A.R. Azzouzi

Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma.

PURPOSE Transitional cell carcinoma (TCC) is a pan-urothelial disease characterized by multiplicity. Although little is known about the molecular events in upper-tract TCC, similar carcinogenic mechanisms are thought to occur throughout the urinary tract. However, we have previously shown that distinct patterns of microsatellite instability occur in upper and lower urinary tract TCC, suggesting biologic differences between these tumors. Here we investigate the extent of promoter hypermethylation in TCC throughout the urinary tract. PATIENTS AND METHODS Tissue was obtained from 280 patients (median follow-up, 56 months) whose tumors comprised 116 bladder and 164 upper-tract tumors (UTT). Analysis for hypermethylation at 11 CpG islands, using methylation-sensitive polymerase chain reaction and bisulfite sequencing, was performed for each sample and compared with the tumors clinicopathologic details, microsatellite instability status, and subsequent behavior. RESULTS Promoter methylation was present in 86% of TCC and occurred both more frequently and more extensively in UTT (94%) than in bladder tumors (76%; P < .0001). Methylation was associated with advanced tumor stage (P = .0001) and higher tumor progression (P = .03) and mortality rates (P = .04), when compared with tumors without methylation. Multivariate analysis revealed that methylation at the RASSF1A and DAPK loci, in addition to tumor stage and grade, were associated with disease progression (P < .04). CONCLUSION Despite morphologic similarities, there are genetic and epigenetic differences between TCC in the upper and lower urinary tracts. Methylation occurs commonly in urinary tract tumors, may affect carcinogenic mechanisms, and is a prognostic marker and a potential therapeutic target.

Distinct patterns of microsatellite instability are seen in tumours of the urinary tract.

To date, two forms of microsatellite instability (MSI) have been described in human cancer. MSI typical of hereditary nonpolyposis colon cancer (HNPCC), is due to deficient DNA mismatch repair (MMR) and is defined with mono- and dinucleotide repeat microsatellites. A second variety of instability is best seen at selective tetranucleotide repeats (EMAST; elevated microsatellite alterations at select tetranucleotides). While MSI occurs infrequently in bladder cancers, EMAST is common. Sporadic tumours with the largest proportion showing MSI are those found most frequently in HNPCC kindreds. While bladder cancer is not frequently seen in HNPCC, upper urinary tract tumours (UTTs) are. Having previously found a low frequency of MSI in bladder cancer, we sought to determine the relative levels of MSI and EMAST in transitional cell carcinoma (TCC) of the upper and lower urinary tracts. Microsatellite analysis was performed at 10 mono- and dinucleotide and eight tetranucleotide loci, in 89 bladder and 71 UTT TCC. Contrasting patterns of instability were seen in urinary tumours. In bladder cancer, MSI was rare and EMAST was common. The presence of EMAST was not related to tumour grade, stage, subsequent outcome or immunohistochemical expression of the MMR proteins. In UTT, while MSI occurred frequently, EMAST was seen less frequently than in bladder cancer. When TCC of the upper and lower urinary tracts are compared, MSI-H is more frequent in UTT and EMAST more frequent in bladder cancer. Our findings show that, as for colorectal cancer, the pattern of MSI varies with location in the urinary tract. In addition, we have confirmed that MSI and EMAST are discrete forms of MSI, and that the presence of EMAST does not affect tumour phenotype.

TOOKAD® Soluble vascular‐targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer

To evaluate the optimal treatment conditions and effects of TOOKAD® Soluble vascular‐targeted photodynamic (VTP) therapy in patients with localised prostate cancer. To evaluate the safety and quality of life after TOOKAD® Soluble VTP treatment in patients with localised prostate cancer.

FGFR3 Mutations Indicate Better Survival in Invasive Upper Urinary Tract and Bladder Tumours

BACKGROUND Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis. OBJECTIVE To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes. DESIGN, SETTING, AND PARTICIPANTS Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1-216 mo) or until death. MEASUREMENTS FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the chi(2), Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model. RESULTS AND LIMITATIONS FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract. CONCLUSIONS FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.

Renal Cell Carcinoma (RCC) in Patients With End-Stage Renal Disease Exhibits Many Favourable Clinical, Pathologic, and Outcome Features Compared With RCC in the General Population

BACKGROUND Patients with end-stage renal disease (ESRD) are at risk of developing renal tumours. OBJECTIVE Compare clinical, pathologic, and outcome features of renal cell carcinomas (RCCs) in ESRD patients and in patients from the general population. DESIGN, SETTING, AND PARTICIPANTS Twenty-four French university departments of urology participated in this retrospective study. INTERVENTION All patients were treated according to current European Association of Urology guidelines. MEASUREMENTS Age, sex, symptoms, tumour staging and grading, histologic subtype, and outcome were recorded in a unique database. Categoric and continuous variables were compared by using chi-square and student statistical analyses. Cancer-specific survival (CSS) was assessed by Kaplan-Meier and Cox methods. RESULTS AND LIMITATIONS The study included 1250 RCC patients: 303 with ESRD and 947 from the general population. In the ESRD patients, age at diagnosis was younger (55 ± 12 yr vs 62 ± 12 yr); mean tumour size was smaller (3.7 ± 2.6 cm vs 7.3 ± 3.8 cm); asymptomatic (87% vs 44%), low-grade (68% vs 42%), and papillary tumours were more frequent (37% vs 7%); and poor performance status (PS; 24% vs 37%) and advanced T categories (≥ 3) were more rare (10% vs 42%). Consistently, nodal invasion (3% vs 12%) and distant metastases (2% vs 15%) occurred less frequently in ESRD patients. After a median follow-up of 33 mo (range: 1-299 mo), 13 ESRD patients (4.3%), and 261 general population patients (27.6%) had died from cancer. In univariate analysis, histologic subtype, symptoms at diagnosis, poor PS, advanced TNM stage, high Fuhrman grade, large tumour size, and non-ESRD diagnosis context were adverse predictors for survival. However, only PS, TNM stage, and Fuhrman grade remained independent CSS predictors in multivariate analysis. The limitation of this study is related to the retrospective design. CONCLUSIONS RCC arising in native kidneys of ESRD patients seems to exhibit many favourable clinical, pathologic, and outcome features compared with those diagnosed in patients from the general population.

Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma

Upper urinary tract transitional cell carcinoma (UUTTCC) accounts for 5% of all urothelial carcinomas.1 Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome predisposing to colorectal cancer that accounts for about 5% of all colorectal cancers.2 It is revealed by colorectal cancer (63%) or extracolonic cancers, most often of the endometrium (9%) or ovary, but sometimes of the upper urinary tract (5%), small bowel, stomach, or hepatobiliary tract.3–5 Patients with hereditary non-polyposis colorectal cancer have a genetic risk of developing these cancers.3,6 This study concerns patients with upper urinary tract transitional cell carcinoma who did not meet the international clinical criteria (Amsterdam criteria)5 for hereditary non-polyposis colorectal cancer. The question that arises is whether the biochemical and molecular biology tests used to screen for hereditary non-polyposis colorectal cancer might not help detect hereditary disease among these cases of upper urinary tract transitional cell carcinoma.7 The tests used in suspected cases of hereditary non-polyposis colorectal cancer are:

Bilan initial, suivi et traitement des troubles mictionnels en rapport avec hyperplasie bénigne de prostate : recommandations du CTMH de l’AFU

AIM To elaborate guidelines for the diagnosis, the follow-up, and the treatment of benign prostatic hyperplasia (BPH). METHOD A systematic review of the literature was conducted to select more relevant publications. The level of evidence was evaluated. Graded recommendations were written by a working group, and then reviewed by a reviewer group according to the formalized consensus technique. RESULTS Terminology of the International Continence Society was used. Initial assessment has several aims: making sure that lower urinary tract symptoms (LUTS) are related to BPH, assessing bother related to LUTS and checking for a possible complicated bladder outlet obstruction (BOO). Initial assessment should include: medical history, LUTS assessment using a symptomatic score, physical examination including digital rectal examination, urinalysis, flow rate recording, and residual urine volume. Frequency volume chart is recommended when storage symptoms are predominant. Serum PSA should be done when the diagnosis of prostate cancer can modify the management. When a surgical treatment is discussed, serum PSA, serum creatinine and ultrasonography of the urinary tract are recommended. BPH patients should be informed of the benign and possibly progressive patterns of the disease. When LUTS cause no bother, annual follow-up should be planned. Medical treatment includes some phytotherapy agents, alpha-blockers and 5-alpha reductase inhibitors. The last two can be associated. The association of antimuscarinics and alpha-blockers can be offered to patients with residual storage symptoms when already under alpha-blockers therapy, after checking for the absence of severe BOO (residual volume more than 200mL or max urinary flow less than 10mL/s). Phosphodiesterase-5 inhibitors could be used in patients complaining for both LUTS and erectile dysfunction. In case of complication, or when medical treatment is inefficient or not tolerated, then a surgical treatment should be discussed. Treatment decision should be done according to type of LUTS and related bother, prostate anatomy, level of obstruction and its consequences on urinary tract, patient co-morbidities, experience of practitioner, and choice of patient. Surgical treatments with the higher level of evidence of efficacy include monopolar or bipolar transurethral resection of the prostate, open prostatectomy, transurethral incision of the prostate, photoselective vaporization of the prostate, and Holmium laser enuclation of the prostate. CONCLUSION Here are the first guidelines of the French Urological Association for the initial assessment, the follow-up and the treatment of urinary disorders related to BPH.

S100A6 (Calcyclin) is a prostate basal cell marker absent in prostate cancer and its precursors

S100A6 (Calcyclin) is a calcium-binding protein that has been implicated in a variety of biological functions as well as tumorigenesis. The aim of our study was to investigate the involvement of S100A6 during prostate cancer development and progression. Using immunohistochemistry, the expression of S100A6 was examined in benign (n=66), premalignant (n=10), malignant (n=66) and metastatic prostate (n=5) tissues arranged in a tissue-microarray or whole sections as well as in prostate cancer cell lines. The S100A6 immunostaining pattern in tissues was compared with that of cytokeratin 5 (a basal cell marker) and 18 (a benign luminal cell marker). In all cases of benign epithelium, intense S100A6 expression was seen in the basal cell layer with absent staining in luminal cells. In all cases of prostatic adenocarcinoma (matched), metastatic lesions and 3/10 high-grade prostatic intraepithelial neoplasia lesions, an absence of S100A6 was seen. Western blotting and RT–PCR analysis of cell lines showed S100A6 expression to be absent in LNCaP, LNCaP-LN3 and LNCaP-Pro5 but present in Du145, PC3, PC-3M and PC-3M-LN4. LNCaP cells treated with 5-Azacytidine, caused re-expression of S100A6 mRNA. Sequencing of bisulphite modified DNA showed CpG methylation within the S100A6 promoter region and exon 1 of LNCaP, LNCaP-LN3 and LNCaP-Pro5 cell lines but not in Du145 cells. Our data suggest that loss of S100A6 protein expression is common in prostate cancer development and may occur at an early stage. The mechanism of loss of expression may involve hypermethylation of CpG sites. The finding of intense S100A6 expression in the basal cells of benign glands but loss of expression in cancer could be useful as a novel diagnostic marker for prostate cancer.

Multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (HoLEP)

To describe the step‐by‐step learning curve of the holmium laser enucleation of the prostate (HoLEP) surgical technique.

RecommandationBilan initial, suivi et traitement des troubles mictionnels en rapport avec hyperplasie bénigne de prostate : recommandations du CTMH de l’AFUInitial assessment, follow-up and treatment of lower urinary tract symptoms related to benign prostatic hyperplasia: Guidelines of the LUTS committee of the French Urological Association

AIM To elaborate guidelines for the diagnosis, the follow-up, and the treatment of benign prostatic hyperplasia (BPH). METHOD A systematic review of the literature was conducted to select more relevant publications. The level of evidence was evaluated. Graded recommendations were written by a working group, and then reviewed by a reviewer group according to the formalized consensus technique. RESULTS Terminology of the International Continence Society was used. Initial assessment has several aims: making sure that lower urinary tract symptoms (LUTS) are related to BPH, assessing bother related to LUTS and checking for a possible complicated bladder outlet obstruction (BOO). Initial assessment should include: medical history, LUTS assessment using a symptomatic score, physical examination including digital rectal examination, urinalysis, flow rate recording, and residual urine volume. Frequency volume chart is recommended when storage symptoms are predominant. Serum PSA should be done when the diagnosis of prostate cancer can modify the management. When a surgical treatment is discussed, serum PSA, serum creatinine and ultrasonography of the urinary tract are recommended. BPH patients should be informed of the benign and possibly progressive patterns of the disease. When LUTS cause no bother, annual follow-up should be planned. Medical treatment includes some phytotherapy agents, alpha-blockers and 5-alpha reductase inhibitors. The last two can be associated. The association of antimuscarinics and alpha-blockers can be offered to patients with residual storage symptoms when already under alpha-blockers therapy, after checking for the absence of severe BOO (residual volume more than 200mL or max urinary flow less than 10mL/s). Phosphodiesterase-5 inhibitors could be used in patients complaining for both LUTS and erectile dysfunction. In case of complication, or when medical treatment is inefficient or not tolerated, then a surgical treatment should be discussed. Treatment decision should be done according to type of LUTS and related bother, prostate anatomy, level of obstruction and its consequences on urinary tract, patient co-morbidities, experience of practitioner, and choice of patient. Surgical treatments with the higher level of evidence of efficacy include monopolar or bipolar transurethral resection of the prostate, open prostatectomy, transurethral incision of the prostate, photoselective vaporization of the prostate, and Holmium laser enuclation of the prostate. CONCLUSION Here are the first guidelines of the French Urological Association for the initial assessment, the follow-up and the treatment of urinary disorders related to BPH.