During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

No description available.

Introdução: com o uso generalizado de métodos de imagem, aumentou-se a detecção de lesões renais como achados incidentais. Tais lesões podem ser tanto benignas, tais como os angiomiolipomas, e outras malignas, como os carcinomas de células renais, portanto torna-se importante um método não-invasivo com boa acurácia para sua distinção . A ultrassonografia é pouco específica para este fim. A tomografia computadorizada e a ressonância magnética são os métodos mais utilizados na caracterização de lesões incidentais renais. Na Ressonância Magnética, o uso de sequências convencionais ponderadas em T2W e T1W, antes e após a administração endovenosa de contraste paramagnético, mostrou-se pouco eficaz para este fim. Técnicas quantitativas associadas às imagens convencionais, tais como a oposição de fase e a restrição a difusão da água, vêm sendo estudadas, devido ao potencial para melhorar a caracterização não-invasiva, evitando nefrectomias parciais ou totais, e outras intervenções invasivas por lesões benignas. Objetivos: avaliar a acuidade diagnóstica de técnicas combinadas de ressonância magnética para diferenciação de angiomiolipomas pobres em gordura de lesões malignas do rim. Métodos: pacientes que obtiveram o diagnóstico histológico das lesões renais entre os anos de 2010 e 2014 e que realizaram exame pré-operatório. As lesões foram estudadas, colocando-se um ROI (region of interest, no inglês) na maior parte da lesão e córtex renal normal, evitando-se área de não-lesões, calculando a intensidade de sinal nas seqüências T1W in e out-phase, T2W, o Wash in, Wash out relativo e absoluto das lesões e o cálculo absoluto do sinal da lesão no ADC (coeficiente de difusão aparente, do inglês). Os resultados foram obtidos na forma de índices padronizados pelo córtex renal e baço, pelas fases pré e pós-contraste, e de forma absoluta pelo ADC. Os resultados foram confrontados com o diagnóstico final e feito associações estatísticas para observar a relevância. Resultados:Foram estudadas 85 lesões em 74 pacientes, sendo 40 do gênero masculino e 34 do feminino. O cálculo do teor de gordura se mostrou ineficaz para distinção entre CCRs e AMLpg; o índice de intensidade de sinal em T2W, lesão/córtex normal foi útil na diferenciação dos CCRs CC de AMLpg. Outro parâmetro importante foi a cálculo de wash out relativo que se mostrou mais acentuado no AMLpg que em todos os subtipos de CCRs estudados e da medida do ADC médio, que apresentou valores maiores nos casos de CCR CC, em comparação com os outros subtipos e com os AMLpg. Conclusão: As técnicas combinadas de RM, principalmente o índice de sinal T2W da lesão, Wash out relativo e IS do ADC, associados a dados epidemiológicos são viáveis, quando utilizados em conjunto, para a diferenciação de lesões malignas renais dos angiomiolipomas, podendo ter implicações na conduta terapêutica, com redução do número de nefrectomias por lesão benignas. / Introduction: With the widespread use of imaging methods, detection of incidental renal masses has steadily increased in recent years, and these may be either benign, such as angiomyolipoma, or malignant, such as renal cell carcinomas. Therefore, it is important to have a method that allows accurate characterization. Ultrassonography is not very specific for this purpose. CT and MRI are the methods used in the characterization of renal incidental lesions. In MRI, the use of conventional sequences, such as T1W and T2W before and after intravenous administration of paramagnetic contrast media, has proved ineffective for this purpose. Quantitative techniques associated with conventional images, such as chemical shift and diffusion weighted imaging (DWI), have played a key role in this differentiation, which aims to improve characterization, avoiding partial or total nephrectomy, and other invasive interventions for benign lesions. Objectives: to evaluate the diagnostic accuracy of combined techniques of MRI to differentiate fat-poor angiomyolipoma from renal cell carcinomas. Methods: Patients who had a histological diagnosis of renal lesions between 2010 and 2014 and underwent pre-operative exam. An ROI (region of interest)cwas placed in most of the lesion and normal renal cortex, avoiding area of non lesions, by calculating the signal intensity in all sequences, in and out phase T1W, T2W, and the wash in, wash out, relative and absolute, of the lesions and estimation of the ADC. The results were obtained in the form of standardized indices for renal cortex and spleen, the pre- and post-contrast phases, and absolute values for ADC. Results were confronted with the final diagnosis and statistical analysis to observe the relevancy. Results: the estimation of intracellular fat content was ineffective for characterization, while the T2W signal intensity index was used for differentiation between CCRs clear cells from fat-poor AML. Another important parameter was the \"wash out\", which was more prominent for AMLpg. ADC values was higher for CCR CC. Conclusion: We concluded that the combined techniques of MRI mainly T2W signal ratio, \"Wash out\" and ADC values, when used in association and correlated with epidemiological data may be feasible for the differentiation among fat-poor angiomyolipomas and renal malignancies, with important therapeutics implications, reducing unnecessary nephrectomies for benign lesions.

Introdução: Apesar da identificação de fatores prognósticos clínicos e patológicos, muitos pacientes portadores de carcinoma de células renais (CCR) apresentam metástases ao diagnóstico e outros irão desenvolver recorrência local ou à distância durante o seguimento. Novos fatores prognósticos e de origem molecular têm sido avaliados no CCR, destacando-se o PTEN como um dos principais genes envolvidos na carcinogênese renal. Objetivos: Avaliar os fatores clínicos e anatomopatológicos mais significativos nas taxas de sobrevida, identificar a frequência de hipermetilação do gene PTEN através da técnica do pirosequenciamento, o impacto da hipermetilação do gene nas taxas de sobrevida global (SG) e livre de doença (SLD), como também, a associação da presença de hipermetilação com os principais fatores prognóticos. Material e métodos: Foram avaliados 137 pacientes portadores de CCR submetidos a tratamento cirúrgico do tumor primário entre 1997 e 2009. Foram considerados os dados epidemiológicos, clínicos, anatomopatológicos, de estadiamento (TNM 2004) e os obtidos da reação de pirosequenciamento. Resultados: O tempo de seguimento médio foi de 32,3 meses e mediana de 28,8 meses. Considerando o estadimento clínico, foram fatores independentes para a SG: idade (p<0,01), ASA (p=0,02), margens cirúrgicas (p=0,04), grau de Fuhrman (p=0,01), estádio clínico (p<0,001) e subtipo histológico (p<0,01). No modelo múltiplo a SLD foi influenciada únicamente pelo estádio clínico (p<0,001). Dos 137 casos analisados, hipermetilação do gene foi detectada em cinco casos (3,6%). Devido a baixa freqüência detectada optou-se por não realizar a associação da metilação do PTEN com os fatores prognósticos. Em relação às taxas de SG e SLD, de acordo com o perfil de hipermetilação do PTEN, não houve a ocorrência de nenhum evento, ou seja, morte, morte por CCR ou recorrência da doença para os cinco casos que apresentavam hipermetilação. Conclusões: A hipermetilação do xv PTEN foi detectada com baixa frequência, sugerindo a participação de outros genes ou mecanismos moleculares diferentes da metilação na inativação deste gene frequentemente envolvido na carcinogênese renal. As taxas de sobrevida não foram influenciadas pelo perfil de hipermetilação do PTEN, permanecendo o estadiamento clínico do TNM como a principal variável determinante da evolução e do risco de recidiva pelo CCR / Introduction: Despite the identification of clinical and pathological prognostic factors, many patients with renal cell carcinoma (RCC) have metastases at diagnosis and others will develop local or distant recurrence during follow-up. New prognostic factors and of molecular origin have been evaluated in RCC, highlighting PTEN, one of the main genes involved in renal carcinogenesis. Objetives: To assess the most significant clinical and pathological factors in survival rates, and identify the frequency of hypermethylation of the PTEN gene by the pyrosequencing technique, the impact of gene hypermethylation on overall survival (OS) rates and disease free interval (DFS), as well as associating presence of hypermethylation with main prognostic factors. Methods: We evaluated 137 patients with RCC that underwent surgical treatment of primary tumor between 1997 and 2009. We considered the epidemiological, clinical, pathological, staging (TNM 2004) data and those obtained from pyrosequencing. Results: Mean follow-up was of 32.3 months and the median of 28.8 months. Considering the clinical TNM stage, the OS was influenced in the multiple model by age (p < 0.01), ASA (p = 0.02), surgical margins (p = 0.04), Fuhrman´s grade (p = 0,01), clinical stage (p <0.001) and cell subtype (p < 0.01). DFS were influenced in multivariate analysis only by presence of clinical stage (p <0.001). Of the 137 cases examined, gene hypermethylation was detected in five cases (3,6%). Because of this low frequency perceived, we elected not to carry out the association of PTEN methylation with prognostic factors. Regarding OS and DFS rates, according to the hypermethylation of PTEN profile, no event occurred, that is to say death, death from RCC or disease recurrence in the five cases with hypermethylation. Conclusions: Hypermethylation of PTEN was detected with low frequency suggesting involvement of other genes or different molecular mechanisms of methylation upon inactivation of this gene, frequently involved in renal xvii carcinogenesis. Survival rates were not influenced by the hypermethylation of PTEN profile, with clinical TNM staging remaining as the main determinant for development and risk of RCC recurrence

No description available.

Abstract Background and aims: Stage and grade are the most widely used prognostic parameters for renal cell carcinoma (RCC). The clinical course of this disease is not, however, always predictable by traditional prognostic factors. In the era of new molecular targeted therapies a more accurate prognostication of RCC patient survival is important for the individualization of treatment and follow-up of patients. Despite exhaustive research there are still no prognostic biomarkers for RCC in clinical practice. In order to find novel prognostic tissue markers for RCC, we examined the expression of 14 biomarkers involved in carcinogenesis and clarified their prognostic significance in RCC. Material and methods: Out of 189 consecutive patients who underwent surgery for kidney cancer at Oulu University Hospital in the 1990s, 152 patients with histologically verified RCC were included in this study. The stage distribution was 70 (46%), 12 (8%), 51 (34%) and 19 (12%) patients with stages I-IV, respectively. The majority of the tumours (83 tumours, 55%) were nuclear grade II and 5 (3%), 40 (27%) and 22 (15%) of the tumours were grades I, III and IV, respectively. Clinical and follow-up data were obtained from patient records, the Finnish Cancer Registry and on demand from the Population Register Centre of Finland. The biomarkers studied included markers of the oxidative and neuroendocrine systems as well as proteins related to cell adhesion and migration, invasion, metastasis, inflammation and immune responses. The expression of various biomarkers was characterized via immunohistochemical tests of archival tumour material. The staining intensity was compared to clinicopathological parameters and patient RCC-specific survival. Results: The 5-year RCC-specific survival was 77%. The expression of Toll-like receptor 9 (TLR9) was an independent marker of favourable RCC-specific survival whereas cytoplasmic myosin VI expression was found to be an independent prognostic factor of poor RCC-specific survival. Cell culture experiments showed how cyclooxygenase-2 (COX-2) expression is regulated by HuR in RCC. HuR and COX-2 immunoexpression were also related to decreased RCC-specific survival. Immunostaining of Keap1 was associated with advanced RCC and a marker of a poorer RCC-specific prognosis. The expression of different neuroendocrine markers was evaluated but we could not establish any prognostic value for them. Conclusions: In particular, TLR9, HuR and myosin VI can be regarded as promising novel prognostic biomarkers in RCC. Stage, however, is the most important single prognostic factor for RCC. / Tiivistelmä Munuaissyöpä on vuosikymmenten ajan jatkuvasti yleistynyt. Vaikka se diagnosoidaan nykyisin useimmiten sattumalöydöksenä vatsan alueen kuvantamistutkimuksissa ja hoitomenetelmät ovat viime vuosikymmenten aikana kehittyneet, munuaissyöpäkuolleisuus ei ole laskenut. Munuaissyövän ennusteen määrittäminen voi olla haasteellista. Perinteiset ennustetekijät, levinneisyys ja erilaistumisaste, eivät riitä selittämään kaikkien potilaiden taudinkulkua, eikä munuaissyövälle vielä ole kliinisessä käytössä ennusteellista merkkiainetta. Munuaissyöpähoitojen kehittyessä taudinkulun ennustaminen on yhä tärkeämpää, jotta potilaiden hoito ja seuranta voidaan yksilöidä. Tämän väitöskirjatyön tarkoituksena oli etsiä uusia ennusteellisia kudosmerkkiaineita munuaissyöpäkasvaimille. Väitöskirjatutkimus perustuu 1990-luvulla Oulun yliopistollisessa sairaalassa leikatun 152 munuaissyöpäpotilaan aineistoon. Lähes puolet aineiston kasvaimista edusti levinneisyysluokkaa I, ja yli puolet munuaissyöpäkasvaimista oli hyvin erilaistuneita (tumagradus I ja II). Tutkimuspotilaista kerättiin kattavat seurantatiedot. Leikkauksessa poistettujen munuaissyöpäkasvainten arkistomateriaalista tutkittiin eri merkkiaineiden ilmenemistä. Tutkitut merkkiaineet käsittivät oksidatiivisen ja neuroendokriinisen järjestelmän merkkiaineita sekä valkuaisaineita, jotka liittyvät keskeisiin syövän ominaisuuksiin, kuten solujen välisiin liitoksiin ja solujen liikkumiseen sekä etäpesäkkeiden syntymiseen. Lisäksi tutkittiin merkkiaineita, jotka liittyvät tulehdusreaktioihin ja immuunipuolustukseen. Väitöskirjatutkimus paljasti useita uusia kudosmerkkiaineita, joiden ilmeneminen munuaissyöpäkasvaimessa on yhteydessä potilaan ennusteeseen. Näistä merkittävimpiä ovat myosiini VI, joka liittyy syöpäkasvainten metastasointiin, sekä immuunipuolustuksessa vaikuttava Tollin kaltainen reseptori 9 (Toll-like receptor 9, TLR9). Molemmat merkkiaineet osoittautuivat itsenäisiksi ennustetekijöiksi munuaissyövässä. Muita ennusteeseen vaikuttavia merkkiaineita ovat tutkimuksen mukaan oksidatiivista stressiä aistiva Keap1 sekä immunologisiin reaktioihin liittyvä syklo-oksigenaasi 2 (COX-2) ja sen ilmenemistä säätelevä HuR.

Les adénocarcinomes rénaux à cellules claires (ccRCC), qui représentent 70% des tumeurs rénales, sont fortement mais irrégulièrement vascularisés, ce qui les rend hypoxiques et donc résistants aux chimiothérapies. L'hypoxie favorise l'agressivité tumorale via l'activation des facteurs de transcription HIF-1alpha et HIF-2alpha (Hypoxia-Inducible Factors). Pour cette raison, le ciblage de l'hypoxie intratumorale et des facteurs HIF dans les ccRCC constitue une stratégie thérapeutique pertinente. Dans ce projet, nous montrons pour la première fois que la voie sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) régule HIF-2alpha in vitro et in vivo. Nos résultats indiquent que la SphK1 régule le taux intracellulaire et l'activité transcriptionnelle de HIF-2alpha dans des lignées de ccRCC représentatives de certains sous-groupes retrouvés en clinique humaine ; et impliquent la S1P extracellulaire, via le récepteur S1P1, dans la régulation de HIF-1alpha et HIF-2alpha. D'autre part, nous avons évalué l'impact de l'inhibition des récepteurs à S1P et de la SphK1 par le FTY720 dans un modèle de ccRCC in vivo. Nos résultats indiquent que le FTY720 entraine une diminution transitoire du taux intratumoral de HIF-1alpha et HIF-2alpha ainsi qu'un remodelage du réseau vasculaire tumoral. En effet, le FTY720 induit une normalisation vasculaire qui aboutit à une oxygénation tumorale transitoire. Enfin, nous montrons que ce traitement permet de sensibiliser un modèle murin de ccRCC à la chimiothérapie. Ces résultats valident le rôle de la voie SphK1/S1P comme régulateur de l'adaptation à l'hypoxie dans les ccRCC. Ils constituent une étape indispensable à la transposition en clinique humaine du concept selon lequel la voie SphK1/S1P peut être ciblée afin de diminuer l'hypoxie intratumorale et de chimiosensibiliser certains cancers, le FTY720 étant déjà sur le marché. / Clear cell renal cell carcinomas (ccRCC) represent 70% of renal tumors. Because of their dense and irregular vascular network, ccRCC become hypoxic and therefore resistant to chemotherapies. Hypoxia promotes tumor aggressiveness via the activation of HIF-1alpha and HIF-2alpha (Hypoxia-Inducible Factors). For this reason, the control of intratumoral hypoxia and HIF in ccRCC could be a relevant therapeutic strategy to improve the efficacy of current treatments. In this study, we show for the first time that the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway regulates HIF-2alpha in vitro and in vivo. Our results indicate that SphK1 regulates HIF-2alpha intracellular level and transcriptional activity in ccRCC cell lines that are representative of some clinical ccRCC subgroups. Our data also involve extracellular S1P, via its receptor S1P1, in the regulation of HIF-1alpha and HIF-2alpha. In addition, in a ccRCC mouse model, we show that FTY720 - an inhibitor of the SphK1/S1P pathway- transiently decreases HIF-1alpha and HIF-2alpha intratumoral level. This is associated with a transient remodeling of the tumor vascular network indicating that FTY720 induces a vascular normalization that leads to transient tumor oxygenation. Finally, we show that this treatment sensitizes a ccRCC mouse model to chemotherapy. Overall, these results validate the key role of the SphK1/S1P pathway in the adaptation to hypoxia in ccRCC cell and animal models. Our results provide a mechanistic basis to target the SphK1/S1P pathway with FTY720 by increasing the efficacy of chemotherapy in ccRCC. They are a prerequisite for clinical transposition as FTY720 is a drug approved used in human clinic.

O carcinoma de célula renal (RCC) subtipo célula clara é o câncer mais letal e prevalente do sistema urinário. O diagnóstico deste tipo de câncer frequentemente é tardio em conseqüência da falta de sintomas perceptíveis aos pacientes. Um dos objetivos deste trabalho é a identificação de novos marcadores moleculares para diagnóstico precoce, o que ajudaria a diminuir a mortalidade em função de complicações resultantes do avanço da doença. Outro objetivo é a identificação de um conjunto de marcadores moleculares de prognóstico, de modo à prever com acurácia a evolução clínica da doença e, por conseqüência, o tempo de sobrevida do paciente. As modificações transcricionais associadas à carcinogênese e à progressão do câncer de rim ainda não foram completamente elucidadas. Além dos oncogenes e genes supressores de tumor, RNAs não-codificadores (ncRNAs) recentemente foram apontados como importantes reguladores da expressão gênica em humanos, e podem ter um papel importante na transformação maligna do câncer de rim. Para analisar a expressão gênica de ncRNAs e de genes codificadores para proteína foram utilizados dois microarranjos desenvolvidos por nosso grupo, enriquecidos em sondas para ncRNAs. Uma das plataformas possui 4 mil sondas de cDNA, das quais 822 sondas são para ncRNAs mapeando em regiões intrônicas. Outra possui 44 mil elementos e combina sondas de oligonucleotídeos (60-mer) intrônicas e exônicas de um mesmo locus genômico. Análises estatísticas foram feitas com a ferramenta Significance Analysis of Microarrays (q &#8804; 0,05) combinadas ou com a técnica de \"patient leave-one-out\" (genes com presença em 8 100% dos subconjuntos), ou alternativamente com o teste discriminante de Golub (p &#8804; 0,01 ou p < 0,05). Com a plataforma de 4 mil sondas foram estudadas 30 amostras de tecido renal de 18 pacientes com RCC subtipo célula clara. Um conjunto de 36 ncRNAs foi identificado como diferencialmente expresso entre amostras tumorais e não-tumorais. Uma assinatura adicional de 265 genes codificadores de proteínas foi identificada, indicando possíveis novos marcadores moleculares. Uma análise estatística supervisionada com dados de 16 pacientes identificou uma assinatura de ncRNAs correlacionada com sobrevida de 5 anos, formada por 27 ncRNAs com significativa expressão alterada em pacientes livres da doença em comparação com pacientes que morreram em função da doença. Uma assinatura adicional de 64 genes codificadores de proteínas também foi identificada como significativamente correlacionada com o acompanhamento clínico dos pacientes. Com a plataforma de 44 mil sondas foram analisados 17 pacientes, com amostras pareadas de tecido renal tumoral e não-tumoral agrupadas em 8 pools, sendo 4 de amostras tumorais e 4 de não-tumorais. Um conjunto de 66 ncRNAs parcialmente intrônicos antisenso e outro de 52 ncRNAs totalmente intrônicos antisenso foram identificados como diferencialmente expressos. Identificamos um subconjunto de 28 ncRNAs totalmente intrônicos antisenso e senso cuja expressão do gene codificador de proteína do mesmo locus estava simultaneamente alterada. Estes dados apontam para possíveis redes de regulação da expressão gênica dos ncRNAs em câncer. A extensa lista de ncRNAs e de genes codificadores para proteína identificados neste estudo podem ser promissores marcadores moleculares de carcinoma renal subtipo célula clara. / Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney, and the clear cell subtype is the most prevalent and lethal cancer of the urinary system. Late diagnosis for this type of cancer is frequent, usually as a consequence of the lack of symptoms. One of the objectives of the present work is the identification of new molecular markers for the early diagnosis, which would help decrease mortality that develops as a function of disease progression. Another objective is the identification of a set of prognosis molecular markers, so as to accurately predict the clinical outcome of the disease, and consequently, patient survival. Transcriptional changes associated to carcinogenesis and to kidney cancer progression have not been entirely elucidated. Besides oncogenes and tumor suppressor genes, non-coding RNAs (ncRNAs) have been recently indicated as important regulators of gene expression in humans, and could have an important role in the malignant transformation in renal cancer. In order to measure ncRNA and protein-coding gene expression we have used two microarray platforms developed by our group, which are enriched in ncRNA probes. One of the platforms has 4 thousand cDNA probes, of which 822 are for ncRNAs that map to intronic regions. Another has 44 thousand elements and combines 60-mer oligonucleotide probes for intronic and exonic regions from the same genomic locus. Statistical analyses have been performed with the Significance Analysis of Microarrays tool (q &#8804; 0.05) combined with a patient leave-one-out approach (genes present in 100% of the sub-sets), or alternatively with Golubs discriminant test (p &#8804; 0.01 or p < 0.05). 11 With the 4-thousand probes platform we studied 30 samples from renal tissue of 18 RCC patients with clear cell subtype. A set of 36 ncRNAs has been identified as differentially expressed between tumor and non-tumor tissue. An additional signature of 265 protein-coding genes has been identified, indicating possible new molecular markers. A supervised statistical analysis with data from 16 patients has identified a ncRNA signature correlated to 5-year survival outcome, comprised of 27 ncRNAs with significantly altered expression in diseasefree patients compared to patients who died from cancer within the 5-year follow-up. An additional 64-gene signature of protein-coding genes has been identified as significantly correlated to clinical outcome. With the 44-thousand probes platform we have analyzed 17 patients, with paired tumor and non-tumor samples grouped into 8 pools, of which 4 were from tumor and 4 from nontumor samples. A set of 66 partially intronic antisense ncRNAs and another of 52 totally intronic antisense ncRNAs have been identified as differentially expressed between tumor and non-tumor tissue. A sub-set of 28 totally intronic antisense or sense ncRNAs were identified as having a simultaneous change in expression of the protein-coding gene from the same locus. Overall, the data point to a possible ncRNA regulatory network in cancer. The extensive lists of ncRNAs and of protein-coding genes identified in the present study can be seen as promising molecular markers of RCC from the clear-cell subtype.

During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Systematic reviews on diagnostic test accuracy studies provide an overview of the current literature in a systematic and transparent manner. They are the highest level of evidence in clinical research, therefore they are critical to decision-making in the healthcare setting. Cancer is the primary source of mortality in Canada, however early detection of tumors can improve the survival rates and long-term health outcomes of patients. The primary method of cancer diagnosis is histopathological assessment, however, its use remains controversial. It is an invasive procedure and requires resources and clinical expertise not readily available. Noninvasive clinical imaging has been studied as a clinically desirable method for cancer diagnosis, however its diagnostic accuracy has yet to be established in the medical setting. With the increased role of DTA research in medicine, the current literature needs to be summarized in an effective way to properly educate and influence clinical decision-making. The objective of this thesis is to address the current evidence gaps in DTA research by conducting several systematic reviews to evaluate the accuracy of diagnostic methods in cancer-related imaging. The last chapter of the thesis will provide a critical reflection on the current landscape of DTA studies in cancer-related imaging, based on the findings of the reviews in the thesis.