Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
JAMA Dermatol ; 154(3): 341-346, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29322178

RESUMO

Importance: Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. Objective: To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. Design, Setting, and Participants: Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. Main Outcomes and Measures: Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. Results: In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. Conclusions and Relevance: This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.


Assuntos
Genes da Neurofibromatose 2 , Neurilemoma/genética , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Masculino , Mutação , Neurilemoma/patologia , Células de Schwann , Neoplasias Cutâneas/patologia
2.
BMC Med Genomics ; 8: 2, 2015 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-25739810

RESUMO

BACKGROUND: A clinical overlap exists between mosaic Neurofibromatosis Type 2 and sporadic Schwannomatosis conditions. In these cases a molecular analysis of tumors is recommended for a proper genetic diagnostics. This analysis is challenged by the fact that schwannomas in both conditions bear a somatic double inactivation of the NF2 gene. However, SMARCB1-associated schwannomas follow a four-hit, three-step model, in which both alleles of SMARCB1 and NF2 genes are inactivated in the tumor, with one of the steps being always the loss of a big part of chromosome 22 involving both loci. CASE PRESENTATION: Here we report a 36-year-old woman who only presented multiple subcutaneous schwannomas on her right leg. To help discriminate between both possible diagnoses, an exhaustive molecular genetic and genomic analysis was performed on two schwannomas of the patient, consisting in cDNA and DNA sequencing, MLPA, microsatellite multiplex PCR and SNP-array analyses. The loss of a big part of chromosome 22 (22q12.1q13.33) was identified in both tumors. However, this loss involved the NF2 but not the SMARCB1 locus. SNP-array analysis revealed the presence of the same deletion breakpoint in both schwannomas, indicating that this alteration was actually the first NF2 inactivating hit. In addition, a distinct NF2 point mutation in each tumor was identified, representing independent second hits. In accordance with these results, no deletions or point mutations in the SMARCB1 gene were identified. None of the mutations were present in the blood. Two of the patient's children inherited chromosome 22 deleted in schwannomas of the mother, but in its wild type form. CONCLUSIONS: These results conclusively confirm the segmental mosaic NF2 nature of the clinical phenotype presented.


Assuntos
Perna (Membro) , Técnicas de Diagnóstico Molecular , Neurilemoma/genética , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Adulto , Sequência de Bases , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Feminino , Genes da Neurofibromatose 2 , Humanos , Repetições de Microssatélites/genética , Neurilemoma/diagnóstico , Polimorfismo de Nucleotídeo Único , Proteína SMARCB1 , Fatores de Transcrição/genética
3.
J Neurooncol ; 117(1): 77-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24395350

RESUMO

Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Cisplatino/uso terapêutico , Dacarbazina/análogos & derivados , Radiossensibilizantes/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Feminino , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Terapia Neoadjuvante , Radiossensibilizantes/administração & dosagem , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida , Resultado do Tratamento , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
4.
Eur J Hum Genet ; 21(7): 769-73, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23188051

RESUMO

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder affecting about 1:33 000 newborns, mainly characterized by the development of tumors of the nervous system and ocular abnormalities. Around 85% of germline NF2 mutations are point mutations. Among them, ∼25% affect splicing and are associated with a variable disease severity. In the context of our NF2 Multidisciplinary Clinics, we have identified a patient fulfilling clinical criteria for the disease and exhibiting a severe phenotype. The patient carries a deep intronic mutation (g. 74409T>A, NG_009057.1) that produces the insertion of a cryptic exon of 167pb in the mature mRNA between exons 13 and 14, resulting in a truncated merlin protein (p.Pro482Profs*39). A mutation-specific antisense phosphorodiamidate morpholino oligomer was designed and used in vitro to effectively restore normal NF2 splicing in patient-derived primary fibroblasts. In addition, merlin protein levels were greatly recovered after morpholino treatment, decreasing patient's fibroblasts in vitro proliferation capacity and restoring cytoeskeleton organization. To our knowledge, this is the first NF2 case caused by a deep intronic mutation in which an in vitro antisense therapeutic approximation has been tested. These results open the possibility of using this approach in vivo for this type of mutation causing NF2.


Assuntos
Morfolinos/administração & dosagem , Neurofibromatose 2/genética , Neurofibromatose 2/terapia , Neurofibromina 2/genética , Adolescente , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Mutação em Linhagem Germinativa/genética , Humanos , Íntrons/genética , Morfolinos/genética , Morfolinos/uso terapêutico , Neurofibromatose 2/patologia , RNA Antissenso/genética
5.
Clin Transl Oncol ; 13(9): 677-85, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21865140

RESUMO

INTRODUCTION: Methylation of the promoter of the MGMT gene and MGMT protein expression are recognized as predictive markers for response to alkylating chemotherapy in glioblastoma (GB). MATERIAL AND METHODS: We have assessed MGMT methylation with the methylation-specific polymerase chain reaction (MSP) in tumor samples from 70 GB patients and in serum samples from 37 of these patients. We have also assessed MGMT protein expression by immunohistochemical (IHC) analysis in tissue samples from 63 of these patients. RESULTS: We found concordance between MGMT methylation status in tissue and serum (Cohen's Kappa = 0.586; p<0.0001). MSP for detection of non-methylated MGMT promoter in serum showed a sensitivity of 95.4% and a specificity of 60%, while the IHC methylation test showed a low specificity (8.9%). Patients whose MGMT promoter was methylated in tissue attained longer progression-free and overall survival. In the multivariate analysis, serum MGMT promoter methylation emerged as an independent factor for longer progression-free and overall survival. CONCLUSION: Serum-based MGMT methylation analysis offers a promising alternative to tumor-based MGMT analysis in cases where tissue samples are unavailable.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Análise Química do Sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Metilação de DNA/fisiologia , Metilases de Modificação do DNA/análise , Metilases de Modificação do DNA/sangue , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/sangue , Feminino , Glioblastoma/sangue , Glioblastoma/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Neoplasias/metabolismo , Regiões Promotoras Genéticas/fisiologia , Estudos Retrospectivos , Soro/química , Soro/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/sangue
6.
Neurochem Int ; 56(6-7): 829-33, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20307616

RESUMO

Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer. During the last years, several studies have demonstrated that cannabinoids induce apoptosis of glioma cells and inhibit angiogenesis of gliomas in vivo. As the effects of cannabinoids rely on CB(1) and CB(2) receptors activation, the aim of the present study was to investigate both receptors protein expression in cellular membrane homogenates of human glial tumors using specific antibodies raised against these proteins. Additionally, we studied the functionality of the cannabinoid receptors in glioblastomas by using WIN 55,212-2 stimulated [(35)S]GTPgammaS binding. Western blot analysis showed that CB(1) receptor immunoreactivity was significantly lower in glioblastoma multiforme (-43%, n=10; p<0.05) than in normal post-mortem brain tissue (n=16). No significant differences were found for astrocytoma (n=6) and meningioma (n=8) samples. Conversely, CB(2) receptor immunoreactivity was significantly greater in membranes of glioblastoma multiforme (765%, n=9; p<0.05) and astrocytoma (471%, n=4; p<0.05) than in control brain tissue (n=10). Finally, the maximal stimulation of [(35)S]GTPgammaS binding by WIN 55,212-2 was significantly lower in glioblastomas (134+/-4%) than in control membranes (183+/-2%; p<0.05). The basal [(35)S]GTPgammaS binding and the EC(50) values were not significantly different between both groups. The present results demonstrate opposite changes in CB(1) and CB(2) receptor protein expression in human gliomas. These changes may be of interest for further research about the therapeutic effects of cannabinoids in glial tumors.


Assuntos
Neoplasias Encefálicas/química , Glioma/química , Receptor CB1 de Canabinoide/análise , Receptor CB2 de Canabinoide/análise , Adulto , Idoso , Astrocitoma/química , Benzoxazinas/farmacologia , Western Blotting , Química Encefálica , Canabinoides/farmacologia , Membrana Celular/química , Feminino , Glioblastoma/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Meningioma/química , Pessoa de Meia-Idade , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/metabolismo , Radioisótopos de Enxofre
7.
Neurochem Int ; 52(1-2): 230-4, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17624626

RESUMO

Glial tumours are the most common type of brain neoplasm in humans. Tumour classification and grading represent key factors for patient management. However, current grading schemes are still limited by subjective histological criteria. In this context, gliosis has been linked to increases in monoamine oxidase B (MAO-B) activity. Thus, in the present study, MAO-B activity in membranes of glial tumours (n=20), meningiomas (n=12) and non-pathological human brains (n=15) was quantified by [14C]PEA oxidation. MAO-B activity was significantly greater in glioblastoma multiformes than in postmortem control brains (p<0.01) or meningiomas (p<0.001). There were no significant differences in MAO-B activity between glioblastoma multiformes (n=11) and low-grade astrocytomas (n=3) or anaplastic astrocytomas (n=6). In conclusion, the present results demonstrate a significant and selective increase in MAO-B activity in human gliomas when compared with meningiomas or non-tumoural tissue. These results suggest that the quantification of MAO-B activity may be a useful diagnostic tool for differentiating glial tumours from other types of brain tumours or surrounding normal brain tissue.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Monoaminoxidase/metabolismo , Adulto , Idoso , Humanos , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA