Highly sensitive and specific novel biomarkers for the diagnosis of transitional bladder carcinoma.

Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry-based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer.

Occupational exposure to polycyclic aromatic hydrocarbons influenced neither the frequency nor the spectrum of FGFR3 mutations in bladder urothelial carcinoma.

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) is associated with an increased risk of urothelial carcinoma (UC). FGFR3 is found mutated in about 70% of Ta tumors, which represent the major group at diagnosis. The influence of PAH on FGFR3 mutations and whether it is related to the emergence or shaping of these mutations is not yet known. We investigated the influence of occupational PAH on the frequency and spectrum of FGFR3 mutations. We included on 170 primary urothelial tumors from five hospitals from France. Patients (median age, 64 yr) were interviewed to gather data on occupational exposure to PAH, revealing 104 non- and possibly PAH exposed patients, 66 probably and definitely exposed patients. Tumors were classified as follows: 75 pTa, 52 pT1, and 43 > or =pT2. Tumor grades were as follows: 6 low malignant potential neoplasms (LMPN) and 41 low-grade and 123 high-grade carcinomas. The SnaPshot method was used to screen for the following FGFR3 mutations: R248C, S249C, G372C, Y375C, A393E, K652E, K652Q, K652M, and K652T. Occupational PAH exposure was not associated with a particular stage or grade of tumors. Thirty-nine percent of the tumors harbored FGFR3 mutations. After adjustment for smoking, occupational exposure to PAH did not influence the frequency [OR, 1.10; 95% CI, 0.78-1.52], or spectrum of FGFR3 mutations. Occupational exposure to PAH influenced neither the frequency nor the spectrum of FGFR3 mutations and there was no direct relationship between these mutations and this occupational hazard.

Predicting tumour location in radical prostatectomy specimens: same-patient comparisons of 21-sample versus sextant biopsy.

OBJECTIVE: To determine the value of a 21-sample biopsy protocol in predicting tumour localization in radical prostatectomy (RP) specimens, compared with sextant biopsies. PATIENTS AND METHODS: In all, 300 consecutive patients underwent 21-sample prostate biopsies, followed by RP. The protocol consisted of sextant, three midline, six far lateral and six transitional zone biopsies. Tumour locations on biopsies and RP specimens were compared. The sensitivity, specificity, positive (PPV) and negative predictive value (NPV) and accuracy were calculated. RESULTS: There was no difference between sextant and 21-sample biopsies for sensitivity (38% vs 36%; P=0.50) and specificity (84% vs 87%; P=0.46), but the NPV was higher for 21-sample biopsies (57% vs 68% ; P<0.001). The PPV was higher in the sextant biopsies (74% vs 59%; P=0.007). Sextant, transitional zone and far lateral biopsies were re-grouped in six regions. Compared with 21-sample biopsies, sensitivity (54%) and PPV (79%) were higher (P<0.001), while specificity (74%) and NPV (46%) were lower (P=0.05 and P=0.001, respectively). CONCLUSION: A negative biopsy does not confirm the absence of cancer in the corresponding site in the RP specimen in a sextant or 21-sample biopsy protocol and cannot be used as a prognostic element before RP. A positive biopsy does not always correspond with a tumour in the same zone of the RP specimen. When 21-sample biopsies are re-grouped in to six regions, the value of a positive biopsy increases. A positive biopsy corresponds thus to a tumour in the same region, rather than in precisely the same location. The results of this study could help in the biopsy protocol used for making surgical decisions, e.g. preserving the bladder neck or neurovascular bundles.

Retroperitoneal laparoscopic radical nephrectomy: intermediate oncological results.

OBJECTIVES: To report the intermediate oncological results of laparoscopic radical nephrectomy by retroperitoneal approach. METHODS: From 1995 to 2006, 146 consecutive patients with removal of a malignant kidney tumor by laparoscopic retroperitoneal radical nephrectomy were analysed retrospectively. The patients were followed clinically, biologically and radiologically every 6 months. Disease-free survival and specific survival were determined among patients free of metastasis at surgery. RESULTS: Patient's average age was 61.1 years (25-85). The pathology of these cancers were: 108 clear cell carcinomas, 26 papillary carcinomas, 10 chromophobe carcinomas, and 2 miscellaneous. The T stage were: 105 pT1, 12 pT2, and 29 pT3 (TNM 2002). The Fuhrman grade were: I in 23 cases, II in 70 cases, III in 40 cases, and IV in 9 cases. The surgical margins were positive in 2. No port site recurrence occurred. The average follow-up was 35.4 months (1-137). Five patients had metastatic disease at presentation. Tumor progression was observed among 19 patients, in the form of a local (1) or remote recurrence (18). Fourteen patients died, including 7 because of their tumor. The disease-free survival at 5 and 10 years, were respectively 87.3 and 73.2%, and the cancer-specific survival were 96.2 and 92.0%, respectively. CONCLUSIONS: The laparoscopic retroperitoneal radical nephrectomy offers intermediate oncological results compatible with appropriate carcinological efficacy.

Gefitinib inhibits the growth and invasion of urothelial carcinoma cell lines in which Akt and MAPK activation is dependent on constitutive epidermal growth factor receptor activation.

PURPOSE: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

Simulation training in video-assisted urologic surgery.

The current system of surgical education is facing many challenges in terms of time efficiency, costs, and patient safety. Training using simulation is an emerging area, mostly based on the experience of other high-risk professions like aviation. The goal of simulation-based training in surgery is to develop not only technical but team skills. This learning environment is stress-free and safe, allows standardization and tailoring of training, and also objectively evaluate performances. The development of simulation training is straightforward in endourology, since these procedures are video-assisted and the low degree of freedom of the instruments is easily replicated. On the other hand, these interventions necessitate a long learning curve, training in the operative room is especially costly and risky. Many models are already in use or under development in all fields of video-assisted urologic surgery: ureteroscopy, percutaneous surgery, transurethral resection of the prostate, and laparoscopy. Although bench models are essential, simulation increasingly benefits from the achievements and development of computer technology. Still in its infancy, virtual reality simulation will certainly belong to tomorrow's teaching tools.

Comparison of early oncologic results of laparoscopic radical prostatectomy by extraperitoneal versus transperitoneal approach.

PURPOSE: Compare the early oncological results of laparoscopic radical prostatectomy performed by either an extraperitoneal or a transperitoneal approach. METHODS: 330 consecutive men underwent laparoscopic radical prostatectomy for localized prostate cancer, the first 165 by transperitoneal approach, and the last 165 by extraperitoneal approach. Clinical stage, serum PSA, Gleason score of biopsy were recorded, as well as operating time, surgical and medical complications, blood loss, length of hospital stay and catheterization time. The weight of the specimen, pathological stage (1997 TNM classification) and status of the surgical margins were noted. The Fisher test as well as the chi2-test were used for statistical analysis. Differences were considered significant when p < 0.05. RESULTS: There were no significant differences between the two groups in terms of preoperative characteristics except for Gleason score of the biopsies which was higher in the extraperitoneal group (p < 0.0001). The operating time was longer with the transperitoneal approach (248.5 min vs. 220.0 min, p < 0.0001). There was no difference in transfusion rate (1.2% vs. 5.4%, transperitoneal vs. extraperitoneal, respectively, p = 0.6). There was no difference in hospital stay, medical and surgical complications. Respectively, in the transperitoneal and extraperitoneal groups, there were 108 and 88 pT2 tumors. There were no differences in terms of positive surgical margins between the two groups, 23% and 29.7% (p = 0.21) overall, 13.0% and 17.0% (p = 0.42) in pT2 tumors and 43.6% and 44.7% (p = 0.99) in pT3 tumors. CONCLUSIONS: Extraperitoneal approach offers the same early oncological results as transperitoneal approach with a shorter operative time.

Introducing a prognostic score for pretherapeutic assessment of seminal vesicle invasion in patients with clinically localized prostate cancer.

PURPOSE: To identify prostate cancer patients who will have the most likely benefit from sparing the seminal vesicles during 3D conformal radiation therapy. METHODS AND MATERIALS: From 1988 to 2001, 532 patients underwent radical prostatectomy for clinically localized prostate cancer. Primary endpoint was the pathological evidence of seminal vesicle invasion. Variables for univariate and multivariate analyses were age, prostate weight, clinical stage, PSA level, Gleason score, number and site of positive prostate sextant biopsies. Multivariate logistic regression with backward stepwise variable selection was used to identify a set of independent predictors of seminal vesicle invasion, and the variable selection procedure was validated by non-parametric bootstrap. RESULTS: Seminal vesicle invasion was reported in 14% of the cases. In univariate analysis, all variables except age and prostate weight were predictors of seminal vesicle invasion. In multivariate analysis, only the number of positive biopsies (P<0.0001), Gleason score (P<0.007) and PSA (P<0.0001) were predictors for seminal vesicles invasion. Based on the multivariate model, we were able to develop a prognostic score for seminal vesicle invasion, which allowed us to discriminate two patient groups: A group with low risk of seminal vesicles invasion (5.7%), and the second with a higher risk of seminal vesicles invasion (32.7%). CONCLUSIONS: Using the number of positive biopsies, Gleason score and PSA, it is possible to identify patients with low risk of seminal vesicles invasion. In this population, seminal vesicles might be excluded as a target volume in radiation therapy of prostate cancer.

Patient reported sexual function following laparoscopic radical prostatectomy.

PURPOSE: We evaluated the sexual function of patients who underwent laparoscopic radical prostatectomy. We assessed the effect of unilateral or bilateral preservation of the neurovascular bundle on the ability to achieve erections and have sexual intercourse postoperatively. MATERIAL AND METHODS: Between May 1998 and September 2001, 232 men underwent laparoscopic radical prostatectomy for localized prostate cancer at our institution. Sexual function questionnaires were given to the patients preoperatively. The study included 143 patients who were potent preoperatively. After the procedure the surgeon noted whether he performed unilateral, bilateral or no nerve sparing. Sexual function questionnaires were collected at 1, 3, 6 and 12 months after surgery. RESULTS: Of the 143 patients, 100, 80, 48 and 26 responded to the questionnaire at 1, 3, 6 and 12 months respectively. Of the nonnerve sparing group 11.7%, 11.1%, 16.6% and 30%, of the unilateral nerve sparing group 20%, 35%, 41.6% and 50% and of the bilateral nerve sparing group 32.5%, 41.1%, 29.1% and 87.5% respectively reported spontaneous erections 1, 3, 6 and 12 months after surgery, respectively. The overall incidence of positive lateral surgical margins in pT2 cases treated with a nerve sparing procedure was 8.4%. CONCLUSIONS: The overall rate of patients who had erections preoperatively and maintained erections after surgery (53.8%) is comparable to the results for open surgery. Patients with bilateral preservation did better than those with unilateral preservation. Our preliminary results show a promising rate of potency at 1 year after laparoscopic radical prostatectomy.

Urinary continence and erectile function: a prospective evaluation of functional results after radical laparoscopic prostatectomy.

OBJECTIVES: To evaluate prospectively functional results (urinary continence and erectile function) after laparoscopic radical prostatectomy. METHODS: From 1998 to 2001, 235 patients underwent laparoscopic radical prostatectomy for localized prostate cancer. All of them completed a confidential, self-administered questionnaire regarding urinary continence and erectile function before, and 1, 3, 6, and 12 months after surgery. Results were analyzed separately for day and night for urinary continence and status of neurovascular bundles as well as age for erectile function. RESULTS: To date, 100 consecutive patients have completed all questionnaires. Diurnal and nocturnal urinary continence have increased to 90% and 97% one year after surgery. Overall, 49.3% of the 77 patients, who were potent preoperatively, and did not receive any form of adjuvant therapy, had erections sufficient for intercourse one year after surgery. Potency rates were 38.4%, 53.8% and 58.8% after no, unilateral, and bilateral nerve bundle preservation, respectively. For younger patients (<60 years) with unilateral and bilateral neurovascular bundle preservation, potency rates were 75% and 83.3%, respectively. CONCLUSION: One year after laparoscopic radical prostatectomy, urinary continence rate is 90% during the day and 97% during the night. Overall potency rates after bilateral preservation of neurovascular bundles are 58.8% and 83.8% for the subgroup of younger patients (<60 years).

Radical prostatectomy by the retropubic, perineal and laparoscopic approach: 12 years of experience in one center.

OBJECTIVES: We retrospectively evaluated the oncological outcome of radical prostatectomy performed by the retropubic, perineal and laparoscopic approaches. METHODS: From 1988 to 2000, 401 patients underwent radical prostatectomy for localized prostate cancer by the retropubic, perineal or laparoscopic approach. Age, clinical stage, preoperative PSA and Gleason score of positive biopsies were noted. Operating time, complication rate, transfusion rate, length of hospital stay, catheterization time and pathological results were reviewed. Kaplan-Meier analysis was used to evaluate the likelihood of biochemical recurrence (PSA > or =0.2 ng/ml). RESULTS: There were no significant differences between the three groups regarding preoperative characteristics, except for PSA (21.4 ng/ml, 13.2 ng/ml, and 11.6 ng/ml for the retropubic, perineal, and laparoscopic approach, p<0.05) and the frequency of stage T1c tumors (31.7%, 47.1% and 63.5%, respectively, p<0.05). The operating time was significantly longer in the laparoscopic approach (285 min) compared to the retropubic and perineal techniques (197 min and 178 min, respectively). The retropubic approach was associated with a higher transfusion rate (26.2% versus 15.9% and 2.9% with the perineal and laparoscopic approaches), longer bladder catheterization time (15.9 days versus 11.7 days and 6.8 days, respectively), and longer hospital stay (15.2 days versus 8.5 days and 7.4 days, respectively) (p<0.05 for each). With the retropubic, perineal and laparoscopic approaches, medical complication rates were 8.3%, 4.2% and 5.1%, and surgical complication rates were 16.5%, 12.7% and 13.1%, respectively. The rates of pathological stage pT2 tumors were 62.1%, 72.2% and 75.9%, in the retropubic, perineal and laparoscopic groups, respectively. Positive surgical margins in pT2 tumors were noted in 19%, 14% and 22%, respectively. The actuarial 3-year recurrence-free survival rates were not significantly different between the three techniques (75%, 85.2% and 84.1%, respectively; 91.7%, 95.8% and 90.4% among patients with organ-confined tumors). CONCLUSION: Despite changes in patient selection criteria over time, and the relatively short follow-up, this study showed no significant difference in oncologic outcome between the retropubic, perineal and laparoscopic approaches to radical prostatectomy.