Immunohistochemical study of GLUT-1 in oral peripheral nerve sheath tumors

AIM: To investigate the immunoexpression and diagnostic applicability of human erythrocyte-type glucose transporter protein (GLUT-1) in oral peripheral nerve sheath tumors. MATERIAL AND METHODS: Specimens diagnosed as oral peripheral nerve sheath tumors archived in the Oral Pathology Service of Universidade Federal de Minas Gerais from 1966 to 2006 were evaluated. Thirty-four lesions were included: 15 traumatic neuromas, 11 neurofibromas, four neurilemmomas, and four malignant peripheral nerve sheath tumors (MPNST). One case of neurofibroma was associated with neurofibromatosis type I. Immunohistochemistry for S-100 and GLUT-1 was performed. S-100 was immunopositive in all lesions. RESULTS: Benign lesions were immunopositive for GLUT-1 except in two (18.2%) cases of neurofibromas. In the traumatic neuroma, the perineuriums were immunopositive for GLUT-1. In the neurofibroma, the immunoreactivity was heterogeneous. Immunopositivity was observed at levels of 54.5% in the periphery of the lesion, 9.1% in the center, and 18.2% in both. The neurilemmoma demonstrated immunopositivity in the capsule. One case (25%) of MPNST presented GLUT-1 positive stain in occasional cells distributed homogeneously in all the tumor area. CONCLUSION: GLUT-1 is a useful marker for perineurial cells and should be included in the oral peripheral nerve sheath tumors immunophenotyping thus aiding in the correct diagnosis of these lesions.

Cancer culture: Epidemics, human behaviour and the dubious search for new risk factors

The rise of melanoma and the almost complete decline of stomach cancer clearly reflect disturbances of human culture during the 20th century. Environmental factors play a dominant role in the epidemiology of melanoma and many other malignancies.

Pathways to Melanoma Development: Lessons from the Mouse

Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major axes of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development.

Acute characteristics of pediatric dysphagia subsequent to traumatic brain injury: Videofluoroscopic assessment

Objective: To document the acute characteristics of swallowing impairment in a group of children post moderate/severe traumatic brain injury (TBI) by means of videofluoroscopy. Participants: Eighteen children with moderate/severe TBI. Main Outcome Measure: Videofluoroscopy at an average of 27.7 days post-injury. Results: Subjects demonstrated a range of dysphagia severity levels: mild-moderate (n = 8), moderate (n = 6), moderate-severe (n = 3), and severe (n = 1) and had a combination of oral and pharyngeal phase characteristics. More specifically; observable features or physiological impairments that were identified included reduced lingual control, hesitancy of tongue movement, repetitive tongue pumping, the presence of aspiration (including silent aspiration), delayed swallow reflex trigger, reduced laryngeal elevation and closure, and reduced peristalsis. Conclusions: These data highlight the diversity of swallowing deficits and dysphagia severity levels in children following TBI and suggest that the former are consistent with a pattern of oropharyngeal impairments.

Second primary oesophageal cancer following radiation for breast cancer

The management of 12 women who presented with a second primary oesophageal cancer following radiotherapy for breast cancer was reviewed. It was concluded that nine cases fitted the classical description of a radiation-induced malignancy. Most cases were successfully managed with combined modality therapy in spite of their previous radiotherapy. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.

Sertoli-Leydig Cell Tumor of the Ovary, a Rare Cause of Precocious Puberty in a 12-Month-Old Infant

We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the G{alpha}s gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER ß genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.

Dysarthria and dysphagia following treatment for a fourth ventricle choroid plexus papilloma

The present case report describes the presence of a persistent dysarthria and dysphagia as a consequence of surgical intervention for a choroid plexus papilloma (CPP). WM was a nine year ten month old male who at the time of the present study was seven years post-surgery. A comprehensive perceptual and instrumental test battery was used to document the nature of the dysarthria incorporating all components of speech production including respiration, phonation, resonance, articulation, and prosody. The nature of the dysphagia was evaluated through the use of videofluoroscopic evaluation of swallowing (VFS). Assessments confirmed the presence of a LMN dysarthria, marked by deficits in phonation, respiration, and prosody. Dysphagia assessment revealed deficits in oral preparatory, oral and pharyngeal stages of the swallow. The presence of persistent dysarthria and dysphagia in this case has a number of important implications for the management of children undergoing surgery for fourth ventricle CPPs, in particular the need for appropriate treatment, as well as counselling prior to surgery of the possible negative outcomes related to speech and swallowing. (C) 2003 Elsevier Science Ltd. All rights reserved.

Geographical patterns of proportionate mortality for the most common causes of death in Brazil

Mortality due to chronic diseases has been increasing in all regions of Brazil with corresponding decreases in mortality from infectious diseases. The geographical variation in proportionate mortality for chronic diseases for 17 Brazilian state capitals for the year 1985 and their association with socio-economic variables and infectious disease was studied. Calculations were made of correlation coefficients of proportionate mortality for adults of 30 years or above due to ischaemic heart disease, stroke and cancer of the lung, the breast and stomach with 3 socio-economic variables, race, and mortality due to infectious disease. Linear regression analysis included as independent variables the % of illiteracy, % of whites, % of houses with piped water, mean income, age group, sex, and % of deaths caused by infectious disease. The dependent variables were the % of deaths due to each one of the chronic diseases studied by age-sex group. Chronic diseases were an important cause of death in all regions of Brazil. Ischaemic heart diseases, stroke and malignant neoplasms accounted for more than 34% of the mortality in each of the 17 capitals studied. Proportionate cause-specific mortality varied markedly among state capitals. Ranges were 6.3-19.5% for ischaemic heart diseases, 8.3-25.4% for stroke, 2.3-10.4% for infections and 12.2-21.5% for malignant neoplasm. Infectious disease mortality had the highest (p < 0.001) correlation with all the four socio-economic variables studied and ischaemic heart disease showed the second highest correlation (p < 0.05). Higher socio-economic level was related to a lower % of infectious diseases and a higher % of ischaemic heart diseases. Mortality due to breast cancer and stroke was not associated with socio-economic variables. Multivariate linear regression models explained 59% of the variance among state capitals for mortality due to ischaemic heart disease, 50% for stroke, 28% for lung cancer, 24% for breast cancer and 40% for stomach cancer. There were major differences in the proportionate mortality due to chronic diseases among the capitals which could not be accounted for by the social and environmental factors and by the mortality due to infectious disease.

Differential expression of the eukaryotic release factor 3 (eRF3/GSPT1) according to gastric cancer histological types

Background: There are now several lines of evidence to suggest that protein synthesis and translation factors are involved in the regulation of cell proliferation and cancer development. Aims: To investigate gene expression patterns of eukaryotic releasing factor 3 (eRF3) in gastric cancer. Methods: RNA was prepared from 25 gastric tumour biopsies and adjacent non-neoplastic mucosa. Real time TaqMan reverse transcription polymerase chain reaction (RT-PCR) was performed to measure the relative gene expression levels. DNA was isolated from tumour and normal tissues and gene dosage was determined by a quantitative real time PCR using SYBR Green dye. Results: Different histological types of gastric tumours were analysed and nine of the 25 tumours revealed eRF3/GSPT1 overexpression; moreover, eight of the 12 intestinal type carcinomas analysed overexpressed the gene, whereas eRF3/GSPT1 was overexpressed in only one of the 10 diffuse type carcinomas (Kruskal-Wallis Test; p , 0.05). No correlation was found between ploidy and transcript expression levels of eRF3/GSPT1. Overexpression of eRF3/GSPT1 was not associated with increased translation rates because the upregulation of eRF3/GSPT1 did not correlate with increased eRF1 levels. Conclusions: Overexpression of eRF3/GSPT1 in intestinal type gastric tumours may lead to an increase in the translation efficiency of specific oncogenic transcripts. Alternatively, eRF3/GSPT1 may be involved in tumorigenesis as a result of its non-translational roles, namely (dis)regulating the cell cycle, apoptosis, or transcription.

Modulation of translation factor's gene expression by histone deacetylase inhibitors in breast cancer cells

The histone deacetylase inhibitors sodium butyrate (NaBu) and trichostatin A (TSA) exhibit anti-proliferative activity by causing cell cycle arrest and apoptosis. The mechanisms by which NaBu and TSA cause apoptosis and cell cycle arrest are not yet completely clarified, although these agents are known to modulate the expression of several genes including cell-cycle- and apoptosis-related genes. The enzymes involved in the process of translation have important roles in controlling cell growth and apoptosis, and several of these translation factors have been described as having a causal role in the development of cancer. The expression patterns of the translation mechanism, namely of the elongation factors eEF1A1 and eEF1A2, and of the termination factors eRF1 and eRF3, were studied in the breast cancer cell line MCF-7 by real-time quantitative reverse transcription-polymerase chain reaction after a 24-h treatment with NaBu and TSA. NaBu induced inhibition of translation factors' transcription, whereas TSA caused an increase in mRNA levels. Thus, these two agents may modulate the expression of translation factors through different pathways. We propose that the inhibition caused by NaBu may, in part, be responsible for the cell cycle arrest and apoptosis induced by this agent in MCF-7 cells.

Efeitos auditivos em doentes com tumores de cabeça e pescoço e tumores cerebrais sujeitos a Radioterapia e terapia combinada

Introdução: A capacidade auditiva dos doentes com neoplasias de cabeça e pescoço e tumores cerebrais pode ser comprometida com os tratamentos antineoplásicos realizados. A Quimioterapia com cisplatina pode provocar perda auditiva de condução ou neurossensorial, podendo agravar-se quando combinada com Radioterapia (RT). O objectivo deste trabalho foi a análise da relação entre a Terapia Combinada (Cisplatina+RT) e a Radioterapia isolada, e os seus efeitos adversos sobre a audição tendo em consideração a inclusão das estruturas do ouvido no campo de tratamento de RT. Métodos: Foram seguidos 10 doentes submetidos a Terapia Combinada (grupo TC) e 11 a Radioterapia isolada (grupo RT). A avaliação audiológica realizou-se antes do inicio (M1), no fim (M2) e um mês após (M3) o termo dos tratamentos e incluiu anamnese audiológica, otoscopia e audiometria tonal. Resultados: No grupo TC, 94,4% dos doentes apresentaram uma relação directamente proporcional entre a dose de radiação na cóclea e a perda auditiva. Esta relação só se verificou em 31% dos doentes do grupo RT, tendo-se verificado diferenças significativas entre grupos (p <0,001). Conclusões: Verificou-se maior incidência da perda auditiva no grupo TC relativamente ao grupo RT. Sugere-se um melhor planeamento do tratamento de RT, reduz - indo a dose à cóclea com o objectivo de minimizar a perda auditiva neurossensorial irreversível, sobretudo quando são utilizadas as duas modalidades de tratamento.

Estrogen receptor dependent genetic and epigenetic factors of tamoxifen resistance

Resumo: A decisão da terapêutica hormonal no tratamento do cancro da mama baseiase na determinação do receptor de estrogénio alfa por imunohistoquímica (IHC). Contudo, a presença deste receptor não prediz a resposta em todas as situações, em parte devido a limitações do método IHC. Investigámos se a expressão dos genes ESR1 e ESR2, bem como a metilação dos respectivos promotores, pode estar relacionada com a evolução desfavorável de uma proporção de doentes tratados com tamoxifeno assim como com a perda dos receptores de estrogénio alfa (ERα) e beta (ERß). Amostras de 211 doentes com cancro da mama diagnosticado entre 1988 e 2004, fixadas em formalina e preservadas em parafina, foram utilizadas para a determinação por IHC da presença dos receptores ERα e ERß. O mRNA total do gene ESR1 e os níveis específicos do transcrito derivado do promotor C (ESR1_C), bem como dos transcritos ESR2_ß1, ESR2_ß2/cx, and ESR2_ß5 foram avaliados por Real-time PCR. Os promotores A e C do gene ESR1 e os promotores 0K e 0N do gene ESR2 foram investigados por análise de metilação dos dinucleotidos CpG usando bisulfite-PCR para análise com enzimas de restrição, ou para methylation specific PCR. Atendendo aos resultados promissores relacionados com a metilação do promotor do gene ESR1, complementamos o estudo com um método quantitativo por matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) suportado pelo software Epityper para a medição da metilação nos promotores A e C. Fez-se a avaliação da estabilidade do mRNA nas linhas celulares de cancro da mama MCF-7 e MDA-MB-231 tratadas com actinomicina D. Baixos níveis do transcrito ESR1_C associaram-se a uma melhor sobrevivência global (p = 0.017). Níveis elevados do transcrito ESR1_C associaram-se a uma resposta inferior ao tamoxifeno (HR = 2.48; CI 95% 1.24-4.99), um efeito mais pronunciado em doentes com tumores de fenótipo ERα/PgR duplamente positivo (HR = 3.41; CI 95% 1.45-8.04). A isoforma ESR1_C mostrou ter uma semi-vida prolongada, bem como uma estrutura secundária da região 5’UTR muito mais relaxada em comparação com a isoforma ESR1_A. A análise por Western-blot mostrou que ao nível da 21 proteína, a selectividade de promotores é indistinguivel. Não se detectou qualquer correlação entre os níveis das isoformas do gene ESR2 ou entre a metilação dos promotores do gene ESR2, e a detecção da proteína ERß. A metilação do promotor C do gene ESR1, e não do promotor A, foi responsável pela perda do receptor ERα. Estes resultados sugerem que os níveis do transcrito ESR1_C sejam usados como um novo potencial marcador para o prognóstico e predição de resposta ao tratamento com tamoxifeno em doentes com cancro da mama. Abstract: The decision of endocrine breast cancer treatment relies on ERα IHC-based assessment. However, ER positivity does not predict response in all cases in part due to IHC methodological limitations. We investigated whether ESR1 and ESR2 gene expression and respective promoter methylation may be related to non-favorable outcome of a proportion of tamoxifen treated patients as well as to ERα and ERß loss. Formalin-fixed paraffin-embedded breast cancer samples from 211 patients diagnosed between 1988 and 2004 were submitted to IHC-based ERα and ERß protein determination. ESR1 whole mRNA and promoter C specific transcript levels, as well as ESR2_ß1, ESR2_ß2/cx, and ESR2_ß5 transcripts were assessed by real-time PCR. ESR1 promoters A and C, and ESR2 promoters 0N and 0K were investigated by CpG methylation analysis using bisulfite-PCR for restriction analysis, or methylation specific PCR. Due to the promising results related to ESR1 promoter methylation, we have used a quantification method by matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF MS) together with Epityper software to measure methylation at promoters A and C. mRNA stability was assessed in actinomycin D treated MCF-7 and MDA-MB-231 cells. ERα protein was quantified using transiently transfected breast cancer cells. Low ESR1_C transcript levels were associated with better overall survival (p = 0.017). High levels of ESR1_C transcript were associated with non-favorable response in tamoxifen treated patients (HR = 2.48; CI 95% 1.24-4.99), an effect that was more pronounced in patients with ERα/PgR double-positive tumors (HR = 3.41; CI 95% 1.45-8.04). The ESR1_C isoform had a prolonged mRNA half-life and a more relaxed 5’UTR structure compared to ESR1_A isoform. Western-blot analysis showed that at protein level, the promoter selectivity is undistinguishable. There was no correlation between levels of ESR2 isoforms or ESR2 promoter methylation and ERß protein staining. ESR1 promoter C CpG methylation and not promoter A was responsible for ERα loss. We propose ESR1_C levels as a putative novel marker for breast cancer prognosis and prediction of tamoxifen response.

Tumor-like lesion due to Chagas' disease in a patient with lymphocytic leukemia

A 73 year-old white male, living in the interior of the state of Mato Grosso do Sul, in central Bra­zil, after an initial diagnosis of sinusitis was transferred to the neurology service with a 3-day evolution of intracranial hypertension. Exams showed lymphocytic leukemia and a tumor-like lesion, either an expanding inflammatory process such as an abscess or a neoplasm. Treatment with Ceftriaxone and Decadron was started and intracranial hypertension was controlled. Methotrexate was injected on the occasion of the next puncture considering a possible leukemia infiltration. Flagellate forms of T. cruzi were observed in the CSF and treatment with Benznidazole was started. After 4 days the CSF presented fractionated forms of trypomastigotes. The protein level was 27%. Signs of intracranial hypertension ceased. Tomography and magnetic resonance images showed an important reduction of the tumor-like lesion. The clinical condition of the patient improved.