Superficial Transitional Cell Carcinoma Of Bladder Research Articles

The Diagnostic and Prognostic Performance of Urinary FGFR3 Mutation Analysis in Bladder Cancer Surveillance: A Prospective Multicenter Study

To assess the diagnostic and prognostic performance of a noninvasive FGFR3 mutation analysis. After transurethral resection (TUR) of noninvasive bladder transitional cell carcinoma (B-TCC), recurrence occurs in 70% of patients, thus justifying cystoscopic surveillance. A prospective multicenter study was carried out with a 2-year follow-up of patients with superficial B-TCC. Urine samples were collected before TUR and then before each cystoscopy during follow-up. Screening for the most prevalent FGFR3 mutations was done using urinary cells. The prognostic significance of an FGFR3 mutation at the time of the initial diagnosis was determined. The performance of the test in diagnosing and/or predicting recurrence during follow-up was assessed by calculating sensitivity and specificity. Of 191 patients studied, 74 (39%) had a positive analysis before TUR (FGFR3 mutation group). The presence of an FGFR3 mutation at the time of diagnosis was associated with a shorter time to recurrence (P=.02). During follow-up, 68 patients from the FGFR3 mutation group were evaluated. FGFR3 mutation analysis showed a sensitivity of 0.73 and a specificity of 0.87 when compared with the results of cystoscopy. A positive urine test was predictive of recurrence either at the time of the positive result or later during the 2-year follow-up, with a sensitivity of 0.70 and a specificity of 0.87. Among patients with an FGFR3 mutation in the initial tumor, a noninvasive urine test during follow-up can be valuable in diagnosing or predicting subsequent recurrence.

Comparative Tissue Proteomics of Microdissected Specimens Reveals Novel Candidate Biomarkers of Bladder Cancer

More than 380,000 new cases of bladder cancer are diagnosed worldwide, accounting for ∼150,200 deaths each year. To discover potential biomarkers of bladder cancer, we employed a strategy combining laser microdissection, isobaric tags for relative and absolute quantitation labeling, and liquid chromatography-tandem MS (LC-MS/MS) analysis to profile proteomic changes in fresh-frozen bladder tumor specimens. Cellular proteins from four pairs of surgically resected primary bladder cancer tumor and adjacent nontumorous tissue were extracted for use in two batches of isobaric tags for relative and absolute quantitation experiments, which identified a total of 3220 proteins. A DAVID (database for annotation, visualization and integrated discovery) analysis of dysregulated proteins revealed that the three top-ranking biological processes were extracellular matrix organization, extracellular structure organization, and oxidation-reduction. Biological processes including response to organic substances, response to metal ions, and response to inorganic substances were highlighted by up-expressed proteins in bladder cancer. Seven differentially expressed proteins were selected as potential bladder cancer biomarkers for further verification. Immunohistochemical analyses showed significantly elevated levels of three proteins-SLC3A2, STMN1, and TAGLN2-in tumor cells compared with noncancerous bladder epithelial cells, and suggested that TAGLN2 could be a useful tumor tissue marker for diagnosis (AUC = 0.999) and evaluating lymph node metastasis in bladder cancer patients. ELISA results revealed significantly increased urinary levels of both STMN1 and TAGLN2 in bladder cancer subgroups compared with control groups. In comparisons with age-matched hernia urine specimens, urinary TAGLN2 in bladder cancer samples showed the largest fold change (7.13-fold), with an area-under-the-curve value of 0.70 (p < 0.001, n = 205). Overall, TAGLN2 showed the most significant overexpression in individual bladder cancer tissues and urine specimens, and thus represents a potential biomarker for noninvasive screening for bladder cancer. Our findings highlight the value of bladder tissue proteome in providing valuable information for future validation studies of potential biomarkers in urothelial carcinoma.

Correlation of tumor relapse and elevated expression of survivin and vascular endothelial growth factor in superficial bladder transitional cell carcinoma

Survivin and vascular endothelial growth factor (VEGF) are newly discovered tumor markers closely correlated with bladder cancer. We analyzed the expression of survivin and VEGF in paraffin-embedded tumor tissues from 78 patients with bladder transitional cell carcinoma (BTCC) using an immunohistochemistry method. Normal bladder mucosae from 10 non-BTCC cases were also included as a control group. All patients were closely followed up for tumor recurrence after undergoing transurethral resection of bladder tumor procedures. The positive expression rates of survivin and VEGF in superficial BTCC were 66.7% (52/78) and 69.2% (54/78), respectively, which were significantly higher than those in the control group, 0% (0/10). A positive correlation was found between survivin and VEGF expression (r = 0.283, P < 0.01). Thirty-two of 78 patients (41.0%) displayed recurrence during follow-up (median: 47; range: 7-62 months). The tumor recurrence rate in survivin(+) patients was 53.8% (28/52), which was significantly higher than that in survivin(-) patients [15.4% (4/26); P < 0.05]. The recurrence rate in VEGF(+)/ VEGF(-) patients was 50.0% (27/54) and 20.8% (5/24), respectively (P < 0.05). The sensitivity for predicting the relapse of superficial BTCC was 87.5% in the survivin(+) group, 84.4% in the VEGF(+) group, and 78.1% in the survivin(+)/VEGF(+) group, and the specificity was 47.8, 41.3, and 65.2%, respectively. Survivin and VEGF interact and jointly regulate the biological behavior of bladder cancer. Our results suggest that overexpression of survivin and VEGF accompany a higher risk of BTCC recurrence, making survivin and VEGF biomarkers for predicting the relapse of bladder cancer.

Biomarker research and some deduction in superficial bladder cancer cells combined with corresponding stroma

To facilitate biomarker discovery and improve cancer biology research of superficial bladder transitional cell carcinoma (SBTCC). Laser capture microdissection and two-dimensional liquid chromatography tandem mass spectrometry was used to identified the proteome expression profile of purified normal urothelial cells (cancer cells)/normal stromal cells (cancer stromal cells). Based on the expression profile, biomarker discovery and the mechanisms of multi-step carcinogenesis were discussed. 775/792 proteins commonly appeared in 4 paired cancer/normal tissue. 339 differential proteins located at the well-known biological KEGG pathways and defined as potential biomarkers. 53/31 proteins specific repeat expression in cancer tissue/normal tissue and thought to play important role in tumor--stroma interactions. Proteins origin from cancer or stromal cells have the same probability to be a biomarker. The significant altered pathways mainly include metabolic pathways, spliceosome, endocytosis, oxidative phosphorylation, etc. Most of the specific repeat expression proteins act important role in cancer biology.

Rare Association of Anti-Hu Antibody Positive Paraneoplastic Neurological Syndrome and Transitional Cell Bladder Carcinoma

Introduction. Paraneoplastic encephalomyelitis (PEM) and subacute sensory neuronopathy (SSN) are remote effects of cancer, usually associated with small-cell lung carcinoma and positive anti-Hu antibody. We describe the rare association of bladder transitional cell carcinoma (TCC) with anti-Hu antibody positivity resulting in this paraneoplastic neurological syndrome. Patient. A 76-year-old female presented with bilateral muscle weakness and paraesthesia of the upper and lower limbs in a length-dependent “glove and stocking” distribution. Central nervous system symptoms included cognitive problems, personality change, and truncal ataxia. Case notes and the literature were reviewed. Result. Autoantibody screening was positive for anti-Hu antibody (recently renamed antineuronal nuclear antibody 1, ANNA-1). The diagnosis of PEM and SSN was supported by MRI and lumbar puncture results. A superficial bladder TCC was demonstrated on CT and subsequently confirmed on histology. No other primary neoplasm was found on full-body imaging. The neurological symptoms were considered to be an antibody-mediated paraneoplastic neurological syndrome and improved after resection of the tumour. Discussion. The association of anti-Hu positive paraneoplastic neurological syndrome and TCC has not been described in the literature previously. We emphasize the need for detailed clinical examination and the importance of a multidisciplinary thought process and encourage further awareness of this rare association.

Cancer stroma proteome expression profile of superficial bladder transitional cell carcinoma and biomarker discovery

To globally characterize the stroma expression profile of superficial bladder transitional cell carcinoma and to discuss the cancer biology as well as biomarker discovery from stromal cells. Laser capture microdissection was used to harvest purified bladder cancer stromal cells and normal stromal cells from 4 paired samples. Next, two-dimensional liquid chromatography-tandem mass spectrometry was used to identify the proteome expression profile. The differential proteins were further analyzed using bioinformatics tools and compared with the published literature. A total of 606/601 proteins commonly appeared in 4 paired samples. Six hundred and thirty-seven proteins were differentially expressed between cancer and normal stroma. Among them, 321/316 proteins specific expressed in cancer/normal stromal cells. Differential proteins were compared with the entire list of the international protein index (IPI). 36/49 GO terms exhibited as enriched and 25/14 exhibited as depleted in biological process; 39/40 GO terms exhibited as enriched and 9/4 exhibited as depleted in cellular component, respectively. Significantly altered pathways between cancer/normal stroma mainly include focal adhesion, EHEC, oxidative phosphorylation, glycolysis/gluconeogenesis, TCA cycle. Finally, descriptive statistics show the data that PI≤8 have normal distribution and the proteins with extremes of PI and MW have the same probability to be a biomarker. The present study identified the proteome expression profile of bladder cancer stromal cells and normal stromal cells. Furthermore, our results confirm proteins origin from stroma play important role in cancer biology and highlight a novel view of cancer and stress the importance of including factors related to the cancer stroma into biomarker discovery.

Safety and Efficacy of Intravesical Bacillus Calmette-Guérin Plus Interferon α-2b Therapy for Nonmuscle Invasive Bladder Cancer in Patients With Prosthetic Devices

Patients with bladder cancer who have prosthetic devices, such as a cardiac pacemaker, artificial heart valve or orthopedic hardware, and who undergo intravesical bacillus Calmette-Guérin therapy are theoretically at higher risk for complications, including bacterial seeding of pacemaker wires or orthopedic hardware, and at further risk for infective endocarditis. We assessed the safety and efficacy of bacillus Calmette-Guérin plus interferon α-2b therapy in patients with nonmuscle invasive bladder cancer and a pacemaker, artificial heart valve or orthopedic hardware. We evaluated 1,045 patients with nonmuscle invasive bladder cancer enrolled in a multicenter American phase II trial of bacillus Calmette-Guérin plus interferon α-2b therapy, including 143 with a prosthetic device (pacemaker in 87, artificial heart valve in 13 and orthopedic hardware in 43). Weekly physician toxicity assessments and standard adverse effect reporting were done. No patient had infective endocarditis or hardware infection. One patient with a pacemaker, 2 with orthopedic hardware and none with an artificial heart valve required treatment cessation for fever greater than 102.5F. All defervesced within 24 hours and had no long-term sequelae. Due to intolerable, nonlife threatening side effects 12 patients with a pacemaker, 2 with orthopedic hardware and 1 with an artificial heart valve stopped treatment. Of the remaining patients with a prosthesis 99 and 24 stopped treatment due to intolerable, nonlife threatening and serious side effects, respectively. Patients with a pacemaker, artificial heart valve or orthopedic hardware were no more likely than the general population to have infection or fever, or discontinue treatment due to side effects. These patients should not be excluded from intravesical bacillus Calmette-Guérin plus interferon α-2b therapy for nonmuscle invasive bladder cancer.

Audit of safety, efficacy, and cost-effectiveness of local anaesthetic cystodiathermy

The aim of this study was to audit our experience of cystodiathermy under local anaesthetic (LA) at the time of flexible cystoscopy for recurrent superficial bladder transitional cell carcinoma (TCC). A total of 264 flexible cystoscopies were performed on patients with a past history of TCC. The number and site of recurrences were recorded and selected patients were offered cystodiathermy. Patient tolerability was noted. At follow-up, any recurrence was recorded. Eighty patients (30%) had 91 procedures showing one or more recurrences. Fifty-one of the 80 patients (64%) were treated with cystodiathermy under LA. All completed treatment. Forty-five (88%) tolerated the procedure well. Forty-seven (92%) treatments were completed within 5 min. At a median follow-up of 15 weeks, 30 (59%) treated patients had no recurrence and three (6%) had recurrence at the site of treatment. LA cystodiathermy is an effective and well-tolerated alternative to general anaesthetic cystodiathermy that enables treatment at the time of detection and may, thereby, reduce patient anxiety.

Identification of genes correlated with early-stage bladder cancer progression.

Transitional cell carcinoma (TCC) of the bladder ranks fourth in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. We have combined a transgenic mouse model for invasive bladder cancer (UPII-SV40Tag mice) with DNA microarray technology to determine molecular mechanisms involved in early TCC development and to identify new biomarkers for detection, diagnosis, and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40Tag mice and their age-matched wild-type littermates at 3, 6, 20, and 30 weeks of age. These are ages that correspond to premalignant, carcinoma in situ, and early-stage and later stage invasive TCC, respectively. Our preliminary analysis of the microarray data sets has revealed approximately 1,900 unique genes differentially expressed (> or =3-fold difference at one or more time points) between wild-type and UPII-SV40Tag urothelium during the time course of tumor development. Among these, there were a high proportion of cell cycle regulatory genes and a proliferation signaling genes that are more strongly expressed in the UPII-SV40Tag bladder urothelium. We show that several of the genes upregulated in UPII-SV40Tag urothelium, including RacGAP1, PCNA, and Hmmr, are expressed at high levels in superficial bladder TCC patient samples. These findings provide insight into the earliest events in the development of bladder TCC as well as identify several promising early-stage biomarkers.

1473 IMMEDIATE MITOMYCIN C INSTILLATION FOLLOWED BY USUAL BCG COURSE VERSUS USUAL BCG ALONE FOR SUPERFICIAL TRANSITIONAL CELL CARCINOMA OF THE BLADDER (4 YEARS EXPERIENCE)

You have accessJournal of UrologyBladder Cancer: Superficial II1 Apr 20101473 IMMEDIATE MITOMYCIN C INSTILLATION FOLLOWED BY USUAL BCG COURSE VERSUS USUAL BCG ALONE FOR SUPERFICIAL TRANSITIONAL CELL CARCINOMA OF THE BLADDER (4 YEARS EXPERIENCE) Osman Abd El Kader Osman Abd El KaderOsman Abd El Kader More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1188AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES we present our experience with combination of chemo-immunotherapy fËmitomycin (MMC) + Bacillus Callmette ¡VGuerin (BCG) fÍ in comparison to single agent BCG immunotherapy as regard efficacy and side effects for superficial cancer bladder transitional cell carcinoma TCC with 6 months follow up at least. METHODS between July 2004 and June 2008, 128 patients (86 men and 42 women) with histologically proven bladder TCC and a mean age of 54 years were included into this prospective study, the definitive stage was Ta in 5 patients and T1 in 123 patients, while thegrade was grade I in 18, grade II in 86 patients and grade III in 24 patients, all patients underwent transurethral resection of the bladder tumor (TURBT) then randomly divided into two groups, group one 68 patients received immediate 40 mg mitomycinC (MMC) followed by BCG weekly for 6 weeks 3 weeks post TURBT, group two 60 patients underwent BCG instillation weekly for 6 weeks post TURBT by 3 weeks with follow up cystoscopy. RESULTS follow up ranged from 6-45 months with a mean of 26 months. Out of the group 1, 43 patients (63 %) were free at last follow up, 17 (25 %) showed recurrence and 8 (12%) showed muscle invasive progression and in group 2; 27 patients (45%) were free at last follow up, 20 (33%) showed recurrence and 13 (22%) showed muscle invasive progression. The mean interval to recurrence was 15 months range (3-45) in group 1 and 13 months range (3-45) in group 2 and the mean interval to progression in group 1 was 18 months (range 3-45) and in group 2 was 15 months range (3-45), Side effect of intravesical instillation distributed in both groups approximately in the same level, in group I; 20 patients (30%) with post instillation symptoms in the form of lower urinary tract symptoms (LUTS) in 14 patients (21%), 2 patients (3%) epidydmitis, 2 patients (3%) by hematuria and 2 patients (3%) presented by fever, chills and flue like symptoms, in group II 18 patients (30%) presented by post instillation symptoms in the form of (LUTS) in 12 patients (20%), one patients (1.5%) epidydmitis, 2 patients (3.5%) by hematuria and 3 patients (5%) presented by fever, chills and flue like symptoms. CONCLUSIONS the efficacy of chemo-immunotherapy in superficial cancer bladder TCC is evident over immunotherapy alone however side effects not appear to be increased however multicenter trial was indicated to consolidate these results. Fakous, Egypt© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e567-e568 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Osman Abd El Kader More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Analysis of the prognostic factors affecting postoperative recurrence and progression in patients with superficial bladder transitional cell carcinoma

Objective To evaluate the prognostic factors affecting postoperative recurrence and progression in patients with superficial bladder transitional cell carcinoma(SBTCC). Methods From 2000 to 2004,150 patients with SBTCC were treated, of which 120 patients were followed up. The possible prognostic factors including clinical and pathological figures were analyzed by Cox's proportional hazard model in these patients. Results The mean fol-low-up period was 84.7 months. The recurrence rates at 3-year,5-year were 27.5% and 36.7% respectively. The main variables affecting recurrence were histological grades,tumor stage,tumor number and recurring tumor,and the first three were the independent risk factors. The progression rotes at 3-year,5-year were 9. 2% and 17.5%. The main variables affecting progression were histological grade,tumor stage, tumor number and recurring tumor, and the first one was the independent risk factor. Conclusion The main variables affecting progression were histological grade, tumor stage,tumor number and recurring tumor,and the first one were the independent risk factor. Key words: Urinary bladder neoplasms; Neoplasms recurrence, local; Prognosis

Response of Bladder Carcinoma Cells to TRAIL and Antisense Oligonucleotide, Bcl-2 or Clusterin Treatments

Bladder transitional cell carcinoma is the second most common urological malignancy, of which 80% are superficial disease limited to the bladder. Superficial bladder transitional cell carcinoma has a high propensity for recurrence and progression after initial resection, necessitating adjuvant intravesical therapy. TRAIL (tumor necrosis factor-related apoptosis inducing ligand) can selectively induce apoptosis in most tumor cells while sparing normal cells. TRAIL drives not only the death receptor pathway, but also the mitochondrial pathway through Bid. Due to the anti-apoptotic functions of Bcl-2 and clusterin on the mitochondrial apoptotic pathway the effects of down-regulating these proteins were examined in partially TRAIL resistant bladder transitional cell carcinoma cell lines. Antisense oligonucleotides targeting Bcl-2 and clusterin were used alone or combined with TRAIL and cytotoxicity was examined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide) proliferation assay. Apoptotic pathway signals were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blotting after the various combination treatments. All statistical tests were 2 sided. Although no direct correlation between TRAIL sensitivity and the relative expression levels of Bcl-2 and clusterin was found in the bladder transitional cell carcinoma cell lines examined, antisense oligonucleotide mediated the down-regulation of Bcl-2 and clusterin, increasing the sensitivity of the partially resistant cells to TRAIL. This was mediated through increased apoptotic signaling of the mitochondrial pathway, as evident by the increased activation of caspase-9 and 3, and cleaved DFF45. There was no benefit of combined antisense oligonucleotide therapy. This study provides proof of principle that TRAIL combined with antisense oligonucleotide-Bcl-2 may have potential as a novel future treatment strategy for bladder transitional cell carcinoma.

UP.99: The Peri-Meatus Location of Superficial Bladder Transitional Cell Carcinoma (T1): Is It a Risk Factor of Recurrence and Progression? Our 278 Cases

Endoscopic resection and bacillus Calmette-Guérin (BCG) therapy is actually considered as the gold standard in treating superficial bladder transitional cell carcinomas (TCC). Many endoscopic, biological and evolutive parameters are considered as risk factors of recurrence: the prior recurrence rate, number of tumours, tumor size, grade, etc. The objective was to determine if the primary tumor location in the bladder (ureteral meatus) affect long-term outcome after endoscopic resection and intravesical BCG therapy.

Differences in shotgun protein expression profile between superficial bladder transitional cell carcinoma and normal urothelium

This study was undertaken to identify differences in protein expression profiles between superficial bladder transitional cell carcinoma (BTCC) and normal urothelial cells. We used laser capture microdissection (LCM) to harvest purified cells, and used two-dimensional liquid chromatography (2D-LC) followed by electrospray ionization-tandem mass spectrometry (ESI-MS/MS) to separate and identify the peptide mixture. A total of 440/438 proteins commonly appeared in 4 paired specimens. Multi-step bioinformatic procedures were used for the analysis of identified proteins; 175/179 of the 293/287 proteins that were specific expressed in tumor/normal cells own gene ontology (GO) biological process annotation. Compared with the entire list of the international protein index (IPI), there are 52/46 GO terms exhibited as enriched and 6/10 exhibited as depleted, respectively. Significantly altered pathways between tumor and normal cells mainly include oxidative phosphorylation, focal adhesion, etc. Finally, descriptive statistics show that the shotgun proteomics strategy has practice directive significance for biomarker discovery by two-dimensional electrophoresis (2-DE) technology.

The Safety and Efficacy of Different Doses of Bacillus Calmette Guérin in Superficial Bladder Transitional Cell Carcinoma

Objectives To conduct a trial using three different doses of bacillus Calmette-Guérin (BCG) to determine whether lowering the dose of BCG could reduce toxicity without compromising its efficacy in the treatment of superficial bladder cancer. Methods From July 2002 to June 2005, 152 patients with superficial bladder cancer entered the trial. The patients were randomized to receive three different doses of BCG: 40, 80, and 120 mg. There were no significant differences in clinical and pathologic characteristics among the three groups. Twenty-four patients could not be followed to the end of the study because of poor compliance. At completion of the study, 40 patients could be evaluated in group A (40 mg), 48 in group B (80 mg), and 40 in group C (120 mg). Results After treatment patients were evaluated for a mean follow-up period of 36 months (range 18 to 52 months). No significant difference in recurrence rate (20% versus 25% versus 20% respectively; P >0.05) was observed among the groups, and no progression of the disease was seen. Significant differences were observed among groups A, B, and C in local toxicity (30% versus 41.7% versus 70%, respectively; P <0.01). Systemic toxicity was more common in group C compared with groups B and A (P <0.01). Conclusions Reduction in the dose of intravesical BCG can reduce the toxicity associated with the treatment of superficial bladder cancer without affecting the efficacy of therapy.

Long-Term Follow-up of Intravesical Bacillus Calmette-Guérin Treatment for Superficial Transitional-Cell Carcinoma of the Bladder Involving the Prostatic Urethra

Background Intravesical bacillus Calmette-Guerin (BCG) is a treatment opton for superficial (≤ T1) transitional cell carcinoma. Transitional cell carcinoma involving the prostatic urethra presents a treatment dilemma. Whereas prostatic urethral involvement might require radical cystectomy, select patients can be offered BCG and careful surveillance to preserve the bladder. We report long-term experience with BCG in this subset of patients with > 5-year follow-up. Patients and Methods Twenty-eight patients with high-risk superficial bladder cancer and prostatic urethral involvement were treated with once-weekly BCG for 6 weeks. Patients with prostatic stromal involvement were excluded. Maintenance was not used before 1995. Currently, we use maintenance BCG after induction. Patients were followed by cystoscopy/cytology and repeat biopsy to detect persistent and/or progressive disease. Results After 1 or 2 courses of once-weekly BCG for 6 weeks, 64.3% (18 of 28 of patients) exhibited a complete response in the bladder and prostate at their 6-month followup. Of those obtaining a complete response, 55.6% (10 of 18) experienced recurrence. Three recurrences were in the prostate: 1 isolated and 2 associated with multifocal bladder involvement. Twenty-eight percent (8 of 28 patients) underwent cystectomy because of failure of treatment to eradicate superficial disease or disease progression. Disease-specific survival was 89% (25 of 28 patients) at a median follow-up of 7.5 years. Conclusion Our long-term data support the durability of intravesical BCG in select patients with superficial bladder transitional cell carcinoma with prostatic urethral involvement. Follow-up biopsy of the prostatic urethra is mandatory and, if positive, cystectomy is indicated. One third of patients will require cystectomy for persistent or progressive disease; therefore, careful surveillance is critical.

Voided Urinary Cytology in Bladder Cancer: Is It Time to Review the Indications?

The sensitivity of voided urinary cytology has been reported as very low. In this study, we investigated the sensitivity and clinical utility of voided urinary cytology in the detection of various grades and stages of transitional cell carcinoma (TCC) of the bladder compared with the urinary nuclear matrix protein-22 (NMP-22) qualitative assay. From March 2004 to April 2006, all patients with TCC of the bladder receiving follow-up care and those presenting with gross hematuria were enrolled in this prospective study. These patients underwent urinary cytologic examination and NMP-22 qualitative assay. The diagnosis, determined from the cystoscopy findings and biopsy findings of the suspicious lesion, was accepted as the reference standard. A total of 196 patients were enrolled in this study, of whom 127 patients had previously been diagnosed with bladder TCC and 69 were presenting for investigation of gross hematuria. A total of 52 cases of bladder TCC were diagnosed. The overall sensitivity of voided urine cytology and NMP-22 assay was 21.1% and 67.3%, respectively (P <0.001). The sensitivity of urinary cytology and urinary NMP-22 for well-differentiated tumors was 9.5% and 52.4%, respectively, and was 18.1% and 77.3%, respectively (P <0.001), in moderately differentiated tumors. The overall specificity of urinary cytology for TCC of the bladder was 98.6% and was greater than the specificity of NMP-22 (80.5%). The results of our study suggest that urinary cytology has a very low sensitivity and can be omitted in favor of NMP-22 in the follow-up of low-grade superficial bladder TCC.

P21-Activated Kinase 1: A New Molecular Marker for Intravesical Recurrence After Transurethral Resection of Bladder Cancer

It is clinically important to identify bladder cancers with a high risk of intravesical recurrence after transurethral bladder tumor resection. We developed molecular markers for predicting intravesical recurrence of superficial bladder transitional cell carcinoma using oligo-microarray analysis. Gene expression profiles associated with intravesical recurrence were analyzed by oligo-microarray in 27 superficial bladder transitional cell carcinoma samples from cases treated with transurethral resection between 2000 and 2004 at Kyoto University Hospital. Of candidate genes the expression of P21-activated kinase (Pak1) was validated by semiquantitative real-time polymerase chain reaction using another set of samples and immunohistochemistry. Furthermore, Pak1 functions in bladder cancer cells were analyzed by the transfection of constitutively active (T423E) or kinase dead (K299R) Pak1. Microarray identified 25 genes whose expression was associated with recurrence, including Pak1. Pak1 mRNA expression was statistically associated with grade and the risk of recurrence but not with stage in 86 bladder cancers. Immunohistochemistry and multivariate analysis demonstrated that high Pak1 protein expression was an independent factor associated with recurrence (relative risk 2.27, p = 0.008). High Pak1 expression was significantly associated with a high risk of recurrence even in low stage/grade cancers. Transfection with T423E Pak1 into 253J cells progressed cell motility on wound healing assay, whereas transfection with K299R Pak1 decreased EJ cell motility. These results suggest that Pak1 expression is associated with recurrence and it might be a useful prognostic marker for superficial bladder transitional cell carcinoma.

Intravesical adjuvant therapy using mitomycin C

Bladder cancer is mostly superficial at first diagnosis. High incidence of recurrence is the major problem after initial management with transurethral resection (TUR) of bladder tumor. Adjuvant chemotherapy has been advocated to reduce the incidence of recurrence. A study was carried out to observe the efficacy of intravesical adjuvant therapy with single immediate versus delayed multi-dose regimen of Mitomycin C (MMC) in preventing recurrence of superficial bladder cancer. One hundred Patients having intermediate risk superficial bladder cancer were randomized into two equal groups. All patients were followed carefully. Total duration of follow-up was minimum 12 months, maximum 36 months, mean 29 months. No recurrence was seen on 3(rd), 6(th) and 9(th) month of intravesical therapy. As much as 94% and 96% of recurrence free rate was observed in immediate single and delayed multi-dose group respectively on 12(th) month; 86% and 84% on 18(th) month; 74% and 72% on 24(th) month; 70% and 68% on 36(th) month of follow-up cystoscopy respectively. Efficacy of post transurethral resection of bladder tumour (TURBT) MMC single immediate dose was found similar to that of MMC delayed multi-dose regimen in preventing the recurrence of intermediate risk superficial bladder transitional cell carcinoma (TCC) in the study. The difference between the two groups insignificant (p>0.05).

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon‐alpha

Nuclear p53 and retinoblastoma protein (pRb) were reported to be poor prognostic indicators for transitional cell carcinoma of the bladder. The authors sought to determine the prognostic value of nuclear p53 and pRb in superficial bladder transitional cell carcinoma patients who were treated with intravesical bacille Calmette-Guerin (BCG) or BCG with interferon-alpha (IFN-alpha). A prospective histological review was performed for 80 superficial bladder transitional cell carcinoma patients who underwent postresection intravesical regimes of BCG (81 mg, n = 33 or 27 mg, n = 20) or BCG (27 mg) with IFN-alpha (n = 27), and followed for a mean of 4.5 years. Hematoxylin and eosin (H & E) and immunoperoxidase staining were performed on tissue sections. Nuclear p53 and pRb immunoreactivity were assessed semiquantitatively, by using a combination of staining extent and intensity, to categorize overexpression or underexpression. Data were analyzed by using chi-square analysis, multiple logistic regression, and Kaplan-Meier curves. pRb expression was not associated with patient outcome after BCG-alone therapy, but pRb underexpression was significantly associated with BCG nonresponse and tumor recurrence (P = .047) after BCG and IFN-alpha (BCG + IFN-alpha) therapy. Low-grade tumors were associated with pRb overexpression, with or without nuclear p53 underexpression (P = .019; P = .043, respectively). p53 expression alone or in combination with pRb expression had no significant relation with tumor response to BCG alone or BCG + IFN-alpha with respect to recurrence, progression, or cancer-specific death. Nuclear pRb underexpression may be predictive of nonresponse and cancer recurrence after intravesical BCG + IFN-alpha therapy. Nuclear p53 expression or its combination with pRb expression is not associated with post-BCG clinical outcome, so p53 expression or p53 with pRb expression should not be used to influence decisions concerning BCG-alone or BCG + IFN-alpha therapy.