Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer

International audienceBackgroundNon-muscle-invasive bladder cancer (NMIBC) is a high incidence form of bladder cancer (BCa), where genetic and epigenetic alterations occur frequently. We assessed the performance of associating a FGFR3 mutation assay and a DNA methylation analysis to improve bladder cancer detection and to predict disease recurrence of NMIBC patients.MethodsWe used allele specific PCR to determine the FGFR3 mutation status for R248C, S249C, G372C, and Y375C. We preselected 18 candidate genes reported in the literature as being hypermethylated in cancer and measured their methylation levels by quantitative multiplex-methylation specific PCR. We selected HS3ST2, SLIT2 and SEPTIN9 as the most discriminative between control and NMIBC patients and we assayed these markers on urine DNA from a diagnostic study consisting of 167 NMIBC and 105 controls and a follow-up study consisting of 158 NMIBC at diagnosis time’s and 425 at follow-up time. ROC analysis was performed to evaluate the diagnostic accuracy of each assay alone and in combination.ResultsFor Diagnosis: Using a logistic regression analysis with a model consisting of the 3 markers’ methylation values, FGFR3 status, age and known smoker status at the diagnosis time we obtained sensitivity/specificity of 97.6 %/84.8 % and an optimism-corrected AUC of 0.96. With an estimated BCa prevalence of 12.1 % in a hematuria cohort, this corresponds to a negative predictive value (NPV) of 99.6 %. For Follow-up: Using a logistic regression with FGFR3 mutation and the CMI at two time points (beginning of the follow-up and current time point), we got sensitivity/specificity/NPV of 90.3 %/65.1 %/97.0 % and a corrected AUC of 0.84. We also tested a thresholding algorithm with FGFR3 mutation and the two time points as described above, obtaining sensitivity/specificity/NPV values of, respectively, 94.5 %/75.9 %/98.5 % and an AUC of 0.82.ConclusionsWe showed that combined analysis of FGFR3 mutation and DNA methylation markers on urine can be a useful strategy in diagnosis, surveillance and for risk stratification of patients with NMIBC. These results provide the basis for a highly accurate noninvasive test for population screening and allowing to decrease the frequency of cystoscopy, an important feature for both patient quality of life improvement and care cost reduction

Determination of Angptl4 mRNA as a Diagnostic Marker of Primary and Metastatic Clear Cell Renal-Cell Carcinoma

International audienceBACKGROUND: We have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors. METHODOLOGY/PRINCIPAL FINDINGS: Using in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status. CONCLUSIONS/SIGNIFICANCE: Angptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10(-49), Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction

Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of salvage radiotherapy (RT) for persistent or rising PSA after radical prostatectomy and to determine prognostic factors identifying patients who may benefit from salvage RT.</p> <p>Methods</p> <p>Between 1990 and 2003, 59 patients underwent RT for PSA recurrence after radical prostatectomy. Patients received a median of 66 Gy to the prostate bed with 3D or 2D RT. The main end point was biochemical failure after salvage RT, defined as an increase of the serum PSA value >0.2 ng/ml confirmed by a second elevation.</p> <p>Results</p> <p>Median follow-up was 38 months. The 3-year and 5-year bDFS rates were 56.1% and 41.2% respectively. According to multivariate analysis, only preRT PSA ≥1 ng/ml was associated with biochemical relapse.</p> <p>Conclusion</p> <p>When delivered early, RT is an effective treatment after radical prostatectomy. Only preRT PSA ≥1 ng/ml predicted relapse.</p

Facteurs pronostiques des tumeurs urothéliales superficielles de la vessie (intérêt du génotype tumoral FGFR3/P53)

Objectifs : Evaluer l'intérêt de déterminer le génotype tumoral par l'étude simultanée des mutations inactivant la protéines p53 et des mutations activatrices du récepteur FGFR3 afin de classer les tumeurs superficielles de la vessie (TSV) et surtout d'apprécier leur pronostic. Matériels et Méthodes : Les données cliniques, histologiques de 89 tumeurs inaugurales ont été revues : âge, sexe, ethnie, tabagisme, révélation, taille, unique ou multiple, localisation, stade TNM, grade histologique, groupe pronostique (AFU), récidive, délai à la 1ère récidive, nombre et fréquence des récidives, progression et délai. Le génotype tumoral FGFR3/TP53 a été évaluer de façon prospective. Résultats : Le tabagisme et les mutations de p53 étaient des facteurs significatifs de récidive tumorale. Analyse de la récidive en fonction du génotype tumoral : l'existence d'une mutation P53 était le facteur le plus important de récidive (HR, 4,02 ; p=0,0068) devant le génotype FGFR3mt/P53wt (HR, 2,10 ; p=0,046). Conclusion : Les mutations de FGFR3 sont préférentiellement retrouvées en cas de tumeurs de faible stade et de faible grade, et leur fréquence diminue alors que le stade et le grade augmentent. Les mutations p53 et FGFR3 sont mutuellement exclusives réaffirmant l'existence de deux voies alternatives dans la carcinogenèse vésicale. Les tumeurs ayant une protéine p53 non fonctionnelle ont une survie sans récidive plus courte. Le génotype FGFR3mt/p53wt est un facteur de récidive tumorale mais semble associé à des tumeurs à faible potentiel de progressionPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Le curage ganglionnaire pelvien étendu dans les cancers de prostate à haut risque (intérêts, limites et perspectives actuelles)

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

ENTERO-CYSTOPLASTIE D'AGRANDISSEMENT POUR VESSIE NEUROLOGIQUE CHEZ LES PATIENTS PORTEURS D'ANOMALIES MEDULLAIRES CONGENITALES

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Tumeur urothéliale de vessie chez le patient " fragile ". [Management of bladder cancer in unfit patients.]

International audienceAdjuvant therapies in bladder cancer are based on risk of recurrence and associated comorbidities (renal failure). Lymph node involvement is the most important prognostic factor for decision. Two adjuvant chemotherapies exist: MVAC or GC. In unfit patients, association (Gemcitabine and Taxanes) could be proposed. Indication of adjuvant radiotherapy depends on metastatic risk and resection margins. Concomitant chemotherapy and radiotherapy should be proposed to selected patients who refuse or are not candidate for radical cystectomy

Primary adenocarcinoma of the seminal vesicle

Primary adenocarcinoma of the seminal vesicle is a rare condition with only about 60 cases described in the literature. The unusual characteristics of this disease makes diagnosis difficult and treatment strategies differ as there are no specific guidelines available. This report presents a case of adenocarcinoma of the seminal vesicle with lung metastases in which surgical and chemotherapeutic treatments have been carried out. The MVAC dose dense regimen following local resection seems effective in this scenario and may be used in the treatment of this disease