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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

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61

Microarray and biochemical analysis of lovastatin-induced apoptosis in human glioblastoma cells: synergism with TRAIL.

January 2006 (has links)
Chan Yiu Leung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 123-149). / Abstracts in English and Chinese. / Abstracts --- p.I / Acknowledgements --- p.VIII / List of Figures --- p.IX / Lists of Abbreviations --- p.X / Contents --- p.XII / Chapter Chapter One: --- Introduction and Literature Review --- p.1 / Chapter 1.1 --- Cancer in General --- p.1 / Chapter 1.2 --- Glioma --- p.3 / Chapter 1.2.1 --- Types of Glioma --- p.6 / Chapter 1.2.1.1 --- Astrocytomas --- p.6 / Chapter 1.2.1.2 --- Oligodendrogliomas --- p.8 / Chapter 1.2.1.3 --- Ependymomas --- p.9 / Chapter 1.2.2 --- Glioblastoma Multiforme (GBM) --- p.10 / Chapter 1.2.3 --- Molecular Biology of GBM --- p.11 / Chapter 1.2.4 --- Current Treatment for GBM --- p.15 / Chapter 1.3 --- HMG-Co A reductase inhibitors --- p.17 / Chapter 1.3.1 --- Pharmacology of HMG-Co A reductase inhibitor --- p.18 / Chapter 1.3.2 --- Epidemiological link between HMG-Co A Reductase Inhibitors and Cancer --- p.20 / Chapter 1.3.3 --- Current HMG-Co A reductase inhibitors research in cancer --- p.21 / Chapter 1.3.3.1 --- Inhibition of tumor cell growth --- p.21 / Chapter 1.3.3.2 --- Inhibition of Angiogenesis --- p.22 / Chapter 1.3.3.3 --- Anti-invasive effects of HMG-Co A reductase inhibitors.… --- p.23 / Chapter 1.3.3.4 --- Apoptosis induction by HMG-Co A reductase inhibitors --- p.24 / Chapter 1.3.4 --- In vivo efficacy and synergistic effects --- p.25 / Chapter 1.4 --- Tumor Necrosis Factor (TNF) related apoptosis-inducing Ligand (TRAIL) --- p.28 / Chapter 1.4.1 --- Molecular mechanisms of TRAIL-induced apoptosis --- p.29 / Chapter 1.4.2 --- Role for TRAIL in cancer therapy --- p.30 / Chapter 1.5 --- Objectives --- p.34 / Chapter Chapter 2 --- Methods and Materials --- p.35 / Chapter 2.1 --- Cell culture --- p.35 / Chapter 2.2 --- Cell proliferation detection (MTT) methods --- p.36 / Chapter 2.3 --- "Caspase 3,9 activities induced by lovastatin" --- p.37 / Chapter 2.4 --- Detection of apoptosis by Annexin V and PI staining --- p.39 / Chapter 2.5 --- Cell cycle analysis protocols --- p.41 / Chapter 2.6 --- DNA fragmentation ELISA detection kit protocols --- p.42 / Chapter 2.7 --- Reverse Transcription (RT) Polymerase Chain Reaction (PCR) --- p.44 / Chapter 2.8 --- Polymerase Chain Reaction (PCR) --- p.46 / Chapter 2.9 --- Bio-molecules extraction/purification protocols --- p.48 / Chapter 2.10 --- "Microarray analysis on lovastatin treated glioblastoma cells A172, M059J and M059K" --- p.51 / Chapter 2.10.1 --- Cells treatment and RNA extraction --- p.51 / Chapter 2.10.2 --- Synthesis of first strand cDNA --- p.53 / Chapter 2.10.3 --- Synthesis of second strand cDNA --- p.54 / Chapter 2.10.4 --- Purification of double stranded cDNA --- p.54 / Chapter 2.10.5 --- Synthesis of cRNA by in vitro transcription (IVT) --- p.55 / Chapter 2.10.6 --- Recovery of biotin-labelled cDNA --- p.56 / Chapter 2.10.7 --- Fragmentation of cRNA --- p.56 / Chapter 2.10.8 --- Preparation of hybridization reaction mixtures --- p.57 / Chapter 2.10.9 --- Loading of reaction mixtures into bioarray chambers --- p.58 / Chapter 2.10.10 --- Hybridization --- p.58 / Chapter 2.10.11 --- Post-hybridization wash --- p.59 / Chapter 2.10.12 --- 2.11.12Detection with streptavidin-dye conjugate --- p.59 / Chapter 2.10.13 --- Bioarray scanning and analysis --- p.61 / Chapter Chapter 3: --- Results --- p.62 / Chapter 3.1 --- Morphological effects of Lovastatin on human glioblastoma cells --- p.62 / Chapter 3.2 --- Anti-proliferation effects on glioblastoma cell lines --- p.64 / Chapter 3.3 --- Lovastatin-induced caspase3 and 9 activation in human glioblastoma cell lines --- p.69 / Chapter 3.4 --- Cell cycle determination by PI staining --- p.77 / Chapter 3.5 --- Quantification of apoptotic cell death by annexin V and propidium iodide staining --- p.79 / Chapter 3.6 --- Microarray analysis of lovastatin-modulated gene expression profiles --- p.82 / Chapter 3.7 --- Synergistic effects induced by lovastatin and Tumor Necrosis Factor related apoptosis-inducing Ligand (TRAIL) --- p.87 / Chapter 3.7.1 --- M059J and M059K glioblastoma cells was resistant to TRAIL attack --- p.87 / Chapter 3.7.2 --- Synergistic cell death was induced by lovastatin and TRAIL --- p.87 / Chapter 3.7.3 --- A combination of TRAIL and lovastatin induces synergistic apoptosis in glioblastoma cells --- p.93 / Chapter 3.7.4 --- DNA fragmentation on glioblastoma cells --- p.98 / Chapter 3.7.5 --- Four TRAIL receptors mRNA expression profiles on glioblastoma cells --- p.102 / Chapter Chapter 4 --- Discussion --- p.105 / Chapter 4.1 --- Lovastatin exhibited anti-proliferation effects in human glioblastoma cells --- p.107 / Chapter 4.2 --- Lovastatin activated caspase 3 and caspase 9 in human glioblastoma cells --- p.108 / Chapter 4.3 --- Gene expression profile modulated by Lovastatin in human glioblastoma cells --- p.110 / Chapter 4.4 --- Lovastatin-sensitized TRAIL-induced apoptosis in human glioblastoma cells --- p.117 / Chapter Chapter Five: --- Conclusion and Future perspective --- p.121 / References --- p.122 / Appendix --- p.150
Apoptosis
Tumor necrosis factor
Glioblastoma multiforme--Treatment
Brain--Tumors--Chemotherapy
Lovastatin--therapeutic use
Apoptosis--drug effects
Glioblastoma--therapy
Brain Neoplasms--drug therapy
62

Late radiation-induced temporal lobe necrosis as a model of radiation-induced cerebral necrosis: a magnetic resonance study. / CUHK electronic theses & dissertations collection

January 2003 (has links)
Chan Yu-leung. / "Nov 2003." / Thesis (M.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 179-193). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.
Brain--Tumors
Temporal lobes--Necrosis
Brain--Radiation injuries
Brain Neoplasms--radiotherapy
Temporal Lobe--radiation effects
Temporal Lobe--physiopathology
Necrosis--physiopathology
Radiation Injuries--complications
Radiation Injuries--physiopathology
Radiotherapy--adverse effects
Magnetic Resonance Imaging
63

Dijagnostički značaj i pouzdanost stereotaksične biopsije u tretmanu pacijenata sa tumorima mozga / Diagnostic value and reliability of stereotactic biopsy in treatment of patients with brain tumors

Jelača Bojan 14 September 2018 (has links)
<p>Uvod: Implementacija brojnih neuroradiolo&scaron;kih modaliteta je značajno uticala na način i efikasnost sprovođenja dijagnostike tumora mozga. Na osnovu neinvazivno dobijenih podataka može se postaviti diferencijalna dijagnoza, ali do sada nije potvrđena nijedna neuroradiolo&scaron;ka metoda koja može samostalno i konačno da postavi definitivnu patohistolo&scaron;ku (PH) dijagnozu. Stereotaksična biopsija je neurohirur&scaron;ka procedura kojom se, bez bitnog naru&scaron;avanja integriteta i funkcije moždanog tkiva, može obezbediti reprezentativni uzorak intrakranijalne tumorske promene radi sprovođenja PH i drugih specifičnih analiza, u cilju postavljanja tačne dijagnoze i potom primene adekvatnog lečenja. Cilj: Cilj ove studije je da se utvrditi mogućnost uzorkovanja reprezentativnog tkiva za postavljanje PH dijagnoze uz pomoć stereotaksične biopsije kod pacijenata sa tumorom mozga, kao i da se utvrdi vrsta i učestalost eventualnih komplikacija same procedure i postojanje korelacije između PH nalaza dobijenog stereotaksičnom biopsijom i rezultata sprovedenih neuroradiolo&scaron;kih ispitivanja. Materijal i metode: Sprovedeno istraživanje je bilo kliničko, prospektivno, a uzorak je činilo ukupno 50 pacijenata koji su bili hospitalizovani na Klinici za neurohirurgiju KCV zbog dijagnostikovane tumorske promene mozga i postavljene indikacije za stereotaksičnu biopsiju, u periodu od septembra 2016. godine do januara 2018. godine. Svi pacijenti koji su uključeni u studiju su u sklopu sprovedene dijagnostičke obrade imali načinjen magnetno rezonanantni (MRI) pregled glave na osnovu kojeg su se određivale morfolo&scaron;ke karakteristike tumora i vr&scaron;ila procena prirode tumorske promene mozga, a kod ukupno 25 pacijenata je dodatno načinjena MR spektroskopija (MRS) dijagnostikovane tumorske promene sa ciljem određivanja biohemijskog profila i dodatne procene i karakterizacije tkiva. Nakon sprovedene detaljne onkolo&scaron;ke obrade i adekvatne pripreme, se sprovodila kompjuterizovanom tomografijom (CT) navođena stereotaksična biopsija sa ramom u cilju uzorkovanja adekvatnog tkiva za PH analizu. U toku istraživanja procena uspe&scaron;nosti uzorkovanja reprezentativnog tkiva se vr&scaron;ila pregledom bioptata od strane patologa, a nakon procedure se kliničkim pregledom i kontrolnim CT pregledom glave utvrđivao stepen komplikacija. Rezultati: Dobijeni rezultati su pokazali da su fokalni neurolo&scaron;ki deficit i moždani sindrom bili najče&scaron;ći klinički simptomi i znaci kod pacijenata kod kojih je indikovana stereotaksična biopsija tumora mozga. Prema MRI nalazu najzastupljenije su bile difuzne tumorske promene sa 36% udela u uzorku, zatim solitarne sa 34% i multifokalne sa 20%, a potom multicentrične tumorske promene koje su predstavljale 10% uzorka. Takođe, na osnovu MRI i MRS nalaza je oko 80% tumora procenjeno kao najverovatnije glijalnog porekla. U 95,9% slučaja je postavljena precizna PH dijagnoza. Nepromenjeno stanje svesti i neurolo&scaron;ki nalaz su imali 92% pacijenata nakon biopsije, a kod 3 pacijenta (6%) je do&scaron;lo do razvoja prolaznog neurolo&scaron;kog deficita, dok je jedan pacijent (2%) razvio trajan neurolo&scaron;ki deficit. Ukupan morbiditet vezan za proceduru je stoga 2%, a nije zabeležen ni jedan smrtni slučaj (mortalitet 0%) tokom sprovođenja studije. Zaključak: Stereotaksična biopsija je dokazana i veoma pouzdana procedura sa malim brojem komplikacija i niskom stopom morbiditeta i mortaliteta, kojom se omogućava dobijanje reprezentativnog uzorka tumorskog tkiva za postavljanje sigurne patohistolo&scaron;ke dijagnoze. Intraoperativna PH analiza dela uzorka tkiva dodatno pobolj&scaron;ava uspe&scaron;nost pri uzorkovanju i postavljanju definitivne PH dijagnoze. Savremene neuroradiolo&scaron;ke metode imaju visoku specifičnost u razlikovanju biolo&scaron;ke prirode tumorskih promena, ali se ne mogu koristi nezavisno od PH analize uzorka tkiva</p> / <p><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> <w:DontVertAlignInTxbx/> <w:Word11KerningPairs/> <w:CachedColBalance/> 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5.4pt;mso-para-margin-top:0in;mso-para-margin-right:0in;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0in;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"Times New Roman";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]-->Introduction: The implementation of numerous neuroradiological techniques has significantly influenced the way and the efficiency in which the diagnosis of brain tumor is established. Based on non-invasive imaging data, a differential diagnosis can be made, but no neuroradiological method has been established so far, which can finally make a definitive diagnosis. Stereotactic biopsy is a neurosurgical procedure that can provide a representative sample of any intracranial tumor in order to performe histopathological and other specific examinations, and to set the exact diagnosis and then apply adequate treatment, but without significantly impairing the integrity and function of brain tissue. Objective: The aim of this study is to determine the diagnostic value of stereotactic biopsy and ability of providing the representative tissue in order to establish a pathohistological diagnosis in patients with brain tumors. Also, the aim is to determine the type and frequency of possible complications of the procedure itself and the correlation between the pathohistological findings obtained and the results of the conducted neuroradiological examinations. Materials and methods: This research was clinical, prospective and included a total of 50 patients who were hospitalized at the Clinical Center of Vojvodina, from September 2016 to January 2018, due to diagnosed brain tumor for which the stereotactic biopsy is indicated. In all patients magnetic resonance (MRI) examination of the head was used to determine morphological characteristics and assesse the nature of the brain tumor tissue, and in a total of 25 patients MR spectroscopy was additionally made with the goal of determining the biochemical profile and additional tissue assessment and characterization. After detailed oncological assessment, completed laboratory and radiological diagnostics, a CT guided framebased stereotactic biopsy was performed for the purpose of sampling tumor tissue for pathohistological analysis. During the research, the success rate of biopsy in providing the representative tissue and establishing the diagnosis was performed by a pathologist, and after the procedure, a clinical and a control head CT examination was used to review the rate of complications. Results: The results obtained showed that focal neurological deficit and psychoorganic syndrome were the most common clinical symptoms and signs in this study. According to MRI, the most common were diffuse brain tumors with 36% of the sample, then solitary with 34% and multifocal with 20%, followed by multicentric tumors representing 10% of the study sample. Also, based on MRI and MRS findings, approximately 80% of tumors are estimated to be most likely of glial origin. In 95.9% of cases, a complete pathohistological (PH) diagnosis was established. The unchanged neurological status was observed in 92% of patients after biopsy, and 3 patients (6%) developed a transient neurological deficit, while only one patient (2%) developed a permanent neurological deficit. The total morbidity associated with the procedure is therefore 2%, and no deaths (mortality 0%) related to the procedure during the study is recorded. Conclusion: Stereotactic biopsy is highly reliable procedure with a small number of complications and a low morbidity and mortality rate, which allows us to acquire the representative sample of brain tumor tissue and to establish a pathohistological diagnosis. Intraoperative PH analysis of acquired tissue samples further enhances the sampling performance and the setting of definitive PH diagnosis. Modern neuroradiological modalities have a high specificity in distinguishing the biological nature of brain tumors, but they still can not be used independently of the pathohistological analysis of the tissue sample.</p>
64

Mortalidade por tumores do sistema nervoso central no Município do Rio de Janeiro, 1980-2007 / Mortality from tumors of the central nervous system in Rio de Janeiro, 1980-2007

Gasparini, Brenda January 2010 (has links)
Made available in DSpace on 2011-05-04T12:36:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2010 / Os tumores do Sistema Nervoso Central (SNC) são raros, porém vêm ganhando importância no cenário epidemiológico devido ao aparente aumento de sua incidência e de sua mortalidadeem vários países ao longo das últimas décadas, especialmente entre idosos. Este incremento parece ser explicado apenas parcialmente pela maior disponibilidade de acesso aos cuidados com a saúde, principalmente aos meios de diagnóstico por imagem. Apesar dos avanços na pesquisa epidemiológica e de genética molecular, a etiologia destes tumores ainda permanece pouco conhecida. Este estudo descritivo tem por objetivo determinar o padrão da mortalidade por tumores do SNC no município do Rio de Janeiro no período de 1980 a 2007. O desenvolvimento deste trabalho deu origem a dois artigos que compõem a estrutura desta dissertação. O primeiro artigo aborda questões mais relevantes que emergem nos estudos da epidemiologia destes tumores em crianças e adolescentes e aponta para a diminuição da mortalidade por estes tumores em menores de 20 anos de idade em ambos os sexos. Já o segundo artigo, aborda as questões que envolvem os adultos acometidos por esta neoplasia e aponta para o aumento da mortalidade de 1,1 por cento ao ano no período. O incremento foi maior nas mulheres: 2 por cento ao ano. Em resumo, os resultados observados acompanham as tendências mundiais. A análise da mortalidade é um passo importante para o conhecimento do perfil epidemiológico das neoplasias do SNC na população estudada, mas idealmente deve ser complementada por estudos de incidência e de sobrevida. / Tumors of the central nervous system (CNS) are rare but have been gaining importance in the epidemiological scenario due to the apparent increase in its incidence and mortality in several countries over the past decades, especially among the elderly. This increase seems to be only partially explained by the greater availability of access to health care, primarily to diagnostic imaging. Despite advances in epidemiological research and molecular genetics, the etiology of these tumors remains unclear. This descriptive study aims to determine the pattern of mortality from CNS tumors in Rio de Janeiro in the period 1980-2007. The development of this work resulted in two articles that make up the structure of this dissertation. The first article discusses the most relevant issues that emerge in studies of the epidemiology of these tumors in children and adolescents and points to the reduction in the mortality from these tumors in individuals less than 20 years of age in both sexes. The second article discusses the issues involving adults affected by this cancer and points to the increased mortality of 1.1% per annum in the period. The increase was higher in women: 2% per year. In summary, the results observed follow worldwide trends. The analysis of mortality is an important step towards the knowledge of the epidemiology of CNS tumors in the studied population, but ideally should be complemented by studies of incidence and survival.
Mortalidade
Neoplasias Encefálicas
Epidemiologia
Sistemas de Informação
Neoplasias Encefálicas/epidemiologia
Neoplasias Encefálicas/mortalidade
Sistemas de Informação
Sistema Nervoso Central/patologia
Mortality
Brain Neoplasms
Epidemiology
Information Systems
Neoplasias Encefálicas/epidemiologia
Neoplasias Encefálicas/mortalidade
Sistemas de Informação
Sistema Nervoso Central/patologia
-Distribuição por Idade e Sexo
65

Ultrassonografia durante cirurgia para metástase cerebral: influência no índice de Karnofsky e volume do tumor residual / Ultrasonography during surgery to treat cerebral metastases: influence on Karnofsky index score and residual tumor volume

Marcelo de Lima Oliveira 30 May 2016 (has links)
Introdução: Os principais objetivos do tratamento das metástases cerebrais (MC) são no auxílio do controle da doença no encéfalo e a melhora da qualidade de vida dos pacientes. A cirurgia convencional tem um importante papel no tratamento das MCs e os métodos de monitoração intraoperatória podem auxiliar na obtenção de resultados cirúrgicos melhores. Objetivos: Avaliar a influência da ultrassonografia encefálica durante cirurgia para ressecção de MC no índice de Karnofsky e no grau de ressecção do tumor. Métodos: Neste estudo prospectivo controlado e não randomizado, doentes com indicação de tratamento cirúrgico de MCs foram incluídos. A ultrassonografia intraoperatória (USIO) foi realizada por um neurossonologista. O índice de Karnofsky foi avaliado por equipe multidisciplinar de oncologia; o grau de dificuldade para ressecção cirúrgica do tumor foi avaliado pelo cirurgião e o volume tumoral foi avaliado pelo neurorradiologista por meio da RM realizada no pré e pós-operatório. Resultados: Dos 78 doentes, 40 homens e 38 mulheres com idade média de 53 anos, 35 foram submetidos a tratamento cirúrgico com auxílio da USIO. Não houve diferença estatística no KPS e volume tumoral pré-operatório entre os grupos. O KPS pós-operatório no grupo da USIO foi de 80 e no grupo-controle de 70 (p=0,045). Considerando-se a melhora do KPS no pós-operatório, a quantidade de doentes tiveram melhora do KPS foi superior no grupo da USIO (p=0,036) destacando-se os seguintes subgrupos: tumores com grau de dificuldade de ressecção < 4 (p=0,037), tumores nas áreas eloquentes (p=0,043), tumores não relacionados aos grandes vasos e nervos (p=0,007), e lesões únicas no leito cirúrgico (p=0,038). O tumor residual na RM pós-operatória foi menor no grupo da USIO: 9,5% no grupo da USIO e 30,8% no grupo-controle; 1,6 mm3 no grupo da USIO e 9 mm3 do grupo-controle; p=0,05. Considerando-se doentes com KPS >= 70, o número de doentes com volume de tumor residual inferior a 10% em relação ao volume pré-operatório foi superior no grupo da USIO (p=0,032 e OR de 3,8). Conclusão: Os achados deste estudo sugerem que a USIO encefálica pode influenciar na melhora do índice de Karnofsky e na redução do volume de tumor residual / Object: The goals of treating a cerebral metastasis (CM) are to achieve local control of the disease and to improve patient quality of life. The aim of this study was to analyse the effect of using conventional surgery supported by intra-operative ultrasound (IOUS) to approach a CM. To perform this analysis, we determined Karnofsky post-operative scores (KPS) and tumour resection grades. Methods: Patients with CM who were eligible to undergo a surgical approach were included in this study. Surgical treatment was either supported or not supported by IOUS. A neural oncology team determined the pre- and post-operative KPS. A radiologist examined the tumour volume using pre- and post-operative magnetic resonance imaging. Before the surgery, the surgeon determined whether it was possible to perform a total CM resection. Results: A total of 78 patients with CM diagnosis were treated using a surgical approach (35 with and 43 without IOUS). The post-operative median KPS was higher in the IOUS group (80 versus 70, p=0.045). Within the IOUS group, KPS evolution was superior (p=0.036), especially in the following CM subgroups: a difficulty of tumour resection ranking score<4 (p=0.037), the tumour was in an eloquent area (p=0.043), the tumour was not associated with vessels or nerves (p=0.007), and solitary lesions (p=0.038). The volume of residual tumours was lower in the IOUS group (9.5% and 1.6 mm3 versus 30.8% and 9 mm3, p=0.05). In patients with a KPS >= 70, the residual tumour volume was categorized as < 10% or >= 10%, and 62% of patients had < 10% residual tumours (76% in the IOUS group and 45% in the non-IOUS group; p=0.032 and OR=3.8). Conclusion: This study suggests that IOUS can play a role in improving post-operative KPS and in decreasing residual tumours in CM surgeries
Avaliação de estado de Karnofsky
Carga tumoral
Metástase neoplásica
Monitoramento intraoperatório
Neoplasia residual
Neoplasias encefálicas/ultrassonografia
Ultrassonografia de intervenção
Brain neoplasms/ultrasonography
Karnofsky performance status
Monitoring intraoperative
Neoplasm metastasis
Neoplasm residual
Tumor burden
Ultrasonography interventional
66

Expressão de CXCR7 e CXCR4 em em astrocitomas iniltrativos em relação ao tecido cerebral não neoplásico e sua interação com HIF1alfa e IDH1 / CXCR7 and CXCR4 expressions in infiltrative astrocytomas and their interactions with HIF1alfa and IDH

Bianco, André de Macedo 12 September 2013 (has links)
Introdução: Existem dados suficientes disponíveis demonstrando a importância da quimiocina CXCL12 e seu receptor CXCR4 na progressão tumoral e angiogênese dos gliomas. O CXCR4 é regulado positivamente pelo HIF1alfa. Recentemente um novo receptor com maior afinidade à CXCL12 foi identificado, o receptor órfão RDC1, agora denominado CXCR7. O objetivo deste estudo é investigar a expressão de mRNA CXCR7 em tecidos astrocitomas difusos e avaliar suas interações com expressão CXCR4 e HIF1alfa, bem como analisar sua relação com mutação do IDH1. Métodos: A expressão do CXCR7, CXCR4, IDH1 e HIF1alfa foram avaliadas por PCR quantitativo em tempo real (qRT-PCR) em 129 amostras congeladas de astrocitomas (25 astrocitoma difuso - AGII, 18 de astrocitoma anaplásico - AGIII e 86 glioblastoma - GBM) e 22 amostras de tecido cerebral não neoplásico (NN) obtidos de cirurgia de epilepsia. A mutação do IDH1 previamente determinada foi analisada em relação aos níveis de expressões de mRNA do CXCR7, CXCR4 e HIF1alfa, combinado com os parâmetros clínico-patológicos e sobrevida global. Adicionalmente, a expressão proteica do CXCR7 foi analisada por imuno-histoquímica em astrocitomas de diferentes graus e em linhagem celular de glioma (U87MG) por microscopia confocal. Resultados: Houve diferença significativa nos níveis de expressão dos genes estudados entre astrocitomas e NN (p < 0,001). Na análise da expressão gênica associada nos AGII não se observou correlação entre os níveis de expressão de CXCR7/HIF1alfa (p = 0,548); observou-se correlação significativa entre CXCR7/IDH1 (p < 0,001) e CXCR7/CXCR4 (p = 0,042). Nos GBM houve correlação significativa entre CXCR7/CXCR4 (p = 0,002), CXCR7/IDH1 (p < 0,001) e CXCR7/HIF1alfa (p = 0,008). Hiperexpressão do HIF1alfa foi associado com maior expressão do CXCR7 e CXCR4 (p = 0,001), enquanto a presença de IDH1 mutado foi associada a menor expressão de mRNA do CXCR7 e CXCR4 (p = 0,009). A expressão proteica de CXCR7 foi identificada em todas as amostras estudadas, e aumentou com malignidade. A proteína CXCR7, na linha celular U87MG, foi localizada principalmente na membrana celular. Conclusão: O CXCR7 é um gene diferencialmente expresso em astrocitomas difusamente infiltrativos em relação tecido cerebral não neoplásico. O nível de expressão do CXCR7 correlacionou-se significativamente com os níveis de expressão do CXCR4 e IDH1 nos AGII e com CXCR4, IDH1 e HIF-1alfa nos GBM. O nível de expressão elevado do CXCR7 e CXCR4 correlacionou-se com nível elevado de expressão de HIF-1a, enquanto a presença da mutação do IDH1 associou-se a níveis reduzidos de CXCR7 e CXCR4. Não se observou associação significativa entre os níveis de expressão de CXCR7 e CXCR4 com os dados de sobrevida / Introduction: There is abundant evidence showing that chemokine CXCL12 and its receptor CXCR4 are involved in glioma progression and angiogenesis. CXCR4 is upregulated by HIF1alfa. The CXCR7, a recent additional receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytoma tissues and to evaluate its interactions with CXCR4 and HIF1alfa expression and IDH1 mutation. Methods: CXCR7, CXCR4, IDH1 and HIF1alfa expressions were evaluated by quantitative real-time PCR (qRT-PCR) in 129 frozen samples of astrocytoma (25 diffuse astrocytomas - AGII, 18 anaplastic astrocytomas - AGIII and 86 glioblastomas - GBM) and 22 samples of non-neoplastic tissue cerebral (NN) from epilepsy surgery. IDH1 mutation status was analyzed with CXCR7, CXCR4 e HIF1alfa mRNA expressions, matched with clinicopathological parameters and overall survival time. Furthermore, CXCR7 protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. Results: There was significant difference in the expression levels of the genes studied between astrocytomas and NN (p < 0.001). The analysis of associated gene expressions in AGII showed no significant correlation between CXCR7/HIF1alfa (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). In GBM, there were significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1alfa (p = 0.008). HIF1alfa overexpression was associated with higher expressions of CXCR7 and CXCR4 (p = 0.001), while presence of IDH1 mutation was associated with lower CXCR7 and CXCR4 mRNA expressions (p = 0.009). Protein expression was identified in all samples studied, and it increased with malignancy. CXCR7 protein, in U87MG cell line, was mainly localized in the cellular membrane. Conclusion: CXCR7 was overexpressed in astrocytoma of different grades of malignancy compared to non-neoplastic brain tissue. CXCR7 expression levels correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1alfa in GBM. Overexpression HIF1alfa was related with higher expressions of CXCR7 and CXCR4, otherwise presence of IDH1 mutation related with lower expression of both genes. Protein expression level was associated with the degree of malignancy. The results revealed no significant association between CXCR7 and CXCR4 expression and survival data
Análise de sobrevida
Astrocitoma/genética
Astrocytoma/genetics
Brain neoplasms/genetics
Brain neoplasms/pathology
CXCR7 protein human
CXCR7 proteína humana
DNA primers/genetics
Expressão gênica
Gene expression
Gioblastoma
Glioblastoma
Hypoxia-Inducible Factor 1 alpha subunit
IDH1 protein human
IDH1 proteína humana
Immunohistochemistry
Imunoistoquímica
Mutação/genética
Mutation/genetics
Neoplasias encefálicas/genética
Neoplasias encefálicas/patologia
Primers DNA/genética
Real-time polymerase chain reaction
Receptores CXCR4
Receptores de quimiocinas
Receptors chemokine
Receptors CXCR4
RNA mensageiro
RNA messenger
Survival analysis
67

Expressão de CXCR7 e CXCR4 em em astrocitomas iniltrativos em relação ao tecido cerebral não neoplásico e sua interação com HIF1alfa e IDH1 / CXCR7 and CXCR4 expressions in infiltrative astrocytomas and their interactions with HIF1alfa and IDH

André de Macedo Bianco 12 September 2013 (has links)
Introdução: Existem dados suficientes disponíveis demonstrando a importância da quimiocina CXCL12 e seu receptor CXCR4 na progressão tumoral e angiogênese dos gliomas. O CXCR4 é regulado positivamente pelo HIF1alfa. Recentemente um novo receptor com maior afinidade à CXCL12 foi identificado, o receptor órfão RDC1, agora denominado CXCR7. O objetivo deste estudo é investigar a expressão de mRNA CXCR7 em tecidos astrocitomas difusos e avaliar suas interações com expressão CXCR4 e HIF1alfa, bem como analisar sua relação com mutação do IDH1. Métodos: A expressão do CXCR7, CXCR4, IDH1 e HIF1alfa foram avaliadas por PCR quantitativo em tempo real (qRT-PCR) em 129 amostras congeladas de astrocitomas (25 astrocitoma difuso - AGII, 18 de astrocitoma anaplásico - AGIII e 86 glioblastoma - GBM) e 22 amostras de tecido cerebral não neoplásico (NN) obtidos de cirurgia de epilepsia. A mutação do IDH1 previamente determinada foi analisada em relação aos níveis de expressões de mRNA do CXCR7, CXCR4 e HIF1alfa, combinado com os parâmetros clínico-patológicos e sobrevida global. Adicionalmente, a expressão proteica do CXCR7 foi analisada por imuno-histoquímica em astrocitomas de diferentes graus e em linhagem celular de glioma (U87MG) por microscopia confocal. Resultados: Houve diferença significativa nos níveis de expressão dos genes estudados entre astrocitomas e NN (p < 0,001). Na análise da expressão gênica associada nos AGII não se observou correlação entre os níveis de expressão de CXCR7/HIF1alfa (p = 0,548); observou-se correlação significativa entre CXCR7/IDH1 (p < 0,001) e CXCR7/CXCR4 (p = 0,042). Nos GBM houve correlação significativa entre CXCR7/CXCR4 (p = 0,002), CXCR7/IDH1 (p < 0,001) e CXCR7/HIF1alfa (p = 0,008). Hiperexpressão do HIF1alfa foi associado com maior expressão do CXCR7 e CXCR4 (p = 0,001), enquanto a presença de IDH1 mutado foi associada a menor expressão de mRNA do CXCR7 e CXCR4 (p = 0,009). A expressão proteica de CXCR7 foi identificada em todas as amostras estudadas, e aumentou com malignidade. A proteína CXCR7, na linha celular U87MG, foi localizada principalmente na membrana celular. Conclusão: O CXCR7 é um gene diferencialmente expresso em astrocitomas difusamente infiltrativos em relação tecido cerebral não neoplásico. O nível de expressão do CXCR7 correlacionou-se significativamente com os níveis de expressão do CXCR4 e IDH1 nos AGII e com CXCR4, IDH1 e HIF-1alfa nos GBM. O nível de expressão elevado do CXCR7 e CXCR4 correlacionou-se com nível elevado de expressão de HIF-1a, enquanto a presença da mutação do IDH1 associou-se a níveis reduzidos de CXCR7 e CXCR4. Não se observou associação significativa entre os níveis de expressão de CXCR7 e CXCR4 com os dados de sobrevida / Introduction: There is abundant evidence showing that chemokine CXCL12 and its receptor CXCR4 are involved in glioma progression and angiogenesis. CXCR4 is upregulated by HIF1alfa. The CXCR7, a recent additional receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytoma tissues and to evaluate its interactions with CXCR4 and HIF1alfa expression and IDH1 mutation. Methods: CXCR7, CXCR4, IDH1 and HIF1alfa expressions were evaluated by quantitative real-time PCR (qRT-PCR) in 129 frozen samples of astrocytoma (25 diffuse astrocytomas - AGII, 18 anaplastic astrocytomas - AGIII and 86 glioblastomas - GBM) and 22 samples of non-neoplastic tissue cerebral (NN) from epilepsy surgery. IDH1 mutation status was analyzed with CXCR7, CXCR4 e HIF1alfa mRNA expressions, matched with clinicopathological parameters and overall survival time. Furthermore, CXCR7 protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. Results: There was significant difference in the expression levels of the genes studied between astrocytomas and NN (p < 0.001). The analysis of associated gene expressions in AGII showed no significant correlation between CXCR7/HIF1alfa (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). In GBM, there were significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1alfa (p = 0.008). HIF1alfa overexpression was associated with higher expressions of CXCR7 and CXCR4 (p = 0.001), while presence of IDH1 mutation was associated with lower CXCR7 and CXCR4 mRNA expressions (p = 0.009). Protein expression was identified in all samples studied, and it increased with malignancy. CXCR7 protein, in U87MG cell line, was mainly localized in the cellular membrane. Conclusion: CXCR7 was overexpressed in astrocytoma of different grades of malignancy compared to non-neoplastic brain tissue. CXCR7 expression levels correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1alfa in GBM. Overexpression HIF1alfa was related with higher expressions of CXCR7 and CXCR4, otherwise presence of IDH1 mutation related with lower expression of both genes. Protein expression level was associated with the degree of malignancy. The results revealed no significant association between CXCR7 and CXCR4 expression and survival data
Análise de sobrevida
Astrocitoma/genética
CXCR7 proteína humana
Expressão gênica
Glioblastoma
IDH1 proteína humana
Imunoistoquímica
Mutação/genética
Neoplasias encefálicas/genética
Neoplasias encefálicas/patologia
Primers DNA/genética
Receptores CXCR4
Receptores de quimiocinas
RNA mensageiro
Astrocytoma/genetics
Brain neoplasms/genetics
Brain neoplasms/pathology
CXCR7 protein human
DNA primers/genetics
Gene expression
Gioblastoma
Hypoxia-Inducible Factor 1 alpha subunit
IDH1 protein human
Immunohistochemistry
Mutation/genetics
Real-time polymerase chain reaction
Receptors chemokine
Receptors CXCR4
RNA messenger
Survival analysis
68

Estudo das alterações na expressão gênica dos ependimomas / Study of gene expression alterations in ependymomas

Andrade, Fernanda Gonçalves de 11 June 2014 (has links)
Ependimomas são tumores gliais raros. Podem ser encontrados em qualquer localização do sistema nervoso central e, apesar de histologia similar, parecem apresentar alterações genômicas distintas. As variáveis clínicas são intercorrelacionadas e, geralmente, incapazes de predizer o curso da doença. O objetivo do presente estudo foi analisar a expressão aumentada de genes e proteínas em ependimomas e correlacionar com dados clínicos dos pacientes. Foram estudados casos de pacientes com ependimoma submetidos à ressecção cirúrgica no Hospital das Clínicas, Universidade de São Paulo, no período entre 1996 e 2011 (33 amostras de tecido congelado para análise de expressão gênica por PCR quantitativo em tempo real e 149 amostras com tecido incluído em parafina, correspondentes a 121 casos devido a recidivas, para análise de proteína por imuno-histoquímica de tissue microarrays). As reações de imuno-histoquímica foram analisadas semiquantitativamente e graduadas com um índice de marcação calculado pelo produto da porcentagem de núcleos marcados pela intensidade de marcação. Oitenta e um casos eram adultos (média de 27,2 anos). Havia 60 casos intracranianos e 61 intramedulares, dos quais 10 eram mixopapilares, 92 grau II e 19 grau III. Ressecção completa foi possível em 62% dos casos e recidiva foi confirmada em 41,1%. Observou-se menor tempo para recidiva em crianças e tumores intracranianos, supratentoriais (p < 0,001 em ambos), histologia anaplásica e ressecções incompletas (p < 0,05 em ambos). Os seguintes genes foram selecionados em dados públicos de SAGE e literatura: ARMC3, CCND1, CHST5, DNALI1, FGFRL1, GNA13, IGF2, MSX1, NOTCH1 e RSPH3. ARMC3, RSHL3, CHST5 e DNALI1 apresentaram maiores níveis de expressão em ependimomas intramedulares (p < 0,05), e FGFRL1, NOTCH1 e CCND1 nos casos supratentoriais (p < 0,01). IGF2 apresentou maiores níveis de expressão em crianças e CHST5 em adultos (p < 0,05 em ambos). Foram observados maiores níveis de expressão de FGFRL1 (p < 0,05), CCND1 e IGF2 (p < 0,01 em ambos) em casos com histologia anaplásica. Nenhum dos genes analisados apresentou impacto no tempo livre de progressão ou na sobrevida. A expressão da proteína codificada por CCND1, ciclina D1, também foi avaliada por imuno-histoquímica, por ser uma proteína com expressão aumentada em diversos tipos de neoplasias e não ter ainda um valor prognóstico bem estabelecido em ependimomas. Houve correlação entre expressão de ciclina D1 a nível de mRNA e da proteína (p < 0,0001). As correlações entre ciclina D1 e histologia anaplásica e localização supratentorial foram confirmadas pela análise proteica (p < 0,0001 em ambos). Adicionalmente, foi também observada maior expressão de ciclina D1 em pacientes mais jovens (p < 0,01). A maior expressão de ciclina D1 em tumores com localização supratentorial foi independente do grau histológico e da idade do paciente. Recidiva foi mais frequente em casos com maiores níveis de expressão de ciclina D1 (p < 0,05), embora uma maior correlação com tempo livre de progressão foi observada apenas em casos com ressecção completa (p < 0,001). Os ependimomas apresentaram expressão gênica diferencial de acordo com idade, localização do tumor e grau histológico nesse estudo. A determinação dos níveis da expressão de ciclina D1 pode ser útil para guiar o seguimento e tratamento dos casos supratentoriais com ressecções completas / Ependymomas are rare glial cell-derived tumors. They can be found in any central nervous system localization and despite the histological similarity, they seem to display distinct genomic abnormalities. Clinical variables are intercorrelated and they are usually unable to predict the disease course. We aimed to analyze increased gene and protein expression in ependymomas and to correlate with patients\' clinical data. We studied patients with ependymoma submitted to surgical resections at Hospital das Clinicas, University of São Paulo, from 1996 to 2011 (33 fresh-frozen samples for gene expression analysis by quantitative real-time PCR and 149 formalin-fixed, paraffin-embedded samples, relative to 121 patients due to relapses, for protein analysis by tissue microarray immunohistochemistry). Immunohistochemical reactions were analyzed semi-quantitatively and scored with a labeling index (LI) calculated as the product of the percentage of the positively stained nuclei by the intensity of staining. Eighty-one cases were adults (mean 27.2 years). There were 60 intracranial and 61 spinal cases, of which 10 tumors were myxopapillary, 92 were grade II and 19 were grade III. Gross total resection was achieved in 62% of cases and relapse was confirmed in 41.4% of cases. We observed a shorther time to relapse in children and supratentorial intracranial tumor localization (p<0.001 for both), anaplastic histology and incomplete resections (p<0.05 for both). The following genes were selected based on public SAGE database and literature: ARMC3, CCND1, CHST5, DNALI1, FGFRL1, GNA13, IGF2, MSX1, NOTCH1 and RSPH3. ARMC3, RSHL3, CHST5 and DNALI1 presented higher expression levels in intramedullary ependymomas (p < 0.05) and FGFRL1, NOTCH1 and CCND1 in supratentorial cases (p < 0.01). IGF2 presented higher expression levels in pediatric cases and CHST5 in adults cases (p < 0.05 in both). Higher expression levels of FGFRLI1 (p < 0.05), CCND1 and IGF2 (p < 0.01 for both) were observed in anaplastic histology cases. None of the genes impacted in progression free survival or overall survival of patients. The expression of protein codified by CCND1, cyclin D1, was also evaluated by immunohistochemistry, because its overexpression has been related with several types of neoplasias and its prognostic value has not yet been fully established in ependymomas. There was a correlation of cyclin D1 expression at mRNA and protein levels (p < 0.0001). Correlations between cyclin D1 and anaplastic histology and supratentorial localization were confirmed by protein analyses (p < 0.0001 for both parameters). Additionally, high expression of cyclin D1 was observed in younger patients (p < 0.01). The higher cyclin D1 expression in supratentorial tumor localization was independent of histological grade and age of patient. Relapse was more frequent in cases with higher cyclin D1 expression levels (p < 0.05) although correlation with progression free survival was just observed in gross total resection cases (p < 0.001). Ependymomas presented differential gene expression according to age, tumor localization and histological grade in our study. Determination of cyclin D1 expression levels may be useful to guide follow-up and treatment in supratentorial cases with gross total resection
Análise serial de tecidos
Brain neoplasms
Ciclina D1
Cyclin D1
Ependimoma/genética
Ependymoma/genetics
Estudos de associação genética
Expressão gênica
Gene expression
Genetic association studies
Glioma/genética
Glioma/genetics
Immunohistochemistry
Imuno-histoquímica
Marcadores biológicos de tumor
Neoplasias da medula espinhal/genética
Neoplasias encefálicas
Prognosis
Prognóstico
Real-time polymerase chain reaction
Spinal cord neoplasms
Tissue array analysis
Tumor markers biological
69

Estudo das alterações na expressão gênica dos ependimomas / Study of gene expression alterations in ependymomas

Fernanda Gonçalves de Andrade 11 June 2014 (has links)
Ependimomas são tumores gliais raros. Podem ser encontrados em qualquer localização do sistema nervoso central e, apesar de histologia similar, parecem apresentar alterações genômicas distintas. As variáveis clínicas são intercorrelacionadas e, geralmente, incapazes de predizer o curso da doença. O objetivo do presente estudo foi analisar a expressão aumentada de genes e proteínas em ependimomas e correlacionar com dados clínicos dos pacientes. Foram estudados casos de pacientes com ependimoma submetidos à ressecção cirúrgica no Hospital das Clínicas, Universidade de São Paulo, no período entre 1996 e 2011 (33 amostras de tecido congelado para análise de expressão gênica por PCR quantitativo em tempo real e 149 amostras com tecido incluído em parafina, correspondentes a 121 casos devido a recidivas, para análise de proteína por imuno-histoquímica de tissue microarrays). As reações de imuno-histoquímica foram analisadas semiquantitativamente e graduadas com um índice de marcação calculado pelo produto da porcentagem de núcleos marcados pela intensidade de marcação. Oitenta e um casos eram adultos (média de 27,2 anos). Havia 60 casos intracranianos e 61 intramedulares, dos quais 10 eram mixopapilares, 92 grau II e 19 grau III. Ressecção completa foi possível em 62% dos casos e recidiva foi confirmada em 41,1%. Observou-se menor tempo para recidiva em crianças e tumores intracranianos, supratentoriais (p < 0,001 em ambos), histologia anaplásica e ressecções incompletas (p < 0,05 em ambos). Os seguintes genes foram selecionados em dados públicos de SAGE e literatura: ARMC3, CCND1, CHST5, DNALI1, FGFRL1, GNA13, IGF2, MSX1, NOTCH1 e RSPH3. ARMC3, RSHL3, CHST5 e DNALI1 apresentaram maiores níveis de expressão em ependimomas intramedulares (p < 0,05), e FGFRL1, NOTCH1 e CCND1 nos casos supratentoriais (p < 0,01). IGF2 apresentou maiores níveis de expressão em crianças e CHST5 em adultos (p < 0,05 em ambos). Foram observados maiores níveis de expressão de FGFRL1 (p < 0,05), CCND1 e IGF2 (p < 0,01 em ambos) em casos com histologia anaplásica. Nenhum dos genes analisados apresentou impacto no tempo livre de progressão ou na sobrevida. A expressão da proteína codificada por CCND1, ciclina D1, também foi avaliada por imuno-histoquímica, por ser uma proteína com expressão aumentada em diversos tipos de neoplasias e não ter ainda um valor prognóstico bem estabelecido em ependimomas. Houve correlação entre expressão de ciclina D1 a nível de mRNA e da proteína (p < 0,0001). As correlações entre ciclina D1 e histologia anaplásica e localização supratentorial foram confirmadas pela análise proteica (p < 0,0001 em ambos). Adicionalmente, foi também observada maior expressão de ciclina D1 em pacientes mais jovens (p < 0,01). A maior expressão de ciclina D1 em tumores com localização supratentorial foi independente do grau histológico e da idade do paciente. Recidiva foi mais frequente em casos com maiores níveis de expressão de ciclina D1 (p < 0,05), embora uma maior correlação com tempo livre de progressão foi observada apenas em casos com ressecção completa (p < 0,001). Os ependimomas apresentaram expressão gênica diferencial de acordo com idade, localização do tumor e grau histológico nesse estudo. A determinação dos níveis da expressão de ciclina D1 pode ser útil para guiar o seguimento e tratamento dos casos supratentoriais com ressecções completas / Ependymomas are rare glial cell-derived tumors. They can be found in any central nervous system localization and despite the histological similarity, they seem to display distinct genomic abnormalities. Clinical variables are intercorrelated and they are usually unable to predict the disease course. We aimed to analyze increased gene and protein expression in ependymomas and to correlate with patients\' clinical data. We studied patients with ependymoma submitted to surgical resections at Hospital das Clinicas, University of São Paulo, from 1996 to 2011 (33 fresh-frozen samples for gene expression analysis by quantitative real-time PCR and 149 formalin-fixed, paraffin-embedded samples, relative to 121 patients due to relapses, for protein analysis by tissue microarray immunohistochemistry). Immunohistochemical reactions were analyzed semi-quantitatively and scored with a labeling index (LI) calculated as the product of the percentage of the positively stained nuclei by the intensity of staining. Eighty-one cases were adults (mean 27.2 years). There were 60 intracranial and 61 spinal cases, of which 10 tumors were myxopapillary, 92 were grade II and 19 were grade III. Gross total resection was achieved in 62% of cases and relapse was confirmed in 41.4% of cases. We observed a shorther time to relapse in children and supratentorial intracranial tumor localization (p<0.001 for both), anaplastic histology and incomplete resections (p<0.05 for both). The following genes were selected based on public SAGE database and literature: ARMC3, CCND1, CHST5, DNALI1, FGFRL1, GNA13, IGF2, MSX1, NOTCH1 and RSPH3. ARMC3, RSHL3, CHST5 and DNALI1 presented higher expression levels in intramedullary ependymomas (p < 0.05) and FGFRL1, NOTCH1 and CCND1 in supratentorial cases (p < 0.01). IGF2 presented higher expression levels in pediatric cases and CHST5 in adults cases (p < 0.05 in both). Higher expression levels of FGFRLI1 (p < 0.05), CCND1 and IGF2 (p < 0.01 for both) were observed in anaplastic histology cases. None of the genes impacted in progression free survival or overall survival of patients. The expression of protein codified by CCND1, cyclin D1, was also evaluated by immunohistochemistry, because its overexpression has been related with several types of neoplasias and its prognostic value has not yet been fully established in ependymomas. There was a correlation of cyclin D1 expression at mRNA and protein levels (p < 0.0001). Correlations between cyclin D1 and anaplastic histology and supratentorial localization were confirmed by protein analyses (p < 0.0001 for both parameters). Additionally, high expression of cyclin D1 was observed in younger patients (p < 0.01). The higher cyclin D1 expression in supratentorial tumor localization was independent of histological grade and age of patient. Relapse was more frequent in cases with higher cyclin D1 expression levels (p < 0.05) although correlation with progression free survival was just observed in gross total resection cases (p < 0.001). Ependymomas presented differential gene expression according to age, tumor localization and histological grade in our study. Determination of cyclin D1 expression levels may be useful to guide follow-up and treatment in supratentorial cases with gross total resection
Análise serial de tecidos
Ciclina D1
Ependimoma/genética
Estudos de associação genética
Expressão gênica
Glioma/genética
Imuno-histoquímica
Marcadores biológicos de tumor
Neoplasias da medula espinhal/genética
Neoplasias encefálicas
Prognóstico
Brain neoplasms
Cyclin D1
Ependymoma/genetics
Gene expression
Genetic association studies
Glioma/genetics
Immunohistochemistry
Prognosis
Real-time polymerase chain reaction
Spinal cord neoplasms
Tissue array analysis
Tumor markers biological

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