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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of Bladder Cancer - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 20503133
AU - Katusin D; Poka Z; Mlinac-Lucijanic M; Kriz M; Klaric-Vucinic S; Ilijanic J
TI - [Carcinoma in situ in the urinary bladder]
SO - Lijec Vjesn 2000 Jul-Aug;122(7-8):177-9
In this paper we have presented seven patients with carcinoma in situ of the urinary bladder, a rare intraepithelial form of transitional cell carcinoma of the urinary bladder, described first in 1952. In all patients malignant cells were detected in urine sediment, and the diagnosis was proven histopathologicaly by random biopsies of the urinary bladder. In five patients carcinoma in situ was associated with papillary bladder tumor, while two patients had primary carcinoma in situ. We have emphasized a high rate of irritative urinary symptoms, that can lead to diagnostic mistakes. Three patients had reduced bladder capacity. In all patients a complete response was achieved after local immunotherapy or local chemotherapy. After a follow-up lasting from 23 to 61 months in one patient a recurrent carcinoma in situ was diagnosed, while six patients show no signs of recurrent disease.

2
UI - 21236981
AU - Weyer PJ; Cerhan JR; Kross BC; Hallberg GR; Kantamneni J; Breuer G; Jones MP; Zheng W; Lynch CF
TI - Municipal drinking water nitrate level and cancer risk in older women: the Iowa Women's Health Study.
SO - Epidemiology 2001 May;12(3):327-38
AD - Center for Health Effects of Environmental Contamination, University of Iowa, USA.
Nitrate contamination of drinking water may increase cancer risk, because nitrate is endogenously reduced to nitrite and subsequent nitrosation reactions give rise to N-nitroso compounds; these compounds are highly carcinogenic and can act systemically. We analyzed cancer incidence in a cohort of 21,977 Iowa women who were 55-69 years of age at baseline in 1986 and had used the same water supply more than 10 years (87% > 20 years); 16,541 of these women were on a municipal supply, and the remainder used a private well. We assessed nitrate exposure from 1955 through 1988 using public databases for municipal water supplies in Iowa (quartile cutpoints: 0.36, 1.01, and 2.46 mg per liter nitrate-nitrogen). As no individual water consumption data were available, we assigned each woman an average level of exposure calculated on a community basis; no nitrate data were available for women using private wells. Cancer incidence (N = 3,150 cases) from 1986 through 1998 was determined by linkage to the Iowa Cancer Registry. For all cancers, there was no association with increasing nitrate in drinking water, nor were there clear and consistent associations for non-Hodgkin lymphoma; leukemia; melanoma; or cancers of the colon, breast, lung, pancreas, or kidney. There were positive associations for bladder cancer [relative risks (RRs) across nitrate quartiles = 1, 1.69, 1.10, and 2.83] and ovarian cancer (RR = 1, 1.52, 1.81, and 1.84), and inverse associations for uterine cancer (RR = 1, 0.86, 0.86, and 0.55) and rectal cancer (RR = 1, 0.72, 0.95, and 0.47) after adjustment for a variety of cancer risk/protective factors, agents that affect nitrosation (smoking, vitamin C, and vitamin E intake), dietary nitrate, and water source. Similar results were obtained when analyses were restricted to nitrate level in drinking water from 1955 through 1964. The positive association for bladder cancer is consistent with some previous data; the associations for ovarian, uterine, and rectal cancer were unexpected.

3
UI - 21243932
AU - Herranz Amo F; Verdu Tartajo F; Diez Cordero JM; Bielsa Carrillo A; Garcia Burgos J; Subira Rios D; Castano Gonzalez I
TI - [Differences in survival of patients with bladder cancer depending on depth of muscle infiltration]
SO - Actas Urol Esp 2001 Feb;25(2):110-4
AD - Servicio de Urologia, Hospital General Universitario Gregorio Maranon, Madrid.
OBJECTIVE: To study the survival of patients with bladder cancer and infiltration into the muscle who undergo radical cystectomy, documenting any survival difference based on the depth of muscle infiltration (pT2a vs. pT2b). MATERIAL AND METHOD: 109 patients with infiltration into the muscle (T2) in the TUR were treated with radical cystectomy between 1986 and 1996; 39 patients were excluded due to infra-staging and 2 died in the immediate postoperative: 68 patients were eligible for the study. Median follow-up was 51 months. At the time of analysis 44 were alive (2 with tumoral disease and one with a second non-urological tumour), 21 had died (4 for causes other than vesical tumour) and 3 patients were considered lost to follow-up at 3, 31 and 111 months. Survival analysis was performed using the Kaplan-Meier method, and the variables were compared with the log-rank test. RESULTS: The 3- and 5-year overall survival of our series was 76% and 62%, while cancer specific survival was 80% and 70% respectively. Cancer specific survival at 5 years by stages was: pT0-83%, pT1-80%, pT2a-66% and pT2b-60% (p = 0.52). The cystectomy specimen (pT0) showed no residual tumour in 15 (22%) patients, and 5-year cancer specific survival in this group was 83% vs. 66% in patients with residual cancer (p = 0.24). CONCLUSIONS: Patients with pT2a and pT2b bladder cancer showed no differences in survival and we believe they should be all included in the same prognostic group (pT2). pT0 patients are a subgroup of patients with significant survival rates in which radical cystectomy should be considered as overtreatment, and a more conservative protocol should be preferred.

4
UI - 21234941
AU - Kamai T; Takagi K; Asami H; Ito Y; Oshima H; Yoshida KI
TI - Decreasing of p27(Kip1)and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer.
SO - Br J Cancer 2001 May 4;84(9):1242-51
AD - Department of Urology, Dokkyo University School of Medicine, Tochigi, Japan.
The p27(Kip1)(p27) protein is a cyclin-dependent kinase inhibitor of the transition from G1 to S phase. It has been reported that decreased p27 protein level is a negative prognostic indicator in human tumours including bladder cancer. We studied the relationship between protein levels of p27, cyclin E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohistochemical staining. Low protein levels of p27 were associated with low staining of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differentiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node metastsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlated with poorly differentiated grade, muscle invasion and lymph node metastsis. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0002). Kaplan-Meier plots of survival rate in patients with low versus high p27 staining showed that low protein levels of p27 were associated with a shortened disease-free and overall survival (P< 0.0001 and P< 0.0001, respectively). Similarly, low staining of cyclin E and high Ki-67 index correlated with a shortened disease-free and overall survival. On multivariate analysis using Cox proportional hazards model, low protein levels of p27 and high Ki-67 index were independent predictors of shortened disease-free (P< 0.0001, P = 0.0031, respectively), and low protein levels of p27, low staining of cyclin E and high Ki-67 index of overall survival (P = 0.0017, P = 0.0009, P = 0.0003, respectively). In superficial bladder tumours (Ta, T1; 86 patients), significant correlations were observed between low p27 staining and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respectively). Among the recurrenced superficial tumours (35 patients), the tumours which remained at a low stage showed high protein levels of p27 and cyclin E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings suggest that decreased protein levels of p27 and cyclin E play a role in the progression of bladder cancer and to evaluate these protein levels may be useful in management of the diseases. Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.

5
UI - 21365669
AU - Burger MS; Torino JL; Swaminathan S
TI - DNA damage in human transitional cell carcinoma cells after exposure to the proximate metabolite of the bladder carcinogen 4-aminobiphenyl.
SO - Environ Mol Mutagen 2001;38(1):1-11
AD - Department of Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
The DNA damage induced by N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP), the proximate carcinogenic metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP), was examined in human transitional cell carcinoma (TCC) cells after exposure to the chemical in vitro. 32P-postlabeling analysis of TCC cultures exposed to N-OH-AABP revealed a minor adduct identified as 3-(deoxyguanosin-N2-yl)-4-acetylaminobiphenyl (dG-N2-AABP) based on comparison of the HPLC and TLC mobility of the product with the synthetic standard. An adduct with the same chromatographic properties was also detected on postlabeling analyses of calf thymus DNA bound to N-OH-AABP by incubation with horseradish peroxidase and hydrogen peroxide. Detection of dG-N2-AABP, which contains the acetyl moiety, suggests that N-acetoxy-4-acetylamino-biphenyl might be formed as a reactive intermediate and could conceivably arise by a free-radical-mediated reaction of N-OH-AABP with endogenous peroxidases. The radical intermediates could also form reactive oxygen species (ROS). To test this possibility, TCC cultures were exposed to N-OH-AABP and the formation of ROS was measured using 2,7-dichlorofluorescein (DCF) fluorescence assay. TCC cultures exposed to N-OH-AABP showed a dose-dependent increase in the ratio of DCF/DNA fluorescence compared to the untreated controls. Formation of ROS was inhibited by butylated hydroxyanisole (BHA). Furthermore, oxidative DNA damage resulting from ROS was monitored by measurement of 8-oxoguanine products by immunochemical staining and the TCC cells treated with N-OH-AABP revealed a characteristic staining. These results suggest that N-OH-AABP caused oxidative DNA damage as well as bulky covalent adducts in urothelial DNA, possibly involving endogenous peroxidases. These findings show that human uroepithelial cells, which are the target cell types in vivo for arylamine-induced cancers, are metabolically capable of activating these proximate carcinogenic metabolites of arylamines, and these reactions might play a determinate role in the genotoxicity of these environmental carcinogens. Copyright 2001 Wiley-Liss, Inc.

6
UI - 21378015
AU - Nakashiro KI; Hayashi Y; Kita A; Tamatani T; Chlenski A; Usuda N; Hattori K; Reddy JK; Oyasu R
TI - Role of peroxisome proliferator-activated receptor gamma and its ligands in non-neoplastic and neoplastic human urothelial cells.
SO - Am J Pathol 2001 Aug;159(2):591-7
AD - Department of Pathology, Northwestern University Medical School, Chicago, Illinois, USA.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is expressed in several types of tissue. Although PPARgamma reportedly is expressed in normal urothelium, its function is unknown. We examined the expression of PPARgamma in normal urothelium and bladder cancer in an attempt to assess its functional role. Immunohistochemical staining revealed normal urothelium to express PPARgamma uniformly. All low-grade carcinomas were positive either diffusely or focally, whereas staining was primarily focal or absent in high-grade carcinomas. A nonneoplastic urothelial cell line (1T-1), a low-grade (RT4) carcinoma cell line, and two high-grade (T24 and 253J) carcinoma cell lines in culture expressed PPARgamma mRNA and protein. Luciferase assay indicated that PPARgamma was functional. PPARgamma ligands (15-deoxy-Delta(12,14)-prostaglandin J(2), troglitazone and pioglitazone) suppressed the growth of nonneoplastic and neoplastic urothelial cells in a dose-dependent manner. However, neoplastic cells were more resistant than were nonneoplastic cells. Failure to express PPARgamma or ineffective transcriptional activity may be some of the mechanisms responsible for resistance to the inhibitory action of PPARgamma ligands.

7
UI - 21412308
AU - Hafner C; Knuechel R; Zanardo L; Dietmaier W; Blaszyk H; Cheville J; Hofstaedter F; Hartmann A
TI - Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract.
SO - Oncogene 2001 Aug 9;20(35):4910-5
AD - Institute of Pathology, University of Regensburg, 93042 Regensburg, Germany.
Multifocality and recurrence of urothelial carcinoma may result from either the field effect of carcinogens leading to oligoclonal tumors or monoclonal tumor spread. Previous molecular studies, favoring the monoclonality hypothesis, are mostly limited to the urinary bladder. We investigated genetic alterations in a total of 94 synchronous or metachronous multifocal tumors from 19 patients with at least one tumor both in the upper and lower urinary tract. Loss of heterozygosity (LOH) was determined using eight markers on chromosome 9 and one marker on 17p13 (p53). Microsatellite instability was investigated at six loci and protein expression of MSH2 and MLH1 was evaluated by immunohistochemistry. In addition, exons 5-9 of the p53 gene were sequenced. Deletions at chromosome 9 were found in 73% of tumors and at 17p13 in 18% of tumors. There was no significant difference in the frequency of LOH in the upper and lower urinary tract. Deletions at 9p21 were significantly correlated with invasive tumor growth. The pattern of deletion revealed monoclonality of all tumors in nine patients. In five patients there were at least two tumor clones with different genetic alterations. In four of these patients the different clones occurred in the bladder and subsequently in the ureter and renal pelvis. All four patients with p53 mutations revealed identical mutations in all tumors. Thus, multifocal urothelial carcinomas are frequently monoclonal, whereas others show oligoclonality, providing molecular evidence for field cancerization. Intraluminal tumor cell seeding appears to be an important mechanism of multifocal occurrence and recurrence of urothelial carcinomas.

8
UI - 21398071
AU - Eleuteri P; Grollino MG; Pomponi D; De Vita R
TI - Chromosome 9 aberrations by fluorescence in situ hybridisation in bladder transitional cell carcinoma.
SO - Eur J Cancer 2001 Aug;37(12):1496-503
AD - Section of Toxicology and Biomedical Sciences, ENEA CR Casaccia, Via Anguillarese 301, 00060 Rome, Italy. eleuteri@casaccia.enea.it
To investigate the role of the monosomy 9 in bladder carcinogenesis, 96 cases of superficial bladder transitional cell carcinoma (TCC) were studied and followed periodically for around 3 years (mean+/-standard error of the mean (SEM); 3.46+/-0.34 years). Samples from bladder washings were analysed by fluorescent in situ hybridisation (FISH) to detect numerical anomalies of chromosome 9. Moreover, to evaluate the relative under representation of this chromosome, we detected numerical changes of chromosome 8 and DNA ploidy by flow cytometric analysis (FCM). Chromosome 8 copy number were related to FCM DNA ploidy and both were related with tumour grade. Monosomy 9 did not correlate with tumour grade, stage, chromosome 8 aneuploidies and abnormal DNA content, but correlated with tumour progression. Comparing the results in the primary and subsequent tumours, we observed an increase in the frequency of aneuploidies by FCM, associated with an increase of chromosome 8 polysomies. The mean chromosome 9 copy number/nucleus remained nearly the same in most of the primary and invasive tumours. Our results confirm that monosomy 9 is an early event and that it is retained during tumour progression and invasion and that the loss occurs before the tetraploidisation process. The relationship between the presence of a sub-population with monosomy 9 and tumour progression suggests the presence of a region that could have a role in the progression of superficial bladder TCC.

9
UI - 21401279
AU - Moore M
TI - Urine detection of survivin and diagnosis of bladder cancer.
SO - J Insur Med 2001;33(2):202-3
AD - Nationwide Insurance, Columbus, Ohio 43215, USA.

10
UI - 21417648
AU - Yoon DS; Li L; Zhang RD; Kram A; Ro JY; Johnston D; Grossman HB; Scherer S; Czerniak B
TI - Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease.
SO - Oncogene 2001 Aug 16;20(36):5005-14
AD - Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Histologic and genetic mapping with 30 hypervariable markers mapped to chromosome 16 were performed on 234 DNA samples of five cystectomy specimens from patients with invasive bladder cancer. Allelic losses of individual markers were related to microscopically identified precursor conditions in the entire bladder mucosa and invasive cancer. Their significance for the development and progression of neoplasia from in situ preneoplastic conditions to invasive disease was analysed by the nearest neighbor algorithm and binomial maximum likelihood analysis. Using this approach we identified five distinct regions of allelic losses defined by their flanking markers and predicted size as follows. p13.3(D16S418-D16S406, 1.2 cM), p13.1(D16S748-D16S287, 12.9 cM), q12 1(D16S409-D16S514, 24.0 cM), q22.1 (D16S496-D16S515, 5.4 cM), and q24 (D16S507-D16S511, 5.9 cM and D16S402-D16S413, 17.4 cM). The regions mapping to p13.1 and q24 were involved in early intraurothelial phases of bladder neoplasia such as mild to moderate dysplasia. On the other hand the deleted region mapping to p13.3 was involved in progression of severe dysplasia/carcinoma in situ to invasive bladder cancer. Testing of markers that exhibited statistically significant LOH in relation to progression of neoplasia from precursor conditions to invasive cancer on 28 tumors and voided urine samples from 25 patients with bladder cancer revealed that q12.1 showed LOH in 46.4% of tumor and 32.0% of voided urine samples. The LOH of a single marker D16S541 could be detected in approximately 28% of tumors and 20% of voided urine samples of patients with bladder cancer. These data imply that the deleted region centered around marker D16S541 spanning approximately 10 cM and flanked by D16S409 and D16S415 contains a novel putative tumor suppressor gene or genes playing an important role in the development of human bladder cancer. To facilitate more precise positional mapping and identification of pathogenetically relevant genes, we analysed of human genome contig and sequence databases spanning the deleted regions. Multiple known candidate genes and several smaller gene-rich areas mapping to the target regions of chromosome 16 were identified.

11
UI - 21417654
AU - Karoui M; Hofmann-Radvanyi H; Zimmermann U; Couvelard A; Degott C; Faridoni-Laurens L; Ahomadegbe JC; Gazzeri S; Brambilla E; Clerici T; Charbonnier P; Tresallet C; Mitry E; Penna C; Rougier P; Boileau C; Thiery JP; Nordlinger B; Franc B; Radvanyi F
TI - No evidence of somatic FGFR3 mutation in various types of carcinoma.
SO - Oncogene 2001 Aug 16;20(36):5059-61
AD - Federation des Specialites Digestives, Hopital Ambroise Pare, Universite Paris V, 92104 Boulogne Cedex, France.
Germline specific point mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are associated with autosomal dominant human skeletal dysplasia and craniosynostosis syndromes. Mutations identical to the germinal activating mutations found in severe skeletal dysplasias have been identified in certain types of cancer: at low frequency in multiple myeloma and cervix carcinoma and at high frequency in bladder carcinoma. We analysed, by SSCP and sequencing, the prevalence of FGFR3 mutations in 116 primary tumours of various types (upper aerodigestive tract, oesophagus, stomach, lung and skin). The regions analysed encompassed all FGFR3 point mutations previously described in severe skeletal dysplasia and cancers. No mutations were detected in the tumour types examined, suggesting that FGFR3 mutations are restricted to a few tumour types, the evidence to date suggesting that they are very specific to bladder carcinomas.

12
UI - 21413533
AU - van Bokhoven A; Varella-Garcia M; Korch C; Miller GJ
TI - TSU-Pr1 and JCA-1 cells are derivatives of T24 bladder carcinoma cells and are not of prostatic origin.
SO - Cancer Res 2001 Sep 1;61(17):6340-4
AD - Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. adrie.vanbokhoven@uchsc.edu
We have shown previously that the putative prostate carcinoma cell lines TSU-Pr1 and JCA-1 share a common origin. The observation that these cell lines have p53 and Ha-ras mutations identical to those in bladder carcinoma cell line T24 prompted us to investigate their possible interrelations. We used cytogenetics and DNA profiling to compare the genetic backgrounds of the three cell lines. At least 12 structural chromosomal abnormalities are shared between T24, TSU-Pr1, and JCA-1 cells. DNA profiles were identical for all three cell lines. These results clearly indicate that the cell lines TSU-Pr1 and JCA-1 are not of prostatic origin but are derivatives of the bladder carcinoma cell line T24. TSU-Pr1 and, to a lesser extent, JCA-1 are frequently used as models in prostate cancer research, and numerous publications have appeared based on these lines. Several other T24 cross-contaminants have been identified in the past, and some of these, such as ECV304, continue to be used under the wrong identity. Our findings highlight the insidious problem that can occur when information regarding cross-contamination does not reach individual researchers and/or the importance of the problem is not fully acknowledged.

13
UI - 21413570
AU - Okegawa T; Pong RC; Li Y; Bergelson JM; Sagalowsky AI; Hsieh JT
TI - The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.
SO - Cancer Res 2001 Sep 1;61(17):6592-600
AD - Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.

14
UI - 21303169
AU - Seraj MJ; Thomas AR; Chin JL; Theodorescu D
TI - Molecular determination of perivesical and lymph node metastasis after radical cystectomy for urothelial carcinoma of the bladder.
SO - Clin Cancer Res 2001 Jun;7(6):1516-22
AD - Department of Urology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
PURPOSE: Current methods used to determine the pathological stage of the primary tumor and associated lymphatics after radical cystectomy are tedious, costly, and may lack the sensitivity afforded by molecular approaches such as reverse transcription-PCR (RT-PCR) for markers specific for urothelial tissue such as the uroplakin II (UPII) gene. Thus, we sought to evaluate an objective and sensitive molecular approach for the assessment of perivesical extension and lymph node status after radical cystectomy, based on the detection of UPII expression using RT-PCR and compare this assay to standard clinical and pathological examination. EXPERIMENTAL DESIGN: From November 1999 to September 2000, 27 patients with clinical T(a)-T(3)N(0)M(0) urothelial bladder cancer underwent radical cystectomy, 19 (70%) of which also had pelvic lymphadenectomy. At the completion of cystectomy, systematic biopsies of the external surface of the bladder specimen as well as from the largest palpable lymph node found at lymphadenectomy were obtained for molecular analysis. RT-PCR analysis for UPII mRNA was carried out on these biopsy specimens, and results were compared with data obtained from conventional pathological examination. RESULTS: Pathologically organ-confined tumors had a 42% (5 of 12) incidence of positive signals in the perivesical tissues and 17% (1 of 7) in the lymph nodes. Corresponding percentages for pT(3a)N(0) and pT(3b)-T(4)N(0) lesions were 67% (4 of 6)/25% (1 of 4) and 67% (4 of 6)/33% (2 of 6), respectively. Overall, pathologically node-negative cancers had a perivesical positivity rate of 54% (13 of 24) and a lymph node positivity rate of 25% (4 of 16). All patients with pathologically positive nodes had positive UPII signals in the lymph node sample. CONCLUSIONS: This molecular assay aimed at assessing perivesical extension and lymph node status after radical cystectomy appears to identify patients that may harbor residual disease not appreciated by conventional histology. Larger studies with 5-7-year follow-up will be required to determine the prognostic significance of such molecular information.

15
UI - 21303190
AU - Stadler WM; Steinberg G; Yang X; Hagos F; Turner C; Olopade OI
TI - Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization.
SO - Clin Cancer Res 2001 Jun;7(6):1676-82
AD - Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. wstadler@medicine.bds.uchicago.edu
PURPOSE: To better define cytogenetic mechanisms of CDKN2 loss at 9p21 and of DBCCR1 loss at 9q33 in bladder cancer, and to determine correlation with p53 and pRb. EXPERIMENTAL DESIGN: Two-color fluorescence in situ hybridization (FISH) using a chromosome 9 centromeric probe and locus-specific probes was performed. p53 and pRb were assessed by immunohistochemistry. RESULTS: Thirty-seven of fifty-five (67%) samples exhibited 9p21 loss, and 32 of 44 (73%) exhibited 9q33 loss. Twelve of 43 informative samples exhibited only 9p21 loss (5 cases) or only 9q33 loss (7 cases). Homozygous deletions were noted at 9p21 and 9q33 in 31 and 14% of cases, respectively, but 9q33 homozygous deletions were generally observed in only a minor clone. There was no correlation of any chromosome 9 loss with stage, but stage did correlate with chromosome 9 ploidy status; aneusomy 9 was observed in 33% of T(a) lesions and 71% of more advanced cases (P = 0.01). Aneusomy 9 was loosely correlated with p53 abnormalities (P = 0.07), but no correlation between any chromosome 9 and pRb abnormalities was discerned. CONCLUSIONS: This study strengthens the proposition that chromosome 9 losses occur early in bladder oncogenesis and before p53 alterations or development of aneusomy. The correlation of aneusomy 9 with p53 abnormalities is consistent with the presumed role of p53 in maintaining cytogenetic stability. Although the observed homozygous deletions strengthen the hypotheses that CDKN2 and DBCCR1 are important tumor suppressor genes, there is no evidence that either is a more critical or an earlier target for oncogenesis.

16
UI - 21334514
AU - Villanueva CM; Kogevinas M; Grimalt JO
TI - [Drinking water chlorination and adverse health effects: review of epidemiological studies]
SO - Med Clin (Barc) 2001 Jun 9;117(1):27-35
AD - Institut Municipal d'Investigacio Medica (IMIM). Unitat de Recerca Respiratoria i Ambiental. Instituto de Investigaciones Quimicas y Ambientales de Barcelona. Departamento de Quimica Ambiental. Barcelona. cvillanueva@imim.es

17
UI - 21403280
AU - Zeegers MP; Swaen GM; Kant I; Goldbohm RA; van den Brandt PA
TI - Occupational risk factors for male bladder cancer: results from a population based case cohort study in the Netherlands.
SO - Occup Environ Med 2001 Sep;58(9):590-6
AD - Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. mpa.zeegers@epid.unimaas.nl
OBJECTIVES: This study was conducted to estimate risk of bladder cancer associated with occupational exposures to paint components, polycyclic aromatic hydrocarbons (PAHs), diesel exhausts, and aromatic amines among the general population in The Netherlands. METHODS: A prospective cohort study was conducted among 58,279 men. In September 1986, the cohort members (55-69 years) completed a self administered questionnaire on risk factors for cancer including job history. Follow up for incident bladder cancer was established by linkage to cancer registries until December 1992. A case-cohort approach was used based on 532 cases and 1630 subcohort members. A case by case expert assessment was carried out to assign to the cases and subcohort members a cumulative probability of occupational exposure for each carcinogenic exposure. RESULTS: Men in the highest tertiles of occupational exposure to paint components, PAHs, aromatic amines, and diesel exhaust had non-significantly higher age and smoking adjusted incident rate ratios (RRs) of bladder cancer than men with no exposure: 1.29 (95% confidence interval (95% CI) 0.71 to 2.33), 1.24 (95% CI 0.68 to 2.27), 1.32 (95% CI 0.41 to 4.23) and 1.21 (95% CI 0.78 to 1.88), respectively. The associations between paint components and PAHs and risk of bladder cancer were most pronounced for current smokers. Among former smokers it seemed that for cumulative probability of exposure to paint components and PAHs, men who had smoked more than 15 cigarettes a day had RRs below unity compared with men who had smoked less than 15 cigarettes a day, whereas among current smokers the opposite was found. Exposure to diesel exhaust was positively associated with risk of bladder cancer among current and former smokers who had smoked more than 15 cigarettes a day. CONCLUSIONS: This study provided only marginal evidence for an association between occupational exposure to paint components, PAHs, aromatic amines, and bladder cancer. Despite the small proportion of exposed subjects, an interaction with cigarette smoking was found, specifically for paint components, suggesting that the carcinogenic effect on the bladder might decrease after stopping smoking.

18
UI - 21412201
AU - Puntoni R; Ceppi M; Reggiardo G; Merlo F
TI - Occupational exposure to carbon black and risk of bladder cancer.
SO - Lancet 2001 Aug 18;358(9281):562
Exposure to carbon black has been linked to risk of lung and bladder cancer. We therefore investigated the frequency of these cancers in a group of 2286 longshoremen who were exposed occupationally to carbon-black dust. We identified 208 cancers (standardised incidence ratio 96, 95% CI 83-109), 53 lung cancers (108, 81-141), and 32 bladder cancers (130, 89-184). Longshoremen exposed to high concentrations of carbon black (n=14) had a significantly increased frequency of bladder cancer (204, 112-343). We conclude that the increase in bladder cancer in longshoremen is probably related to high exposure to carbon black.

19
UI - 21433634
AU - van Rhijn BW; Lurkin I; Kirkels WJ; van der Kwast TH; Zwarthoff EC
TI - Microsatellite analysis--DNA test in urine competes with cystoscopy in follow-up of superficial bladder carcinoma: a phase II trial.
SO - Cancer 2001 Aug 15;92(4):768-75
AD - Department of Pathology, Josephine Nefkens Institute, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands.
BACKGROUND: It has been shown that microsatellite analysis (MA) is able to detect bladder carcinoma in urine. Relatively small groups of patients often with high stage and grade disease were investigated. However, greater than 85% of cystoscopies are performed for follow-up of superficial bladder carcinoma. The authors evaluated this DNA-based method in a group of consecutive patients in follow-up after transurethral resection of superficial disease. METHODS: Matched blood and urine samples from 109 patients were obtained before cystoscopy and subjected to MA. The BTA stat test (Bard Diagnostic Sciences, Inc., Redmond, WA) and cytology were used for comparison. RESULTS: Sixteen patients were excluded: the DNA was of insufficient quality for 7 patients and leukocyte abundance rendered the result of MA unreliable for 9 patients. For the remaining 93 patients, MA detected 18 of the 24 recurrent tumors. The six undetected tumors were small pTaG1 lesions for which immediate surgery was not necessary. Conversely, 5 of 9 patients with a positive MA and a negative cystoscopy had a tumor recurrence within 6 months after urine collection. In contrast, a recurrence occurred in only 7 of 60 patients who were negative in both MA and cystoscopy (P = 0.006). The MA (74%) appeared more sensitive than the BTA stat test (56%) or urine cytology (22%). CONCLUSIONS: Microsatellite analysis is a DNA test in urine that reliably signals the presence of recurrent bladder carcinoma, sometimes even before cystoscopic evidence of the disease. This noninvasive diagnostic tool has the potential to replace cystoscopy in many cases. The authors' results warrant the need for randomized trials. Copyright 2001 American Cancer Society.

20
UI - 21397888
AU - Raitanen MP; Kaasinen E; Rintala E; Hansson E; Nieminen P; Aine R; Tammela TL; Finn Bladder Group
TI - Prognostic utility of human complement factor H related protein test (the BTA stat Test).
SO - Br J Cancer 2001 Aug 17;85(4):552-6
AD - Department of Urology, Tampere University Hospital, Box 2000, 33521 Tampere, Finland.
The purpose of the study was to determine, in addition to well-known prognostic factors, histological grade, stage, tumour size and multiplicity, the correlation of BTA stat Test on disease free interval (DFI) on primary superficial bladder cancer. A total of 116 patients with newly diagnosed bladder cancer were evaluated in a prospective multicentre study. A voided urine sample was obtained prior to TURB and split for culture, cytology and BTA stat testing. Follow-up data for the patients were collected until the first recurrence or the last visit and the DFI was analysed by Kaplan-Meier method and Cox analysis. Ninety-seven of the 116 (83.6%) patients were eligible for analysis. The BTA stat Test was positive in 73 (75.3%) patients, whereas cytology detected 20 (20.6%) cases. The DFI was found to be shorter among patients with a positive BTA stat Test, and also among those with intermediate or high-grade tumours. The BTA stat Test result divided patients with grade 2 tumours into two prognostic groups, in that those testing positive had 68.6% risk of recurrence during the first year compared to 42.9% risk of those with a negative test result (P = 0.041). Although the effect of tumour size on DFI was notable, the difference did not reach statistical significance (P = 0.064). Number of tumours was not related to DFI, nor was the difference between different stage of tumour of significance. BTA stat Test is not only sensitive in detection of primary bladder cancer, but also might have some independent prognostic significance. Copyright 2001 Cancer Research Campaign.

21
UI - 21397891
AU - Thykjaer T; Christensen M; Clark AB; Hansen LR; Kunkel TA; Orntoft TF
TI - Functional analysis of the mismatch repair system in bladder cancer.
SO - Br J Cancer 2001 Aug 17;85(4):568-75
AD - Department of Clinical Biochemistry, Skejby University Hospital, 8200 Aarhus N, Denmark.
In bladder cancer the observed microsatellite instability indicates that mismatch repair deficiency could be a frequently involved factor in bladder cancer progression. To investigate this hypothesis we analysed extracts of seven bladder cancer cell lines and, as a novel approach, five clinical cancer samples for mismatch repair activity. We found that one cell line (T24) and three of the clinical samples had a reduced repair capacity, measured to approximately 20% or less. The T24 cell extract was unable to repair a G-G mismatch and showed reduced repair of a 2-base loop, consistent with diminished function of the MSH2-MSH6 heterodimer. The functional assay was combined with measurement for mutation frequency, microsatellite analysis, sequencing, MTT assay, immunohistochemical analysis and RT-PCR analysis of the mismatch repair genes MSH2, MSH3, MSH6, PMS1, PMS2 and MLH1. A >7-fold relative increase in mutation frequency was observed for T24 compared to a bladder cancer cell line with a fully functional mismatch repair system. Neither microsatellite instability, loss of repair nor mismatch repair gene mutations were detected. However, RT-PCR analysis of mRNA levels did detect changes in the ratio of expression of the Mut S and Mut L homologues. The T24 cell line had the lowest MSH6 expression level of the cell lines tested. Identical RT-PCR analysis of seventeen clinical samples (normal urothelium, 7; pTa low stage, 5; and pT1-4 high stage, 5) indicated a significant change in the expression ratio between MSH3/MSH6 (P< 0.004), MSH2/MSH3 (P< 0.012) and PMS2/MLH1 P< 0.005, in high stage bladder tumours compared to normal urothelium and low stage tumours. Collectively, the data suggest that imbalanced expression of mismatch repair genes could lead to partial loss of mismatch repair activity that is associated with invasive bladder cancer. Copyright 2001 Cancer Research Campaign.

22
UI - 21160506
AU - Wada S; Yoshimura R; Masuda C; Hase T; Ikemoto S; Kishimoto T; Fukushima S
TI - Are tobacco use and urine pH indicated as risk factors for bladder carcinoma?
SO - Int J Urol 2001 Mar;8(3):106-9
AD - Departments of Urology and Pathology, Osaka City University Medical School, Osaka, Japan.
BACKGROUND: Many case-control and cohort studies have shown a positive relationship between bladder carcinoma and tobacco use. Recently, urine pH has been reported to influence aromatic amine carcinogenesis, which have been implicated as potent carcinogens in bladder carcinoma patients. Herein the correlation between bladder carcinoma, tobacco use and urine pH is reported. METHOD: One hundred and forty-one patients with bladder carcinoma and 128 patients with benign prostatic hyperplasia or urolithiasis as controls were selected. All patients were admitted to Osaka City University Hospital for the purpose of surgical treatment. Urine pH was checked by a test tape. RESULTS: Of the patients with bladder carcinoma, 106 were smokers and 35 were non-smokers. In contrast, the number of smokers in the control group was 76 and that of non-smokers was 52. The odds ratio in the bladder carcinoma group calculated for the smoker patients was 2.07, showing a significant correlation between bladder carcinoma and tobacco use. Regarding urine pH, acidic urine was found in 126 patients in the bladder carcinoma group and in 116 patients in the control group. The odds ratio in the bladder carcinoma group for acidic urine was 0.87, showing no significant relationship between bladder carcinoma and urine pH. CONCLUSION: The study found a positive relationship between bladder carcinoma and tobacco use; however, it could not establish a clear relationship between bladder carcinoma and urine pH, even in the smoker group.

23
UI - 21217016
AU - Porcaro AB; D'Amico A; Ficarra V; Balzarro M; Righetti R; Martignoni G; Cavalleri S; Malossini G
TI - Nephrogenic adenoma of the urinary bladder: our experience and review of the literature.
SO - Urol Int 2001;66(3):152-5
AD - Department of Urology, Medical University of Verona, Italy.
OBJECTIVE: To assess our experience in the treatment and clinical outcome of bladder nephrogenic adenoma (NA) updating and reviewing the literature concerning this issue. PATIENTS and METHODS: From September 1976 to June 1999, bladder NA was diagnosed in 8 patients: 6 men and 2 women with a 3:1 male ratio, aged 26-80 (mean 58.3) years. Follow-up ranged from 4 to 194 (mean 93.5) months. RESULTS: NA was associated with transitional cell carcinoma in 3 cases. Predisposing factors were assessed in all patients. Previous surgery of the lower urinary tract was detected in 5 cases: ureterocystoneostomy in 2, partial cystectomy in 1, repair of vesicouterine fistula in 1, and multiple urethroplasties in 1. Previous endoscopic treatments were carried out in 2 patients, transurethral resection of the prostate in 1 and repeated transurethral resection of the vesicle in the other. A history of intravesical instillation of bacillus Calmette-Guerin was assessed in 1 case. Patients complained of irritative voiding symptoms in 6 cases and hematuria in 2. Endoscopically, the lesions appeared polypoid and multifocal in 5 patients, and flat and single in 3. The lesions were removed endoscopically, providing relief of symptoms in all cases. Histopathology assessed the diagnosis of nephrogenic adenoma, detecting focal atypic cells in 1 case only. Five patients (63%) relapsed 2-24 months after management. Recurrences were also treated endoscopically. CONCLUSIONS: Clinical and endoscopic features of bladder NA are not specific, simulating urothelial carcinoma or chronic cystitis. Endoscopic management allows accurate histological diagnosis and provides long-lasting relief of symptoms. NA needs careful and long-term follow-up, because of the high risk of recurrences and the potential neoplastic degeneration of the metaplastic urothelium. Copyright 2001 S. Karger AG, Basel

24
UI - 21238970
AU - Lin S; Hirschowitz SL; Williams C; Shintako P; Said J; Rao JY
TI - Cytokeratin 20 as an immunocytochemical marker for detection of urothelial carcinoma in atypical cytology: preliminary retrospective study on archived urine slides.
SO - Cancer Detect Prev 2001;25(2):202-9
AD - Department of Pathology, Jonsson Comprehensive Cancer Center, University of California at Los Angeles Medical Center, 90095, USA.
Previous studies have shown that expression of cytokeratin 20 (CK20), a constituent of intermediate filaments, is increased in malignant versus benign urine samples. To evaluate whether immunocytochemical staining of CK20 on archived urine slides could be used as a potential adjunct marker for triage of atypical urine cytology, we analyzed a total of 77 archived urine slides obtained from a spectrum of patients with various risks of developing urothelial carcinoma. These patients were divided into four groups on the basis of initial urine cytologic results and subsequent follow-up biopsy findings; group 1 had negative results in both evaluations, whereas the results in group 4 were positive for both cytology and biopsy. Groups 2 and 3 had a diagnosis of atypical urine cytology; however, patients in group 3 had a positive follow-up biopsy, and patients in group 2 did not. The Papanicolaou-stained archived urine slides were destained and then restained immunocytochemically with monoclonal antibody against CK20. With 5% positively stained nonumbrella cells as a threshold, CK20 was positive in 94.4% of group 3 or 4 patients. In contrast, CK20 was positive in 27.3% of group 2 patients and in 10.5% of group 1 patients. The overall sensitivity and specificity for CK20 for the detection of urothelial carcinoma in this population of patients were 94.4% and 80.5%, respectively. This study demonstrated that immunocytochemical analysis of CK20 on archived urine slides could be used to triage atypical urine cytology into low- and high-risk categories and that CK20 might be a simple and useful early detection marker for urothelial carcinoma.

25
UI - 21294353
AU - Bernardini S; Chabannes E; Bittard H
TI - [Usefulness of p53 in the clinical management of bladder tumors]
SO - Prog Urol 2001 Apr;11(2):201-8
AD - Service d'Urologie, Hopital Saint-Jacques, Besancon, France.
The antioncogene p53 has been the subject of many studies in the field of bladder cancer, for many years and there appears to be a good correlation between p53 protein overexpression and pejorative clinicopathological factors, but contradictory results have been reported concerning its prognostic value. These discordances can be partly explained by the various immunohistochemical methods used in published series. Standardization of a highly sensitive and specific immunohistochemical method for the detection of p53 alterations now appears to be essential in order to accurately determine the value of p53 in the clinical management of bladder cancer.

26
UI - 21356613
AU - Saad A; Hanbury DC; McNicholas TA; Boustead GB; Woodman AC
TI - The early detection and diagnosis of bladder cancer: a critical review of the options.
SO - Eur Urol 2001 Jun;39(6):619-33
AD - Department of Urology, Lister Hospital, Stevenage, Herts, UK. adnansaad99_@hotmail.com
Bladder cancer has a high worldwide incidence matched by a tendency to recur, necessitating close and regular follow-up. Current methods of investigation of bladder cancer involve cystoscopy, ultrasound scanning and contrast urography, with additional information provided by cytology. These methods, although having a high detection rate, are expensive, time-consuming, invasive and uncomfortable. There is, therefore, a need for an inexpensive, noninvasive, quick and simple investigation with a high sensitivity and specificity for the detection of bladder cancer. There are an increasing number of molecular assays available for the detection of bladder cancer. From bladder tumour antigens to nuclear matrix proteins to adhesion molecules, cytoskeletal proteins and growth factors, urology has looked at them all to support the early detection and diagnosis of bladder cancer. This review critically discusses both the commercial as well as the research-based diagnostic assays available (their mode of action, overall accuracy - both by stage and grade, and their uses and limitations from both a clinical as well as a practical point of view). Aiming to give an insight into the options currently available for noninvasive bladder cancer diagnosis, it also provides prospective comment on what new methods/technologies may be useful in the medium term.

27
UI - 21405429
AU - Amling CL
TI - Diagnosis and management of superficial bladder cancer.
SO - Curr Probl Cancer 2001 Jul-Aug;25(4):219-78
AD - Department of Urology, Naval Medical Center, San Diego, California, USA.
Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as "superficial" disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as "flat" mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guerin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-alpha with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened.

28
UI - 21407944
AU - Scrimger RA; Murtha AD; Parliament MB; Venner PM; Hanson J; Houle G; Chetner M
TI - Muscle-invasive transitional cell carcinom

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