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International audience; Objective: To assess PD-L1 expression in tumor (TC) and tumor infiltrating immune cells (IC) as a predictive factor of BCG therapy failure in high-risk NMIBC.Materials and methods: Patients treated with complete resection followed by bladder BCG instillation for high-risk NMIBC were included. Early recurrence (ER) was defined as tumor recurrence after BCG induction course. The association between ER and immuno-histochemistry PD-L1 (E1L3N clone) expression by tumors cells (TC) and tumor infiltrating immune cells (IC) was investigated using an exact Fisher test variant.Results: A total of 186 patients were included, of whom 38 (20.4%) were ER, 35 (18.8%) were positive for TC PD-L1 expression and 60 (32.3%) were positive for IC PD-L1. ER was not significantly (p = 0.97) more frequent in the TC PD-L1 ≥ 1% group (n = 7, 20.0%) than in the TC PD-L1-negative group (n = 31, 20.5%). Patients with IC PD-L1 negative had ER in 15 (19.2%) cases and patients with IC PD-L1 ≥ 1% had ER in 23 (21.3%) cases. PD-L1-positive expression for IC (threshold > 1%) was correlated with immune infiltrate density (95.2% dense immune infiltrate vs 47.2% low immune infiltrate, p < 0.05), with increased expression of PD-L1 by IC after BCG therapy (p = 0.006).Conclusion: No association was observed between immuno-histochemistry PD-L1 positivity and ER after BCG therapy. Nevertheless, the relationship between immune infiltrate and PD-L1 positivity confirmed the interest of assessing the immune infiltrate density to define tumor's profile.

Background The current pathological tumour-node-metastasis (pTNM) classification for upper tract urothelial carcinoma (UTUC) does not include any risk stratification of pT3 renal pelvicalyceal tumours. Objective To assess the prognostic impact of pT3 subclassification in a multicentre cohort of patients with UTUC of the renal pelvicalyceal system undergoing radical nephroureterectomy (RNU). Design, setting, and participants Data from all consecutive patients treated with RNU for pT3 renal pelvicalyceal UTUC at 14 French centres from 1995 to 2013 were reviewed retrospectively. Intervention A central pathology review (CPR) was used to stratify pT3 patients into those with infiltration of the renal parenchyma on a microscopic level (pT3a) versus those with infiltration of the renal parenchyma visible on gross inspection of the resection specimen and/or invasion of peripelvic fat (pT3b). Outcome measurements and statistical analysis Inverse probability weighting (IPW)-adjusted Cox regression analyses were used to compare recurrence-free survival (RFS) and cancer-specific survival (CSS) between pT3a and pT3b patients. Results and limitations Overall, 202 patients were included and further stratified into pT3a (n = 98; 48.5%) and pT3b (n = 104; 51.5%) subgroups. Median time to follow-up in the weighted population was 68 (interquartile range, 50–95) mo. In IPW-adjusted Cox regression analyses, pT3b versus pT3a substage was associated with a significant adverse effect on RFS (hazard ratio [HR] = 2.02; 95% confidence interval [CI] = [1.36–3.01]; p Conclusions Using IPW-adjusted analyses after the CPR, we observed that RNU patients with pT3b renal pelvicalyceal UTUC had adverse prognosis as compared with those with pT3a disease. As such, this subclassification could help refine the current pTNM system for UTUC. Patient summary In this report, we looked at the prognostic interest of stratifying patients with pT3 renal pelvicalyceal upper tract urothelial carcinoma based on the extent of local invasion. We found that those with extensive infiltration (pT3b) had adverse prognosis as compared with those with limited infiltration (pT3a). This information could be provided on pathology reports to further guide clinical decision making.

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes., Adrenal aldosterone production is regulated by plasma angiotensin and potassium levels. Here the authors report that the neuropeptide substance P stimulates aldosterone production via neurokinin type 1 receptors (NK1R), and report a proof-of-concept placebo controlled clinical trial showing that a NK1R antagonist decreases aldosterone levels.

Context In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. Objective To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Methods Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. Results TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Conclusion Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.

International audience

Objective Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients. Design and methods Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test. Results 26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance. Conclusion The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

International audience; OBJECTIVES:To compare the diagnostic performance of computed tomography, magnetic resonance imaging and contrast enhanced ultrasonography for the assessment of complex renal cysts.METHODS:We carried out a prospective single-center study from January 2012 to December 2013. We included patients with Bosniak category 2F or 3 renal cysts found on computed tomography and reviewed by two expert radiologists. Magnetic resonance imaging and contrast-enhanced ultrasonography were then carried out. Patients with a Bosniak ≥3 cyst on magnetic resonance imaging, as well as those upgraded as appearing malignant on contrast-enhanced ultrasonography, were surgically managed. Imaging results were compared with histological data. For patients without surgery, imaging examinations were compared with follow-up data. For each imaging examination, diagnostic performance and Cohen's kappa coefficient were assessed.RESULTS:A total of 47 patients were included. The median follow up was 36 months (range 17-48 months). At initial computed tomography, cysts were classified as Bosniak 2F and Bosniak ≥3 in 34 and 13 patients, respectively. Magnetic resonance imaging found 13 Bosniak ≥3 cysts, and contrast-enhanced ultrasonography upgraded six more patients with cysts that appeared malignant. A total of 19 patients had surgery. Histological analysis reported 14 malignant tumors. No tumor progression was found in followed-up patients. Computed tomography showed poor sensitivity (36%) and specificity (76%; κ = 0.11). Magnetic resonance imaging showed 71% sensitivity and 91% specificity (κ = 0.64). Contrast-enhanced ultrasonography showed high sensitivity (100%) and specificity (97%), and a negative predictive value at 100% (κ = 0.95).CONCLUSIONS:The present results suggested that contrast-enhanced ultrasonography could be useful in improving the assessment of complex renal cysts. Indeed, computed tomography accuracy might be limited in this indication requiring further investigations to determine the best treatment strategy.

Resume Introduction L’objectif de cette etude retrospective etait d’evaluer l’interet de la fluorescence vesicale lors du controle endoscopique et histologique systematique d’un traitement d’attaque par instillations vesicales de BCG dans la prise en charge d’une TVNIM. Patients et methodes Cinquante-quatre patients ont ete inclus avec l’histologie suivante : Ta (15 cas), T1 (27 cas), carcinome in situ (CIS) isole (12 cas) ou associe (14 cas). Les cytologies urinaires etaient de haut grade et un second look endoscopique etait systematique lorsqu’il existait une infiltration du chorion. Un traitement d’attaque de six instillations endovesicales de BCG (dose 81 mg) a ete propose, suivi d’une evaluation du bas appareil urinaire (endoscopique et histologique) au troisieme mois apres la resection trans-uretrale de vessie (RTUV) initiale utilisant la fluorescence par hexylaminolevulinate (Hexvix ® 85 mg). Resultats Les cytologies urinaires etaient negatives dans 27 cas, suspectes dans 12 cas et positives dans 15 cas. En endoscopie standard avec lumiere blanche, la muqueuse vesicale etait normale dans 32 cas, mais 8 lesions tumorales etaient visualisees en fluorescence confirmees par l’histologie (existence de CIS residuel). Lorsque l’aspect de la muqueuse vesicale etait suspect en lumiere blanche (22 patients), la fluorescence etait positive dans 16 cas avec une concordance des resultats histologiques (existence de CIS et/ou lesion tumorale residuelle) dans 10 cas. Au total, meme si le taux de faux-positif etait important lorsqu’il persistait une inflammation de la muqueuse vesicale (38 %), l’utilisation de la fluorescence vesicale a permis le diagnostic de lesions non detectees en lumiere blanche pour lesquelles les cytologies urinaires etaient non contributives. Conclusion L’utilisation de la fluorescence par Hexvix ® , lors de l’evaluation endoscopique et histologique systematique a trois mois apres traitement d’attaque par BCG, a permis dans notre etude la detection du carcinome in situ residuel, cependant, ces donnees preliminaires meritent d’etre confirmees par une etude multicentrique avec une cohorte plus importante de patients. Niveau de preuve 5.

Predictive factors of T1 nonmuscle invasive bladder cancer evolution that could guide treatment decision making are lacking. We assessed the prognostic value of muscularis mucosa invasion in nonmuscle invasive bladder cancer.In a national multicenter study patients with primary T1 nonmuscle invasive bladder cancer were recruited from 6 French hospitals. All patients had undergone transurethral resection of bladder tumor. All T1 tumors were substaged according to muscularis mucosa invasion as T1a-no invasion beyond the muscularis mucosa or T1b-invasion beyond the muscularis mucosa with muscle preservation. Subsequent central pathology review was then done by a single referent uropathologist. Muscularis mucosa invasion was tested as a prognostic factor for survival on univariate and multivariate analysis.A total of 587 patients were enrolled in the study, including 388 (66%) with T1a and 199 (34%) with T1b tumors. Median followup after transurethral resection of bladder tumor was 35 months (IQR 14-54). There was no significant difference between groups T1a and T1b except high tumor grade in T1b cases (p0.0001). After central review, initial pathological substaging was confirmed in 84% of cases. On multivariate analysis muscularis mucosa invasion (T1b substage) was significantly associated with recurrence-free (p = 0.03), progression-free (p = 0.0002) and cancer specific (p = 0.02) survival. The main study limitation was absent systematic subsequent transurethral resection of bladder tumor.Muscularis mucosa invasion appears to be highly predictive of T1 nonmuscle invasive bladder cancer behavior. Consequently, systematic T1a vs T1b discrimination should be highly advocated by urologists and pathologists. We believe that it could aid in crucial decision making when choosing between conservative management and radical cystectomy remains a moot point.

Resume Introduction Deux voies majeures existent dans la cancerogenese vesicale : l’une pour les tumeurs infiltrantes ou de haut grade caracterisee par l’alteration du gene suppresseur de tumeur p53 et l’autre pour les tumeurs non infiltrantes ou de bas grade impliquant des mutations du gene FGFR3 . L’objectif de notre etude etait de valider la recherche dans les urines des mutations de ces deux genes pour des patients ayant une tumeur de vesicale. Patients et methodes Dans notre etude preliminaire, nous avons recherche chez 36 patients les mutations de p53 et FGFR3 dans les tumeurs et les urines prelevees lors de la resection endoscopique. Les mutations de p53 ont ete recherchees en FASAY, qui permet une analyse fonctionnelle de la proteine P53. Les mutations de FGFR3 ont ete recherchees en SNaPshot, qui recherche les huit mutations ponctuelles les plus frequentes de ce gene. Resultats Pour 24 patients (66 % des cas), il existait au moins l’une des deux mutations dans la tumeur. Cette mutation existait dans les urines chez 15 patients (sensibilite = 62,5 %). Chez seulement un patient, il y avait une mutation dans le culot urinaire qui n’existait pas dans la tumeur (specificite = 91,7 %). Conclusion La recherche des mutations de p53 et FGFR3 dans les urines a ete un test simple, non invasif, qui etait dans notre etude superieur aux cytologies urinaires pour la detection des tumeurs de vessie laissant esperer un interet de ce bio-assay pour la surveillance des tumeurs de vessie et le depistage des populations a risque.

The Weiss score is the reference method to distinguish between a benign and a malignant adrenocortical tumor (ACT). A program was initiated to improve the reproducibility of the pathologic diagnosis of ACTs in France through the National INCa-COMETE Network. Twelve pathologists from all Reference Centers of the Network analyzed 50 selected ACTs using a web-based virtual microscopy approach in a blind design, allowing to determine the intraobserver and interobserver reproducibilities of the Weiss system. All ACTs were read twice in random order before and after a coaching meeting organized to harmonize and improve analyses and create an online tutorial. The validity of the virtual approach was first established by comparing the 2 consensuses (virtual and microscopic) obtained for each tumor by 3 pathologists who performed the 2 approaches in a blinded manner. For the "dichotomized Weiss score" (separating malignant ≥3 from benign ≤2 tumors) interobserver reproducibility was "substantial" at the first "virtual" reading (κ = 0.70) and increased at the second "virtual" reading (κ = 0.75). In parallel, 7 of the 9 items of the Weiss system showed improvement. The diagnostic accuracy of the observers as a group, using the modal group score approach, showed an improved sensitivity from 86% to 95% for the diagnosis of malignant ACTs. We show the validity of the virtual microscopy approach and that the program improved the practice of the Weiss system reading and therefore the diagnosis of ACT. This tool can now be extended for other research and/or routine purposes in this rare cancer.

Bronchogenic cysts are benign lesions, which are usually described at the chest level. We present here a case report of a retroperitoneal bronchogenic cyst. A 77-year-old man presented with a left retroperitoneal tumor discovered by scanner. There was no endocrine disruption. Excision of the lesion was performed and final diagnosis was a bronchogenic cyst. Current widespread use of modern radiology enables increased discovery of such "incidentalomes". In the future, pathologists will be routinely faced with this type of diagnosis, which up to now has been described as exceptional.

Objectifs Le traitement des TVNIM repose sur les instillations endovesicales de BCG. En pratique, 45 % des patients sont en echec de traitement et une alternative therapeutique doit etre proposee. L’immunotherapie par anticorps anti-PD-1 et PD-L1 a demontre son efficacite dans le carcinome urothelial metastatique. L’objectif de cette etude etait d’evaluer l’impact pronostic de l’expression anti-PD L1 dans les TVNIM refractaires au BCG. Methodes Cent trente patients (18 femmes, 112 hommes) presentant une TVNIM a haut risque ayant recu un traitement d’attaque par instillations de BCG de 2000 a 2015 ont ete inclus retrospectivement. Deux groupes : bon repondeur (BR) au BCG ( n = 102) et mauvais repondeur (MR) au BCG ( n = 28) defini par une recidive tumorale precoce apres 6 instillations d’attaque. Pour chaque patient la premiere lame de resection et la lame de controle apres BCG en cas de recidive tumorale ont ete marquees par un Ac mono-clonal : anti PD L1 E1L3 N (Cell Signaling Technology), puis classees selon l’intensite de marquage des cellules tumorales (TC) et des cellules inflammatoires du stroma (IC). Resultats La positivite etait fixee par un seuil de marquage >ou egal a 1 %. avec comparaison des groupes par test exact de Fisher. La positivite de PD-L1 sur les TC et les IC a ete observee respectivement chez 25 (19,2 %) et 82 (63 %) patients. Le taux de MR etait de 21,9 % avec taux TC = 0, de 20 % avec taux TC ≥ 1 (OR = 0,89, p = 1). Le taux de MR etait de 16,7 % avec taux IC = 0, de 24,3 % avec taux IC ≥ 1 (OR = 1,60, p = 0,37). Le marquage immunohistochimique des TC demeurait stable entre tumeur initiale et lame apres BCG, tandis que celui des IC etait variable : 14 patients sur 28 (50 %) ayant gagne 1 ou 2 points de marquage. Le test de Wilcoxon sur series appariees montrait une hausse significative de l’intensite IC ( p = 0,021). Conclusion Dans cette etude preliminaire, il n’a pas ete retrouve de lien statistique entre l’expression de l’anticorps anti-PD-L1 des cellules tumorales, l’infiltrat inflammatoire de la lame initiale et l’echec de reponse au traitement par BCG. Une cohorte plus importante de patients semble necessaire pour valider un eventuel facteur pronostic anatomoclinique.

Resume Objectif Evaluer l’efficacite du traitement de la cystite interstitielle par instillation intravesicale de hyaluronate de sodium. Patientes et methodes De mars 2008 a aout 2009, une etude prospective, en intention de traiter, a inclus 31 patientes. Les patientes repondaient a la definition de la cystite interstitielle etablie par l’ICS en 2002, le bilan comportait un examen des urines, une cystoscopie, un test d’hydrodistension et des biopsies vesicales. Les patientes ont recu six instillations hebdomadaires de 40 mg (50 ml) de hyaluronate de sodium en intravesical. Nous avons evalue l’efficacite et la tolerance du traitement par deux questionnaires specifiques de la cystite interstitielle remplis avant et apres six semaines de traitement : l’O’Leary-Sant et le pelvic pain and urgency/frequency (PUF). Resultats Quatre groupes ont ete definis : bonne reponse, reponse partielle, faible reponse, absence de reponse au traitement. Ils etaient composes respectivement de 14 patientes (45 %), deux (7 %), sept (22 %) et huit patientes (26 %). Nous avons obtenu 52 % de reponse positive (bonne reponse et reponse partielle) apres six semaines de traitement. Les patients dont la cystoscopie et l’histologie etaient anormales avaient un taux de reponse de 60 %. Aucun effet secondaire grave n’a ete observe. Conclusion Le hyaluronate de sodium a sa place dans l’arsenal therapeutique de la cystite interstitielle avec une efficacite comparable aux autres traitements et une bonne tolerance. Le taux de reponse au traitement aurait pu etre ameliore par une meilleure selection des patientes notamment celles dont la cystoscopie comportant un test d’hydrodistension et l’histologie etaient anormales.

Objectifs Le BCG est le traitement de reference des TVNIM a haut risque. Recemment, l’immunotherapie par anticorps anti-PD-L1 dans les TVIM a apporte des resultats prometteurs, meme si l’expression de PD-L1 en immunohistochimie reste controversee. L’objectif de notre etude etait d’evaluer la place de PD-L1 en tant que marqueur predictif dans les TVNIM a haut risque recidivant precocement apres instillations endo-vesicales de BCG. Methodes Notre etude bicentrique retrospective a inclus 186 patients presentant une TVNIM a haut risque survenue de novo de 2000 a 2015, traites par 6 instillations de BCG, puis classes en deux groupes : bons repondeurs (n = 148) et mauvais repondeurs (n = 38), definis comme presentant une recidive tumorale precoce apres traitement d’attaque. Le lien entre recidive tumorale et expression de PD-L1 en IHC par les cellules tumorales et les cellules inflammatoires du stroma a ete etudie, via une variante du test exact de fisher. Le lien entre expression de PD-L1 et infiltrat inflammatoire ainsi que l’evolution de son expression entre tumeurs initiales et recidives ont ete etudies. Resultats Pour un seuil de positivite de PD-L1 pour les cellules tumorales (TC) > 1 %, 20,5 % des patients MR etaient PD-L1 negatifs contre 20 % PD-L1 positifs (p = 0,97). Les resultats etaient similaires pour les cellules inflammatoires du stroma (IC) aux seuils 1 et 5 %. La positivite de PD-L1 par les IC (seuil > 1 %) etait correlee a la densite de l’infiltrat inflammatoire peri-tumoral (95,2 % infiltrat dense vs 47,2 % infiltrat faible, p1 %) etait correlee au stade tumoral initial, le stade pt1 marquant le plus l’anticorps (CIS vs pt1, p = 0,023). Conclusion Nous n’avons pas pu mettre en evidence de lien entre positivite de PD-L1 et recidive tumorale precoce. Le lien entre infiltrat inflammatoire et positivite de PD-L1 nous permet d’asseoir l’interet d’associer l’evaluation de la densite de l’infiltrat inflammatoire. L’intensification de l’expression de PD-L1 apres BCG therapie conforte la place des traitements combines BCG/anticorps anti-PD-L1 dans les TVNIM refractaires au BCG.

ResumeObjectifs L’objectif de cette etude multicentrique etait d’etudier l’influence de la profondeur d’infiltration tumorale du chorion et plus particulierement du franchissement de la muscularis mucosae sur les differents parametres de survie des tumeurs urotheliales de vessie T1. Patients Nous avons inclus les patients issus de six centres ayant eu une premiere tumeur de vessie T1 entre 1994 et 2004 et subdivise ces tumeurs en T1a lorsque la tumeur ne depassait pas la muscularis mucosae et T1b lorsqu’elle la depassait. Sur les 387 patients inclus, 269 (69,5 %) ont ete classes T1a et 118 (30,5 %) T1b. Le suivi moyen a ete de 45,4 mois. Les deux groupes etaient comparables a l’exception du grade tumoral, plus eleve dans le groupe T1b (p

Resume But L’objectif de ce travail etait d’evaluer l’incidence du carcinome prostatique chez des patients traites par BCG-therapie endovesicale pour tumeur vesicale superficielle ayant une prostatite granulomateuse (PG). Les auteurs discutent les problemes d’interpretation du taux de PSA total et les indications potentielles de biopsies prostatiques dans cette population. Materiel et methodes Nous avons realise une etude retrospective de janvier 1997 a decembre 2006 des differents cas de prostatite granulomateuse symptomatique recenses parmi les patients traites par instillations endovesicales de BCG. Au total, 153 hommes ont ete traites pour une tumeur superficielle de vessie de haut risque ou de risque intermediaire selon les recommandations usuelles. La souche de BCG attenuee Connaught a ete utilisee a la dose de 81 mg. Le schema retenu des instillations etant un traitement d’induction consistant en six instillations hebdomadaires, puis traitement d’entretien sur une periode de trois ans. Resultats Six patients ont eu une prostatite granulomateuse symptomatique (4 % des cas). Cette complication survenait en moyenne vers la dixieme instillation endovesicale (6–13) du traitement d’entretien. La valeur moyenne du PSA total a trois mois etait de 8 ng/ml (5–11,6). Devant la persistance d’un taux de PSA eleve, l’indication de biopsies echoguidees a ete retenue confirmant l’atteinte granulomateuse tuberculoide de la prostate dans tous les cas et faisant decouvrir pour deux patients un adenocarcinome prostatique. Conclusion Apres BCG endovesicale, en cas de prostatite granulomateuse clinique et une persistance d’un taux de PSA eleve trois mois apres les instillations, la recherche d’un carcinome prostatique par la realisation de biopsies echoguidees doit rester systematique.

To assess the potential predictive value of natural resistance-associated macrophage protein 1 (NRAMP1) and human glutathione peroxidase 1 (hGPX1) polymorphism in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG) instillation, we conducted an original ancillary multicenter study.We evaluated patients included in the multicenter URO-BCG 4 trial, who received three weekly instillations of one-third dose BCG every 6 months (group I) or two weekly instillations every 3 months (group II) for 3 years. For clinical evaluation we also evaluated tumor recurrence and muscle progression. NRAMP1 and hGPX1 polymorphism analyses were performed on blood DNA. NRAMP1 exon 15 and hGPX1 exon 1c were amplified using Type-it Microsatellite PCR Kit® for multiplex polymerase chain reaction.From June 2004 to April 2010, 146 randomized patients were included in this retrospective study. Blood samples were obtained from 107 patients. With 36 months of follow-up, 13.6% of patients had a tumor recurrence and muscle-invasive progression was observed in 4.3% of patients. Concerning NRAMP1 D543N polymorphism, patients with allele A had no tumor recurrence or muscle-invasive progression. No significant difference was observed in gene polymorphism distribution between groups I and II. Moreover, we did not observe any significant association of gene polymorphisms, tumor recurrence or muscle-invasive progression, event time and disease-free survival.Our results suggest that no significant difference was found for NRAMP1 and hGPX1 gene polymorphisms associated with recurrence time, muscle invasion frequency and disease-free survival, nevertheless, we observed that the NRAMP1 D543N GG genotype group had a shorter time to tumor recurrence.

International audience; RésuméCO-021Implication de la sérotonine dans la physiopathologie de l’adénome de ConnC. Duparc*a (Dr), J. Wilsb (Dr), F. Gobetc (Dr), T. Meatchid (Dr), MC. Zennaroe (Dr), E. Louisetf (Dr), H. Lefebvreg (Pr)a INSERM, U982, Université de Rouen, Mont-Saint-Aignan, FRANCE ; b INSERM, U982, Université de Rouen, CHU de Rouen, Mont-Saint-Aignan, FRANCE ; c Service d'Anatomo-pathologie, CHU de Rouen, Mont-Saint-Aignan, FRANCE ; d Service d'Anatomo-pathologie, Hôpital Européen georges Pompidou, APHP, Paris, FRANCE ; e INSERM, U970; PARCC; Hôpital Européen georges Pompidou, APHP, Paris, FRANCE ; f INSERM, U982, Université de Rouen,, Mont-Saint-Aignan, FRANCE ; g INSERM, U982, Université de Rouen; Service d'Endocrinologie, CHU de Rouen, Rouen, FRANCE* celine.duparc@univ-rouen.frDans la surrénale humaine normale, la sérotonine (5-HT) produite localement par les mastocytes stimule la sécrétion d’aldostérone via l’activation de récepteurs 5-HT4 (5-HT4R). Cet effet a été confirmé in vivo, l’administration de cisapride (agoniste 5-HT4R) à des volontaires sains augmentant les taux plasmatiques d’aldostérone. Le cisapride stimule également la sécrétion d’aldostérone chez des patients atteints d’hyperaldostéronisme primaire. En outre, des études moléculaires ont révélé que le 5-HT4R est fortement surexprimé dans les adénomes de Conn. Nous avons récemment montré que les adénomes de Conn étaient le siège d’une prolifération mastocytaire. Ces résultats suggèrent que la 5-HT produite par les mastocytes serait impliquée dans la physiopathologie de l’adénome de Conn. Nous avons localisé par immunohistochimie, l’enzyme de synthèse de la sérotonine, la tryptophane hydroxylase (TPH) et le 5-HT4R dans une série d’adénomes de Conn. Nous avons également exploré l’influence de la sérotonine sur la production d’aldostérone par des explants d’adénome de Conn en périfusion. Nos résultats montrent que le 5-HT4R et la TPH sont exprimés de façon hétérogène dans les adénomes de Conn. La TPH n’est pas limitée aux mastocytes mais est également présente dans des cellules stéroidogènes. L’administration d’un dégranulant mastocytaire, le composé C48/80 à des explants d’adénomes de Conn, entraine la libération d’un pic de 5-HT suivi d’une augmentation de la sécrétion d’aldostérone. L’administration de BIMU-8 (agoniste 5-HT4R) stimule également la production d’aldostérone. Ces effets sont inhibés par l’administration de GR113808, antagoniste 5-HT4R. Nos résultats montrent l’implication de la 5-HT dans la physiopathologie de l’adénome de Conn.L’auteur n’a pas transmis de déclaration de conflit d’intérêt.

To assess, in a prospective clinical research study, a new non-invasive and reliable test to accurately detect tumor protein 53 (TP53) and fibroblast growth factor receptor-3 (FGFR3) mutations in cells in urine.TP53 mutations were analyzed using the functional analysis of separated allele in yeast (FASAY) method, which allows functional analysis of the P53 protein, and FGFR3 mutations were assessed with the SNaPshot system, detecting the eight most frequent point-mutations of this gene. Chi-square test or Fisher's exact test were used to compare TP53 and FGFR3 mutations in the tumors according to tumor stage and grade.TP53 and FGFR3 mutations in bladder tumors increased and decreased respectively with increasing tumor stage and cellular grade (p0.05 and p0.001, respectively). A total of 103 tumor/urinary sediment couples were analyzed. TP53 or FGFR3 mutations were observed in 76 tumors. The sensitivity for the detection of this type of mutation in urine was 46%, the specificity was 81%, the positive predictive value was 94% and the negative predictive value was 37%.Our original data confirmed the feasibility of TP53 and FGFR3 mutation detection in urine sediment. These measurements, together with urine cytology, may increase tumor detection. The sensitivity of the TP53/FGFR3 phenotype test in the urine was less than 50% and was not able to replace standard cystoscopy in the diagnosis of bladder tumors.

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.

International audience; Context: Adrenal mast cells can stimulate aldosterone secretion through the local release of serotonin (5-HT) and activation of the 5-HT4 receptor (5-HT4). In aldosterone-producing adenomas (APAs), 5-HT4 receptor is overexpressed and the administration of 5-HT4 receptor agonists to patients with APA increases plasma aldosterone levels. These data and the well-documented role of mast cells in tumorigenesis suggest that mast cells may be involved in the pathophysiology of APA. Objective: The study aimed at investigating the occurrence of mast cells in a series of APA tissues and to examine the influence of mast cells on aldosterone secretion. Design: The occurrence of mast cells in APAs was investigated by immunohistochemistry. Mast cell densities were compared with clinical data. The influence of mast cells on aldosterone production was studied by using cultures of human mast cell and adrenocortical cell lines. Results: In APA tissues, the density of mast cells was found to be increased in comparison with normal adrenals. Mast cells were primarily observed in adrenal cortex adjacent to adenomas or in the adenomas themselves, distinguishing two groups of APAs. A subset of adenomas was found to contain a high density of intratumoral mast cells, which was correlated with aldosterone synthase expression and in vivo aldosterone secretory parameters. Administration of conditioned medium from cultures of human mast cell lines to human adrenocortical cells induced a significant increase in aldosterone synthase (CYP11B2) mRNA expression and aldosterone production. Conclusion: APA tissues commonly contain numerous mast cells that may influence aldosterone secretion through the local release of regulatory factors.

Resume La gangrene de la verge constitue une complication rare et grave de l’insuffisance renale terminale, entrant dans le cadre de la calciphylaxie systemique. Nous rapportons le cas d’un patient de 58 ans, insuffisant renal et diabetique qui a eu une necrose du gland. L’IRM a permis de preciser les limites de la necrose. Le traitement a consiste en une amputation partielle de la verge. L’examen anatomopathologique a conclu a une calciphylaxie.

International audience; Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.

Angiomyolipoma is generally a benign and noninvasive tumor. We report a case of angiomyolipoma with tumor thrombus from the renal vein into the inferior vena cava suggesting a malignant disease.

Objectifs Le traitement des kystes renaux atypiques (Bosniak IIF et III) repose sur les donnees de l’evaluation radiologique. La tomodensitometrie est largement utilisee dans cette indication. Cependant, il semblerait que l’IRM et l’echographie de contraste (EC) permettent une meilleure discrimination des lesions malignes. L’objectif de notre etude etait de comparer les performances diagnostiques du TDM de l’IRM et de l’EC pour les kystes IIF et III. Methodes Une etude prospective monocentrique a ete realisee de janvier 2012 a decembre 2013. Les patients presentant un kyste Bosniak IIF ou III sur un TDM etaient inclus. Le bilan d’imagerie etait relu et complete par une IRM et une echographie de contraste par le meme radiologue referent. Les resultats de l’imagerie etaient compares aux resultats anatomo-pathologiques pour les patients operes et aux donnees de suivi pour les patients surveilles. Pour chaque examen d’imagerie, la sensibilite et la specificite nous avons calcule le coefficient kappa de Cohen. Resultats Quarante-sept patients ont ete inclus dans l’etude pour un suivi median de 22 mois. Deux patients etaient symptomatiques au diagnostic. L’âge median au diagnostic etait de 64 ans (37–76). Trente-quatre patients avaient un kyste IIF au TDM et 13 un kyste classe III. L’EC retrouvait 14 lesions d’allure maligne et l’IRM 13 lesions ≥ Bosniak 3. Dix-neuf patients ont ete operes, l’analyse histologique a retrouve 14 lesions malignes. Parmi les patients surveilles, aucun n’a presente d’evolutivite du kyste sur les imageries de controle. Le TDM avait de faible sensibilite (36 %) et specificite (76 %) (kappa = 0,11). L’IRM avait une sensibilite de 71 % et une specificite de 91 % (kappa = 0,64). L’EC avait une sensibilite de 100 %, une specificite de 97 %, et une valeur predictive negative de 100 %, (kappa = 0,95). Conclusion Nos resultats suggerent que l’EC serait un examen potentiellement utile pour mieux caracteriser les kystes renaux atypiques en complement du scanner lorsque cela s’avere necessaire pour l’aide au choix therapeutique. L’IRM semblerait egalement etre une alternative interessante, ce d’autant que l’EC demeure un examen operateur dependant et necessite donc un radiologue experimente.

In the present study, we have examined the presence of orexins and their receptors in prostate cancer (CaP) and investigated their effects on the apoptosis of prostate cancer cells.We have localised the orexin type 1 and 2 receptors (OX1R and OX2R) and orexin A (OxA) in CaP sections of various grades and we have quantified tumour cells containing OX1R. Expression of OX1R was evaluated in the androgeno-dependent (AD) LNCaP and the androgeno-independent (AI) DU145 prostate cancer cells submitted or not to a neuroendocrine differentiation. The effects of orexins on the apoptosis and viability of DU145 cells were also investigated.OX1R is strongly expressed in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of OX1R-stained cancer cells increases with the grade of the CaP. In contrast, OX2R is only detected in scattered malignant cells in high grade CaP. OX1R is expressed in the AI DU145 cells but is undetectable in the LNCaP cells. Acquisition of a neuroendocrine phenotype by the DU145 cells is associated with an overexpression of OX1R. Orexins induce the apoptosis of DU145 cells submitted to a neuroendocrine differentiation.The present data indicate that OX1R-driven apoptosis is overexpressed in AI CaP exhibiting a neuroendocrine differentiation opening a gate for novel therapies for these aggressive cancers which are incurable until now.

Bronchogenic cysts are benign lesions, which are usually described at the chest level. We present here a case report of a retroperitoneal bronchogenic cyst. A 77-year-old man presented with a left retroperitoneal tumor discovered by scanner. There was no endocrine disruption. Excision of the lesion was performed and final diagnosis was a bronchogenic cyst. Current widespread use of modern radiology enables increased discovery of such "incidentalomes". In the future, pathologists will be routinely faced with this type of diagnosis, which up to now has been described as exceptional.

Peyronie's disease is relatively frequent and can cause pain and penile induration. Penile soft tissue tumors, however, are exceptional, with fewer than 45 cases reported since 1930. Some clinical and imagery elements could lead to earlier diagnosis through biopsy, enabling more extensive resections and, ultimately, better prognosis.

Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome.The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.Detection of 17alpha-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17alpha-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.

Secondary testicular tumors are rare, we report a case of a solitary testicular metastasis of prostate cancer in 58-year-old man treated using hormonal therapy associated with radiotherapy. Ultrasound is the imaging modality of choice, but metastasis might be difficult to differentiate from primary tumors. The diagnosis confirmed by histologic examination includes routine microscopic and immunohistochemical findings, and therefore systemic treatment was required.

The management of congenital urological malformations is sometimes complex and may require urinary diversion. Cystectomy is usually performed, but sometimes the bladder is left in place due to the presence of a pelvic cloaca and the morbidity related to this type of surgery.The authors report three cases of patients treated by urinary diversion for a congenital malformation without primary resection of the bladderIn the absence of any infectious complications, bladder carcinoma on an excluded native bladder was diagnosed at the age of 3 years, 4 years and 38 years, respectively. Histological examination showed transitional cell carcinoma in two cases and gastrointestinal-type adenocarcinoma of the bladder in 1 case.The risk of secondary development of carcinoma in an excluded bladder during management of (congenital urological malformations is not negligible. Primary cystectomy therefore appears to be preferable. In the presence of a pelvic cloaca making this surgical resection unreasonable, it appears important to exclude the formation of a pyocyst by annual abdominal ultrasound. The authors also recommend cystoscopy and urine cytology with lavage to detect degeneration of the bladder mucosa.

Nested variant urothelial carcinoma is a recently identified variant of urothelial carcinoma which is difficult to diagnose due to its resemblance to other benign bladder lesions, such as hyperplasia of Von Brünn nests. The authors present three clinical cases of this variant of urothelial carcinoma and emphasize the importance of clinical, cytological, histological and immunohistochemical criteria for the diagnosis and the need for early and adapted therapeutic management, as this type of bladder tumour, wrongly considered to be benign up until the early 1990s, is just as invasive as high-grade urothelial carcinoma.

On a routine basis we performed systematic molecular screening for FGFR3 and TP53 mutations in 121 bladder tumors. We then specifically analyzed the predictive value of the recurrence of FGFR3 and TP53 genotypes in superficial lesions.The FGFR3 gene was analyzed by direct sequencing of exons 7, 10 and 15, whereas TP53 status was determined using the p53 functional assay in yeast.We identified a missense FGFR3 mutation in 66% of pTa, 26% of pT1 and 12% of pT2 tumors. Of activating FGFR3 mutations 54% and 85% were found in low G1 and intermediate G2 grade tumors, respectively, but in only 20% of high grade G3 tumors. We detected inactivating TP53 mutations in 10% of pTa, 42% of pT1 and 58% of pT2 tumors. Moreover, TP53 mutations were found only in 23% of grade G1 and 3% of grade G2 tumors but in 44% of high grade G3 tumors. When the 2 genotypes were combined, we observed that 58% of pTa tumors had the (mutant FGFR3, WT TP53) genotype, whereas 58% of invasive lesions harbored the inverse genotype (WT FGFR3, mutant TP53). The (mutant FGFR3, WT TP53) genotype and the (WT FGFR3, mutant TP53) genotype were detected in 23% and 38% of pT1G3 tumors, respectively. In the subgroup of 92 patients with superficial pTa-T1 bladder tumors we did not find that the TP53 or FGFR3 genotype alone or combined had a predictive value for tumor recurrence.Our data again represent solid proof for the pivotal role of FGFR3 and TP53 mutations in superficial and invasive bladder tumors, respectively. However, other molecular markers should be identified for borderline pT1G3 bladder tumors, which are probably at the crossroads of these 2 distinct molecular pathways.

The authors report two clinical cases of cystic nephroma in adults observed in the department over the last 10 years. The nonspecific clinical findings and the poor contribution of imaging examinations make this rare disease difficult to diagnose. Only histological examination can confirm the diagnosis and eliminate multilocular cystic renal carcinoma or necrotic pseudocystic carcinoma. Based on a review of the literature, the authors emphasize recent pathophysiological and immunohistochemical data that could improve the management of this benign disease, in which malignant transformation is also possible.

The authors report a case of fibro-epithelial polyp in a young woman with Turner syndrome with features of a right ureteropelvic junction syndrome in a horseshoe kidney. The patient presented a history of chronic low back pain associated with macroscopic haematuria leading to various complementary investigations including ureteroscopy. The endoscopic appearance of the tumour suggested the diagnosis despite the presence of atypical renal pelvis cytology. Pyeloplasty and proximal ureterectomy allowed confirmation and treatment of this rare lesion.

Solitary fibrous tumours are spindle cell tumours initially described in the pleura, but which can also occur in a large number of other sites. The authors report a case of solitary fibrous tumour involving the kidney and present a brief review of the main sites currently described in the urogenital tract and the most characteristic elements of the diagnosis based on histological and immunohistochemical examination designed to improve their subsequent recognition within the wide range of spindle cell tumours.

Malignant tumours of the renal parenchyma are accompanied by extension to the inferior vena cava in 4% to 10% of cases. The objective of this study was to compare DNA ploidy and proliferation index of renal cell carcinoma (RCC) with renal vein (RV) thrombus and RCC with inferior vena cava (IVC) thrombus and to investigate a correlation between these markers and Fuhrman grade and patient survival.A retrospective study was conducted in 58 patients with RCC and venous thrombus (40 in the RV and 18 in the IVC). Flow cytometry (FCM) and MiBI antibody immunolabelling (Ki-67 index) were performed on the healthy parenchyma, the renal tumour and the venous thrombus. Eighteen tumours with inferior vena cava thrombus were compared to 40 tumours with renal vein thrombus. Fuhrman grade, the presence of capsular rupture, invasion of the perirenal fat, and the presence of sarcomatoid transformation were investigated for a possible correlation with survival.No difference of expression of Ki-67 antigen expression was observed between the two populations of renal tumours with thrombus (RV/IVC), but a significant difference was observed for the two types of thrombus (RV/IVC). A difference in ploidy index was observed was also observed between tumours with RV and IVC thrombus (p0.005). The tumours had less intense MiB1 immunolabelling and a lower DNA ploidy than their corresponding renal vein and inferior vena cava thrombi (Ki-67: 1.07% vs 5.12%, p0.01: DNA index: 1.61 vs 1.87, p0.01). A correlation between Fuhrman grade and tumour DNA index was demonstrated (1.149 for low grade tumours and 1.857 for high grade tumours, p0.05). Sarcomatoid transformation, capsular effraction and capsular rupture were significantly correlated with Fuhrman grade (p0.01) and patient survival (p0.05).The proliferation index is not a prognostic factor, but DNA ploidy appears to be more useful because of its correlation with Fuhrman grade and the level of extension of the thrombus (RV/IVC). The proliferation index and ploidy appear to be involved in the process of carcinogenesis and venous thrombus.

The authors report their experience of four cases of bladder leiomyoma. Although MRI is currently the reference radiological examination, the diagnosis must be confirmed by histological examination. The various diagnostic steps and resulting therapeutic indications are described with a review of the literature.

The aim of the study was to assess the sensitivity and specificity of fluorescence immunocytochemistry (uCyt+ assay) as combined with urinary cytology for detection of primary and recurrent urothelial carcinomas. We analyzed 694 urinary samples from 236 new symptomatic patients and 458 patients followed after transurethral resection (TUR) for bladder tumor. Lesions suspicious for cancer at cystoscopy were sampled by biopsies or TUR. Sensitivity and specificity of tests were calculated using cystoscopy and histopathology, whether or not combined as gold standards. In new symptomatic patients, sensitivity of uCyt+ was 40%, 88.2%, and 76.7%, whereas that of urinary cytology was 30%, 70.6%, and 83.3%, respectively, in G1, G2, and G3 tumors. In follow-up cases, sensitivity of uCyt+ was 61.9%, 66.7%, and 76.9%, whereas that of urinary cytology was 38.1%, 58.3%, and 64.1%, respectively, in G1, G2, and G3 tumors. The combination of uCyt+ and urinary cytology significantly increased mean sensitivity in newly diagnosed cases (86.4% versus 71.2% with urinary cytology only, p < 0.05), as well as in patients followed after TUR (79.3% versus 55.2%, p < 0.001). Specificity of uCyt+ and urinary cytology was identical in new patients (83.3%) and was 81.9% and 86.2%, respectively, in patients followed after TUR. In patients with negative cystoscopy, positive uCyt+ tests had a strong predictive value for tumor recurrence at 1 year (47.0% versus 11.9% in patients with negative assay, p < 0.01). We conclude that combining uCyt+ with urinary cytology improves the detection of urothelial carcinomas as well in patients with symptoms suggesting bladder cancer as in those followed after treatment.