Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma.

Glioblastoma (GBM), the most frequent and aggressive brain tumor, is characterized by marked angiogenesis directly related to invasiveness and poor prognosis. Hypoxia is considered to be an important stimulus for angiogenesis by inducing hypoxia-inducible factor 1-alpha (HIF-1α) overexpression that activates platelet-derived growth factor (PDGF) and VEGF. The aim of this study is to analyze the expression of PDGF-C, VEGF in endothelial and tumor cells of GBM and their relation to HIF-1α expression. Two hundred and eight GBM cases were studied by tissue microarray immunohistochemical preparation. Expression of HIF-1α, VEGF and PDGF-C was observed in 184 (88.5%), 131 (63%) and 160 (76.9%) tumor cases, respectively. The numbers of vessels were quantified by CD34, PDGF-C, VEGF and CD105 staining, and were in median 20, 16, 5 and 6, respectively. The GBMs that showed positive or negative expression for HIF-1α showed a median vascular density of 30 and 14, respectively, for CD34 (P < 0.015). Positive expression for HIF-1α was correlated with VEGF and PDGF-C expression in tumors (P < 0.001). There was a significant correlation between VEGF and PDGF-C expression in the cytoplasm of GBM tumor cells (P < 0.0001). We showed that VEGF expression in tumor cells was correlated with its expression in blood vessels (P < 0.0001). Endothelial cells with PDGF-C and VEGF positive expression were also positive for CD105 and their nuclei for Ki-67, confirming the neoangiogenic and proliferative influence of VEGF and PDGF-C. VEGF nuclear staining in tumor cells (P = 0.002) as well as nuclear staining for HIF-1α and VEGF (P = 0.005) correlated with survival. In summary, our present findings of the concomitant upregulation of PDGF-C with VEGF in GBM tumor cells and vessels further reinforce the benefit of using combined anti-angiogenic approaches to potentially improve the therapeutic response for GBM.

Incidence of venous thromboembolism and bleeding in patients with malignant central nervous system neoplasm: Systematic review and meta-analysis.

Central nervous system (CNS) malignant neoplasms may lead to venous thromboembolism (VTE) and bleeding, which result in rehospitalization, morbidity and mortality. We aimed to assess the incidence of VTE and bleeding in this population. METHODS: This systematic review and meta-analysis (PROSPERO CRD42023423949) were based on a standardized search of PubMed, Virtual Health Library and Cochrane (n = 1653) in July 2023. After duplicate removal, data screening and collection were conducted by independent reviewers. The combined rates and 95% confidence intervals for the incidence of VTE and bleeding were calculated using the random effects model with double arcsine transformation. Subgroup analyses were performed based on sex, age, income, and type of tumor. Heterogeneity was calculated using Cochran's Q test and I2 statistics. Egger's test and funnel graphs were used to assess publication bias. RESULTS: Only 36 studies were included, mainly retrospective cohorts (n = 30, 83.3%) from North America (n = 20). Most studies included were published in high-income countries. The sample size of studies varied between 34 and 21,384 adult patients, mostly based on gliomas (n = 30,045). For overall malignant primary CNS neoplasm, the pooled incidence was 13.68% (95%CI 9.79; 18.79) and 11.60% (95%CI 6.16; 18.41) for VTE and bleeding, respectively. The subgroup with elderly people aged 60 or over had the highest incidence of VTE (32.27% - 95%CI 14.40;53.31). The studies presented few biases, being mostly high quality. Despite some variability among the studies, we observed consistent results by performing sensitivity analysis, which highlight the robustness of our findings. CONCLUSIONS: Our study showed variability in the pooled incidence for both overall events and subgroup analyses. It was highlighted that individuals over 60 years old or diagnosed with GBM had a higher pooled incidence of VTE among those with overall CNS malignancies. It is important to note that the results of this meta-analysis refer mainly to studies carried out in high-income countries. This highlights the need for additional research in Latin America, and low- and middle-income countries.

EGFL7 expression profile in IDH-wildtype glioblastomas is associated with poor patient outcome.

BACKGROUND: Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches. METHODS: Spearman's correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients' samples, and was associated with clinicopathological data and overall survival. RESULTS: In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase-Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041). CONCLUSIONS: This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.

Copy Number Profiling of Brazilian Astrocytomas.

Copy number alterations (CNA) are one of the driving mechanisms of glioma tumorigenesis, and are currently used as important biomarkers in the routine setting. Therefore, we performed CNA profiling of 65 astrocytomas of distinct malignant grades (WHO grade I-IV) of Brazilian origin, using array-CGH and microsatellite instability analysis (MSI), and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. Furthermore, in silico analysis using the Oncomine database was performed to validate our findings and extend the findings to gene expression level. We found that the number of genomic alterations increases in accordance with glioma grade. In glioblastomas (GBM), the most common alterations were gene amplifications (PDGFRA, KIT, KDR, EGFR, and MET) and deletions (CDKN2A and PTEN) Log-rank analysis correlated EGFR amplification and/or chr7 gain with better survival of the patients. MSI was observed in 11% of GBMs. A total of 69% of GBMs presented TERT mutation, whereas IDH1 mutation was most frequent in diffuse (85.7%) and anaplastic (100%) astrocytomas. The combination of 1p19q deletion and TERT and IDH1 mutational status separated tumor groups that showed distinct age of diagnosis and outcome. In silico validation pointed to less explored genes that may be worthy of future investigation, such as CDK2, DMRTA1, and MTAP Herein, using an extensive integrated analysis, we indicated potentially important genes, not extensively studied in gliomas, that could be further explored to assess their biological and clinical impact in astrocytomas.

CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1α Expression and IDH1 Mutation.

The CXCR7, a new 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 astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1α expression and IDH1 mutation. CXCR7, CXCR4 and HIF1α mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1α (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1α (p = 0.008). HIF1α overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1α in GBM. Overexpression HIF1α was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.

Meningioma of the Fourth Ventricle: Literature Review

Meningiomas are among the most common central nervous system tumors, with an incidence that ranges from 15% to 40% of intracranial tumors. Of these, only 0.5% to 3% are intraventricular, and the rarest of them occurs in the fourth ventricle. Fourth-ventricle meningiomas originate generally fromthe choroid plexus and have no dural adhesions. Most often, they manifest in young patients, around 41 years of age, with a possible predominance in females, through intracranial hypertension and cerebellar syndromes. The treatment consists of surgical resection, which commonly presents good results due to the characteristics of the tumor. So, for better preoperative planning, the radiological differentiation of the most frequent tumors in this location is important. Themost common histologic subtypes are fibroblastic and meningothelial, both grade I according to the World Health Organization (WHO), although there are reports of tumors of grades II and III. We report a case ofmeningioma of the fourth ventricle operated in our institution, and we have conducted a literature review, through which we found that 57 cases have been reported so far, with the first one reported in 1938.

Molecular Profiling of a Rare Rosette-Forming Glioneuronal Tumor Arising in the Spinal Cord.

Rosette-forming glioneuronal tumor (RGNT) of the IV ventricle is a rare and recently recognized brain tumor entity. It is histologically composed by two distinct features: a glial component, resembling pilocytic astrocytoma, and a component forming neurocytic rosettes and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in the spinal cord. Following an immunohistochemistry validation, we further performed an extensive genomic analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. We observed the loss of 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9 and 16. Local amplifications in 9q34.2 and 19p13.3 (encompassing the gene SBNO2) were identified. Moreover, we observed focal gains/losses in several chromosomes. Additionally, on chromosome 7, we identified the presence of the KIAA1549:BRAF gene fusion, which was further validated by RT-PCR and FISH. Across all mutational analyses, we detected and validated the somatic mutations of the genes MLL2, CNNM3, PCDHGC4 and SCN1A. Our comprehensive molecular profiling of this RGNT suggests that MAPK pathway and methylome changes, driven by KIAA1549:BRAF fusion and MLL2 mutation, respectively, could be associated with the development of this rare tumor entity.

Trigone ventricular meningiomas: surgical approaches.

OBJECTIVE: Report our experience with trigone ventricular meningiomas and review the surgical approaches to the trigone. METHOD: From 1989 to 2006, six patients with meningiomas of the trigone of the lateral ventricles underwent microsurgical resection. Their clinical features, image, follow up, and surgical approaches were retrospectively analyzed. RESULTS: Five patients presented with large and one with small volume meningioma. Unspecific symptoms occurred in three patients; intracranial hypertension detected in three patients; homonymous hemianopsy in three; and motor deficit present in one patient. Three patients were operated by transparietal transcortical approach, two by middle temporal gyrus approach, and one by parieto-occipital interhemispheric precuneus approach. Total resection was achieved in all patients without additional deficits. CONCLUSION: Judicious preoperative plan, adequate knowledge of anatomy, and use of correct microsurgical techniques are fundamental in achieving complete resection of trigone meningioma with low morbidity.

The A61G EGF polymorphism is associated with development of extraaxial nervous system tumors but not with overall survival.

Epidermal growth factor can activate several signaling pathways, leading to proliferation, differentiation, and tumorigenesis of epithelial tissues by binding with its receptor. The EGF protein is involved in nervous system development, and polymorphisms in the EGF gene on chromosome band 4q25 are associated with brain cancers. The purpose of this study was to investigate the association between the single-nucleotide polymorphism of EGF+61G/A and extraaxial brain tumors in a population of the southeast of Brazil. We analyzed the genotype distribution of this polymorphism in 90 patients and 100 healthy subjects, using the polymerase chain reaction-restriction fragment length polymorphism technique. Comparison of genotype distribution revealed a significant difference between patients and control subjects (P < 0.001). The variant genotypes of A/G and G/G were associated with a significant increase of the risk of tumor development, compared with the homozygote A/A (P < 0.0001). When the analyses were stratified, we observed that the genotype G/G was more frequent in female patients (P=0.021). The same genotype was observed more frequently in patients with low-grade tumors (P=0.001). Overall survival rates did not show statistically significant differences. Our data suggest that the EGF A61G polymorphism can be associated with susceptibility to development of these tumors.

Tratamento intracístico de craniofaringioma com interferon alfa: relato de caso / Intracystic Treatment of Craniopharyngiomas with Interferon Alpha: A Case Report

Craniofaringiomas são tumores histologicamante benignos, extrínsecos ao parênquima cerebral. Visando ao controle da doença, preconiza-se, como tratamento padrão, a tentativa de ressecção completa, meticulosamente planejada com vistas a preservar as funções habituais do paciente. Outras formas de terapias podem ser utilizadas como alternativas ou comoadjuvantes à cirurgia. Considerando-se quemuitos craniofaringiomas apresentam componente cístico, a utilização de cateteres posicionados no interior do lúmen cístico para aplicação de agentes quimioterapêuticos, como o interferon alfa (IFNa), tem-se mostrado promissora. Administração intratumoral de 3 milhões de unidades de IFNa em dias alternados, totalizando doze ciclos, tem sido utilizada empiricamente. Relatamos o caso de uma paciente de 12 anos de idade, com diagnóstico de craniofaringioma de predomínio cístico, tratada no Hospital de Câncer de Barretos (HCB) utilizando a aplicação de IFNa semanalmente, que apresentou evolução favorável.

Craniopharyngiomas are histologicaly benign tumors, whose ideal brain treatment requires its complete surgical resection, while preserving most of the usual functions of the patient. Due to the complexity of the surgical procedure, related to location (surrounded by paraselar structures), it is often difficult to achieve its complete resection. Thus, alternative therapies have been reported, including the use of intracystic IFNa on alternate days. We report the case of a 12 year-old female, diagnosed with cystic craniopharyngioma, weekly treated with intracystic IFNa, for a total of 12 cycles, with favorable outcome.

Trigone ventricular meningiomas: surgical approaches / Meningiomas do trígono ventricular: abordagens cirúrgicas

OBJECTIVE: Report our experience with trigone ventricular meningiomas and review the surgical approaches to the trigone. METHOD: From 1989 to 2006, six patients with meningiomas of the trigone of the lateral ventricles underwent microsurgical resection. Their clinical features, image, follow up, and surgical approaches were retrospectively analyzed. RESULTS: Five patients presented with large and one with small volume meningioma. Unspecific symptoms occurred in three patients; intracranial hypertension detected in three patients; homonymous hemianopsy in three; and motor deficit present in one patient. Three patients were operated by transparietal transcortical approach, two by middle temporal gyrus approach, and one by parieto-occipital interhemispheric precuneus approach. Total resection was achieved in all patients without additional deficits. CONCLUSION: Judicious preoperative plan, adequate knowledge of anatomy, and use of correct microsurgical techniques are fundamental in achieving complete resection of trigone meningioma with low morbidity.

OBJETIVO: Relatar a experiência com seis meningiomas do trígono ventricular e discutir as várias vias de abordagem para o trígono descritos na literatura. MÉTODO: Seis pacientes com meningiomas do trígono ventricular operados entre 1989 e 2006 foram analisados quanto às suas características clínicas, de imagem, evolução e às vias de abordagem. RESULTADOS: Cinco pacientes apresentaram meningiomas de grande volume e um pequeno. Sintomas inespecíficos ocorreram em três pacientes, hipertensão intracraniana em outros três pacientes; hemianopsia homônima em três e déficit motor em um paciente. Três pacientes foram operados por via transcortical transparietal, dois através do giro temporal médio, e um por abordagem interhemisférica precuneus. A ressecção total foi possível em todos os pacientes, sem défices adicionais. CONCLUSÃO: Planejamento operatório cuidadoso aliado ao uso de técnicas microcirúrgicas são fundamentais na ressecção completa dos meningiomas do trígono com baixa morbidade.

Estudo das expressões imunoistoquímicas dos marcadores HIF-1alfa, VEGF e PDGF-C correlacionados com a angiogênese e o prognóstico em glioblastomas / Study of immunohistochemical expressions on the HIF-1alfa, VEGF and PDGF-C markers, correlated to angiogenesis and to glioblastoma prognosis

O glioblastoma multiforme (GBM) é o tumor mais agressivo do Sistema Nervoso Central (SNC) e caracteriza-se por um alto poder angiogênico que está diretamente relacionado com a capacidade invasiva e inversamente com o prognóstico. A angiogênese contribui para a malignidade por prover a oxigenação e o suprimento nutricional necessários para o crescimento e invasão do tumor. O GBM prolifera sob um ambiente de hipóxia e o fator induzido por hipóxia (HIF-1) apresenta um papel fundamental na ativação da transcrição de genes alvo que favorecem a angiogênese e evitam a morte celular. O fator de crescimento do endotélio vascular (VEGF) e o fator de crescimento derivado da plaqueta C (PDGF-C) são agentes de grande interesse na angiogênese tumoral e que podem ser modulados pelo HIF-1. Foi realizado tissue microarray(TMA) de 208 casos de GBM e estudados pelo método de imunoistoquímica os marcadores HIF-1, VEGF e PDGFC. Os resultados foram correlacionados com a angiogênese avaliada através da densidade microvascular (DMV) pelo CD34, CD105, VEGF e PDGF-C, com a proliferação celular endotelial através da marcação nuclear pelo KI-67 e também com a sobrevida. A expressão tumoral do HIF-1 foi observada em 184 casos (88,5%), a do VEGF em 131 (63%) e a do PDGF-C em 160 (77%). As DMVs medianas pelo CD34, PDGF-C, VEGF e CD105 foram, respectivamente, 20, 16, 5 e 6. Os GBMs com marcação positiva pelo HIF-1 tiveram uma DMV mediana pelo CD34 de 30, enquanto que nos negativos a DMV mediana foi 14 (p<0,001). A expressão tumoral positiva pelo HIF-1 teve correlação com a marcação tumoral pelo VEGF e PDGF-C (p<0,001). Houve também uma correlação entre a marcação do VEGF e do PDGF-C tanto no tumor (p=0,001) como na célula endotelial (p<0,001). A expressão do VEGF no tumor teve correlação com a sua expressão no vaso (p<0,001). Células endoteliais marcadas pelo PDGF-C e pelo VEGF também foram marcadas pelo CD105 e seus núcleos pelo KI-67 confirmando seu padrão neoangiogênico...

Glioblastoma multiforme (GBM) is the most aggressive tumour of the central nervous system (CNS) and is characterized by a high angiogenic power that is directly related to the invasiveness and inversely to the prognosis. Angiogenesis contributes to malignancy by providing the necessary oxygenation and nutritional supplement for the tumour's growth and invasion. GBM proliferates under a hypoxia environment and the hypoxia-inducible factor (HIF-1) plays a key role on the transcription of essential genes which promote angiogenesis and prevent cellular death. The vascular endothelial growth factor (VEGF) and the platelet-derived growth factor C (PDGF-C) are agents of great interest on tumour angiogenesis and may be modulated by the HIF-1. Tissue micro-array (TMA) was conducted on 208 cases of GBM and the HIF-1, VEGF and PDGF-C markers were studied under immunohistochemistry method. The results were correlated with angiogenesis assessed by micro-vessel density (MVD) for CD34, CD105, VEGF and PDGF-C, with endothelial cell proliferation by nuclear staining for KI-67, and also with survival. The tumour expression by HIF-1 was observed in 184 cases (88.5%), by VEGF in 131 (63%) and by PDGF-C in 160 (77%). The median MVD for CD34, PDGF-C, VEGF and CD105 was respectively 20, 16, 5 and 6.The GBMs which stained positive for HIF-1 showed a median MVD of 30 for CD34, whereas in negative ones, median MVD was 14 (p <0.001). The positive tumour expression for HIF-1 was correlated with tumour markings for VEGF and PDGF-C (p <0.001). There was also a correlation between the markings for VEGF and PDGF-C in both the tumour (p = 0.001) and endothelial cell (p <0.001). VEGF expression in the tumour was correlated with its expression in the blood vessel (p <0.001). Endothelial cells marked for the PDGF-C and VEGF were also marked for CD105 and their nuclei for KI-67 confirming its neoangiogenic and proliferative pattern. The nuclear staining on tumour cells for VEGF had an impact...

Craniofaringioma cístico gigante de fossa posterior: relato caso / Giant cystic posterior fossa craniopharyngioma. Case report

O craniofaringioma localizado na fossa posterior é uma entidade rara, estimada em torno de 4 por cento. Geralmente está associado a quadros clínicos graves que necessitam de tratamento cirúrgico. O seu prognóstico está relacionado com a possibilidade de remoção do tumor.Apresentamos um caso de craniofaringioma c´stico localizado na fossa posterior, de dimensões gigantes, tratado cirurgicamente e com bom resultado.