Microdeletion 1p32p31 Presenting with Moyamoya Disease and Incomplete Hippocampal Inversion.

Background: The chromosome 1p32p31 deletion syndrome is a contiguous gene disorder with a variable phenotype characterized by brain malformations with or without urinary tract defects, besides neurodevelopmental delay and dysmorphisms. An expanded phenotype was proposed based on additional findings, including one previous report of a patient presenting with moyamoya disease. Case Presentation: The authors report a patient presenting with early neurodevelopmental delay, hydrocephalus, renal malformation, and dysmorphisms. After presenting with a sudden choreic movement disorder, the neuroimaging investigation revealed an ischemic stroke, moyamoya disease, and bilateral incomplete hippocampal inversion. Chromosomal microarray analysis revealed a deletion of 13.2 Mb at 1p31.3p32.2, compatible with the contiguous gene syndrome caused by microdeletions of this region. Discussion/Conclusion: This is the second report of a patient who developed Moyamoya disease and the first to describe bilateral incomplete hippocampal inversion in this microdeletion syndrome.

Replication Timing Aberration of KIF14 and MDM4 / PI3KC 2 ß Alleles and Aneuploidy as Markers of Chromosomal Instability and Poor Treatment Response in Ewing Family Tumor Patients.

Replication timing of allelic gene pairs is strictly regulated according to expression, genome stability, and epigenetic changes, and tumorigenesis may be associated with changes in the allelic replication in various tumors. Our aim was to determine whether such alterations had a prognostic value in Ewing's family tumor (EFT) patients. The KIF14 and MDM4 / PI3KC 2ß and the centromeric satellite sequence of chromosomes 8 and 12 were used for replication timing assessments. Aneuploidy was assessed by enumerating the copy numbers of chromosomes 8 and 12. Replication timing and aneuploidy were detected cytogenetically using multicolors fluorescence in situ hybridization assay applied in 135 EFT. Patients with trisomy 8 presented an association with an asynchronous replication pattern (SD) of MDM4 / PI3KC 2ß genes ( p = 0.013). Trisomy 12 was associated with a synchronous pattern (DD) of KIF14 probe signals ( p = 0.04). The DD synchronous replication pattern of KIF14 showed a correlation with age ( p < 0.0001), and the SS synchronous replication pattern of the same locus showed a correlation with lung metastatic ( p = 0.012). The subgroup of patients presenting with multiplet signals of MDM4 / PI3KC 2ß showed an association with treatment response ( p = 0.045) and age ( p = 0.033). Replication pattern of KIF14 may, significantly, be associated with chromosomal instability as MDM4 / PI3KC 2ß may be a considerably new marker of poor treatment response in EFT patients.

Positive psychological characteristics in patients with metabolic syndrome associated with prospective changes in diet and anthropometric factors.

The prevalence of metabolic syndrome (MetS) is increasing worldwide, and diet therapy plays a key role in treating this disease. Since most patients show difficulties in adhering to nutritional interventions, research on the association of positive psychological characteristics with greater engagement in physical health is relevant to this field. The present study aimed to evaluate the association between positive psychology attributes (optimism, hope, self-esteem, positive/negative affect and life satisfaction) and changes in diet quality and anthropometric parameters of individuals with MetS who received nutritional counseling. The study assessed 63 patients at a nutrition outpatient clinic. Anthropometric parameters and 24-hour food recall data (for evaluation of the Brazilian Healthy Eating Index-Revised-BHEI-R) were collected at the first visit and subsequent return visit (on average five months later). Psychological data were collected at the first visit using validated and standardized scales. The results were adjusted in relation to the depression scores of the patients, which were evaluated using the Beck Depression Inventory-II (BDI-II). Changes in anthropometric factors and in the BHEI-R were assessed, and their associations with the psychological attributes were investigated. The results indicated that positive affect and hope were associated with improvement in the BHEI-R scores (Cohen effect sizes -0.65 and -0.58; p = 0.012 and 0.025, respectively). A significant association was also observed between optimism and a reduction in abdominal circumference (Cohen effect size 0.56; p = 0.031). The associations remained significant even after adjusting for the BDI-II scores (p = 0.022, p = 0.037 and p = 0.05, respectively). No statistically significant associations were observed for the other attributes assessed.The study suggests that some attributes may have a greater influence on the nutritional treatment of MetS and that future studies should be conducted in order to enable effective multidisciplinary interventions to treat MetS.

ERBB4 confers metastatic capacity in Ewing sarcoma.

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES.

GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker.

OBJECTIVE: To analyze glucose transporter 1 expression patterns in malignant tumors of various cell types and evaluate their diagnostic value by immunohistochemistry. INTRODUCTION: Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans. Glucose transporter 1 is aberrantly expressed in several tumor types. Studies have implicated glucose transporter 1 expression as a prognostic and diagnostic marker in tumors, primarily in conjunction with positron emission tomography scan data. METHODS: Immunohistochemistry for glucose transporter 1 was performed in tissue microarray slides, comprising 1955 samples of malignant neoplasm from different cell types. RESULTS: Sarcomas, lymphomas, melanomas and hepatoblastomas did not express glucose transporter 1. Forty-seven per cent of prostate adenocarcinomas were positive, as were 29% of thyroid, 10% of gastric and 5% of breast adenocarcinomas. Thirty-six per cent of squamous cell carcinomas of the head and neck were positive, as were 42% of uterine cervix squamous cell carcinomas. Glioblastomas and retinoblastomas showed membranous glucose transporter 1 staining in 18.6% and 9.4% of all cases, respectively. Squamous cell carcinomas displayed membranous expression, whereas adenocarcinomas showed cytoplasmic glucose transporter 1 expression. CONCLUSION: Glucose transporter 1 showed variable expression in various tumor types. Its absence in sarcomas, melanomas, hepatoblastomas and lymphomas suggests that other glucose transporters mediate the glycolytic pathway in these tumors. The data suggest that glucose transporter 1 is a valuable immunohistochemical marker that can be used to identify patients for evaluation by positron emission tomography scan. The function of cytoplasmic glucose transporter 1 in adenocarcinomas must be further examined.

The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases.

BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors. METHODS: The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3'-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival. RESULTS: The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004). CONCLUSIONS: Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC.

Impacto prognóstico de aberrações cromossômicas em tumores de Ewing/PNET / Prognostic impact of chromosomal aberration in Ewing/PNET tumors

Introdução: A fusão EWS-ETS é um evento genético envolvido na patogênesis dos tumores de Ewing (TE); entretanto, a progressão dessa doença é devido à adição de outras alterações genéticas. Objetivo: Analisar o impacto prognóstico de regiões genéticas específicas em um série de pacientes com TE. Material e Métodos: Através de análises in silico usando o banco de dados Progenetix, os cromossomos 7, 8 e 12 e as regiões 1q e 16q foram identificadas como alterações genéticas mais recorrentes na progressão de TE, mas sem consistência quanto ao prognóstico. Lâminas de TMA, incluindo 132 pacientes com TE do Hopsital A.C. Camargo, foram construídas para análises de alterações no número de cópias gênicas (ANC) dos cromossomos 7, 8 12 e regiões 1q32.1 (KIF14/MDM4/PIK3C2B/DDX59) e 16q21 (CDH11), por hidridação por fluorescência in situ em núcleos interfásicos (iFISH). Essas análises foram feitas através da construção de sondas caseiras (BAC) (laboratório de citogenética molecular, Canadá) para as regiões 1q32.1 e 16q21 e através de sondas comerciais de centrômeros 7, 8 e 12. Ao final, a frequência de ANC foram correlacionadas com as características clínico-patológicas e sobrevida dos pacientes. Resultados: Análises de ANC mostraram ganhos em 1q32.1 em 15/121 (12.4%) pacientes. Anormalidades em 16q21 foram vistas em 24/115 (20.9%) pacientes: um grupo com 11/115 (9.6%) pacientes apresentaram deleções por hemizigose, e o outro, 13/115 (11.3%) pacientes apresentaram ganhos em 16q21. Aneussomias dos cromossomos 7, 8 e 12 foram vistas em 9.7%, 21.8% e 14.5%, respectivamente. Análises univariadas mostraram associação entre ganhos de 16q21 (p=0.029) ou 1q32.1 (p=0.005) e recorrência da doença em pacientes portadores de TE com doença localizada. As curvas de sobrevida global mostraram ganhos em 16q21 como prognóstico desfavorável (p=0.04) para doença localizada. ...

GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker

OBJECTIVE: To analyze glucose transporter 1 expression patterns in malignant tumors of various cell types and evaluate their diagnostic value by immunohistochemistry. INTRODUCTION: Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans. Glucose transporter 1 is aberrantly expressed in several tumor types. Studies have implicated glucose transporter 1 expression as a prognostic and diagnostic marker in tumors, primarily in conjunction with positron emission tomography scan data. METHODS: Immunohistochemistry for glucose transporter 1 was performed in tissue microarray slides, comprising 1955 samples of malignant neoplasm from different cell types. RESULTS: Sarcomas, lymphomas, melanomas and hepatoblastomas did not express glucose transporter 1. Fortyseven per cent of prostate adenocarcinomas were positive, as were 29 percent of thyroid, 10 percent of gastric and 5 percent of breast adenocarcinomas. Thirty-six per cent of squamous cell carcinomas of the head and neck were positive, as were 42 percent of uterine cervix squamous cell carcinomas. Glioblastomas and retinoblastomas showed membranous glucose transporter 1 staining in 18.6 percent and 9.4 percent of all cases, respectively. Squamous cell carcinomas displayed membranous expression, whereas adenocarcinomas showed cytoplasmic glucose transporter 1 expression. CONCLUSION: Glucose transporter 1 showed variable expression in various tumor types. Its absence in sarcomas, melanomas, hepatoblastomas and lymphomas suggests that other glucose transporters mediate the glycolytic pathway in these tumors. The data suggest that glucose transporter 1 is a valuable immunohistochemical marker that can be used to identify patients for evaluation by positron emission tomography scan. The function of cytoplasmic glucose transporter 1 in adenocarcinomas must be further examined.

GLUT1 and GLUT3 as potential prognostic markers for Oral Squamous Cell Carcinoma.

UNLABELLED: We associated clinical-pathological features of 142 OSCC with the expression pattern of GLUT1 and GLUT3 in order to estimate their prognostic value. METHODS: Clinical-pathological features and overall survival data of 142 patients with Oral Squamous Cell Carcinoma (OSCC) were retrospectively reviewed from A.C.Camargo hospital records. A tissue microarray (TMA) was built for the immunohistochemical (IHC) analysis of GLUT 1 and GLUT 3. IHC results were evaluated according to the staining pattern and number of positive cells. RESULTS: GLUT 1 was over expressed in 50.3% of OSSC cases showing membrane staining pattern. However, nuclear expression was observed in 49.7% of the analyzed cases. GLUT 3 over expression was detected in 21.1% of OSCC cases. The pattern of GLUT 1 expression showed significant association with alcohol consumption (p = 0.004). Positive cell membrane GLUT 3 protein expression was associated with advanced clinic-staging of tumours (p = 0.005) as well as with vascular embolization (p = 0.005). Positive expression of GLUT 3 was associated with unfavorable free-disease survival (p = 0.021). CONCLUSION: GLUT1 and GLUT3 protein expression evaluated by immunohistochemistry are, significantly, indicators of poor prognosis outcome in oral squamous cell carcinoma, probably due to the enhanced glycolytic metabolism of more aggressive neoplastic cells.

O arranjo em matriz de amostras teciduais (tissue microarray): larga escala e baixo custo ao alcance do patologista / Tissue microarrays: high throughput and low cost avaiable for pathologists

O arranjo em matriz de amostras teciduais, ou tissue microarray (TMA), é uma técnica descrita em 1998 por Kononen et al. com ampla aceitação pela literatura mundial. Com um conceito extremamente simples, trata-se de agrupar um grande número de amostras teciduais em um único bloco de parafina, permitindo o estudo de expressão de marcadores moleculares em larga escala com grande aproveitamento do material arquivado, do tempo e dos custos. Discutimos as vantagens e limitações do método, as estratégias e técnica de construção, as aplicações e dificuldades encontradas para a patologia investigativa nos últimos cinco anos de uso no Hospital do Câncer A. C. Camargo.

Tissue microarrays (TMA) is a worldwide well accepted technique described in 1998 by Kononen et al. It uses an extremely simple concept of ordering hundreds of samples in just one paraffin block to evaluate protein expression in large cohorts with great advantages on costs, time and sample saving. We discuss the technique, its advantages and limitations, strategies to construct the receptor block, its usefulness and difficulties experienced in the last five years at Hospital do Cancer A.C. Camargo.

Cuerpo extraño en vía aérea: desafío diagnóstico y terapéutica / Foreign body in airway: diagnostic and therapeutic challenge

La aspiración de un cuerpo extraño es una emergencia médica con riesgo vital. La población afectada es predominantemente infantil, con mayor mortalidad en el grupo de menores de dos años. Cuando está el antecedente de aspiración en la historia, el diagnóstico no crea mayores dificultades. Pero cuando no está presente y los síntomas no son tan acentuados la sospecha clínica es baja. La evolución crónica de un cuerpo extraño en vía aérea puede llevar al diagnóstico equivocado de asma, neumonías a repetición u otras complicaciones. La medicina más importante en el manejo está dado en la prevención. Los objetivos de este artículo son profundizar más en esta patología y fomentar su pesquisa precoz para disminuir su impacto en la morbimortalidad infantil.