A Novel Epigenetic Phenotype Associated With the Most Aggressive Pathway of Bladder Tumor Progression

International audienceBackground: Epigenetic silencing can extend to whole chromosomal regions in cancer. There have been few genome-wide studies exploring its involvement in tumorigenesis.Methods: We searched for chromosomal regions affected by epigenetic silencing in cancer by using Affymetrix microarrays and real-time quantitative polymerase chain reaction to analyze RNA from 57 bladder tumors compared with normal urothelium. Epigenetic silencing was verified by gene re-expression following treatment of bladder cell lines with 5-aza-deoxycytidine, a DNA demethylating agent, and trichostatin A, a histone deacetylase inhibitor. DNA methylation was studied by bisulfite sequencing and histone methylation and acetylation by chromatin immunoprecipitation. Clustering was used to distinguish tumors with multiple regional epigenetic silencing (MRES) from those without and to analyze the association of this phenotype with histopathologic and molecular types of bladder cancer. The results were confirmed with a second panel of 40 tumor samples and extended in vitro with seven bladder cancer cell lines. All statistical tests were two-sided.Results: We identified seven chromosomal regions of contiguous genes that were silenced by an epigenetic mechanism. Epigenetic silencing was not associated with DNA methylation but was associated with histone H3K9 and H3K27 methylation and histone H3K9 hypoacetylation. All seven regions were concordantly silenced in a subgroup of 26 tumors, defining an MRES phenotype. MRES tumors exhibited a carcinoma in situ-associated gene expression signature (25 of 26 MRES tumors vs 0 of 31 non-MRES tumors, P < 10⁻¹⁴), rarely carried FGFR3 mutations (one of 26 vs 22 of 31 non-MRES tumors, P < 10⁻¹⁶), and contained 25 of 33 (76%) of the muscle-invasive tumors. Cell lines derived from aggressive bladder tumors presented epigenetic silencing of the same regions.Conclusions: We have identified an MRES phenotype characterized by the concomitant epigenetic silencing of several chromosomal regions, which, in bladder cancer, is specifically associated with the carcinoma in situ gene expression signature

Evaluation de l'intérêt diagnostique de l'héxaminolevulinate (Hexvix) dans les tumeurs non infiltrantes de la vessie dans une série monocentrique

Evaluer l impact du diagnostic photodynamique sur les patients présentant des tumeurs de vessie urothéliales non infiltrantes, et de préciser le profil des tumeurs ciblées par l hexaminolevulinate (Hexvix ).Entre juin 2007 et décembre 2010, 44 patients (Groupe A) ont présenté au moins une tumeur ou lésion vésicale de novo visible en cystoscopie standard, pour laquelle une résection sous Hexvix a été réalisée. Sur cette même période, 40 patients (Groupe B) avec des tumeurs à haut risque après une première résection Hexvix ont bénéficié d une résection de second look avec l aide du diagnostic photodynamique.Chez 13 patients du groupe A, des tumeurs complémentaires de vessie ont pu être diagnostiquées avec l aide du diagnostic photodynamique, mais uniquement 1 seul patient s est vu trouver une tumeur de risque de recidive ou de progression supérieure à celle obtenue en cystoscopie conventionnelle. Dans le groupe B, l utilisation de l Hexvix a permis à 14 patients de bénéficier de diagnostic complémentaire de tumeur de la vessie. 7 d entre eux, sans tumeur apparente en lumière blanche, avaient en lumiere bleue, des tumeurs de haut risque de recidive et progression. Le taux de faux positif Hexvix était de 57,58% contre 0% en lumière blanche. Quelque soit le groupe observé, le tumeur majoritairement retrouvée par le diagnostic photodynamique est à plus de 50% du carcinome in situ. Le diagnostic photodynamique entraine une résection plus complète en augmentant le taux de détection des tumeurs de la vessie chez plus de 25% des patients. L Hexvix , à son intérêt dans la mise en evidence des lésions de type CIS.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Analysis of complications from 600 retroperitoneoscopic procedures of the upper urinary tract during the last 10 years.

International audienceINTRODUCTION: The aim of this study is to review 10 years experience of retroperitoneoscopy procedures. METHODS: A total of 600 patients treated between 1995 and 2007 by retroperitoneoscopy (nephrectomy, partial and total nephrectomy, adrenalectomy, pyeloplasty, renal cyst, calyceal diverticulectomy) were reviewed for per, peri and postoperative complications including patients in the learning curve. RESULTS: The mean blood loss was 159 mL. Conversion to open surgery was required in 28 patients (4.6%) primarily due to technical problems during dissection (elective). There were 32 (5.3%) surgical complications, including bleeding or hematomas in 12 cases and 2 of them required reintervention, urinomas in 8 which were treated by installation of a ureteral drainage (JJ stent). Wound or deep abscesses happened in four, urinary fistula in one and pancreatic fistula in another. Evisceration (hernias) was seen in three patients. Intestinal injury occurred in two. The complication rate depended on the difficulty of the procedure and learning curve of the surgeon. A total of 28 patients (4.6%) presented medical postoperative complications (hyperthermias, deep venous thrombosis, pyelonephritis, pulmonary superinfections, pulmonary atelectasia and transient vascular ischemic accident). Mean postoperative hospital stay was 6.2 days (ranged from 2 to 20). CONCLUSION: Retroperitoneoscopy can be the technique of choice for accessing and carrying out all the surgery of the upper urinary tract respecting the principles of oncological surgery. After experience with 600 cases during the last 10 years the technique has become safe, simplified, reproducible and effective although not easy. Most complications are minor and easily managed

Robot-assisted extraperitoneal laparoscopic radical prostatectomy: experience in a high-volume laparoscopy reference centre.

International audienceOBJECTIVE: To describe our current procedure of robot-assisted laparoscopic radical prostatectomy (RALP), and to assess the effect of the learning curve on perioperative data, early oncological outcomes and functional results, as RALP has increasingly become a treatment option for men with localized prostate cancer. PATIENTS AND METHODS: In all, 206 consecutive men had a RALP between July 2001 and November 2008 for localized prostate cancer. Among the overall cohort, the 175 men operated on by the same surgeon were distributed into five groups according to the chronological order of the procedures. The mean follow-up after RALP was 18.3 months. Patient demographics, surgical data and postoperative variables were collected into a prospective database. Data were compared by chronological groups into single-surgeon cohort. RESULTS: The median operative time and blood loss were 140 min and 350 mL, respectively. The complication rate was 8.3%. Cancers were pT3-4 in 34.5%. The mean hospital stay and duration of bladder catheterization were 4.3 and 8.2 days, respectively. The rate of positive surgical margins (PSMs) was 17.2% in pT2 cancers. The recovery rate of continence was 98% at 12 months. Intraoperative time, blood loss and length of hospital stay were significantly improved after a short learning curve. The continence recovery, the rate and the length of PSM were also improved beyond the learning curve, but difference was not statistically significant. CONCLUSIONS: RALP is a safe and reproducible procedure and offers a short learning curve for experienced laparoscopic surgeons. Beyond the learning curve, continued experience might also provide further improvements in terms of operative, pathological and functional results

Predictive factors for final pathologic ureteral sections on 700 radical cystectomy specimens: Implications for intraoperative frozen section decision-making

International audiencePurpose: To identify preoperative predictive factors for final ureteral section invasion after radical cystectomy (RC) and to validate significant factors on an external independent cohort. Material and methods: We retrospectively reviewed data of all consecutive RC performed for bladder cancer in 2 high-volume institutions. Clinical, pathological, and follow-up data were collected prospectively and reviewed retrospectively. Pathological evaluation was performed by 2 well-trained uropathologists in each center. Logistic regression analyses were performed to identify predictive factors for final ureteral sections involvement. Significant factors in cohort A were validated in cohort B. Receiver operating curve and area under curve were modeled to evaluate predictive accuracy of the markers. Results: A total of 441 RC were performed in center A and 307 RC were performed in center B. Mean follow-ups were 36.2 and 38.1 months, respectively. Invasion of the final ureteral section was observed on 5.5% of patients in cohort A and 4.8% of patients in cohort B. In cohort A, multivariable logistic regression identified preoperative hydronephrosis on computed tomography scan (odds ratio [OR] = 4.9, P = 0.004) and presence of Carcinoma in situ (CIS, OR = 3.9, P = 0.01) as the only factors associated with ureteral sections positivity. In cohort B, hydronephrosis and CIS were both associated with ureteral sections positivity in univariable analysis. In multivariable analysis, only hydronephrosis remained significant (OR = 5.9, P = 0.01). Predictive accuracy of hydronephrosis and CIS combined in 1 variable was 0.72. Conclusion: Hydronephrosis and bladder CIS have good accuracy in predicting ureteral sections positivity after RC. In the presence of those factors, ureteral frozen sections should be performed. (C) 2017 Elsevier Inc. All rights reserved

Pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance--does the risk of misclassification vary according to biopsy criteria?

International audiencePURPOSE: We compared the pathological findings and prostate specific antigen outcome after radical prostatectomy in men eligible for active surveillance according to 3 biopsy inclusion criteria. MATERIALS AND METHODS: The study population included 177 men eligible for active surveillance who fulfilled clinicobiological criteria and biopsy criteria as group 1-less than 3 positive cores and less than 3 mm total tumor length, group 2-less than 3 positive cores with cancer involvement of less than 50% in any core and group 3-less than 33% of positive cores. Prostate specific antigen density cutoffs were also studied in these groups. Pathological findings on radical prostatectomy specimens and biochemical recurrence-free survival were studied. Median followup after radical prostatectomy was 34 months. RESULTS: A majority of Gleason score 6 disease was observed in group 1 (51.7%) whereas a majority of Gleason score 7 or greater disease was reported in groups 2 (53.6%) and 3 (55.4%). Extracapsular extension was noted in 17.5% of radical prostatectomy specimens in group 3 vs 11.2% in group 1 (p = 0.175). The risk of overall unfavorable disease (defined as pT3-4 stage and/or Gleason score 8 or greater) was significantly higher in men with cancer involvement of 3 mm or greater on initial biopsy (27.3% vs 13.5%, respectively, p = 0.023). The 3-year biochemical recurrence-free survival rate was 94.0% and was not affected by the 3 active surveillance definitions. CONCLUSIONS: Even with the use of a 21-core biopsy protocol the rate of unfavorable disease in radical prostatectomy specimens remains increased in men eligible for active surveillance. Patients must be informed of this risk of misclassification which ranges from 20% to 28% in men who fulfill the less stringent biopsy criteria

Pathological findings and prostate-specific antigen outcomes after laparoscopic radical prostatectomy for high-risk prostate cancer.

International audienceSTUDY TYPE: Therapy (case series) Level of Evidence 4. OBJECTIVE: To review the biochemical recurrence-free survival (RFS) rates of laparoscopic radical prostatectomy (LRP) in patients with a high risk of disease progression as defined by preoperative criteria of D'Amico et al. PATIENTS AND METHODS: Between October 2000 and May 2008, 110 patients had extraperitoneal LRP and bilateral pelvic lymph node sampling for high-risk prostate cancer in our department. High-risk prostate cancer was defined as a prostate-specific antigen (PSA) level of >20 ng/mL, and/or a biopsy Gleason score >or=8, and/or a clinical stage of T2c-T4 stage. The median follow-up was 37.6 months. Risk factors for time to biochemical recurrence were tested using log-rank survivorship analysis and Cox proportional hazards regression. RESULTS: Prostate cancer was organ-confined in 36% of patients; the Overall RFS was 79.4% and 69.8% at 1 and 3 years, respectively. The 3-year RFS rates for organ-confined cancer vs extracapsular extension were 100% and 54.3%, respectively (P < 0.001). The 3-year RFS rates for tumour-free seminal vesicle vs seminal vesicle invasion were 81.8% and 33.6%, respectively (P < 0.001). The 3-year RFS rates for negative surgical margins vs positive were 85.2% and 47.3%, respectively (P = 0.001). Compared with men with any single pathological risk factor or any two risk factors, men with all three risk factors had a significantly shorter time to PSA failure after LRP (log-rank test, P < 0.001). CONCLUSION: Among patients at increased risk of disease progression as defined by preoperative criteria, a third of men with organ-confined disease have a favourable prognosis. Men at high risk for early PSA failure could be better identified by pathological assessment of RP specimens, and selected for phase III randomized trials investigating adjuvant systemic treatment