Grade Bladder Tumors Research Articles

Ureterectomy in the treatment of urothelial carcinoma of the distal ureter

IntroductionSegmental ureterectomy with preservation of the kidney is a treatment option for the low grade urothelial carcinoma (LG-UC) in distal ureter that is not a candidate for endoscopic resection. Laparoscopic distal ureterectomy (LDU) with ureteral reimplantation is common in benign conditions (stenosis, iatrogenic lesion, endometriosis). However, it has been hardly described in malignant ureteral condition. The literature is reviewed in this regard and the surgical technique is described. Material and methodsThe experience regarding two cases of LDU due to low grade urothelial carcinoma in distal ureter is presented. In both, previous bladder transurethral resection (RTU) was performed. The urinary cytology was negative and the imaging studies identified urinary obstruction and distal ureter filling defect. One of the patients had a background of T1G3 bladder cancer and suffered renal failure. In both, the ureter was ligated early. Segmental ureterectomy was performed using a combined endoscopic and laparoscopic procedure with ureteral desinsertion in one case. In the other, it was exclusively laparoscopic. Both were done with 4 trocars. Ureteral reimplantation was conducted with continuous hermetic suture and without tension. In one case with background of high grade bladder tumor, pelvic lymphadenectomy was also performed. ResultsOperating time was 180 and 240min, respectively, with estimated bleeding of 100 and 250ml. Hospitalization time was 6 and 4 days. The only post-operatory complication was paralytic ileum (Clavien I) in the first case. With a 20 and 12 month follow-up, there is no evidence of recurrence or dilatation. In the patient with renal failure, creatinine clearance improved. ConclusionsThe LDU with ureteral reimplantation is a complex technique. However, it represents a feasible and effective alternative for the treatment of LG-UC in distal ureter, as long as the oncological and reconstructive principles are respected.

929 NEXT-GENERATION DEEP SEQUENCING IDENTIFIES RECURRENT AND TARGETABLE GENETIC ALTERATIONS IN HIGH GRADE BLADDER UROTHELIAL CARCINOMA

INTRODUCTION AND OBJECTIVES: High grade urothelial carcinoma (UC) is an aggressive malignancy with limited therapeutic options in the advanced, metastatic, or recurrent disease setting. Targeted genetic analysis of high grade tumors was performed to determine the prevalence of known cancer genes and to identify potential targets for therapy. METHODS: Frozen high grade bladder tumors and matched germline blood DNA were obtained from 60 patients undergoing transurethral resection (TUR) or cystectomy. Specimens were analyzed using a targeted, deep-sequencing assay designed to identify point mutations, indels, and copy number alterations in 275 cancer-associated genes. RESULTS: The cohort was predominantly male (N 49, 81%) with a median age of 71 (IQR 61, 76). Frozen tumor was obtained from radical cystectomy(RC) in 53 patients (88%), TUR in 6 (10%), and partial cystectomy in 1 (2%). 11 patients (18%) had a history of intravesical therapy. Tumor pathologic stage was Ta in 5 (8%), T1 in 5 (8 %), T2 in 11 (18%), T3 in 30 (50%), and T4 in 9 (15%). Of the 53 patients undergoing RC and lymph node dissection, 17 received neoadjuvant chemotherapy (32%) and 24 (45%) had lymph node metastases. Mean target coverage for all sequenced exons was 512X. The most common genomic event was somatic mutation of TP53, identified in 33 patients (55%). RB mutations were identified in 11 (18%). Alterations in the PI3K/AKT/mTOR signaling pathway were also common; 12 patients had mutations in PIK3CA (20%), and non-overlapping mutations were identified in other genes within the pathway including AKT1, PTEN, and MTOR. Frequent mutations in chromatin remodeling genes were also identified. KDM6A mutations were identified in 21 tumors (35%), MLL2 in 18 (30%), and ARID1A in 17 (28%). Overall, 60% of all analyzed tumors harbored potentially targetable genomic alterations, including those with alterations in ERBB2, BRAF, and FGFR3 (Figure). CONCLUSIONS: Genetic alterations are frequent in high grade bladder UC. Over half of the tumors analyzed harbor alterations in genes that have been targeted for therapeutic benefit in other solid tumors, thus providing a compelling case for clinical trials using novel agents. Analysis for correlations with clinical outcomes is ongoing to assess for the prognostic significance of these genetic events. Source of Funding: Sidney Kimmel Center for Prostate and Urologic Cancers, Michael and Zena Wiener Research and Therapeutics Program in Bladder Cancer

1621 ONCOLOGICAL OUTCOME OF RADICAL CYSTECTOMY FOR BCG FAILURE COMPARED TO PRIMARY INVASIVE DISEASE

You have accessJournal of UrologyBladder Cancer: Invasive (II)1 Apr 20131621 ONCOLOGICAL OUTCOME OF RADICAL CYSTECTOMY FOR BCG FAILURE COMPARED TO PRIMARY INVASIVE DISEASE Alexandra Masson-Lecomte, Dimitri Vordos, René Yiou, Yves Allory, Claude Abbou, Alexandre de la Taille, and Laurent Salomon Alexandra Masson-LecomteAlexandra Masson-Lecomte Creteil, France More articles by this author , Dimitri VordosDimitri Vordos Créteil, France More articles by this author , René YiouRené Yiou Créteil, France More articles by this author , Yves AlloryYves Allory Créteil, France More articles by this author , Claude AbbouClaude Abbou Créteil, France More articles by this author , Alexandre de la TailleAlexandre de la Taille Créteil, France More articles by this author , and Laurent SalomonLaurent Salomon Créteil, France More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.3171AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES BCG therapy deeply modified prognosis of high risk non muscle invasive (NMI) urothelial carcinomas. However, these tumors remain potentially lethal. The objective of this study was to compare oncological outcome of radical cystectomy (RC) for BCG failure to primary invasive(PI) tumors. METHODS RC performed between 2001 and 2011 were retrospectively reviewed. Clinico-pathological and follow up data were compared between RC performed for (i) NMI high grade recurrence under BCGtherapy (ReNMI) (ii), MI recurrence (ÂiÝT2) under BCGtherapy (ReMI) (iii) Primary Invasive tumors (PI). The three groups were defined according to tumor status on last TUR before RC. All NMI high grade bladder tumors at diagnosis had maintenance BCG immunotherapy. RESULTS 200 patients were included, 155 PI, 21 ReNMI et 24 ReMI. Median follow up was 42 months (1.74-135.9). Mean BCG instillations number was 8±4.2 vs 9.5±4.3 for ReNMI and ReMI respectively (p=0.24). Upgrading (ÂiÝpT2) occurred in 33% of ReNMI. The rate of pN+ was 24%, 42% and 30% for the ReNMI, ReMI et PI respectively (p=0.39). No differences were observed between the groups for lymphovascular invasion, extracapsular extension if pN+, soft tissue surgical margins and adjuvant chemotherapy. 5-year cancer specific survival (CSS) was 48% for the ReNMI, 18% for the ReMI and 47% for the PI (p=0.02) (Figure). Progression to muscle invasion under BCG therapy was an independent pejorative prognostic factor for CSS (p=0,05). CONCLUSIONS BCG failure leads to poor prognosis, particularly when tumors progress to muscle invasion. Recurrent NMI high grade tumors seem to have comparable prognosis than PI tumors because of the high amount of upstaging and nodal invasion. BCG failure is a therapeutic emergency. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e666 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexandra Masson-Lecomte Creteil, France More articles by this author Dimitri Vordos Créteil, France More articles by this author René Yiou Créteil, France More articles by this author Yves Allory Créteil, France More articles by this author Claude Abbou Créteil, France More articles by this author Alexandre de la Taille Créteil, France More articles by this author Laurent Salomon Créteil, France More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

La ureterectomía distal laparoscópica en el tratamiento del carcinoma urotelial del uréter distal

IntroductionSegmental ureterectomy with preservation of the kidney is a treatment option for the low grade urothelial carcinoma (LG-UC) in distal ureter that is not a candidate for endoscopic resection. Laparoscopic distal ureterectomy (LDU) with ureteral reimplantation is common in benign conditions (stenosis, iatrogenic lesion, endometriosis). However, it has been hardly described in malignant ureteral condition. The literature is reviewed in this regards and the surgical technique described. Material and methodsThe experience regarding two cases of LDU due to low grade urothelial carcinoma in distal ureter is presented. In both, previous bladder transurethral resection (RTU) was performed. The urinary cytology was negative and the imaging studies identified urinary obstruction and distal ureter filling defect. One of the patients had a background of T1G3 bladder cancer and suffered renal failure. In both, the ureter was ligated early. Segmental ureterectomy was performed using a combined endoscopic and laparoscopic procedure with ureteral desinsertion in one case. In the other, it was exclusively laparoscopic. Both were done with 4 trocars. Ureteral reimplantation was conducted with continuous hermetic suture and without tension. In one case with background of high grade bladder tumor, pelvic lymphadenectomy was also performed. ResultsOperating time was 180 and 240min, respectively, with estimated bleeding of 100 and 250ml. Hospitalization time was 6 and 4 days. The only post-operatory complication was paralytic ileum (Clavien I) in the first case. With a 20 and 12 month follow-up, there is no evidence of recurrence or dilatation. In the patient with renal failure, creatinine clearance improved. ConclusionsThe LDU with ureteral reimplantation is a complex technique. However, it represents a feasible and effective alternative for the treatment of LG-UC in distal ureter, as long as the oncological and reconstructive principles are respected.

Evaluation of tissue and urinary survivin expression in non-muscle-invasive bladder cancer

Approximately 70% of bladder cancers are non-muscle-invasive (NMIBC), and respond well to endoscopic transurethral resection. However, 70% of these patients experience tumor recurrence. As the tendency for local recurrence and/or progression extends over the lifetime, patients with superficial bladder cancer must undergo life-long surveillance. Combination of cystoscopy and urine cytology is considered the “gold standard” for this surveillance. However, they suffer from drawbacks where cystoscopy is an invasive procedure and urine cytology shows limited ability to detect low grade bladder tumors. Therefore, new non-invasive tests with high sensitivity and specificity that are easy to perform are needed not only for initial diagnosis but also in surveillance for recurrent tumors. To investigate the magnitude investigate the magnitude of survivin expression in non-muscle-invasive bladder cancer and its possible value as a non invasive diagnostic tool. From March 2010 to October 2010, 68 patients with known history of NMIBC who were scheduled for follow-up cystoscopy in the department of Urology, Alexandria University were included in this study prospectively. All patients underwent cystoscopy under general anaesthesia, and those who were found to have a definite or suspicious lesion(s) in the bladder underwent complete TURBT. Survivin expression was determined in urine and in bladder cancer tissue both by Western blotting and by ELISA. The study included 68 patients. Tumor recurrence was detected in 38 patients, of whom, 24 had low grade recurrence. The urinary concentration of survivin was significantly higher in the recurrence group by both detection methods ( U = 141, P = 0.018 and χ 2 = 10.46, P = 0.001 for ELISA and WB respectively). Survivin by ELISA showed higher sensitivity and specificity (84.4% and 100%) than that by WB (55.3% and 93.3%). In tumor tissue, by both methods, survivin was detected in higher levels than in urine but there was no significant correlation between urinary and tissue levels neither in the whole recurrence group nor in the low grade subgroup. Urinary survivin is a useful marker for non-invasive detection of non-muscle-invasive bladder cancer recurrence. Its detection is better using ELISA technique than WB and there is no correlation between its expression in tissue and urine.

Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India

Background:Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer.Aims:As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy.Materials and Methods:A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic. Results:Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells.Conclusions:The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria.

Potentiation of Mitomycin C Tumoricidal Activity for Transitional Cell Carcinoma by Histone Deacetylase Inhibitors In Vitro

Histone deacetylase inhibitors represent promising cancer treatments since they offer improved access to target DNA/protein complexes by cytotoxic agents. We hypothesized that histone deacetylase inhibitors would be most effective when combined with DNA damaging agents such as mitomycin C. Valproic acid is a safe, affordable histone deacetylase inhibitor. We examined the effect of the combination of valproic acid and mitomycin C on human bladder cancer cells in vitro and compared this to the effect of valproic acid or mitomycin C alone on the cells. We used HTB5 and HTB9 cells derived from low and high grade bladder tumors, respectively. HTB5 and HTB9 cells were grown in modified Eagle's and RPMI medium, respectively. Cell growth and proliferation were measured by standard methods. Apoptosis was evaluated microscopically after dual staining of cells with annexin V-fluorescein isothiocyanate/propidium iodide. The change in protein expression was analyzed by Western blot. Treatment of HTB5 and HTB9 bladder cancer cells for 24 to 72 hours with valproic acid and mitomycin C resulted in concentration and time dependent decreases in viability and proliferation. HTB9 cells showed marked sensitivity to mitomycin C with a 48-hour 50% median inhibitory concentration of 1 μg. Cells were less sensitive to valproic acid alone with a 48-hour 50% median inhibitory concentration of 2.5 mM. The chromatin structure relaxation induced by valproic acid pretreatment sensitized the bladder cancer cell lines, augmenting the cytotoxic action of mitomycin C. Valproic acid potentiated the induction of cell death by mitomycin C in each cell line in synergistic fashion. The effect of combining the 2 drugs was greater than the sum effect of each drug alone. Results indicate that the valproic acid and mitomycin C combination is effective, likely due to synergistic mechanisms. Animal model validation is needed but early results suggest promising intravesical treatments for superficial bladder cancer.

Clinical significance of simultaneous transurethral resection of a bladder tumor and the prostate in the treatment of non-muscle invasive bladder cancer with benign prostatic hyperplasia

Objective To evaluate the clinical significance of simultaneous transurethral resection (TUR) of a bladder tumor and the prostate in the treatment of non-muscle invasive bladder cancer with benign prostatic hyperplasia (BPH).Methods Patients were divided into two groups.Group A contained 46 male patients who accepted TUR for the treatment of both bladder cancer and benign prostatic hyperplasia.Group B contained 69 male patients who accepted TURBt only.Clinical data were retrospectively collected and analyzed to compare clinical outcomes and safety in these two groups.Results The bladder cancer recurrence rates in group A and B were 50.0％ and 50.7％,the average recurrence free time was 20 and 18 months,and the progression rates were 6.5％ and 7.2％,respectively.There were no significant differences between the two groups for either average recurrence free time or progression rates (P ＞ 0.05).Recurrences in the prostatic urethra were found in two cases in group A and one case in group B and all three cases were in T1 G3.Conclusions Simultaneous TUR for bladder tumor and the prostate can be safely and effectively performed in terms of oncologica] control in patients who have non-muscle invasive and low grade bladder tumors ( T1G1 - G2 ) with lower urinary tract obstruction caused by BPH.But this procedure should be cautiously performed on patients with T1 G3 bladder tumors. Key words: Bladder neoplasms; Benign prostatic hyperplasia; Transurethral resection

1240 DIAGNOSTIC, PREDICTIC AND PROGNOSTIC IMPORTANCE OF URINE INTERLEUKIN (IL)8, IL6, IL5 AND IL4 CONCENTRATION IN PATIENTS WITH BLADDER CARCINOMA

1240 DIAGNOSTIC, PREDICTIC AND PROGNOSTIC IMPORTANCE OF URINE INTERLEUKIN (IL)8, IL6, IL5 AND IL4 CONCENTRATION IN PATIENTS WITH BLADDER CARCINOMA

FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population

Bladder cancer accounts for nearly 5% of all newly diagnosed cancers in Jordan, with a much higher frequency in males. Recent studies have shown that activating mutations in FGFR3 are the most common findings in non-invasive low grade bladder tumors. In this study, we, retrospectively, investigated a cohort of 121 bladder cancer patients with various grades and stages of the tumor for molecular changes in FGFR3. Overexpression of FGFR3 was observed in 49%, 34%, 15%, and 2% of pTa, pT1, pT2, and pT3 cases, respectively. Further, FGFR3 expression was positive in 45%, 26%, and 30% of G1, G2 and G3 cases, respectively. Mutational analysis of exons 7, 10 and 15 of FGFR3 identified four previously reported mutations, namely R248C ( n = 4; 10%), S249C ( n = 23; 59%), Y375C ( n = 7; 18%), G382R ( n = 4; 10%), and one novel mutation, G382E ( n = 1; 3%). Our results indicate that both mutations and overexpression of FGFR3 are correlated together, and are more prevalent in early stage (pTa and pT1) and low grade (G1 and G2) bladder tumors. Survival analysis showed no contribution of changes in FGFR3 on the patient's survival. Multivariate Cox proportional hazards model analysis of overall survival for the following variables: age, gender, stage and grade of tumor, and FGFR3 (expression and mutation) revealed that age, stage and grade of tumor are independent predictors of overall survival in patients with bladder cancer. Our work is the first to address the molecular status of FGFR3 in Jordanian patients with bladder cancer, and provides further support for FGFR3 as a key player in the initiation of bladder tumors.

The Prognostic Predictors of Primary Ureteral Transitional Cell Carcinoma After Radical Nephroureterectomy

We studied the long-term prognosis, and evaluated the predictors of disease specific and recurrence-free survival in a large cohort of patients who had undergone radical nephroureterectomy for primary transitional cell carcinoma of the ureter. From January 1990 to December 2006, 145 patients with primary ureteral transitional cell carcinoma treated with nephroureterectomy and bladder cuff removal at our institution were included in the study. The medical records of these patients were reviewed retrospectively. The clinical and histopathological data were analyzed to evaluate the prognostic predictive factors. Univariate and multivariate statistical analyses were performed. The 5-year disease specific survival rates of stage pTa/Tis/T1, pT2, pT3 and pT4 were 94.6%, 81.8%, 47.4% and 0%, respectively. The 5-year recurrence-free survival rates according to tumor grade were 68.4% for low grade and 35.7% for high grade disease. Of the 145 patients subsequent bladder tumors developed in 38 (26.2%), local recurrence developed in 11 (7.6%) and metachronous contralateral upper urinary tract tumor developed in 3 (2.1%). Most patients had subsequent tumor recurrence within the first year after radical surgery. On univariate and multivariate analyses tumor stage, tumor grade, severity of chronic renal disease, synchronous bladder tumor and hematuria were the significant prognostic variables predicting disease specific and recurrence-free survival. Advanced tumor and chronic renal disease stages were significantly associated with a worse prognosis in patients with primary ureteral transitional cell carcinoma who had undergone radical nephroureterectomy. With regard to tumor recurrence, advanced tumor stage, high tumor grade and synchronous bladder tumor were independent risk factors.

Fibroblast Growth Factor Receptor 3 Mutations in Bladder Tumors Correlate with Low Frequency of Chromosome Alterations

The aim of this study was to analyze the distribution of FGFR3 mutations in bladder tumors of different grade and stage and determine the relation of mutations to chromosomal alterations detected by comparative genomic hybridization (CGH). One hundred bladder cancer samples served as templates for manual microdissection. DNA was isolated from dissected samples containing at least 80% tumor cells. Mutations in FGFR3 were analyzed by SNaPshot analysis. CGH was carried out according to standard protocols. FGFR3 mutations were detected in 45 of 92 samples (48.9%). Concerning T-category, the following mutation frequencies occurred: pTa, 69%; pT1, 38%; and pT2-3, 0%. The mutation frequency was significantly associated with tumor grade: G1, 72%; G2, 56%; and G3, 4%. In pTaG1 tumors, mutations were found in 74%. A significantly lower number of genetic alterations per tumor detected by CGH was associated with FGFR3 mutations (2 vs 8). This association was also seen in pTaG1 tumors: 2.5 (with mutation) vs 7.5 (without mutation). FGFR3 mutations characterize noninvasive low-risk tumors of low malignancy. The low malignant potential of these tumors is underlined by a low number of genetic alterations per tumor. Therefore, FGFR3 represents a valuable prognostic marker of tumors with low malignant potential and can be used as surrogate marker for the detection of genetically stable bladder tumors.

Conservative Management of Low Risk Superficial Bladder Tumors

The most common approach for nonmuscle invasive urothelial cancers of the bladder is transurethral resection of the bladder tumor, often under regional or general anesthesia. Due to the high rate of recurrence, many such patients experience the potential risks and morbidity of frequent surgical intervention, despite the often slow growth rate and low risk of progression of such tumors. Recent experiences have suggested that some patients with low grade superficial tumors may be treated expectantly. We report on our experience with expectant management of low risk superficial bladder tumors. We retrospectively evaluated 173 patients with superficial bladder cancer who are currently actively treated at our institution and who have complete clinical information. From this population we identified 22 cases (12.7%) under expectant management for bladder tumors in the last 12 months. Demographic and clinical information on this cohort are described as well as clinical and pathological outcomes, and disease interventions on followup. All patients had a prior history of recurrent low risk (Ta, low grade) bladder tumors. The mean followup was 25 months. Of the 22 patients 8 had no growth, 9 had minimal growth and 5 had moderate growth of their tumors. Fifteen patients have required no intervention, 3 have undergone office fulguration and 4 have undergone repeat transurethral bladder tumor resection. Two men (9%) had evidence of grade progression on followup transurethral bladder tumor resection, and 1 of these men (4.5%) had stage progression (T1 disease). Both men had evidence of moderate tumor growth and suspicious/malignant cytology which resulted in the repeat transurethral bladder tumor resection. Interestingly, these 2 men had a 6 and 11 year history of recurrent Ta, low grade disease before progression and had been under expectant management for 18 and 12 months before progression. Interestingly all smokers had a recurrence during the surveillance period and this represented a 3.3-fold increased rate of recurrence over nonsmokers. Expectant management of recurrent bladder tumors may be an appropriate option for some patients with a history of Ta, low grade tumors, especially those who are older and with significant medical comorbidities. Such a strategy may avoid potential risks and morbidities associated with frequent, repeat transurethral bladder tumor resection. However, under such an expectant management strategy, patients should remain under careful cystoscopic and cytologic surveillance as there remains some risk for grade and stage progression in this patient population.

Management of Low Grade Papillary Bladder Tumors

We evaluated the management and treatment outcomes of low grade papillary bladder tumors. We evaluated 215 patients diagnosed with low grade and noninvasive papillary bladder tumors, and followed them every 6 months with flexible cystoscopy for 6 to 10 or more years. Tumor recurrence was treated with transurethral resection or outpatient cystoscopic fulguration. Of the 215 patients 143 (67%) had at least 1 recurrence (positive cystoscopy). With a median followup of 8 years tumor recurrences averaged 6.2 (range 1 to 19) requiring 0.34 transurethral resections per year or 1 transurethral resection every 3 years, or 0.61 fulgurations or 1 fulguration approximately every 2 years. There were 17 patients (8%) who had progression in grade or stage and 1 patient (0.5%) died of bladder cancer. Patients most likely to have recurrence had multiple tumors, low grade (TaLG) carcinoma or tumor at first followup cystoscopy. Surveillance cystoscopy at 6-month intervals coupled with outpatient fulguration controls recurrent tumors and reduces the therapeutic burden for patients diagnosed with low grade papillary bladder tumors.

Fibroblast Growth Factor Receptor 3 Mutations in Epidermal Nevi and Associated Low Grade Bladder Tumors

Epidermal nevi (EN) are benign lesions presenting at birth or in childhood. Based on the occurrence of fibroblast growth factor receptor 3 (FGFR3) mutations in seborrheic keratosis and urothelial carcinomas (UC), and the identification of two young patients with EN and UC, we hypothesized that mutations might occur in EN. The R248C mutation was found in 6/23 (26.1%) EN but it was absent from unaffected skin. In two patients with EN and UC, both lesions were FGFR3 wild type. Our findings indicate that: (1) FGFR3 mutations occur in mosaicism and can cause EN and (2) other genes are involved in EN.

771: Low Frequency of Chromosomal Alterations in CGH Analysis in Low-Risk Papillary Bladder Tumors with FGFR3 Mutations

Proc Amer Assoc Cancer Res, Volume 47, 2006 4205 FGFR3 was shown to be mutated frequently in bladder cancer. Furthermore, it was suggested, that mutation of FGFR3 is associated with non-invasive tumors of low malignant potential and low risk of recurrence and progression. We hypothesize that FGFR3-mutated tumors are more genetically stable than bladder tumors without mutation.The aim of this study was to analyze the distribution of FGFR3 mutations in bladder tumors of different grade and stage and determine the relation of FGFR3 mutations to chromosomal alterations detected by CGH. Frozen sections of 100 bladder cancer samples served as templates for manual microdissection. DNA was isolated from dissected samples containing at least 80% tumor cells. Mutations in FGFR3 were analyzed by SNAPShot analysis. CGH was carried out according to standard protocols. Results of mutation analysis were obtained from 92 samples. FGFR3 mutations were detected in 45 samples (48.9%). Concerning T-category, the following mutation frequencies occurred: pTa- 61%, pT1-40%, pT2/3- 0%. The mutation frequency was also significantly associated with tumor grade: G1-70%, G2-46%, G3-4%. In pTaG1 tumors, mutations were found in 72%. A significantly lower number of genetic alterations per tumor detected by CGH was associated with FGFR3 mutations (3.3 vs. 10 alterations per tumor ). This association was also seen in pTaG1 tumors: 3.2 (with mutation) vs. 6.8 (without mutation). In pTa/pT1 tumors gain of 8q was detected more frequently in non-mutated tumors (86% vs. 25%). Our results confirm that FGFR3 mutations characterize non-invasive low-risk tumors of low malignancy. The low malignant potential of these tumors is underlined by a low number of genetic alterations per tumor. Therefore, FGFR3 represents a valuable prognostic marker of tumors with low malignant potential and could be used as surrogate marker for detection of genetic stable bladder tumors with good clinical outcome.

MP-12.04: Low frequency of chromosomal alterations in CGH analysis in low-risk papillary bladder tumors with FGFR3 mutations

It has been suggested that mutation of FGFR3 is associated with non-invasive tumors of low malignant potential and low risk of recurrence and progression. We hypothesize that FGFR3-mutated tumors are more genetically stable than bladder tumors without mutation. The aim of this study was to analyze the distribution of FGFR3 mutations in bladder tumors of different grade and stage and determine the relation of FGFR3 mutations to chromosomal alterations detected by CGH.

Urinary Survivin Test Compared to the Nuclear Matrix Protein (NMP)-22 Test and Urine Cytology for the Diagnosis of Bladder Cancer

Purpose: The aim of this study was to compare the sensitivity and specificity of the urinary survivin test for the diagnosis of bladder cancer with the nuclear matrix protein (NMP)-22 test and the urine cytology, and we wanted to correlate survivin with the tumor stage and grade. Materials and Methods: Between October 2002 and March 2004, voided urine samples were obtained from 41 patients with bladder cancer and also from 36 controls who had no evidence of bladder cancer. The urinary survivin and NMP-22 levels were measured using a DuoSet IC ELISA kit and an automated chemiluminescent assay system. The results were compared with the cytologic results and the pathologic findings. Results: The comparative results showed the higher sensitivity for the urinary survivin test (78.0%) and the NMP-22 test (75.6%) than for the urine cytology (65.8%) for the detection of bladder cancer. The specificity of urinary survivin (86.1%) and urine cytology (97.2%) were higher than that for the NMP-22 test (66.6%). Measuring the urinary survivin level was a more accurate test than the urinary NMP-22 test and the urine cytology for the detection of lower grade and superficial bladder cancer. Conclusions: The urinary survivin test was superior to urine cytology for sensitivity and specificity, and these two parameters of the urinary survivin test were higher than those of the NMP-22 test. Especially, the urinary survivin test is an accurate diagnostic test for superficial and lower grade bladder tumor. Our results suggested that the urinary survivin test appears to be a reliable diagnostic test to identify patients with bladder cancer. (Korean J Urol 2006;47:1041-1045) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Praxis der intravesikalen Instillationsprophylaxe beim oberflächlichen Harnblasenkarzinom - Ergebnisse einer Umfrage in Sachsen

For patients with superficial bladder cancer, adjuvant intravesical chemotherapy or immunotherapy with Bacillus Calmette-Guerin (BCG) is recommended in national and international guidelines. We analyzed whether the recommended therapeutic regimens are used in daily urological practice. Questionnaires concerning the adjuvant intravesical therapy were sent to 152 urologists in the German Federal State of Saxony. Of the surveyed physicians, 134 practiced in an outpatient medical facility and 18 in a hospital. Of the questionnaires, 73 (48.02 %) were returned and evaluated. An adjuvant intravesical therapy after transurethral bladder tumor resection was performed in every second patient (median value 50.07 %). The majority of the urologists (79.4 %) treated the bladder tumors with intravesical chemotherapy or BCG depending on tumor stage and grade of malignancy. Chemotherapeutic agents or BCG was exclusively used in 13.6 % and 4.1 % of treated patients, respectively. Chemotherapeutic agents were predominantly applied up to the primary tumor stage T1 and malignancy grade G2. In cases with recurrent T1 bladder tumors of G2 or higher grade of malignancy, BCG was the main agent for intravesical treatment. In patients with recurrent T1G3 tumors, the majority of urologist (57.1 %) preferred another therapeutic regimen than intravesical instillation. Only 23.2 % of the urologists believed that intravesical BCG is superior to chemotherapeutic agents. These data demonstrate that adjuvant intravesical instillation with chemotherapeutic agents and BCG is well established in urological practice. In contrast to the recommendations of national and international guidelines, chemotherapeutic agents are more frequently used in cases with a high risk of progression.

Urine Detection of Survivin is a Sensitive Marker for the Noninvasive Diagnosis of Bladder Cancer

In a preliminary study urine detection of survivin, an integrator of cell death and mitosis, accurately detected bladder cancer. The objectives of this study were to confirm these findings in a large cohort of subjects undergoing cystoscopy, to assess the diagnostic performance of urine survivin and to test whether evaluation of urine survivin adds independent value to urine NMP22 (Matritech, Cambridge, Massachusetts) and cytology for the detection of bladder cancer. Urine survivin was measured using a Bio-Dot microfiltration detection system (Bio-Rad, Hercules, California) in voided urine specimens collected before cystoscopy in 117 cases and 92 controls. Bladder washout samples for cytology were collected in 174 subjects. Urine levels of NMP22 were measured using a commercially available enzyme-linked immunosorbent assay. Higher levels of urine survivin were associated with an increased risk of bladder cancer (p <0.001) and tumors of higher grade (p = 0.037), but not with invasive stage, after adjustment for the effects of urine cytology, NMP22 and age. The sensitivity, specificity, and positive and negative predictive values of survivin for the diagnosis of bladder cancer (64%, 93%, 92% and 67%, respectively), are superior to those of NMP22 and cytology. Survivin had the highest specificity and positive predictive value for the detection of bladder cancer across each tumor stage and grade. Urine survivin was a strong, independent predictor of the presence of bladder cancer and higher tumor grade. Urine detection of survivin is an accurate diagnostic test for bladder cancer that retains its efficiency regardless of cancer stage and grade.