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1.
Biomarkers ; 24(7): 677-683, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31496301

RESUMO

Background/Context: Glioblastoma (GB) is the most common primary brain tumour in adults and it is associated with a high mortality rate. According to the stem cell theory, the growth, relapse and treatment response of GB is determined by the stem cell subpopulation present in the tumour. Objective: Our aim is to study the prognostic value of stem cell markers (CD44, Nestin, Olig2 and SOX2) in a series of homogeneously treated GBs. Material and methods: We study 280 GBs treated with STUPP acheme with a histologican review of the cases and TMA with a máximum of 4 spots for each case. Each slide was immunohistochemically stained and Reading. We compared the immunohistochemical results with survival tme. Results: Only SOX2 immunoexpression (IE) excedding 10% of the tumour cells was found to be related to good survival (p= 0.037) in univariate analysis. However, amultivariate analysis indicate the age, surgery and MGMT promotes methylation but no SOX2 IE are prognostic factors. Conclusions: We conclude the immunohistochemical studies of stem cell markers in GB are not useful for predicting prognosis in daily practice.

2.
Acta Neuropathol ; 138(6): 1053-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31428936

RESUMO

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

3.
Sci Rep ; 9(1): 11125, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366977

RESUMO

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.

6.
Int J Cardiol ; 269: 298-303, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30057168

RESUMO

BACKGROUND: Type B intramural hematoma (IMH) is considered a low-risk entity for aortic complications if aortic dilation, containing rupture or clinical instability are absent. However, the development of intimal disruptions (ID), present in >40% of cases, poses an unknown risk. OBJECTIVES: To establish which ID characteristics imply a higher risk of aortic complications and, therefore, merit invasive treatment. METHODS: A systematic review and a meta-analysis were made following a search in EMBASE, MEDLINE and PsycINFO for articles published between January 1995 and December 2017. The combined endpoint was defined as aortic mortality, invasive treatment for aortic disease and/or increase in maximum aortic diameter ≥55 mm. Lesions with communicating orifice ≤3 mm were defined as tiny ID (TID) and those with >3 mm as focal ID (FID). RESULTS: Six studies with 564 participants diagnosed of type B IMH were included. Incidence of ID was 54.3% (306 individuals): 27.7% (156 individuals) initially met TID criteria; however, 13.9% of these (21 of 151 with morphologic evolution) evolved to FID within the first 6 months. Ninety-two cases suffered clinical aorta-related events (16.3%; mean follow-up range: 15-85 months; median: 52 months). Patients with TID had a similar risk of aorta-related events to those without ID (RR = 0.904; 95% CI, 0.335-2.440; P = 0.842; I2 = 42.5%), but lower than those with FID (RR = 0.299; 95% CI, 0.094-0.952; P = 0.041; I2 = 26.9%). CONCLUSIONS: Tiny intimal disruption in type B IMH evolution is not related to an increased risk of complications and should not be considered an indication for invasive treatment. However, since 14% of TID evolve to FID within the first 6 months, close follow-up with imaging techniques is advisable.


Assuntos
Doenças da Aorta/diagnóstico , Hematoma/diagnóstico , Túnica Íntima/patologia , Doenças da Aorta/epidemiologia , Doenças da Aorta/fisiopatologia , Hematoma/epidemiologia , Hematoma/fisiopatologia , Humanos
8.
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
9.
Cancer Med ; 6(12): 2858-2866, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29105360

RESUMO

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression-free survival (PFS), post-progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5-fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606-7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter-though not significantly so-for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Distribuição de Qui-Quadrado , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Espanha , Fatores de Tempo , Resultado do Tratamento , Proteínas Supressoras de Tumor/genética , Adulto Jovem
10.
J Neurooncol ; 135(2): 273-284, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28884377

RESUMO

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Glioma/patologia , Glioma/terapia , Humanos , Masculino , Análise Multivariada , Gradação de Tumores , Prognóstico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Adulto Jovem
11.
PLoS One ; 12(1): e0170632, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28122052

RESUMO

The molecular classification of glioblastoma (GBM) based on gene expression might better explain outcome and response to treatment than clinical factors. Whole transcriptome sequencing using next-generation sequencing platforms is rapidly becoming accepted as a tool for measuring gene expression for both research and clinical use. Fresh frozen (FF) tissue specimens of GBM are difficult to obtain since tumor tissue obtained at surgery is often scarce and necrotic and diagnosis is prioritized over freezing. After diagnosis, leftover tissue is usually stored as formalin-fixed paraffin-embedded (FFPE) tissue. However, RNA from FFPE tissues is usually degraded, which could hamper gene expression analysis. We compared RNA-Seq data obtained from matched pairs of FF and FFPE GBM specimens. Only three FFPE out of eleven FFPE-FF matched samples yielded informative results. Several quality-control measurements showed that RNA from FFPE samples was highly degraded but maintained transcriptomic similarities to RNA from FF samples. Certain issues regarding mutation analysis and subtype prediction were detected. Nevertheless, our results suggest that RNA-Seq of FFPE GBM specimens provides reliable gene expression data that can be used in molecular studies of GBM if the RNA is sufficiently preserved.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Biologia Computacional , Perfilação da Expressão Gênica/métodos , Glioblastoma/metabolismo , Glioblastoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
12.
Am J Dermatopathol ; 39(5): 363-366, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27655127

RESUMO

Folliculitis is defined as the inflammation of the follicles. The most common cause of folliculitis is infection. Here, we report an unusual cause of suppurative infundibulitis-which had not yet been described in the literature-due to Leishmania infection, and exemplified by 6 cases that occurred in the setting of an epidemic outbreak. The 6 individuals were immigrants from Morocco. Most of them were men (4 men and 2 women), and most of them were less than 30 years old (apart from one 40-year-old woman). In all cases, a cutaneous biopsy was performed. There was a granulomatous folliculitis with suppurative granulomas in all the cases. All cases showed prominence of plasma cells in the inflammatory infiltrate, and leishmanias were found in all cases. They were mainly seen in the abscessified central areas. The amount of organisms varied from a few to a moderate amount. They were stained by the anti-CD1a antibody (Novocastra) and by a polyclonal homemade anti-leishmania antibody. In addition, in 1 case, microbiological culture was performed, and Leishmania major was demonstrated as the causative agent of the infection.


Assuntos
Surtos de Doenças , Foliculite/epidemiologia , Foliculite/patologia , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/patologia , Adolescente , Adulto , Biópsia por Agulha , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Foliculite/diagnóstico , Humanos , Imuno-Histoquímica , Incidência , Leishmaniose Cutânea/diagnóstico , Masculino , Pessoa de Meia-Idade , Espanha/epidemiologia
14.
Reumatol. clín. (Barc.) ; 12(2): 85-90, mar.-abr. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-150874

RESUMO

La enfermedad de Behçet es una vasculitis caracterizada por úlceras bucales y genitales. La afectación neurológica o neuro-Behçet es una manifestación infrecuente, de predominio en el género masculino y que aparece de 2 a 4 años después de la primera manifestación clínica. El neuro-Behçet cursa ocasionalmente lesiones cerebrales pseudotumorales. Presentamos 2 casos de pacientes diagnosticados de neuro-Behçet tras la detección de lesiones cerebrales pseudotumorales y se realiza una revisión de la literatura (AU)


Behçet‘s disease is a systemic vasculitis characterized by the presence of oral and genital ulcers. Neurological involvement or neuro-Behçet is an uncommon manifestation. It manifestation has predominance in the male gender appearing 2 to 4 years after the first clinical manifestation. However, neuro-Behçet disease sometimes occurs with pseudotumoral brain lesions. Herein, we present the cases of two patients diagnosed with neuro-Behçet after detection of pseudotumoral brain lesions. A review of the literature is performed (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Síndrome de Behçet/patologia , Síndrome de Behçet , Pseudotumor Cerebral/patologia , Pseudotumor Cerebral , Metilprednisolona/uso terapêutico , Prednisona/uso terapêutico , Colchicina/uso terapêutico , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Agressão/fisiologia , Anamnese/métodos , Foliculite/complicações , Foliculite/patologia , Foliculite , Esclerose/complicações , Esclerose , Antígenos HLA/isolamento & purificação , Glucocorticoides/uso terapêutico , Infliximab/uso terapêutico
15.
J Neurooncol ; 127(3): 569-79, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26847813

RESUMO

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Terapia Neoadjuvante , Adulto , Idoso , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/patologia , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Temozolomida
16.
Reumatol Clin ; 12(2): 85-90, 2016.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-26078022

RESUMO

Behçet's disease is a systemic vasculitis characterized by the presence of oral and genital ulcers. Neurological involvement or neuro-Behçet is an uncommon manifestation. It manifestation has predominance in the male gender appearing 2 to 4 years after the first clinical manifestation. However, neuro-Behçet disease sometimes occurs with pseudotumoral brain lesions. Herein, we present the cases of two patients diagnosed with neuro-Behçet after detection of pseudotumoral brain lesions. A review of the literature is performed.


Assuntos
Síndrome de Behçet/diagnóstico , Encefalopatias/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
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
19.
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
20.
Hum Pathol ; 44(3): 412-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23026194

RESUMO

Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer syndrome, is caused by germ-line mutations in the mismatch repair system genes. Recently, a new mechanism involving the epithelial cell adhesion molecule (EPCAM)/TACSTD1 gene has been shown to be responsible in cases with abnormal MSH2 expression. Of interest, 3' exons deletions of the EPCAM gene, which is located upstream of MSH2 in chromosome 2, are associated with MSH2 promoter hypermethylation. EPCAM protein, expressed in epithelial tissues, is encoded by the EPCAM/TACSTD1 gene. Our study's aim was to explore EPCAM expression in colorectal carcinomas of MSH2-associated LS cases to evaluate the usefulness of EPCAM protein expression in the algorithm approach to LS population screening. We included a total of 19 MSH2-negative colorectal carcinomas from 14 different patients in whom we were able to perform a complete germ-line analysis. Nine patients showed a deleterious germ-line mutation that involved the MSH2 gene in 3 instances and the EPCAM gene exon 9 in 6 instances. All patients harboring the EPCAM mutation belonged to the same family. Of the 19 colorectal carcinomas, EPCAM expression loss was seen in only 5 tumors, all of them from patients showing a germ-line EPCAM deletion. Of interest, 6 tumors from 3 different patients carrying the same germ-line EPCAM deletion showed normal EPCAM expression. In conclusion, owing to the high specificity of EPCAM protein expression to identify LS patients carrying an EPCAM deletion, we recommend adding EPCAM immunohistochemistry to the LS diagnostic algorithm in MSH2-negative colorectal carcinoma.


Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Molécula de Adesão da Célula Epitelial , Feminino , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/deficiência , Proteína 2 Homóloga a MutS/genética , Estudos Prospectivos , Deleção de Sequência
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