RESUMO
EPNs comprise a heterogeneous group of neuroepithelial tumors, accounting for about 10% of all intracranial tumors in children and up to 30% of brain tumors in those younger than 3 years. Actually, the pattern therapy for low-grade EPNs includes complete surgical resection followed by radiation therapy. Total surgical excision is often not possible due to tumor location. The aim of this study was to evaluate, for the first time, the anti-tumor activity of Amblyomin-X in 4 primary cultures derived from pediatric anaplastic posterior fossa EPN, Group A (anaplastic, WHO grade III) and one primary culture of a high grade neuroepithelial tumor with MN1 alteration, which was initially misdiagnosed as EPN: i) by in vitro assays: comparisons of temozolomide and cisplatin; ii) by intracranial xenograft model. Amblyomin-X was able to induce cell death in EPN cells in a more significant percentage compared to cisplatin. The cytotoxic effects of Amblyomin-X were not detected on hFSCs used as control, as opposed to cisplatin-treatment, which promoted a substantial effect in the hAFSCs viability. TEM analysis showed ultrastructural alterations related to the process of cell death: mitochondrial degeneration, autophagosomes and aggregate-like structures. MRI and histopathological analyzes demonstrated significant tumor mass regression. Our results suggest that Amblyomin-X has a selective effect on tumor cells by inducing apoptotic cell death and may be a therapeutic option for Group AEPNs.
RESUMO
EPNs comprise a heterogeneous group of neuroepithelial tumors, accounting for about 10% of all intracranial tumors in children and up to 30% of brain tumors in those younger than 3 years. Actually, the pattern therapy for low-grade EPNs includes complete surgical resection followed by radiation therapy. Total surgical excision is often not possible due to tumor location. The aim of this study was to evaluate, for the first time, the anti-tumor activity of Amblyomin-X in 4 primary cultures derived from pediatric anaplastic posterior fossa EPN, Group A (anaplastic, WHO grade III) and one primary culture of a high grade neuroepithelial tumor with MN1 alteration, which was initially misdiagnosed as EPN: i) by in vitro assays: comparisons of temozolomide and cisplatin; ii) by intracranial xenograft model. Amblyomin-X was able to induce cell death in EPN cells in a more significant percentage compared to cisplatin. The cytotoxic effects of Amblyomin-X were not detected on hFSCs used as control, as opposed to cisplatin-treatment, which promoted a substantial effect in the hAFSCs viability. TEM analysis showed ultrastructural alterations related to the process of cell death: mitochondrial degeneration, autophagosomes and aggregate-like structures. MRI and histopathological analyzes demonstrated significant tumor mass regression. Our results suggest that Amblyomin-X has a selective effect on tumor cells by inducing apoptotic cell death and may be a therapeutic option for Group AEPNs.
RESUMO
Background Previous studies have demonstrated remarkable tropism of mesenchymal stem cells (MSCs) toward malignant gliomas, making these cells a potential vehicle for delivery of therapeutic agents to disseminated glioblastoma (GBM) cells. However, the potential contribution of MSCs to tumor progression is a matter of concern. It has been suggested that CD133+ GBM stem cells secrete a variety of chemokines, including monocytes chemoattractant protein-1 (MCP-1/CCL2) and stromal cell-derived factor-1(SDF-1/CXCL12), which could act in this tropism. However, the role in the modulation of this tropism of the subpopulation of CD133+ cells, which initiate GBM and the mechanisms underlying the tropism of MSCs to CD133+ GBM cells and their effects on tumor development, remains poorly defined. Methods/results We found that isolated and cultured MSCs (human umbilical cord blood MSCs) express CCR2 and CXCR4, the respective receptors for MCP-1/CCL2 and SDF-1/CXCL12, and demonstrated, in vitro, that MCP-1/CCL2 and SDF-1/CXC12, secreted by CD133+ GBM cells from primary cell cultures, induce the migration of MSCs. In addition, we confirmed that after in vivo GBM tumor establishment, by stereotaxic implantation of the CD133+ GBM cells labeled with Qdots (705 nm), MSCs labeled with multimodal iron oxide nanoparticles (MION) conjugated to rhodamine-B (Rh-B) (MION-Rh), infused by caudal vein, were able to cross the blood-brain barrier of the animal and migrate to the tumor region. Evaluation GBM tumors histology showed that groups that received MSC demonstrated tumor development, glial invasiveness, and detection of a high number of cycling cells. Conclusions Therefore, in this study, we validated the chemotactic effect of MCP-1/CCL2 and SDF-1/CXCL12 in mediating the migration of MSCs toward CD133+ GBM cells. However, we observed that, after infiltrating the tumor, MSCs promote tumor growth in vivo probably by release of exosomes. Thus, the use of these cells as a therapeutic carrier strategy to target GBM cells must be approached with caution.
RESUMO
Background: Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. Results: We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. Conclusions: We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. Methods: In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients (n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model.
RESUMO
Background Previous studies have demonstrated remarkable tropism of mesenchymal stem cells (MSCs) toward malignant gliomas, making these cells a potential vehicle for delivery of therapeutic agents to disseminated glioblastoma (GBM) cells. However, the potential contribution of MSCs to tumor progression is a matter of concern. It has been suggested that CD133+ GBM stem cells secrete a variety of chemokines, including monocytes chemoattractant protein-1 (MCP-1/CCL2) and stromal cell-derived factor-1(SDF-1/CXCL12), which could act in this tropism. However, the role in the modulation of this tropism of the subpopulation of CD133+ cells, which initiate GBM and the mechanisms underlying the tropism of MSCs to CD133+ GBM cells and their effects on tumor development, remains poorly defined. Methods/results We found that isolated and cultured MSCs (human umbilical cord blood MSCs) express CCR2 and CXCR4, the respective receptors for MCP-1/CCL2 and SDF-1/CXCL12, and demonstrated, in vitro, that MCP-1/CCL2 and SDF-1/CXC12, secreted by CD133+ GBM cells from primary cell cultures, induce the migration of MSCs. In addition, we confirmed that after in vivo GBM tumor establishment, by stereotaxic implantation of the CD133+ GBM cells labeled with Qdots (705 nm), MSCs labeled with multimodal iron oxide nanoparticles (MION) conjugated to rhodamine-B (Rh-B) (MION-Rh), infused by caudal vein, were able to cross the blood-brain barrier of the animal and migrate to the tumor region. Evaluation GBM tumors histology showed that groups that received MSC demonstrated tumor development, glial invasiveness, and detection of a high number of cycling cells. Conclusions Therefore, in this study, we validated the chemotactic effect of MCP-1/CCL2 and SDF-1/CXCL12 in mediating the migration of MSCs toward CD133+ GBM cells. However, we observed that, after infiltrating the tumor, MSCs promote tumor growth in vivo probably by release of exosomes. Thus, the use of these cells as a therapeutic carrier strategy to target GBM cells must be approached with caution.
RESUMO
Background: Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. Results: We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. Conclusions: We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. Methods: In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients (n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model.
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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.
RESUMO Objetivo Analisar o papel da reoperação em pacientes com glioblastoma recidivado em um serviço público no Brasil. Métodos Foram analisados retrospectivamente 39 pacientes submetidos à reoperação por recorrência de glioblastoma no Departamento de Neurocirurgia da Universidade Federal de São Paulo, no período de janeiro de 2000 até dezembro de 2013. Resultados A sobrevida global mediana foi de 20 meses (IC 95% = 14.9–25.2), e a sobrevida mediana após a reoperação foi de 9.1 meses (IC 95% = 2.8–15.4). A realização de tratamento adjuvante após a primeira cirurgia foi o único fator associado com a sobrevida global numa análise multivariada (RR = 0.3; IC 95% = 0.2–0.7; p = 0.005). Conclusão A sobrevida dos pacientes submetidos à reoperação em um serviço público no Brasil é semelhante à reportada pela literatura. A reoperação deve ser considerada como uma opção terapêutica em pacientes selecionados.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Reoperação/mortalidade , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Reoperação/normas , Fatores de Tempo , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/terapia , Análise de Sobrevida , Estudos Retrospectivos , Glioblastoma/cirurgia , Glioblastoma/terapia , Neoplasia Residual , Quimiorradioterapia Adjuvante/métodos , Recidiva Local de Neoplasia/cirurgiaRESUMO
The intracranial schwannomas cover about 8% of all the brain tumors, although, those localized inside the encephalic parenchyma are rare only 55 cases being reported in the literature. The histopathologic diagnosis is based on the cellular type and arrangement common to the nervous sheath tumors, the immunohistochemical findings (GFAP, S-100 protein, EMA) and electronmicroscopic findings as well. The clinical presentation related to the intraparenchimatous schwannoma is variable, depending on its localization, the image diagnosis does not show any typical aspect. The surgical treatment is curative once a complete extirpation is obtained. These tumors are benign but one case reported presented malignant signs. We present a patient that had a thalamic schwannoma with histological confirmation. We found no case with this localization in the literature.
Assuntos
Neoplasias Encefálicas/patologia , Neurilemoma/patologia , Tálamo/patologia , Adolescente , Neoplasias Encefálicas/química , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Neoplasias/análise , Neurilemoma/química , Proteínas S100/análise , Tálamo/químicaRESUMO
Os schwanomas intracranianos compreendem cerca de 8 por cento de todos os tumores cerebrais porém, aqueles classificados como intra-axiais säo mais raros, havendo somente 55 casos relatados na literatura. O diagnóstico é feito pelo tipo e arranjo celular comum aos tumores de bainha nervosa, pela imuno-histoquímica (GFAP, proteína S-100, EMA) e pela microscopia eletrônica. Sua apresentaçäo clínica é variável, dependendo de sua localizaçäo; suas características neurorradiológicas näo se apresentam de maneira típica. O tratamento cirúrgico, com exérese total da lesäo, propicia a cura. Possuem caracteres benignos; um dos casos relatados na literatura, possuía entretanto caracteres de malignidade. Apresentamos um caso de schwanoma cerebral intra-axial supratentorial localizado na regiäo talâmica esquerda, com confirmaçäo diagnóstica anatomopatológica e imuno-histoquímica. Em tal localizaçäo näo fora encontrado nenhum caso na literatura
