One-year prospective real-world assessment of effectiveness and safety of erenumab in migraine prevention: results of the French FHU INOVPAIN registry study.

BACKGROUND: Randomized clinical trials have demonstrated efficacy and safety of erenumab. The aim of this study is to evaluate the effectiveness and safety of erenumab in a real-world setting in French patients with migraine associated with extreme unmet needs. METHODS: This is a one year-prospective real-word study with enrolment of all consecutive adult patients included in the FHU InovPain registry who participated in a compassionate erenumab use program. RESULTS: Of 144 patients included, 140 patients (82.1% female / mean age of 50.9 ± 11.4) received at least one dose of erenumab and were concerned by effectiveness and safety assessment. All patients had failed 11 oral preventive treatments. Most of them suffered from chronic migraine (88.6%) and presented a medication overuse (90.7%) at baseline. Thirty-eight (27.1%) discontinued treatment during the 12-month follow-up, with 22 (15.7%), 11 (7.9%) and 5 (3.6%) patients before 3, 6 or 9 months of treatment. The proportion of ≥ 50% responders at M3, M6, M9 and M12 was 74/140 (52.9%), 69/118 (58.5%), 61/107 (57.0%) and 60/102 (58.8%) respectively. At M3, the rate of reversion from chronic migraine to episodic migraine was 57.3% and the rate of transition from medication overuse to non-overuse was 46.5%. For monthly migraine days, the median (IQR) was 18.0 (13.0-26.0), 9.0 (5.0-17.0), 7.5 (5.0-14.0), 8.0 (5.0-12.5) and 8.0 (5.0-12.0) at M0, M3, M6, M9 and M12 respectively. For HIT-6 score, the median (IQR) was 68.0 (63.8-73.3), 60.0 (54.0-65.0), 60.0 (50.3-53.0), 59.0 (50.0-63.0) and 58.0 (50.0-62.9) at M0, M3, M6, M9 and M12 respectively. Fifty-three (37.9%) patients reported at least one of the following adverse events: cutaneous erythema and/or pain at the injection site for 42 (30%) patients, constipation for 22 (15.7%) patients, muscle spasm for 2 (1.4%) patients, alopecia for one (0.7%) patient and blood pressure increase in one (0.7%) patient. There was no serious adverse event. One female patient became pregnant after 5 months of exposure to erenumab with a safe evolution after treatment discontinuation. CONCLUSION: This first French real-world study related to migraine prevention with CGRP-mAbs confirms effectiveness and safety of erenumab in patients with extreme unmet needs.

Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics.

One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of "biomarker signatures" that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an "epitranscriptomics-based signature" that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.

Spinal cord stimulation for neuropathic pain.

Spinal cord stimulation (SCS) is used for more than 40years to treat localized chronic medically refractory neuropathic pain involving limb(s) and trunk. The most frequent indications remain complex regional pain syndrome (CRPS) failed back surgery syndrome (FBSS), and peripheral neuropathy. Stimulation-induced paresthesias, perceived by the patient, prevent blinded evaluation and increase the placebo effect, decreasing the credibility of the tonic SCS efficacy. Retrospective studies reported that about 50% of the patients are improved more than 50% at short-term, but long-term improvement is less. Several comparative randomized trials (RCT) are now available. In CRPS, a RCT demonstrated the superiority of SCS plus physiotherapy compared to physiotherapy alone. In FBSS, two RCTs have shown that SCS was superior to reoperation and conventional medical treatment, (CMM) respectively. New stimulation waveforms, namely burst, high frequency (10KHz) stimulation and close-loop SCS, have been proposed recently to avoid the perception of paresthesias and/or increase the pain relief. RCTs in FBSS have suggested that these new SCS modalities were as least as efficient than conventional tonic SCS and perhaps slightly superior. Two RCTs confirmed SCS efficacy in painful diabetic neuropathy in comparison with CMM. Complications are frequent (hardware dysfunction or migration, superficial infection) but exceptionally serious. Consequently, the risk/benefit ratio is favorable to SCS, considering that chronic pain patients undergoing this procedure are usually resistant to all the other therapies.

Intracranial nociception.

Understanding intracranial nociceptive innervation is essential to understand the pathophysiology of headaches. Our knowledge about human intracranial nociception comes from sparse observations during neurosurgical procedures performed in awake patients, from human anatomical studies and from experimental studies in animals. In this article we review the anatomical and functional organization underlying nociceptive innervation. Intracranial nociception is mainly mediated by the trigeminal system, except in the posterior cranial fossa that is innervated by the first cervical roots. For decades, the dura mater, its vessels and major cerebral blood vessels were considered as the only intracranial pain-sensitive structures. Recent animal and human studies have suggested that smaller brain arteries and potentially pia mater might also be pain sensitive. Nociceptive neurons innervating intracranial blood vessels project via the ophthalmic division (V1) to the trigeminal ganglion and store several neurotransmitters including glutamate, substance P and calcitonin gene-related peptide (CGRP). The trigeminal ganglion, root and brainstem nuclei have a specific topographic and functional somatotopy. Progressive transition between the trigeminal spinal nucleus and the dorsal horn of the cervical spinal cord, and convergence of nociceptive inputs from the face, intracranial structures and the occipital area on the so-called "trigemino-cervical complex" may explain some headache features, relations between facial and occipital pain, and efficacy of occipital nerve stimulation in headache. The specific anatomic organization of the trigeminal system, from the primary-order neuron in the trigeminal ganglion, to the second-order neuron is the trigeminal nuclei, may explain a part of the various characteristics of headaches.

Neurostimulation methods in the treatment of chronic pain.

The goal of this narrative review was to give an up-to-date overview of the peripheral and central neurostimulation methods that can be used to treat chronic pain. Special focus has been given to three pain conditions: neuropathic pain, nociplastic pain and primary headaches. Both non-invasive and invasive techniques are briefly presented together with their pain relief potentials. For non-invasive stimulation techniques, data concerning transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), remote electrical neuromodulation (REN) and vagus nerve stimulation (VNS) are provided. Concerning invasive stimulation techniques, occipital nerve stimulation (ONS), vagus nerve stimulation (VNS), epidural motor cortex stimulation (EMCS), spinal cord stimulation (SCS) and deep brain stimulation (DBS) are presented. The action mode of all these techniques is only partly understood but can be very different from one technique to the other. Patients' selection is still a challenge. Recent consensus-based guidelines for clinical practice are presented when available. The development of closed-loop devices could be of interest in the future, although the clinical benefit over open loop is not proven yet.

MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma.

AIMS: MET gene amplification is rare in glioblastoma (GBM) and represents a potential target for MET inhibitors. An immunohistochemical screening may be useful to identify MET amplification. The aim of our study was to establish how MET immunolabelling correlates with MET amplification. METHODS: Three cohorts including 108 GBM (cohort 1, prospective), 104 GBM (cohort 2, retrospective) and 52 GBM (cohort 3, prospective) were investigated for MET expression by immunohistochemistry. MET amplification was assessed by comparative genomic hybridization on microarray (CGH-array) in all cohorts and by fluorescent in situ hybridization (FISH) in cohorts 2 and 3. Active form of MET was assessed using p-MET (Y1349) immunohistochemistry. RESULTS: Diffuse MET amplification detectable by CGH-array was associated with diffuse, strong MET immunolabelling (four cases in cohort 1 and one case in cohort 2). Focal MET amplification detectable only by FISH was observed in small foci of strongly immunopositive cells in two GBM (cohort 2). In both cohorts, MET amplification was never detected in GBM devoid of strongly immunopositive cells. MET overexpression, observed in 23% of unamplified GBM, was associated with a predominant weak-to-moderate staining intensity and with necrosis (P < 0.005). p-MET was detected in all MET-amplified GBM and in perinecrotic areas of nonamplified GBM. A strong MET immunostaining intensity, at least focal and distant from necrosis, showed 100% sensitivity and 84% specificity for predicting MET amplification in cohort 3. CONCLUSIONS: MET amplification is characterized by strongly immunopositive cells. Only GBM showing strong MET immunostaining is appropriate for the assessment of MET amplification.

Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

[Treatment of neurotrophic ulceration following alcohol injection of the gasserian ganglion in trigeminal neuralgia: Case report and review of the literature]. / Traitement de l'ulcération neurotrophique après alcoolisation du ganglion de Gasser dans l'atteinte du nerf trijumeau : cas clinique et revue de la littérature.

INTRODUCTION: Trigeminal trophic syndrome (TTS) can occur after any injury on the fifth cranial nerve. The etiology is dominated by iatrogenic causes, especially after gasserian ganglion ablation. Middle-aged women are mostly involved and the differential diagnosis is vast. PRESENTATION OF CASE: A 88-year old woman presented with TTS and destruction of the right nasal ala 25 years after retrogasserian alcohol injection for trigeminal neuralgia. Facing iterative failure of medical treatment, topics and neurostimulation, we performed lipofilling for the lesion. In the third month, we found a 50 % decrease in size of the lesion, as well as a complete disappearance of pruritus, thus allowing to consider reconstructive surgery. DISCUSSION: Our literature review reports 28 cases of TTS subsequent to alcohol injection of the gasserian ganglion. Age of presentation ranges from 49 to 88 years, with a time of onset between trigeminal injury and TTS ranging from 2 weeks to 17 years. Recurrences are frequent. The management varies a lot according to the authors (topics, antibiotics, flaps), however the efficiency of lipofilling has not been reported yet. CONCLUSION: The pathophysiology of TTS remains unknown, nevertheless the therapeutical care has to be multidisciplinary. Even though not described yet, lipofilling seems to be an interesting treatment of TTS following alcohol injection in the trigeminal ganglion.

Sex and age-related differences in perceived, desired and measured percentage body fat among adults.

BACKGROUND: Body image distortion/discrepancy leads to psychological stress, disordered eating and mental and physical disease. To begin to assess body image distortion/discrepancy, we compared perceived, desired and measured percentage body fat in male versus female and college-aged versus non-college aged individuals. In addition, we assessed the acute stress response to body composition measurement. METHODS: Body fat percentage of 15 college aged ('College Students'; CS) (mean = 19 years) and 16 non-college aged ('Non-College Aged Students'; NCS) (mean = 39 years) males and females was assessed with the BodPod Body Composition Tracking System (Life Measurement Instruments, Concord, CA, USA). Participants indicated their perception of body fat and their desired body fat using a somatomorphic matrix. Salivary cortisol, heart rate and blood pressure were also measured. Data were analysed by analysis of variance and alpha was set at 0.05. RESULTS: Mean (SD) percentage body fat of males [15.2% (6.1%)] was significantly lower than that of females [28.4% (6.4%)] (P < 0.0001). Both CS and NCS females perceived their body fat to be lower (5%) than measured body fat and desired their body fat to be lower (12%) than measured (P < 0.05). CS and NCS male participants demonstrated the opposite result; both CS and NCS male populations perceived their body fat to be higher (5%) than measured body fat and desired their body fat to be higher (4%) than measured (P < 0.05). No differences between any groups were observed in heart rate, blood pressure or cortisol response to body fat measurement. CONCLUSIONS: Sex-related but not age-related differences in perceived, desired and measured percentage body fat were observed.

Primitive cerebral melanoma: a diagnostic and management challenge. About 2 cases.

In this report of two cases of solitary cerebral meningeal melanoma, a rare tumor that presents both diagnostic and management challenges, the diagnosis of these lesions was based on a solitary leptomeningeal mass on MRI, a high mitotic rate on histology and the absence of extracerebral localizations. Although the radiological patterns can mimic those of other melanocytic tumors, MRI is a useful diagnostic tool for narrowing the differential diagnosis. Surgical removal remains the only effective treatment of these lesions, and can lead to prolonged survival in a few cases.

Post-traumatic cerebral venous sinus thrombosis associated with epidural hematoma: A challenging clinical situation.

Post-traumatic cerebral venous sinus thrombosis (ptCVST) is often associated with brain hemorrhage; consequently, the anticoagulation may be challenging. We report the case of a 42-year-old man who presented with post-traumatic epidural hematoma and rapidly developed transverse sinus thrombosis extending to the internal jugular vein. As the patient was asymptomatic, we decided not to use anticoagulants: close clinical and radiological monitoring was implemented. The hematoma resolved within 2 months, and the CVST diminished by the third month. Such a good outcome is not always the case in ptCVST. The present article also discusses pathophysiological mechanisms and treatment options when hematoma is associated with ptCVST.

Electrostriction at the LaAlO3/SrTiO3 interface.

We present a direct comparison between experimental data and ab initio calculations for the electrostrictive effect in the polar LaAlO(3) layer grown on SrTiO(3) substrates. From the structural data, a complete screening of the LaAlO(3) dipole field is observed for film thicknesses between 6 and 20 uc. For thinner films, an expansion of the c axis of 2% matching the theoretical predictions for an electrostrictive effect is observed experimentally.

Functional and dysfunctional impulsivities changes after subthalamic nucleus-deep brain stimulation in Parkinson disease.

OBJECTIVES: We investigated changes of impulsivity after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients, distinguishing functional from dysfunctional impulsivity and their contributing factors. METHODS: Data of 33 PD patients treated by STN-DBS were studied before and 6 months after surgery: motor impairment, medication (dose and dopaminergic agonists), cognition, mood and occurrence of impulse control disorders. Impulsivity was assessed by the Dickman Impulsivity Inventory, which distinguishes functional impulsivity (FI), reflecting the potential for reasoning and rapid action when the situation requires it, and dysfunctional impulsivity (DI), reflecting the lack of prior reasoning, even when the situation demands it. The location of DBS leads was studied on postoperative MRI using a deformable histological atlas and by compartmentalization of the STN. RESULTS: After STN-DBS, DI was significantly increased (mean pre- and postoperative DI scores 1.9±1.6 and 3.5±2.4, P<0.001) although FI was not modified (mean pre- and postoperative FI scores 6.2±2.7 and 5.8±2.6). Factors associated with a DI score's increase≥2 (multivariable logistic regression model) were: low preoperative Frontal Assessment Battery score and location of the left active contact in the ventral part of the STN. CONCLUSION: Our study suggests that STN-DBS may have a different impact on both dimensions of impulsivity, worsening pathological impulsivity without altering physiological impulsivity. The increase in dysfunctional impulsivity may be favoured by the location of the electrode in the ventral part of the STN.

Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) results from truncating mutations of the CDH1 (E-cadherin) gene. It is an autosomal dominant cancer susceptibility syndrome with a lifetime risk of diffuse gastric cancer (DGC) of 60-80%, with a mean age of onset of 37 years. There exists no adequate screening test for DGC. Early intramucosal diffuse/signet-ring cell carcinomas have been found in prophylactic total gastrectomy (PTG) specimens following normal preoperative endoscopy. Total gastrectomy has been advocated on a prophylactic basis. The aim of this study was to report our experience with PTG in 23 patients from the Canadian province of Newfoundland and Labrador. This is the largest series worldwide. METHODS: A retrospective study of consecutive patients undergoing PTG for HDGC was performed. All patients were confirmed to have a truncating mutation of the CDH1 gene. RESULTS: Twenty-three patients underwent PTG between February 2006 and November 2008. Major complications were found in 4/23 patients (17%), with no mortality. Two of 23 patients (9%) had positive mucosal biopsies on preoperative EGD. Twenty-two of 23 patients (96%) had evidence of diffuse/signet-ring carcinoma on final standardized pathological evaluation. Therefore, 21/23 (91%) were not picked up by preoperative EGD screening. CONCLUSIONS: PTG can be performed in patients with HDGC with a low rate of serious complications. Methods of reconstruction incorporating a pouch reservoir and preservation of the postgastric branches of the vagus nerves need to be explored. More refined penetrance estimates, effective screening protocols, and long-term psychological and functional outcomes following PTG require organized multicenter collaborative efforts.

[Cranial nerve functional neurosurgery: evaluation of surgical practice]. / La neurochirurgie fonctionnelle des nerfs crâniens Evaluation de l'activité

We report the results of an investigation carried out on the activity of functional neurosurgery of the cranial nerves in the French-speaking countries, based on the analysis of a questionnaire addressed to all the members of the SNCLF. Eighteen centers responded to this questionnaire, which showed that activities and indications varied greatly from one unit to another. The results appear homogeneous and comparable with those reported in the literature. The questionnaire sought to provide a global perspective, open to the comments and questions of all responders on the various techniques raised, with the objective of establishing a common decisional tree for these pathologies and providing if possible to a consensus for better dissemination of these therapies.

Acute effect of sidestream cigarette smoke extract on vascular endothelial function.

Acute exposure to passive smoking adversely affects vascular function by promoting oxidative stress and endothelial dysfunction. However, it is not known whether tobacco sidestream (SS) smoke has a greater deleterious effect on the endothelium than non-tobacco SS smoke and whether these effects are related to nicotinic endothelial stimulation. To test these hypotheses, endothelial-dependent relaxation and superoxide anion production were assessed in isolated rat aortas incubated with tobacco SS smoke, non-tobacco SS smoke, or pure nicotine. Tobacco SS smoke decreased the maximal relaxation to acetylcholine (Ach) from 79 +/- 6% to 57 +/- 7.3% (% inhibition of phenylephrine-induced plateau, P < 0.001) and increased superoxide anion production from 31 +/- 9.7 to 116 +/- 24 count/10 sec/mg (P < 0.01, lucigenin-enhanced chemiluminescence technique). The non-tobacco SS smoke extract had no significant effect on the response to Ach but increased superoxide anion production in the aortic wall to 133 +/- 2 count/10 sec/mg (P < 0.001). Furthermore, concentration-response curves to Ach and superoxide production remained unaltered with nicotine (0.001, 0.01, or 0.1 mM). In conclusion, despite similar increases in vascular wall superoxide production with tobacco and non-tobacco SS smoke, only the tobacco SS smoke extracts affected endothelium-dependent vasorelaxation. Nicotine alone does not reproduce the effects seen with tobacco SS smoke, suggesting that the acute endothelial toxicity of passive smoking cannot simply be ascribed to a nicotine-dependent mechanism.

[Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice]. / Valeurs diagnostique et pronostique des délétions 1p et 19q dans les gliomes de l'adulte. Revue critique de la littérature et implications en pratique clinique.

Losses of chromosomes 1p and 19q are deemed correlated with diagnosis of oligodendroglioma, higher chemosensitivity and better prognosis. We reviewed the literature to evaluate the usefulness of these correlations in daily clinical practice. The rates of deletions relative to histology (WHO classifications) were extracted from 33 studies, including 2666 patients. The 1p deletions and 1p19q codeletion mean rates were respectively 65.4 and 63.3% in oligodendrogliomas, 28.7 and 21.6% in oligoastrocytomas, 13.2 and 7.5% in astrocytomas, 11.6 and 2.9% in glioblastomas. The presence of 1p deletion and 1p19q codeletion were strongly correlated with the histological diagnosis corresponding to oligodendroglioma. Calculation of specificity, sensitivity, predictive positive values and false negative rates suggests that presence of deletion 1p or codeletion represents a strong argument in favor of the diagnosis of oligodendroglioma. However, considering the high false negative rate, absence of such deletions does not rule out the diagnosis. In grade 3 oligodendroglial tumors, the probability of responding to chemotherapy, and the duration of response, were higher when codeletions were present. This suggests that, in these tumors, the presence of codeletion is a strong argument in favor of adjuvant chemotherapy. However, chemotherapy should not be systematically excluded when codeletions are absent, as the chances of response are about 33% in this situation. Data concerning low-grade gliomas were more controversial. Oligodendroglial tumors with 1p deletion or 1p19q codeletion seemed to have a better prognosis, as five-year survival rates were 50% higher than in tumors without deletion. This might be explained by the correlation between 1p deletion and other identified prognosis factors: (1) higher chemosensitivity, (2) tumor location more frequently in the frontal lobe, leading to better resection and lower risk of neurological deficit, (3) slower growth rate, (4) higher risk of epilepsy, leading to an early detection.

[Molecular biology of adult gliomas: some landmarks for neurosurgeons]. / Biologie moléculaire des gliomes de l'adulte : quelques repères pour le neurochirurgien.

BACKGROUND AND PURPOSE: Recent developments in molecular biology have provided the clinician with opportunities to investigate a number of new biomarkers. This has led to an abundant literature reporting the biological role, the relation to survival, and the predictive value of treatment responses in adult glioma patients. Consequently, the clinician must assimilate a large amount of information, raising the question of the genuine role of these biomarkers in the daily care of these patients. METHODS: The authors report the data on biomarkers from the literature relevant to this context. DISCUSSION: Molecular biology today sheds new and valuable light on the natural history of adult glioma, bringing to the forefront a number of therapeutic principles for glioma patients as a group. However, each of these biomarkers does not have sufficient power to amount to a criterion for individual patient therapeutics. CONCLUSIONS: Biomarkers are not pertinent today for decision making, but the authors believe that the principle of including this approach in adult glioma workups must be encouraged as a promising means of study in the years to come.

DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression.

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.

Treatment of newly diagnosed symptomatic pure low-grade oligodendrogliomas with PCV chemotherapy.

Based on studies relating to anaplastic oligodendroglioma (OG) chemosensitivity and benefit of time to progression or overall survival, chemotherapy for pure OG has been proposed. Several studies have reported the efficacy of various chemotherapeutic agents in a small number of patients with low-grade gliomas, e.g. pure astrocytomas, OG or mixed histologies. The 5-year survival rate varies from 61% to 89% with a mean time to progression of 5 years. We report the outcome of 33 consecutive patients with pure low-grade OG diagnosed between 1990 and 2006 systematically treated for residual or non-removable tumor with PCV chemotherapy regimen as the front-line treatment after surgery. All the tumors were low grade (grade II) pure OG according to the WHO classification. All patients were symptomatic at presentation and underwent neurosurgical procedure for histological diagnosis. Response was evaluated by clinical assessment and brain magnetic resonance imaging. Twenty-one men and 12 women with a mean age at pathological diagnosis of 46.5 years were studied. The most common first symptom was partial epileptic seizure (73.7%). Six patients (18%) had initial gadolinium enhancement, associated with methoxyisobutyl (MIBI) hypermetabolism (P < 0.001). The resection was partial in seven cases (21%), and 26 patients (79%) had biopsy only. Eleven patients (36%) had a malignant transformation during the follow-up with a median time to progression of 19 months. Favorable prognostic factors were lack of contrast enhancement (P < 0.0001), and age <40 years (P < 0.0003); 90% of patients were progression-free at 1 year. Survival rates at 2, 5 and 10 years were 85%, 75% and 50%, respectively. Up-front chemotherapy with PCV regimen is a good treatment for symptomatic pure low-grade OG, as it increases the number of progression-free patients and time to progression. These results suggest that radiotherapy could be postponed until the malignant transformation occurs to delay cognitive side effects of irradiation.