[Concordances and predictors of biopsies in renal tumors]. / Concordances et facteurs prédictifs des biopsies dans les tumeurs rénales.

AIM: Evaluate the concordance between the renal lesions biopsy's histology and the final histology of the surgical specimen according to histological subtype, and search for predictive factors of non-concordance. MATERIAL: We performed a monocentric retrospective study that included 156 patients suffering from a renal tumor that benefited a lesion biopsy before surgical treatment. Sensibility and specificity of the renal lesion's biopsy for histological diagnostic of the different renal tumors where calculated. RESULTS: One hundred and fifty-eight renal tumor biopsies were realized between 2001 and 2016. One hundred and forty-three renal cell carcinoma were found on the surgical piece, 135 were diagnosed on prior biopsy. Global concordance rate was 88%. For the establishment of the nuclear Fuhrmann grade, the concordance rate (low vs. high grade) was 72.9%. The cohort was divided into 2 groups according to the existence (group 1, n=139) or the absence (group 2, n=19) of concordance. Group 1 and 2 differed by the predominance of men in group 1 (66% vs. 37%, P=0.013), distance between the sinus and the tumor above 4mm (65% vs. 42%, P=0.05). CONCLUSION: In renal tumor care, renal biopsy is a reliable testing. However, some factors most likely linked to the tumor anatomy (intra-sinusal tumor) and their histological composition were involved in the lack of non-contribution to the diagnosis. LEVEL OF EVIDENCE: 4.

[Flexible ureterorenoscopy vs percutaneous nephrolithotomy for renal stone management: Retrospective study]. / Étude rétrospective comparant la néphrolithotomie percutanée et l'uréterorénoscopie souple pour le traitement des calculs intrarénaux.

PURPOSE: The aim of this study was to evaluate the efficacy and tolerance of renal stone fragmentation by flexible ureterorenoscopy (URS), compared to percutaneous nephrolithotomy (PCNL). MATERIAL AND METHODS: Patients treated between 1998 and 2010 by URS and PCNL for intrarenal stone were reviewed. Patients' and stones' characteristics were analyzed. The preoperative parameters were reported as well as the procedure's efficiency and its complications. Success was defined by the absence of residual lithiasis visualized on renal imaging at 6 months of follow-up. RESULTS: Among 531 patients included, there were 159 PCNL and 372 URS. The mean duration of hospitalization after PCNL was 8±4.6 days and 3±1.7 days after URS. The mean stones' size was higher in the PCNL group (19.9±7.5mm) than for the URS group (9.7±5.6mm; P<0.0001). The stone-free rate was significantly better in the PCNL group for stones measuring between 10 and 20mm (P<0.0001) and for stones of more than 20mm (P=0.017). Postoperative complications were significantly more frequent (27 %) and more severe (8.8 % vs Clavien III and IV) in the PCNL, than in the URS group, respectively (P=0.0001). CONCLUSION: PCNL is a successful technique for renal stone fragmentation. However, URS seemed more tolerated despite a lower stone-free rate. LEVEL OF EVIDENCE: 4.

[Impact of obesity on pathologic outcomes and biochemical reccurence after radical prostatectomy]. / Effets de l'obesité sur les résultats anatomopathologiques de la prostatectomie totale et sur la survie sans recidive biologique.

OBJECTIVE: To determine whether obesity is associated with adverse pathologic characteristics, positive surgical margins and the biochemical recurrence free survival (bRFS) after primary treatment with radical prostatectomy (RP). PATIENTS AND METHODS: Medical charts of patients managed with RP between 1999 and 2011 for localized prostate cancer (PCa) were retrospectively reviewed. Population study was split into two groups according to the body mass index (BMI): non obese (BMI< 30 kg/m(2)) and obese (BMI ≥ 30 kg/m(2)). Correlations between obesity and adverse pathological features or bRFS were assessed using univariable and multivariable analyses. RESULTS: Overall, 328 patients were included in the present study: 278 (84.8%) obese and 50 (15.2%) non obese. In multivariable analysis, obesity was associated with positive surgical margins (P=0.014), extracapsular extension (P=0.004) and pathologic Gleason score ≥ 7 (P=0.048). Obesity was not associated with seminal vesicle invasion (P=0.636) and lymph node metastasis (P=0.132). After a mean follow-up of 60.51 ± 28.82 months, no statistical difference in terms of bRFS was observed between the two groups (P=0.186). Furthermore, obesity was not an independent predictor of bFS in multivariable analysis. CONCLUSION: Obesity was associated with adverse pathologic characteristics and positive surgical margins but no statistical correlation was found with bRFS. LEVEL OF EVIDENCE: 5.

[Flexible ureterorenoscopy in obese patients: results from a large monocenter cohort]. / Urétérorénoscopie souple avec laser Holmium-YAG dans la prise en charge des lithiases urinaires chez le patient obèse: résultats d'une cohorte monocentrique.

OBJECTIVE: To analyze results and morbidity after flexible ureterorenoscopy (fURS) in patients with a body mass index (BMI)>30 kg/m² and to compare with results obtained in a large cohort of non-obese patients. METHODS: We conducted a retrospective monocenter study including all fURS for urinary lithiasis performed in our institution between January 2004 and December 2010. During the study period, 497 procedures were performed. Twenty-three had to be excluded because of missing data on BMI. Thus, a total of 474 procedures were included in the final analysis, 93 for obese patients (OP) and 381 for non-obese patients (NOP). Characteristics of the patients, stones and procedures were analyzed. Success was defined as clear imaging (completely stone-free) on renal tomography and ultrasonography. RESULTS: Mean BMI was 33.5 ± 0.3 in OP vs 23.9 ± 0.1 kg/m² in NOP (P<0.0001). Mean stone size, location, and composition were not significantly different between groups. Technical aspects (operative time, ureteral dilatation, access sheath, monobloc extraction) were also similar in OP and NOP. The immediate (63.5% for OP vs 66.1% in NOP, P=0.62) and follow-up (65.1% for OP vs 71% in NOP, P=0.26) stone-free rate were not significantly different between the groups. For stone size<1cm, SFR raised to 77% in OP vs 83% in NOP (P=0.28). The rate of minor complications Clavien II was similar in OP (7.5%) and NOP (12%). No major complication (Clavien III or IV) was observed. CONCLUSION: fURS is a safe and efficient option for the management of urinary lithiasis in obese patients.

[Existence of pattern 5 on radical prostatectomy: poor prognostic factor associated with a lower biochemical recurrence-free survival]. / Existence de grade 5 sur pièce de prostatectomie totale: facteur de mauvais pronostic associé à une moindre survie sans récidive biologique.

OBJECTIVES: To analyze the impact of the existence of Gleason grade 5 on the adverse pathology and biochemical recurrence-free survival of patients. PATIENTS: Three hundred and seventy-two prostatectomies were performed between 1999 and 2011 in our institution for localised prostate adenocarcinoma. We examined the existence of grade 5 of the specimen to determine the reliability of prostate biopsies in the diagnosis of grade 5 and the association of grade 5 with other histoprognostic factors. Biochemical recurrence-free survival was analyzed according to the presence of grade 5 in the final specimen. RESULTS: In total, all histological data and biochemical recurrence-free survival were available for 321 patients who were included in the study. Sixty-eight had Gleason grade 5 (majority or third minority pattern) on the specimen while 253 had not. Grade 5, rarely diagnosed on biopsy (sensitivity=26.47 %) was correlated independently with the extracapsular extension (OR=2.1; CI 95 [1.1-3.9]), the seminal vesicle invasion (OR=3.8; CI 95 [1.7-8.7]) and positive surgical margins (OR=2.0; CI 95 [1.1-3.6]). Overall survival was similar in both groups but the biochemical recurrence-free survival was statistically lower in the presence of grade 5 (HR=3.7; CI 95 [1.8-7.6]). Biochemical recurrence-free survival was not different than grade 5 is predominant or third minority pattern (HR=1.01; CI 95 [0.3-2.8]). On multivariate analysis, grade 5 was an independent risk factor for biochemical recurrence (P=0.005) as well as seminal vesicle invasion (P=0.047). CONCLUSION: The existence of grade 5 in the surgical specimen whatever the percentage was a poor prognostic factor associated with increased tumor aggressiveness and reduced biochemical recurrence-free survival. LEVEL OF EVIDENCE: 5.

[Evaluation of the activity of a urological emergency unit in university hospital]. / Évaluation de l'activité d'une unité d'urgences urologiques en centre hospitalier universitaire.

AIM OF THE STUDY: To determine the epidemiology of urological emergencies in a university hospital and the interest of a dedicated urological emergency unit. PATIENTS AND METHODS: In 2008, a dedicated urological emergency unit was individualized in our department of urology. We conducted a retrospective study including all patients consulting in this unit in 2009 with epidemiological, clinical and therapeutic data. RESULTS: During 2009, 1257 patients consulted in this unit. Main diagnoses were acute urinary retention (303, 24.11%), renal colic (219, 17.42%), urinary infections (278, 22.11%), postoperative complications (141, 11.22%), symptomatic benign prostate hyperplasia (65, 5.17%), genitourinary cancers (61, 4.85%), trauma of urinary apparel (41, 3.26%), and spermatic cords torsion (10, 0.8%). In 99 cases (7.88%) diagnosis did not involved the urinary system. The treatment was surgical in 213 (17.7%) cases, technical procedure under local anesthesia in 368 (29.3%) and a medical treatment in 675 (53.7%) cases. Six hundred and sixty (52.5%) patients were managed ambulatory whereas 596 (47.5%) needed hospitalization. CONCLUSION: The opening of a dedicated urological emergency unit lead to 1257 emergency consultations. Frequent etiologies were acute urinary retention, renal colic and urinary infection. The creation of this unit allowed to register and to valorize this emergency activity through the ATU emergency amount.

Outcomes of renal transplantation in obese recipients.

PURPOSE: Although obesity has been shown to paradoxically increase dialysis patient survival, its impact has not been clearly defined on renal transplantation. We assessed outcomes of obesity renal transplant patients by evaluating graft and patient survivals. PATIENTS AND METHODS: A single-institution, retrospective study was performed on 202 renal transplant recipients from January 2004 to December 2008 excluding two combined kidney and liver transplantations. Recipients were classified based on body mass index (BMI) at the time of transplantation: obese (BMI ≥ 30 kg/m(2)) and nonobese recipients (BMI < 30 kg/m(2)). The comparative analysis included surgical complications, hospital stay, onset of delayed graft function (DGF), acute rejection episodes and graft patient survivals. RESULTS: Twenty-one renal transplants were performed in obese recipients versus 179 in the control group. Obese patients were older (53.3 ± 11.2 versus 46.4 ± 14.4 years old; P = .035) and more often diabetic (29% ± 0.46 versus 60% ± 0.24, P = .001), but there were no differences among other combidities of high blood pressure, arteriopathy, thrombophilia, and smoking. Obesity did not appear to be a risk factor for urinary or vascular as well as parietal complications, but did tend to augment lymphatic complications (14.3% ± 0.36 versus 4.5% ± 0.21; P = .065). DGF occurred more frequently in obese patients (38% ± 0.50 versus 14% ± 0.34; P = .004) and hospital stays were therefore longer in this group (24.9 ± 23.53 days versus 15.6 ± 13.67 days; P = .008). Graft (hazard ratio [HR] 1.22; 95% confidence interval [CI] [0.25-6.0], P = .63) and patient survivals (HR:0,81; 95% CI [0.12- 5.3], P = .83) were comparable between the groups. CONCLUSION: Obese patients seeking renal transplantation are usually older and more often diabetic compared with nonobese recipients. The higher rate of lymphatic complications and DGF lead to longer hospital stays among the group with BMI ≥ 30 kg/m(2). However, long-term results showed similar graft and patient survivals as nonobese patients. Consequently, there seemed to be no reason to avoid renal transplantation in obese recipients.

[Accuracy of prostate biopsies to evaluate tumor location in prostate cancer]. / Fiabilité des biopsies prostatiques pour l'étude de la topographie tumorale dans le cancer de prostate.

INTRODUCTION: The therapeutic approach of prostate cancer depends mainly on pathological criteria obtained through prostate biopsy. The low accuracy of prostate biopsy for Gleason grade determination is well known but its accuracy for bilateral or multifocal tumor has not been evaluated. The goal of this study was to assess the concordance between prostate biopsy and whole prostate specimen obtained after radical prostatectomy especially for bilateral and/or multifocal tumor. METHODS: We retrospectively compared the pathological results of prostate biopsy cores to the prostate specimen in patients who underwent radical prostatectomy in our department between the 01/01/1999 and the 31/12/2008. The criteria analyzed were the Gleason score, tumor bilaterality or multifocality. The impact of the number of prostate biopsy cores was also analyzed. RESULTS: Two hundred and five complete histological records were studied. Regarding the Gleason score overall concordance was 55%. In 38%, prostate biopsies downgraded the Gleason score. This concordance decreased with tumor differentiation (90.6% for Gleason 6 vs. 31% for Gleason greater than 7). For the tumor bilaterality, 78% of cancers affected both lobes at the definitive specimen analysis while only 49% were bilateral at prostate biopsies, achieving a concordance of 61%. Multifocal disease was observed in 36% at definitive pathology analysis with low concordance with prostate biopsies (36%). The number of biopsies increased the concordance for the Gleason score (60 to 81% for Gleason 7 and from 28 to 50% for Gleason greater than 7) and tumor location (44 to 70%). CONCLUSION: Pathological criteria and tumor mapping obtained from prostate biopsies were not very reliable especially when the tumor was poorly differentiated. An increased number of prostate biopsy core improved the sensitivity and specificity for the Gleason score diagnostic and of the tumor mapping.

[Muscularis mucosae invasion: prognostic factor for intravesical BCG immunotherapy failure for T1 bladder carcinoma]. / Atteinte de la Muscularis Mucosae dans les tumeurs urothéliales T1 de vessie : facteur pronostique de progression après immunothérapie par BCG.

OBJECTIVES: To study the prognostic impact of muscularis mucosae (MM) invasion for pT1 bladder cancer treated by transurethral resection (TUR) and adjuvant Bacille Calmette-Guerin (BCG) intravesical immunotherapy. METHODS: Sixty-six patients treated by BCG intravesical instillations were substaged into pT1a and pT1b, regarding Muscularis Mucosae invasion. Tumor grade, associated carcinoma in situ (CIS), multifocality, tumoral size up to 3cm, BCG maintenance were noted. With a mean follow-up of 50.5±38 months, we studied recurrence, progression, overall and specific survival. Cox's model method was used for multivariate analysis. RESULTS: Tumor recurrence was observed in 30±7% and 43±10% (P=0.29) and tumor progression in 16.3±5% and 39±10% (P=0.04) for pT1a and pT1b. The rate of progression was higher (P=0.04) and progression free survival was decreased (P=0.04) for pT1b. Specific death rates were 11±5% and 21±9% (P=0.28), median overall survival was 80.9 [1.5-92] and 48.2 [12-93] months for pT1a and pT1b. Overall and specific survival weren't different between the two populations (P=0.38; P=0.3). Cystectomy rates were 2.3±2% and 30±9% for pT1a and PT1b (P=0.0006). For pT1a patients, recurrence (P=0.8) or progression rates (P=0.64) were no different regarding BCG maintenance immunotherapy but pT1b population had a better progression free survival with BCG maintenance than without (P=0.0051). Only CIS had prognostic value in multivariate analysis. CONCLUSIONS: Tumors with Muscularis Mucosae invasion have a higher risk of progression and BCG failure. Maintenance immunotherapy should be given to improve results with these patients.

[Urinary complications of one-stitch ureteroneocystostomy in renal transplantation]. / Complications urinaires après réimplantation urétérovésicale selon la technique du "one-stitch" en transplantation rénale.

PURPOSE: To assess urinary complications related to the "one-stitch" technique extravesical ureteroneocystostomy in renal transplantation, and evaluate the impact of such complications on kidney graft and patient survival. PATIENTS AND METHODS: A single-institution, retrospective study was performed on 202 renal transplant recipients, from January 2004 to December 2008. Two combined kidney and liver transplantations were excluded. The "one-stitch" extravesical ureteroneocystostomy technique, fast and easy to perform, was systematically used. The evaluated urinary complications were urinary fistula, ureteral stenosis, symptomatic ureteral reflux, stone formation and complicated hematuria. We tried to point out factors impacting urinary complications occurrence and studied grafts and patients survival according to the existence of urinary complications. RESULTS: Fifty-five patients presented urinary complications (27.5%). The most frequent urinary complications were complicated hematuria (36 over 200, 18%), ureteral stenosis (15 over 200, 7.5%). Few cases of stone disease (one over 200, 0.5%), urinary fistula (two over 200, 1%) and symptomatic ureteral reflux (one over 200, 0.5%) were noted. Male gender (100 vs 34, P=0.95), age (46.78 ± 14.17 vs 48.06 ± 14.19 years, P=0.58), Body mass index (24.14 ± 5.04 vs 24.28 ± 4.83, P=0.86) and past history of renal transplantations (16 ± 3% vs 10 ± 3%, P=0.27) as well as cold ischemia time (17.08 ± 7.07 vs 16.9 ± 8.95 hours, P=0.71) were not significantly different in the urinary complications group and the non-urinary complications group. Median hospitalization time was similar in both groups (14 vs 12 days, P=0.37). The existence of urinary complications didn't affect the 5 years kidney graft survival (91.9% vs 89.9%, HR 1.21, CI 95% [0.37-3.3], P=0.83) neither the 5 years patient survival (94.8% vs 92.15%, HR 0.52 CI 95% [0.13-2.07], P=0.85). CONCLUSION: If benign urinary complications in "one-stitch" ureteroneocystostomy were frequent in our study (17% grade II Clavien Dindo), kidney graft and patients survivals were not affected.

Hospital costs of renal transplant management.

Renal transplantation is considered to be a cost-effective therapy, but hospital medical costs are not accurately known. The aim of this work was to evaluate the costs of hospital stay for renal transplantation. This retrospective study included all patients who underwent renal transplantation between January 1, 2004, and December 31, 2005, in our University hospital. The incurred costs were determined using our center's analytical accounting (AA). The mean local cost was then compared with the median national cost of hospitalization for renal transplantation, based on a sample of participating centers contributing to the National Cost Scale (NCS) per homogenous diagnosis-related group (DRG). These mean costs were weighed against the financing obtained by national rates of the case-mix based payment system (termed T2A). Data were collected from 77 patients. Their mean length of stay was 19.4 days. AA determined the cost of management to be euro14,100 per patient. National economic approaches were significantly higher: euro16,389 for NCS and euro17,369 for national rates. Thus, the specific DRG rate (case mix index) of renal transplantation covers the expenses incurred by our center. These results are rather interesting; however, it is unlike those obtained for the management of other diseases such as acute myeloid leukemia, where T2A underestimates the actual cost by 2-4 times. Last, the hospital budget and T2A must be considered as a whole. The fact that DRGs with favorable and unfavorable pricing balance out should be taken into account.

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

Detection of the human papillomavirus and analysis of the TP53 polymorphism of exon 4 at codon 72 in penile squamous cell carcinomas.

Human papillomaviruses (HPV) are thought to be involved in penile squamous cell carcinomas (SCC). A common polymorphism at codon 72 of exon 4 encoding either arginine (Arg) or proline (Pro) has been shown to affect HPV-mediated degradation of p53 in vitro, and may represent a risk factor for HPV-induced carcinogenesis. The presence of HPV DNA as well as the TP53 polymorphism at codon 72 of exon 4 were investigated in a series of 45 penile SCC. HPV detection and typing were carried out by polymerase chain reaction (PCR) with generic primers (MY09-MY11 and FAP59-FAP64), and type-specific DNA probes. TP53 polymorphism was further investigated using Denaturing Gradient Gel Electrophoresis (DGGE). HPV DNA was detected in 67% of penile SCC and 32% of benign lesions (BL) (P<0.05). Among the TP53 amplified samples, the rate of Arg homozygosity in penile SCC was 61% compared with 68% in BL (non-significant (NS)). Our results demonstrate a strong association between penile SCC and the presence of HPV DNA. The TP53 Arg/Arg genotype does not appear to represent a risk factor for the development of genital SCC in men, and no correlation was found between the TP53 polymorphism at codon 72 and the presence of HPV DNA.

Absence of anti-Müllerian hormone (AMH) and M2A immunoreactivities in Sertoli cell-only syndrome and maturation arrest with and without AZF microdeletions.

BACKGROUND: Some genes identified in the AZF locus are expressed only in germinal cells; others are ubiquitous. AZF microdeletions seem to occur at the earliest stages of ontogenetic development, and one might therefore assume that Sertoli cells preserve some immature characteristics and that their immunophenotype may be modified by the existence of a molecular defect. MATERIALS AND METHODS: Two immunohistological markers of Sertoli cell immaturity [anti-Müllerian hormone (AMH) and M2A] were tested in two histopathological groups (maturation arrest at spermatocyte I stage and Sertoli cell-only syndrome). We analysed 68 testicular samples obtained from 39 patients with non-obstructive azoospermia associated or not with AZF microdeletions. RESULTS: The absence of M2A and AMH immunoreactivity in adult gonads was observed without any correlation to spermatogenetic impairment or molecular deficit in the AZF region. In the samples of these two series, Sertoli cells showed a mature phenotype for AMH and M2A markers. CONCLUSIONS: In patients with AZF microdeletions, the genotype-phenotype correlations seem to be more complex than has been suggested previously; more detailed characterization of the immunohistochemical phenotype associated with the molecular defect may be useful in understanding the spermatogenic failure mechanism.

Variants of renal angiomyolipoma closely simulating renal cell carcinoma: difficulties in the histological diagnosis.

Renal angiomyolipoma is considered to be a benign renal tumor composed of atypical blood vessels, smooth muscles and fat cells. We report 2 cases of unilateral renal angiomyolipoma. In both cases, our preoperative diagnosis was renal cell carcinoma, because no low density area compatible with fat tissue was noted in the tumors on radiographic evaluation. Through histological examination, both tumors proved to be angiomyolipomas mainly composed of epithelioid cells in 1 case, and spindle-shaped smooth muscle cells mimicking a leiomyoma in the other case. Both patients are well showing no evidence of metastases 16 and 14 months after nephrectomy, respectively.

Influence of cigarette smoking on P53 gene mutations in bladder carcinomas.

BACKGROUND: The aim of this study was to analyse the influence of cigarette smoking on bladder carcinomas. PATIENTS AND METHODS: 98 cases of bladder cancers were examined by single strand conformation polymorphism analysis of exons 5 to 9, followed by DNA direct sequencing. RESULTS: The incidence of p53 gene mutations was not significantly influenced by habitual smoking. However, the p53 mutation spectrum of current smokers differed significantly from the pattern for non-smokers and ex-smokers. Differences between the two populations included multiple mutations in the current-smokers and an absence in non- and ex-smokers (p<0.01), with the predominance of G:C to A:T transitions at CpG sites in non-smokers (60.0%) in comparison with current smokers (7.6%) (p<0.02). Moreover, G:C to T:A and G:C to C:G transversions were found solely in current smokers. CONCLUSION: It would appear that, in current-smokers, the spectrum of p53 gene mutations is related to tobacco-smoke carcinogens and that the habit of smoking increases the extent of DNA damage.

Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer.

PURPOSE: Vascular endothelial growth factor is an overriding growth factor mediating tumor angiogenesis. We correlated serum vascular endothelial growth factor in patients with bladder cancer with clinical parameters. MATERIALS AND METHODS: Serum vascular endothelial growth factor in 58 patients with bladder cancer, including superficial and invasive tumors in 42 and 16, respectively, and 41 healthy controls was measured by sandwich enzyme immunoassay. RESULTS: Significant differences in serum vascular endothelial growth factor were observed in healthy controls and patients with bladder cancer (mean 248 versus 100 pg./ml., p <0.001). The serum level was significantly associated with tumor stage (p <0.0001), grade (p <0.002), vascular invasion (p <0.001) and carcinoma in situ (p <0.01). Patients with metastasis had a significantly higher levels than those with localized diseases (mean 582 versus 194 pg./ml., p <0.0001). At a cut-off of 400 pg./ml. the sensitivity and specificity of the test for differentiating patients with and without metastatic diseases was 87.5% and 98%, respectively (p <0.0001). Univariate statistical analysis showed that an increase in serum vascular endothelial growth factor level greater than 400 pg./ml. was significantly related to disease-free survival. On multivariate analysis only stage remained as an independent prognostic factor. CONCLUSIONS: Although vascular endothelial growth factor did not remain an independent prognostic factor on multivariate analysis, our data indicate that the level of vascular endothelial growth factor may be a valuable angiogenic marker for identifying metastatic bladder cancer. It may be used as a new predictor of disease.

Protein kinase C signalling pathway is involved in the regulation of vascular endothelial growth factor expression in human bladder transitional carcinoma cells.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the growth and metastasis of various cancers and plays a prominent role in vesical angiogenesis regulation. In this study, we investigated the effect of the phorbol 12-myristate 13-acetate (PMA) on the expression of VEGF in human bladder transitional carcinoma cells (RT4). RT4 cells expressed three VEGF isoforms (VEGF(189), VEGF(165), VEGF(121)). PMA increased VEGF mRNA expression time-dependently with a peak at 4 h. PMA increased the half-life of VEGF mRNA. The amount of VEGF protein in conditioned media was increased by PMA in a dose-dependent manner with a maximal effect at 10(-7) M. Staurosporine and calphostin C (PKC inhibitors) decreased PMA-induced VEGF mRNA expression as opposed to protein kinase A or cyclic nucleotide-dependent protein kinase inhibitors. Thus, in RT4 cells, VEGF expression is up-regulated by PMA via the PKC signalling pathway and according to a posttranscriptional mechanism.