L’administration du blocage androgénique de façon intermittente pourrait offrir plusieurs avantages dans le traitement du cancer de la prostate. Toutefois, ce mode d’administration demeure controversé. Nous avons donc effectué une revue systématique et méta-analyse d’essais cliniques randomisés afin de comparer l’efficacité et la tolérabilité du blocage androgénique intermittent versus continu. Une analyse de non-infériorité a été effectuée pour la survie avec un seuil préétabli de 1,15 pour la borne supérieure de l’intervalle de confiance (IC). Au total, 15 études étaient éligibles. Le blocage androgénique intermittent était non inférieur au blocage androgénique continu avec un hazard ratio de 1,02 (IC à 95%: 0,93-1,11). Il y avait peu de différence entre les deux groupes pour la qualité de vie globale. Toutefois, plusieurs études ont rapporté une meilleure fonction physique et sexuelle avec le traitement intermittent. Le blocage androgénique intermittent est une alternative thérapeutique acceptable dans le cancer de la prostate. / Intermittent androgen deprivation may offer several advantages over continuous androgen deprivation in the treatment of prostate cancer. However, it remains controversial. We thus conducted a systematic review and meta-analysis of randomized controlled trials to compare the effectiveness and tolerability of intermittent versus continuous androgen deprivation. A non-inferiority analysis was performed for overall survival with a pre specified margin of 1.15 for the upper boundary of the confidence interval (CI). Overall, 15 studies were eligible. Intermittent androgen deprivation was non-inferior to continuous androgen deprivation with a hazard ratio of 1.02 (95% CI: 0.93-1.11). There were minimal differences in global quality of life between the two interventions. However, more of the included studies observed an improvement in physical and sexual functioning with intermittent therapy. Intermittent androgen deprivation can be considered as an alternative option in patients with prostate cancer.

Avec une incidence de 23 300 nouveaux cas en 2020 (ce qui représente 20% de tous les nouveaux cas de cancer chez l'homme) et de 4200 décès (10% de tous les décès par cancer chez l'homme), le cancer de la prostate est le cancer le plus fréquemment diagnostiqué chez l'homme au Canada. Il s'agit d'un cancer hormono-dépendant, traité depuis plus de 70 ans par thérapie anti-androgénique. Le succès des nouvelles immunothérapies basées sur la réactivation des lymphocytes T dans certaines pathologies cancéreuses (vessie, poumon, peau, etc.) et leur échec retentissant dans d'autres (incluant le cancer de la prostate) poussent la communauté scientifique à explorer l'impact de la composante innée du système immunitaire dans la réponse aux immunothérapies. Les tumeurs évoluent en tant qu'écosystèmes complexes, constitués entre autres de cellules tumorales, stromales et de cellules immunitaires. Longtemps considéré comme une tumeur « froide »,caractérisée par une faible infiltration immunitaire et comme cancer peu immunogènique, une population de cellules d'origine myéloïdes, les macrophages, sont depuis quelques années reconnus pour leur rôle majeur dans cet écosystème. Dans un premier temps ils seraient impliqués dans une séquence inflammatoire qui favoriserait le développement de la tumeur, puis, une fois la tumeur installée, les macrophages associés aux tumeurs (Tumor-associated macrophages – TAM) grâce à leur très grande plasticité, favoriseraient un environnement immunosuppresseur, l'angiogenèse, l'invasion de cellules tumorales et la formation de niche pré-métastatiques tout en supprimant la réponse des lymphocytes T cytotoxiques. On parle alors de rééducation du système immunitaire par la tumeur. De plus, de solides évidences ont montré l'implication des macrophages dans la résistance à la chimiothérapie et à la radiothérapie dans le cancer de la prostate Basé sur ces observations, nous avons, dans un premier temps, étudié la rééducation de macrophages, au départ à vocation anti-tumorale, en TAM dans le microenvironnement du cancer de la prostate. Nous avons ainsi pu montrer par que les TAM qui apportent le plus d'information sur la progression de la maladie semblent localisés en dehors de la tumeur, dans le tissu adjacent d'apparence normale. Nous avons ainsi pu mettre en place un nouveau système de culture ex vivo de biopsies de patients et trouvé que des TAM avec un phénotypemixte M1 (CCR7+) /M2 (CD163+) étaient présents en grande quantité dans les cancers de prostate agressifs. Nous avons finalement recréé artificiellement dans un modèle de co-culture une façon innovante d'obtenir des macrophages avec le même phénotype et observé qu'indépendamment de leur phénotype de polarisation de base (M1 ou M2), les cellules de cancer de la prostate changeaient ces macrophages pour leur donner une fonction identique tout en les empêchant d'être rééduqués en macrophage M1. Le séquençage des différents macrophages subvertis nous a permis de déterminer que la ré-éducation des macrophages M2 vers un M1 en présence de cellules cancéreuses était accompagnée d'un changement dans le réseau de chimiokines transcrites vers un profil de chimiokines qui favorisent le recrutement de neutrophiles et le remodelage tissulaire et osseux. ans un second temps, nous avons utilisé les informations sur la localisation spatiale des TAM pour inclure plus de tissu adjacent d'apparence normale dans notre système de culture ex vivo. Nous avons alors évalué l'impact d'un traitement actuellement utilisé en clinique, l'enzalutamide, sur la composante immune du microenvironnement tumoral, plus précisément sur les macrophages. Nous avons pu déterminer que l'observation seule de marqueurs à la surface des macrophages via une dichotomie positive/négative ne permettait pas de visualiser de changements. À l'inverse, l'utilisation de sous-populations basées sur la forte/faible expression de marqueurs (CD163, CCR7, CD206) nous permettait d'observer un changement dans la composition du type de macrophages associé à une augmentation de points de contrôle immunologique à leur surface (PD-L1, PD-L2 et B7-H3). Une forte proportion de macrophages PD-L1+ était associée à un plus faible volume tumoral et un ratio neutrophiles/lymphocytes plus élevé tandis qu'une forte proportion de macrophages B7-H3+ était associée avec la présence de carcinome intracanalaire de la prostate, une forme agressive du cancer de la prostate. Ce projet nous a aussi permis de mettre en exergue l'importance de l'utilisation de la cytométrie de flux multiparamétrique comme technique de phénotypage de ces macrophages dans des échantillons biologiques mais surtout l'utilité de cibler à l'aide du multimarquage des sous-populations définies par l'expression de biomarqueurs spécifiques afin de mieux caractériser cette composante importante du microenvironement tumoral prostatique. Enfin, ce travail permet de mieux comprendre la plasticité des macrophages dans un contexte de cancer de prostate agressif ainsi que l'ontogénie des macrophages pro-tumoraux recrutés ou subvertis. Il permet d'amener une approche nouvelle sur l'obtention de macrophages pro-tumoraux et leur utilisation comme modèle pour mimer in vitro les TAM. / With an incidence of 23,300 new cases in 2020 (representing 20% of all new cancer cases in humans) and of4,200 deaths (10% of all cancer deaths in humans), prostate cancer is the non-cutaneous cancer most frequently diagnosed in men in Canada. It is a hormone-dependent cancer, treated for over 70 years with anti-androgen therapy. The success of new immunotherapies based on the reactivation of T lymphocytes in certain cancers(bladder, lung, skin, etc.) and their failure of checkpoint immunotherapy in prostate cancers and others have prompted further exploration of the impact of the innate component of the immune system in the response to immunotherapies. Tumors evolve as a complex ecosystem, mainly made up of tumor cells, stromal cells, andimmune cells. Long considered as a "cold" tumor characterized by low immune cell infiltration and poorlyimmunogenic, the role of innate immune cells such as macrophages within the prostate tumor ecosystem remainto be fully defined. Initially, macrophages may be involved in an inflammatory sequence which promotes tumor development. Later, tumor-associated macrophages (TAMs) due to their very high plasticity, may play a role inpromoting an immunosuppressive environment, angiogenesis, tumor cell invasion and pre-metastatic niche formation while suppressing the response of cytotoxic T cells. These activities mediated by TAMS which are effectively re-educated o by the tumor. This is consistent with the association of macrophages and resistance to chemotherapy and radiotherapy in prostate cancer. Based on these observations, first, we studied the re-education of macrophages, particularly thoses which first present with an anti-tumor phenotype within the prostate cancer microenvironment. We show that the TAMs,which coincide most strongly with clinical outcomes are in fact located peripherally to the tumor in the adjacent normal tissue. We developed a novel system for ex vivo culture of patient biopsies and observed in aggressive prostate cancers that TAMs with a mixed M1 (CCR7+) / M2 (CD163+) phenotype were present in larger quantities. We modeled in a co-culture system an innovative way to obtain TAMs with this same phenotype and observed that regardless of their starting polarization phenotype (M1 or M2), prostate cancer cells changed these macrophages to give them an identical function while preventing them from being re-educated as M1macrophage. The sequencing of the different subverted macrophages allowed us to determine that the reeducation of M2 macrophages to M1 in the presence of cancer cells was accompanied by a change in the chemokine network transcribed towards a profile of chemokines that promote the recruitment of neutrophils and tissue and bone remodeling. Second, we used the information on the spatial location of the TAMs to include more adjacent, apparently normaltissue in our ex vivo culture system. We then evaluated the impact of a treatment currently used in the clinic,enzalutamide, on the immune composition of the tumor microenvironment, more specifically on TAMs We were able to determine that the observation of markers on the surface of macrophages alone via a dichotomous classification did not permit identification of any induced changes. However, with macrophage subpopulations based on the high/low expression of markers (CD163, CCR7, CD206), we observed a change in the compositionof the type of macrophages associated with an increase in immune checkpoints on their surface (PD-L1, PD-L2and B7-H3). A high proportion of PD-L1+ macrophages was associated with a lower tumor volume and a highneutrophil to lymphocyte ratio with a high proportion of B7-H3+ macrophages was associated with the presenceof intracanal carcinoma of the prostate, an aggressive form of prostate cancer. This project allowed us to highlight the importance of the use of multiparametric flow cytometry as a technique of phenotyping on these macrophages in biological samples but above all the usefulness of targeting, using multiple markers, subpopulations defined by expression of specific biomarkers in order to better characterizethis important component of the tumor microenvironment. Finally, this work allows us to better understand the plasticity of macrophages in a context of aggressive PCa as well as the ontogeny of recruited or subverted protumoral macrophages. It provides a new approach to obtain human pro-tumoral macrophages and an in vitromodel which mimics TAMs.

No description available.

Dans le cadre de mon doctorat j'ai développé des approches appliquées d'analyse de données pour effectuer une analyse multi omique du cancer de la prostate (CaP). Mon projet s'est défini en deux parties distinctes correspondant aux deux articles intégrés dans le corps de mon document. Une première partie du travail a consisté à récupérer des données omiques de différents types (RNA-Seq, Methylation, CNA, SNA, miRNA, données cliniques) associées au CaP et à les préparer avec un pipeline bioinformatique adapté. Ensuite j'ai eu pour objectif de chercher à mettre en avant de nouveaux points de contrôles de l'immunité associés à la récidive biochimique (BCR) dans le CaP au travers de ces données. Pour remplir cet objectif j'ai utilisé une approche particulière basée sur des algorithmes d'analyse en composante principale (PCA) et de régression des moindres carrés (PLS). Cela a permis de faire ressortir une famille spécifique de points de contrôle de l'immunité, la famille des LILR, qui peut potentiellement être une famille cible en immunothérapie. Dans un second temps, j'ai utilisé ces mêmes données pour développer un protocole d'analyse d'apprentissage machine (ML). Le but de ce travail était de montrer qu'il était possible de prédire si des patients allaient récidiver ou pas à partir de données RNA-Seq. J'ai montré que même avec des petits jeux de données on pouvait atteindre des scores de prédiction très bon et que les algorithmes actuels de ML prenaient bien en compte la variabilité technique de la diversité des sources de données dans le CaP. Il est donc possible d'utiliser les biobanques actuelles possédées par les structures de recherches à travers le monde pour créer des jeux de données plus importants. / As part of my PhD, I developed applied data analysis approaches to perform a multi-omic analysis of prostate cancer (CaP). My project was split into two distinct parts corresponding to the two articles integrated into the body of my document. A first part of the work consisted in recovering omics data of different types (RNA-Seq, Methylation, CNA, SNA, miRNA, clinical data) associated with CaP and preparing them with an adapted bioinformatics pipeline. Then, my goal was to seek to highlight new immunity checkpoints associated with biochemical recurrence (BCR) in CaP through these data. To fulfill this objective, I used a special approach based on Principal Component Analysis (PCA) and Partial Least Squares Regression (PLS) algorithms. This has brought out a specific family of immunity checkpoints, the LILR family, which can potentially be a target family in immunotherapy. Second, I used the same data to develop a machine learning (ML) analysis protocol. The aim of this work was to show that it was possible to predict whether or not patients would relapse from RNA-Seq data. I have shown that even with small datasets, one can achieve very good prediction scores and that current ML algorithms take into account the technical variability of the diverse data sources in the CaP. It is therefore possible to use current biobanks owned by research structures around the world to create larger datasets.

Le CaP est fréquent et demeure une cause principale de mortalité et de morbidité chez l'homme. Il persiste un dilemme clinique concernant la prise en charge optimale des patients atteints de CaP en maladie localisée en raison de l'estimation imparfaite du risque de progression. Ainsi, il importe de développer de nouveaux biomarqueurs pour améliorer la classification du risque de progression après un traitement à visée curative. Le CaP est une maladie hormono-sensible pour laquelle les voies des estrogènes demeurent encore peu étudiées. Certaines études récentes supportent une association entre les niveaux des dérivés de l'estradiol et le risque de CaP. Nous croyons que l'estradiol (E₂) et ses dérivés des voies de la 2-, 4- et 16- hydroxylation, pourraient représenter des marqueurs de progression en raison de leurs propriétés de nature proliférative, angiogénique et apoptotique. La quantification absolue et précise de ces dérivés est désormais possible en raison du développement d'une méthode robuste de spectrométrie de masse en tandem avec chromatographie liquide par notre équipe de recherche. Notre étude portait sur l'évaluation de l'association entre les niveaux urinaires des dérivés de l'estradiol et les issues oncologiques défavorables, soient la récidive biochimique, la survenue de métastases et le décès. Des hommes atteints d'un CaP en stade de maladie localisée ont été sélectionnés dans la cohorte prospective et multi-institutionnelle PROCURE pour les étapes de découverte (n=259) et de validation (n=253). Notre étude a montré que la voie de la 16-hydroxylation semble favorable (rapport de risque (HR) entre 0.74-0.75; p<0.006) mettant en évidence un risque plus faible de récidive biochimique. À l'inverse, la voie de la 2-hydroxylation semble défavorable avec un risque accru de développer une maladie métastatique et de décès de près de 1.6 fois (p=0.028). Le potentiel prédictif de ces dérivés de l'estradiol est supporté par la plausibilité biologique. Ces composés stéroïdiens semblent pertinents à étudier plus en détail comme marqueurs pronostiques potentiels en CaP. / Prostate cancer (PCa) is a main and persisting cause of mortality and morbidity in men. A clinical equipoise remains concerning the optimal management of localized PCa. Indeed, the estimation of the risk of progression still needs to be perfected. Hence, the development or improvement of biomarkers to improve the estimation of the risk of progression after curative-aimed treatment is needed. PCa is a hormone-sensible disease in which estrogenic hormones have not been studied extensively. There were recent studies that supported an association between E₂ derivates and PCa risk. We believe that the E₂ derivates of the 2-, 4- and 16-hydroxylation could represent markers of progression risk through their proliferative, angiogenic and apoptotic related properties. The absolute and comprehensive quantification of these derivates was recently made possible with the development, by our research team, of a robust tandem mass spectrometry with liquid chromatography method. Our study aimed to estimate the associations between urinary levels of E₂ derivates and unfavorable oncologic outcomes, namely biochemical recurrence, metastasis, and death. Men with localized PCa were selected in the prospective and multi-institutional PROCURE cohort for the discovery cohort (n=259) and validation cohort (n=253). Our study has demonstrated that the 16-hydroxylation pathway seemed favorable and associated with a decreased risk of biochemical recurrence (hazard ratio between 0.74-0.75; p<0.006). On the contrary, the 2-hydroxylation pathway seemed unfavorable and associated with an increased risk of metastasis or death by close to 1.6-fold (p=0.028). The potential of E₂ derivates as biomarkers of progression is supported by biological plausibility and clinical evidence. Hence, these steroid compounds are most relevant targets that must be further studied as potential prognostic biomarkers of PCa.

Les antigènes testiculaires du cancer sont des cibles idéales pour l’immunothérapie du cancer car ce sont des protéines immunogéniques dont l’expression est restreinte aux cellules germinales et au cancer. Le but de cette étude est d’évaluer le potentiel de MAGE-A11, un antigène testiculaire du cancer, comme cible pour développer un vaccin contre le cancer de la prostate. Pour ce faire, l’anticorps monoclonal 5C4 qui a la capacité de reconnaître la présence de MAGE-A11 dans les tissus fixés et inclus en paraffine a été produit. De plus, l’expression de MAGE-A11 a été analysée sur plusieurs lignées de cellules cancéreuses. Il a été démontré que MAGE-A11 est exprimé dans plusieurs types de cancers notamment dans le cancer du côlon et du cerveau. Finalement, nous avons identifié trois épitopes du CMH classe II HLA-DR1 dans la protéine MAGE-A11 confirmant ainsi l’immunogénicité de cet antigène et son potentiel comme cible pour l’immunothérapie du cancer. / Cancer/testis antigens are ideal targets for cancer immunotherapy because of their limited expression in normal tissues, aberrant expression in malignancies and their immunogenic properties. The aim of this study was to evaluate the potential of cancer/testis antigen, MAGE-A11, as an immunotherapeutic target for development of a prostate cancer vaccine. To accomplish this, we produced the monoclonal antibody 5C4 that is capable of recognizing MAGE-A11 in formalin-fixed paraffin-embedded tissues. We also investigated the expression of MAGE-A11 in a wide variety of cancer cell lines to determine the scope of its expression in cancer. It was shown that MAGE-A11 is widely expressed in malignancies. The highest MAGE-A11 expression was observed in colon cancer and astrocytoma brain tumors. Finally, we identified three naturally processed MHC class II HLA-DR1 epitopes in MAGE-A11 protein, thus confirming its immunogenicity and its potential as a target for cancer immunotherapy.

L’hypertrophie bénigne de la prostate (HBP) est une pathologie qui affecte 50% des hommes dès l’âge de 60 ans et qui conduit à des troubles de la miction. L’HBP se caractérise par une hypertrophie exclusive ou composite de plusieurs compartiments tissulaires de la prostate que sont l’épithélium, le stroma et les fibres musculaires qui définissent respectivement les composantes glandulaire, fibreuse et musculaire de cette pathologie. Il a récemment été montré que les souris dépourvues en récepteurs nucléaires LXR (Liver‐X‐receptor) α (souris lxrα‐/‐) développent une hypertrophie de la prostate dont les signes histologiques évoquent une HBP de type fibreuse. Par ailleurs, un des traitements de l’HBP, vise à éteindre la signalisation androgénique en inhibant la conversion de la testostérone en son métabolite actif, la dihydrotestostérone (DHT). Le phénotype d’hypertrophie de la prostate pourrait donc également s’expliquer par une altération de la signalisation androgénique dans les souris lxrα‐/‐. Dans ce contexte, notre projet de recherche a été centré sur l’étude du rôle des LXR dans l’apparition de l’HBP dans sa composante glandulaire et l’analyse des relations moléculaires associant les signalisations dépendantes de LXRα et du récepteur des androgènes (AR) au sein de la prostate. Le phénotype d’HBP observé dans les souris lxrα‐/‐ résulte d’altérations importantes de l’homéostasie de l’épithélium qui miment la composante glandulaire : 1) une activité sécrétoire accrue ; 2) une altération des processus de sécrétion associée à une altération de l’expression des gènes codant des protéines du transport vésiculaire ; 3) une réponse altérée de certains gènes androgéno‐dépendants associée à une hypersensibilité aux androgènes ; 4) des modifications du réseau paracrine reliant le stroma et l’épithélium. Au final, ces travaux définissent LXRα comme un acteur clé de l’homéostasie prostatique et ouvrent des pistes intéressantes pour la compréhension de l’étiologie de l’HBP chez l’homme. Ces résultats montrent qu’il est possible de moduler la réponse androgénique de la prostate en ciblant LXRα. Ainsi, à plus long terme, l’activation pharmacologique de LXRα constitue une piste potentielle dans le traitement de l’HBP. / Benign prostate hyperplasia (BPH) is a very common prostatic disorder that affects 50% of men after 60 years. In BPH, prostate enlargement causes urinary disorders. BPH is characterized by a hypertrophy of several tissue compartments such as the epithelium, stroma and/or muscle fibers. Hence, three main forms of BPH have been described : glandular, fibrous and muscular form. It has been recently shown that LXR (Liver‐X‐receptor) α (lxrα‐/‐) mice develop a prostate enlargement with histological signs of fibrous BPH. Inhibition of testosterone conversion into DHT is one the most effective pharmacological treatment of BPH. Thus, the lxrα‐/‐ prostate phenotype could be in part due to an alteration of androgen signaling. In this context, the aim of this work was to study the role of LXR in glandular BPH development and to understand the relationships between LXRα and the androgen receptor (AR) dependent signaling pathway in prostate. The prostate enlargement observed in lxrα‐/‐ mice results from major alterations in epithelium homeostasis mimicking the glandular alteration of BPH : 1) increase of secretory activity ; 2) alteration of the secretory process associated with altered expression of vesicular transport protein encoding genes ; 3) a disruption in the response of androgen‐dependent genes associated with androgen hypersensitivity ; 4) changes in the paracrine network between stroma and epithelium. Finally, this work defines LXRα as a key player in prostate homeostasis and opens interesting way to the understanding of BPH etiology. These results show that targeting LXRα modulate the prostate androgenic response. Thus, pharmacological activation of LXRα could constitute a new option for the treatment of BPH.

Abstract Title: The Relationship between Perceived Personal Risk of getting Prostate cancer and Prostate-Specific Antigen (PSA) Screening Yeatoe G. McIntosh, MPH Candidate Advisor: Emmanuel Anum, MBChB, MPH, PHD Preceptor: Emmanuel Anum, MBChB, MPH, PHD Background: Prostate cancer is one of the most common cancer diagnoses in the United States. The American Cancer Society estimates that in 2008 28,660 deaths would be attributed to prostate cancer, projecting it to be the leading cause of cancer deaths in U.S. men. Despite the potential threat this cancer presents to men and the potential for improved disease outcomes from early detection, guidelines for screening for prostate cancer are varied, and disparities in screening prevalence exist. In addition, disparities in knowledge about prostate cancer screening and misconceptions about the disease seem widespread. The main purpose of this study was to determine the relationship between perceived personal risk of getting prostate cancer and prostate cancer screening with the Prostate-specific antigen (PSA) test. Methods: Data were collected from the 2003 Health Information National Trends Survey (HINTS). Overall, 1,815 men ages 35 and above were included in the sample after exclusion of men ages 18-34. Logistic regression analyses were conducted to assess the association between perceived personal risk and prostate cancer screening with PSA test, while testing for interaction and further adjusting for possible confounders. A reduced model, in which variables with non-significant Wald chi-squared statistic had been excluded, was compared to the full model to access the change in parameter estimates. Using the model-based approach, we compared models with interaction terms to the one without interaction terms using the likelihood ratio test. Parameter estimates from the best fitting model were reported using the design-based method. SAS version 9.1 statistical software was used for analyses. Results: Among men ages 35-49, those who perceived their risk as high, were significantly less likely to screen than those who perceived their risk as low (OR: 0.20 95% CI: 0.05-0.78). Within ages 50-64 and 65 and above, there were no significant differences between perceived risk levels and PSA testing. Men, who did receive healthcare provider recommendation for screening, were more likely to obtain prostate cancer (PSA) screening than men who did not receive such recommendation (OR: 92.56 95% CI 36.56, 234.36). Conclusions: The relationship between perceived personal risk of getting prostate cancer and PSA screening is modified by age. As men aged, their odds of screening increased. The most significant predictor of PSA screening was health provider recommendation. PSA screening showed no association with either race or household income.

INTRODUÇÃO: O câncer de próstata é responsável por 15% dos casos novos de câncer que acometem os homens e pela 5ª causa de morte. As técnicas minimamente invasivas, sobretudo a cirurgia robótica tornou-se a técnica comumente empregada nos Estados Unidos. Muitos artigos tentam demonstrar a curva de aprendizado necessária para a estabilização dos resultados, mas a implementação de novas tecnologias passa por diversos desafios, além da avaliação de seus resultados e dos custos, o que em países em desenvolvimento pode ter um importante impacto no sistema de saúde. OBJETIVO: Avaliar a curva de aprendizado da prostatectomia radical laparoscópica robótica assistida (PRRA) para o tratamento do câncer de próstata, de acordo com a continência urinária, a potência sexual, o tempo cirúrgico e o controle oncológico. MÉTODOS: Duzentos pacientes com neoplasia de próstata localizada submetidos à PRRA por um único cirurgião foram divididos em quatro grupos de acordo com a sequência das cirurgias. Foram avaliados os dados intra-operatórios, como: tempo cirúrgico, perda sanguínea estimada e as margens cirúrgicas. Também durante o pósoperatório foram avaliadas a potência (IIEF) e a continência (ICIQ). RESULTADOS: Os pacientes apresentaram idade média de 60,6 anos (59,72-61,61), volume prostático ao toque retal de 40 gramas e valor do PSA 6,95 ng/ml (5,79-8,10) semelhantes em todos os grupos (p > 0,05). A biópsia prostática pré-operatória mostrou diferença no escore de Gleason e no tamanho da próstata, sendo que o escore 6 foi menos frequente no grupo 4, representado por 23 pacientes (46%) e no grupo 1, com 39 pacientes (78%) (p < 0,01). Já o tamanho prostático avaliado pelo USTR foi de 39,6 gramas (29,75-48,7) no grupo 4 e 30,5 gramas (23,0-38,15) no grupo 2. A curva de aprendizado estabelecida demonstrou uma diminuição no tempo cirúrgico de 157 minutos (145-170) no grupo 1, para 132 minutos (119-140) no grupo 2 (p < 0,01). A perda sanguínea estimada também se reduziu aproximadamente pela metade: de 395 ml (250-500) no grupo 1, para 200 ml (150-250) no grupo 3 (p < 0,01). As margens positivas reduziram de 16% para apenas 8%, mas se mostraram estatisticamente semelhantes (p=0,236). A capacidade de penetração com doze meses praticamente dobrou de 38% (19 pacientes) no grupo 1 para 80% (40 pacientes) no grupo 4 (p=0,003). A continência avaliada com um ano mostrou-se melhor no grupo 4 (98%) quando comparado aos pacientes do grupo 1 (94%) (p=0,001). As complicações foram estatisticamente semelhantes entre os quatro grupos (p = 0,668). A análise da recidiva bioquímica não demonstrou diferença (p > 0,05). CONCLUSÕES: A curva de aprendizado da PRRA é variável de acordo com o parâmetro a ser avaliado, e apesar do equipamento e da tecnologia, à medida que se aumenta a experiência do cirurgião, melhores resultados são obtidos. O tempo de cirurgia e o sangramento estabilizaram-se, respectivamente, após 50 e 100 PRRA. A potência e a continência, por sua vez, estabilizaram-se após 150 PRRA. É importante ressaltar que o controle oncológico necessita de um período de acompanhamento mais longo para ser avaliado / BACKGROUND: Prostate cancer is responsible for 15% of new cases of male cancer and is the fifth leading cause of death. Minimally invasive and mainly, robotic surgery technique became the technique most widely utilized in the United States. Many articles have tried to demonstrate the required learning curve to achieve the plateau. Although, new techniques implementation go through many challenges besides the evaluation of its results, costs also became an issue, which may impact in developing countries health system. OBJECTIVE: We aim to evaluate the learning curve of robot-assisted radical prostatectomy (RARP) for the treatment of prostate cancer, according to continence, potency, surgical time and oncologic control. METHODS: Two hundred patients with localized prostate cancer that underwent RARP by a single surgeon were divided into four groups according to its surgical sequence. Intraoperative data, such as surgical time, estimated blood loss and margins were recorded. Also postoperative functional parameters as continence and potency were gathered using validated questionnaires (ICIQ and IIEF). RESULTS: Patients mean age were 60.6 years (59.72- 61.61), mean prostate volume at digital rectal examination was 40 grams and PSA value 6.95 ng/ml (5.79-8.10) were similar in all groups (p > 0.05). Pre-operative prostate biopsy showed difference in Gleason score and prostate size. Gleason score 6 was less frequent in group 4, 23 patients (46%), than group 1, 39 patients (78%)(p <0.01) and prostate size at TRUS was 39.6 grams (29.75- 48.7) in group 4 and 30.5 grams (23.0- 38.15) in group 2. The established learning curve showed a reduction on surgical time from 157 minutes (145-170) in group 1 to 132 minutes (119-140 min) in group 2 (p < 0.01). The estimated blood loss also decreased almost to half, from 395 ml (250-500) in group 1 to 200 ml (150-250) in group 3 (p < 0.01). Positive margins decreased from 16% to only 8 %, but were statistically similar (p=0.236). Nineteen patients (38%) could have sexual intercourse at an year after the surgery, in the first group but latest, in the fouth group, it doubled to 40 patients (80%) (p=0.003). Also continence improved in group 4(98%) when compared with group 1 (94%) (p=0.001). Complications were similar between groups (p=0.668). Biochemical recurrence also showed no difference (p > 0.05). CONCLUSIONS: Therefore, the learning curve of the RARP is variable according to the evaluated parameter and obviously, despite the equipment and technology, the increase of surgical experience the best the outcome. Surgery time plateau were achieved at 50 RARP, estimated blood loss stabilized after 100 surgeries, sexual function and urinary continence after 150 RARP. Cancer control requires a longer follow-up period for review

Objetivo: Determinar a correlação entre os níveis de PSA, escore Gleason e a estimativa de volume tumoral em fragmentos de biópsia de próstata em pacientes portadores de CaP. Material e Métodos: No período de 26 de abril a 15 de setembro de 2000 foram avaliados 64 pacientes submetidos à dosagem do PSA sérico e com biópsia transretal da próstata compatível com carcinoma. Os fragmentos biopsiados foram analisados quanto ao diagnóstico anatomo-patológico, graduação histológica pelo sistema Gleason e estimativa de volume tumoral através da determinação da proporção de carcinoma nos fragmentos obtidos na biópsia e medida do maior eixo tumoral. Resultados: Este estudo demonstrou a associação positiva entre estimativa de volume tumoral e níveis séricos de PSA. Entre as medidas de volume tumoral a correlação foi de maior magnitude quando se considera a proporção objetiva de carcinoma na amostra. Em relação ao escore Gleason, foi demonstrada associação significativa com níveis séricos de PSA (p<0,01) e com as medidas de volume tumoral (p<0,05). Conclusão:Existe correlação entre níveis séricos de PSA, escore Gleason e estimativa de volume tumoral em fragmentos de biópsia da próstata de pacientes com adenocarcinoma da próstata, porém o impacto dessa associação na determinação prognóstica desses pacientes permanece indeterminada. / Purpose: To determine the correlation between serum prostate specific antigen (PSA) levels, Gleason score and tumor volume in prostate needle biopsy cores in patients with prostate cancer. Materials and Methods: A total of 64 patients who underwent prostate biopsy between april 26th and September 15th 2000 had the histologic diagnosis of prostate cancer. Prostate needle biopsy specimens where examined for histologic diagnosis, Gleason score and tumor volume measure through the determination of the cancer ratio in the biopsy cores and by the linear measurement of the biggest tumor axle . Serum PSA levels obtained previously to the biopsy were also determined. Results: We found a positive correlation between tumor volume estimative and PSA serum levels. Considering the tumor volume measures, the cancer ratio in the biopsy cores was the independt measure wich had the strongest correlation. Considering Gleason score, a significant association with PSA serum levels was demonstrated (p<0,01) as well when associated to tumor volume measures, Gleason (p<0,05). Conclusions: There is correlation between PSA serum levels, Gleason score and tumor volume measures in prostate needle biopsy cores in men with prostate cancer, however the impact of this association in the prognostic determination of these patients remains unclear.