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Malignant gliomas are highly infiltrative and invasive tumors, which precludes the few treatment options available. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying gliomas aggressive phenotype and poor prognosis. The Raf Kinase Inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. Its role in the prognosis and tumourigenesis of gliomas remains unclear. In the present study, we found that RKIP protein is absent in a low frequency (10%, 20/193) of glioma tumors. Nevertheless, the absence of RKIP expression was an independent prognostic marker in glioma. Additionally, by in vitro downregulation of RKIP, we found that RKIP inhibition induces a higher viability and migration of the cells, having no effect on cellular proliferation and angiogenesis, as assessed by in vivo CAM assay. In conclusion, this is the largest series studied so far evaluating the expression levels of this important cancer suppressor protein in glioma tumors. Our results suggest that in a subset of tumors, the absence of RKIP associates with highly malignant behavior and poor survival of patients, which may be a useful biomarker for tailored treatment of glioma patients., This study was partially funded by the Fundacao para a Ciencia e Tecnologia, Portugal (PTDC/SAU-TOX/114549/2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.

The authors present the case of a 41-year-old woman with nasal and laryngeal involvement by sarcoidosis, review the literature and discuss the otolaryngologic manifestations, the diagnostic evaluation, treatment and prognostic of this entity.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology. The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker, but some controversial data have precluded its clinical use. We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol). The Kaplan-Meier method was used to construct survival curves, and the log-rank test and a Cox-regression model were used to analyze patient survival. The methylation status of MGMT was successfully determined in 89% (80/90) of the tumors. The frequency of tumoral MGMT promoter methylation was 47.5%. The median overall survivals (OSs) were 16 months (95% CI 12.2-19.8) and 13 months (95% CI 13.3-18.7) for patients whose tumors had a methylated or unmethylated MGMT, respectively. Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS (P=0.583 by the log-rank test; P=0.617 by the Cox-regression test) or progression-free survival (P=0.775 by the log-rank test; P=0.691 by the Cox-regression test). None of the patient clinical features were significantly correlated with survival. This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients. Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide. Additional robust prospective studies are warranted to clarify whether the MGMT status should be used in clinical decisions., This project was sponsored, in part, by Schering-Ploug Farma (Portugal). B.M.C. and O.M. are recipients of fellowships from the Portuguese Science and Technology Foundation (SFRH/BPD/33612/2009 and SFRH/BD/36463/ 2007). The funding institutions had no role in the study design, data collection and analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.

Evidence from brain imaging studies indicates that white matter volume, density and fractional anisotropy may be altered in individuals with schizophrenia and bipolar disorder. However, the molecular correlates of these deficits remain unknown. In this study we performed a cytoarchitectural assessment of the white matter adjacent to the planum temporale (PT), an auditory association region located within the superior temporal gyrus, in subjects with schizophrenia, bipolar disorder, major depressive disorder and controls (15 subjects per group). Using two-dimensional measures, we recorded the cell density, distribution and size of all neurons and glial nuclei within this region. Glial density was lower in the schizophrenia group, relative to the control group. Neuronal density, neuronal size, and glial nuclear size did not differ between groups. No significant differences in neuronal clustering were observed in the patient groups. Further studies are required to examine whether the observed decrease in glial density within the superior temporal white matter in schizophrenia reflects a deficit in any individual glial cell population.

Study Design. Case report. Objective. To describe a case of monostotic fibrous dysplasia of the first cervical vertebra. Summary of Background Data. Fibrous dysplasia is a disorder of bone development of unknown etiology in which cancellous bone is replaced with fibrous tissue, resulting in expansion of the bone. The disease presents in either a monostotic or polyostotic form. Although fibrous dysplasia can involve any bone in the body, vertebral involvement is quite unusual. Methods. A case of monostotic fibrous dysplasia of the first cervical vertebra is presented. Results. A 53 year-old woman presented with a 1-month history of occipito-cervicalgia associated with great restriction of neck movements. Computed tomography and magnetic resonance imaging revealed an expansile, destructive lesion involving the right lateral mass of the first cervical vertebra, without involvement of the spinal cord. She was submitted to surgery and the lesion was removed. Microscopic examination was consistent with the diagnosis of fibrous dysplasia. Four years after surgery there was no clinical or imagiological recurrence. Conclusion. Although there are descriptions of vertebral fibrous dysplasia, this is the 12th case of monostotic fibrous dysplasia of the cervical spine described in the literature. Computed tomography and magnetic resonance imaging were essential for making the preoperative diagnosis.

Intraspinal solitary fibrous tumors are rare: to our knowledge, the literature reports only 27 cases. We present a histologically and immunohistochemically confirmed solitary fibrous tumor involving the intradural extramedullary compartment of the thoracic spine. Microsurgical gross-total resection was achieved. A definitive role for adjuvant treatments in this type of tumor has not been established and therefore, they were not used. The patient was well, without clinical or radiological recurrence, 18 months after surgery.

Resume Il s’agit d’un cas de tumeur fibreuse solitaire de l’orbite avec malignite histologique, revelee par une exophtalmie sans baisse de l’acuite visuelle, chez une femme de 28 ans. La resection totale de la tumeur a ete realisee par craniotomie fronto-orbitaire. L’efficacite des traitements complementaires dans ce type de tumeur est controversee et la deterioration visuelle est un effet lateral possible. Ils n’ont pas ete proposes. La patiente ne presente pas de recidive tumorale apres deux ans de suivi.

Objective: To determine whether it is worth pursuing surgery for the treatment of epilepsy in patients with normal neuroimaging. Methods: Two patient populations were studied: (1) 136 consecutive patients who were surgically treated; (2) 105 consecutive patients assessed with chronically implanted intracranial electrodes within the same period. Sixty patients belonged to both groups, and included all 21 patients who had normal neuroimaging. Results: There were no differences in the proportion of patients with favourable outcome between those with normal and those with abnormal neuroimaging, irrespective of whether intracranial recordings were required. Among the 19 operated patients with normal neuroimaging, 74% had a favourable outcome (Engel’s seizure outcome grades I and II), and among the 93 patients with abnormal neuroimaging, 73% had favourable outcome (p = 0.96). In patients with temporal resections, 92% of the 13 patients with normal neuroimaging had a favourable outcome, whereas among the 70 patients with abnormal neuroimaging, 80% had a favourable outcome (p = 0.44). In patients with extratemporal resections, two of the six patients with normal neuroimaging had a favourable outcome, while 12 of the 23 patients with abnormal neuroimaging had a favourable outcome (p = 0.65). Among the 105 patients studied with intracranial electrodes, five suffered transitory deficits as a result of implantation, and two suffered permanent deficits (one hemiplegia caused by haematoma and one mild dysphasia resulting from haemorrhage). Conclusions: It is worth pursuing surgery in patients with normal neuroimaging because it results in good seizure control and the incidence of permanent deficits associated with intracranial studies is low.

Summary Seventy-two patients submitted to meningioma surgery at Pedro Hispano Hospital from 1997 to 2001 were reviewed to analyze the association between size (largest diameter of the lesion obtained from imaging examinations) and other variables regarding the biological behavior and clinical outcome of these patients. Statistically significant associations were found between tumor size and location, type of first symptom, type of physical examination, histological grade, surgical complications, postoperative CSF bursae and the need for blood transfusion. Patient's age, gender, duration of first symptom, clinical status at discharge and persistent complaints were not associated to tumor size. There was a trend towards a statistically significant association between tumor size and both grade of resection and persistent deficits. The causes and implications of the findings are discussed. Tumor size is a parameter that may interfere with the neurosurgeon's capacity to treat these patients as well as with their recovery.

Objective: To assess the value of single-pulse electrical stimulation (SPES) to identify frontal epileptogenic cortex during presurgical assessment. Methods: SPES (1-millisecond pulses, 4 to 8 mA, 0.1 Hz) has been used during chronic recordings in 30 patients with intracranial electrodes in the frontal lobes. As a result of presurgical assessment, 17 patients were considered to have frontal epilepsy and 13 extrafrontal epilepsy. Results: Two types of responses to SPES were seen: 1) early responses: starting immediately after the stimulus and considered as normal responses; 2) late responses: two types of responses seen in some areas after the initial early response: a) delayed responses: spikes or sharp waves occurring between 100 milliseconds and 1 second after stimulation. Frontal delayed responses were seen in 11 frontal patients and 1 extrafrontal patient, whereas extrafrontal delayed responses were seen in 1 frontal and 10 extrafrontal patients. b) Repetitive responses: two or more consecutive sharp-and-slow-wave complexes, each resembling the initial early response. Repetitive responses were seen only when stimulating the frontal lobes of 10 frontal patients. Among the 17 frontal patients, 13 had late responses exclusively in the epileptogenic frontal lobe, whereas only 3 showed them in both frontal lobes. Frontal late responses were associated with neuropathologic abnormalities, and complete resection of abnormal SPES areas was associated with good postsurgical seizure outcome. Conclusions: Single-pulse electrical stimulation (SPES) could be an important additional investigation during presurgical assessment to identify frontal epileptogenicity. SPES can be useful in patients who have widespread or multiple epileptogenic areas, normal neuroimaging, or few seizures during telemetry.

Six cases of cavernous abducens nerve schwannoma have been reported. A new case of a 39 year old female with abducens nerve paresis, exophtalmos, chemosis and headache due to a 1,36 x 2,58 cm cystic right cavernous abducens nerve schwannoma is presented and discussed. The cavernous sinus was opened between the trochlear and ophthalmic nerves. A portion of the tumor capsule adherent to the internal carotid artery was not resected. No deficits were added by surgery. After 30 months of follow up there is no evidence of relapse and only abducens nerve paresis persists.

Description of the demographic, clinical and neuropathological features of 11 cases of Creutzfeldt-Jakob disease (CJD).Review of the clinical and neuropathological features of patients with CJD diagnosed in hospitals in the North of Portugal between 1993 and 2002.Eleven patients were identified, 4 females: mean age of onset of symptoms--64 years, mean duration of disease--8 months. All presented with a syndrome of progressive dementia with myoclonus, with four patients presenting with cerebellar signs. Neuropathological examination of brain at autopsy showed spongiosis and reactive gliosis associated with neuronal loss. In eight cases immunocytochemistry for prion protein (PrP) was carried out and was positive.The group of patients described represents the heterogeneity of the clinical phenotypes possible in CJD. Neuropathological examination is still indispensable to make the definitive diagnosis of the disease.

A case of conventional intramedullary osteosarcoma (epithelioid subtype) with 10 years of evolution and another of high grade surface osteosarcoma of the chondroblastic type, both in the skull, gave rise to several diagnostic and therapeutic difficulties. Key points concerning the definition, classification, imaging, clinical series data and treatment options available for skull osteosarcoma are highlighted.

Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented.Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, video-EEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients.Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients.Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered.

OBJECTIVES To evaluate the influence of clinical, investigative, and pathological factors on seizure remission after temporal lobectomy for medically intractable epilepsy associated with focal lesions other than hippocampal sclerosis. METHODS From a series of 234 consecutive “en bloc” temporal resections for medically intractable epilepsy performed between 1976 and 1995, neuropathological examination disclosed a focal lesion in 80. The preoperative clinical, neuropsychological, interictal EEG, and neuroimaging characteristics of these patients were assembled in a computerised database. The original neuropathological material was re-examined for lesion classification and completeness of removal. The presence of additional cortical dysplasia and mesial temporal sclerosis was also noted. Survival analysis was performed using Kaplein-Meier curves and actuarial statistics. Logistic regression analysis was used to establish the independent significance of the clinical variables. RESULTS The probability of achieving a 1 year seizure remission was 71% by 5 years of follow up. Factors predicting a poor outcome on multivariate analysis included the need for special schooling and a long duration of epilepsy. Generalised tonic-clonic seizures, interictal EEG discharges confined to the resected lobe, demonstration of the lesion preoperatively on CT, and complete histological resection of the lesion were not predictive of outcome. Neuropsychological tests correctly predicted outcome in left sided cases but apparently congruent findings in right sided resections were associated with a poor outcome. Pathological reclassification established the dysembryoplastic neuroepithelial tumour as the commonest neoplasm (87%) in this series, with a significantly better seizure outcome than for developmental lesions, such as focal cortical dysplasia. CONCLUSIONS The findings highlight the importance of dysembryoplastic neuroepithelial tumour in the pathogenesis of medically refractory lesional temporal lobe epilepsy and the prognostic significance of preoperative duration of epilepsy emphasises the need for early recognition and surgical treatment. Cognitive and behavioural dysfunction, however, is associated with a lower seizure remission rate, independent of duration of epilepsy.

Determination of neuroglial cell fate and neural tube development during embryogenesis is influenced by the Notch/Wnt signalling pathway. We have studied the localisation of several proteins in the Wnt pathway in focal cortical dysplasia (FCD). This disorder, thought to be due to abnormalities of neuronal migration and differentiation, contains regions of morphologically normal neocortex interrupted by areas of neuronal laminar disorganisation, heterotopic white matter neurons, abnormal large neurons and balloon cells of uncertain histogenesis. We found that the subcellular distribution of several proteins involved in the Wnt pathway differed in regions of FCD from normal cortex, and that within the areas of FCD, the pattern varied with cellular phenotype. Thus, in balloon cells, elevated cytoplasmic levels of dishevelled (Dvl-1) protein were accompanied by an absence of Notch-1, increased adenomatous poliposis coli (APC), altered cytoplasmic beta-catenin, and reduced nuclear expression of beta-catenin. A contrasting pattern of expression was found in abnormal large neurons, which demonstrated elevated levels of Notch-1, and glycogen synthase kinase-3beta (GSK-3beta), and normal levels of APC. Our results are consistent with the notion that Wnt/Notch signalling influences neuroglial cell fate, and suggest that a perturbation of Wnt/Notch signalling may contribute to the neuropathology of FCD.

OBJECTIVE: Rosette-forming glioneuronal tumor is a newly described mixed glial and neuronal tumer. We describe two cases and review the literature to better characterize this entity. METHODS: Patients were surgically treated, and tumors were diagnosed by light microscopy and immunohistochemistry using the avidin-biotin complex method. PubMed was searched for previously reported cases. RESULTS: Patient 1 was a 38-year-old woman who presented with headaches and no neurological abnormality. Magnetic resonance imaging showed a solid mass in the fourth ventricle. Subtotal excision of the mass caused transient gait ataxia. Patient 2 was a 51-year-old woman with dizzines who fell and sustained head trauma. Magnetic resonance imaging revealed a right paramedian cerebellar cystic and nodular mass and a separate nodule in the vermis, which were excised gross totally with non morbidity. Microscopic examination showed neuroepithelial tumors composed of neurocytic cells focally forming well-defined rosettes that were immunopositive for neuronal markers and of elongated, glial fibrillary acidic protein-immunoreactive astrocytes. No histological anaplasia was present. Both patients were well 18 and 8 months after surgery, respectively. Eighteen rosette-forming glioneuronal tumors were identified with the literature search. CONCLUSION: These are tumors of young adulthood (range, 12-59 yr) usually in or close to the fourth ventricle. Histologically, they are low-grade, although multiple foci or local extension may prevent total excision and account for some recurrences. On imaging, they are cystic, solid, or both, with minimal perilesional edema or mass effect. They are composed of neurocytic and glial elements, probably arising from a common progenitor in the suberpendymal plate, and need to be differentiated from a variety of glioneuronal tumors.

HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA and protein of the GluR-A flop subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor in cerebellar Purkinje cells. Although Purkinje cells are relatively resistant to loss, the observed disturbance of AMPA receptors may contribute to the neurotoxic process in other vulnerable brain regions and clinically to the development of dementia.

Activity of the enzyme which synthesizes acetylcholine, choline acetyltransferase, was estimated in the neocortex of three series of control and demented cases. Clinically demented cases were divided into those with the classical neuropathological features of Alzheimer's disease (numerous neocortical plaques and tangles) and those with Lewy bodies in the brain stem and cortex (together with plaques and variable neurofibrillary pathology). In the Lewy body cases neocortical choline acetyltransferase was consistently lower than in the classical Alzheimer-type cases. Two of the Lewy body cases with extremely low cholinergic activity were responders in therapeutic trials of the cholinesterase inhibitor, tacrine, and the combined data suggest that cholinergic therapy may be particularly relevant to patients with Lewy body type dementia.

The postmortem findings are reported from 9 cases of the Guillain-Barre syndrome with survival between 10 days and 1 yr. In 8 cases there was multifocal loss of myelin throughout the peripheral nervous system with relative preservation of axons. In 1 case there was predominant loss of axons. Inflammatory mononuclear cell infiltration was present in the peripheral nervous system of all cases except 1 case surviving a year. The extent and severity of cell infiltration was variable, usually being less prominent than in previous reports, and sometimes sparing nerves in which myelin destruction was severe. Vesicular dissolution of myelin noted by electron microscopy was considered to be a postmortem artefact. In cases examined within 30 days after the onset, immunohistochemical studies with monoclonal antibodies identified more leucocytes (PD7/2B11+) and T cells (UCHL1+) in the endoneurium than in cases examined later or control cases. These findings and recent single case reports indicate that the pathology of the Guillian-Barre syndrome is variable. This variability may reflect differences in pathogenesis, with greater cell-mediated immunity in some cases and greater antibody targeted macrophage-mediated demyelination in others.

11528 Background: The authors analyse retrospectively the impact on tumour control and toxicity of concomitant radiotherapy (RT) and Temozolomide (TMZ) in high grade gliomas (HGG) of the CNS, in patients treated in the Clínica de Radioterapia do Porto - Portugal. Methods: This cohort represents all patients with HGG treated between January 2002 and January 2006, with concomitant RT a median total dose of 60 Gy, 2 Gy per treatment given once daily 5-days/week and TMZ 75mg/m2 for 42 days, followed by adjuvant treatment with TMZ 5-days schedule every 28 days (150 mg/m2 for the first cycle increased to 200mg/m2). The cohort was retrospectively analyzed for gender distribution, age, extent of surgical resection, initial KPS, median overall survival (OS) and haematological toxicity. Results: 23 with HGG (6 females, 17 males) were treated with concomitant RT (44–72 Gy) and TMZ followed by adjuvant TMZ; median age was 58 (ranging from 17–72); median KPS was 80 (ranging from 40–90); 3 patients had complete resection, 17 partial resection and 3 biopsy. All patients except one, who had treatment interruption for thrombocytopenia, completed the concomitant phase of treatment; 19 patients continued to received adjuvant treatment with TMZ (median number of cycles was 5 (ranging from 1–20). Median OS (measured from the date of diagnosis to the date of death) was 20.4 month and 1 yr OS was 54%. During concomitant phase, one patient had grade 3–4 thrombocytopenia. During the adjuvant TMZ therapy 4 patients had grade 3–4 haematological toxicity (anaemia: 1; thrombocytopenia: 1; leucopoenia and thrombocytopenia: 2). Conclusions: The results of concomitant RT+TMZ followed by TMZ in these patients with HGG showed values in accordance with the latest data published on literature for this association. Differences observed might be due to the small sample size.RT+TMZ followed by adjuvant TMZ is a well tolerated treatment with better results in median OS comparatively with previous results of RT only treatment in HGG. Treatment related toxicity was within acceptable levels, and this approach became routine practice in this set of patients. No significant financial relationships to disclose.

The reactivation or reexpression of telomerase (TERT) is a widespread feature of neoplasms. TERT promoter mutations were recently reported that were hypothesized to result from UV radiation. In this retrospective study, we assessed TERT promoter mutations in 196 cutaneous basal cell carcinomas (BCCs), including 102 tumors from X-irradiated patients, 94 tumors from patients never exposed to ionizing radiation treatment, and 116 melanomas. We sought to evaluate the effects of UV and X-ray irradiation on TERT mutation frequency. TERT mutations were detected in 27% of BCCs from X-irradiated patients, 51% of BCCs from nonirradiated patients, and 22% of melanoma patients. TERT mutations were significantly increased in non-X-irradiated BCC patients compared with X-irradiated BCC patients; the mutations also presented a different mutation signature. In nonirradiated patients, TERT mutations were more frequent in BCCs of sun-exposed skin, supporting a possible causative role of UV radiation. In melanoma, TERT promoter mutations were generally restricted to intermittent sun-exposed areas and were associated with nodular and superficial spreading subtypes, increased thickness, ulceration, increased mitotic rate, and BRAFV600E mutations. Our results suggest that various carcinogenic factors may cause distinct TERT promoter mutations in BCC and that TERT promoter mutations might be associated with a poorer prognosis in melanoma.

The ultrastructure of the cells and capillaries of the frontal cortex and hippocampus was studied in marmosets to assess age-related changes. The appearances in the brains of four marmosets, more than 12 years of age, were compared with those of two young marmosets aged 26 and 21 months. There was widespread accumulation of lipofuscin in neurons, glial cells, perivascular macrophages and pericytes, but not in endothelial cells. Many of the nerve cell nuclei showed marked membrane infolding, alteration of nuclear morphology and occasional inclusions. A few degenerated and dystrophic axons containing abnormal organelles were seen. The capillaries displayed irregularly thickened and split basal laminae. No neurofibrillary tangles, neuritic plaques, amyloid deposits or granulovacuoles were present. These changes are compared to those occurring in other animal species and in man during ageing.