Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro.

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

Cryptococcoma mimicking a brain tumor in an immunocompetent patient: case report of an extremely rare presentation

ABSTRACT CONTEXT: Central nervous system (CNS) infectious diseases have high prevalence in developing countries and their proper diagnosis and treatment are very important for public health planning. Cryptococcus neoformans is a fungus that may cause several CNS manifestations, especially in immunocompromised patients. Cryptococcal meningitis is the most common type of involvement. Mass-effect lesions are uncommon: they are described as cryptococcomas and their prevalence is even lower among immunocompetent patients. The aim here was to report an extremely rare case of cryptococcoma causing a mass effect and mimicking a brain tumor in an immunocompetent patient. The literature on CNS cryptococcal infections was reviewed with emphasis on cryptococcomas. Clinical, surgical and radiological data on a female patient with this rare presentation of cryptococcoma mimicking a brain tumor are described. Case Report: A 54-year-old female patient presented to the emergency department with a rapid-onset progressive history of confusion and completely dependency for basic activities. Neuroimaging showed a left occipital lesion and neurosurgical treatment was proposed. From histopathological evaluation, a diagnosis of cryptococcoma was established. She received clinical support with antifungals, but despite optimal clinical treatment, her condition evolved to death. CONCLUSIONS: Cryptococcal infections have several forms of presentation and, in immunocompetent patients, their manifestation may be even more different. Cryptococcoma is an extremely rare presentation in which proper surgical and clinical treatment should be instituted as quickly as possible, but even so, there is a high mortality rate.

The prostanoid pathway contains potential prognostic markers for glioblastoma.

Prostanoids derived from the activity of cyclooxygenases and their respective synthases contribute to both active inflammation and immune response in the tumor microenvironment. Their synthesis, deactivation and role in glioma biology have not yet been fully explored and require further study. Using quantitative real time PCR, gas chromatography/ electron impact mass spectrometry and liquid chromatography/ electrospray ionization tandem mass spectrometry, we have further characterized the prostanoid pathway in grade IV glioblastoma (GBM). We observed significant correlations between high mRNA expression levels and poor patient survival for microsomal PGE synthase 1 (mPGES1) and prostaglandin reductase 1 (PTGR1). Conversely, high mRNA expression levels for 15-hydroxyprostaglandin dehydrogenase (15-HPGD) were correlated with better patient survival. GBMs had a higher quantity of the prostanoid precursor, arachidonic acid, versus grade II/III tumors and in GBMs a significant positive correlation was found between arachidonic acid and PGE2 content. GBMs also had higher concentrations of TXB2, PGD2, PGE2 and PGF2α versus grade II/III tumors. A significant decrease in survival was detected for high versus low PGE2, PGE2 + PGE2 deactivation products (PGEMs) and PGF2α in GBM patients. Our data show the potential importance of prostanoid metabolism in the progression towards GBM and provide evidence that higher PGE2 and PGF2α concentrations in the tumor are correlated with poorer patient survival. Our findings highlight the potential importance of the enzymes 15-HPGD and PTGR1 as prognostic biomarkers which could be used to predict survival outcome of patients with GBM.

Cryptococcoma mimicking a brain tumor in an immunocompetent patient: case report of an extremely rare presentation.

CONTEXT: Central nervous system (CNS) infectious diseases have high prevalence in developing countries and their proper diagnosis and treatment are very important for public health planning. Cryptococcus neoformans is a fungus that may cause several CNS manifestations, especially in immunocompromised patients. Cryptococcal meningitis is the most common type of involvement. Mass-effect lesions are uncommon: they are described as cryptococcomas and their prevalence is even lower among immunocompetent patients. The aim here was to report an extremely rare case of cryptococcoma causing a mass effect and mimicking a brain tumor in an immunocompetent patient. The literature on CNS cryptococcal infections was reviewed with emphasis on cryptococcomas. Clinical, surgical and radiological data on a female patient with this rare presentation of cryptococcoma mimicking a brain tumor are described. CASE REPORT: A 54-year-old female patient presented to the emergency department with a rapid-onset progressive history of confusion and completely dependency for basic activities. Neuroimaging showed a left occipital lesion and neurosurgical treatment was proposed. From histopathological evaluation, a diagnosis of cryptococcoma was established. She received clinical support with antifungals, but despite optimal clinical treatment, her condition evolved to death. CONCLUSIONS: Cryptococcal infections have several forms of presentation and, in immunocompetent patients, their manifestation may be even more different. Cryptococcoma is an extremely rare presentation in which proper surgical and clinical treatment should be instituted as quickly as possible, but even so, there is a high mortality rate.

Opposing roles of PGD2 in GBM.

BACKGROUND: The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D2 (PGD2) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD2 on GBM cell activities in vitro. METHODS: First we looked to identify the presence of the PGD2 synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD2's effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (<1µM) and/or supraphysiological (>1µM) concentrations of PGD2 over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM. RESULTS: We identified the presence of endogenous PGD2 with its corresponding enzymes and receptors. Exogenous PGD2 both increased cell count (<1µM) and decreased cell count (10µM) in a concentration-dependent manner. There were no significant effects on apoptosis. A significant decrease in mitotic activity was seen only in U251MG, and a significant increase was seen in migration with 5µM PGD2 treatments. A very significant increase of PGD2 was seen from Grade II/III gliomas to GBM. CONCLUSIONS: Our study demonstrates that prostaglandin D2 possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD2 production in GBM patients suggests a pro-tumorigenic role of PGD2 in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies.

Glioblastoma multiforme em idosos: uma revisão sobre seu tratamento com ênfase na abordagem cirúrgica / Glioblastoma multiforme in the elderly: a review on their treatment with emphasis in the surgical approach

O glioblastoma multiforme (GBM) é o tumor primário mais comum do sistema nervoso central (SNC). Em virtude do envelhecimento populacional, entre outros fatores, sua ocorrência em faixas etárias avançadas tem se mostrado crescente nas últimas décadas. Os objetivos da ressecção do GBM incluem: alívio do efeito de massa, citorredução tumoral, diagnóstico histopatológico, controle dos sintomas e melhoria nas taxas de sobrevivência. Por muito tempo acreditou-se que a idade seria fundamental na decisão pelo tratamento, embora alguns autores afirmem que a extensão da ressecção cirúrgica constitui o principal fator determinante do prognóstico, sobretudo para pacientes que foram eleitos para radioterapia e quimioterapia. A ressecção de mais de 98% do volume tumoral é capaz de interferir na sobrevivência, e ressecções menores proporcionaram sobrevivência semelhante à dos pacientes não abordados. O presente trabalho tem por objetivo realizar uma revisão da literatura atual a respeito do tratamento do GBM nos idosos, com enfoque especial na abordagem cirúrgica...

The glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system (CNS). Due to the aging population, among other factors, its occurrence in older age groups has shown increasing in recent decades. The goals of resection of GBM include: relieve mass effect, tumor debulking, histopathological diagnosis, symptom control and improvement in survival rates. For a long time it was believed that age would be crucial in deciding the treatment, although some authors state that the extent of surgical resection is the main determinant of prognosis, especially for patients who were elected to radiotherapy and chemotherapy. The resection of more than 98% of the tumor volume can interfere with the survival and minor resections provided similar to survival of patients not operated. This paper aims to review the current literature regarding the treatment of GBM in the elderly, with special focus on surgical approach...

Brain metastasis from primary peritoneal carcinoma

Los tumores cerebrales metastásicos son el tipo más frecuente de cáncer que afecta el sistema nervioso central (SNC). Muchos sitios pueden generar implantes para todo el cerebro, pero hay órganos que raramente generan metastasis para el SNC. Carcinoma peritoneal primario es un cáncer raro, y su patología no es bien conocida, así como sus vías metastásicas. Se presenta un caso de una paciente que se presentó con lesiones cerebrales difusas debido a un carcinoma peritoneal primario diagnosticado previamente. También realizamos una breve revisión sobre el tema.

Brain metastatic tumors are the most frequent type of cancer affecting central nervous system. Many sites can generates implants for the entire brain, but there are organs that rarely generate metastasis. Primary peritoneal carcinoma is a rare cancer, and its pathology is not well known as well as its metastatic pathways. It is reported a case of a female patient who presented with diffuse brain lesions due to a primary peritoneal carcinoma previously diagnosed. We also perform a brief review about the theme.

Manejo das neoplasias metastáticas da coluna vertebral - uma atualização / Management of metastatic spinal column neoplasms - an update

O aumento da sobrevivência do paciente oncológico decorrente da melhoria e do avanço das modalidades terapêuticas promove progressivo aumento da prevalência das neoplasias metastáticas da coluna vertebral, tornando o seu conhecimento condição sine qua non para os profissionais da área de saúde. As metástases na coluna vertebral são usualmente procedentes de neoplasia maligna da mama, pulmão e próstata, o gênero masculino é o mais acometido e a dor é o sintoma inicial em mais de 90% dos pacientes. Estima-se que 30-90% dos pacientes com câncer em estágio terminal apresentem metástase em algum segmento da coluna vertebral. A alta prevalência das neoplasias malignas e a significativa experiência dos autores no tratamento das metástases na coluna vertebral motivaram uma atualização do tema. Acreditamos que a padronização da conduta e o conhecimento pormenorizado dos principais aspectos da doença, podem promover a melhor opção terapêutica. O presente estudo visa à revisão e descrição didática dos principais aspectos relacionados à fisiopatologia, diagnóstico e tratamento desta entidade.

The increased survival of cancer patients due to the improvement and advancement of therapeutic modalities has promoted progressive increase in the prevalence of metastatic tumors of the spine, making it important for healthcare professionals to acquire knowledge in the field. Spinal column metastases are usually secondary to malignant neoplasm of the breast, lung and prostate, male gender being the most often affected and pain being the initial symptom in 90% of patients. It is estimated that 30-90% of terminally ill patients with cancer have metastases at some spinal column segment. Clinical history, physical and neurological assessments are critical to determine the degree and extent of the lesion, and therefore choose the appropriate imaging method to be requested. This study aims to perform a review and didactic description of the main aspects related to the physiopathology, diagnosis and treatment of this disease.

Management of metastatic spinal column neoplasms--an update.

The increased survival of cancer patients due to the improvement and advancement of therapeutic modalities has promoted progressive increase in the prevalence of metastatic tumors of the spine, making it important for healthcare professionals to acquire knowledge in the field. Spinal column metastases are usually secondary to malignant neoplasm of the breast, lung and prostate, male gender being the most often affected and pain being the initial symptom in 90% of patients. It is estimated that 30-90% of terminally ill patients with cancer have metastases at some spinal column segment. Clinical history, physical and neurological assessments are critical to determine the degree and extent of the lesion, and therefore choose the appropriate imaging method to be requested. This study aims to perform a review and didactic description of the main aspects related to the physiopathology, diagnosis and treatment of this disease.

Apnéia do sono associada a obesidade: alguma influência na formação dos aneurismas cerebrais? / May sleep apnea associated with obesity play a role in brain aneurysm grouth?

Os autores selecionaram um grupo de pacientes com apnéia do sono e aneurismas cerebrais e procuraram correlacionar com casos de sobrepeso e obesidade, encontrando 80% de pacientes com obesidade do sexo feminino, com idades entre49 e 72 anos (média de 60,6 anos), todas submetidas a gastroplastia prévia, e tendo sido submetidas a repetidos regimes para emagrecer , com 60% de aneurismas rotos, todos Hunt-Hess entre III e V e Fisher 4 .. Aqueles com sobrepeso, idadeentre 53 e 70 anos ( média 60,5 anos), 50% tabagistas, 75%com aneurismas rotos, com gradação Hunt-Hess 3.3 em média,e Fisher de 3.3 em média. Concluir sobre a correlação é muito incipiente e mais estudos devem ser feitos neste sentido.

The authors have selected a group of patients with sleep apnea and brain aneurysms and sought to correlate with cases of overweight and obesity. They have found a high incidence of bleeding among those patients in both groups of obesity, most of them at computed tomography with Fisher score of III to IV,in patients with ruptured aneurysms (60% of rupture in severe obesity and 75% in overweight), and clinical status of Fisher I Vin obese patients and 3.3 in over weighed patients. Beyond any doubts, further studies should be accomplished to establish a strong correlation between associated obesity and sleep apnea and the patophysiology of brain aneurysms.

Abordagem atual aos aneurismas do topo da artéria basilar / Approaches to the basilar artery aneurysm

Objetivo: Revisão crítica das abordagens atuais para aneurismas do topo da artéria basilar. Análise dos aspectos anatômicos e angiográficos relevantes para cirurgia. Métodos: Revisão crítica da literatura e relato da experiência dos autores. Resultados: Os principais acessos para aneurismas de topo de basilar de acordo com sua posição em relação ao dorso da sela são: Kawase transpetroso para os aneurismas baixos, transcavernoso para os médios e temporopolar para os altos. A monitoração eletrofisiológica e com doppler pode minimizar complicações isquêmicas por clipagem prolongada, estenose ou fechamento inadvertido de perfurantes. Neuroproteção e hipotermia devem ser consideradas em lesões gigantes e complexas. Lesões complexas geralmente excedem ao tratamento endovascular. Conclusão: Existe uma tendência na literatura a considerar o tratamento cirúrgico dos aneurismas como método ultrapassado; entretanto a tecnologia de novas formas de proteção cerebral, técnicas microcirúrgicas e evolução dos clipes são indispensáveis para lidar com o cérebro em condições ruins na fase aguda. Os procedimentos endovasculares não drenam hematomas, não tratam hidrocefalia nem retiram coágulos das cisternas para prevenir o vasoespasmo. Entretanto é necessário um seguimento a longo prazo para uma avaliação mais precisa. O neurocirurgião deve dominar as duas opções de tratamento e ser hábil para indicar o tratamento mais apropriado.

Objective: To review the main approaches to basilar aneurysms and discuss relevant anatomy and angiographic features to choose the appropriate approach in each case. Methods: Literature review and author´s experiences are presented. Results: Current main approaches to basilar aneurysms regarding the level of the lesion from sellae dorsum are: Kawase transpetrosous for lower, transcavernous for middle and temporopolar for higher positioned aneurysms. Doppler, electroencephalography, somatosensory and motor evoked potential might minimize incidence of ischemic complications attributable to prolonged temporary occlusion or inadvertent perforator occlusion. Circulatory arrest and hypotermia may be considered for giant and complex aneurysms. The main principle applied is maximization of bone resection, which facilitates the use of surgical instruments and minimizes brain retraction. Complex basilar aneurysms frequently outdo endovascular treatment. Conclusion: There is a tendency in literature to consider the aneurysm surgery as an outdated method; however, technology of intensive care and anesthesia for brain protection, surgical techniques and clips evolution are indispensable for manipulate angry brain in aneurysms surgery after subarachnoid hemorrhage. Endovascular procedures do not remove clots from cisterns to avoid vasospasm, treat hydrocephalus or fenestrate the lamina terminalis to the same purpose; besides, longer follow up is necessary according to the final result. The neurosurgeon must dominate both treatment options and be able to differentiate exact indications.

Olfactory groove meningiomas: approaches and complications.

Olfactory groove meningiomas (OGM) account for 4.5% of all intracranial meningiomas. We report 21 patients with OGMs. Tumors were operated on using three surgical approaches: bifrontal (7 patients), fronto-pterional (11 patients) and fronto-orbital (3 patients). Total tumor removal (Simpson Grade 1) was achieved in 13 patients and Simpson II in 8 patients. Perioperative mortality was 4.76%. The average size of the OGM was 4.3+/-1.1cm. The overall recurrence rate was 19%. We preferred to use the pterional approach, which provides quick access to the tumor with less brain exposure. It also allows complete drainage of cisternal cerebrospinal fluid, providing a good level of brain relaxation during surgery. However, for long, thin tumors, hemostasis can be difficult using this approach.

Petroclival meningiomas: surgical management and common complications.

Petroclival meningiomas are technically challenging lesions. They have a tendency to grow slowly, involve cranial nerves and compress the brainstem and basilar artery, pushing them to the opposite side. Their natural history is marked by clinical deterioration and fatal outcome. They were once considered inoperable lesions; decades ago, mortality rates were higher than 50%. The authors describe 15 petroclival meningiomas treated surgically between 1995 and 2007. The main approaches used were combined anterior petrosectomy and retrosigmoid (3 cases), retrosigmoid (8 cases), and pre-sigmoid and subtemporal (4 cases). The mortality rate was 13.5% due to surgical bed hematoma and brain ischemia. The post-operative complications were hydrocephalus in 2 cases, cerebrospinal fluid leak in 2 cases and infection of surgical flap in one case. Limiting factors for surgical removal are tumor consistency, encasement of brainstem perforators and pre-operative clinical status.

Tratamento cirúrgico dos aneurismas do complexo da artéria comunicante anterior: detalhes técnicos / Surgical treatment of anterior communicating artery aneurysms: technical details

Objetivo: Discutir as nuances técnicas das abordagens cirúrgicas dos aneurismas do complexo da artéria comunicante anterior conforme as características anatômicas e angiográficas das lesões.Métodos:com base na experiência obtida com craniotomia pterional realizada em 30 casos de aneurismas do complexo da artéria comunicante anterior, complementada com retirada do processo clinoide anterior e teto orbitário.Resultados:A direção do segmento A1 se correlaciona com a do aneurisma.A patência dos segmentos A1 e A2 contralaterais deve ser observada.A aderência do aneurisma ao nervo óptico restringe a retração do lobo frontal.A aspiração do giro reto é útil quando o aneurisma tem localização alta.Conclusões:Os aneurismas da comunicante anterior estão entre os aneurismas intracranianos mais complexos.Os detalhes técnicos acima apontados são essenciais para o sucesso terapêutico.

Expression of cell adhesion proteins and proteins related to angiogenesis and fatty acid metabolism in benign, atypical, and anaplastic meningiomas.

Most meningiomas are benign tumours of arachnoidal origin, although a small number have high proliferative rates and invasive properties which complicate complete surgical resection and are associated with increased recurrence rates. Few prognostic indicators exist for meningiomas and further research is necessary to identify factors that influence tumour invasion, oedema and recurrence. Paraffin sections from 25 intracranial meningiomas were analysed for expression of the proteins vascular endothelial growth factor (VEGF), VEGF receptors Flt1 and Flk1, E-cadherin, metalloproteinases 2 and 9 (MMP2, MMP9), CD44, receptor for hyaluronic acid-mediated motility (RHAMM), hyaluronic acid (HA), CD45, cyclooxygenase 2 (COX2), brain fatty acid binding protein (BFABP), Ki67, and proliferating cell nuclear antigen (PCNA). Correlations among protein expression were found for several markers of proliferation (Ki67, PCNA, MI) and microvessel density (MVD). COX2 expression increased with increasing with tumour grade and correlated with Ki67, PCNA, MI, MVD, and BFABP. BFABP expression also correlated with Ki67 and PCNA expression. Relationships were also identified among angiogenic factors (VEGF, Flt1, Flk1) and proliferation markers. Oedema was found to correlate with MMP9 expression and MMP9 also correlated with proliferation markers. No correlations were found for MMP2, E-cadherin, or CD44 in meningiomas. In conclusion Ki67, PCNA, MI, MVD, BFABP, and COX2 were significantly correlated with meningioma tumour grade and with each other. These findings, by correlating both intracellular fatty acid transport and eicosanoid metabolism with tumour proliferation, as determined by Ki67 labelling and mitotic index, suggest fatty acids are involved in the progression of meningiomas.

[Radiation-induced meningioma]. / Meningeoma pós-radioterapia.

Meningiomas are neoplasms derived from arachnoid cells with their origin linked to idiopathic genetic abnormalities (deletion of the long arm of chromosome 22), predisposing diseases and radiotherapy induction. We report the case of a 50 years-old man radiation-induced meningioma 20 years after the diagnosis, surgical and radiation treatment of an oligodendroglioma. The supporting diagnostic criteria of radiation-induced meningiomas are discussed and the pertinent literature of the theme is revised.

Meningeoma pós-radioterapia / Radiation-induced meningioma

Os meningeomas são neoplasias derivadas das células aracnóideas, sendo sua origem ligada a alterações genéticas idiopáticas (deleção do braço longo do cromossomo 22), doenças predisponentes à sua formação e indução por radioterapia. Relata-se o caso de um homem de 50 anos com meningeoma pós-radioterapia diagnosticado 20 anos após o tratamento de um oligodendroglioma. Os critérios que suportam o diagnóstico de meningeoma induzido por radioterapia são discutidos, assim como é revisada a literatura pertinente ao assunto.

Meningiomas are neoplasms derived from arachnoid cells with their origin linked to idiopathic genetic abnormalities (delection of the long arm of chromosome 22), predisposing diseases and radiotherapy induction. We report the case of a 50 years-old man radiation-induced meningioma 20 years after the diagnosis, surgical and radiation treatment of an oligodendroglioma. The supporting diagnostic criteria of radiation-induced meningiomas are discussed and the pertinent literature of the theme is revised.

Tratamento cirúrgico dos aneurismas da circulação anterior / Tratamento cirúrgico dos aneurismas da circulação anterior

Objetivos: Os autores fazem uma análise crítica dos métodos atuais de tratamento dos aneurismas da circulação anterior, além de salientarem os aspectos anatômicos e acessos cirúrgicos.Métodos: Os aspectos evolutivos da técnica cirúrgica e endovascular de tratamento de aneurismas são discutidos, bem como as indicações e principais complicações. Resultados: Uma análise dos aneurismas da circulação anterior é feita e discutida quanto aos aspectos de sua localização, classificação e formas de tratamento. Os aneurismas paraclinóideos são os mais difíceis de serem abordados e tratados. Conclusão: A via pterional é a mais adequada e em aneurismas gigantes a ponte com enxerto venoso da carótida externa para cerebral média pode ser muito útil.