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BackgroundGliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.MethodsAn international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power.ResultsAmong consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm2) significantly influences PFS (P = .0098) and marginally the OS (P = .07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data.ConclusionThe mitotic index (cut-off 2 per 10 40× HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.

The brain is endowed with a unique cellular composition and organization, embedded within a vascular network and isolated from the circulating blood by a specialized frontier, the so-called blood-brain barrier (BBB), which is necessary for its proper function. Recent reports have shown that increments in the permeability of the blood vessels facilitates the entry of toxic components and immune cells to the brain parenchyma and alters the phenotype of the supporting astrocytes. All of these might contribute to the progression of different pathologies such as brain cancers or neurodegenerative diseases. Although it is well known that BBB breakdown occurs due to pericyte malfunctioning or to the lack of stability of the blood vessels, its participation in the diverse neural diseases needs further elucidation. This review summarizes what it is known about BBB structure and function and how its instability might trigger or promote neuronal degeneration and glioma progression, with a special focus on the role of pericytes as key modulators of the vasculature. Moreover, we will discuss some recent reports that highlights the participation of the BBB alterations in glioma growth. This pan-disease analysis might shed some light into these otherwise untreatable diseases and help to design better therapeutic approaches. Work was supported by Ministerio de Economía y Competitividad and FEDER funds: PI13/01258 to AHL, by “Asociación Española contra el Cancer (AECC) grant: INVES192GARG to RG and by Ministerio de Ciencia, Innovación y Universidades and FEDER funds: RTI2018-093596 to PSG. Sí

Cocaine consumption is associated with a variety of clinical manifestations. Though cocaine intranasal inhalation always determines nasal mucosal damages, extensive septum perforations, and midline destructions-known as cocaine-induced midline destructive lesions (CIMDL)-affect only a limited fraction of patients. CIMDL is viewed as a cocaine-associated autoimmune phenomenon in which the presence of atypical anti-neutrophil cytoplasmic antibody (ANCA) promotes and/or defines the disease phenotype. A 51-year-old man presented with an intracranial tumor-like lesion by its space-occupying effect. CT also revealed the destruction of the nasal septum and skull base. A diagnosis of CIMDL was made in light of the patient's history as well as findings of the physical and endoscopic examinations, imaging studies, and laboratory testing. There was no evidence of other pathologies. Histopathological results from cerebral biopsy led us to consider the intracranial pathology as an extension of the CIMDL. CIMDL is the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of predisposed patients. The reported case is the first CIMDL consistent with brain extension mimicking a tumor-like lesion. While the presence of atypical ANCA seems to promote and/or define the disease phenotype, the specific role of these and other circulating autoantibodies needs further investigation.

DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A>T; p.Lys286Ter), or homozygous missense variants (c.74G>A; p.Arg25Gln and c.785T>C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.

Exercise intolerance is the most common phenotype in McArdle disease. Fixed weakness can be present in advanced ages, mainly affecting the shoulder girdle.

In a previous report of a new phenotype with predominant scapulo-humeral-peroneal-distal myopathy associated with the Glu197Asp mutation in ACTA1, muscle biopsies did not show nemaline rods, nor could nemaline rods formation be demonstrated in an exhaustive functional in vivo or in vitro study. However, muscle biopsy in members of our family, carrying a similar clinical phenotype of some members of the original family and the same ACTA1 mutation, revealed the presence of numerous nemaline rods, suggesting that there must be other factors that explain the absence of nemaline rods.

Background and purpose Our objectives were: (1) compare dynamic susceptibility-weighted (DSC) and dynamic contrast-enhanced (DCE) permeability parameters, (2) evaluate diagnostic accuracy of DSC and DCE discriminating high- and low-grade tumors, (3) analyze relationship of permeability parameters with overall (OS) and progression-free survival (PFS) and (4) assess differences in high-grade tumors classified according to molecular biomarkers. Materials and methods 49 patients with histologically proved diffuse gliomas underwent DSC and DCE imaging. Parametric maps of cerebral blood volume (CBV), CBV-leakage corrected, volume transfer coefficient (Ktrans), fractional volume of the extravascular extracellular space (EES) (Ve), fractional blood plasma volume (Vp) and rate constant between EES and blood plasma (Kep) were calculated. High-grade gliomas were also classified according to isocitrate dehydrogenase (IDH), alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-dna-methyltransferase promoter methylation (MGMT) status. Results There is correlation between parameters leakage, Ktrans and Vp. ROC curve analysis showed significance in both Ktrans and Ve for glioma grading. Threshold value of 0.075 for Ve generated the best combination of sensitivity (80%) and specificity (75%) in tumor gradation. Leakage was the only permeability parameter related to OS (P = 0.006) and PFS (0.012); with prolonged survival for leakage values lower than 1.2. IDH-mutated high-grade tumors showed lower leakage and Ktrans values. High-grade tumors with loss of ATRX presented lower leakage and Vp values. Conclusions Both DSC and DCE permeability parameters serve as non-invasive method for glioma grading. Leakage was the unique permeability parameter related to survival and the best discriminating high-grade gliomas classified according to IDH and ATRX status.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients’ skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP’s role in normal and diseased skeletal muscle homeostasis.

Craniopharyngiomas (CPs) are histologically benign tumors that are associated with high levels of morbidity. Two clinicopathological variants - adamantinomatous (ACP) and papillary (PCP) - have been described. They differ in their molecular features, whereby activating mutations in BRAF (V600E) and CTNNB1 genes characterize PCP and ACP, respectively. Recently, both variants have been shown to express elevated PD-L1 protein expression, but ACP also exhibited tumor cell-intrinsic PD-1 expression. In this study we analyze these molecular alterations in 52 cases with a long follow-up and examine their associations with immunohistochemical and clinical characteristics. ACPs comprise 73.1% of cases, while 21.2% are PCPs. Aberrant nuclear immunoreactivity for β-catenin was observed in all ACPs. BRAF p.V600E mutations were observed in 90.9% of PCPs. Only one ACP case featured both alterations. Both types of CP exhibited strong nuclear staining for p63 with diffuse and basal distribution. ACP and PCP consistently expressed PD-L1, most in a substantial percentage of tumor cells, with a distinctive spatial distribution of expression in each subtype; only ACP demonstrated PD-1 expression. There was no evidence of differences in clinical prognosis between ACPs and PCPs. The identification of hallmark molecular signatures in the two CP variants is useful for sub-categorization in routine histopathology reporting. It is also pertinent to personalized therapy and for the development of improved non-invasive therapeutic strategies in this disease.

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. Mutations in novel genes have been described in recent years. Among these, MUSK gene mutations are extremely rare, with only 8 families identified worldwide to date. We report a Spanish case, a carrier of one known hetero-allelic missense mutation and one newly identified MUSK gene variant. Our patient presented with congenital onset ophthalmoplegia and palpebral ptosis associated with limb-girdle weakness and exercise intolerance without prominent fatigability, developed during his twenties. He was misdiagnosed as mitochondrial myopathy because of paraclinic and histologic findings, but detailed clinical examination prompted us to reassess him with repetitive stimulation technique, demonstrating decremental response and suggesting myasthenic syndrome. A genetic study confirmed the clinical diagnosis allowing us to started treatment with excellent clinical response.

Carey-Fineman-Ziter syndrome is a congenital myopathy associated with mutations in the MYMK gene. It is clinically defined by the combination of hypotonia, Moebius-Robin sequence, facial anomalies and motor delay. Historically it was considered a brainstem dysgenesis syndrome. We provide detailed information of a Spanish boy with compound heterozygous variants in MYMK gene. A muscle biopsy performed as a toddler only disclosed minimal changes, but muscle MRI showed severe fatty infiltration of gluteus muscles and to a lesser extent in adductors magnus, sartorius and soleus muscles. Clinical course is fairly static, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

The radiological diagnosis of glioma progression is still challenging. A 33-year-old woman diagnosed with a frontal tumor underwent awake craniotomy with total tumor resection. The diagnosis was IDH-mutated diffuse astrocytoma, WHO grade II. The patient did not receive additional radiotherapy or chemotherapy. Periodic MRI scans showed a T2/FLAIR nodular enlargement which appeared de novo and grew slowly and gradually until 4 years post surgery. The patient underwent a second craniotomy to completely resect the T2/FLAIR hyperintensity. In the histological and molecular study of the second resection, no tumor cells were identified. We could hypothesize that the reactive changes favored by surgery could explain the ongoing radiologic findings. .

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.

BACKGROUND AND PURPOSE: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously. MATERIALS AND METHODS: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006–2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis. RESULTS: Age (P < .001, hazard ratio = 2.11, c-index = 0.705), surgery (P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width (P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity (P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width (P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity (P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes (P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival (P < .001, hazard ratio = 18.67, c-index = 0.967). CONCLUSIONS: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups.

A 29-year-old man, born from consanguineous parents, started with toe walking and frequent falls during his second year of life. He developed weakness in lower limbs during the first decade that subsequently extended to upper limbs. On examination, the patient had weakness in proximal muscles of all four limbs and in the tibialis anterior muscle. In addition, he had bilateral Achilles and patellar contractures, bilateral scapular winging, asymmetric calves and a positive Beevor sign, an upward movement of the umbilicus on contraction of rectus femoris due to weakness in the lower part. The muscle biopsy showed dystrophic changes and lobulated fibers. Genetic analysis through a next-generation sequencing panel of genes related to neuromuscular disorders revealed a novel homozygous nonsense mutation (p.Tyr85*) in the TCAP gene. Subsequent western blot assay showed a complete telethonin deficiency. Our observation expands the phenotypic spectrum of TCAP mutations and indicates that telethonin deficiency should be considered in the differential diagnosis of patients presenting with asymmetric calves and early joint retractions.

BACKGROUND Despite some evidence for the adoption of endoscopic transnasal trans-sphenoidal surgery (ETSS) for pituitary adenomas, the advantages of this technique over the traditional approach have not been robustly confirmed. OBJECTIVE To compare ETSS with the microscopic sublabial trans-septal trans-sphenoidal surgery (MTSS) for pituitary adenomas. METHODS We retrospectively reviewed 2 cohorts of ETSS and MTSS performed at our institution from 1995 to 2017. Patient characteristics, surgical data, and outcomes were recorded prospectively. We performed a univariate and multivariable analysis to determine the best surgical approach. To improve the quality of the results, we matched the distribution of patient characteristics between groups by propensity score (PS) method. RESULTS A total of 187 procedures (90 MTSS, 97 ETSS) were reviewed. We found better results in the ETSS group in terms of gross total resection (P = .002) and hormone-excess secretion control (P = .014). There was also a lower incidence of cerebrospinal fluid leakage (P = .039), transitory diabetes insipidus (P = .028), and postoperative hypopituitarism (P = .045), as well as a shorter hospital length of stay (P

Introduction: Sarcoglycanopathies (LGMD 2C 2F) are a subgroup of limb-girdle muscular dystrophies (LGMD), caused by mutations in sarcoglycan genes. They usually have a childhood onset and rapidly progressive course with loss of ability to walk over 12–16 years. Methods : Next generation sequencing (NGS) targeted gene panel was performed in three adult patients with progressive muscle weakness in which routine muscle histology and immunohistochemistry were not diagnostic. Results: Genetic analysis revealed homozygous or compound heterozygous mutations in SGCA gene and Western Blot demonstrated protein reduction confirming the diagnosis of α-sarcoglicanopathy. Discussion: Our cases evidence that the diagnosis of mild forms of alfa sarcoglicanopathy could be a challenge and suggest the possibility that they could be underdiagnosed. The use of Next generation Sequencing targeted gene panels is very helpful in the diagnosis of these patients.

Background Mutations in the LAMA2 gene cause autosomal recessive laminin α2 related congenital muscular dystrophy. In patients with partial laminin α2 deficiency the phenotype is usually milder than in those with absent protein. Apart from the typical white matter abnormalities, there is an increased risk of cerebral complications such as epilepsy and mental retardation, despite a structurally normal brain. Methods/results We present a patient with primary partial laminin α2 deficiency due to a homozygous novel LAMA2 missense mutation who developed West syndrome in his first year of life. To our knowledge, this combination has not previously been reported. A 5 year-old boy exhibited global hypotonia with generalized muscle weakness from birth. At 8 months of age he presented infantile spasms and an EEG finding of hypsarrhythmia. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, followed by valproic acid. Two years later antiepileptic medication was withdrawn. He achieved unsupported walking at the age of 4, but his cognitive status corresponded to a 2 year-old child. Epilepsy has not recurred and brain MRI showed the typical white matter abnormalities without associated neuronal migration defects. Conclusion This report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. The beginning of a severe epileptic encephalopathy modifies the natural history of the disease.

McArdle disease is a metabolic myopathy that presents with exercise intolerance and episodic rhabdomyolysis. Excessive muscle recruitment has also been shown to be present during strenuous exercise, suggesting decreased power output. These findings could potentially be explained by either impaired contractility, decreased fiber size, or altered fiber type proportion. However, there is a paucity of data on the morphological features seen on muscle histology. Methods We examined muscle biopsies of patients with McArdle disease from a Spanish cohort and compared the findings with healthy controls. Results We found no significant difference in the fiber type proportion or mean fiber size between McArdle patients and controls in the biceps brachii or vastus lateralis muscles. Conclusions No alterations in muscle fiber type proportion or size were found on muscle histology of patients with McArdle disease. Future research should focus on assessment of muscle fiber contractility to investigate the functional impairment. Muscle Nerve 55: 916–918, 2017 Sin financiación 2.496 JCR (2017) Q3, 106/197 Clinical Neurology, 168/261 Neurosciences 1.072 SJR (2017) Q2, 112/378 Neurology (clinical), 75/191 Physiology, 43/107 Physiology (medical); Q3, 57/92 Cellular and Molecular Neuroscience No data IDR 2017 UEM

Enteroviruses are a common cause of aseptic meningitis and mild infections in childhood. However, in immunocompromised patients they may cause severe neurologic conditions such as encephalitis or polio-like paralysis. Acknowledgment: The authors thank the patient and his family.

Background We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Background Glioblastoma (GBM) is one of the most lethal tumor types. Hypercellular regions, named pseudopalisades, are characteristic in these tumors and have been hypothesized to be waves of migrating glioblastoma cells. These "waves" of cells are thought to be induced by oxygen and nutrient depletion caused by tumor-induced blood vessel occlusion. Although the universal presence of these structures in GBM tumors suggests that they may play an instrumental role in GBM's spread and invasion, the recreation of these structures in vitro has remained challenging. Methods Here we present a new microfluidic model of GBM that mimics the dynamics of pseudopalisade formation. To do this, we embedded U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we can mimic and control blood-vessel obstruction events associated with this disease. Results Through the use of this new system, we show that nutrient and oxygen starvation triggers a strong migratory process leading to pseudopalisade generation in vitro. These results validate the hypothesis of pseudopalisade formation and show an excellent agreement with a systems-biology model based on a hypoxia-driven phenomenon. Conclusions This paper shows the potential of microfluidic devices as advanced artificial systems capable of modeling in vivo nutrient and oxygen gradients during tumor evolution.

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.

BACKGROUND: The 2016 updated World Health Organization (WHO) classification system recognizes the morphological variant giant cell glioblastoma (GBM) as one rare variant of IDH-wildtype (IDH-wt) GBM. This variant account for 30%), had frequently (around 75% of the cases) molecular alterations in TP53 accompanied of alterations in the chromatin remodeling genes ATRX or DAXX genes. CONCLUSION: Our results suggest that giant cell GBMs may have specific molecular characteristics, such as the presence of concurrent TP53 and ATRX/DAXX alterations in the absence of IDH or H3F3A driver mutations. These findings may be relevant for the development of targeted therapies and a personalized medicine.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by focal neurological dysfunction with a relapsing and remitting course. Tumor-like presentation of MS (or “tumefactive”/“pseudotumoral” presentation) has been described before with a certain frequency; it consists of a large single plaque (>2 cm) with presence of edema and mass effect and it is hard to distinguish from a brain tumor. However, we present a very rare case of a 53-year-old woman with a right temporal mass that turned out to be a MS plaque, who deteriorated within hours (brain herniation with loss of consciousness and unilateral mydriasis) and required an emergency craniotomy. We also present a review of the literature. It appears that only 4 cases of emergency craniotomy/craniectomy required in a patient with a tumor-like MS plaque have been reported before.

Diagnosis of radiologic pseudoprogression remains a challenge because its radiologic pattern is often indistinguishable from tumor recurrence.1 Pseudoprogression has been attributed to radiation therapy; the role of chemotherapy in pseudoprogression is uncertain. Acknowledgment: The authors thank Dr. Joaquin Arenas, director of Instituto de Investigacion Hospital 12 de Octubre (i+12), for correcting this manuscript.

Introduction: Hypercellular regions surrounding necrotic areas in glioblastoma (GBM), named pseudopalisades, are characteristic of these tumors and have been hypothesized to be waves of migrating GBM cells. These structures are thought to be induced by oxygen depletion caused by the accumulation of cells far from nutrient supplies (chronic hypoxia) and/or tumor-induced blood vessel occlusion (acute hypoxia). The universal appearance of these structures in GBM suggests that they may play an instrumental role in their spreading and invasion. However the validation of the mechanisms of pseudopalisade formation has remained challenging. Materials and methods: A mathematical model was developed incorporating the main mechanisms of pseudopalisade formation. Oxygen coming from straight vessels drives phenotype changes. A third phenotype was included accounting for hypoxic cells switching back to a more proliferative phenotype in regions of normoxia. Experiments were done by embedding different densities of U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we mimic and control blood-vessel obstruction events associated with this disease. Results: Nutrient and oxygen starvation triggered a strong migratory process leading to pseudopalisade generation in silico and in vitro. Also, cells at greatest distance from oxygen supply became hypoxic after a critical point in tumor growth was reached (due to increased metabolism) forming pseudopalisades both in silico and in vitro. All the elements included in the mathematical model were necessary to describe both types of phenomena pointing out to the insufficiency of the go-or-grow hypothesis to describe pseudopalisade formation on-chip. Conclusions: Using a combination of computational and experimental techniques, we proved the feasibility of the two hypotheses of pseudopalisade formation, driven by either acute or chronic hypoxia. Additionally, we verified the potential of microfluidic devices as advanced artificial systems capable of experimentally modeling nutrient and oxygen gradients during tumor evolution.

Muscle-eye-brain disease is a congenital muscular dystrophy characterized by structural brain and eye defects. Here, we describe a 12-year-old boy with partial agenesis of corpus callosum, ventriculomegaly, flattened brain stem, diffuse pachygyria, blindness, profound cognitive deficiencies, and generalized muscle weakness, yet without a clear dystrophic pattern on muscle biopsy. There was no glycosylation of α-dystroglycan and the genetic screening revealed a novel truncating mutation, c.1545delC (p.Tyr516Thrfs*21), and a previously identified missense mutation, c.1469G>A (p.Cys490Tyr), in the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene. These findings broaden the clinical spectrum of muscle-eye-brain disease to include pronounced hypotonia with severe brain and eye malformations, yet with mild histopathologic changes in the muscle specimen, despite the absence of glycosylated α-dystroglycan.

Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP− tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP−), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP− subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP−) prognosis. Furthermore, transcriptomic analyses revealed CIMP-specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs.

BACKGROUND The clinical course of oligodendroglial tumors is variable and there is a lack of consensus with regard to precisely diagnose which minimal criteria are required to make a diagnosis of a high-grade oligodendrial tumor. The aims of the present study are to assess pathologic factors with prognostic significance, in addiction to clinical and neuroradiologic variables, in an attempt to identify reproducible histological parameters that are useful for classification of oligodendroglial tumors. METHODS 80 oligodendroglial tumors diagnosed between 1977 and 2004 were analyzed. To make a diagnosis of anaplastic tumor we used reproducible parameters: endothelial proliferation, high cellularity, increased mitotic activity and necrosis. Oligoastrocytomas (mixed gliomas) were diagnosed when the astrocytic component was clearly identified as part of the neoplastic cell population. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log-rank probability test. A Cox regression model was made for multivariable analysis. RESULTS The histologic diagnosis was low-grade oligodendroglioma in 35 patients (43.75%), anaplastic oligodendroglioma in 23 patients (28.75%), low-grade oligoastrocytoma in 11 patients (13.75%) and anaplastic oligoastrocytoma in 11 patients (13.75%). Median overall survival of the whole series was 80 months. The median overall survival of oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma and anaplastic oligoastrocytoma was 148, 105, 47 and 7 months, respectively (p < 0.0001). Multivariate analysis revealed that age, Karnofsky performance status, histological grade and histological diagnosis (oligodendroglioma vs. oligoastrocytoma) were independently associated with survival. CONCLUSIONS Clear cut histopathological criteria (endothelial proliferation, high cellularity, mitotic activity and necrosis) allow to establish different oligodendroglial tumor entities with distinct survival outcome.