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Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

International audience; Introduction: Bladder cancer is currently ranked as the 8th most common cancer in France. However, the patient care pathway for this cancer is still not well known.Methods: A telephone survey was conducted with fifteen healthcare professionals, ten patients, and five family caregivers between November 2020 and March 2021. The objectives of this survey were to identify the major steps in the care pathway according to the medical, emotional and societal dimensions, for patients with locally advanced or metastatic bladder cancer, the associated barriers, and the initiatives to be implemented to improve it.Results: Several barriers were identified at different stages of the overall care pathway, including lack of knowledge of risk factors and warning signs of the disease by the general population and some healthcare professionals, difficulties linked to the announcement consultation, lack of psychological support for patients and their caregivers, and lack of information given about the disease and supportive care.Discussion: These results allowed us to identify three major initiatives which could improve the overall care pathway and the quality of life of patients and their caregivers: 1/implementation of a public awareness campaign on bladder cancer; 2/creation of booklets for patients and their caregivers to provide them with a source of reliable information; and 3/the creation of communication tools between healthcare professionals and patients to facilitate exchanges during consultations.; Introduction > Le cancer de la vessie est aujourd'hui classé en huitième position des cancers lesplus fréquents en France. Le parcours de soins de ce cancer est, cependant, mal connu.Méthodes > Une enquête téléphonique a été menée en France auprès de quinze professionnels desanté, dix patients et cinq aidants entre novembre 2020 et mars 2021. Les objectifs de cetteenquête étaient d'identifier les grandes étapes du parcours de soins des patients atteints d'uncancer de la vessie localement avancé ou métastatique, selon l'angle médical, émotionnel etsociétal, les freins y étant associés et les initiatives à mettre en place pour l'améliorer. IntroductionLe cancer d'origine vésicale est dans 90 % des cas un carcinomeurothélial, dont l'incidence est de 13 000 nouveaux cas diag-nostiqués chaque année en France [1], le plaçant en huitièmeposition des cancers les plus fréquents. Il arrive au quatrièmerang des cancers masculins et au quatorzième rang des cancersféminins et est responsable d'environ 5000 décès par an enFrance (3778 décès chez les hommes et 1235 décès chez lesfemmes, observés en 2017). Il est ainsi le septième cancer leplus mortel en France [1].Les principaux facteurs de risque du cancer de la vessie sontl'âge, avec une moyenne d'âge au diagnostic de 73 ans chezl'homme et 78 ans chez la femme [2], et le tabagisme [3]. Unfumeur a, en effet, environ 5,5 fois plus de risque de développerla maladie par rapport à un non-fumeur. En France, le tabagismeserait responsable de 53 % des cas de tumeurs de la vessie chezles hommes et de 39 % chez les femmes [4]. Les autres facteursde risque sont l'exposition professionnelle à des substances,comme les amines aromatiques, à des agents infectieux (ex :schistosome), ou à certains médicaments (ex : traitement anté-rieur à base de cyclophosphamide). Les facteurs de risqueassociés au carcinome urothélial en font historiquement uncancer principalement masculin [5].Le diagnostic de ce cancer peut être retardé, à cause de symp-tômes cliniques non spécifiques pouvant laisser penser, notam-ment, à une infection urinaire, tels qu'une augmentation de lafréquence urinaire, de l'urgence mictionnelle et une dysurie, quiRésultats > Plusieurs freins ont été identifiés à différentes étapes du parcours, notamment lemanque de connaissance des facteurs de risque et signes d'alerte de la maladie par le grand publicet certains professionnels de santé, les difficultés liées à la consultation d'annonce, le manqued'accompagnement psychologique pour les patients et aidants, le manque d'informations don-nées sur la maladie et les soins de support.Discussion > Ces résultats ont permis d'identifier ainsi trois grandes initiatives qui permettraientd'améliorer le parcours de soins dans sa globalité et la qualité de vie des patients et de leursaidants : 1/mise en place d'une campagne de sensibilisation du grand public sur le cancer de lavessie ; 2/création de livrets à destination des patients et de leurs aidants pour leur fournir unesource d'informations fiables ; et 3/la création d'outils de communication entre soignants etpatients pour faciliter les échanges lors des consultations.

International audience; Ageing is correlated with elevated bladder cancer incidence, morbidity and mortality. Advanced age is also associated with elevated markers of chronic inflammation and perturbations in gut and urinary tract microbiota. One reason for the increased incidence and mortality of bladder cancer in the elderly might be that age-associated changes in multiple microbiomes induce systemic metabolic changes that contribute to immune dysregulation with potentially tumorigenic effects. The gut and urinary microbiomes could be dysregulated in bladder cancer, although the effect of these changes is poorly understood. Each of these domains - the immune system, gut microbiome and urinary microbiome - might also influence the response of patients with bladder cancer to treatment. Improved understanding of age-related alterations to the immune system and gut and urinary microbiomes could provide possible insight into the risk of bladder cancer development and progression in the elderly. In patients with bladder cancer, improved understanding of microbiota might also provide potential targets for therapeutic intervention.

International audience; Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Resume Objectifs On observe dans l’Herault une nette augmentation de l’incidence des cancers urologiques. Le registre des tumeurs de l’Herault (RTH) a recueilli 1961 tumeurs urologiques en 2016, soit 21,4 % de l’ensemble des tumeurs de l’Herault pour cette annee-la. La creation d’un registre specialise en onco-urologie nous est apparue necessaire. L’objectif de cet article est de decrire le fonctionnement de RHESOU et de donner quelques exemples de resultats. Materiel et methodes En novembre 2018, RHESOU (Registre de l’herault specialise en onco-urologie) a ete cree sur le meme mode de fonctionnement qu’un registre. Il permet de completer les donnees du RTH sur beaucoup d’autres parametres oncologiques. Pour chaque type de cancer urologique et genital masculin et urologique feminin, une fiche de recueil a ete realisee pour recueillir le maximum de donnees presentes dans le dossier des cas signales. Cette etude a evalue les donnees concernant les patients domicilies dans l’Herault pour l’annee 2017. Resultats Nous avons denombre pour l’annee 2017, 970 cancers de la prostate, 581 tumeurs de vessie, 212 cancers du rein, 51 tumeurs de la voie excretrice superieure, 28 cancers du testicule et 9 cancers du penis. Le recueil de ces donnees permet de creer des requetes et de fournir des analyses pertinentes et detaillees sur les cancers urologiques et genitaux masculins. Nous rapportons les donnees analysees sur le rein, la vessie et la prostate. Conclusions RHESOU est un outil accessible pour permettre une vue d’ensemble sur les cancers en urologie dans l’Herault et leur prise en charge. Avec l’apparition de nouveaux traitements, il saura s’adapter en permettant une evolution des fiches. Niveau de preuve 3.

International audience; Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

International audience; Purpose: In 2016, the Herault tumor registry collected 1961cancers in urology (21.4 % from all Herault cancers this year). RHESOU was created to complete RTH' data with specific parameters in onco-urology. The aim of this study is to describe RHESOU and to give some examples with our first results.Material and methods: In November 2018, RHESOU (Registry HErault Specialised in Onco-Urology) was founded with the same registry recommendations. It collects specific oncologic parameters and also complete RTH's data. For each urological cancer, a specific survey with different choices was performed to collect a maximum of data which could be present in patients' file. These surveys were used for urological cancers cases that live in Herault in 2017.Results: In 2017, we collected 970 prostate cancers, 581 bladder cancers, 212 kidney cancers, 51 upper excretory tract cancers, 28 testicle cancers and 9 penil cancers. Our urological data collection gives many possibilities to create many requests for detailed analysis in urological cancers. In this article, we reported data from kidney, bladder and prostate cancers.Conclusions: RHESOU is a new tool opened to the different urologic corporations (urologists, pathologists, oncologists, radiotherapists, radiologists) that permits an overview in urological cancers in Herault. Finally, one important aim is that this tool will be adapted when new treatments or new important parameters appear in the years ahead.Level of evidence: 3.

International audience; We report the natural history and prognosis of tumors after augmentation enterocystoplasty, with a molecular analysis using an oncogene panel to search for potential targeted therapies.Materials and methods: this multicenter, nationwide, retrospective study included 16 patients. A panel of 21 clinically relevant oncogenes was tested on archival tumor specimens using next-generation sequencing. Survival rate was the main clinical outcome and sequences were compared to the reference genome for the genetic outcome.Results: augmentation enterocystoplasties were performed mainly for congenital neurogenic bladder and bladder exstrophy at a median patient age of 17 years (range 4 months to 45 years). Most of the malignancies were diagnosed because of clinical manifestations, with a median latency period of 20 years. Adenocarcinomas were mainly found after gastrocystoplasty, whereas urothelial cell carcinomas were typically found after colocystoplasty. Of the 16 patients 13 were diagnosed at an advanced stage of the disease (positive lymph nodes in 7, distant metastases in 6). The overall 1-year survival rate was 56%. Only 3 patients remained disease-free at a median followup of 70 months. Of the 9 tumors with analyzable DNA 4 were wild-type and 5 harbored missense mutations (KIT-p.Pro573Ser, PDGFRA-p.Glu587Lys, KRAS-p.Gly12Asp, ERBB4p.Arg484Lys, CTNNB1-p.Ser37Phe and p.Ser47Asn).Conclusions: malignancy after augmentation enterocystoplasty is diagnosed late with frequent metastases and a very low 1-year survival rate. More than half the tested samples harbored missense mutations in oncogenes accessible to targeted therapies. An international collaboration to enlarge the genetic panel analysis of these tumors may offer new therapeutic hope to patients.

International audience; OBJECTIVE:To propose updated French guidelines for non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers.METHODS:A Medline search was achieved between 2015 and 2018, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence.RESULTS:Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS60 mL/min) allow it (only in 50% of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival.CONCLUSION:These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC.

Introduction : la sarcopénie évaluée à partir de la mesure de l’indice de masse musculaire striée (SMI) a été étudié comme facteur prédictif de morbi-mortalité en chirurgie. L’objectif de cette étude était d’évaluer si elle était prédictive de la morbi-mortalité chez les patients pris en charge par cystectomie ou par traitement tri modal (TTM), associant radiothérapie et chimiothérapie après résection endoscopique de la tumeur, pour une TVIM localisée. Matériels et méthodes : les patients consécutifs de 2 centres hospitalo-universitaires traités par cystectomie ou par TTM ont été inclus. Le SMI était calculé à partir de coupes axiales en L3 sur les scanners pré-thérapeutiques. La sarcopénie a été évaluée de deux façons : soit par le SMI sans ajustement de la masse musculaire, soit en utilisant la définition de Martin prenant en compte le sexe et l’IMC des patients, alors appelée « sarcopénie ajustée ». Le critère de jugement principal était la survie globale (SG) en fonction de la sarcopénie. Les critères secondaires étaient la SG, la survie sans progression (SSP) et la survie sans ré-hospitalisation (SSR) pour la population totale et pour chaque groupe de traitement. Les analyses de survie ont été réalisées selon le modèle de Cox. L’association entre sarcopénie et complications a été recherchée par le test du Chi 2. Résultats : les caractéristiques des patients sarcopéniques et non sarcopéniques étaient comparables excepté pour 2 critères : patients plus âgés dans le groupe sarcopénique et proportion plus importante de chimiothérapie néo-adjuvante chez les patients non sarcopéniques. La sarcopénie ajustée n’était significativement associée à aucun type de survie contrairement au SMI qui était associé à la SG et à la SSR dans la population totale (p = 0.01 et p = 0.02) et à la SG dans le groupe de patients traités par cystectomie (p = 0.02). La sarcopénie n’était associée ni à la proportion ni à la sévérité des complications. Conclusion : le SMI calculé avant la prise en charge des TVIM était associé à la survie dans notre étude contrairement à la sarcopénie ajustée. Le choix d’un seuil de SMI faciliterait son utilisation par le praticien mais se heurte à la définition d’un seuil applicable à toutes les populations.

International audience; INTRODUCTION:Neoadjuvant chemotherapy (NAC) is recommended for localized muscle-invasive bladder cancer when patients are fit for cisplatin-based chemotherapy. A pathological complete response can be observed, corresponding to ypT0N0 stage on the radical cystectomy specimen. This review discusses the incidence, prognosis and potential therapeutic impact of complete response on pathological specimen in NAC treated patients.METHODS:A comprehensive review of the literature was conducted using Medline database, with no time frame. The articles were selected using the following keywords association: "Bladder cancer" (Mesh) AND "Neoadjuvant chemotherapy" (Mesh) AND "pT0" (Mesh).RESULTS:After NAC, ypT0N0 rates vary from 9 to 46% among the series, reported rates that are higher compared to those of pT0 without NAC administration. The incidence depends on the chemotherapy regimen (maximal local effect with cisplatin-based chemotherapy) and the pathological type of the disease (presence of variant histologies). Molecular analyses of bladder cancer could probably help in the near future to identify and predict NAC responders. Pathological complete response is associated with a favorable prognosis in terms of recurrence-free and overall survival. Nevertheless, disease recurrences are still observed in 10-15% of cases, which underlies the importance of local treatment and close follow-up even in these patients.CONCLUSION:ypT0N0 rate is approximately 25% after NAC, that is 4.3 higher than after bladder resection alone. The prognosis is better than that with residual tumor on specimen and is comparable to that of pT0 without NAC administration.

Introduction: platinum-based Neo Adjuvant Chemotherapy (NAC) before Radical Cystectomy (RC) is the gold standard in the treatment of Muscle Invasive Bladder Cancer (MIBC). We aimed to compare the peri operative morbidity in patients treated by NAC then RC and patients having RC alone.Methods: between January 1st, 2008 and December 31st, 2015, we retrospectively included consecutive patients performing RC for MIBC in 2 centres. We collected clinical, pathological and peri operative data (30-day post operative complications according to the Clavien-Dindo score, delayed complications, pathological results). Patients treated by NAC (NAC-RC group) before RC were compared to patients performing RC alone. The NAC-RC group received 1 to 6 cycle of high-dose MVAC, MVAC or gemcitabine-cisplatine chemotherapy. Logistic regression identified independent factors of peri operative complications. Results: we included 199 patients : 48 in the NAC-RC group and 151 in the RC group. Complications rate was 73.9% in the NAC-RC group versus 73.8% in the RC group (p = 1.0). In multivariate analyses, only the Charlson score was associated with an increased risk of peri operative complications (p=0.05). pT0 tumour rate was significantly higher in the NAC-CR group (50% vs 7%, p< 0.001). Conclusion: NAC does not increase the peri operative morbidity of the RC. Patients’ pre operative comorbidities is the main risk factor for peri operative complications.; Introduction : la himiothérapie néo adjuvante (CNA) est le traitement de référence avant cystectomie radicale (CR) pour tumeurs infiltrantes de vessie (TVIM). Nous avons comparé la morbidité péri-opératoire entre les patients ayant reçu une CNA avant CR et les patients traités par CR seule.Patients et Méthodes : tous les patients consécutifs ayant eu une CR pour TVIM dans deux centres entre le 1er janvier 2008 et 31 décembre 2015 ont été inclus rétrospectivement. Les caractéristiques cliniques, anatomopathologiques et péri-opératoires des patients traités par CNA (groupe CNA-CR) ont été comparées au groupe CR seule (groupe CR). Les patients du groupe CNA-CR ont reçu entre 1 et 6 cycles de chimiothérapie par MVAC, MVAC dose dense ou gemcitabine-cisplatine. Nous avons identifié les facteurs associés à la survenue de complications péri opératoires par régression logistique. Résultats : 199 patients ont été inclus : 48 dans le groupe CNA-CR et 151 dans le groupe CR. Le taux de complications tous Clavien confondus était de 73.9% dans le groupe CNA-CR et 73.8% dans le groupe CR (p=1.0). Il n’existait pas de différence sur la durée moyenne d’hospitalisation (19.26 ± 7.10 jours dans le groupe CNA-CR contre 20.49 ±11.86 jours (p = 0.5)). En analyse multivariée, seul le score de Charlson était associé à la morbidité péri opératoire (p = 0.05), contrairement à la réalisation d’une CNA (p = 0.98). Le taux de tumeurs pT0 était significativement supérieur dans le groupe CNA (50% vs 7%, p

International audience; PURPOSE:Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.METHODS:A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.RESULTS:Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.CONCLUSIONS:Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.

International audience; Surgery (radical cystectomy) is the standard treatment of muscle-invasive bladder cancer. Radiochemotherapy has risen as an alternative treatment option to surgery as part as organ-sparing combined modality treatment or for patients unfit for surgery. Radiochemotherapy achieves 5-year bladder intact survival of 40 to 65% and 5-year overall survival of 40 to 50% with excellent quality of life. This article introduces the French recommendations for radiotherapy of bladder cancer: indications, exams, technique, dosimetry, delivery and image guidance.

International audience; PURPOSE:Although radical cystectomy is still considered the standard of care for most localized muscle-invasive bladder cancer (MIBC) patients, bladder-sparing strategies with chemoradiotherapy have demonstrated comparable local control and survival rates when adjusting for tumor stage. We present a pooled analysis of individual patient data out of published trials with gemcitabine-based chemoradiotherapy for MIBC.METHODS AND MATERIALS:Individual patient data were collected from Institutions that enrolled patients into trials that evaluated gemcitabine-based chemoradiotherapy for MIBC.RESULTS:We identified eight studies published on gemcitabine-based radiochemotherapy and 190 patients were included in this analysis. A complete response (CR) was observed in 166 patients (93%). After a median follow up of 44.5months, 36 patients (18.9%) presented a bladder recurrence and 14 subsequently underwent cystectomy. The 5-year overall survival (OS), disease-specific survival (DSS), and cystectomy-free survival (CFS) rates were 59%, 80.9%, and 93.3%, respectively. The achievement of CR after chemoradiotherapy was the main prognostic variable which was associated with improved OS, DSS, and CFS. The treatment was well tolerated.CONCLUSION:This pooled analysis strengthens the evidence that chemoradiotherapy regimens with concurrent gemcitabine are feasible and well tolerated. Prospective randomized controlled trials are on-going to definitively assess the efficacy of gemcitabine-based chemoradiotherapy for MIBC.

International audience; PURPOSE: We assessed the prognostic value of extranodal extension and other lymph node parameters in a large multicenter cohort of patients with lymph node metastasis after radical nephroureterectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 222 patients with lymph node metastasis treated with radical nephroureterectomy for upper tract urothelial carcinoma without neoadjuvant therapy. Each lymph node metastasis was microscopically evaluated for extranodal extension. RESULTS: A median of 4 lymph nodes (IQR 8) was removed. Two lymph nodes (IQR 2) were positive. Lymph node density was 51.3% (IQR 71.7%). Overall 110 patients (49.5%) had extranodal extension, which was associated with more advanced pT stage (p = 0.026). On multivariable analysis extranodal extension was associated with disease recurrence (p = 0.01) and cancer specific mortality (p = 0.013). When stratified by a 30% cutoff, lymph node density was associated with disease recurrence and cancer specific mortality on univariable but not multivariable analysis (p = 0.048 and 0.049, respectively). Adding extranodal extension to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p

International audience; BACKGROUND: Epidemiologic evidence regarding the association between a history of allergic diseases and different cancer types has been inconsistent. OBJECTIVE: To examine whether a history of asthma or eczema is associated with various cancers among Canadian men in a population based case-control study conducted in the 1980s. METHODS: Questionnaire-based interviews were performed by a team of trained interviewers from August 1979 to March 1986. Information collected included self-reported history of a prior medical diagnosis of asthma and of eczema, medication use, and several covariates among 3,300 cancer cases and 512 population controls. Logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between asthma or eczema and more than 20 cancer types combined, as well as for each of the 8 most common cancer types (stomach, colon, rectum, lung, prostate, bladder, skin, and lymph nodes). RESULTS: Considering study participants who reported a prior medical diagnosis of the disease and medication use, a history of asthma was negatively associated with all cancer types combined (OR, 0.72; 95% CI, 0.5-1.1) and similarly for a history of eczema (OR, 0.66; 95% CI, 0.4-1.1). Although ORs between asthma and eczema and most individual types were below 1.0, only 2 ORs were significantly below 1.0: that between asthma and stomach cancer (OR, 0.27; 95% CI, 0.1-0.9) and that between eczema and lung cancer (OR, 0.34; 95% CI, 0.2-0.7). CONCLUSION: Allergic conditions that result from a hyperreactive immune system might lead to a more efficient elimination of abnormal cells, thus lowering cancer risks.

International audience; OBJECTIVE: To identify the prognostic factors predictive of metachronous bladder transitional cell carcinoma (TCC) in a multi-institutional dataset of patients who had undergone nephroureterectomy (NU) for nonmetastatic upper urinary tract (UUT) TCC. PATIENTS AND METHODS: The clinical and pathological data of 231 patients who had had NU for UUT-TCC from 1989 to 2005 in three European centres were collected retrospectively, and analysed for clinical and pathological variables. RESULTS: The median follow-up was 38 months; during the follow-up, bladder TCC was detected in 109 patients (47.2%), and was significantly more common in patients who had UUT-TCC after previous bladder TCC (P < 0.001), in those with ureteric cancer (P = 0.022), and in those with pT2 UUT-TCC (P = 0.017). On multivariate analysis, a previous history of bladder TCC was the only independent predictor of metachronous bladder TCC (hazard ratio 2.825; P < 0.001). The 5-year probability of being free from metachronous bladder TCC was 45.5%. A history of bladder TCC (P < 0.001) and UUT tumour site (P = 0.01) were significantly associated with the probability of bladder recurrence-free survival. On multivariate analyses, a previous history of bladder TCC (hazard ratio 2.226; P < 0.001) and the presence of ureteric TCC (1.562; P = 0.036) were independent predictors of the probabilities of being free from metachronous bladder TCC. CONCLUSION: In this multi-institutional study of patients who had had NU for UUT-TCC, a history of bladder TCC was the only independent predictor of metachronous bladder TCC, while both a history of bladder TCC and the presence of ureteric tumours were predictive of the probabilities of being free from metachronous bladder TCC.

International audience; The expression pattern of tight junction (TJ) proteins is frequently disrupted in epithelial tumors. In particular, isoform- and organ-specific alterations of claudins have been detected in human cancers, highlighting them as interesting tools for the prognosis or treatment of various carcinomas. However, the molecular mechanisms responsible for these alterations are seldom identified. Here, we analyzed the expression and localization of claudins 1, 4, and 7 in human bladder carcinoma. Claudin-4 expression was significantly altered in 26/39 tumors, contrasting with the rare modifications detected in the expression of claudins 1 and 7. Overexpression of claudin-4 in differentiated carcinomas was followed by a strong downregulation in invasive/high-grade tumors, and this expression pattern was associated to the 1-year survival of bladder tumor patients. A CpG island was identified within the coding sequence of the CLDN4 gene, and treatment with a methyl-transferase inhibitor restored expression of the protein in primary cultures prepared from high-grade human bladder tumors. In addition, claudin-4 expression correlated with its gene methylation profile in healthy and tumoral bladders from 20 patients, and downregulation of claudin-4 expression was detected in the urothelium of mice overexpressing DNA methyl transferase 3a (Dnmt3a). Delocalization of claudins 1 and 4 from TJs was observed in most human bladder tumors and in the bladder tumor cell line HT-1376. Although the CLDN4 gene was unmethylated in these cells, pharmacological inhibition of methyl transferases re-addressed the two proteins to TJs, resulting in an increase of cell polarization and transepithelial resistance. These biological effects were prevented by expression of claudin-4-specific siRNAs, demonstrating the important role played by claudin-4 in maintaining a functional regulation of homeostasis in urothelial cells. Results of this study indicate that the TJ barrier is disrupted from early stages of urothelial tumorigenesis. In addition, we identified hypermethylation as the mechanism leading to the alteration of claudin-4 expression, and maybe also localization, in bladder carcinoma.

Objective To assess the diagnostic and prognostic performance of a noninvasive FGFR3 mutation analysis. After transurethral resection (TUR) of noninvasive bladder transitional cell carcinoma (B-TCC), recurrence occurs in 70% of patients, thus justifying cystoscopic surveillance. Materials and Methods A prospective multicenter study was carried out with a 2-year follow-up of patients with superficial B-TCC. Urine samples were collected before TUR and then before each cystoscopy during follow-up. Screening for the most prevalent FGFR3 mutations was done using urinary cells. The prognostic significance of an FGFR3 mutation at the time of the initial diagnosis was determined. The performance of the test in diagnosing and/or predicting recurrence during follow-up was assessed by calculating sensitivity and specificity. Results Of 191 patients studied, 74 (39%) had a positive analysis before TUR ( FGFR3 mutation group). The presence of an FGFR3 mutation at the time of diagnosis was associated with a shorter time to recurrence ( P = .02). During follow-up, 68 patients from the FGFR3 mutation group were evaluated. FGFR3 mutation analysis showed a sensitivity of 0.73 and a specificity of 0.87 when compared with the results of cystoscopy. A positive urine test was predictive of recurrence either at the time of the positive result or later during the 2-year follow-up, with a sensitivity of 0.70 and a specificity of 0.87. Conclusion Among patients with an FGFR3 mutation in the initial tumor, a noninvasive urine test during follow-up can be valuable in diagnosing or predicting subsequent recurrence.

The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β–glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG., Author Summary Next to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects on immune cells to increase their ability to control unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. Little is known regarding the intracellular events controlling its induction. In this study we identified autophagy as a key player in trained immunity. Pharmacological inhibition of autophagy as well as polymorphisms in autophagy-related genes blocked BCG-induced trained immunity. Furthermore, BCG vaccine is also used to treat bladder cancer. Genetic polymorphisms in autophagy-related genes correlated with progression and recurrence of bladder cancer after treatment with BCG therapy. These findings open new possibilities for improvement of future BCG-based vaccines to be used against infections and malignancies.

International audience; Bladder cancer is one of the most common cancers worldwide. A number of genetic and epigenetic alterations have been identified in bladder tumorigenesis, including activating mutations in fibroblast growth factor receptor 3 (FGFR3) and RAS family genes. In this study, we have analysed the mutational spectrum of FGFR3 and RAS genes (HRAS, NRAS and KRAS). We have also studied the relationship between mutations. A total of 234 patients with different stages and grades were included in the present study (58 superficial low-grade, 53 superficial high-grade and 123 muscle-invasive tumours). Mutations in exons 1 and 2 of HRAS, KRAS and NRAS genes were screened by PCR and direct sequencing. The hot spot mutations in exons 7, 10 and 15 of the FGFR3 oncogene were studied by multiplex PCR and the SNaP-shot protocol. Overall, 8.97% (21/234) of samples were mutant for one of the RAS genes. Among these mutations 47.61% were detected in KRAS, 33.33% in HRAS and only 19.04% most frequent RAS mutations were KRAS p.G12C and p.G12D. The correlation between RAS mutations and tumour subgroups does not report a statistical significant association (p=0.876). The FGFR3 mutations were detected in 31.19% (73/234) of bladder tumours and were associated with low stages and grades. The study of relationship between RAS and FGFR3 genes revealed that FGFR3 mutations were mutually exclusive with RAS ones (p=10(-4)). In conclusion we retain that activated RAS and FGFR3 do not appear to be drivers in bladder cancer but the mutually exclusive relationship between RAS and FGFR3 mutations indicates a possible clonal advantage of modified signaling via a common pathway.

Objective: Carcinoma in situ (OS) is associated with increased risk of progression when found with high-grade non-muscle-invasive bladder cancer, yet its impact is less clear in the upper urinary tract. In the current study, we evaluated the impact of concomitant CIS on recurrence-free survival and cancer-specific survival following radical nephroureterectomy for upper tract urothelial carcinoma (UTUC). Materials and methods: A multi-institutional retrospective cohort of 1,387 patients undergoing radical nephroureterectomy was identified. Concomitant CIS was defined as the presence of CIS in association with another pathologic stage; patients with CIS alone were excluded from the analysis. The presence of concomitant CIS served as the exposure variable with disease recurrence and cancer-specific mortality as the outcomes. Organ-confined disease was defined as AJCC/UICC stage II or lower. Results: Concomitant CIS was identified in 371 of 1,387 (26.7%) patients and was significantly more common in patients with a previous bladder cancer history, high grade, and high stage tumors. In a multivariable analysis, concomitant CIS was a predictor of disease recurrence (HR = 1.25, P = 0.04) and cancer specific mortality (HR = 1.34, P = 0.05) for patients with organ-confined UTUC, but not in the entire cohort. Other prognostic variables, such as grade, stage, lymphovascular invasion, and lymph node status, were associated with poorer overall and recurrence-free survival for all patients. Conclusion: The presence of concomitant CIS in patients with organ-confined UTUC is associated with a higher risk of recurrent disease and cancer-specific mortality. This information may be useful in refining surveillance protocols and in more appropriate selection of patients for adjuvant chemotherapy. (C) 2012 Elsevier Inc. All rights reserved.

International audience; OBJECTIVES: To study the prognostic impact of muscularis mucosae (MM) invasion for pT1 bladder cancer treated by transurethral resection (TUR) and adjuvant Bacille Calmette-Guerin (BCG) intravesical immunotherapy. METHODS: Sixty-six patients treated by BCG intravesical instillations were substaged into pT1a and pT1b, regarding Muscularis Mucosae invasion. Tumor grade, associated carcinoma in situ (CIS), multifocality, tumoral size up to 3cm, BCG maintenance were noted. With a mean follow-up of 50.5±38 months, we studied recurrence, progression, overall and specific survival. Cox's model method was used for multivariate analysis. RESULTS: Tumor recurrence was observed in 30±7% and 43±10% (P=0.29) and tumor progression in 16.3±5% and 39±10% (P=0.04) for pT1a and pT1b. The rate of progression was higher (P=0.04) and progression free survival was decreased (P=0.04) for pT1b. Specific death rates were 11±5% and 21±9% (P=0.28), median overall survival was 80.9 [1.5-92] and 48.2 [12-93] months for pT1a and pT1b. Overall and specific survival weren't different between the two populations (P=0.38; P=0.3). Cystectomy rates were 2.3±2% and 30±9% for pT1a and PT1b (P=0.0006). For pT1a patients, recurrence (P=0.8) or progression rates (P=0.64) were no different regarding BCG maintenance immunotherapy but pT1b population had a better progression free survival with BCG maintenance than without (P=0.0051). Only CIS had prognostic value in multivariate analysis. CONCLUSIONS: Tumors with Muscularis Mucosae invasion have a higher risk of progression and BCG failure. Maintenance immunotherapy should be given to improve results with these patients.

International audience; Organ preservation protocols that incorporate chemoradiotherapy have shown good efficacy in bladder cancer. Owing to changes in rectal filling, urinary inflow and subsequent bladder volume with bladder wall deformations, irradiation must take into account interfractional and intrafractional internal target motion. Growing evidence suggests that image guidance during irradiation is essential in order to appropriately treat bladder cancer in this way. We performed a literature search on the imaging techniques and margins used for radiation therapy planning in the context of whole-bladder and partial-bladder irradiation. The most common image-guided radiation therapy (IGRT) method was based on cone-beam CT using anisotropic margins. The role of cine-MRI for the prediction of intraindividual bladder changes, in association with cone-beam CT or ultrasonography, is promising. Drinking protocols, diet and laxatives were used in most cases to minimize large variations in bladder size and shape. IGRT is crucial for avoiding tumor undercoverage and undue toxicity during radiation therapy for bladder cancer. IGRT-based adaptive radiation therapy can be performed using cone-beam CT or ultrasonography: modeling of bladder changes with cine-MRI or other imaging techniques might also be useful for facilitating adaptive radiation therapy with personalized margins.

International audience; BACKGROUND: Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Using RT4 (derived from a well differentiated grade I papillary tumor) and T24 (derived from an undifferentiated grade III carcinoma) bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21(waf1/CIP1) and p27(Kip1) in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism. CONCLUSIONS/SIGNIFICANCE: Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.

International audience; Several epidemiological studies suggested an association between the risk of bladder cancer and the exposure to trihalomethanes (THMs), the main disinfection by-products (DBPs) of chlorinated water. A previous pooled analysis of case-control studies from North America and Europe estimated a summarized dose-response relation. For policy guidance of drinking water disinfection in Europe and because major differences exist in water disinfection practices and DBPs occurrence between both continents, specific risk estimates for bladder cancer in relation to DBPs exposure for European populations were needed. We conducted a pooled and a two-stage random-effect meta-analyses of three European case-control studies from France, Finland, and Spain (5467 individuals: 2381 cases and 3086 controls). Individual exposure to THMs was calculated combining information on residential history, estimates of the average total THMs (TTHM) level in tap water at the successive residences and personal water consumption. A significant odds-ratio was observed for men exposed to an average residential TTHM level > 50 μg/l (OR = 1.47 (1.05; 2.05)) when compared to men exposed to levels ≤ 5 μg/l. The linear trend of the exposure-risk association was significant (p = 0.01). Risks increased significantly for exposure levels above 25 μg/l and with more than 30 years of exposure to chlorinated water, but were mainly driven by the level rather than the duration of exposure. No significant association was found among women or with cumulative exposure through ingestion. There was no evidence of a differential exposure-response relation for TTHM and bladder cancer in Europe and North America. Consequently, a global exposure-risk relation based on 4351 cases and 7055 controls is now available.

International audience; PURPOSE: To assess the postsurgical survival of patients with urothelial carcinoma of the bladder with pT0 tumor at pathologic examination of cystectomy specimens. METHODS: A multi-institutional, retrospective database was analyzed with data from 4758 radical cystectomy (RC) patients who underwent RC without neoadjuvant chemotherapy and who were diagnosed with pT0 on the basis of the pathologic specimen. Survival curves were estimated. A multivariate Cox model was used to evaluate the association between prognosis factors and disease recurrence or survival. RESULTS: Overall, 258 patients (5.4%) were included in the study. The median age was 64 years. At last resection, 171 tumors were invasive (at least pT2), and 87 were not. Median follow-up was 51 months. At multivariate analysis, initial location of the tumor and absence of lymphadenectomy were associated with tumor recurrence (P = 0.03 and P = 0.005, respectively) and specific mortality (P = 0.005 and 0.001, respectively). The main limitation of the study is its retrospective design, which is due to the rarity of this situation. Cancer-specific and recurrence-free survival rates were 89 and 85%, respectively, at 5 years and 82 and 80%, respectively, at 10 years. CONCLUSIONS: Despite acceptable oncological outcomes, patients with a pT0 tumor at the time of RC are still at risk of recurrence and progression and should not be considered to be entirely cured. In this population, stringent follow-up according to current recommendations should be effective.

International audience; Folates are the common sources of DNA synthesis and methylation. Cigarette smoking and genetic susceptibility of folate enzymes are two suspected factors most closely associated with bladder cancer development. This study sought to determine the effect of smoking and genetic polymorphisms in folate metabolizing enzymes on the histological stage and grade of bladder tumors in Tunisian patients. A total of 130 patients with urothelial cell carcinomas were examined with respect to smoking status, MTHFR (5,10-methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase) and TYMS (thymidylate synthase) genotypes distribution. Our data have reported that tobacco, MTHFR, MTR and MTRR genotypes were not associated with bladder tumor stage. Only TYMS 3R*G/3R*C genotype was associated with increased risk of developing invasive tumors compared to reference group (RR = 1.74; 95% CI: 0.97-3.12). When we studied the superficial bladder tumor group, we have shown a significant statistical differences for the TYMS 3R*G/2R genotype. This genotype presented a 1.68-fold increased risk of developing high grade tumors compared to reference group (RR = 1.68; 95% CI: 1.12-2.54). Moreover, we have shown that patients having at least one copy of 2R allele were at 4.23-fold increased risk for developing high grade tumors compared to reference group (P = 0.022).

Background XPC is involved in the nucleotide excision repair of DNA damaged by carcinogens known to cause bladder cancer. Individuals homozygous for the variant allele of XPC c.1496C > T (p.Ala499Val) were shown in a large pooled analysis to have an increased bladder cancer risk, and we found two 3'UTR variants, *611T > A and c.*618A > G, to be in strong linkage disequilibrium with c.1496T. Here we determined if these two 3'UTR variants can affect mRNA stability and assessed the impact of all three variants on mRNA and protein expression. Methods In vitro mRNA stability assays were performed and mRNA and protein expression measured both in plasmid-based assays and in lymphocytes and lymphoblastoid cell lines from bladder and breast cancer patients. Results The two 3'UTR variants were associated with reduced protein and mRNA expression in plasmid-based assays, suggesting an effect on mRNA stability and/or transcription/translation. A near-significant reduction in XPC protein expression (p = 0.058) was detected in lymphoblastoid cell lines homozygous for these alleles but no differences in mRNA stability in these lines was found or in mRNA or protein levels in lymphocytes heterozygous for these alleles. Conclusion The two 3'UTR variants may be the variants underlying the association of c.1496C > T and bladder cancer risk acting via a mechanism modulating protein expression.

International audience; PURPOSE: We evaluated the outcome of repeat transurethral bladder tumor resection for high risk nonmuscle invasive bladder cancer before induction and maintenance bacillus Calmette-Guerin. MATERIALS AND METHODS: Included in the study were 151 consecutive patients with a mean age of 68.6 years (range 32 to 86) with primary high grade, nonmuscle invasive (Ta, T1 or CIS) bladder cancer. All patients underwent repeat transurethral bladder tumor resection and were shown by repeat resection to be tumor-free or have residual tumor before bacillus Calmette-Guerin. The bacillus Calmette-Guerin response was evaluated by disease recurrence and progression. RESULTS: A total of 70 tumor-free patients and 47 with residual tumor received bacillus Calmette-Guerin induction and maintenance therapy after repeat transurethral bladder tumor resection, of whom 84 (71.8%) were disease-free during followup. In the tumor-free group 11.4% of tumors recurred compared with 27.7% in the residual tumor group (p

International audience

International audience; The present investigation was conducted first to determine whether correlation exists between VEGF-A and -B mRNA levels and clinicopathological parameters and to assess their prognostic value in bladder cancer, then to clarify the expression level and biological significance of VEGF-A isoforms. Total RNA was isolated from 37 specimens of bladder cancer. Northern blot analysis revealed that VEGF-B mRNA was not expressed either in normal urothelium or in bladder cancer and detected three VEGF-A transcripts of 5.2, 4.5 and 1.7 kb in length, respectively. The VEGF-A transcript levels were greater in cancer tissues than in normal urothelium. They were significantly higher in pT2-T4 than in pTa and pT1 urothelial tumors and thus, were correlated to the pathologic stage. Contrary to the 4.5 kb transcript, elevated expression of the 5.2 and 1.7 kb transcripts was correlated with the histologic grade and the presence of carcinoma in situ. Patients with higher VEGF-A mRNA levels had a significantly shorter survival without progression compared to those with lower levels. Three VEGF-A splice variants were detected by southern blotting namely, VEGF121, 165 and 189. The expression intensity of each isoform was evaluated by quantitative real-time RT-PCR in 20 new fresh frozen recent tumors. VEGF121 and VEGF165 were expressed at the similar level. On the contrary, they were significantly more expressed than VEGF189 (p

International audience; Superficial pT1 bladder tumors are characterized by a high risk of recurrence and progression in grade and stage. Few studies provided evidence that loss of adipocyte-fatty acid binding protein (A-FABP) expression was associated with bladder cancer progression. A-FABP is a lipid binding protein playing a role in intracellular lipid transport and metabolism, as well as in signal transduction. We reported from bladder tumors that decrease of A-FABP transcript level significantly correlated to tumor stage and to histologic grade (p < 0.05). Namely, in poor prognosis high grade pT1 tumors there was a loss of A-FABP expression compared to good prognosis tumors suggesting that re-expression of A-FABP could be a therapeutic approach in early stage bladder cancer to prevent disease progression. We demonstrated for the first time that this marker is upregulated by Peroxisome Proliferator-Activated Receptor (PPAR) alpha, beta and gamma in T24 cells (derived from an undifferentiated grade III carcinoma) and only by PPARbeta in RT4 cells (derived from a well differentiated grade I papillary tumor). This effect occurred through a PPAR-dependent transcriptional mechanism without modifying mRNA stability and interestingly required de novo protein synthesis. Data as a whole suggest a prognostic significance of A-FABP in bladder cancer outcome and the potential utility of overexpression of this protein by PPAR agonists open up new perspectives in the treatment of bladder cancer. (c) 2008 Wiley-Liss, Inc.

International audience; We present experiments involving cancer cells adhering to microchannels, subjected to increasing shear stresses (0.1-30 Pa). Morphological studies were carried out at different shear stresses. Cells exhibit spreading patterns similar to those observed under static conditions, as long as the shear stress is not too high. At critical wall shear stresses (around 2-5 Pa), cell-substrate contact area decreases until detachment at the larger stresses. Critical shear stresses are found to be lower for higher confinements (i.e. smaller cell height to channel height ratio). Fluorescent techniques were used to locate focal adhesions (typically 1 lm(2) in size) under various shearing conditions, showing that cells increase the number of focal contacts in the region facing the flow. To analyze such data, we propose a model to determine the critical stress, resulting from the competition between hydrodynamic forces and the adhesive cell resistance. With this model, typical adhesive stresses exerted at each focal contact can be determined and are in agreement with previous works.

International audience; OBJECTIVES: Twist is considered as transcription factor that regulates epithelial mesenchymal transition (EMT) by at least inhibition of E-cadherin expression. EMT is a key event in the tumor invasion process. The purpose of this study is to investigate the expression of Twist but also those of E- and N-cadherin in human primary bladder tumor and to evaluate its prognostic value. As smoking cigarettes is a strong bladder cancer risk factor, we tried to evaluate the impact of the tobacco status on these molecular abnormalities. MATERIALS AND METHODS: To delineate on the oncogenic role for Twist in human bladder cancer, we evaluated the E- and N-cadherin but also Twist expression (n = 70) by immunohistochemistry. We evaluated the prognostic value of these expressions. Moreover, we tried to correlate these protein expressions to the smoking status of the patients. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. RESULTS: Of the 70 bladder tumors, 28 (40%) cases were positive for Twist expression, 16 (23%) cases were negative for E-cadherin expression, and 12 (17%) were positive for N-cadherin expression. When categorized into negative vs. positive expression, Twist was associated with the stage (P = 0.001), the grade (P < 0.001), the progression (P = 0.02), and the E-cadherin expression (P = 0.01). Moreover, positive Twist expression clearly predicted poorer PFS (P = 0.02). In the multivariate analysis, both positive Twist expression and loss of E-cadherin expression were independent prognostic factors for PFS (P = 0.046 and P = 0.001, respectively) and only loss of E-cadherin expression for the OS (P < 0.001). We also demonstrated that almost 60% (16/28) of patients with Twist-positive expression were current smokers at the time of the diagnosis, corroborating the fact that smoking modulates the expression of EMT markers including Twist. CONCLUSION: Positive Twist expression may be a useful prognostic marker for patients with bladder cancer. Its expression seems to be correlated to the tobacco status of the patients.

International audience; PURPOSE OF REVIEW: An estimated 300,000 new cases of bladder cancer worldwide are diagnosed annually. Although new cytotoxic chemotherapeutic agents for either advanced or metastatic bladder cancer or both are used, no improvement in survival has been observed. Indeed, the 5-year survival rate of metastatic bladder cancer is very low (6%). The target-directed approach is an attractive challenge for treating specific genetic alterations involved in progression and metastasis development. This article aims to describe the new targeted therapies available to cure advanced cancer or metastatic bladder cancer or both according to the signalling pathways potentially involved. RECENT FINDINGS: The rapidly expanding understanding of the pathogenesis of bladder cancer at the molecular level has led to the identification of signalling pathways involved in this disease and provided molecular targets for new biological agents directed against tumorigenesis and progression. The recent results of clinical trials have not only highlighted the need to select patients who could benefit from such a therapy but also the fact that oncology has completely entered into a new era. SUMMARY: Toxic chemotherapeutic agents are slowly being supplemented by a new generation of drugs that recognize specific targets in or on cancer cells. Recent technological advances in pharmacogenomics and proteomics have led to an improvement in identifying biomarkers predictive of response and thereby to identify patients who would be more likely to respond to such a therapy. There is a real hope to improve both the efficiency and the tolerability of bladder cancer treatment.

International audience; Cancer is a complex disease characterized by a multitude of molecular and genetic abnormalities affecting cell proliferation and differentiation, apoptosis, and mobility (invasion). Each of these alterations represents a potential target for the development of targeted therapy. These new therapies inhibit cell growth and are said to be "cytostatic" in contrast with conventional "cytotoxic" chemotherapy. As a result of a better understanding of the molecular biology of bladder cancers, various signalling pathways involved in both carcinogenesis and tumour progression have been defined, and some of the key molecules in these pathways have been isolated and can be used as prognostic markers and as potential therapeutic targets. Locally advanced, and/or metastatic bladder cancer, is characterized by mutations of the p53 and retinoblastoma (Rb) genes, regulators of the cell cycle, which interact with the Ras-mitogen activated protein kinase (MPAK) transduction pathway. Overexpression of tyrosine kinase receptors, including EGFR, VEFGR and HER2/neu, is correlated with tumour progression and activation of the phosphatidyl-inositol-3 kinase (PI-3K) pathway is involved in tumour invasion and inhibition of apoptosis. Due to their molecular heterogeneity, optimal targeted therapy of bladder cancers will require the combined use of several molecules. Modulation of signalling pathways by these new molecules can restore chemosensitivity to cytotoxic drugs, which can then be associated with targeted therapy.

International audience; "Superficial bladder tumours" term is progressively abandoned in the urological community because of its ambiguity leading possibly to harmful confusions. The French Oncologic Society proposes to designate by non-infiltrating bladder neoplasm by the muscle Ta, T1 and Tis tumours.

Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is higher than in the general population. We previously reported that CD4 lymphocytopenia is associated with a high incidence of skin cancer in RTR. Here, we investigate whether persistent CD4 T cell lymphopenia is associated with GUT occurrence. Patients and Methods: A total of 433 patients were included in this study. All patients underwent annually systematic lymphocyte subset (CD3, CD4, CD8, CD19) determination by flow cytometry. Results and Conclusion: During the follow-up period, 13 patients developed GUT: 6 patients a prostate adenocarcinoma (incidence 0.06%/year) and 7 patients a renal cell carcinoma (incidence 0.07%/year). The patients with GUT were older than those without. Both groups did not differ in posttransplant duration, dialysis mode and duration, induction regimen, or acute rejection history. No persistent CD4 lymphopenia was observed in the patients with GUT. Although CD4 T cell lymphopenia is associated with skin cancer in long-term RTR, it did not appear to be a risk factor for GUT. This suggests that other factors encountered in the setting of kidney transplantation (e.g., immunosuppressive drugs, end-stage renal failure, etc.) favor the development of GUT in RTR.

International audience; Local Bacillus Calmette-Guerin (BCG) immunotherapy is an effective and widely used treatment for superficial bladder carcinoma. Local side effects are frequent, whereas systemic side effects are rare, but more serious. We report four cases of systemic BCG reaction. Although uncommon, this infectious complication of BCG therapy should always be considered in the appropriate clinical setting. The best approach to minimize this complication is a strict compliance with precautions and a close and rigorous surveillance of this drug.; L'efficacité anti-tumorale de la BCG-thérapie endovésicale dans le traitement de la tumeur superficielle de la vessie est actuellement bien établie. Néanmoins, les réactions systémiques au BCG demeurent l'effet secondaire le plus redoutable. L'apparition de quatre cas de réaction systémique au BCG dont trois survenus en 2003 nous a incité à ré-étudier les signes cliniques et biologiques de cette complication ainsi que les facteurs favorisant son apparition. La difficulté de manier la BCG-thérapie endovésicale et la gravité de ses complications impose le respect scrupuleux des bonnes pratiques de conduite du traitement et des recommandations en vigueur afin de limiter la survenue des réactions systémiques au BCG. Celles-ci doivent être dépister le plus précocement possible afin d'éviter les conséquences qui peuvent être redoutables.

International audience; Carcinoma progression is associated with the loss of epithelial features, and the acquisition of mesenchymal characteristics and invasive properties by tumour cells. The loss of cell-cell contacts may be the first step of the epithelium mesenchyme transition (EMT) and involves the functional inactivation of the cell-cell adhesion molecule E-cadherin. Repression of E-cadherin expression by the transcription factor Snail is a central event during the loss of epithelial phenotype. Akt kinase activation is frequent in human carcinomas, and Akt regulates various cellular mechanisms including EMT. Here, we show that Snail activation and consequent repression of E-cadherin may depend on AKT-mediated nuclear factor-kappaB (NF-kappaB) activation, and that NF-kappaB induces Snail expression. Expression of the NF-kappaB subunit p65 is sufficient for EMT induction, validating this signalling module during EMT. NF-kappaB pathway activation is associated with tumour progression and metastasis of several human tumour types; E-cadherin acts as a metastasis suppressor protein. Thus, this signalling and transcriptional network linking AKT, NF-kappaB, Snail and E-cadherin during EMT is a potential target for antimetastatic therapeutics.

International audience; The impact of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism on bladder cancer is unknown. We found no clear correlations between the FGFR4 genotype and risk of bladder cancer or pathological parameters. Neither the polymorphism nor TP53 mutation status was an independent predictor of prognosis, but they might act jointly on the disease-specific survival of patients.

Purpose: Loss of intercellular adhesion and increased cell motility promote tumor cell invasion and spreading. In bladder cancer, loss or reduced E-cadherin expression has been associated with poor survival, and aberrant expression of N-cadherin has been associated with the invasive phenotype of bladder carcinoma cells. The purpose of this study was to investigate whether N-cadherin expression was associated with the bladder tumor progression. Experimental Design: E-cadherin and N-cadherin expression was evaluated by immunohistochemistry in 101 tumors (pT1 and pT2-T3) and by reverse transcription-PCR analysis and immunohistochemistry in 28 other fresh frozen tumors (pTa, pT1, and pT2-T3). Results: N-cadherin expression was absent in normal urothelium, appeared in stage pT1, and increased in pT2-pT3 tumors. In most cases, increased N-cadherin expression in invasive tumors was associated with loss of E-cadherin expression. Progression-free survival and multivariate analyses revealed that N-cadherin expression is an independent prognostic marker for pT1 tumor progression. Analysis of the 28 frozen tumors by immunohistochemistry and reverse transcription-PCR showed a good correlation between protein and gene expression in pT1 and pT2-T3 tumors. Interestingly, in pTa tumors, N-cadherin was not immunodetected, whereas mRNA was present in 50% of cases. Conclusion: Regulatory defects in the N-cadherin promoter, abnormalities at the translational, or protein processing levels could explain the discrepancies between protein and mRNA expression. Most importantly, this study identified N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors. Clearly, N-cadherin acts in an invasive mode in bladder cancer, but whether it has a primary role in urothelial neoplastic progression has yet to be investigated.

We pooled the data from 6 case-control studies of bladder cancer with detailed information on fluid intake and water pollutants, particularly trihalomethanes (THM), and evaluated the bladder cancer risk associated with total and specific fluid consumption. The analysis included 2,729 cases and 5,150 controls. Odds ratios (OR) and 95% confidence intervals (CI) for fluid consumption were adjusted for age, gender, study, smoking status, occupation and education. Total fluid intake was associated with an increased risk of bladder cancer in men. The adjusted OR for 1 l/day increase in intake was 1.08, (95% CI 1.03-1.14, p-value for linear trend0.001), while no trend was observed in women (OR=1.04, 0.94-1.15; p-value=0.7). OR was 1.33 (1.12-1.58) for men in the highest category of intake (3.5 l/day) as compared to those in the lowest (or=2 l/day). An increased risk was associated with intake of tap water. OR for2 l/day vs.or=0.5 l/day was 1.46 (1.20-1.78), with a higher risk among men (OR=1.50, 1.21-1.88). No increased risk was observed for the same intake groups of nontap water in men (OR=0.97, 0.77-1.22) or in women (OR=0.85, 0.50-1.42). Increased bladder cancer risks were observed for an intake of5 cups of coffee daily vs.5 and for THM exposure, but neither exposure confounded or modified the OR for tap water intake. The association of bladder cancer with tap water consumption, but not with nontap water fluids, suggests that carcinogenic chemicals in tap water may explain the increased risk.

International audience

International audience; Loss of intercellular adhesion facilitates tumor invasion. To clarify the relation between altered expression of cell adhesion molecules and progression of T1 superficial bladder tumors, 101 cases (71 T1 tumors, 30 T2/T3 tumors) were examined immunohistochemically for E-cadherin and alpha-, beta-, and gamma-catenins. A highly significant correlation was observed between the decreased expression of all molecules and increased TNM stage (P < .001). Univariate analysis, performed in cases of T1 tumors, revealed association of abnormal E-cadherin with beta-catenin diminution. Survival curves were established with the Kaplan-Meier method and analyzed according to clinical and histopathologic parameters using the log-rank test. Cox multivariate analysis revealed only gamma-catenin as an independent predictor of progression-free survival in patients with stage T1 bladder urothelial tumors. The characterization of T1 tumors that will progress could lead to the identification of patients who might benefit from surgery to avoid vesical muscle invasion and, consequently, metastasis.

International audience; OBJECTIVE: A recent study suggested that risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes. We pooled primary data from 14 case-control studies of bladder cancer from Europe and North America and evaluated differences in risk of smoking by gender. METHODS: The pooled analysis included 8316 cases (21% women) and 17,406 controls (28% women) aged 30-79 years. Odds ratios (ORs) and 95% confidence intervals (95% CI) for smoking were adjusted for age and study. Exposure-response was evaluated in a stratified analysis by gender and by generalized additive models. RESULTS: The odds ratios for current smokers compared to nonsmokers were 3.9 (95% CI 3.5-4.3) for males and 3.6 (3.1-4.1) for females. In 11 out of 14 studies, ORs were slightly higher in men. ORs for current smoking were similar for men (OR = 3.4) and women (OR = 3.7) in North America, while in Europe men (OR = 5.3) had higher ORs than women (OR = 3.9). ORs increased with duration and intensity in both genders and the exposure-response patterns were remarkably similar between genders. CONCLUSION: These results do not support the hypothesis that women have a higher relative risk of smoking-related bladder cancer than men.

International audience; Transcriptome microarrays have become one of the tools of choice for investigating the genes involved in tumorigenesis and tumor progression, as well as finding new biomarkers and gene expression signatures for the diagnosis and prognosis of cancer. Here, we describe a new database for Integrated Tumor Transcriptome Array and Clinical data Analysis (ITTACA). ITTACA centralizes public datasets containing both gene expression and clinical data. ITTACA currently focuses on the types of cancer that are of particular interest to research teams at Institut Curie: breast carcinoma, bladder carcinoma and uveal melanoma. A web interface allows users to carry out different class comparison analyses, including the comparison of expression distribution profiles, tests for differential expression and patient survival analyses. ITTACA is complementary to other databases, such as GEO and SMD, because it offers a better integration of clinical data and different functionalities. It also offers more options for class comparison analyses when compared with similar projects such as Oncomine. For example, users can define their own patient groups according to clinical data or gene expression levels. This added flexibility and the user-friendly web interface makes ITTACA especially useful for comparing personal results with the results in the existing literature. ITTACA is accessible online at http://bioinfo.curie.fr/ittaca.

International audience; OBJECTIVE: Investigating whether extracellular factors are possible actors in tumoral progression in bladder carcinoma. METHODS: RT112/G2 bladder tumour cells were grown in presence of TGFbeta and analysed by immunological and cDNA microarray techniques. RESULTS: TGFbeta inhibited cell proliferation, reduced TNFalpha- and IFNgamma-induced apoptosis by decreasing TNFalpha-RI and IFNgamma-R antigen expression. It also inhibited cleaved caspase 8 and 9 expression, decreased E-cadherin, and increased BclxL and cyclooxygenase-2 expression. The cDNA microarray approach showed that TGFbeta up-regulated the expression of genes with defined roles in tumoral progression sometimes associated with poor outcome in bladder cancer. CONCLUSION: These results suggest that a part of the bladder tumoral progression process may be related to the action of exogenous TGFbeta confirming the possible role for the microenvironment.