Study of hTERT and Histone 3 Mutations in Medulloblastoma

CNPq/Universal (475358/2011-2), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2012/19590-0) and Fundação para a Ciência e Tecnologia (FCT; PTDC/SAU-ONC/115513/2009) grants to R.M.R. The project was cofinanced by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referência Estratégico Nacional (QREN) and Fundo Europeu de Desenvol- vimento Regional (FEDER). M.V.-P. is the recipient of an FCT Post-Doctorate Research Fellowship (SFRH/BPD/104290/2014)Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in nnedulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in nnedulloblastoma.This study was partially supported by CNPq/Universal (475358/2011-2), Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; 2012/19590-0) and Fundacao para a Ciencia e Tecnologia (FCT; PTDC/SAU-ONC/115513/2009) grants to R.M.R. The project was cofinanced by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN) and Fundo Europeu de Desenvolvimento Regional (FEDER). M.V.-P. is the recipient of an FCT Post-Doctorate Research Fellowship (SFRH/BPD/104290/2014).info:eu-repo/semantics/publishedVersio

IDH1 mutations in a Brazilian series of Glioblastoma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Albert Einstein Jewish HospitalUniversidade de São Paulo Faculdade de Medicina Department of NeurologyUniversidade de São Paulo Faculdade de Medicina Department of PathologyCancer Institute of São PauloFundação Pio XII Barretos Cancer HospitalFederal University of São Paulo School of Medicine Department of NeurologyFederal University of São Paulo School of Medicine Department of PathologyNove de Julho HospitalAlbert Einstein Jewish HospitalUNIFESP, EPM, Department of NeurologyUNIFESP, EPM, Department of PathologyFAPESP: 04/12133-6SciEL

Metastase medular tardia de germinoma supra-selar: registro de um caso

Paciente operado de tumor intramedular que evoluiu para o óbito, cuja necrópsia revelou presença de germinoma intramedular e germinoma supra-selar remanescente de tratamento cirúrgico e radioterápico realizado 11 anos antes. São discutidas a etiologia e a conduta cirúrgica e radioterápica

Regional mild hypothermia in the protection of the ischemic brain A hipotermia regional moderada na proteção do encéfalo isquêmico

Objective: To demonstrate that mild hypothermia can be a protective element when an ischemic onset occurs in rabbit brains. Methods: A rabbit model of focal ischemia was used to test the protection provided by mild hypothermia regionally produced by means of the placement of ice bag on the scalp of a hemicranium which has had previously its bone removed. Twenty New Zealand White rabbits were divided into two groups as follows: (A) a control group where an ischemic lesion was produced by coagulation of the middle cerebral artery and (B) a brain protected group where mild hypothermia was provided during 80 to 100 minutes after the same ischemic lesion. The brains slices were stained with 2,3,5-Triphenyletrazolium (TTC). The sections were photographed with a digital camera and the infarct volume was measured through a computer program. Results: The average of infarct volume was 70.53 mm³ in the control group. In the protected group, the average of infarct volume was 41,30 mm³ only in five animals. Five animals of this group did not demonstrate macroscopically and microscopically infarct area. Conclusions: We concluded that mild hypothermia regionally produced may protect ischemic brains of rabbits.<br>Objetivo: Demonstrar a proteção que a hipotermia moderada pode fornecer em casos de isquemia em encéfalos de coelhos. Métodos: Foi utilizado um modelo de isquemia focal em coelhos, para avaliar a proteção fornecida por meio de hipotermia moderada, produzida através da colocação de pedras de gelo contidas no interior de um pequeno saco plástico, em contato com o couro cabeludo de um hemicrânio onde a tábua óssea foi previamente removida. Vinte coelhos da raça Nova Zelândia Branca, pesando de 3,100 Kg a 3,750 Kg foram divididos em dois grupos: (A) um grupo controle onde foi produzida uma lesão isquêmica por meio da coagulação da artéria cerebral média e (B) um grupo submetido a neuroproteção por hipotermia moderada regional durante 80 a 100 minutos após a produção da mesma lesão isquêmica. As secções de encéfalos foram coradas com 2,3,5-Tryphenyltetrazolium (TTC). As lâminas foram fotografadas com câmara digital e o volume de infarto foi calculado através de um programa de computador. Resultados: O volume médio de infarto foi de 70,53 mm³ no grupo controle, enquanto que o grupo com neuroproteção apresentou média de 41,30 mm³ em 5 animais.Cinco animaisdeste grupo não demonstraram macroscópica e microscopicamente áreas de infarto. Conclusões: Concluímos que a hipotermia moderada, localmente aplicada, pode proteger encéfalos isquêmicos de coelhos

Performance of adjuvant treatment correlates with survival in reoperated glioblastomas

ABSTRACT Objective To analyze cases of recurrent glioblastoma subjected to reoperation at a Brazilian public healthcare service. Methods A total of 39 patients subjected to reoperation for recurrent glioblastoma at the Department of Neurosurgery, São Paulo Hospital, Federal University of São Paulo, from January 2000 to December 2013 were retrospectively analyzed. Results The median overall survival was 20 months (95% confidence interval – CI = 14.9–25.2), and the median survival after reoperation was 9.1 months (95%CI: 2.8–15.4). The performance of adjuvant treatment after the first operation was the single factor associated with overall survival on multivariate analysis (relative risk – RR = 0.3; 95%CI = 0.2–0.7); p = 0.005). Conclusion The length of survival of patients subjected to reoperation for glioblastoma at a Brazilian public healthcare service was similar to the length reported in the literature. Reoperation should be considered as a therapeutic option for selected patients