reported by one-third of our patients. Despite being widely misunderstood, ophthalmologists and neurologists should be aware of this complication to adequately reassure patients.

BackgroundThe conventional dose rate of radiation therapy is 0.01–0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT).Materials and MethodsA single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT.ResultsThere were 127 patients identified, with a median follow up of 14.8 months (3–42.9 months). The median age was 55 years (1.6–89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30–74 Gy), dose per fraction of 2 Gy (1–3 Gy), and CTV size of 47.6 ml (5.6–2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively.ConclusionIn this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.

Transfacet screws (TFS) are an alternative to the classic bilateral pedicular screws (BPS) in addition to anterior (ALIF) or oblique (OLIF) lumbar interbody fusion. Spinal navigation could help the surgeon in technically demanding procedures in order to avoid screw malposition. Although spinal navigation is commonly used in BPS, its contribution in TFS remains unclear. Our aim here was to assess the feasibility of TFS using spinal navigation in addition to anterior lumbar fusion. Five patients suffering from lumbar degenerative disc disease were included. During the same general anaesthesia, we performed successively an ALIF or OLIF and then a TFS according to Boucher technique using spinal navigation (O-arm). No peri-operative complication occurred, and all the screws were successfully positioned (n = 10). All clinical scores (ODI, VAS L and VAS R) improved at 6-month follow-up. Segmental lordosis increased from 6° [2.4°–12°] to 13.6° [8°–17°]. Fusion was achieved for the five patients. TFS using O-arm in addition to ALIF/OLIF is feasible. To confirm our early favourable outcomes on clinical and radiological data, this technique must be evaluated on larger samples of patients.

PURPOSE Phantom eye syndrome (PES) is an underestimated complication of eye amputation (EA) characterized by phantom eye pain (PEP), phantom visions and/or phantom sensations. The aim of this study was to assess PEP prevalence, features, risk factors, social and psychological consequences and associated quality of life. METHODS A questionnaire study was conducted in three oculoplastic departments between April 2016 and July 2017. Patients >18 years who had undergone EA ≥3 months earlier were included and asked to complete a prestamped questionnaire. Patient's characteristics, preoperative, surgical and postoperative data were collected. RESULTS Of the 185 questionnaires given, 115 (62%) were returned for analysis. Hundred patients with a mean age of 65.1 years (29-92; SD = 13.0) were included. Eye amputation (EA) indications were uveal melanoma (n = 24, 24%), trauma (n = 20, 20%), retinal detachment (n = 20, 20%), glaucoma (n = 14, 14%) and endophthalmitis (n = 12, 12%). Forty-seven (47%), 30 (30%) and 38 (38%) patients experienced PEP, phantom visions and phantom sensations, respectively. Anxiety and depression [Hospital Anxiety Depression scale (HADS) score ≥8 for both] were diagnosed in 34 (34%) and 42 (42%) patients, respectively. The mean EQ-5D-3L and EQ-5D visual analogue scale scores were 0.8 (0.06-1; SD = 0.2) and 68 (0-100; SD = 22), respectively. Preoperative eye pain (p = 0.031), glaucoma (p = 0.027), postoperative anxiety with HADS score ≥8 (p = 0.012) and ≥11 (p = 0.014), aesthetic discomfort (p = 0.002) and EQ-5D-3L score

International audience; Propagation of Cortico-Cortical Evoked Potentials (CCEPs) varies depending on numerous structural features of brain tissue. In this work, we show that dMRI-based connectivity enriched with microstructure data has the potential to measure cortico-cortical communication as it predicts CCEP-based effective connectivity. Our multiple linear regression model incorporates q-space indices like Q-space Inverse Variance, Non-Gaussianity and Return to Plane Probability with minimum streamline lengths obtained from tractography to predict delays and amplitudes of the N1 peaks in CCEPs. In our experiment, we use presurgical dMRI and intrasurgical ECoG recordings of 9 patients operated on brain tumor in the awake condition.

International audience; Background: Awake surgery has become a key treatment of diffuse low-grade gliomas (DLGG) and is divided in three main phases: opening, tumor resection - during which the patient needs to be fully awake - and closure. The anesthetic management of awake neurosurgery is a challenge, and there are currently no guidelines.Objective: The objective of the survey was to explore differences and commonalities regarding the anesthetic management of awake DLGG surgery within the European Low-Grade Glioma Network (ELGGN) centers.Methods: A form that contained 14 questions about the anesthetic management was sent to 28 centers in May 2015.Results: Twenty centers responded. During the opening and closing non-awake periods, 56% of teams chose general anesthesia with mechanical ventilation for at least one period (asleep-awake-asleep, SAS protocol), and 44% monitored anesthesia care including sedation without mechanical ventilation (MAC protocol). In case of SAS, all the teams chose intravenous anesthesia, 82% used laryngeal mask instead of endotracheal intubation during the opening sequence, and 71% during closure. Local and regional anesthesia was practiced by all the teams. The most frequently reported cause of pain was dural and cerebral vessels manipulation (77%). Pain management was mostly based on paracetamol (70%) and remifentanil (55%).Conclusion: Our survey showed that there was an equivalent proportion of centers using SAS or MAC protocols in the anesthetic management of awake surgery in ELGGN centers. The advantages and disadvantages of each anesthesia protocol were reviewed.

There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells. Significance: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency. See related commentary by Koncar and Agnihotri, p. 3195

Orbitorrhea is defined as a leak of cerebrospinal fluid from a cranio-orbital fistula. It is usually related to anterior skull base trauma. Orbitorrhea is an exceptional and life-threatening condition which should be promptly managed. We herein report the case of a right post-traumatic orbitorrhea following anterior skull base trauma. Conservative treatment was initially attempted. At 6 weeks, recurrence was noted, and the patient underwent neurosurgical management. A few months later, a secondary upper lid retraction was diagnosed and treated by full-thickness skin graft with favourable outcome. To our knowledge, fewer than 30 cases have been previously reported. Ophthalmologists should be aware of this life-threatening condition which could be underestimated.

Diffuse low-grade glioma form a rare entity affecting young people. Despite advances in surgery, chemotherapy, and radiation therapy, diffuse low-grade glioma are still incurable. According to current guidelines, maximum safe resection, when feasible, is the first line of treatment. Apart from surgery, all other treatment modalities (temozolomide, procarbazine-CCNU-vincristine regimen, and radiation therapy) are handled very differently among different teams, and this in spite of recent results of several phase 3 studies. Based on a European survey, this paper aimed to get a picture of this heterogeneity in diffuse low-grade glioma management, to identify clinically relevant questions raised by this heterogeneity of practice, and to propose new methodological frameworks to address these questions.

Objectifs Analyser les caracteristiques texturales (Radiomics) pour decrire une signature correlee aux mutations IDH et codeletion 1p/19q dans les gliomes de bas grade (classification OMS 2016, Figure 1 ). Evaluer l’impact des parametres d’acquisition sur les indices radiomiques. Materiels et methodes Les patients presentant un gliome de bas grade diagnostique au CHU de Nice entre 2009 et 2016 avec une imagerie FLAIR pre operatoire disponible ont ete inclus dans notre etude retrospective. Les donnees concernant le statut IDH, la codeletion 1p/19q, l’expression ATRX et les mutations type glioblastome moleculaire ont ete recueillies. Les sequences FLAIR, T2, T1 et T1 injectee ont ete normalisees en intensite (methode hybride WhiteStripes) et en resolution spatiale (Matlab SPM12), puis un contourage des tumeurs a ete realise avec positionnement de 6 VOI en substance blanche saine (logiciel LifeX). Quarante-huit indices de radiomiques ont ete extraits avec calcul du coefficient de Spearman entre index et realisation d’un test de Wilcoxon pour chaque tâche de classification. Resultats Trente-neuf patients ont ete inclus (16 astrocytomes IDH mutes, 13 astrocytomes IDH wild-type et 10 oligodendrogliomes, Tableau 1 ). Les correlogrammes sont presentes Figure 2 . Pour le statut IDH, 26 indices etaient discriminant sur l’ensemble des sequences (p Conclusion L’analyse radiomics pourrait permettre de quantifier a partir des donnees IRM une organisation tissulaire specifique au genotype IDH dans les gliomes de bas grade, mais necessite une poursuite des investigations sur une plus grande cohorte afin de valider une signature specifique.

International audience; We aimed to validate structural connectivity measures based on diffusion MRI with Electrical Stimulation (ES) of the human brain cortex. For this, we combined white matter fiber tractography with propagation of Cortico-Cortical Evoked Potentials (CCEPs) induced by in-trasurgical ES in the language system of brain tumor patients. Our results showed high correlation (Pearson's coefficient 0.5-0.9) between delays of CCEPs and pathways connecting stimulation sites with recording electrodes. Our approach outperformed earlier study based on Diffusion Tensor Imaging. This potentially indicates that probabilistic tractogra-phy is an effective tool to quantify cortico-cortical communication non-invasively.

International audience; The role of the left inferior longitudinal fasciculus (ILF) in language processing has been called into question by recent studies showing that disruption of this tract in glioma patients did not necessarily lead to detrimental effects on spoken language, especially on picture naming. Here we show that disruption of the left ILF with axonal stimulation in patients undergoing an "awake" surgery for a slow-growing tumour systematically induces pure anomia, but only when the temporal pole (TP) is not infiltrated by the tumour. This finding not only confirms that the ILF plays a role in lexical retrieval in normal circumstances but also suggests that the information conveyed by this tract can be rerouted to alternative pathways when the TP is widely lesioned and abandons its function. This conclusion is further supported by the case of a patient who developed a long-lasting anomic aphasia after a surgically preplanned interruption of the ILF.

ObjectiveTo assess the homotopic structural plasticity in case of unilateral damage of the insula.MethodsTo detect changes in gray matter volumes of the contralesional insula from structural MRIs, we used voxel-based morphometry (VBM) in a sample of 84 patients with a diffuse low-grade glioma invading the left insula (insL group; n = 47) or the right insula (insR group; n = 37).ResultsThe region of interest–based VBM analysis highlighted a large cluster of voxels with gray matter volume increase in the contralesional insula in both patient groups (k = 2,214 voxels for insL and k = 879 voxels for insR, p < 0.05, family-wise error corrected) compared with 24 age-matched healthy controls. Gray matter volume was increased for the entire insula (t69 = 3.63, p = 0.0016 for insL; t59 = 3.54, p = 0.0024 for insR, Bonferroni corrected), whereas no significant changes were found in 2 control regions for both patient groups. Furthermore, an increase of 24.6% and 31.6% in the gray matter volume was observed in the insula-related VBM cluster for insL and insR patients, respectively, compared with healthy controls (t69 = 7.39, p = 2.59 × 10−10 and t59 = 7.51, p = 3.61 × 10−10).ConclusionsThe reported results demonstrate that slow-growing but massive lesion infiltration of the insula induces marked increase of gray matter volume in the contralateral one. Our findings give support for a homotopic reorganization that might be a physiologic basis for the high level of functional compensation observed in patients with glioma.

Contains fulltext : 195164.pdf (Publisher’s version ) (Open Access) Objective: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers. Methods: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery. Results: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI. Conclusion: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of

International audience; Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

[18F]-FDOPA is a labeled amino acid (AA) analog used for positron emission tomography (PET) which is gaining increasing interest in the evaluation of brain tumors (BT). The AA-transporter LAT1 has been shown to be involved in [18F]-FDOPA uptake. The aim of this study was to determine whether the [18F]-FDOPA uptake was correlated with level of LAT1 expression in BT. Twenty-eight BT (including 19 gliomas and 9 metastases) were investigated by [18F]-FDOPA-PET prior to surgery and by anti-LAT1 immunohistochemistry on surgical specimens. The quantitative [18F]-FDOPA measured parameters were SUVmax, SUVmean and SUVpeak. LAT1 expression was quantified using a score (0 to 400). A significant [18F]-FDOPA uptake was associated with a LAT1 score ≥ 100 (p = 0.02) but there was no linear correlation between intensity of [18F]-FDOPA uptake and score of LAT1 expression whatever the parameters considered. LAT1 expression alone is not sufficient to explain variation of intensity of [18F]-FDOPA uptake in BT.

International audience; Background - Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods - Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results - Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions - We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Introduction: Randomized Controlled Trial (RCTs) is the gold standard to objectively assess the effect of a treatment. The RCTs methodology must be particularly rigorous to achieve strong evidence of efficiency. To help improve the quality of RCTs, a group of experts established a list of recommendations, adopted by most international journals, called the CONSORT (CONsolidated Standards of Reporting Trials) Statement. First published in 1996, it was actualised in 2001 and 2010. In this study, we assessed the implementation of the CONSORT Statement criteria in the field of adult high grade gliomas. We also aimed to identify criteria associated with higher quality of RCTs. METHODS: We searched PUBMED to retrieve all RCTs concerning high grade gliomas published between the 1st January 1990 and the 1st March 2016. The quality of these RCTs was assessed by completing a modified CONSORT Score containing 33 items. This work was done independently by two investigators and every discordance was resolved by consensus. We also extracted data that seemed relevant to assess the quality of RCTs. Results: Eighty-four published RCTs were identified. The median CONSORT Score was 19 (range: 3-30). Items were not equally reported and items regarding the method of randomization, the blinding or the accessibility of the protocol were reported in less than 25% of RCTs which could raise important biases and led to inappropriate interpretation of the results. However, the CONSORT Score constantly improved over the years. Before the onset of the CONSORT Statement in 1996, the median CONSORT Score was 13 (range: 4-19) whereas it was equal to 18 (range: 3-26) for the period 1996-2004 and equal to 22 (range: 6-30) after 2005. A higher CONSORT Score was observed when RCTs were published in journal with impact factor above 10 (24 vs 17, p

International audience; Intraoperative mapping and monitoring techniques for eloquent area tumors are routinely used world wide. Very few data are available regarding mapping and monitoring methods and preferences, intraoperative seizures occurrence and perioperative antiepileptic drug management. A questionnaire was sent to 20 European centers with experience in intraoperative mapping or neurophysiological monitoring for the treatment of eloquent area tumors. Fifteen centers returned the completed questionnaires. Data was available on 2098 patients. 863 patients (41.1%) were operated on through awake surgery and intraoperative mapping, while 1235 patients (58.8%) received asleep surgery and intraoperative electrophysiological monitoring or mapping. There was great heterogeneity between centers with some totally AW oriented (up to 100%) and other almost totally ASL oriented (up to 92%) (31% SD). For awake surgery, 79.9% centers preferred an asleep-awake-asleep anesthesia protocol. Only 53.3% of the centers used ECoG or transcutaneous EEG. The incidence of intraoperative seizures varied significantly between centers, ranging from 2.5% to 54% (p < 0.001). It there appears to be a statistically significant link between the mastery of mapping technique and the risk of intraoperative seizures. Moreover, history of preoperative seizures can significantly increase the risk of intraoperative seizures (p < 0.001). Intraoperative seizures occurrence was similar in patients with or without perioperative drugs (12% vs. 12%, p = 0.2). This is the first European survey to assess intraoperative functional mapping and monitoring protocols and the management of peri- and intraoperative seizures. This data can help identify specific aspects that need to be investigated in prospective and controlled studies.

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Our understanding of brain movement control has changed over the last two decades. Recent findings in the monkey and in humans have led to a parallel and interconnected network. Nevertheless, little is known about these networks. Here, we present two cases of patients with a parietal low-grade glioma. They underwent surgery under local anesthesia with cortical and subcortical mapping. For patient 1, subcortical electrostimulation immediately posterior to thalamocortical fibers induced movement disorders, with an inhibition of leg and arm movements medially and, more laterally, an acceleration of arm movement. For patient 2, electrostimulation of white matter immediately posterior to thalamocortical fibers induced an inhibition of both arm movement. It means that the detected fibers in the parietal lobe may be involved in the motor control modulation. They are distributed veil-like immediately posterior to thalamocortical pathways and could correspond to a fronto-parietal movement control subnetwork. These two cases highlight the major role of the subcortical connectivity in movement regulation, involving parietal lobe, thus the necessity to be identified and preserved during brain surgery.

Jerome Barriere was inadvertently missing in the original version of this article. He has participated to the study design, protocol writing and inclusion of a significant number of patients.

Introduction Awake craniotomy for brain tumor resection is usually well-tolerated and most of the patients are satisfied. However, in studies reporting the patients’ postoperative perception of the awake craniotomy procedure, about half of them have experienced some degree of intraoperative pain. Pain was mild (intensity between 1 and 2 on the visual analogical score) short lasting in most cases, and did not challenge the procedure. Pain was reported as moderate in about 25% and exceptionally severe. Methods We conducted a preliminary survey among French centers (n = 9) routinely performing awake craniotomy. Results Neurosurgeons’ opinions were concordant with patient's reports. Intraoperative pain exceptionally challenged the awake craniotomy procedure or led to changes in the resection strategy. For neurosurgeons, the most challenging causes of intraoperative pain were the patient's inadequate installation, the contact of surgical tools with pain-sensitive intracranial structures, especially the dura mater of the skull base, falx cerebri, and the leptomeninges of the lateral fissure and neighboring sulci. Conclusion Strategies to deal with these causes included focusing the patient on the intraoperative functional tests to distract their attention away from the pain, and avoiding contacts with the pain-sensitive intracranial structures during the awake phase. Adequate preoperative patient information and preparation, trained anesthesiologists and application of recommendations for awake craniotomy procedures as well as adaptation of surgical technique to avoid contact with pain-sensitive intracranial structures are key factors to prevent intraoperative pain and ensure patient's postoperative satisfaction.

International audience; Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.

Introduction Bone echinococcosis or bone hydatidosis is mainly caused by the larva of a dog taenia, Echinococcus granulosus. We described a rare imported case in metropolitan France of spinal cord compression from a primary vertebral hydatidosis. Case A 25-year-old woman, native of a rural area in the South of Romania, was admitted for backache and slight weakness of both legs. Radiological findings showed a paravertebral pluricystic lesion invading the spinal canal with spinal cord compression at the T9 level, without associated visceral localization. We performed an urgent surgical decompression using a posterior approach. The whole extradural cysts were carefully excised with irrigation of the cystic fluid with hypertonic saline. Treatment was completed with long-term anti-parasitic chemotherapy. Discussion Bone echinococcosis is rare and represents about 2% of hydatidosis. The spine localization is found in half of the cases. This pathology particularly occurs in the Eastern and Southern countries of Mediterranean sheep breeding areas, but still rare in metropolitan France. Spinal cord compression is a frequent presentation of spinal hydatidosis but neurological symptoms are various and non-specific. The reference treatment is removal surgery with particular precautions, followed by an anti-parasitic chemotherapy (albendazole) to limit recurrences. However, a long-term follow-up is mandatory due to later recurrences.