Made available in DSpace on 2014-06-11T19:27:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-27Bitstream added on 2014-06-13T19:57:00Z : No. of bitstreams: 1 ihlaseh_sm_me_botfm.pdf: 228425 bytes, checksum: d8ddb66a9f9af259ca5de94c447588a1 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer de próstata (CaP) é um problema de saúde pública devido suas altas taxas de incidência e de mortalidade. Atualmente, os marcadores disponíveis para o diagnóstico e prognóstico não são capazes de diferenciar os CaPs indolentes dos que progridem mais agressivamente. Estudos moleculares usando análises em larga escala, como hibridação genômica comparativa baseada em arrays (aCGH), permitem a identificação de vários genes candidatos a marcadores. Estudos prévios de nosso grupo usando hibridação aCGH em CaP demonstraram amplificação em 7q21.13, onde estão mapeados os genes STEAP1 e STEAP2 (sixtransmembrane epithelial antigen of prostate 1 e 2). Esses genes apresentam expressão aumentada em diversas linhagens de células neoplásicas, incluindo as de próstata. No entanto, seu papel no desenvolvimento e progressão do CaP permanece desconhecido. Há evidências de que eles codificam antígenos tumorais com potencial para serem utilizados como marcadores prognósticos. O presente trabalho visou determinar o perfil de expressão dos genes STEAP1 e STEAP2 por RT-PCR quantitativa em tempo real (qRT-PCR) em adenocarcinomas primários de próstata, em amostras de tecido não-neoplásico adjacente aos tumores e em hiperplasias nodulares da próstata (HNP). Amostras de próstatas avaliadas histologicamente como normais foram obtidas de necropsias e usadas como controles. Os pacientes foram agrupados em três classes segundo o risco de recorrência do tumor (baixo, moderado e alto) de acordo com o PSA (antígeno prostático sérico), a graduação histológica e o estadiamento dos tumores. Foi observado aumento de expressão dos genes STEAP1 e STEAP2 em 28% e 38% das amostras, respectivamente; em três pacientes com alto risco de recorrência houve aumento simultâneo da expressão dos dois genes. A expressão... / Available prognostic markers as serum PSA levels, Gleason differentiation scores and tumor staging have not been able to discriminate indolent from aggressive tumors. Increased expressions of STEAP1 and STEAP2 genes (six-transmembrane epithelial antigen of prostate 1 e 2) have been shown in neoplastic cell lineages from prostate, urinary bladder, ovary and other tumors. Previously, using comparative genomic hybridization based in arrays in prostate adenocarcinomas and their metastasis, we described genomic gains at the 7q21.13. In this region are mapped the STEAP1 and STEAP2 genes. The involvement of these genes in PCa development and progression remains to be clarified. These genes possibly express tumoral antigens and are putative molecular markers.The objective of the present study was to determine the gene expression profiles of the STEAP1 e STEAP2 genes by real time quantitative PCR in primary prostate adenocarcinomas, surrounding non-neoplastic tissues, and in nodular hyperplasia of the prostate. The results were associate with tumor pathologic characteristics and patients clinical features. Samples from histologically confirmed normal prostates obtained from necropsies were used as normal controls. According to potential risk for tumor recurrence (low, moderate and high risk) patients were classified in three groups depending on the serum PSA levels, Gleason scores, and tumor stages. Increased expression of STEAP1 e STEAP2 genes were registered in 28% and 38% of samples, respectively; both genes presented simultaneously increased expression level in three high-risk cases. Similar pattern of expression were detected in the majority of CaP (Spearman r=0,63; p<0,0001) and non-neoplastic surrounding tissue (Spearman r=0,78; p=0,0002) samples. Compared to the non-neoplastic surrounding tissues there was significant increase of STEAP1 gene expression in PCa samples... (Complete abstract click electronic access below)

Resumo: O câncer de próstata (CaP) é um problema de saúde pública devido suas altas taxas de incidência e de mortalidade. Atualmente, os marcadores disponíveis para o diagnóstico e prognóstico não são capazes de diferenciar os CaPs indolentes dos que progridem mais agressivamente. Estudos moleculares usando análises em larga escala, como hibridação genômica comparativa baseada em arrays (aCGH), permitem a identificação de vários genes candidatos a marcadores. Estudos prévios de nosso grupo usando hibridação aCGH em CaP demonstraram amplificação em 7q21.13, onde estão mapeados os genes STEAP1 e STEAP2 (sixtransmembrane epithelial antigen of prostate 1 e 2). Esses genes apresentam expressão aumentada em diversas linhagens de células neoplásicas, incluindo as de próstata. No entanto, seu papel no desenvolvimento e progressão do CaP permanece desconhecido. Há evidências de que eles codificam antígenos tumorais com potencial para serem utilizados como marcadores prognósticos. O presente trabalho visou determinar o perfil de expressão dos genes STEAP1 e STEAP2 por RT-PCR quantitativa em tempo real (qRT-PCR) em adenocarcinomas primários de próstata, em amostras de tecido não-neoplásico adjacente aos tumores e em hiperplasias nodulares da próstata (HNP). Amostras de próstatas avaliadas histologicamente como normais foram obtidas de necropsias e usadas como controles. Os pacientes foram agrupados em três classes segundo o risco de recorrência do tumor (baixo, moderado e alto) de acordo com o PSA (antígeno prostático sérico), a graduação histológica e o estadiamento dos tumores. Foi observado aumento de expressão dos genes STEAP1 e STEAP2 em 28% e 38% das amostras, respectivamente; em três pacientes com alto risco de recorrência houve aumento simultâneo da expressão dos dois genes. A expressão... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Available prognostic markers as serum PSA levels, Gleason differentiation scores and tumor staging have not been able to discriminate indolent from aggressive tumors. Increased expressions of STEAP1 and STEAP2 genes (six-transmembrane epithelial antigen of prostate 1 e 2) have been shown in neoplastic cell lineages from prostate, urinary bladder, ovary and other tumors. Previously, using comparative genomic hybridization based in arrays in prostate adenocarcinomas and their metastasis, we described genomic gains at the 7q21.13. In this region are mapped the STEAP1 and STEAP2 genes. The involvement of these genes in PCa development and progression remains to be clarified. These genes possibly express tumoral antigens and are putative molecular markers.The objective of the present study was to determine the gene expression profiles of the STEAP1 e STEAP2 genes by real time quantitative PCR in primary prostate adenocarcinomas, surrounding non-neoplastic tissues, and in nodular hyperplasia of the prostate. The results were associate with tumor pathologic characteristics and patients clinical features. Samples from histologically confirmed normal prostates obtained from necropsies were used as normal controls. According to potential risk for tumor recurrence (low, moderate and high risk) patients were classified in three groups depending on the serum PSA levels, Gleason scores, and tumor stages. Increased expression of STEAP1 e STEAP2 genes were registered in 28% and 38% of samples, respectively; both genes presented simultaneously increased expression level in three high-risk cases. Similar pattern of expression were detected in the majority of CaP (Spearman r=0,63; p<0,0001) and non-neoplastic surrounding tissue (Spearman r=0,78; p=0,0002) samples. Compared to the non-neoplastic surrounding tissues there was significant increase of STEAP1 gene expression in PCa samples... (Complete abstract click electronic access below) / Orientador: João Lauro Viana de Camargo / Coorientador: Silvia Regina Rogatto / Banca: Maria Inês Pardini / Banca: Luciano João Nesrallah / Mestre

no / The cytochrome P450 family of enzymes is involved in the Phase I metabolism of a wide variety of compounds. Although generally involved with detoxification, overexpression of one family member, cytochrome P450 1B1 (CYP1B1), has been associated with human epithelial tumors. As such, CYP1B1 was hypothesized to be a novel target for the development of anticancer therapies. We investigated expression of CYP1B1 protein in 61 human colorectal adenocarcinomas and compared this to that observed in 14 histologically normal human large bowel samples removed from patients undergoing surgery for large bowel tumors. Although we confirmed that CYP1B1 was expressed at high levels in human colorectal tumor epithelia, we also found that CYP1B1 was not absent from normal colonic epithelia but was expressed at low levels. The expression of CYP1B1 in colon tumors does not correlate with tumor stage or degree of lymph node invasion in this study. Furthermore, in addition to expression in colon epithelia, CYP1B1 is also observed in blood vessels within the colon. As with the epithelia, levels of CYP1B1 were higher in tumor vasculature than that of the normal colon. Although these observations greatly support the development of CYP1B1 targeted anticancer therapies, they also indicate the caution that should be observed when developing such drugs.

Objective: Chronic recurrent multifocal osteomyelitis/ chronic non-bacterial osteomyelitis (CRMO/CNO) is a rare auto-inflammatory disease and typically manifests in terms of musculoskeletal pain. Because of a high frequency of musculoskeletal disorders in children/ adolescents, it can be quite challenging to distinguish CRMO/ CNO from nonspecific musculosketetal pain or from malignancies. The purpose of this study was to evaluate the visibility of CRMO lesions in a whole-body diffusion-weighted imaging (WB-DWI) technique and its potential clinical value to better characterize MR-visible lesions. Materials and methods: Whole-body imaging at 3T was performed in 16 patients (average: 13 years) with confirmed CRMO. The protocol included 2D Short Tau Inversion Recovery (STIR) imaging in coronal and axial orientation as well as diffusion-weighted imaging in axial orientation. Visibility of lesions in DWI and STIR was evaluated by two readers in consensus. The apparent diffusion coefficient (ADC) was measured for every lesion and corresponding reference locations. Results: A total of 33 lesions (on average 2 per patient) visible in STIR and DWI images (b = 800 s/mm2 and ADC maps) were included, predominantly located in the long bones. With a mean value of 1283 mm2/s in lesions, the ADC was significantly higher than in corresponding reference regions (782 mm2/s). By calculating the ratio (lesion to reference), 82% of all lesions showed a relative signal increase of 10% or higher and 76% (25 lesions) showed a signal increase of more than 15%. The median relative signal increase was 69%. Conclusion: This study shows that WB-DWI can be reliably performed in children at 3T and predominantly, the ADC values were substantially elevated in CRMO lesions. WB-DWI in conjunction with clinical data is seen as a promising technique to distinguish benign inflammatory processes (in terms of increased ADC values) from particular malignancies.

Objective: Chronic recurrent multifocal osteomyelitis/ chronic non-bacterial osteomyelitis (CRMO/CNO) is a rare auto-inflammatory disease and typically manifests in terms of musculoskeletal pain. Because of a high frequency of musculoskeletal disorders in children/ adolescents, it can be quite challenging to distinguish CRMO/ CNO from nonspecific musculosketetal pain or from malignancies. The purpose of this study was to evaluate the visibility of CRMO lesions in a whole-body diffusion-weighted imaging (WB-DWI) technique and its potential clinical value to better characterize MR-visible lesions. Materials and methods: Whole-body imaging at 3T was performed in 16 patients (average: 13 years) with confirmed CRMO. The protocol included 2D Short Tau Inversion Recovery (STIR) imaging in coronal and axial orientation as well as diffusion-weighted imaging in axial orientation. Visibility of lesions in DWI and STIR was evaluated by two readers in consensus. The apparent diffusion coefficient (ADC) was measured for every lesion and corresponding reference locations. Results: A total of 33 lesions (on average 2 per patient) visible in STIR and DWI images (b = 800 s/mm2 and ADC maps) were included, predominantly located in the long bones. With a mean value of 1283 mm2/s in lesions, the ADC was significantly higher than in corresponding reference regions (782 mm2/s). By calculating the ratio (lesion to reference), 82% of all lesions showed a relative signal increase of 10% or higher and 76% (25 lesions) showed a signal increase of more than 15%. The median relative signal increase was 69%. Conclusion: This study shows that WB-DWI can be reliably performed in children at 3T and predominantly, the ADC values were substantially elevated in CRMO lesions. WB-DWI in conjunction with clinical data is seen as a promising technique to distinguish benign inflammatory processes (in terms of increased ADC values) from particular malignancies.

Das Adenokarzinom ist weltweit das häufigste nicht-kleinzellige Lungenkarzinom mit ansteigender Inzidenz insbesondere bei Frauen. Zur genetischen Analyse dieses Tumortyps haben wir 60 Fälle mittels der Comparativen Genomische Hybridisierung (CGH) untersucht, dabei wurden 60 Primärtumoren und von 10 Fällen zusätzlich 23 Metastasen (pro Primärtumor max. 4 korrespondierende Metastasen) analysiert. Bei den 60 Primärtumoren wurden folgende Veränderungen in über 50% der Fälle beobachtet: Deletionen auf den Chromosomen 3p, 4p, 4q, 5q, 6q, 8p, 9p, 9q, 13q, 15q und 18q sowie Überrepräsentationen auf den Chromosomen 1q, 5p, 8q, 11q. 17q. 19q und 20q. Häufigste Veränderung war die Überrepräsentation auf Chromosom 1q22-q23 (73,3%), gefolgt von Überrepräsentationen auf den Chromosomen 20q11.2-q13.2 (66,7%) und 8q23-q24.1 (61,7%) und Deletionen auf 3p22-p21 (61,7% ), 4q26-q28 (63,3%), 6q16 (60,0%), 6q22 (60,0%), 9p13-p21 (63,3%), 13q21 (68,3%) und 13q31 (68,3%). Beim statistischen Vergleich mittels c2-Test von 24 nicht-metastasierten Primärtumoren mit der Gruppe von 23 metastasierten Primärtumoren und 10 Metastasen waren folgende Veränderungen statistisch signifikant mit Metastasierung verbunden: Deletionen von 3p22-p25, 4p13-p15.1 und 17p12-p13 sowie Überrepräsentationen von 1q21, 11q12-13, 14q11.1-q13, 15q24 und 20q12-13.1. Statistisch signifikant häufiger mit dem nicht-metastasierten Phänotyp assoziiert waren dagegen folgende Veränderungen: Deletion von 19p13.1-p13.3 und Überrepräsentationen von 3p12-p14 , 4q26-q28 und 5p14. Die Analyse der Primärtumoren und ihrer korrespondierenden Metastasen konnten in jedem Fall einen klonalen Zusammenhang aufzeigen. Zusammenfassend sind Adenokarzinome der Lunge durch wiederkehrende Muster chromosomaler Veränderungen charakterisiert, die eine Korrelation zwischen Tumor-Genotyp und -Phänotyp ermöglichen. / Adenocarcinomas are the most common non small cell lung carcinomas worldwide with increasing incidence especially in women. For the genetic analysis of this tumor type we screened 60 primary tumors and additionally 23 metastases from 10 cases (4 corresponding metastases per primary tumor as maximum) by Comparative Genomic Hybridization (CGH). The following alterations were found in over 50% of the 60 primary tumors: Deletions on chromosomes 3p, 4p, 4q, 5q, 6q, 8p, 9p, 9q, 13q, 15q, and 18q as well as overrepresentations on chromosomes 1q, 5p, 8q, 11q. 17q. 19q und 20q. The most frequent alteration was the overrepresentation on chromosome 1q22-q23 (73,3%), followed by overrepresentations on chromosomes 20q11.2-q13.2 (66,7%), and 8q23-q24.1 (61,7%), and deletions on 3p22-p21 (61,7% ), 4q26-q28 (63,3%), 6q16 (60,0%), 6q22 (60,0%), 9p13-p21 (63,3%), 13q21 (68,3%), and 13q31 (68,3%). At the comparison between 24 non metastasizing primary tumors versus 23 metastasizing tumors and 10 metastases the following changes were statistically significant (c2 test) associated with the metastasizing phenotype: deletions on chromosomes 3p22-p25, 4p13-p15.1, and 17p12-p13, as well as overrepresentations on 1q21, 11q12-13, 14q11.1-q13, 15q24, and 20q12-13.1 whereas the deletion on chromosome 19p13.1-p13.3 and overrepresentations on chromosomes 3p12-p14 , 4q26-q28, and 5p14 were associated with the non metastasizing phenotype. A clonal relationship could be shown in every case with primary tumor and corresponding metastases. In summary, adenocarcinomas of the lung are characterized by recurrent patterns of chromosomal imbalances allowing a correlation between tumor genotype and tumor phenotype.

Since its introduction, contrast-enhanced ultrasonography (CEUS) has significantly extended the value of ultrasonography (US). CEUS can be used to more accurately determine pancreatic lesions compared to conventional US or to characterize lesions already detectable by US. Thus, CEUS can aid in the differential diagnosis of pancreatic tumors. Using US contrast media, it is possible to visually detect microvessels in the majority of pancreatic ductal adenocarcinomas. Thus, the use of quantitatively evaluated transabdominal CEUS can help in the differentiation of patients with mass-forming pancreatitis from patients with pancreatic adenocarcinomas. In neuroendocrine pancreatic tumors, different enhancement patterns can be observed in relation to the tumor mass: larger ones show a rapid early enhancement sometimes combined with necrotic central structures, and smaller ones disclose a capillary-blush enhancement. Pseudocysts, the most widespread cystic lesions of the pancreas, are not vascularized. They do not show any signal in CEUS and remain entirely anechoic in all phases, while true cystic pancreatic tumors usually have vascularized septa and parietal nodules. In summary, CEUS is effective for differentiating solid pancreatic tumors in most cases. CEUS is safe and cost effective and can better discriminate solid from cystic pancreatic lesions, thereby directing further imaging modalities. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Since its introduction, contrast-enhanced ultrasonography (CEUS) has significantly extended the value of ultrasonography (US). CEUS can be used to more accurately determine pancreatic lesions compared to conventional US or to characterize lesions already detectable by US. Thus, CEUS can aid in the differential diagnosis of pancreatic tumors. Using US contrast media, it is possible to visually detect microvessels in the majority of pancreatic ductal adenocarcinomas. Thus, the use of quantitatively evaluated transabdominal CEUS can help in the differentiation of patients with mass-forming pancreatitis from patients with pancreatic adenocarcinomas. In neuroendocrine pancreatic tumors, different enhancement patterns can be observed in relation to the tumor mass: larger ones show a rapid early enhancement sometimes combined with necrotic central structures, and smaller ones disclose a capillary-blush enhancement. Pseudocysts, the most widespread cystic lesions of the pancreas, are not vascularized. They do not show any signal in CEUS and remain entirely anechoic in all phases, while true cystic pancreatic tumors usually have vascularized septa and parietal nodules. In summary, CEUS is effective for differentiating solid pancreatic tumors in most cases. CEUS is safe and cost effective and can better discriminate solid from cystic pancreatic lesions, thereby directing further imaging modalities. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.