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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; 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.

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; 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.

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.

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; 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; 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; 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; 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.

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; 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.