Identification of a three-gene expression signature of early recurrence in non-muscle-invasive urothelial cell carcinoma of the bladder.

OBJECTIVES: To identify the expression profile of early recurring non-muscle-invasive bladder cancer (NMI-BC). MATERIALS AND METHODS: We selected primary NMI-BC according to the following criteria: complete resection, primary occurrence of urothelial cell carcinoma, stage cTa or T1, low grade, no carcinoma in situ. All patients underwent a transurethral resection of the bladder and were followed according to the Guidelines of European Association of Urology. Expression of 110 target genes was studied by using real time quantitative RT-PCR. The correlation between the absolute expression and early recurrence was analyzed by using a Cox regression model. The ability of a gene to distinguish the tumors with early recurrence from those with late recurrence was determined by using a ROC-AUC test. A hierarchical classification was established by using the software of GeneANOVA and tested by a χ(2) test. RESULTS: Forty-seven tumors were studied: 25 with early recurrence vs. 22 with late or null recurrence. These 2 groups of tumors have a significantly different expression profile in 3 genes among the 110-gene expression profile: peroxysome proliferator-activated receptor-γ (PPARG) (P = 0.031), stathmin-1 (STMN1) (P = 0.041), Caveolin-2 (CAV2) (P = 0.004). The combination of the expression of these 3 genes was significantly predictive for early recurrence leading to a correct hierarchical classification of the NMI-BC regarding the time-to-recurrence (P < 0.001). CONCLUSIONS: This study identifies a concise 3-gene panel that is associated with time to recurrence. This 3-gene signature has to be confirmed in a prospective study and in larger cohort of patients. However, our preliminary results are promising and gene expression profiling seems to be an interesting approach in cTa-T1 tumors for recurrence prediction.

The prognostic value of FGFR3 mutational status for disease recurrence and progression depends on allelic losses at 9p22.

Developing molecular markers that define high-risk lesions is clinically critical for improving the prognosis determination of the tumors and their treatment. We decided to focus on the two pathways involving FGFR3 and allelic losses at 9p22 to identify a potential combined role in predicting tumor recurrence, progression and/or muscle. Microsatellite and mutational FGFR3 status analyses was performed in tumor tissue of 58 patients in a prospective unicentre study. The results of microsatellite and FGFR3 analyses were dichotomized as follows: loss of heterozygos-ity (LOH) versus retention of heterozygosity (ROH) on the one hand; mutant FGFR3 (mtFGFR3) versus wild-type FGFR3 (wtFGFR3) on the other hand. The combined 9p22/FGFR3 status was strongly correlated with stage (p=0.001) and grade (p<0.001) whereas the single FGFR3 mutational status was not able to predict recurrence, progression or muscle invasion. The survival curves corresponding to each combined status (mtFGFR3/ROH, wtFGFR3/ROH, mtFGFR3/LOH, wtFGFR3/LOH) were significantly different for recurrence (p=0.008), progression (p=0.046) and progression to muscle invasive disease (p=0.004). In case of 9p22 LOH, the FGFR3 mutational status was strongly associated with different clinical outcomes. In a multivariate model, the combined wtFGFR3/9p22 LOH status remained significant in predicting oncologic outcomes. FGFR3 mutations strongly characterize tumors with low malignant potential and favourable clinical outcome in case of allelic losses at 9p22, whereas its prognostic value becomes null or slightly inverts in case of allelic stability. Thus, our findings may also lead to further experiments in order to study interactions between FGFR3 and genes located at 9p22, as CDKN2A.

Prevalence and spectrum of microsatellite alterations in nonmuscle invasive bladder cancers.

We aimed to identify interesting deleted chromosomal regions for bladder cancer diagnosis and carcinogenesis, and to evaluate the association between loss of heterozygosity (LOH) and clinico-pathological parameters. Microsatellite analysis was performed on urine sediment and tumor tissue from 43 consecutive patients with superficial transitional cell carcinoma (TCC) and from 42 consecutive controls. Informative cases were scored as LOH or allelic loss (AL) according to the decrease of the allelic-imbalance ratio. The prevalence of LOH and AL was 39.5% and 86%, respectively. Chromosome 9 was the most frequently altered, especially at 9p (35%). The total number of microsatellite alterations per analysis was correlated with age, grade, stade and EAU classification. The locus 17p13.1 was strongly associated with high-stage (p=0.01) and high-grade tumors (p=0.02). Specificity and sensitivity of LOH was 100% and 39.3% for diagnosis of malignant urinary disease. Specificity and sensitivity of AL was 73.8% and 88%, respectively. Allelic losses are a frequent and early event in bladder cancer, especially at 9p. Thanks to its high specificity, LOH may serve as a complementary tool for non invasive diagnosis of bladder cancer. Further study is warranted to evaluate the prognostic value of LOH on recurrence, progression and muscle invasion.

Prognostic value of loss of heterozygosity at chromosome 9p in non-muscle-invasive bladder cancer.

OBJECTIVE: To investigate the prognostic value of loss of heterozygosity (LOH) at chromosome 9p in patients with non-muscle-invasive bladder cancer (NMI-BC). METHODS: Between 2000 and 2006, we included in the study 84 patients with NMI-BC. LOH analyses were performed on tumor tissue using 3 microsatellite markers at chromosome 9p. Associations of LOH with recurrence and progression of the tumors were evaluated. RESULTS: Frequency of LOH at 9p was 11.1%, 29.0%, and 31.6% in pTaG1, pTaG2, and pT1G3 tumors, respectively. Recurrence occurred in 27 patients. None of the markers was able to predict recurrence. Progression occurred in 9.5% of the cases, with progression to muscle-invasive bladder cancer (MI-BC) in 4.8% of the cases. LOH at IFN-alpha was significantly associated with progression to MI-BC (P = .006). In the case of LOH at IFN-alpha, 2-year progression-free survival and progression-free survival to MI-BC were both 59.3%, compared with 97.1% and 98.6%, respectively, in case of conservation of LOH in multivariable analysis, LOH at IFN-alpha remained statistically associated with progression and progression to MI-BC. LOH at IFN-alpha was a significant and independent predicting factor of progression and progression to MI-BC, with P = .05 and 0.01 (HR 4.8 for progression; HR 24.2 for muscle invasion). CONCLUSIONS: Our study suggests that LOH at IFN-alpha is an independent prognostic factor for progression to MI-BC. LOH analysis of bladder tumors may help in the management of NMI-BC. Specifically, it could be of use in selecting patients for early aggressive treatment and/or in planning close follow-up schedule.

Extensive biopsies and transurethral prostate resection in men with previous negative biopsies and high or increasing prostate specific antigen.

PURPOSE: We determined the diagnostic role of an extensive biopsy protocol associated with transurethral prostate resection in patients with persistently increased or increasing prostate specific antigen without evidence of prostate cancer after 2 or more extended negative sets of biopsies. MATERIALS AND METHODS: A new set of 21-core biopsies was done in 113 patients under general anesthesia in association with transurethral prostate resection. Demographics, clinical and biological data, operative parameters, pathological results and followup were recorded prospectively. RESULTS: Extended biopsies provided an 18.6% detection rate and detected 77.8% of prostate cancers. Transurethral prostate resection significantly increased the detection rate by 28.5% for an overall 23.9% prostate cancer detection rate (p = 0.035). Most prostate cancer detected on chips and/or biopsy was clinically significant and 30% were scored as Gleason 7 or greater. Of prostatectomy specimens 19% showed pT3a-pT4 cancer with a median Gleason score of 7. In patients with no cancer mean prostate specific antigen 1 year after transurethral prostate resection was 4.5 ng/ml (range 0.3 to 16.3), which remained stable during followup. A third of these patients underwent repeat biopsy with a 16.7% prostate cancer detection rate. CONCLUSIONS: About a fourth of patients with at least 2 extended negative sets of prostate biopsies remain at risk for prostate cancer and most tumors missed on initial procedures are clinically significant. Repeat biopsy using general anesthesia detects three-fourths of these prostate cancers. However, the diagnostic yield of transurethral prostate resection appears significant and may provide additional data of clinical importance in select, informed patients.

[Prospective evaluation of the effects of a practical introduction to urology session on the recruitment of urology intern in Paris: final results]. / Evaluation prospective des effets du stage d'initiation pratique sur le recrutement des internes d'urologie 'a Paris: résultats définitifs.

OBJECTIVES: To evaluate the effects of a practical introduction to urology session on the recruitment of Parisian interns since introduction of the National Classifying Examination. MATERIALS AND METHODS: Since 2004, all surgery interns appointed in Paris have participated in a practical introduction to urology session before starting work in hospital. They were asked to complete a questionnaire. The prospective survey studied: age, gender, urology training as a medical student and the intern's preferences in relation to 11 surgical specialties. Interns were recontacted annually to determine their choice of specialization. RESULTS: Population. 255 interns participated, including 145 females (56.9%) and 110 males (43.1%). The mean age was 24.6 +/- 5 years (range: 22-31). 173 interns were attached to a Parisian teaching hospital (67.8%) and 82 (32.2%) were attached to a provincial teaching hospital. 52 interns (21.2%) had completed at least one attachment in a urology department during their medical training. Surgical specialties. Orthopaedics was most frequently listed (n = 48 ; 28.9%). Urology was chosen by 32 interns (12.5%), 28 of whom had completed an urology attachment during their medical training. At the end of the introductory training sessions, 18 interns were tempted by urology. At one year, 31/34 interns (91.2%) confirmed their choice in favour of urology. CONCLUSION: A practical training sessions very early in the training of young surgeons is a good solution to introduce them to urology. Based on a more informed choice, the most motivated interns are encouraged to preferentially choose this discipline.

[Is the surgical training of French urologists more effective than that of urologists in other European countries?]. / La formation chirurgicale des urologues français est-elle plus efficace que celle des autres pays européens?

OBJECTIVE: To compare the level of surgical training of French interns with that of interns in other European countries. MATERIAL AND METHODS: Between 2005 and 2006, an exhaustive questionnaire (www.esnz.net) was sent to 288 young urologists in 30 different European countries. Interns were classified into 3 groups: France (group 1, n = 28), Western Europe (group 2, n = 75) and Eastern Europe (group 3, n = 85). Items concerning surgical practice were analysed. RESULTS: The mean age of the interns was 30.8 years (25.7-35.8), 34.6 years (27.4-48.0) and 31.3 years (25.3-51.3) in groups 1 to 3, respectively. The mean number of months of urology training was 28 months (6-60), 44 months (6-72) and 37 months (2-120), respectively. The mean of weekly working time was 70 hours (40-90), 60 hours (35-90) and 65 hours (40-100). French interns were technically more at ease than interns in groups 2 or 3 for all surgical procedures (open, laparoscopic, endourological). Certain criteria were significantly (p < 0.05) associated with a better level of technical skills: the number of weekly working hours, the small number of interns per department, the diversity of internships, the use of the intern record and the presence of an active tutor CONCLUSION: French interns appear to learn urological surgical procedures more easily than other European interns. However the scientific training of interns must also be evaluated in order to propose a global assessment system of urology training in Europe.

New-generation flexible ureterorenoscopes are more durable than previous ones.

OBJECTIVES: To determine the deterioration in the maximal active deflection and flow capabilities of a new-generation flexible ureteroscope (URS). METHODS: We performed 50 ureterorenoscopies using the same URS: a Karl Storz 11278 AU1 Flex-X, which is capable of a 270 degree active deflection in the ventral and dorsal directions. Postoperatively, we evaluated the maximal active ventral and dorsal deflection, irrigation flow at 100 cm H2O, and the number of broken optical fibers. RESULTS: The URS was used for a total of 76 hours, 15 minutes (average 95 minutes per procedure). The maximal ventral deflection had deteriorated from 270 degrees to 208 degrees at the last procedure. The maximal dorsal deflection had decreased from 270 degrees to 133 degrees. The irrigation flow at 100 cm H2O had decreased from 50 mL/min initially to 40 mL/min at the last procedure. The number of broken image fibers had reached six at the 50th procedure. One repair was necessary at the 50th procedure because of a laser perforation of the working channel. CONCLUSIONS: The need for repair occurs less frequently with the new-generation of URSs, especially when they are used by an experienced endourologist. In the future, improvements in the durability of the flexible URS will still be key for widespread use of the technique and especially to limit damage by the laser to the working channel.

[How to anticipate specialization at the Examen National Classant (National Entrance Examination) to encourage interns to choose urology]. / Comment anticiper la filiarisation à l'Examen National Classant pour motiver les internes vers l'urologie?

OBJECTIVES: To analyse the value of an introduction to urology session to recruit interns following the Examen National Classant (ENC) (National Entrance Examination). MATERIALS AND METHODS: Over a 2-year period, interns appointed to surgery in Paris participated in a one-day introduction to urology session before starting work as surgical interns. A questionnaire at the beginning of internship recorded: age, gender, teaching hospital, student attachment in urology and desired specialization as a function of the surgical training programmes proposed by the ENC. Items concerning the desired specialization were resubmitted to the interns at the end of the session. RESULTS: Population. 166 interns, 98 females (59%) and 68 males (41%) with a mean age of 24.8 +/- 5 years (range: 22-31) participated in this study. 110 interns had trained at a Parisian teaching hospital (66.2%) and 56 (33.8%) had trained at a provincial teaching hospital. 31 interns (18.7%) had completed at least one urology attachment during their medical training. Desired specialization: Orthopaedics was the discipline most frequently cited (n=48; 28.9%). Urology was selected by 19 interns (11.4%), 17 of whom had completed an urology attachment during their medical training. At the end of the introduction to urology session, another 15 interns initially oriented towards other specializations were interested in urology training. CONCLUSION: Specialization of certain surgical disciplines during internship could become inevitable in the medium term. In this case, the organization of national introduction to urology sessions in each ENC allocation region would be a solution to encourage motivated interns to immediately choose urology as their surgical speciality by preference rather than by default.

Endoscopic lithotripsy and the FREDDY laser: initial experience.

BACKGROUND AND PURPOSE: The frequency-doubled double-pulse neodymium:YAG (FREDDY) laser has been developed for endoscopic lithotripsy and combines the characteristics of solid and dye lasers with a thin flexible optical fiber enabling it to be used with flexible ureterorenoscopy. Furthermore, it is less expensive and easier to maintain than other lasers. Our goal was to evaluate its efficacy and role in the ureteroscopic treatment of urinary stones. PATIENTS AND METHODS: We used a FREDDY laser in 26 patients (29 stones). For 4 stone cases, this was the first line of treatment; for the remaining cases, this was the second line of treatment, following SWL in 23 cases and nephrolithotomy in 2 cases. The mean stone size was 9 mm, with a range of 6 to 15 mm. There were 13 renal and 16 ureteral stones. The absence of residual fragments at 3-month postoperative radiography was considered to reflect successful treatment. RESULTS: Twenty-six stones were treated with satisfactory results. Within 3 months, 18 patients were stone free (69%), and 72.4% of the stones (21/29) had been treated completely. Fragments of 8 stones still remained in 8 patients. Of these stones, 5 were >10 mm and persisted at 3 months. Fragmentation was ineffective for 2 cystine stones and poor for 1 calcium oxalate monohydrate stone. Hospitalization, on average, was 1.5 days with a range of 1 to 3 days. A ureteral perforation was observed in the case of an impacted ureteral stone. CONCLUSIONS: Because of the wavelengths used, endoscopic FREDDY laser lithotripsy is an effective and harmless method. This laser can be used as a therapeutic tool because of its moderate cost and ability to be used with flexible ureterorenoscopy. However, it is important to be aware of the FREDDY laser's limited fragmentation capabilities for cystine stones and its inability to treat tissue lesions such as urinary-tract stenosis and tumors.

[Renal cell carcinoma and trichloroethylene]. / Carcinome rénal et trichloréthylène.

The authors report the case of a 51-year-old man with a history of trichloroethylene (TCE) poisoning. He was treated by radical nephrectomy after discovery ofa right renal mass corresponding to renal cell carcinoma. The objective of this study is to discuss the role of TCE abuse as a renal carcinogen. TCE is an excellent solvent used to degrease metal parts. It can enter the body by inhalation, ingestion or cutaneous contact, but the respiratory tract is the main route of absorption of TCE. Many epidemiological studies have been conducted on workers exposed to TCE, but they have not been able to clearly establish a link between exposure by inhalation to TCE and cancer. The International Agency for Research on Cancer has accumulated sufficient evidence to consider TCE to be carcinogenic to animals and considers that TCE is probably carcinogenic to humans. Toxic metabolites derived from TCE induce chronic renal tubular lesions and may exert a genotoxic effect on the proximal convoluted tubule. The initial genotoxic effect appears to be related to mutations of the VHL suppressor gene. The chronic toxic effects and the possible role of TCE in the development of cancer have not been specifically studied in the context of TCE abuse behaviour. To our knowledge, this is the first case of renal cell carcinoma reported in a TCE addict.

[How to avoid accumulation of stone fragments in the lower calix during flexible ureterorenoscopy]. / Comment éviter l'accumulation de fragments lithiasiques dans le calice inférieur au cours de l'urétérorénoscopie.

Flexible ureterorenoscopy combined with Holmium:YAG laser is an emerging technology that already has its place among the urologist's treatment options for the management of urinary stones. The main indication for the technique is renal stones, particularly lower caliceal stones. After mobilization of the stone in the renal pelvis or upper caliceal group, fragmentation is achieved by Holmium:YAG laser and the largest fragments are removed. When small fragments persist that are difficult to extract, the patient's blood is injected into the lower caliceal group to obtain a blood clot This clot then fills the lower caliceal group and prevents secondary accumulation of residual stone fragments, facilitating elimination of fragments towards the ureter. This article describes this technique.

[Comparative study of two latest generation flexible ureterorenoscopes]. / Etude comparative de deux urétérorénoscopes souples de dernière génération.

INTRODUCTION AND OBJECTIVES: Miniaturization and development of flexible instruments have led to the development of flexible ureterorenoscopy. The objective of this study was to compare the capacities of active deflection of two latest generation flexible ureterorenoscopes and to evaluate alteration of deflection and flow of irrigating fluid in the presence of instruments in the operating channel. MATERIAL AND METHODS: Two ureterorenoscopes were evaluated in this study. The Karl STORZ Flex-X and the ACMI DUR-8 Elite. Comparison of deflection movements was performed ex situ by super-imposing all active movements of the two ureterorenoscopes. Alteration of deflection was performed by alternately placing an extraction or fragmentation instrument of variable dimensions in the operating channel. Alteration of flow was also assessed in the presence of the same instruments. RESULTS: The ex situ deflection capacities of the DUR-8 Elite flexible ureterorenoscope were more extensive than those of the Flex-X, but it was more complicated to manipulate. Alterations of deflection and flow of irrigation fluid were comparable for the two ureterorenoscopes. CONCLUSION: On the basis of these data, we can confirm that the two latest generation ureterorenoscopes present comparable capacities, but different functioning modalities. We therefore recommend that each operator test the two ureterorenoscopes to become familiar with their manipulation. Other studies are necessary to evaluate the optical properties, ease of use in clinical practice and fragility of these new ureterorenoscopes.

[Endoscopic lithotripsy and FREDDY laser technology. Initial experience]. / Intérêt et place de la lithotritie endocorporelle Nd:YAG en urétéroscopie souple et semi-rigide: une alternative au laser Holmium:YAG?

INTRODUCTION AND PURPOSE: FREDDY laser technology was developed for endocorporeal lithotripsy. The purpose of this study was to evaluate, based on our initial experience, the efficacy and place of this technology in the treatment of urinary calculi by ureterorenoscopy. (World of Medicine) to treat 26 patients (29 stones) by ureterorenoscopy. This was the second procedure for 25 stones: after ESWL (23 cases) or percutaneous nephrolithotomy (2 cases) and the first procedure for 4 stones. The mean stone diameter was 9 mm (range: 6-15 mm). Thirteen stones were situated in the kidney and 16 were in the ureter. Success of treatment was defined by the absence of residual fragments immediately after the operation or at one month on plain abdominal x-ray. RESULTS: Twenty-six stones were satisfactorily fragmented. At three months, 21 out of 26 (80.7%) patients were stone-free corresponding to 21 out of 29 (72.4%) stones). Failures concerned 8 stones (5 patients). For five stones, measuring more than 10 mm, residual fragments persisted at three months. For three other stones, two cystine stones and one calcium oxalate monohydrate stone, fragmentation was insufficient or even nonexistent for the cystine stones. The mean length of hospital stay was 1.5 days (range: 1-3 days). A ureteric perforation due to a stone impacted in the ureteric wall was observed. CONCLUSIONS: FREDDY laser endoscopic lithotripsy is a safe and effective method due to the wavelength used. This laser could constitute an alternative treatment option in view of its moderate cost and the fact that it is adapted to flexible ureterorenoscopy. However, it presents certain limitations in terms of fragmentation, particularly in the case of cystine stones, and cannot be used to treat solid lesions (urinary tract strictures and tumours).

[Improvement of the recruitment of surgery interns derived from the Epreuves Nationales Classantes (National-Ranking Exam): practical solution applied to urology]. / Amélioration du recrutement des internes de chirurgie issus des Epreuves Nationales Classantes: solution pratique appliquée a la filière urologique.

OBJECTIVES: To analyse the value of an urology initiation session proposed to young interns to improve recruitment of the discipline since the introduction of the new National-Ranking Exam (NRE). MATERIALS AND METHODS: In October 2004, the 77 interns appointed to surgery in Paris on the basis of the ENC participated in a one-day urology initiation session organized by the AFUF, at the AP-HP School of Surgery. All interns were given a questionnaire at the beginning of the session to record the following data: age, gender, teaching hospital, a student attachment in urology and desired specialization as a function of the surgical training programmes proposed by the ENC. Items concerning the desired specialization were resubmitted to the interns at the end of the session. RESULTS: Population. 77 interns, 48 females (62.3%) and 29 males (37.7%) with a mean age of 25.2 +/- 5 years (range: 23-31). 55 interns had trained at a Parisian teaching hospital (67%) and 22 (28.6%) had trained at a provincial teaching hospital. 16 interns (20.8%) had completed at least one urology attachment during their medical training. Desired specialization. Orthopaedics was the discipline most frequently cited (n = 20; 26%). Urology was chosen by 8 interns (10.40%), who had all completed an urology attachment during their medical training. At the end of the urology initiation session, another 8 interns expressed the desire to specialize in urology. Of the 16 potential urology interns, 9 (56.2%) confirmed that their decision was final. CONCLUSION: Urology occupies a special place and remains a popular surgical speciality among students. Organization of practical sessions constitutes a solution to inform, create an emulation and motivate surgery interns to choose urology.

[Spontaneous renal haematoma: diagnostic and therapeutic approach in 7 cases]. / Hématomes spontanés du rein: conduite à tenir diagnostique et thérapeutique. A propos de 7 cas.

OBJECTIVE: Spontaneous renal haematomas are rare. The authors discuss the aetiological diagnosis and management of these haematomas. MATERIAL AND METHODS: Seven cases (3 females and 4 males) of spontaneous renal haematoma were managed between July 1999 and December 2002 and the case files were studied retrospectively. RESULTS: The circumstances of discovery were nonspecific. One patient presented with haemorrhagic shock. Radiological work-up comprised abdominal ultrasound and CT scan in almost every case. Ultrasound failed to demonstrate the aetiological diagnosis. CT revealed the cause of bleeding in 7 cases. MRI was performed in 4 cases, but urgent angiography was not performed. Four total nephrectomies were necessary, while two patients were treated by conservative surgery. One patient was simply followed by repeat CT scan. The short-term course was favourable with a mean follow-up of 23 months. CONCLUSION: Spontaneous renal haematomas raise 2 problems, that of their aetiology: tumours are the commonest causes (angiomyolipoma and renal cell carcinoma), and that of their management. Three therapeutic approaches are possible: radical surgery in the case of uncontrollable bleeding, conservative surgery or surveillance in the absence of a life-threatening emergency and when the aetiological diagnosis has not been established. Rigorous and repeated radiological surveillance can identify the cause of the bleeding allowing conservative surgery to be performed when indicated.

[Management of dog bite trauma of the external genital organs]. / Conduite a tenir devant un traumatisme des organes génitaux externes par morsure de chien.

Animal bites to the scrotum are rare, but potentially serious. In the light of a personal case, the authors discuss the management of these lesions. An animal bite comprises a triple infectious risk: bacterial, tetanus and rabies. Surgical exploration is indicated for assessment of the structures involved and debridement. The morbidity is related to the severity of the bite and the waiting time before consultation, and complications are rare. Orchidectomy is sometimes necessary, as in the case reported here, and the patient must be warned about this possibility. Antibiotic therapy is empirical: tetracycline and anti-anaerobe antibiotic. Rabies and tetanus prophylaxis must be performed according to vaccine guidelines.