RESUMO
INTRODUCTION: Low-grade neuroepithelial tumors are a heterogeneous group of central nervous system tumors that are generally indolent in nature but in rare instances can progress to include leptomeningeal dissemination. CASE PRESENTATION: We present a case of a patient with a low-grade neuroepithelial tumor of indeterminate type with symptomatic leptomeningeal dissemination despite 3 chemotherapy regimens and radiotherapy. Somatic targetable mutation testing showed an FGFR1_TACC1 fusion. Therapy with pazopanib/topotecan was initiated, and disease stabilization was achieved. He received pazopanib/topotecan for a total of 2 years and is now >2 years from completion of treatment and continues to do well with no evidence of disease. DISCUSSION: This case highlights the utility of targetable mutation testing in therapeutic decision-making and the novel use of systemic pazopanib/topotecan therapy for refractory low-grade neuroepithelial tumor within the context of this clinical situation and specific mutation profile.
Assuntos
Neoplasias Neuroepiteliomatosas , Topotecan , Proteínas Fetais , Humanos , Indazóis , Masculino , Proteínas Associadas aos Microtúbulos , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/genética , Proteínas Nucleares , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Sulfonamidas/uso terapêuticoRESUMO
A 35-year-old man was admitted to our department for loss of consciousness. CT and MRI revealed diffuse enhancement of the subarachnoid space surrounding the brainstem and the cerebellar sulci, without any parenchymal lesions in the brain or the spinal cord. Furthermore, gadolinium-enhanced MRI revealed a nodular lesion with heterogeneous enhancement in the right prepontine cistern, at the site from which a biopsy was obtained via right lateral suboccipital craniotomy on the day following admission. Histopathological examination of the resected specimen revealed glioblastoma multiforme. Based on the radiological and histopathological findings, the patient was diagnosed with primary leptomeningeal gliomatosis (PLG). The patient received temozolomide chemotherapy with concurrent radiotherapy and showed radiological remission, 12 months after diagnosis. However, he developed local recurrence 6 months later and died 23 months after diagnosis. Autopsy findings showed tumor cell infiltration of the leptomeninges, as well as the brain and spinal parenchyma. PLG should be considered in the differential diagnosis in patients with diffuse leptomeningeal enhancement even without parenchymal lesions on radiological imaging. A surgical biopsy is recommended for prompt and accurate diagnosis in such cases.
Assuntos
Neoplasias Meníngeas , Neoplasias Neuroepiteliomatosas , Temozolomida , Adulto , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/tratamento farmacológico , Meninges , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/tratamento farmacológicoRESUMO
The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced ß-catenin binding resulting in increased cytosolic and nuclear ß-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/ß-catenin signaling.
Assuntos
Antígenos CD/genética , Neoplasias Encefálicas/genética , Caderinas/genética , Carcinoma/genética , Neoplasias Neuroepiteliomatosas/genética , Adenoma/genética , Adenoma/patologia , Compostos de Anilina/uso terapêutico , Animais , Diversidade de Anticorpos , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma/tratamento farmacológico , DNA de Neoplasias/genética , Técnicas de Introdução de Genes , Variação Genética , Células HEK293 , Humanos , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Oligodendroglioma/genética , Oligodendroglioma/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sequenciamento Completo do GenomaRESUMO
Gliomatosis cerebri (GC) is a rare diffusely infiltrating glial neoplasm that carries a poor prognosis. Because tumors are undetectable in most patients at early-stage of the onset, a useful diagnostic method is expected. We compared serum vascular endothelial growth factor (VEGF)-121 levels in patients with GC or glioblastoma and controls. VEGF-121 levels were significantly higher in one patient with GC and patients with glioblastoma than in controls. VEGF-121 levels decreased in a patient with GC after bevacizumab-based therapy. Thus, VEGF-121 may be useful for diagnosing GC, its disease-monitoring and understanding its etiology.
Assuntos
Astrocitoma/patologia , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/patologia , Neoplasias Neuroepiteliomatosas/patologia , Fator A de Crescimento do Endotélio Vascular/sangue , Antineoplásicos Imunológicos/uso terapêutico , Astrocitoma/sangue , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/tratamento farmacológico , Criança , Glioblastoma/sangue , Humanos , Masculino , Neoplasias Neuroepiteliomatosas/sangue , Neoplasias Neuroepiteliomatosas/tratamento farmacológicoAssuntos
Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Diabetes Insípido Neurogênico/patologia , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Doenças Raras/patologia , Temozolomida/efeitos adversos , Neoplasias Encefálicas/patologia , Criança , Diabetes Insípido Neurogênico/induzido quimicamente , Humanos , Masculino , Neoplasias Neuroepiteliomatosas/patologia , Prognóstico , Doenças Raras/induzido quimicamenteRESUMO
Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Astrocitoma/diagnóstico , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Criança , Ganglioglioma/diagnóstico , Ganglioglioma/tratamento farmacológico , Ganglioglioma/genética , Ganglioglioma/patologia , Glioma/diagnóstico , Glioma/tratamento farmacológico , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Gradação de Tumores , Neoplasias Neuroepiteliomatosas/diagnóstico , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Patologia Molecular , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Regulação para Cima , Organização Mundial da Saúde , Proteínas ras/genéticaRESUMO
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonas/uso terapêutico , Adulto , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Pré-Escolar , Aberrações Cromossômicas , Metilação de DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Terapia de Alvo Molecular , Neoplasias Neuroepiteliomatosas/patologia , Análise de Componente Principal , Pirimidinas/farmacologia , Receptor Notch1/metabolismo , Sulfonas/farmacologia , Transcriptoma/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class "HGNET-BCOR" and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Pirimidinas/farmacologia , Receptores de Somatomedina/metabolismo , Sulfonas/farmacologia , Vimblastina/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Metilação de DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Terapia de Alvo Molecular , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Proteínas Repressoras/genética , Células Tumorais CultivadasRESUMO
Astroblastoma is an uncommon neuroepithelial primary tumor of the brain which is of uncertain origin. We present a case of high-grade astroblastoma in an 18-year-old female with a severe headache, loss of appetite, vomiting and generalized weakness. The patient had undergone a right frontoparietal craniotomy. Large subfalcine meningioma was excised. The lesion was suspected to be a meningioma. Primary radiological investigation revealed a 6.8 cm × 5.8 cm × 5.4 cm lesion. Although the radiological and intraoperative findings were of an extra-axial tumor, the histology and immunophenotype was of an astroblastoma. The patient was treated with cyclophosphamide, cisplatin and etoposide chemotherapy regimen. The patient was later treated with bi-weekly bevacizumab. The patient had improved symptomatically post-chemotherapy. However, there was no significant difference in lesion size. The patient died after 2 weeks. The prognosis of patients with astroblastoma is extremely poor as observed in our case.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/patologia , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Gradação de Tumores , Neoplasias Neuroepiteliomatosas/diagnóstico por imagemRESUMO
PURPOSE: Glioblastoma multiforme (GBM) is the most common malignant brain tumor originating in the central nervous system in adults. Based on nanotechnology such as liposomes, polymeric nanoparticles, and lipid nanoparticles, recent research efforts have been aimed to target drugs to the brain. METHODS: In this study, lactoferrin- and arginine-glycine-aspartic acid (RGD) dual- ligand-comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers (L/RT/V-NLCs) were introduced for GBM combination therapy. The physicochemical properties of L/R-T/V-NLCs such as particle size, zeta potential, and encapsulated efficiency are measured. The drug release profile, cellular uptake, cytotoxicity, tissue distribution, and antitumor activity of L/R-T/V-NLCs are further investigated in vitro and in vivo. RESULTS: L/R-T/V-NLCs were stable with nanosize and high drug encapsulation efficiency. L/R-T/V-NLCs exhibited sustained-release behavior, high cellular uptake, high cytotoxicity and synergy effects, increased drug accumulation in the tumor tissue, and obvious tumor inhibition efficiency with low systemic toxicity. CONCLUSION: L/R-T/V-NLCs could be a promising drug delivery system for glioblastoma chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/química , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Lactoferrina/administração & dosagem , Lactoferrina/química , Lipídeos/química , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Oligopeptídeos/química , Temozolomida , Distribuição Tecidual , Vincristina/administração & dosagem , Vincristina/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway is a target for the treatment of a growing number of malignancies. The cutaneous reactions to medications that inhibit this pathway have not been described in children. METHODS: A retrospective chart review was completed for eight children with neural tumors treated with the MAPK extracellular signal-regulated kinase inhibitor trametinib. All children were evaluated by a pediatric dermatologist with documentation of cutaneous findings. RESULTS: All patients had at least two separate skin reactions while on treatment with trametinib. Common skin findings included xerotic dermatitis, bacterial folliculitis, acneiform eruptions, paronychia, and hair thinning. No child needed to discontinue use of trametinib due to cutaneous toxicities. CONCLUSIONS: Cutaneous reactions are common in children receiving trametinib. Identification of these reactions is the initial step in establishing treatment guidelines that will minimize skin eruptions and subsequent interruption of trametinib treatment.
Assuntos
Exantema/induzido quimicamente , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Adolescente , Criança , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Humanos , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Estudos RetrospectivosRESUMO
High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity with a dismal prognosis. The objective of this study was to identify and validate pathways deregulated in CNS HGNET-BCOR as basis for targeted therapy approaches.We characterized the BCOR alteration in a pediatric patient with CNS HGNET-BCOR diagnosis by Sanger sequencing and demonstrated an elevated BCOR expression by qRT-PCR and western blot. By whole transcriptome sequencing and Ingenuity Pathway Analysis, we identified the activation of the Sonic Hedgehog (SHH) and of the WNT signaling pathway in two different regions of the primary tumor and of one inoculation metastasis compared to normal brain. We validated the activation of the SHH and of the WNT pathway by qRT-PCR analysis of GLI1 and AXIN2 respectively. GLI1 and AXIN2 were upregulated in the primary tumor and in two inoculation metastases compared to normal brain. Mutational analysis of SMO, PTCH1 and SUFU, three key components of the SHH pathway, revealed a Single Nucleotide Polymorphism (SNP) in PTCH1 (rs357564). We tested the effect of the GLI-inhibitor arsenic trioxide (ATO) on a short-term cell culture isolated from the metastasis. ATO was able to reduce the viability of the cells with an IC50 of 1.3 µM.In summary, these results provide functional evidence of altered BCOR expression and homogeneous coactivation of both the SHH and WNT signaling pathways, building the basis for potential novel therapeutic approaches for patients with a CNS HGNET-BCOR diagnosis.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Carcinoma Basocelular/genética , Neoplasias Neuroepiteliomatosas/genética , Medicina de Precisão , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Antineoplásicos/farmacologia , Trióxido de Arsênio , Arsenicais/farmacologia , Proteína Axina/genética , Biomarcadores Tumorais/metabolismo , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/secundário , Sobrevivência Celular/efeitos dos fármacos , Criança , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Proteínas Hedgehog/genética , Humanos , Concentração Inibidora 50 , Imageamento por Ressonância Magnética , Masculino , Mutação , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/metabolismo , Neoplasias Neuroepiteliomatosas/secundário , Óxidos/farmacologia , Receptor Patched-1/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Receptor Smoothened/genética , Células Tumorais Cultivadas , Regulação para Cima , Via de Sinalização Wnt/genética , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioma/radioterapia , Neoplasias Neuroepiteliomatosas/radioterapia , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Dacarbazina/uso terapêutico , Feminino , Glioma/tratamento farmacológico , Glioma/cirurgia , Humanos , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/cirurgia , TemozolomidaRESUMO
BACKGROUND: Co-delivery of gene and anticancer drug into the same cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, nanostructured lipid carriers (NLCs) were constructed as multifunctional nanomedicine for co-delivery of enhanced green fluorescence protein plasmid (DNA) and temozolomide (TMZ). METHODS: TMZ- and DNA-loaded NLCs (TMZ/DNA-NLCs) were prepared. Their particle size, zeta potential, gene-loading capacity (GL) and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study TMZ/DNA-NLCs was tested in U87 malignant glioma cells (U87 MG cells). In vivo gene transfection and anti-tumor efficacy of the carriers were evaluated on mice bearing malignant glioma model. RESULTS: The optimum TMZ/DNA-NLCs formulations with the particle size of 179 nm and with a +23 mV surface charge; got 91% of GL and 83% of EE. The growth of U87 MG cells in vitro was obviously inhibited. TMZ/DNA-NLCs also displayed the highest gene transfection efficiency and the best antitumor activity than other formulations in vivo. CONCLUSION: The results demonstrated that TMZ/DNA-NLCs were efficient in selective delivery to malignant glioma cells. Also TMZ/DNA-NLCs transfer both drug and gene to the gliomatosis cerebri, enhance the antitumor capacity and gene transfection efficacy. Thus, TMZ/DNA-NLCs could prove to be a superior co-delivery nanomedicine to achieve therapeutic efficacy and this report could be a new promising strategy for treatment in malignant gliomatosis cerebri.
Assuntos
Antineoplásicos/química , DNA/química , DNA/farmacologia , Dacarbazina/análogos & derivados , Lipídeos/química , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica , DNA/genética , Dacarbazina/química , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Nanomedicina , Nanoestruturas , Neoplasias Neuroepiteliomatosas/química , Temozolomida , TransfecçãoRESUMO
INTRODUCTION: Primary neuroepithelial brain tumors encompass a wide variety of glial and glioneuronal neoplasms. Malignant tumors, tumors located in surgically inaccessible locations (e.g., eloquent brain areas, deep structures, brain stem) and recurrent or progressive tumors pose considerable treatment challenges and are candidates for novel therapeutics based on molecular insights. Small kinase inhibitors of v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) have shown considerable antineoplastic activity in some tumor types harboring activating BRAF-V600 mutations (e.g., melanoma) and promising data are emerging on BRAF inhibitor therapy of mutation-bearing primary brain tumors. AREAS COVERED: This review summarizes the available data on BRAF-V600 point mutations and the antineoplastic activity and toxicity profiles of BRAF inhibitors in neuroepithelial brain tumors including diffuse gliomas (glioblastomas, astrocytomas, oligodendrogliomas), pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas. EXPERT OPINION: Activating BRAF-V600 mutations are recurrently found in several glial and glioneuronal brain tumors and the available data indicate that BRAF inhibitors are active and well-tolerated in such tumors. Thus, BRAF inhibitors represent a novel and promising therapeutic opportunity that may alter the disease course of molecularly selected CNS neoplasms in a clinically meaningful way. However, so far the evidence is anecdotal and prospective clinical studies should be conducted.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ganglioglioma/tratamento farmacológico , Ganglioglioma/genética , Ganglioglioma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Mutação Puntual , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
We present an unusual case of a 56-year-old man presenting with abdominal swelling. Imaging revealed a large abdominal 23 cm cystic mass, which radiologically appeared to be related to the small bowel. There was an attempted surgical removal by the general surgeons. It was histologically confirmed as a retroperitoneal cystic teratoma with immature neural elements with incomplete resection margins. Residual disease was found at re-imaging 3 months later and a further block dissection was performed, with histology confirming recurrence. Thirteen months later, imaging revealed recurrent disease with peritoneal involvement. At laparoscopic exploration, there was peritoneal seeding, and biopsies confirmed a diagnosis of gliomatosis peritonei, secondary to the retroperitoneal teratoma. The patient proceeded to have combination chemotherapy to achieve stable disease on imaging. A month after completion, sadly, the disease progressed; the patient received best supportive care.
Assuntos
Neoplasias Neuroepiteliomatosas/diagnóstico , Neoplasias Retroperitoneais/diagnóstico , Teratoma/diagnóstico , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/patologia , Neoplasias Abdominais/cirurgia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasia Residual/diagnóstico , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/patologia , Doenças Raras , Neoplasias Retroperitoneais/patologia , Teratoma/patologia , Teratoma/cirurgia , Resultado do TratamentoAssuntos
Corticosteroides/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/diagnóstico , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Idoso , Neoplasias Encefálicas/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias Neuroepiteliomatosas/fisiopatologiaRESUMO
The cytotoxic effects of N-acetylsphingosine (C2-Cer) and N-hexanoylsphingosine (C6-Cer) were compared together with their specific intracellular accumulation profiles and metabolism in human CHP-100 neuroepithelioma cells. The two short-chain ceramides, administered in the culture medium at an equimolar concentration, evoked a differential apoptotic response, with C6-Cer showing markedly more cytotoxic than C2-Cer. Apoptosis, that was suppressed in both cases by inhibition of caspase-9, but not of caspase-8, associated with a higher intracellular accumulation of C6-Cer over C2-Cer, notwithstanding C6-Cer was actively metabolized by direct glucosylation or by conversion to natural ceramide via the sphingosine salvage pathway, whereas C2-Cer was apparently metabolically inhert. C2-Cer cytotoxicity was markedly enhanced by increasing its concentration in the culture medium, and this response associated with a higher intracellular accumulation of this compound, in the absence of any natural ceramide elevation. These results support the notion that the differential apoptotic effect evoked by C2-Cer and C6-Cer in CHP-100 cells is driven by their differential intracellular accumulation profiles, but not by their differential property to generate natural ceramide via the sphingosine salvage pathway.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ceramidas/farmacologia , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Células Neuroepiteliais/efeitos dos fármacos , Células Neuroepiteliais/patologia , Esfingosina/análogos & derivados , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Ceramidas/metabolismo , Humanos , Neoplasias Neuroepiteliomatosas/metabolismo , Neoplasias Neuroepiteliomatosas/patologia , Células Neuroepiteliais/metabolismo , Esfingosina/metabolismo , Esfingosina/farmacologiaAssuntos
Antineoplásicos Alquilantes/uso terapêutico , Abscesso Encefálico/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Nocardiose/diagnóstico , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Encéfalo/patologia , Abscesso Encefálico/patologia , Neoplasias Encefálicas/patologia , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Neuroepiteliomatosas/patologia , Nocardiose/patologia , TemozolomidaRESUMO
PURPOSE: To evaluate the efficacy of radiotherapy and factors affecting the prognosis of gliomatosis cerebri. METHODS: Twenty-eight patients with pathologically confirmed gliomatosis cerebri underwent radiotherapy between August 1988 and September 2003. The median age of the patients was 39 years (range 18-67). Performance status was good (ECOG score ≤2) in 23 patients (82 %). The extent of radiotherapy was partial brain in 17 patients, whole brain in 2 patients, and whole brain followed by partial brain in 9 patients. The median radiation dose was 55.8 Gy (range 46.8-70.4). The median duration of follow-up was 136 months for survivors (range 39-191). RESULTS: The median overall and progression-free survival times of all patients were 20 and 11 months, respectively. When initial response to radiotherapy was grouped as improved, stationary, and aggravated, the median overall survival times in patients with improved, stationary, and aggravated responses were 76, 20, and 7 months, respectively (p = 0.0129). However, radiation parameters such as dose and irradiation volume had no impact on overall survival. On multivariate analysis, both performance status and initial response to radiotherapy were significant prognostic factors affecting overall survival (p = 0.0249 and 0.0065, respectively). CONCLUSIONS: This study showed that gliomatosis cerebri could be effectively treated with radiotherapy and that initial response to radiotherapy was a significant prognostic factor affecting the survival (AU)
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