<p>Supplementary Figures S1-S9; Supplementary Tables S1-S5.</p>

Life evolution is a fascinating theme. According to Lamarck, “creation” is in a constant state of advancement, a result of cumulative changes of unclear etiology, although the potential role of stem cells has not been analyzed. Hierarchical and somatotopic development suggests that the whole organism’s cells are linked through complex hierarchical clustering network systems that provide several advantages to the organism cells, including cell feedback controls, which allow somatic cells to promote and/or repress gene behaviors of anybody’s cell, including germ stem cells (GSCs). Gene flexibility for accepting duplicated genetic elements is mandatory for evolution; thus, the updated selected epigenetic information of SC is transmitted to GSCs and consequent generations. However, we should consider the competition between the two parental chromosomes. This dual parental occurrence of an epigenetic modification could create an “optimum selective peak”; therefore, life “sexualization” was the first primordial step of evolution. The second primordial step was brain emergence, which was initiated by the development of motor, sensing, and sensorial functions. This has contributed, by successive cascades, to brain evolution across species. In mammals and primates, comport functions are imprinted as “fixed brain engrams” because genes have been fixed at the level of genomic organization, whereas in humans, the brain genome has escaped “fixation.” Consequently, the plasticity of brain gene regulatory mechanisms has reduced the genetically predetermined gene expression of “brain engrams,” leading to the development of complex brain regions and brain functional diversification, with their complex interaction.

BACKGROUND:Incidence of spontaneous subarachnoid hemorrhages (SAH) varies wildly across the world and seems to be low in Central and South America (4.2 per 100 000 person-years; CI 95%; 3.1-5.7). The objective of our study was to describe the characteristics of SAH and to estimate its incidence and severity in Martinique, a small French island located in the Caribbean Sea. METHODS:Due to its insular nature and small captive population, Martinique is ideal for the setting up of population-based epidemiological studies with good exhaustiveness. Our study, spanning a 7 year period (2007-2013), consisted of retrospective case ascertainment with multiple overlapping methods. Crude incidence and 30 day case-fatality rates for SAH among the Martinican population were computed for the study period. Incidence and disease severity was also analyzed according to age, gender and aneurysm presence. World age-standardized incidence rates were also calculated. RESULTS:A total of 121 patients had a SAH during the study period, with a higher frequency of female cases (71.1% versus 28.9%, p<0.001). Patient mean age was 57.1 years (median = 55 [46-66]). An aneurysmal origin was found in 96 SAH cases (79.3%). Crude annual incidence was 4.36 per 100 000 person-years (CI 95% 2.30-6.42). World age-standardized incidence was 3.29 per 100 000 person-years (CI 95% 1.74-4.84). During the 30 days following SAH diagnosis, 29 patients died (case fatality rate: 24% (CI 95% 16.4-31.6)). CONCLUSIONS:The incidence of spontaneous subarachnoid hemorrhage in Martinique is much lower than in other parts of the world and similar to countries in Central and South America. These results are possibly related to environmental factors and most particularly to a low rate of smoking in the Martinican population. Thirty-day case-fatality rate is similar to what is observed in developed countries.

Primary cell lines derived as neurospheres, enriched in cancer stem cells, are currently the focus of interest in glioblastoma to test new drugs, because of their tumor initiating abilities and resistance to conventional therapies. However, not all glioblastoma samples are propagatable under neurosphere culture and not all neurosphere cell lines are tumorigenic. These cells therefore cannot recapitulate the heterogeneity of glioblastoma samples. We have conducted a proteomic analysis of primary glioblastoma cell lines derived either as adherent cells in the presence of serum (n=11) or as neurospheres (n=12). A total of 963 proteins were identified by nano-LC/Q-TOF MS: 342 proteins were found only in neurosphere lines and were mostly implicated in various metabolic and cellular processes, while 112 proteins were found only in adherent cells and mostly linked to cell adhesion. A protein signature of 10 proteins, 9 of them involved in a cell adhesion pathway, characterized adherent lines. Neurospheres were characterized by 73 proteins mostly linked to DNA metabolic processes associated to cell cycle and protein metabolism. In the Repository of Molecular Brain Neoplasia Data, expression of genes coding for several proteins related to adherent cells or neurospheres were of prognostic relevance for glioblastoma. BIOLOGICAL SIGNIFICANCE:Primary cell lines enriched in cancer stem cells (CSC) have become popular models for testing new drugs for glioblastoma. In this proteomic study on an important number of cell lines obtained either as adherent cells in the presence of serum (a classic way to derive cell lines) or as neurospheres (enriched in CSC), we show that each type of cell line displays different GBM-specific features, highlighting that these two culture types are complementary tools for drug screening.

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency. SEH is characterized by an archetypal clinical presentation including abrupt spinal pain followed more or less rapidly by various degrees of neurological deficit. The diagnosis of SEH, often based on a clinical presumption, represents a clinical challenge. Several reports have outlined missed or delayed diagnosis due to unusual and confusing onsets or unawareness of this diagnosis by physicians. Therefore, physicians should keep in mind the possibility of SEH in their differential diagnosis when confronted with patients complaining of sudden onset of acute spinal pain with or without neurological sign, because the impact of a delayed diagnosis can be disabling catastrophic neurological sequelae. We suggest that SEH is a dynamic disease, which occurs in patients with an abnormal vasculature structural degenerative change. The bleeding is probably of multifactorial origin incriminating veins as well as arteries. Therefore, we proposed a classification of SEH, according to the most probable etiology whatever the associated factors, in six groups: spontaneous, secondary, iatrogenic, traumatic, recurrent, and idiopathic SEH.

Background Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Several recent transcriptomic studies in GBM have identified different signatures involving immune genes associated with GBM pathology, overall survival (OS) or response to treatment. Methods In order to clarify the immune signatures found in GBM, we performed a co-expression network analysis that grouped 791 immune-associated genes (IA genes) in large clusters using a combined dataset of 161 GBM specimens from published databases. We next studied IA genes associated with patient survival using 3 different statistical methods. We then developed a 6-IA gene risk predictor which stratified patients into two groups with statistically significantly different survivals. We validated this risk predictor on two other Affymetrix data series, on a local Agilent data series, and using RT-Q-PCR on a local series of GBM patients treated by standard chemo-radiation therapy. Results The co-expression network analysis of the immune genes disclosed 6 powerful modules identifying innate immune system and natural killer cells, myeloid cells and cytokine signatures. Two of these modules were significantly enriched in genes associated with OS. We also found 108 IA genes linked to the immune system significantly associated with OS in GBM patients. The 6-IA gene risk predictor successfully distinguished two groups of GBM patients with significantly different survival (OS low risk: 22.3 months versus high risk: 7.3 months; p < 0.001). Patients with significantly different OS could even be identified among those with known good prognosis (methylated MGMT promoter-bearing tumor) using Agilent (OS 25 versus 8.1 months; p < 0.01) and RT-PCR (OS 21.8 versus 13.9 months; p < 0.05) technologies. Interestingly, the 6-IA gene risk could also distinguish proneural GBM subtypes. Conclusions This study demonstrates the immune signatures found in previous GBM genomic analyses and suggests the involvement of immune cells in GBM biology. The robust 6-IA gene risk predictor should be helpful in establishing prognosis in GBM patients, in particular in those with a proneural GBM subtype, and even in the well-known good prognosis group of patients with methylated MGMT promoter-bearing tumors.

Un nouvel auto-anticorps, appelé anti-MDA-5, a été récemment identifié en association à un phénotype particulier de dermatomyosite (DM), au cours duquel l’atteinte musculaire est minime ou absente mais où le risque de survenue de pneumopathie interstitielle rapidement évolutive est particulièrement élevé. Nous rapportons une observation de DM associée à la présence d’anticorps anti-MDA-5 et compliquée de pneumopathie interstitielle sévère rapidement évolutive ; le phénotype cutané de ce patient est original du fait de la constitution d’une atteinte ichtyosiforme diffuse et d’une calcinose sous-cutanée profuse.Un homme de 35 ans était hospitalisé pour une éruption cutanée associée à des arthralgies, une toux sèche, une asthénie et un amaigrissement de 8 kg en cinq mois. L’examen dermatologique mettait en évidence un érythème lilacé des paupières supérieures et des joues, un état ichtyosiforme diffus acquis du tronc et des membres ainsi qu’un érythème en bandes des articulations métacarpo- et interphalangiennes proximales et distales des doigts. Le diagnostic de DM était suspecté et le patient traité par prednisolone, 1,5 mg/kg par jour. Les examens immunologiques identifiaient la présence d’anticorps anti-MDA-5. Un mois plus tard, les signes cutanés progressaient, marqués par le développement d’ulcérations douloureuses sur les faces dorsales des doigts, accompagnés d’une dyspnée au moindre effort. L’imagerie thoracique mettait en évidence des lésions de fibrose pulmonaire constituée. Parallèlement se développaient en quelques mois des calcifications diffuses et pseudo-tumorales du tissus sous-cutané du tronc et des membres. Le patient était traité successivement par gammaglobulines intraveineuses, cyclophosphamide, mycophénolate mofétil, azathioprine puis rituximab en association avec une corticothérapie orale sans amélioration de la fonction respiratoire ni des lésions cutanées. Devant la dégradation de l’état respiratoire, une greffe pulmonaire était envisagée, mais récusée en raison d’un état général trop précaire.L’anticorps anti-MDA-5 constituerait le marqueur immunologique spécifique d’un phénotype dermatologique particulier de la DM adulte, significativement associé à la présence : 1) de papules kératosiques situées sur les plis palmaires des doigts et des paumes ; 2) d’ulcérations cutanées situées en regard des bords péri-unguéaux, de papules de Gottron du dos des mains ainsi que sur les faces d’extension des coudes et des genoux ; 3) de douleurs et d’ulcérations de la muqueuse orale, d’une alopécie diffuse, d’un aspect de « mains de mécanicien » et d’un signe de Gottron des coudes et des genoux. La présence d’une atteinte ichtyosiforme étendue et d’une calcinose sous-cutanée profuse n’a pas été rapportée à notre connaissance dans cette forme particulière de DM. Le risque de pneumopathie interstitielle rapidement évolutive est particulièrement élevé et assombrit le pronostic puisque 40 % des patients avec anti-MDA-5 décèdent, essentiellement dans la première année.Nous décrivons un patient atteint d’une DM amyopathique compliquée d’une pneumopathie interstitielle agressive associée à la présence d’anticorps anti-MDA-5, mais dont le phénotype cutané associant un état ichtyosiforme diffus et une calcinose sous-cutanée profuse n’avait jusqu’à présent pas été rapporté.A new antibody known as anti-MDA-5 has recently been identified in association with a specific phenotype of dermatomyositis (DM), in which muscular involvement is minimal or absent, but where there is a particularly high risk of onset of aggressive interstitial lung disease. Below, we report a case associated with the presence of anti-MDA-5 antibodies complicated by aggressive interstitial lung disease ; the cutaneous phenotype of this patient is novel due to the constitution of diffuse ichthyosis and of profuse subcutaneous calcinosis.A 35-year-old man was hospitalised for a skin rash associated with arthralgia, dry cough, asthenia and weight-loss of 8 kg in 5 months. The dermatological examination revealed purple erythema of the upper eyelids and cheeks, diffuse acquired ichthyosis of the trunk and limbs, and striated erythema on the proximal and distal metacarpal and interphalangeal joints of the fingers. A diagnosis of DM was suspected in patients treated with prednisolone, 1.5 mg/kg/d. Immunological tests identified the presence of anti-MDA-5 antibodies. One month later, the cutaneous signs continued to progress and were marked by the development of painful ulcers on the back of the fingers, as well as dyspnoea accompanying the slightest effort. Chest images showed constituted pulmonary fibrosis lesions. At the same time, within several months, diffuse, pseudo-tumoural calcifications developed in the subcutaneous tissue of the trunk and limbs. The patient was treated successively with intravenous gammaglobulins, cyclophosphamide, mycophenolate mofetil, azathioprine and rituximab in combination with oral corticosteroids, but with no improvement in respiratory function or in the skin lesions. Because of the decline in the patient's respiratory status, a lung graft was envisaged but subsequently abandoned because of the patient's excessively precarious state of health.Anti-MDA-5 antibody appears to constitute a specific immunological marker for a special dermatological phenotype of adult DM, significantly associated with the presence of: 1) keratotic papules in the skin folds of the palms and fingers ; 2) cutaneous ulcers along the periungueal edges, Gottron's papules on the back of the hands and on the extensor surface of the elbows and knees ; 3) pain and ulceration in the oral mucosa, diffuse alopecia, and appearance of “mechanic's hands” and Gottron's sign on the elbows and knees. To our knowledge, the presence of extensive ichthyosis and profuse subcutaneous calcinosis has not been previously reported in this particular form of DM. The risk of aggressive interstitial lung disease is particularly high and worsens the prognosis, since 40% of patients with anti-MDA-5 die, usually within the first year.Herein, we describe a patient presenting amyopathic DM complicated by aggressive interstitial lung disease associated with the presence of anti-MDA-5 antibodies, but with a hitherto unreported cutaneous phenotype combining diffuse ichthyosis and profuse subcutaneous calcinosis.

Purpose Type IIB odontoid fractures (OF) in elderly patients are life-threatening conditions. Optimal treatment of these fractures is still controversial. The aim of this study was to assess the clinical and radiological outcome of surgically treated type IIB OF by anterior screw fixation in octogenarians. Methods Eleven octogenarians with type IIB OF were operated using anterior screw fixation. Follow-up assessment included operative mortality and morbidity rates, long-term functional outcome and fracture union and stability. Results There was neither operative mortality nor morbidity. Five patients had excellent clinical outcome, two good outcome, one fair and three poor. Two patients died of unrelated causes 2 months after surgery. Radiographs showed stable bone union in four patients and stable fibrous union in five patients. Conclusions Given the results in this short series, we suggest that anterior screw fixation of Type IIB OF may be offered as primary treatment in octogenarians.

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency. SEH is characterized by an archetypal clinical presentation including abrupt spinal pain followed more or less rapidly by various degrees of neurological deficit. The diagnosis of SEH, often based on a clinical presumption, represents a clinical challenge. Several reports have outlined missed or delayed diagnosis due to unusual and confusing onsets or unawareness of this diagnosis by physicians. Therefore, physicians should keep in mind the possibility of SEH in their differential diagnosis when confronted with patients complaining of sudden onset of acute spinal pain with or without neurological sign, because the impact of a delayed diagnosis can be disabling catastrophic neurological sequelae. We suggest that SEH is a dynamic disease, which occurs in patients with an abnormal vasculature structural degenerative change. The bleeding is probably of multifactorial origin incriminating veins as well as arteries. Therefore, we proposed a classification of SEH, according to the most probable etiology whatever the associated factors, in six groups: spontaneous, secondary, iatrogenic, traumatic, recurrent, and idiopathic SEH.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

Nontraumatic spinal epidural hematoma (SEH) during pregnancy is rare. Therefore, appropriate management of this occurrence is not well defined. The aim of this study was to extensively review the literature on this subject, to propose some novel treatment guidelines. Electronic databases, manual reviews and conference proceedings up to December 2011 were systematically reviewed. Articles were deemed eligible for inclusion in this study if they dealt with nontraumatic SEH during pregnancy. Search protocols and data were independently assessed by two authors. In all, 23 case reports were found to be appropriate for review. The mean patient age was 28 years and gestational age was 33.2 weeks. Thirteen cases presented with acute interscapular pain. The clinical picture consisted of paraplegia, which occurred approximately 63 h after pain onset. Spinal cord decompression was performed within an average time of 20 h after neurological deficit onset. Fifteen patients had cesarean deliveries, even when the gestational age was less than 36 weeks. This review failed to identify articles, other than case reports, which could assist in the formation of new guidelines to treat SEH in pregnancy. However, we believe that SEH may be managed neurosurgically, without requiring prior, premature, cesarean section.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

Objective: Nontraumatic spinal epidural hematoma (SEH) during pregnancy is rare. Therefore, appropriate management of this occurrence is not well defined. The aim of this study was to extensively review the literature on this subject, to propose some novel treatment guidelines. Methods: Electronic databases, manual reviews and conference proceedings up to December 2011 were systematically reviewed. Articles were deemed eligible for inclusion in this study if they dealt with nontraumatic SEH during pregnancy. Search protocols and data were independently assessed by two authors. Results: In all, 23 case reports were found to be appropriate for review. The mean patient age was 28 years and gestational age was 33.2 weeks. Thirteen cases presented with acute interscapular pain. The clinical picture consisted of paraplegia, which occurred approximately 63 h after pain onset. Spinal cord decompression was performed within an average time of 20 h after neurological deficit onset. Fifteen patients had cesarean deliveries, even when the gestational age was less than 36 weeks. Conclusion: This review failed to identify articles, other than case reports, which could assist in the formation of new guidelines to treat SEH in pregnancy. However, we believe that SEH may be managed neurosurgically, without requiring prior, premature, cesarean section.

MGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose.

BACKGROUND:Genomics, transcriptomics and proteomics of glioblastoma multiforme (GBM) have recently emerged as possible tools to discover therapeutic targets and biomarkers for new therapies including immunotherapy. It is well known that macroscopically complete surgical excision, radiotherapy and chemotherapy have therapeutic limitations to improve survival in these patients. In this study, we used a differential proteomic-based technique (2D-Difference Gel Electrophoresis) coupled with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to identify proteins that may serve as brain tumor antigens in new therapeutic assays. Five samples of patients presenting a GBM and five samples of microscopically normal brain tissues derived from brain epileptic surgery specimen were labeled and run in 2D-PAGE (Two-Dimensional Polyacrylamide Gel Electrophoresis) with an internal pool sample on each gel. Five gels were matched and compared with DIA (Difference In-gel Analysis) software. Differential spots were picked, in-gel digested and peptide mass fingerprints were obtained.RESULTS:From 51 protein-spots significantly up-regulated in GBM samples, mass spectrometry (MS) identified twenty-two proteins. The differential expression of a selected protein set was first validated by western-blotting, then tested on large cohorts of GBM specimens and non-tumor tissues, using immunohistochemistry and real-time RT-PCR.CONCLUSIONS:Our results confirmed the importance of previously described proteins in glioma pathology and their potential usefulness as biological markers but also revealed some new interesting targets for future therapies.

Synovial cysts (SCs) are well-recognized entities occurring at various spinal sites, although atlanto-occipital joint cyst is a rare occurrence. Similarly both hypoglossal nerve palsy (as an initial clinical onset) and spontaneous cervical cyst resolution are rare. In this report, the authors describe an atlanto-occipital SC revealed by hypoglossal nerve palsy in a 75-year-old woman. Due to the paucity of neurological signs and the patient's advanced age, she was managed conservatively; 8 months later the cyst resolved completely. We discuss the potential factors involved in the pathogenesis and the therapeutic options for this uncommon cervical entity. We advise conservative treatment as a first therapeutic option for SC without signs of spinal cord compression.

The authors present the case of an inflammatory myofibroblastic tumor that involves the cervical spinal cord meninges, presenting in a manner mimicking en plaque meningioma, which has never been previously reported. During the first surgical procedure, which did not involve exploration of the intradural space, inflammatory epidural tissue was found. We performed a second operation to remove the tumor that was finally intradural, dural-based and very tough. Imaging studies, surgical findings, and histopathological examinations were used to support the diagnosis. Intradural extramedullary inflammatory myofibroblastic tumor is a rare entity that has only been described nine times in the literature. Surgery remains the treatment of choice. Although histologically benign, spinal inflammatory myofibroblastic tumor can be aggressive and requires a large resection and long-term follow-up of the entire central nervous system with magnetic resonance imaging.

Glioblastoma multiforme (GBM) is the most dramatic primary brain cancer with a very poor prognosis because of inevitable disease recurrence. The median overall survival is less than 1 year after diagnosis. Cancer stem cells have recently been disclosed in GBM. GBM stem-like cells (GSCs) exhibit resistance to radio/chemotherapeutic treatments and are therefore considered to play an important role in disease recurrence. GSCs are thus appealing targets for new treatments for GBM patients. In this study, we show that GBM cells with stem cell characteristics are resistant to lysis mediated by resting natural killer (NK) cells because of the expression of MHC class I molecules. However, GSCs are killed by lectin-activated NK cells. Furthermore, in experiments using the therapeutic antibody CetuximAb, we show that GSCs are sensitive to antibody-mediated cytotoxicity. We confirm the sensitivity of GSC to cytotoxicity carried out by IL2-activated NK cells and tumor-specific T cells. More importantly, we show that GSCs are more sensitive to NK and T cell-mediated lysis relatively to their corresponding serum-cultured GBM cells obtained from the same initial tumor specimen. Altogether, these results demonstrate the sensitivity of GSC to immune cell cytotoxicity and, therefore, strongly suggest that GSCs are suitable target cells for immunotherapy of GBM patients.