Hypermethylation of BRCA1 Gene in Meningioma in Elderly Males.

BACKGROUND/AIM: Breast cancer 1, early onset (BRCA1) gene is expressed in the cells of the breast and other tissues, where it plays a role in cell-cycle regulation, transcription, repair of DNA double-stranded breaks, ubiquitination, transcriptional regulation as well as other functions, such as cell response regulation to mitogenic signals triggered by estrogens. Considering that meningioma shows greater tumor growth during pregnancy, can express estrogen receptors and proliferate in response to estrogenic stimulation, the hypothesis that this type of tumor may share molecular mechanisms that involve exposure to estrogen should be investigated. Therefore, the aim of the present study was to investigate the BRCA1 gene methylation profile in meningioma. MATERIALS AND METHODS: Methylation-specific polymerase chain reaction (PCR) assay was performed on 50 meningioma samples from male and female patients. Statistical analysis was carried out using Fisher's exact test. RESULTS: The most important finding of this study was that 100% of the male patients over 55 years with meningioma showed BRCA1 methylated in their tumor cells. CONCLUSION: The silencing of BRCA1 through hypermethylation seems to play an important role in meningioma.

Melanotic schwannoma of the cervical spine progressing with pulmonary metastasis: case report.

Melanotic schwannoma (MS) is an unusual variant of nerve sheath neoplasm. Only 10% of these tumors will undergo malignant degeneration, with exceedingly rare reported metastasis. We present a 32-year-old woman with a 6-month history of cervical pain and left arm progressive weakness. Neurological examination showed a left upper limb radicular pain, with pyramidal syndrome at C5 level. The magnetic resonance imaging (MRI) study highlighted an intradural extramedullary heterogeneous mass along the spinal cord at the C4-C5 level, slightly hyperintense with T1 and hypointense with T2-weighted sequences, invading the left neural foramen. The patient underwent C3-C5 laminectomy with total resection of a black tumor. In the postoperative period, a patent deficit of shoulder abduction ensued related to the nervous section. Microscopically, compactly fascicles of spindle-shaped cells with pleomorphic and hypercromatic nuclei, dark brown intracellular pigments, as well as some mitotic figures were seen. Immunohistochemical stains for S-100, Human Melanoma Black-45 (HMB-45), and vimentin were positive, with Ki-67 Labelling Index (LI) of 15% compatible with MS. Six months after radiotherapy she presents local recurrence and lung metastatic dissemination of the MS. She underwent left pulmonary segmentectomy, followed by chemotherapy and radiosurgery. The patient developed a febrile neutropenia and worsening of general status, and died after 3 months due to respiratory complications. MS are rare tumors with potential for local recurrence and distal metastasis. Complete surgical resection remains as the treatment of choice, once the uncommon cases with malignant progression shows low response to chemo and radiotherapy.

CDKN2A promoter hypermethylation in astrocytomas is associated with age and sex.

CDKN2A promoter hypermethylation has been widely related to many cancers. In astrocytomas, although CDKN2A (p16(INK4A) protein) is often inactivated, there are still some controversial issues regarding the mechanism by which this alteration occurs. Thus, we analyzed a series of astrocytomas to assess the association between CDKN2A expression and methylation of grade I-IV tumors (WHO) and clinicopathological parameters. DNA extracted from formalin-fixed paraffin-embedded material of 93 astrocytic tumors was available for CDKN2A promoter methylation analysis and p16(INK4A) expression by methylation-specific PCR and immunohistochemistry, respectively. A strong negative correlation between nuclear and cytoplasmic immunostaining and CDKN2A promoter methylation was found. Additionally, a significant negative correlation between CDKN2A promoter methylation and age was observed; also, female patients had statistically more CDKN2A methylated promoters (p = 0.036) than men. In conclusion, CDKN2A inactivation by promoter methylation is a frequent event in astrocytomas and it is related to the age and sex of patients.

Central giant cell lesion of the jaws: study of CCND1 gene amplification and p16INK4a protein levels.

Central giant cell lesions (CGCLs) are uncommon benign jaw lesions with uncertain etiology and a variable clinical behavior. In neoplasms, alterations in molecules involved in the G1/S checkpoint are frequently found. Loss of p16(INK4a) expression or overexpression of cyclin D1 may stimulate cell proliferation. The purpose of this study was to analyze CCND1 gene amplification and the expression of p16(INK4a) in CGCLs. Structural analysis of the CCND1 was performed using chromogenic in situ hybridization. Immmunohistochemistry was used to identify p16(INK4a) protein levels. Statistical analysis correlated the two biomarkers with clinical behavior and between each other. Twenty-four lesions were included, being 11 aggressive and 13 non-aggressive. Moderate/high-level CCND1 amplification was found in 12 lesions. Also, immunoreactivity for p16(INK4a) was present in 12 cases, mainly in mononuclear cells. There was a significantly higher level of p16(INK4a) expression in mononuclear cells of non-aggressive lesions and lesions with moderate/high-level CCND1 amplification in mononuclear cells. It could be speculated that some CGCLs may develop as a true benign neoplasm. The higher expression of p16(INK4a) in non-aggressive lesions and in cases with moderate/high-level CCND1 amplification may show that these molecules have a role in CGCLs.

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats.

PURPOSE: To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN). METHODS: Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software. RESULTS: The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls. CONCLUSION: Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats / Inibição da angiogênese pela própolis verde e efeito angiogênico da L-lisina no câncer de bexiga em ratos

PURPOSE: To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN). METHODS: Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software. RESULTS: The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls. CONCLUSION: Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.

OBJETIVO: Determinar os efeitos da própolis verde solúvel em água na angiogênese de câncer de bexiga em ratos que receberam n-butil-(-4-hidroxibutil) nitrosamina (BBN). METODOS: Nove grupos foram estabelecidos, onde em seis destes (grupos de 1 a 6) os animais receberam BBN a 0,05% em água de beber por 14 semanas. Na 32ª semana das 40 semanas, os grupos 1, 2, 3 e 4 foram tratados respectivamente com água, L lisina (300 mg/kg/dia), celecoxibe (30 mg/kg/dia) e própolis (300 mg/kg/dia). Os grupos 5 e 6 receberam própolis e L lisina da 1ª a 40ª semana (150 mg/ kg/dia). A densidade microvascular foi determinada por cortes histológicos corados pelo CD-31 e analisados por programa de computador específico. RESULTADOS: A densidade microvascular em carcinomas de bexiga foi menor com p<0,01 nos ratos que receberam própolis do que nos carcinomas do grupo controle que recebeu apenas carcinógeno. Por outro lado, a densidade microvascular de tumores de ratos que receberam carcinógeno e L-Lisina por 40 semanas desde o início do carcinógeno foi significantemente maior com p<0,01 que a densidade microvascular dos tumores de seu respectivo grupo controle. CONCLUSÃO: A própolis verde solúvel em água inibiu a angiogênese em câncer de bexiga induzido pelo BBN, enquanto a L- lisina estimulou a angiogênese quando iniciada juntamente com o BBN.

Cyclooxygenase-2 expression in central giant cell lesion of the jaws: an immunohistochemical study.

Central Giant Cell Lesion (CGCL) is an uncommon benign jaw lesion, with uncertain etiology, and a variable clinical behavior. Studies of molecular markers of CGCL, may help understanding better the nature and behavior of this lesion, and eventually may represent a definitive target to pharmacological approach in the treatment of CGCL. Chronic inflammation has been found to mediate a wide variety of diseases including neoplasms. Among the gene products involved in the induction of the inflammatory process, Cyclooxygenase 2 (COX-2) has been shown to have a close relationship with tumorigenesis, however COX-2 expression has never been evaluated in CGCL. The aim of the study was to investigate the expression of COX-2 in CGCL. Immunohistochemical assessment for COX-2 expression was performed in 18 patients previously diagnosed with CGCL. Multinucleated giant cells (MGC) and mononucleated stromal cells (MSC) were used in the slide analysis. Among the patients studied, 10 were male and 8 were female, with a median age of 15.4 years. Lesions in the mandible were observed in 11 cases and 7 were found in the maxilla. There were 9 aggressive and 9 non-aggressive CGCLs. COX-2 immunopositivity was present in only 3 cases stained in both MGC and MSC. All 3 cases presented with ulcerations in the mucosa lesion, suggesting that the COX-2 expression is due to the presence of inflammation. This study does not support the involvement of COX-2 in the etiophatogenesis of CGCL.

Polymorphisms of folate pathway enzymes (methylenetetrahydrofolate reductase and thymidylate synthase) and their relationship with thymidylate synthase expression in human astrocytic tumors.

Two important polymorphisms of folate cycle enzymes, methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) enhancer region (TSER) 28-bp tandem repeat, are related to risk of various types of cancer, including brain tumors, although there are few studies on this subject. A case-control study of these two polymorphisms in astrocytomas of different grades was carried out using polymerase chain reaction-restriction fragment length polymorphism, also determining the immunohistochemical expression of TS. The MTHFR 677 TT genotype was less associated with astrocytic tumors (odds ratio [OR]=0.00; p=0.0238), but the TSER polymorphism did not show any significant association. Combined genotype TT-double repeats/triple repeats (2R/3R) had a protective effect against astrocytomas (OR=0.00; p=0.0388). Expression of TS protein was observed in the majority of cases, with grade IV tumors being the exception. Moreover, the median H-score for the pilocytic astrocytomas was significantly higher when compared with that for diffuse tumors. There was an inverse correlation between the 2R/2R genotype and the highest TS-expressing tumors, and 3R/3R was relatively more frequent among the tumors grouped in the third and fourth quartiles. Our results provide support for the role of MTHFR and TS polymorphism in gliomagenesis, possibly because of the alteration of DNA methylation and repair status. Moreover, high levels of TS expression were detected in these tumors.

A novel TBX5 missense mutation (V263M) in a family with atrial septal defects and postaxial hexodactyly.

BACKGROUND: Congenital heart diseases are the most frequent birth defects and are commonly associated with skeletal malformations. Mutations in the TBX5 gene, a T-box transcription factor located on chromosome 12q24.1, have been demonstrated to be the underlying molecular alteration in individuals with different congenital cardiac disorders, notably the Holt-Oram syndrome. METHODS: Six members from a two-generation family from a consanguineous couple, which had atrial septal defects associated with postaxial hexodactyly in all extremities were clinically assessed and submitted to TBX5 mutational analysis performed by direct sequencing. RESULTS: We detected a new TBX5 missense mutation (V263M) in all four individuals studied with cardiac abnormalities. The genotype-phenotype correlations in light of unusual features are extensively discussed, as well as the possible significance of these atypical findings. CONCLUSIONS: These new data extend our clinical and molecular knowledge of TBX5 gene mutations and also raise interesting questions about the phenotype heterogeneity regarding these gene alterations.

Immunoexpression of tumor suppressor genes p53, p21WAF1/CIP1 and p27KIP1 in humam astrocystic tumors

The aim of the present study was to evaluate the tumor suppressor genes p53, p21WAF1/CIP1 and p27KIP1 expression in astrocytic tumors, correlating the findings with the histopathological grade (WHO). An immunohistochemical study of the p53, p21 and p27 proteins using the streptavidin-biotin-peroxidase method was performed in fifty-five astrocytomas (13 grade I, 14 grade II, 7 grade III and 21 grade IV) and five samples of non-tumor brain tissue (negative control). p53 positive indices (PI) and labeling indices (LI) showed tendency to increase according to malignant progression. The nuclear expression of p27 presented similar inclination, except for the PI reduction verified in grade IV tumors. Otherwise, the cytoplasmic p27 staining was more evident between high-grade tumors (III and IV). p53 and nuclear p27 expression was correlated with the histological classification (p<0.01; test H). On the other hand, p21 indices revealed a propensity to reduction in agreement with malignant evolution of the astrocytic tumors, except for high scores observed in grade IV tumors. The non-tumor samples did not show any expression of these proteins. These results indicated the p53 mutation as an initial, relevant and potentially predictor of tumor progression event in astrocytomas, with the detection of p21 protein as an important resource for the deduction of functional situation of this gene. Moreover, the activation of p27KIP1 was preserved in the astrocytic tumors and its cytoplasmic manifestation seems to be resultant of its nuclear expression, not demonstrating a direct impact in astrocytomas tumorigenesis.

O presente estudo objetivou avaliar a expressão dos supressores tumorais p53, p21WAF1/CIP1 e p27KIP1 em tumores astrocíticos humanos, correlacionando os achados com a graduação histopatológica (OMS). Procedeu-se o estudo imuno-histoquímico para as proteínas p53, p21 e p27 utilizando o método da estreptavidina-biotina-peroxidase em 55 astrocitomas (13 do grau I, 14 do grau II, 7 do grau III e 21 do grau IV) e 5 amostras de tecido cerebral não-tumoral (controle negativo). Os índices de positividade (PI) e de marcação (LI) para p53 demonstraram tendência de aumento conforme a progressão maligna. A expressão nuclear do p27 apresentou semelhante inclinação, exceto pela redução do PI verificada nos tumores do grau IV. Já a marcação citoplasmática do p27 foi mais evidente entre tumores de alto grau (III e IV). As expressões de p53 e p27 nuclear demonstraram correlação com a classificação histológica (p<0,01; teste H). Por outro lado, os índices para p21 manifestaram propensão à redução conforme a evolução maligna dos tumores astrocíticos, salvo significante aumento observado nos tumores do grau IV. Não houve expressão dessas proteínas nas amostras não-tumorais. Tais resultados indicaram a mutação do p53 como um evento inicial, relevante e potencialmente indicador de progressão maligna nos astrocitomas, sendo a detecção da proteína p21 um importante recurso para a dedução da situação funcional desse gene. Além disso, a ativação do p27KIP1 mostrou-se preservada nos tumores astrocíticos e sua manifestação citoplasmática parece ser reflexo de sua expressão nuclear, não demonstrando impacto direto na tumorigênese dos astrocitomas.

Ketone bodies metabolism during ischemic and reperfusion brain injuries following bilateral occlusion of common carotid arteries in rats

PURPOSE: To evaluate the in vivo alterations on ketone bodies metabolism after cerebral ischemia/reperfusion through an experimental model of brain ischemia induced by simple occlusion of common carotid arteries (CCAs) in Wistar rats. METHODS: Forty-eight male Wistar rats were randomly distributed on two groups (S - Sham; T - Test) and further redistributed into four times sets of study. After bilateral occlusion of CCAs for 30min, the animals of group T were allowed reperfusion for 0, 5, 10 and 15min. Samples of cerebral tissue and systemic arterial blood were collected and the metabolites acetoacetate (ACT) and beta-hydroxybutyrate (BHB) were determined. RESULTS: Cerebral ACT and BHB levels increased significantly in Group T after 30min of carotid occlusion (time 0). The highest brain ketone bodies (ACT+BHB) concentration was verified at 5min of reperfusion, decreasing after 10min of recirculation. Systemic ketone bodies levels increased similarly between test and sham groups. Group S demonstrated a significant increase in cerebral and systemic ACT and BHB concentrations mainly after 40-45min of study. CONCLUSIONS: The partial transient acute global brain ischemia induced by the bilateral carotid occlusion in Wistar rats triggered ketogenesis probably due to a central stimulation of catecholamine secretion. There was an increased cerebral uptake of ketone bodies following brain ischemia, reaffirming these metabolites as alternative energy substrates under conditions of cerebral metabolic stress as well as its potential role on neuroprotection. The greatest changes in ketone bodies metabolism were verified at initial minutes of recirculation as a result of the reperfusion injury phenomenon.

OBJETIVO: Avaliar as alterações in vivo no metabolismo dos corpos cetônicos após isquemia/reperfusão cerebral através de um modelo experimental de isquemia cerebral induzido pela simples oclusão das artérias carótidas comuns (CCAs) em ratos Wistar. MÉTODOS: Quarenta e oito ratos Wistar machos foram distribuídos aleatoriamente em dois grupos (S - Controle; T - Teste) e cada um deles redistribuídos em quatro tempos de estudos. Após oclusão bilateral das CCAs por 30min, permitiu-se reperfusão aos animais do grupo T nos tempos 0, 5, 10 e 15min. Foram coletadas amostras de tecido cerebral e sangue arterial sistêmico e quantificados os metabólitos acetoacetato (ACT) e beta-hidroxibutirato (BHB). RESULTADOS: Os níveis cerebrais de ACT e BHB aumentaram significantemente no Grupo T após 30min de oclusão carotídea (tempo 0). A maior concentração de corpos cetônicos (ACT+BHB) foi verificada aos 5min de reperfusão, diminuindo após 10min de recirculação. Os níveis de corpos cetônicos sistêmicos aumentaram de modo semelhante entre os grupos teste e controle. O Grupo S demonstrou significante aumento nas concentrações sistêmicas e cerebrais de ACT e BHB principalmente após 40-45min de estudo. CONCLUSÕES: A isquemia cerebral aguda transitória e parcial induzida pela oclusão bilateral das carótidas em ratos Wistar ativou a cetogênese provavelmente devido à estimulação central da secreção de catecolaminas. Houve um aumento da captação dos corpos cetônicos após isquemia cerebral, reafirmando esses metabólitos como substratos energéticos alternativos em condições de estresse metabólico cerebral, bem como suas potencialidades na neuroproteção. As maiores alterações no metabolismo dos corpos cetônicos foram verificadas nos minutos iniciais de recirculação como resultado do fenômeno da lesão de reperfusão.

Ketone bodies metabolism during ischemic and reperfusion brain injuries following bilateral occlusion of common carotid arteries in rats.

PURPOSE: To evaluate the in vivo alterations on ketone bodies metabolism after cerebral ischemia/reperfusion through an experimental model of brain ischemia induced by simple occlusion of common carotid arteries (CCAs) in Wistar rats. METHODS: Forty-eight male Wistar rats were randomly distributed on two groups (S - Sham; T - Test) and further redistributed into four times sets of study. After bilateral occlusion of CCAs for 30 min, the animals of group T were allowed reperfusion for 0, 5, 10 and 15 min. Samples of cerebral tissue and systemic arterial blood were collected and the metabolites acetoacetate (ACT) and beta-hydroxybutyrate (BHB) were determined. RESULTS: Cerebral ACT and BHB levels increased significantly in Group T after 30 min of carotid occlusion (time 0). The highest brain ketone bodies (ACT+BHB) concentration was verified at 5 min of reperfusion, decreasing after 10 min of recirculation. Systemic ketone bodies levels increased similarly between test and sham groups. Group S demonstrated a significant increase in cerebral and systemic ACT and BHB concentrations mainly after 40-45 min of study. CONCLUSIONS: The partial transient acute global brain ischemia induced by the bilateral carotid occlusion in Wistar rats triggered ketogenesis probably due to a central stimulation of catecholamine secretion. There was an increased cerebral uptake of ketone bodies following brain ischemia, reaffirming these metabolites as alternative energy substrates under conditions of cerebral metabolic stress as well as its potential role on neuroprotection. The greatest changes in ketone bodies metabolism were verified at initial minutes of recirculation as a result of the reperfusion injury phenomenon.

Immunoexpression of tumor suppressor genes p53, p21 WAF1/CIP1 and p27 KIP1 in humam astrocystic tumors.

The aim of the present study was to evaluate the tumor suppressor genes p53, p21 WAF1/CIP1 and p27 KIP1 expression in astrocytic tumors, correlating the findings with the histopathological grade (WHO). An immunohistochemical study of the p53, p21 and p27 proteins using the streptavidin-biotin-peroxidase method was performed in fifty-five astrocytomas (13 grade I, 14 grade II, 7 grade III and 21 grade IV) and five samples of non-tumor brain tissue (negative control). p53 positive indices (PI) and labeling indices (LI) showed tendency to increase according to malignant progression. The nuclear expression of p27 presented similar inclination, except for the PI reduction verified in grade IV tumors. Otherwise, the cytoplasmic p27 staining was more evident between high-grade tumors (III and IV). p53 and nuclear p27 expression was correlated with the histological classification (p<0.01; test H). On the other hand, p21 indices revealed a propensity to reduction in agreement with malignant evolution of the astrocytic tumors, except for high scores observed in grade IV tumors. The non-tumor samples did not show any expression of these proteins. These results indicated the p53 mutation as an initial, relevant and potentially predictor of tumor progression event in astrocytomas, with the detection of p21 protein as an important resource for the deduction of functional situation of this gene. Moreover, the activation of p27 KIP1 was preserved in the astrocytic tumors and its cytoplasmic manifestation seems to be resultant of its nuclear expression, not demonstrating a direct impact in astrocytomas tumorigenesis.

Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma.

AIM: To investigate chromosome 8 numerical aberrations, C-MYC oncogene alterations and its expression in gastric cancer and to correlate these findings with histopathological characteristics of gastric tumors. METHODS: Specimens were collected surgically from seven patients with gastric adenocarcinomas. Immunostaining for C-MYC and dual-color fluorescence in situ hybridization (FISH) for C-MYC gene and chromosome 8 centromere were performed. RESULTS: All the cases showed chromosome 8 aneuploidy and C-MYC amplification, in both the diffuse and intestinal histopathological types of Lauren. No significant difference (P < 0.05) was observed between the level of chromosome 8 ploidy and the site, stage or histological type of the adenocarcinomas. C-MYC high amplification, like homogeneously stained regions (HSRs) and double minutes (DMs), was observed only in the intestinal-type. Structural rearrangement of C-MYC, like translocation, was observed only in the diffuse type. Regarding C-MYC gene, a significant difference (P < 0.05) was observed between the two histological types. The C-MYC protein was expressed in all the studied cases. In the intestinal-type the C-MYC immunoreactivity was localized only in the nucleus and in the diffuse type in the nucleus and cytoplasm. CONCLUSION: Distinct patterns of alterations between intestinal and diffuse types of gastric tumors support the hypothesis that these types follow different genetic pathways.

Estratégias auxiliares para graduação dos tumores astrocíticos segundo os critérios histopatológicos estabelecidos pela OMS / Auxiliary strategies for astrocytic tumor graduation according to histopathological criteria established by WHO

INTRODUÇÃO: Apesar das recentes descobertas acerca das alterações moleculares envolvidas na tumorigênese dos astrocitomas, a análise histológica convencional permanece o melhor método diagnóstico e razoável indicador prognóstico dos tumores astrocíticos. Todavia, a rotina histopatológica preconizada pela Organização Mundial da Saúde (OMS) mostra-se laboriosa, sendo marcada pela baixa reprodutibilidade. OBJETIVO: O presente estudo objetivou desenvolver estratégias auxiliares para graduação dos tumores astrocíticos a partir dos critérios histológicos estabelecidos pela OMS. MATERIAL E MÉTODO: Procedeu-se à análise clínico-epidemiológica e à reavaliação histopatológica de 55 astrocitomas de diferentes gradações (13 grau I, 14 grau II, sete grau III e 21 grau IV) e de cinco amostras de tecido cerebral não-tumoral (grupo controle). RESULTADOS: A distribuição por idade, por sexo e pela localização tumoral dos portadores dessas neoplasias reproduziu, de um modo geral, as tendências mundiais. A presença de células gigantes multinucleadas e de gemistócitos foi associada à malignidade tumoral. Os achados histopatológicos avaliados segundo critérios semiquantitativos e pelo modelo de aprendizagem CART confirmaram a gradação original, reiterando a aplicabilidade e a reprodutibilidade dos mesmos. CONCLUSÃO: Tais resultados indicaram a árvore de decisão CART e o somatório de escores semiquantitativos como estratégias práticas e auxiliares para a graduação dos astrocitomas segundo os critérios da OMS.

BACKGROUND: Despite recent discoveries concerning molecular alterations involved in astrocytoma tumorigenesis, the conventional histological analysis remains the best diagnostic method and a reasonable prognostic indicator for astrocytic tumors. However, the histopathological routine recommended by the World Health Organization (WHO) is laborious and marked by low reproducibility. OBJECTIVE: The present study aimed to develop auxiliary strategies for astrocytic tumor graduation according to histological criteria established by WHO. MATERIAL AND METHOD: A clinical and epidemiological analysis and a histopathological evaluation were performed in 55 astrocytomas of different graduations (13 grade I, 14 grade II, seven grade III, 21 grade IV) and five samples of non-tumor tissue (control group). RESULTS: The distribution by age, sex, and tumor localization of astrocytomas in patients reproduced, in a general way, worldwide trends. The presence of multinucleated cells and gemistocytes was associated with tumoral malignancy. The histopathological findings evaluated through semi-quantitative criteria and CART modeling confirmed the primary classification, reaffirming their applicability and reproducibility. CONCLUSION: These results indicate the CART decision tree and the totality of semi-quantitative scores as practical and auxiliary strategies for astrocytoma graduation as stated by WHO criteria.

Expressão das proteínas BCL-2 e BAX em tumores astrocíticos humanos / Expression of BCL-2 and BAX proteins in human astrocytic tumors

INTRODUÇÃO: Os astrocitomas constituem os mais freqüentes tumores primários do sistema nervoso central (SNC). Admite-se que parte do crescimento tumoral seja resultante da inibição da morte celular programada: a apoptose. Tal fenômeno é basicamente regulado pelo equilíbrio entre moléculas antiapoptóticas (ex.: B-cell lymphoma protein 2 [BCL-2]) e pró-apoptóticas (ex.: BCL-2 associated protein X [BAX]). OBJETIVO: O presente estudo objetivou avaliar a expressão de BCL-2 e BAX em tumores astrocíticos humanos. MATERIAL E MÉTODOS: Procedeu-se ao estudo imuno-histoquímico dessas proteínas utilizando-se o método da avidina-biotina-peroxidase em 55 astrocitomas (13 do grau I, 14 do II, sete do III e 21 do grau IV) e cinco amostras de tecido cerebral não-tumoral (grupo controle). RESULTADOS: Os índices de positividade para BCL-2 e BAX demonstraram propensão ao acréscimo, de acordo com a gradação tumoral, com positividade geral de 43,26 por cento e 24,67 por cento, respectivamente. Essas proteínas não foram detectadas entre os espécimes não-tumorais. Os escores de marcação para BCL-2 apresentaram tendência ao aumento conforme a progressão histológica, enquanto os para BAX mostraram-se semelhantes nas diversas graduações. A análise conjunta dessas proteínas demonstrou significativa correlação com a gradação tumoral (p < 0,05; teste H), sendo mais evidente nos glioblastomas (grau IV) em comparação com os astrocitomas de baixo grau (I e II) (p < 0,05; teste U). A relação BCL-2/BAX indicou o aumento da orientação à sobrevida celular dos tumores astrocíticos de acordo com a progressão maligna. CONCLUSÕES: Tais resultados indicam as alterações na expressão das proteínas BCL-2 e BAX como resultantes do processo tumorigênico nos astrocitomas, com o crescente predomínio do perfil antiapoptótico de acordo com a transformação maligna. Nesse sentido, sugere-se que a superexpressão de BCL-2 nos tumores astrocíticos possa ser indicativa de fenótipos mais agressivos, ...

BACKGROUND: Astrocytomas represent the most frequent primary tumors of the central nervous system. Admittedly, part of tumor growth is due to inhibition of programmed cell death: the apoptosis. This phenomenon is basically regulated by the balance between anti-apoptotic (e.g.: B-cell lymphoma protein 2 [BCL-2]) and pro-apoptotic (e.g.: BCL-2 associated protein X [BAX]) molecules. OBJECTIVE: The present study aimed to evaluate the expression of BCL-2 and BAX in human astrocytic tumors of different histopathological grades. MATERIAL AND METHOD: An immunohistochemical study of those proteins using the avidin-biotin-peroxidase method was performed in 55 astrocytomas (13 grade I, 14 grade II, seven grade III and 21 grade IV) and five samples of non-tumor brain tissue (control group). RESULTS: The BCL-2 and BAX positive indices tended to increase according to astrocytomas graduation, with general positivity of 43.26 percent and 24.67 percent, respectively. These proteins were not detected among non-tumor specimens. BCL-2 labeling scores demonstrated a tendency to increase in accordance with histopathological advancing, while BAX values were similar in all graduations. The combined analyses of these proteins expression presents a significant correlation with tumor grade (p < 0.05; H test), witch is more evident among glioblastomas (grade IV) in comparison with low-grade astrocytomas (I and II) (p < 0.05; U test). BCL-2/BAX ratio denoted increasing of cellular survival orientation of the astrocytic tumors according to malignant progression. CONCLUSIONS: The results indicate alterations in BCL-2 and BAX proteins expression as resultant of the tumorigenic process in astrocytomas, with increasing predominance of the anti-apoptotic profile in consonance of malignant transformation. In this way, we propose that BCL-2 overexpression in astrocytic tumors may be indicative of more aggressive phenotypes, furthermore configuring a potential therapeutic target.

Impacto do oncogene C-MYC no câncer / Impact of the C-MYC oncogene on cancer

O oncogene C-MYC tem sido apontado como peça central no processo tumorigênico em diversos cânceres humanos. Recentes evidências reforçam as participações direta e indireta da proteína C-MYC na regulação do ciclo celular, diferenciação, metabolismo, crescimento celular, apoptose, instabilidade genômica, imortalidade e angiogênese. Novos esforços estão sendo direcionados no sentido da identificação dos genes-alvo regulados pelo C-MYC e da elucidação dos mecanismos moleculares implicados na transformação neoplásica. O maior desafio, todavia, consiste no desenvolvimento de ferramentas capazes de modular a interação entre a proteína C-MYC e os seus alvos moleculares, desvendando potenciais estratégias terapêuticas. A presente revisão aborda aspectos gerais e peculiaridades quanto à ativação e à regulação do C-MYC, bem como discute os diversos programas celulares modulados pela proteína C-MYC.

Astrocitomas: uma revisão abrangente / Astrocyomas: a comprehensive review

A presente revisão aborda os atuais conceitos sobre a origem celular, a etiologia, aclassificação e a graduação dos astrocitomas. Os achados neuropatológicos característicos dos diferentes tipos de neoplasias astrocíticas são apresentados de acordo com o sistema adotado pela Organização Mundial da Saúde. Além disso, relata-se o presente estado da arte acerca da gen´stica molecular desses tumores. Após descrever o perfil epidemiológico e os aspectos clínicos gerais, a situação atual do tratamento multidisciplinar e as novas perspectivas terapêuticas para os astrocitomas são comentadas.

Avaliação metabólica das lesões de isquemia e reperfusão cerebrais após oclusão bilateral das artérias carótidas comuns: estudo experimental em ratos / Metabolic evaluation of ischemic and reperfusion brain injury following bilateral occlusion of common carotid arteries: an experimental study in rats

OBJETIVO: Caracterizar as alterações no metabolismo energético após isquemia/reperfusão cerebral através de um modelo experimental de isquemia global reversível por simples oclusão das artérias carótidas comuns (ACCs) em ratos da linhagem Wistar. MÉTODOS: Quarenta e oito ratos Wistar machos foram distribuídos aleatoriamente em dois grupos (C - Controle; T - Teste) e cada um deles redistribuídos em quatro tempos de estudos. Após oclusão bilateral das ACCs por 30min, permitiu-se reperfusão aos animais do grupo T nos tempos 0, 5, 10 e 15min. Foram coletadas amostras de tecido cerebral e sangue arterial sistêmico e quantificados os metabólitos D-glicose (GLI), piruvato (PRV), lactato (LCT) e adenosina trifosfato (ATP). RESULTADOS: Observou-se aumento nos níveis sangüíneos de GLI e PRV de, respectivamente, 85,00 por cento (p<0,05) e 51,72 por cento (p<0,01) aos 5min de reperfusão, refletindo uma resposta sistêmica à lesão isquêmica cerebral. O LCT cerebral manteve-se estável, apesar da redução de 52,66 por cento (p<0,05) na concentração sanguínea aos 15min de reperfusão. As concentrações cerebrais de ATP caíram 85,40 por cento (p<0,05) após isquemia, seguindo-se aumento de 3.033,40 por cento (p<0,05) aos 5min de reperfusão, evidenciando a retomada da respiração celular via cadeia fosforilativa. CONCLUSÕES: O modelo experimental proposto produziu isquemia global transitória parcial, com repercussão sistêmica. As maiores alterações metabólicas foram verificadas após os primeiros minutos de reperfusão, tipificando a lesão de reperfusão. Tais constatações mostram sua utilidade como ferramenta no estudo da fisiopatologia e de recursos terapêuticos da doença cerebrovascular isquêmica.