Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

The investigation of an abdominal mass in a child is a common problem in the radiology department of the Red Cross Children's Hospital. The majority of these masses involve the urinary tract. The commonest neoplasm is a Wilms' tumour of the kidney. Against a pathological and clinical background, the investigation of Wilms' tumour by diagnostic imaging is presented. The imaging modalities currently utilised are the intravenous urogram (IVU), ultrasound (US), computed tomography (CT) and magnetic resonance (MR). Using the material available in the last decade, the principles, techniques and imaging characteristics of these modalities are investigated and compared. These results are reflected against those reported in the medical literature. This literature is not yet extensive as the current technology has only been available for the last six to seven years. The IVU has in the past been the main imaging modality and we still use it extensively. Its strengths and weaknesses are discussed. In the last five years US has taken its place as the primary method of diagnostic imaging. We have found that with our increasing experience that this is justified. The use of US and IVU in a practiced hand is a powerful diagnostic combination. CT as a primary investigation is not readily available at our institution. We have used it for comparative purposes in about 20% of our recent cases. CT has not added greatly to our initial diagnostic impression. However, it has been most useful for follow up of metastasis and for assessing the normality of the lungs before ceasing chemotherapy. Our experience with MRI is limited and confined to unusual presentations in the last year. Other modalities such as arteriography and nuclear medicine have special indications which are to be discussed. The remaining tumours of the upper urinary tracts are all rare, but are reported and the literature researched. In the lower urinary tract the main pelvic lesion is a rhabdomyosarcoma. The comparative advantages of the IVU, US, CT and MRI are also noted. In the pelvis, US has also become the primary imaging modality, and is replacing contrast medium cystography. However, examples of the latter are included as it still has a place, particularly in the less sophisticated institutes. CT and MRI, when available, have imaging advantages in the pelvis and are becoming the methods of choice for follow up. The main objective of this document has been to investigate the available imaging techniques, but, against this overall theme, the clinical care of the child is most important. With this in mind the treatment protocols that are used at our hospital are noted in the appendices to the thesis.

Introdução: O carcinoma urotelial de bexiga (CUB) é o segundo tumor mais frequente do trato urinário. A perda da função do p53 é a alteração mais conhecida do carcinoma urotelial de alto grau invasivo. Prima-1 é uma pequena molécula, a qual restaura a função do p53 mutado promovendo a morte celular em vários tipos celulares. O objetivo do nosso estudo foi analisar o efeito do Prima-1 na indução da apoptose mediada por p53 após indução do dano ao DNA em linhagens de CUB. Material e métodos: O mecanismo de ação do Prima-1 foi avaliado em duas linhagens celulares de câncer de bexiga, T24 que tem como característica a mutação do p53 e RT4 que possui p53 intacto. Características morfológicas da apoptose, alterações no potencial de membrana mitocondrial e análise da expressão de treze genes envolvidos na apoptose mediada por p53 foram avaliados através de observação microscópica e reação em cadeia da polimerase em tempo real quantitativa (qRT-PCR). Resultados: Prima-1 foi capaz de reativar a função da P53 na linhagem de câncer de bexiga com p53 mt, promovendo a apoptose através da expressão de Bax e Puma, ativação da cascata das caspases e ruptura da membrana mitocondrial, independente de Bax, na linhagem celular T24 (p53 mt). Conclusão: Prima-1 foi capaz de restaurar a atividade transcricional de p53. Estudos experimentais in vivo poderiam ser conduzidos no intuito de testar essa molécula como um novo agente terapêutico do CUB de alto grau, invasivo, que apresenta caracteristicamente mutação de p53 / Introduction: Urothelial carcinoma of the bladder is the second most common tumor of the urinary tract. Loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cell death in various cancer types. Our aim is to investigate the ability of Prima-1 to induce apoptosis after DNA damage in BC cancer cell lines. Material and Methods: The therapeutic effect of Prima-1 was studied in two BC cell lines, T24, characterized by p53 mutation, and RT4, with no mutation in the p53 gene. Morphological features of apoptosis, mitochondrial membrane potential changes and expression of thirteen genes involved in p53-induced apoptosis were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR) Results: Prima-1 is able to reactivate P53 function in p53-mutated bladder cancer cell line promote apoptosis through the induction of Bax and Puma expression, activating the caspase cascade and disruption of mitochondrial membrane, independent of Bak, in T24 cell line (p53 mt). Conclusion: Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo could be conducted in order to test this molecule as a new therapeutic agent of the urothelial carcinoma of the bladder, which characteristically presents p53 mutation

Introdução: O carcinoma urotelial de bexiga (CUB) é o segundo tumor mais frequente do trato urinário. A perda da função do p53 é a alteração mais conhecida do carcinoma urotelial de alto grau invasivo. Prima-1 é uma pequena molécula, a qual restaura a função do p53 mutado promovendo a morte celular em vários tipos celulares. O objetivo do nosso estudo foi analisar o efeito do Prima-1 na indução da apoptose mediada por p53 após indução do dano ao DNA em linhagens de CUB. Material e métodos: O mecanismo de ação do Prima-1 foi avaliado em duas linhagens celulares de câncer de bexiga, T24 que tem como característica a mutação do p53 e RT4 que possui p53 intacto. Características morfológicas da apoptose, alterações no potencial de membrana mitocondrial e análise da expressão de treze genes envolvidos na apoptose mediada por p53 foram avaliados através de observação microscópica e reação em cadeia da polimerase em tempo real quantitativa (qRT-PCR). Resultados: Prima-1 foi capaz de reativar a função da P53 na linhagem de câncer de bexiga com p53 mt, promovendo a apoptose através da expressão de Bax e Puma, ativação da cascata das caspases e ruptura da membrana mitocondrial, independente de Bax, na linhagem celular T24 (p53 mt). Conclusão: Prima-1 foi capaz de restaurar a atividade transcricional de p53. Estudos experimentais in vivo poderiam ser conduzidos no intuito de testar essa molécula como um novo agente terapêutico do CUB de alto grau, invasivo, que apresenta caracteristicamente mutação de p53 / Introduction: Urothelial carcinoma of the bladder is the second most common tumor of the urinary tract. Loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cell death in various cancer types. Our aim is to investigate the ability of Prima-1 to induce apoptosis after DNA damage in BC cancer cell lines. Material and Methods: The therapeutic effect of Prima-1 was studied in two BC cell lines, T24, characterized by p53 mutation, and RT4, with no mutation in the p53 gene. Morphological features of apoptosis, mitochondrial membrane potential changes and expression of thirteen genes involved in p53-induced apoptosis were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR) Results: Prima-1 is able to reactivate P53 function in p53-mutated bladder cancer cell line promote apoptosis through the induction of Bax and Puma expression, activating the caspase cascade and disruption of mitochondrial membrane, independent of Bak, in T24 cell line (p53 mt). Conclusion: Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo could be conducted in order to test this molecule as a new therapeutic agent of the urothelial carcinoma of the bladder, which characteristically presents p53 mutation

O diagnóstico do câncer urológico causa profundas consequências na vida dos pacientes. Ainda que sejam considerados tumores com boas respostas terapêuticas, tal diagnóstico não é isento de sofrimento e interfere na qualidade de vida. O objetivo deste estudo foi analisar os sentidos atribuídos à QV por sobreviventes do câncer urológico. Para subsidiar essa compreensão, foram utilizados o referencial teórico da antropologia médica e a metodologia narrativa. Participaram do estudo 12 participantes com diagnóstico de câncer urológico sob seguimento terapêutico em um hospital público no interior de São Paulo. A coleta de dados ocorreu de novembro de 2016 a novembro de 2017, por meio de entrevistas semiestruturas gravadas e observação direta, realizadas nos domicílios dos participantes e nas dependências da instituição de saúde. Com base nas entrevistas, foram construídas as narrativas, segundo o modelo centrado na experiência, utilizando os modelos explicativos empregados pelos participantes. A análise dos dados narrativos fundamentou-se na análise temática indutiva, e esses foram integrados em três sínteses narrativas temáticas, que correspondem às unidades de sentido. A primeira, O itinerário do câncer urológico: descobrindo-se como sobrevivente, destacou o processo de busca para identificação da anormalidade no corpo. A reação ao diagnóstico foi de surpresa e medo diante uma doença culturalmente associada à morte. Porém, de acordo com o modelo cultural dos participantes, diante de uma doença grave, faziase necessário aderir aos tratamentos médicos propostos, ainda que causassem sofrimento. A segunda síntese narrativa, O que eu era e o que sou hoje: as limitações no corpo e na vida, descreveu as complicações causadas pela tentativa de eliminar o câncer por meio dos diversos protocolos terapêuticos, o que ocasionou sofrimento do corpo físico, social, tristeza e baixa autoestima. Assim, essa síntese apresentou como sentido a liminaridade, pois, após o adoecimento, os sobreviventes assumiram outra identidade, que implicou viver com um novo conceito de normalidade de vida. Na terceira síntese, Qualidade de vida: sobreviver com harmonia, diante do processo de liminaridade vivenciado pelos sobreviventes e com base nas reações culturais aprendidas e compartilhadas pela comunidade onde estavam inseridos, eles buscaram harmonia para continuarem a viver e viver com QV. O sentido revelado por esta síntese foi sobreviver em harmonia com o corpo e suas limitações, assim como na esfera social e familiar, ter esperança e espiritualidade. Esta investigação permitiu analisar os sentidos atribuídos à QV por sobreviventes do câncer urológico e evidenciou como a cultura exerce influência na experiência da QV durante a sobrevivência a este tipo de câncer / The diagnosis of urologic cancer causes profound consequences in the life of patients. Although they are considered tumors with good responses to therapy, their diagnosis is not free from suffering and this interferes in their quality of life. The objective of this study was to analyze the meanings attributed to QOL for urologic cancer survivors in the medical anthropology approach. To support this understanding, we chose the theoretical framework of Medical Anthropology and the narrative method. After ethical approval, data collection began. Twelve participants diagnosed with urologic cancer were included in a therapeutic follow-up at a public hospital in the interior of São Paulo. Data collection took place from November 2016 to November 2017, through recorded semi-structured interviews and direct observation, carried out at the participants\' homes and in the premises of the health institution. Based on the interviews, the narratives were constructed according to the experience-centered model, using the explanatory models employed by the participants. The analysis of the narrative data was executed occurred according to the thematic and inductive analysis, where these were integrated into three thematic narrative syntheses, corresponding to the units of meaning. The first synthesis, The path of urologic cancer: discovering oneself as a survivor, highlighted the search process to identify the abnormality in the body. The reaction to the diagnosis was of surprise and fear when faced with a disease culturally associated with death. In their cultural model, however, in the face of a serious illness, adherence to the proposed medical treatments is necessary, even if it entails a burden of suffering. The second narrative synthesis, What I was and what I am today: limitations in the body and in life, describes the complications caused by the attempt to eliminate cancer from the body through the therapies, causing suffering of the physical and social body, sadness and low self-esteem. Thus, this synthesis presented liminality as a meaning because, after the illness, the survivors assume another identity, which implies living with a new normality in life. In the third synthesis, Quality of life: surviving with harmony, in view of the liminality process the survivors experience, based on cultural reactions learned and shared by their community, the survivors seek a harmony to continue living and to live with QoL. The sense of this synthesis is to survive in harmony with the body and its limitations, with the social, with the family, to have hope and spirituality. This research allowed us to analyze the meanings attributed to QoL for survivors of urologic cancer. The results presented show how culture influences the QoL experience in urologic cancer survival

Orientadores: Ubirajara Ferreira, Valeria H. A. Cagnon Quitete / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T17:35:54Z (GMT). No. of bitstreams: 1 Reis_LeonardoOliveira_M.pdf: 4339458 bytes, checksum: 1e103884dabb1194ecfd6161caeed83d (MD5) Previous issue date: 2009 / Resumo: A destruição do complexo da distroglicana dependente da metaloproteinase da matriz pode ter papel importante no desenvolvimento e progressão do tumor urotelial. O carcinoma urotelial humano é frequente na bexiga e menos comum no trato urinário superior. Não há um modelo experimental animal bem definido e reprodutível de carcinoma urotelial do trato superior. Objetivos: Propor um novo modelo experimental de carcinoma urotelial que resulta de refluxo vesicoureteral em animais submetidos a tratamento com associação entre n-metil-n-nitrosourea e citrato de sódio intravesicais. Caracterizar a imunolocalização dos receptores de ?-distroglicana e metaloproteinase 9 na bexiga urinária, ureter e pelve renal deste modelo, assim como descrever aspectos morfológicos, imunohistoquímicos e proliferativos nestes órgãos. Metodologia: Cinqüenta ratas Fisher 344 foram divididas em dois grupos: Controle - recebeu 0,30ml de solução salina 0,9% intravesical; MNU-citrato - recebeu 0,15ml de MNU e 0,15ml de citrato de sódio intravesical, ambos em semanas alternadas, nas semanas 0, 2, 4 e 6, totalizando quatro doses. Após 15 semanas de tratamento, a bexiga, os ureteres, e as pelves renais foram coletados para análises morfológicas e imunohistoquímicas. Resultados: O grupo MNU-Citrato apresentou imunoreatividade reduzida de ?-DG e aumentada de MMP-9 e Ki-67. O tratamento associado de MNU e citrato de sódio levou ao desenvolvimento de carcinoma urotelial na bexiga e no trato urinário superior de todos os animais. Conclusões: O modelo proposto induziu lesão maligna de diversos graus em 100 % dos animais, sem comprometimento muscular. A imunolocalização da ?-DG foi muito diminuída em contraposição ao aumento da imunolocalização da MMP-9 nos diferentes órgãos estudados neste modelo e os aspectos morfológicos, imunohistoquímicos e proliferativos ao longo do urotélio (bexiga urinária, ureter e pelve renal) foram muito semelhantes, sendo que ocorreu aumento de apoptose e proliferação celular com expressivo predomínio deste último. Palavras chave: Distroglicana; Metaloproteinase de matriz; Carcinoma urotelial; Modelo animal experimental; Trato urinário superior / Abstract: The dystroglican complex destruction is done by matrix metalloproteinase and plays a critical role in the urothelial carcinoma development and progression. The human urothelial carcinoma is frequent on the bladder and less common on the upper urinary tract. There is no reproducible and well described experimental upper urothelial carcinoma model on this issue. Purposes: Describe a novel experimental upper urothelial carcinoma animal model which results in vesicoureteral reflux in animals submitted to associate treatment with the carcinogen n-methyl-n-nitrosourea and sodium citrate intravesically. Characterize the ?-DG and the MMP-9 immunolocalization in the bladder as well as in the upper urinary tract, and describe morphological, immunohistochemistry and proliferative aspects utilizing a novel experimental model. Materials and Methods: Fifty female Fischer 344 rats were divided into two groups: the control group received a 0.30ml dose of 0.9% physiological saline intravesically every other week for a total of 4 doses; the MNU-citrate group received 0.15 ml of MNU and 0.15ml of sodium citrate intravesically every other week for a total of 4 doses. After 15 weeks of treatment, bladder, ureters and renal pelvis were collected for morphological and immunohistochemistry analyses. Results: The MNU-Citrate group showed reduced ?-DG and increased MMP-9 and Ki-67 immunoreactivities. Associated treatment with MNU and sodium citrate was able to lead to both urinary bladder and upper urinary tract tumors in all animals. Conclusions: The proposed model showed cancer in several grades in 100 % of animals, with no muscular invasion. The immunolocalization was decreased for ?-DG and increased for MMP-9 in the analyzed tissues and the morphological, immunohistochemical and proliferative aspects of the urothelium (bladder, ureter e renal pelvis) were similar. Apoptosis and proliferation were increased, being the last one more intense / Mestrado / Cirurgia / Mestre em Cirurgia

The skeletal system is the most common site of metastatic cancer spread. Bone metastases are often associated with severe morbidity, pain and functional impairment. Timely diagnosis and proper treatment may decrease morbidity, improve quality of life and in some cases even improve survival. External beam radiotherapy may effectively give pain relief in patients with painful bone metastases. In bone metastases from castration-resistant prostate cancer or urothelial bladder cancer, treatment with zoledronic acid or denosumab may reduce skeletal-related events. In contrast to castration-resistant prostate cancer, in patients with bone metastases from bladder cancer such treatment may even improve survival. On the other hand, the efficacy of these agents is questionable in patients with bone involvement from metastatic renal cell carcinoma or germ cell tumors. When bisphosphonates or denosumab are considered in such cases, the potential benefits of treatment should be critically weighed against the risk of side effects. In germ cell tumors, bone metastases may be cured by cisplatin-based chemotherapy, however, there are only limited data on the specific management of residual disease. Oligometastases may be treated by stereotactic radiotherapy or – especially in patients with renal cell carcinoma – by surgical resection and endoprosthetic replacement. Limited data are available on the management of bone involvement in germ cell tumors. Decisions on the resection or local radiotherapy of residual disease should be individualized considering the overall response and the feasibility and risks of resection.

Background: Data on the impact of gender on mortality after radical cystectomy is conflicting. We investigated a large single center sample with long-term follow-up in order to determine the relationship between gender and outcome. Patients and Methods: A total of 1,184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated bladder cancer between 1993 and 2015 were stratified by gender. Demographic data was compared using Mann-Whitney U test, chi-square test, or Fisher exact test. Cox proportional hazard models were used for the analysis of competing risks and logit models were used for the prediction of the receipt of adjuvant cisplatin-based chemotherapy. Results: Female patients were older, healthier, less frequently current smokers and had more extravesical tumors. In the multivariate analyses, female gender was an independent predictor of (lower) non-bladder cancer (competing) mortality (hazards ratio [HR] 0.68, 95% CI 0.49–0.95, p = 0.0248) but no predictor of bladder cancer-specific mortality (HR in the full model 1.20, 95% CI 0.94–1.54, p = 0.15). Gender was no predictor of the receipt of adjuvant cisplatin-based chemotherapy. Conclusions: Female gender was associated with an increased risk of extravesical disease but was no independent predictor of bladder cancer-specific mortality. Anatomical differences might be a plausible explanation for these observations.

Introdução: O seguimento de pacientes com câncer de bexiga superficial apresenta embargos financeiros e psicológicos ao paciente, devido à realização frequente de exames invasivos. Com fim de substituir ou diminuir os exames invasivos, busca-se biomarcadores urinários acurados, que permitam diagnosticar a recidiva tumoral e estratificar pacientes com maior risco de recidiva futura. O objetivo deste estudo é avaliar se expressão na urina de PAI-1, DJ-1, ApoA-1, MMP-9 e IL-8 permite identificar e antecipar a recidiva de câncer de bexiga. Método: A expressão da PAI-1, DJ-1, ApoA-1, MMP-9 e IL-8 foi mensurada por ELISA na urina de 152 pacientes tratados previamente de carcinoma urotelial superficial de bexiga e em seguimento. Os níveis das proteínas foram comparados entre pacientes com e sem recidiva de câncer de bexiga (1) no momento da coleta de urina e (2) durante o seguimento. A ocorrência de recidiva tumoral foi confirmada por análise histopatológica da biópsia de lesões suspeitas, investigadas quando havia alterações na cistoscopia, ultrassom ou citologia oncótica. Pacientes com recidiva diagnosticada no momento da coleta de urina foram excluídos da análise para avaliar o papel antecipatório das cinco proteínas. Foi avaliado se o uso prévio de BCG intra-vesical exercia influência no nível das cinco proteínas estudadas. Resultados: Entre os pacientes avaliados, 16 (10,5%) apresentaram recidiva de carcinoma urotelial no momento da coleta de urina e 21 (15,4%) apresentaram recidiva de carcinoma urotelial durante o seguimento. O seguimento mediano foi de 47 meses (interquartis de 39 e 50 meses). Um painel para o diagnóstico de recidiva tumoral incluindo três biomarcadores (ApoA-1, MMP-9 e IL-8) apresentou razão de risco de 12,9 (IC 95% =3,5-47,4) e um painel para prever pacientes que desenvolverão recidiva durante o seguimento incluindo dois biomarcadores (PAI-1 e IL-8) apresentou razão de risco de 4,1 (IC 95% =1,4-11,4). Os resultados dos painéis não foram influenciados pelo uso prévio de BCG intra-vesical. Conclusão: Os painéis apresentados permitem identificar pacientes com recidiva de carcinoma urotelial de bexiga e prever quais pacientes terão maior risco de desenvolver recidiva no futuro. O uso prévio de BCG intra-vesical não alterou a expressão dos biomarcadores / Purpose: To evaluate if the urinary levels of PAI-1, DJ-1, ApoA-1, MMP-9 and IL-8 can identify and predict tumor recurrence in patients on follow-up of superficial bladder cancer. Methods: We prospectively analyzed the urine of 152 patients previously treated of superficial bladder cancer on follow-up regimen. Five biomarkers (PAI-1, DJ-1, ApoA-1, MMP-9 and IL-8) were assessed by ELISA and compared among patients with and without bladder cancer recurrence (1) in the moment of urine collection and (2) during follow-up. Tumor recurrence was evaluated with cystoscopy, ultrasound and urine oncotic cytology and confirmed by pathological analysis. Patients with recurrence at urine collection were excluded from prediction analysis. A correlation between the level of the biomarkers and previous use of intravesical BCG was investigated. Results: Median follow-up was 47 months (IQR =39-50 months). Among patients included, 16 (10,5%; N =152) and 21 (15,4%; N =136) had bladder cancer recurrence diagnosed in the moment of urine collection and during follow-up, respectively. The panel to diagnose recurrence including 3 biomarkers (ApoA-1, MMP-9 and IL-8) presented OR =12,9 (CI =3,5-47,4), while the panel to predict patients who will have a recurrence during follow-up including 2 biomarkers (PAI-1 and IL-8) presented OR =4,1 (CI =1,4- 11,4). Previous use of intra-vesical BCG didn\'t influence urine biomarkers expression. Conclusions: The 3-biomarker panel can be used to identify patients with bladder cancer recurrence. The 2-biomarker panel can be used to predict patients at greater risk of bladder cancer recurrence during follow-up. Both are reliable in patients with previous use of intravesical BCG