No description available.

Meningiomas petroclivais são tumores da base do crânio desafiadores para ressecção cirúrgica devido a sua localização profunda e relação com estruturas neurovasculares vitais. Geralmente são lesões benignas, mas podem envolver ou infiltrar o osso da base do crânio, dura-máter, tronco encefálico e todas as estruturas neurovasculares desta região, tornando a remoção total difícil sem causar déficits neurológicos. O objetivo deste estudo é revisar uma série de casos de meningiomas petroclivais tratados cirurgicamente em centro de referência de base de crânio, considerando os fatores determinantes para a escolha da abordagem. A casuística foi analisada com coleta retrospectiva dos dados. Devido à dificuldade de acesso, essas lesões geralmente requerem diferentes abordagens cirúrgicas e apresentam dificuldades cirúrgicas distintas. Embora as abordagens fronto-órbito-zigomática, petrosas, incluindo présigmoide retrolabiríntica, translabiríntica e petrosectomia total, e a retrossigmoide sejam as mais utilizadas para ressecção destes tumores, não foi realizado até o presente momento estudo comparativo que determine qual abordagem apresenta maior grau de ressecção cirúrgica associada a menor taxa de morbidade. / Petroclival meningiomas are challenging skull base tumors for surgical resection because of its deep location and their relationship to vital neurovascular structures. They are usually benign, but may involve or infiltrate the bone of the skull base, dura, brain stem and all neurovascular structures in this region, making it difficult to completely remove without causing neurological deficits. The aim of this study is to review a surgical series of petroclival meningioma treated in a referral center for skull base tumors, considering the determining factors to the choice of approach. The casuistry was analyzed with retrospective data collection. Due to difficult access, these injuries usually require different surgical approaches and have different surgical difficulties. Although the fronto-orbital-zygomatic, petrous, including retrolabyrinthine pre-sigmoid, translabyrinthine and total petrosectomy, and retrosigmoid are frequently used for resection of these tumors, it has not been realized to date comparative study to determine which approach has greater degree of surgical resection associated with lower morbidity rate.

Meningiomas petroclivais são tumores da base do crânio desafiadores para ressecção cirúrgica devido a sua localização profunda e relação com estruturas neurovasculares vitais. Geralmente são lesões benignas, mas podem envolver ou infiltrar o osso da base do crânio, dura-máter, tronco encefálico e todas as estruturas neurovasculares desta região, tornando a remoção total difícil sem causar déficits neurológicos. O objetivo deste estudo é revisar uma série de casos de meningiomas petroclivais tratados cirurgicamente em centro de referência de base de crânio, considerando os fatores determinantes para a escolha da abordagem. A casuística foi analisada com coleta retrospectiva dos dados. Devido à dificuldade de acesso, essas lesões geralmente requerem diferentes abordagens cirúrgicas e apresentam dificuldades cirúrgicas distintas. Embora as abordagens fronto-órbito-zigomática, petrosas, incluindo présigmoide retrolabiríntica, translabiríntica e petrosectomia total, e a retrossigmoide sejam as mais utilizadas para ressecção destes tumores, não foi realizado até o presente momento estudo comparativo que determine qual abordagem apresenta maior grau de ressecção cirúrgica associada a menor taxa de morbidade. / Petroclival meningiomas are challenging skull base tumors for surgical resection because of its deep location and their relationship to vital neurovascular structures. They are usually benign, but may involve or infiltrate the bone of the skull base, dura, brain stem and all neurovascular structures in this region, making it difficult to completely remove without causing neurological deficits. The aim of this study is to review a surgical series of petroclival meningioma treated in a referral center for skull base tumors, considering the determining factors to the choice of approach. The casuistry was analyzed with retrospective data collection. Due to difficult access, these injuries usually require different surgical approaches and have different surgical difficulties. Although the fronto-orbital-zygomatic, petrous, including retrolabyrinthine pre-sigmoid, translabyrinthine and total petrosectomy, and retrosigmoid are frequently used for resection of these tumors, it has not been realized to date comparative study to determine which approach has greater degree of surgical resection associated with lower morbidity rate.

INTRODUÇÃO: O edema peritumoral (EP) está presente em aproximadamente 60% dos meningiomas. Os fatores responsáveis pela formação do edema e sua importância clínica permanecem como foco de discussão. OBJETIVOS: Analisar a correlação entre a presença de edema com características clínicas, cirúrgicas, radiológicas e recorrência tumoral. MÉTODOS: Foram selecionados 61 pacientes portadores de meningiomas benignos submetidos a tratamento cirúrgico pelo Grupo de Tumores Encefálicos e Metástases do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Foram incluídos no estudo os portadores de meningiomas benignos submetidos a ressecção tumoral completa (Simpson 1 e 2). Foram excluídos pacientes portadores de meningiomas malignos ou atípicos e aqueles localizados em tubérculo selar, seio cavernoso, forame magno, intraventriculares e região petroclival. RESULTADOS: Encontramos correlação entre as maiores medidas de edema peritumoral e recorrência tumoral (p = 0,042) e tumores com margens irregulares (p < 0,011) na análise bivariada. Além disso, os pacientes que apresentaram maiores volumes tumorais apresentaram maiores medidas de edema (p = 0,035) e nos pacientes com menores medidas de edema a localização tentorial foi mais freqüente (p = 0,032). Verificamos que ao estudo de regressão logística, o EP apresenta correlação com tumores maiores que 40 cm3 (Odds ratio=15,977), crises convulsivas (Odds ratio=3,469) e para cada cm3 acrescida ao tamanho tumoral o risco de edema cresce 1,082 vez (Odds ratio). CONCLUSÕES: Considerando os resultados obtidos, o EP esteve associado a maior recorrência tumoral, tumores multilobulados, grandes e a presença de crises convulsivas. A localização tentorial mostrou-se como um fator protetor ao EP. O EP pode estar associado a um potencial invasivo aumentado em meningiomas. Desta forma, o seu estudo aprofundado poderá trazer dados adicionais para o esclarecimento dos mecanismos de formação dos meningiomas e de seu comportamento biológico levando ao melhor manejo clínico dos pacientes. / INTRODUCTION: Approximately 60% of meningiomas are associated with peritumoral edema.Various causative factors have been discussed in the literature. PURPOSES: Investigate the correlation of peritumoral edema with clinical, radiological and surgical aspects, and recurrence rate of meningiomas. METHODS: Sixty one benign meningiomas submitted to surgical treatment by the Group of Brain Tumors and Metastasis of the Division of Neurosurgery of the Hospital das Clínicas of São Paulo Medical School of São Paulo University. All patients underwent complete surgical ressection (Simpson 1 and 2) and were excluded the atypical and malignant hystopathological grades. The tumors located in the cavernous sinus, tuberculum sellae region, foramen magnum region, ventricular space and petroclival region were excluded. RESULTS: Edema extention had a positive correlation with the higher recurrence rates (p = 0,042) and with the presence of irregular margins (p < 0,011) on bivariate analysis. Meningiomas with greater edema sizes also showed correlation with large meningiomas (p = 0,035) and the ones with smaller edema sizes correlated with the tentorial location (p=0,032). Multivariate analysis showed an association between peritumoral brain edema and the presence of seizures (Odds ratio=3,469), large meningiomas (Odds ratio=15,977), and for each cubic centimeter added to its size, the risk of edema increased 1,082 times (Odds ratio). CONCLUSION: Peritumoral brain edema correlated with recurrence, irregular margins, seizures and larger tumors. The tentorial location demonstrated smaller edema sizes. Peritumoral brain edema may be related to meningioma\'s invading potentiality and may play a role in the recurrence pontential of the tumor. As a consequence, it\'s reasonable to consider edema\'s presence as an additional factor to be taken into account when arranging layout of strategies for meningiomas treatment.

Os tumores extra-axias do sistema nervoso são de localização extra-cerebral e na maioria das vezes benignos; meningiomas, schwanomas e metástases fazem parte deste grupo. O aparecimento de um tumor ocorre a partir do acúmulo de alterações genéticas e epigenéticas nas células. Para entender o mecanismo molecular da progressão tumoral e a formação de metástases é indispensável identificar os genes que acumulam essas alterações. Sendo assim, este trabalho teve como objetivo analisar o perfil de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 e das DNA metiltransferases 3A, 3B e 3L e sua associação com os tumores extra-axiais e ainda, avaliar, através de um estudo caso-controle, a influência dos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61, GSTP-1 Ile105Val e WRN Cys1367Arg no desenvolvimento e prognóstico desses tumores. A técnica utilizada para a análise de hipermetilação foi a MSP, e através dela observamos que a atividade das DNMTs não está associada à metilação dos tumores extra-axiais e ainda, os perfis de metilação das DNMTs de novo não estão associados com alterações no padrão de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN- 1 e NDRG2. Observamos que a metilação do gene TP53 está associada principalmente aos tumores de maior grau de malignidade, a uma deficiência na resposta a tratamentos e, conseqüentemente, a um maior número de óbitos. A metilação do gene TP16 está envolvida mais freqüentemente na formação de schwanomas e a de NDRG2 na progressão dos meningiomas. A análise de polimorfismos foi realizada através da técnica de PCR-RFLP e observamos diferenças nas distribuições genotípicas entre pacientes e controles nos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61 e GSTP-1 Ile105Val, onde as variantes Ser47, Pro72, EGF G61 e Val105 foram observadas com maior freqüência entre os portadores de tumores extra-axiais. Dessa forma, estas variantes podem ser fatores de susceptibilidade para o desenvolvimento dos tumores. / The extra-axial brain tumors have extra-brain localization and in most of the time they are benign, meningiomas, schwannomas and metastasis are included in this group. The appearance of a tumor occurs because of the accumulation of genetic and epigenetic alterations in the cells. In order to understand the molecular mechanism of the tumor progression and the metastasis formation it is important to identify the genes that accumulate the alterations. Thereby, the objective of this study was to analyze the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 and the DNA methyltransferases 3A, 3B and 3L and their association with the extra-axial brain tumors. Another purpose was to determine, in a case-control study, the roles of the TP53 Pro47Ser and Arg72Pro, EGF + 61, GSTP-1 Ile105Val and WRN Cys1367Arg SNPs in the development and prognosis of these tumors. We used the MSP to screen the hypermethylation profile and we observed no association between the DNMTs activity and the hypermethylation of the tumors. We also did not find association between the methylation of the DNMTs de novo and alterations in the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1 and NDRG2. We observed that TP53 hypermethylation was associated with the high grade tumors, a poor response to the treatments and, consequently, the high number of obits. The TP16 methylation was involved with the shwannomas formation and the NDRG2 gene was involved in the meningiomas progression. For the polymorphism analysis, we used the PCR-RFLP technique and we observed differences in the genotype distributions between cases and controls of TP53 Pro47Ser and Arg72Pro, EGF + 61 and GSTP-1 Ile105Val SNPs, where the variants Ser47, Pro72, EGF G61 and Val105 were more frequent in patients than in controls. Thus, these variants can be important factors of susceptibility to the tumor development.

No description available.

Os tumores extra-axias do sistema nervoso são de localização extra-cerebral e na maioria das vezes benignos; meningiomas, schwanomas e metástases fazem parte deste grupo. O aparecimento de um tumor ocorre a partir do acúmulo de alterações genéticas e epigenéticas nas células. Para entender o mecanismo molecular da progressão tumoral e a formação de metástases é indispensável identificar os genes que acumulam essas alterações. Sendo assim, este trabalho teve como objetivo analisar o perfil de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 e das DNA metiltransferases 3A, 3B e 3L e sua associação com os tumores extra-axiais e ainda, avaliar, através de um estudo caso-controle, a influência dos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61, GSTP-1 Ile105Val e WRN Cys1367Arg no desenvolvimento e prognóstico desses tumores. A técnica utilizada para a análise de hipermetilação foi a MSP, e através dela observamos que a atividade das DNMTs não está associada à metilação dos tumores extra-axiais e ainda, os perfis de metilação das DNMTs de novo não estão associados com alterações no padrão de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN- 1 e NDRG2. Observamos que a metilação do gene TP53 está associada principalmente aos tumores de maior grau de malignidade, a uma deficiência na resposta a tratamentos e, conseqüentemente, a um maior número de óbitos. A metilação do gene TP16 está envolvida mais freqüentemente na formação de schwanomas e a de NDRG2 na progressão dos meningiomas. A análise de polimorfismos foi realizada através da técnica de PCR-RFLP e observamos diferenças nas distribuições genotípicas entre pacientes e controles nos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61 e GSTP-1 Ile105Val, onde as variantes Ser47, Pro72, EGF G61 e Val105 foram observadas com maior freqüência entre os portadores de tumores extra-axiais. Dessa forma, estas variantes podem ser fatores de susceptibilidade para o desenvolvimento dos tumores. / The extra-axial brain tumors have extra-brain localization and in most of the time they are benign, meningiomas, schwannomas and metastasis are included in this group. The appearance of a tumor occurs because of the accumulation of genetic and epigenetic alterations in the cells. In order to understand the molecular mechanism of the tumor progression and the metastasis formation it is important to identify the genes that accumulate the alterations. Thereby, the objective of this study was to analyze the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 and the DNA methyltransferases 3A, 3B and 3L and their association with the extra-axial brain tumors. Another purpose was to determine, in a case-control study, the roles of the TP53 Pro47Ser and Arg72Pro, EGF + 61, GSTP-1 Ile105Val and WRN Cys1367Arg SNPs in the development and prognosis of these tumors. We used the MSP to screen the hypermethylation profile and we observed no association between the DNMTs activity and the hypermethylation of the tumors. We also did not find association between the methylation of the DNMTs de novo and alterations in the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1 and NDRG2. We observed that TP53 hypermethylation was associated with the high grade tumors, a poor response to the treatments and, consequently, the high number of obits. The TP16 methylation was involved with the shwannomas formation and the NDRG2 gene was involved in the meningiomas progression. For the polymorphism analysis, we used the PCR-RFLP technique and we observed differences in the genotype distributions between cases and controls of TP53 Pro47Ser and Arg72Pro, EGF + 61 and GSTP-1 Ile105Val SNPs, where the variants Ser47, Pro72, EGF G61 and Val105 were more frequent in patients than in controls. Thus, these variants can be important factors of susceptibility to the tumor development.

No description available.

Merlin is a tumour suppressor protein that is frequently mutated or downregulated in cancer. Biallelic Merlin inactivation is causative of tumour formation, including schwannoma, meningioma and ependymoma. These tumours can occur sporadically or as part of the genetic condition Neurofibromatosis type 2 (NF2) and cause significant morbidity. The current treatment options are restricted to surgery and radiotherapy, which are invasive and may cause further tumour development. The activity of both the E3 ubiquitin ligase complex Cullin 4 really interesting new gene (RING) E3 ubiquitin ligase- DNA damage binding protein (DDB1) and Cullin 4 associated factor 1 (CRL4-DCAF1) and Kinase suppressor of RAS 1 (KSR1) have been shown to be upregulated in schwannoma to drive tumour growth. KSR1 has also been shown to interact with components of the CRL4-DCAF1 complex. We investigated the expression, interaction and therapeutic potential of targeting these proteins in Merlin deficient schwannoma and meningioma using a primary human cell model and relevant cell lines. We found that DCAF1 and KSR1 protein were overexpressed in schwannoma and meningioma and confirmed that targeting both DCAF1 and KSR1 in meningioma had additive effects on proliferation. We also identified that CRL4-DCAF1 facilitates KSR1 dependent RAF/Mitogen-activated protein kinase (MAPK)/ Extracellular signal regulated kinase (ERK) kinase (MEK)/ERK pathway activity. We showed MLN3651, a neddylation inhibitor that targets ubiquitin ligase activity, reduced proliferation and activated apoptosis in Merlin-deficient tumours. We also showed that Merlin-positive tumours were less sensitive to MLN3651 than Merlin-deficient tumours; therefore, MLN3651 sensitivity may be CRL4-DCAF1-dependent. Finally, combination of MLN3651 and the MEK1/2 inhibitor AZD6244 had additive effects, particularly in meningioma. Combinatorial therapy activated the Hippo pathway, inhibited RAF/MEK/ERK pathway activity and proliferation demonstrating that targeting the activity and downstream pathways of both DCAF1 and KSR1 represents an attractive novel therapeutic strategy in Merlin-deficient tumours.

Primary brain tumours, and especially the most common form malignant gliomas, usually display a pronounced resistance to other treatment modalities when surgery fails to cure. Growth factors, such as EGF and its receptor, frequently amplified and overexpressed in malignant gliomas, and factors associated with multidrug resistance have been suggested to at least partially explain the poor outcome. The aim of this thesis was to characterise factors in primary brain tumours associated with the development of resistance with focus on the epidermal growth factor receptor (ErbB) family, and multidrug resistance (MDR). Influences of irradiation on the expression and activity of P-glycoprotein (Pgp) in malignant gliomas was evaluated. The effects showed that irradiation increased the efflux activity of Pgp in rat brain vascular endothelial cells, but not in glioma cells. In the intracranial BT4C glioma model, Pgp was detected in the capillary endothelium in the tumour tissue but not in glioma cells. Expression of several factors coupled to MDR (Pgp, MRP1, LRP, and MGMT) in primary brain tumours were analysed and correlated to clinical data. In gliomas, Pgp and MRP1 were predominantly observed in capillary endothelium and in scattered tumour cells, whereas LRP occurred only in tumour cells. In meningiomas, expression of the analysed markers was demonstrated in the capillary endothelium, with a higher expression of Pgp and MRP1 in transitional compared to meningothelial meningiomas. A pronounced expression of MGMT was found independently of the histopathological grade or tumour type. Survival analysis indicated a shorter overall survival for patients suffering from low-grade gliomas with high expression of Pgp. To explore the importance of the epidermal growth factor receptor (EGFR), expression levels of the family members (EGFR, ErbB2-4) were analysed and their relations to various clinical parameters were evaluated in gliomas and meningiomas. In gliomas, the highest EGFR expression was observed in high-grade tumours, while ErbB4 expression was most pronounced in low-grade tumours. In meningiomas, expression of EGFR, ErbB2, and ErbB4 was observed in the majority of the tumours. An intriguing observation in low-grade gliomas was a significantly decreased overall survival for patients with high EGFR protein expression. The effects of different time schedules for administration of the selective EGFR inhibitor ZD1839 in relation to irradiation of glioma cells were analysed. The analyses showed a heterogeneity in the cytotoxic effects of ZD1839 between cell lines, and it was obvious that some of the cell lines showed sensitivity to ZD1839 despite no or low expression of EGFR. The study also demonstrated the importance of timing of ZD1839 administration when this agent is combined with irradiation. In conclusion, in order to enhance the efficacy of radiotherapy by various drugs in malignant gliomas it may be essential to inhibit drug efflux activity in endothelial cells and to deliver drugs in an optimal timing in relation to radiotherapy. The heterogeneity in expression of drug resistance markers, as well as the ErbB family reflects the complexity in classification of primary brain tumours, and indicates that subgroups of patients with low-grade gliomas expressing Pgp and EGFR might benefit from more aggressive and individualised treatment.