National Cancer Institute®
Last Modified: April 1, 2002
UI - 11851614
AU - El-Sheikh SS; Madaan S; Alhasso A; Abel P; Stamp G; Lalani EN
TI - Cyclooxygenase-2: a possible target in schistosoma-associated bladder cancer.
SO - BJU Int 2001 Dec;88(9):921-7
AD - Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital Campus, London, UK.
OBJECTIVE: To analyse and compare the expression of cyclooxygenase (COX) enzymes in schistosoma-associated bladder cancer, and to determine any association with tumour grade or stage. MATERIALS AND METHODS: Sixty paired samples of tumour and adjacent nonmalignant urothelium were identified. There were 25 squamous and 28 transitional cell carcinomas, and seven adenocarcinomas. Serial sections were obtained and a standard three-layer immunohistochemistry protocol, using COX-1- and COX-2-specific mouse monoclonal antibodies, applied. RESULTS: COX-1 was expressed mostly in nonvascular smooth muscle with weak reactivity in malignant and nonmalignant urothelium. Nonmalignant urothelium expressed COX-2 weakly, notably in areas of dysplasia and squamous metaplasia whereas there was a significant increase in COX-2 (P < 0.001) with moderate to strong granular cytoplasmic expression in all three malignant histological types. The COX-2 reactivity was higher in transitional and adenocarcinomas than in squamous cell carcinoma (P < 0.001). Areas of carcinoma in situ showed COX-2 reactivity comparable with that in invasive areas and more intense than that detected in dysplastic or metaplastic urothelium (P < 0.001). There was a statistically significant positive correlation between COX-2 expression and tumour grade (P = 0.0052). CONCLUSION: COX-2 is over-expressed in schistosoma-associated bladder cancer, consistent with a potential role for COX-2 inhibitors in the prevention and management of this disease.
UI - 11228547
AU - Fouladi B; Sabatier L; Miller D; Pottier G; Murnane JP
TI - The relationship between spontaneous telomere loss and chromosome instability in a human tumor cell line.
SO - Neoplasia 2000 Nov-Dec;2(6):540-54
AD - Radiation Oncology Research Laboratory, University of California, San Francisco, 1855 Folsom Street, MCB 200, San Francisco, CA 94103, USA.
Chromosome instability plays an important role in cancer by promoting the alterations in the genome required for tumor cell progression. The loss of telomeres that protect the ends of chromosomes and prevent chromosome fusion has been proposed as one mechanism for chromosome instability in cancer cells, however, there is little direct evidence to support this hypothesis. To investigate the relationship between spontaneous telomere loss and chromosome instability in human cancer cells, clones of the EJ-30 tumor cell line were isolated in which a herpes simplex virus thymidine kinase (HSV-tk) gene was integrated immediately adjacent to a telomere. Selection for HSV-tk-deficient cells with ganciclovir demonstrated a high rate of loss of the end these "marked" chromosomes (10-4 events/cell per generation). DNA sequence and cytogenetic analysis suggests that the loss of function of the HSV-tk gene most often involves telomere loss, sister chromatid fusion, and prolonged periods of chromosome instability. In some HSV-tk-deficient cells, telomeric repeat sequences were added on to the end of the truncated HSV-tk gene at a new location, whereas in others, no telomere was detected on the end of the marked chromosome. These results suggest that spontaneous telomere loss is a mechanism for chromosome instability in human cancer cells.
UI - 11872630
AU - Wang L; Habuchi T; Takahashi T; Mitsumori K; Kamoto T; Kakehi Y;
TI - Kakinuma H; Sato K; Nakamura A; Ogawa O; Kato T Cyclin D1 gene polymorphism is associated with an increased risk of urinary bladder cancer.
SO - Carcinogenesis 2002 Feb;23(2):257-64
AD - Department of Urology, Akita University School of Medicine, Akita 010-8543, Japan.
Cyclin D1 is believed to play an important role in the genesis and/or progression of transitional cell cancer (TCC) of the urinary bladder. Cyclin D1 gene (CCND1) mRNA is alternatively spliced to produce two transcripts, and the splicing pattern may be modulated by a G to A single nucleotide polymorphism within the splice donor site of exon 4. This study was conducted to explore the association between the polymorphism and the susceptibility to and disease status of TCC of the bladder in 222 cases and 317 native Japanese controls. The relationship between the CCND1 polymorphism and the mRNA splicing pattern in TCC cells was evaluated by semi-quantitative reverse-transcription PCR. The CCND1 A allele was more frequently observed in the TCC group than the control group (P = 0.032) with a significant difference in the genotype frequency between the two groups (P = 0.029). The AA genotype was associated with a significantly higher risk of TCC compared with the AG+GG genotypes (adjusted odds ratio (aOR) = 1.76, 95% confidence interval (CI) = 1.09-2.84, P = 0.022). This association was observed more significantly in nonsmoking cases (aOR = 2.53; 95% CI = 1.28-4.51, P = 0.008). Looking at tumor grade, the presence of the A allele was associated with higher grade (= grade 3) tumors with a gene dosage effect (aOR = 1.77, CI = 1.16-2.69, P = 0.008). In tumor stage, although not significant, the AA + AG genotypes tended to be more frequently observed in cases with T1-4 tumors than those with Ta tumors (aOR = 1.94, 95% CI = 0.98-3.82, P = 0.057). The genotype seemed to influence the two alternatively spliced forms of the CCND1 mRNA because the ratio of the CCND1 transcript-b/transcript-a was significantly higher in cases with the AA genotype compared with those with the AG + GG genotypes. These data suggest that the CCND1 variant A allele may be associated with an increased risk of TCC of the bladder, especially in men without a history of smoking, and it may also have an effect on its disease status.
UI - 11888856
AU - Leonard C; Huret JL; Gfco; Le Groupe francais de cytogenetique
TI - oncologique [From cytogenetics to cytogenomics of bladder cancers]
SO - Bull Cancer 2002 Feb;89(2):166-73
AD - Service de cytogenetique, Hopital du Kremlin-Bicetre, 78, rue du General-Leclerc, 94270 Le Kremlin-Bicetre, France.
Bladder cancers are classified as: transitional cell carcinoma (TCC), the most frequent in Europe/USA, squamous cell carcinoma (SCC), more frequent in the Middle East and in Africa, adenocarcinoma and small cell carcinoma, rare. TCC exhibit pseudo diploid karyotypes with only a few anomalies in early stages, evolving towards pseudo-tetraploides complexes karyotypes. Partial or complete monosomy 9 (-9) is an early event, found in half cases. Deletion (11p) or -11 is found in 20-50% of cases, more often in high grade and invasive tumours. Del(13q) is found in 25% of cases and correlated with high grade/stage; tumours with Rb alterations are invasives. Del(17p) is a late event, found in 40% of cases; P53 alterations are correlated with grade and stage, tumour progression, and a worse prognosis. Del(1p), i(5q), +7, and many other rearrangements - more often deletions than duplications - are frequently found. These losses of heterozygocity point to a multistep complex process involving tumor suppressor genes. In SCC, monosomy 9 is also an early event, even more frequent than in TCC; homozygous deletion of P16 is frequent. Trisomy 7 seems to be more frequent than in TCC. Chromosome 17 is often implicated, especially in high grades/stages; the profile of mutations of P53 is different from what is found in TCC. Allelic losses of 3p, 8p, 9p, 9q, 17p are frequent. The karyotype is more complex in advanced grades/stages, as in TCC.
UI - 11917583
AU - Chu YC; Han JY; Han HS; Kim JM; Suh JK
TI - Cytologic evaluation of low grade transitional cell carcinoma and instrument artifact in bladder washings.
SO - Acta Cytol 2002 Mar-Apr;46(2):341-8
AD - Departments of Anatomical Pathology and Urology, Inha University Hospital, 7-206, 3rd Street, Shinheung-Dong, Choong-Gu, Inchon, Korea 400-103.
OBJECTIVE: To identify key cytologic features for the separation of low grade transitional cell carcinomas (TCCs) from nonneoplastic lesions in bladder washings. STUDY DESIGN: The cytomorphologic features of 95 bladder washing specimens showing papillary fragments, which included 50 low grade TCCs and 45 nonneoplastic lesions, were reviewed retrospectively. RESULTS: Bladder washings from low grade TCCs showed papillary and irregular groups of cells with ragged borders, cytoplasmic homogeneity and subtle nuclear changes, such as increased nuclear/cytoplasmic ratio and irregular nuclear border. Bladder washings after instrumentation from nonneoplastic lesions of the bladder showed cellular specimens with cohesive, ball-shaped and papillary clusters with smooth borders lined with a denser-staining cytoplasmic collar. Reactive urothelial cells often displayed loose aggregates with irregular borders but no cytoplasmic collar. CONCLUSION: In bladder washing cytology, nuclear changes and cytoplasmic homogeneity play a major role in the diagnosis of carcinoma.
UI - 11779696
AU - Han KR; Pantuck AJ; Belldegrun AS; Rao JY
TI - Tumor markers for the early detection of bladder cancer.
SO - Front Biosci 2002 Jan 1;7():e19-26
AD - Depratment of Urology, University of California School of Medicine, Los Angeles, California 90095-1738, USA.
Several urine markers have been and are currently being investigated for the diagnosis and prognostication of bladder malignancies. While cystoscopy and urine cytology remain the gold standard in the detection of bladder cancer, cystoscopy is invasive and cytology yields low sensitivities in low-grade disease. The availability of a non-invasive, accurate, office-based test would be ideal. In this review, we discuss markers that are useful in the prevention and detection of transitional cell carcinoma of the bladder. In general, each of the markers has better sensitivities than cytology, but lower specificities. Furthermore, each of these markers must still be used in adjunct with cystoscopy.
UI - 11779714
AU - Skacel M; Liou LS; Pettay JD; Tubbs RR
TI - Interphase fluorescence in-situ hybridization in the diagnosis of bladder cancer.
SO - Front Biosci 2002 Jan 1;7():e27-32
AD - Department of Anatomic and Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. firstname.lastname@example.org
Interphase FISH is a technique that uses fluorescent molecules to detect chromosomes or specific regions of DNA. It is a rapid and powerful technique for detection of cytogenetic abnormalities in malignant cells independent of their cell cycle status. Using variety of pericentromeric and locus-specific probes, numerical chromosomal changes (aneusomy) as well as loss or gain/amplification of specific genetic regions can be detected in clinical samples. Numerous studies have identified genetic alterations at the DNA level, occurring in the pathogenesis of variety of human neoplasms including bladder cancer, some of which can be used for detection, prognosis, and as intermediate endpoints for evaluating the response to therapy. Recently, sensitivity and specificity of a multicolor FISH assay consisting of four probes (3, 7, 17 and 9p21) was analyzed in several prospective and retrospective studies. The data suggest that this method applicable to voided urine specimens may allow safe extension of the interval between cystoscopies in routine surveillance of patients with transitional cell carcinoma of the bladder. FISH analysis of cells isolated from bladder washings or voided urine is also holding promise for monitoring of treatment outcome and predicting recurrence and progression of the disease. Therefore, this technique can be an important aid in the efforts to reduce mortality from transitional cell carcinoma of the bladder, since it increases our ability to prevent progression to incurable muscle invasive disease.
UI - 11920528
AU - Rodriguez-Alonso A; Pita-Fernandez S; Gonzalez-Carrero J; Nogueira-March
TI - JL Multivariate analysis of survival, recurrence, progression and development of mestastasis in T1 and T2a transitional cell bladder carcinoma.
SO - Cancer 2002 Mar 15;94(6):1677-84
AD - Urology Service, Xeral-Cies Hospital, Vigo, Spain. Arodri68@Terra.es
BACKGROUND: Determination of prognosis factors associated with survival, recurrence, progression, and development of metastasis in T1 and T2a transitional cell carcinoma (TCC) of the bladder is discussed. METHODS: A study was conducted of a group of 210 patients with primary bladder TCC at classification T1 (n = 175) and T2aN0M0 (n = 35). A total of 177 variables were studied in each patient. The monoclonal antibodies used were the following: DO7 (p53) and MIB-1 (Ki-67). Prognosis was obtained using Kaplan-Meier methodology and Cox proportional hazards model. RESULTS: The average follow-up period was 6.7 years. Cancer-related survival rates at 5 and 10 years were 82.96% and 74.78%, respectively. The independent survival variables were the following: age and expression of p53. Recurrence free survival at 5 and 10 years stood at 51.80% and 42.71%, respectively. The independent recurrence variables were T2a classification, tumor multifocality, tumor size of greater than 3 cm, carcinoma in situ in random biopsy, and expression of Ki-67. Progression free survival rates at 5 and 10 years were 75.31% and 69.16%, respectively. The independent progression variables were age, T2a classification, and expression of p53. Metastasis free survival rates at 5 and 10 years stood at 87.23% and 84.55%, respectively. The expression of p53 was the sole variable to provide an independent prediction of metastasis. CONCLUSIONS: The expression of p53 clearly has an independent effect on the prediction of survival, progression and development of metastasis, showing a dose-response effect. Tumor multifocality and T2a classification are the variables that best predict recurrence. Copyright 2002 American Cancer Society.
UI - 11877919
AU - Cannon SB
TI - Staging and terminology of superficial urinary bladder tumors.
SO - J Insur Med 2001;33(4):360-2
AD - Northwestern Mutual Life Insurance Company, 720 East Wisconsin Avenue, Milwaukee, WI 53202, USA.
Ta and T1 transitional cell urinary bladder tumors are prone to recurrence in a large percentage of cases, but they uncommonly progress to invasive tumors. On the other hand, Tis bladder tumors progress to invasive tumors in a majority of cases. Even though all of these tumors are found in the superficial layers of the bladder wall, their natural histories are significantly different. In addition, new terminology has been developed for these lesions.
UI - 11801555
AU - Lu ML; Wikman F; Orntoft TF; Charytonowicz E; Rabbani F; Zhang Z;
TI - Dalbagni G; Pohar KS; Yu G; Cordon-Cardo C Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods.
SO - Clin Cancer Res 2002 Jan;8(1):171-9
AD - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
This study was designed to define the potential clinical relevance of identifying alterations affecting p53 pathway in bladder cancer and to test a new, low-cost, high-throughput, and array-based TP53 sequencing technology. Tumor samples from 140 evaluable patients with bladder cancer were analyzed with two methods to detect TP53 gene mutations, including single-stranded conformational polymorphism followed by direct sequencing and an oligonucleotide array-based sequencing method. Immunohistochemistry was used to assess patterns of expression of p53, p21/WAF1, and mdm2. Median follow-up time was 27.6 months. Results from the above analyses were correlated with clinicopathological parameters and outcome. Combining the mutation-detection assays, 79 cases (56.4%) were found to harbor TP53 gene mutations. Direct sequencing identified 66 point mutations and five frameshift mutations. The p53 oligonucleotide array detected 65 point mutations and four splice site mutations in different exons but missed all five frameshift mutations. p53 nuclear overexpression was observed in 71 cases (50.7%), lack of p21 nuclear expression was found in 81 cases (57.9%), and mdm2 nuclear overexpression was seen in 64 cases (45.7%). In multivariate analysis, 17 patients (12.1%) had an altered p53 pathway, defined by the detection of mutant TP53 and/or p53 nuclear overexpression, loss of p21 nuclear expression, and mdm2 nuclear overexpression, and exhibited the worst clinical outcome in the observation period (P = 0.015), and it appears to be a significant prognostic factor associated with patient survival.
UI - 11801538
AU - Utting M; Werner W; Dahse R; Schubert J; Junker K
TI - Microsatellite analysis of free tumor DNA in urine, serum, and plasma of patients: a minimally invasive method for the detection of bladder cancer.
SO - Clin Cancer Res 2002 Jan;8(1):35-40
AD - Department of Urology, Friedrich-Schiller-University Jena, 07743 Jena, Germany. email@example.com
PURPOSE: Tumor cells may release DNA into circulation, which is subsequently carried as free DNA and enriched in blood and urine. The detection of tumors by microsatellite analysis of free DNA offers a possibility to establish a minimally invasive method for the detection of bladder cancer. EXPERIMENTAL DESIGN: We performed microsatellite analysis of free DNA of urine, serum, and plasma in comparison with DNA of lymphocytes and tumors of 40 patients with conspicuous bladder lesions. Six microsatellite markers were used for the detection of alterations on chromosomes 4, 9, and 17. RESULTS: Twenty-six of 36 bladder tumor tissue samples showed alterations. Microsatellite changes matching those in the tumor tissues were detected in at least one of the body fluids in 23 cases. CONCLUSIONS: The study indicates that simultaneous and multiple investigations of microsatellite markers on free DNA of urine and blood could have clinical relevance as a minimally invasive method for diagnosis and screening of bladder cancer.
UI - 11890237
AU - Herr H W
TI - Does cystoscopy correlate with the histology of recurrent papillary tumours of the bladder?
SO - BJU Int 2001 Nov;88(7):683-5
AD - Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
OBJECTIVE: To correlate the cystoscopic appearance of recurrent papillary bladder tumours with the histology after transurethral resection, and thus ascertain whether cystoscopy can reliably identify low-grade, noninvasive papillary tumours suitable for outpatient fulguration. PATIENTS AND METHODS: In all, 150 recurrent papillary tumours of the bladder identified at outpatient flexible cystoscopy were classified as either low-grade and noninvasive (TaG1), high-grade and noninvasive (TaG3), or invasive (TIG3) tumours, and correlated with urine cytology and histology of tumour stage and tumour grade after transurethral resection. RESULTS: Cystoscopy classified 84 of the 150 papillary tumours as TaG1 and 66 as either TaG3 or T1G3. Cystoscopy correctly predicted the histology of 78 of 84 (93%) TaG1 tumours, 71 of 72 (98%) TaG1 tumours associated with a negative urine cytology, and 92% of TaG3 or T1G3 tumours. CONCLUSIONS: A skilled urologist can identify noninvasive, low-grade recurrent papillary bladder tumours on follow-up cystoscopy that do not require biopsy and that may be treated by outpatient fulguration alone.
UI - 11890238
AU - Simms M S; Perkins A C; Price M R; Scholfield D P; Bishop M C
TI - 99mTechnetium-C595 radioimmunoscintigraphy: a potential staging tool for bladder cancer.
SO - BJU Int 2001 Nov;88(7):686-91
AD - Department of Urology, City Hospital Nottingham, UK. firstname.lastname@example.org
OBJECTIVES: To assess whether immunoscintigraphy using a conjugate of the anti-MUC1 monoclonal antibody C595 and 99mTc could be used to target transitional cell bladder cancer after intravenous administration to patients. PATIENTS AND METHODS: Twenty-one patients with invasive or metastatic transitional cell carcinoma were recruited. Patients received 1 mg of C595 labelled with 800 MBq 99mTc followed by imaging at 0.5, 6 and 24 h using a combination of planar and single-photon emission computed tomography. Of these patients, 14 subsequently underwent cystectomy, four underwent radiotherapy and the remaining three had histologically confirmed metastatic disease. The results of immunoscintigraphy were compared with surgical findings and conventional radiology. RESULTS: There were no adverse reactions in any patient. Of the 20 patients who were found to have tumour at the time of the study, positive localization of antibody in tumour was apparent in 16. Of the remaining four patients, false-positive localization of antibody in presumed nodal tissue was detected in two. The remaining scan results were equivocal. In three patients, histologically confirmed pelvic nodal metastases that had not been detected on preoperative computed tomography were identified. CONCLUSION: These early results show the potential of 99mTc-C595 immunoscintigraphy for staging bladder cancer. A larger study is needed to fully evaluate the technique.
UI - 11890239
AU - Poulakis V; Witzsch U; De Vries R; Altmannsberger H M; Manyak M J; Becht
TI - E A comparison of urinary nuclear matrix protein-22 and bladder tumour antigen tests with voided urinary cytology in detecting and following bladder cancer: the prognostic value of false-positive results.
SO - BJU Int 2001 Nov;88(7):692-701
AD - Department of Urology and Paediatric Urology, Hospital Nordwest, Academic Hospital of Johann-Wolfgang-Goethe-University Frankfurt, Frankfurt/Main, Germany. email@example.com
OBJECTIVES: To evaluate the diagnostic and prognostic value of the nuclear matrix protein-22 (NMP22) and bladder tumour antigen (BTAstat) tests compared with voided urinary cytology (VUC) in detecting and following bladder cancer, assessing particularly the prognostic value of false-positive test results in patients followed up for bladder cancer. PATIENTS AND METHODS: From 739 patients suspected of having bladder cancer, voided urine samples for the NMP22 and BTAstat tests, and for VUC and urine analysis, were collected before cystoscopy. All patients underwent transurethral resection of bladder lesions or mapping. and were followed for a mean (range) of 27.3 (3-65) months. RESULTS: In the 406 patients with bladder cancer, the overall sensitivity was 85% for NMP22, 70% for BTAstat and 62% for VUC. For histological grades 1-3 the sensitivity in detecting transitional cell carcinoma was 82%, 89% and 94% for NMP22, 53%, 76% and 90% for BTAstat, and 38%, 68% and 90% for VUC, respectively. Although the sensitivity in detecting invasive carcinoma was >85% for all the tests. NMP22 and BTAstat were statistically more sensitive than VUC for superficial tumours. The optimal threshold value for NMP22, calculated using the receiver operating characteristics curve was 8.25 U/mL. The specificity was 68% for NMP22, 67% for BTAstat, and 96% for VUC. The specificity of VUC remained >87% and was independent of benign histological findings. In contrast, in patients with no apparent genitourinary disease on histology, NMP22 and BTAstat had significantly higher specificity (94% and 92%, respectively: P=0.003) than in the group with chronic cystitis (52% for both tests). Forty patients having no bladder cancer at biopsy had a recurrence after a mean (range) follow-up of 7.7 (3-15) months: all had a previous history of bladder cancer. According to subsequent recurrence, the prognostic positive and negative predictive values were 18% and 91% for NMP22, 13% and 88% for BTAstat, and 79% and 91% for VUC. Both false-positive VUC and NMP22 tests predicted recurrence (log-rank test, P<0.001 and P=0.004, respectively), but the BTAstat test produced no similar correlation (P=0.778). CONCLUSION: The NMP22 and BTAstat tests are better than VUC for detecting superficial and low-grade bladder cancer but they have significantly lower specificity. After excluding diseases with the potential to interfere in these tests the overall specificity of both tests is increased considerably. False-positive results from NMP22 and VUC but not from BTAstat in patients followed up for bladder cancer correlate with future recurrences.
UI - 11259468
AU - Hemstreet GP 3rd; Yin S; Ma Z; Bonner RB; Bi W; Rao JY; Zang M; Zheng Q;
TI - Bane B; Asal N; Li G; Feng P; Hurst RE; Wang W Biomarker risk assessment and bladder cancer detection in a cohort exposed to benzidine.
SO - J Natl Cancer Inst 2001 Mar 21;93(6):427-36
AD - Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA. firstname.lastname@example.org
BACKGROUND: Cancer screening with highly sensitive, specific biomarkers that reflect molecular phenotypic alterations is an attractive strategy for cancer control. We examined whether biomarker profiles could be used for risk assessment and cancer detection in a cohort of Chinese workers occupationally exposed to benzidine and at risk for bladder cancer. METHODS: The cohort consisted of 1788 exposed and 373 nonexposed workers, followed from 1991 through 1997. We assayed urothelial cells from voided urine samples for DNA ploidy (expressed as the 5C-exceeding rate [DNA 5CER]), the bladder tumor-associated antigen p300, and a cytoskeletal protein (G-actin). Workers were stratified into different risk groups (high, moderate, and low risk) at each examination based on a predefined biomarker profile. For workers who developed bladder cancer, tumor risk assessment was analyzed from samples collected 6-12 months before the cancer diagnosis. The associations between risk group and subsequent development of bladder cancer were analyzed by Cox proportional hazards regression analysis and logistic analysis, after adjustment. All statistical tests were two-sided. RESULTS: Twenty-eight bladder cancers were diagnosed in exposed workers and two in nonexposed workers. For risk assessment, DNA 5CER had 87.5% sensitivity, 86.5% specificity, an odds ratio (OR) of 46.2 (95% confidence interval [CI] = 8.1 to 867.0), and a risk ratio (RR) of 16.2 (95% CI = 7.1 to 37.0); p300 had 50.0% sensitivity, 97.9% specificity, an OR of 40.0 (95% CI = 9.0 to 177.8), and an RR of 37.9 (95% CI = 16.8 to 85.3). The risk of developing bladder cancer was 19.6 (95% CI = 8.0 to 47.9) times higher in workers positive for either the DNA 5CER or p300 biomarkers than in workers negative for both biomarkers and 81.4 (95% CI = 33.3 to 199.3) times higher in workers positive for both biomarkers. G-actin was a poor marker of individual risk. CONCLUSIONS: Occupationally exposed workers at risk for bladder cancer can be individually stratified, screened, monitored, and diagnosed based on predefined molecular biomarker profiles.
UI - 11942574
AU - Lopez-Beltran A; Cheng L; Andersson L; Brausi M; de MA; Montironi R;
TI - Sesterhenn I; van KT; Mazerolles C Preneoplastic non-papillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation.
SO - Virchows Arch 2002 Jan;440(1):3-11
AD - Department of Pathology, Cordoba University Medical School, Facultad de Medicina, Spain. email@example.com
BACKGROUND AND AIMS: This paper summarizes the work done by the members of the Committee no. 2 at the International Consultation on the Diagnosis of Non-Invasive Urothelial Neoplasms held in Ancona, Italy regarding the optimal contemporary diagnosis and classification of the preneoplastic non-papillary lesions of the urothelium. An important objective was to promote a precise terminology and to use it consistently in daily practice in pathology and urology. RESULTS AND CONCLUSIONS: The result of the meeting is represented by a refined classification of the non-papillary intraepithelial lesions and conditions of the urothelium. This classification includes epithelial abnormalities (reactive urothelial atypia and flat urothelial hyperplasia), presumed preneoplastic lesions and conditions (keratinizing squamous and glandular metaplasia, and malignancy-associated cellular changes), as well as preneoplastic (dysplasia) and neoplastic non-invasive (carcinoma in situ) lesions. Each of these lesions is defined with strict morphological criteria in order to provide more accurate information to urologists in managing patients.
UI - 8622895
AU - Bringuier PP; Tamimi Y; Schuuring E; Schalken J
TI - Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification.
SO - Oncogene 1996 Apr 18;12(8):1747-53
AD - Urological Research Laboratory, University Hospital Nijmegen, The Netherlands.
11q13 amplifications have been found in several cancers, including bladder tumours. However, the biological significance of this genetic alteration is not yet fully understood. To get more insight into the role of 11q13 amplification in bladder tumour development, we have studied the level of amplification and expression of 4 (protoonco)genes lying within the amplicon; cyclin D1, FGF3, FGF4 and EMS1 DNA amplification was found in 5/46 tumours. There was no correlation between amplification and clinico-pathological data. No expression of FGF3 and FGF4 was detected whereas both cyclin D1 and EMS1 were expressed at higher level in tumours with amplifications. Thus cyclin D1 and EMS1, but not FGF3 and FGF4, are likely to play a pathogenic role in the 11q13 amplification in bladder cancer. However, amplification is not the unique way of activation of these genes. Indeed, in situ hybridisation and Northern blot analysis have shown that most bladder tumours have a fair to high expression of cyclin D1 and EMS1 in contrast to normal urothelium with a moderate expression. Interestingly, a trend towards higher expression occurs in superficial versus invasive tumours (8.8 +/- 2.0 versus 1.9 +/- 0.4; P approximately equal to 13% for cyclin D1 and 4.5 +/- 1.4 versus 2.0 +/- 0.4; P approximately equal to 8% for EMS1). Moreover, the 9 tumours with low expression are all highly malignant, leading to the hypothesis that the tumours developing through a cyclin D1/EMS1 independent pathway are more aggressive.
UI - 9829746
AU - Ito H; Kyo S; Kanaya T; Takakura M; Koshida K; Namiki M; Inoue M
TI - Detection of human telomerase reverse transcriptase messenger RNA in voided urine samples as a useful diagnostic tool for bladder cancer.
SO - Clin Cancer Res 1998 Nov;4(11):2807-10
AD - Department of Urology, School of Medicine, Kanazawa University, Ishikawa, Japan.
Activation of telomerase and stabilization of telomeres are thought to be required for cellular immortality and oncogenesis. Telomerase activity is detected in >90% of various cancers, including urothelial cancers. Of the three subunits comprising telomerase complex, human telomerase reverse transcriptase (hTERT) is a rate-limiting determinant of the enzymatic activity of telomerase. In the present study, spontaneously voided urine specimens from 33 patients with bladder cancer and 26 without bladder lesions were examined for the expression of hTERT mRNA, and the usefulness of detecting hTERT mRNA in urine samples for screening of bladder cancer was evaluated. RT-PCR analysis revealed that approximately 80% of urinary sediments from patients with bladder cancer expressed hTERT mRNA, regardless of clinical stage or pathological grade, whereas only 4% of sediments from patients without urothelial lesions did. Interestingly, hTERT mRNA expression was observed, even in some urine samples from bladder cancer patients with negative urinary cytology. These findings suggest that the expression of hTERT in urine sample may be a useful diagnostic marker for bladder cancer.
UI - 10702516
AU - de Kok JB; Ruers TJ; van Muijen GN; van Bokhoven A; Willems HL; Swinkels
TI - DW Real-time quantification of human telomerase reverse transcriptase mRNA in tumors and healthy tissues.
SO - Clin Chem 2000 Mar;46(3):313-8
AD - Departments of Clinical Chemistry, Surgery, Pathology, and Urology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. J.firstname.lastname@example.org
BACKGROUND: Expression of the hTERT gene, which codes for the catalytic subunit of telomerase, is associated with malignancy. We recently developed a real-time reverse transcription-PCR assay, based on TaqMan technology, for accurate and reproducible determination of hTERT mRNA expression (Lab Investig 1999;79:911-2). This method may be of interest for molecular tumor diagnostics in tissues and corresponding body fluids, washings, or brushes. METHODS: In this study, we measured hTERT expression in a subset of healthy tissues and tumors to select those tumor types with the best potential for quantification of hTERT in corresponding body fluids. To demonstrate the use of the method in body fluids, we quantified hTERT expression in voided urine of patients with bladder cancer and controls. RESULTS: Real-time measurement of hTERT expression could discriminate between all healthy and malignant tissue samples from pancreas, lung, esophagus, and bladder, but not for colon tissues. Moreover, in five of nine (55%) urine samples, hTERT could be quantified. CONCLUSIONS: The present study demonstrates that accurate quantitative measurement of hTERT expression has high potential for discrimination between healthy and tumor cells in tissues and urine and supports future measurements in pancreatic fluid, bronchoalveolar lavage fluid, esophageal brushings, and urine or bladder washings.
UI - 11106338
AU - de Kok JB; van Balken MR; Roelofs RW; van Aarssen YA; Swinkels DW; Klein
TI - Gunnewiek JM Quantification of hTERT mRNA and telomerase activity in bladder washings of patients with recurrent urothelial cell carcinomas.
SO - Clin Chem 2000 Dec;46(12):2003-7
AD - Department of Clinical Chemistry, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands. Departments of Urology and Clinical Chemistry, Canisius-Wilhelmina Hospital, 6500 GS Nijmegen, The Netherlands.
UI - 11106340
AU - de Kok JB; van Balken MR; Ruers TJ; Swinkels DW; Klein Gunnewiek JM
TI - Detection of telomerase activity in urine as a tool for noninvasive detection of recurrent bladder tumors is poor and cannot be improved by timing of sampling.
SO - Clin Chem 2000 Dec;46(12):2014-5
UI - 11172490
AU - Bialkowska-Hobrzanska H; Bowles L; Bukala B; Joseph MG; Fletcher R;
TI - Razvi H Comparison of human telomerase reverse transcriptase messenger RNA and telomerase activity as urine markers for diagnosis of bladder carcinoma.
SO - Mol Diagn 2000 Dec;5(4):267-77
AD - Molecular Biology Diagnostic Laboratory, Lawson Research Institute, St. Joseph's Health Centre, University of Western Ontario, 268 Grosvenor Street, London, Ontario, N6A 4V2, Canada.
BACKGROUND: Human telomerase reverse transcriptase (hTERT) has been identified as the catalytic subunit of telomerase ribonucleoprotein complex known to be required for cellular immortality and oncogenesis. Although human telomerase activity (hTA) is considered as a general marker for malignancy based on its presence in most malignant tumors including bladder cancer, its detection in urine is affected by many factors. The objective of this study was to compare the clinical utility of detecting urine hTERT messenger RNA (mRNA) by multiplex hTERT/GAPDH RT-PCR and urine hTA by telomerase repeat amplification protocol (TRAP) in the diagnosis of bladder cancer. METHODS AND RESULTS: Cystoscopy urine samples or bladder washes prospectively collected from 35 patients with confirmed (35) or clinically suspected (5) transitional cell carcinoma (TCC) of the bladder were examined by TRAP, hTERT/GAPDH RT-PCR, and urine cytology. The control group comprised 21 healthy volunteers and 3 patients without TCC. The hTERT/GAPDH RT-PCR test showed significantly higher diagnostic sensitivity than TRAP assay (94.3% vs 48.6%, P <.001) and urine cytology (95.2% vs 61.9%, P =.008) for confirmed TCCs. In particular, for superficial TCCs low grade (I-II), the hTERT/GAPDH RT-PCR test outperformed TRAP (90% vs 25%, P <.001) and urine cytology (91.7% vs 58.3%, P =.46). The overall specificity of the hTERT/GAPDH RT-PCR, TRAP and urine cytology was 92% (22/24), 100% (24/24), and 100% (3/3), respectively. A positive hTERT mRNA expression was also detected in urologic specimens from 3 patients with previous history of TCC, 3 to 6 months before cystoscopic evidence of cancer. CONCLUSION: In this pilot study, the hTERT mRNA expression in urine sediments is a more sensitive marker for diagnosis of TCC of the bladder than hTA and cytology. However, there is a higher false-positive rate.
UI - 11745306
AU - Stronati L; Gensabella G; Lamberti C; Barattini P; Frasca D; Tanzarella
TI - C; Giacobini S; Toscano MG; Santacroce C; Danesi DT Expression and DNA binding activity of the Ku heterodimer in bladder carcinoma.
SO - Cancer 2001 Nov 1;92(9):2484-92
AD - Section of Toxicology and Biomedical Sciences, ENEA CR Casaccia, Via Anguillarese 301, 00060 Rome, Italy.
BACKGROUND: The Ku protein is a tightly associated heterodimer, comprised of 70-kilodalton (kD) and 86-kD subunits, that forms the DNA-dependent protein kinase (DNA-PK) complex together with the 470-kD DNA-PKcs catalytic subunit, and is involved mainly in DNA double-strand breaks (DSBs) repair. The objective of the current study was to investigate the expression and DNA-binding activity of the Ku protein in fresh tissues from patients with bladder carcinoma and to compare it with that in nontumor tissues obtained from the same organ. Moreover, the DNA-binding activity of Ku was assessed after exposure of the tumor cells to 1 or 2 grays (Gy) of X-rays. Furthermore, the level of phosphorylated Ku was analyzed in both the nuclear and cytoplasmic compartment of normal tissue after exposure to 2 Gy of X-rays. METHODS: The expression and DNA-binding activity of Ku protein were assessed in tumor samples from patients who all were diagnosed with transitional cell carcinoma (TCC) of the bladder using Western blot analysis and the electrophoretic mobility shift assay, respectively. RESULTS: Enhanced Ku activity and expression were found in tumor tissue compared with normal tissue for each patient. Moreover, variations in Ku activity were found in a dose-dependent manner after the tumor cells were exposed to 1 or 2 Gy of X-rays. A decrease in phosphorylated Ku in the cytoplasm and a parallel increase in the nucleus of normal tissue cells were observed after exposure to X-rays. CONCLUSIONS: The results of the current study suggest a possible role of Ku in regulating the DNA-PK activity of DSBs repair in bladder tumors. Copyright 2001 American Cancer Society.
UI - 11832713
AU - Neves M; Ciofu C; Larousserie F; Fleury J; Sibony M; Flahault A;
TI - Soubrier F; Gattegno B Prospective evaluation of genetic abnormalities and telomerase expression in exfoliated urinary cells for bladder cancer detection.
SO - J Urol 2002 Mar;167(3):1276-81
AD - Laboratoire d'Histologie, Biologie Tumorale et Genetique Moleculaire, Service d'Urologie, Hopital TENON, Paris, France.
PURPOSE: To evaluate alternative procedures to cytoscopic examination we prospectively compared noninvasive procedures for detecting bladder cancer namely cytology, loss of heterozygosity (LOH), microsatellite instability and human telomerase catalytic subunit reverse transcriptase (hTERT) messenger (m) RNA detection. MATERIALS AND METHODS: Specificity and cutoff values were established in the blood and urine sediment of 50 controls. Sensitivity was analyzed in the urine and tissue samples of 50 patients with bladder cancer. The diagnosis was established by cystoscopic and histological examination. Genomic alterations were studied using a panel of 24 microsatellite markers to detect LOH events, while 3 additional mononucleotide repeats were analyzed for microsatellite instability detection. Telomerase expression was detected in urinary cells by nested RT-polymerase chain reaction amplification of hTERT mRNA. All techniques were compared by cytological examination. RESULTS: Sensitivity and specificity were 31% and 100% for cytological testing, 96% and 100% for LOH, and 75% and 69% for RT-polymerase chain reaction of hTERT, respectively. No alteration was detected on microsatellite instability analysis in urine or tumor tissue cells. Using only the 5 markers most strongly associated with bladder cancer selected by logistic regression analysis, namely ABL1, IFNa, D9S12, MJD58 and D18S364, LOH test sensitivity slightly decreased to 90%. CONCLUSIONS: Urinary LOH analysis was the most sensitive and specific method for bladder cancer detection and it appeared less dependent on urine sediment quality. The logistic regression score may be an interesting complement to cystoscopy. The specificity of hTERT mRNA detection was incomplete since false-positives were observed in 31% of cases. Absent microsatellite instability in our cohort showed that these genomic alterations are not present at the early step of bladder cancer.
UI - 11921286
AU - Williams SV; Sibley KD; Davies AM; Nishiyama H; Hornigold N; Coulter J;
TI - Kennedy WJ; Skilleter A; Habuchi T; Knowles MA Molecular genetic analysis of chromosome 9 candidate tumor-suppressor loci in bladder cancer cell lines.
SO - Genes Chromosomes Cancer 2002 May;34(1):86-96
AD - Imperial Cancer Research Fund Clinical Centre, St. James's University Hospital, Leeds, United Kingdom.
Underrepresentation of chromosome 9 is a common finding in bladder cancer. Frequent loss of the whole chromosome suggests the presence of at least one relevant tumor suppressor gene on each arm. Candidate regions identified by loss of heterozygosity (LOH) analysis include a region at 9p21 containing CDKN2A, which encodes p16 and p14(ARF), a large region at 9q12-31 including PTCH and many other genes, a small region at 9q32-33, which includes the DBCCR1 gene, and a region at 9q34 including the TSC1 gene. Experimental replacement of genes or chromosomes into tumor cells with appropriate deletions or mutations represents an important approach to test the functional significance of candidate tumor suppressor genes. Loss of an entire copy of chromosome 9 in many bladder tumor cell lines provides no indication of which gene or genes are affected, and selection of appropriate recipient cells for gene replacement is difficult. We have investigated three candidate tumor suppressor genes on chromosome 9 (CDKN2A, DBCCR1, and TSC1), at the DNA level and by expression analysis in a panel of bladder tumor cell lines, many of which have probable LOH along the length of the chromosome, as indicated by homozygosity for multiple polymorphic markers. Cytogenetically, we found no reduction in the numbers of chromosomes 9 relative to total chromosome count. Homozygous deletion of the CDKN2A locus was frequent but homozygous deletion of TSC1 was not found. A new cell line, DSH1, derived from a pT1G2 transitional cell carcinoma with known homozygous deletion of DBCCR1, is described. This study identifies suitable cell lines for future functional analysis of both CDKN2A and DBCCR1. Copyright 2002 Wiley-Liss, Inc.
UI - 11350401
AU - Smeulders N; Woodhouse CR
TI - Neoplasia in adult exstrophy patients.
SO - BJU Int 2001 May;87(7):623-8
AD - The Institute of Urology and Nephrology, University College, London, UK.
OBJECTIVE: To document the incidence of neoplasia in a cohort of 103 patients born with classical exstrophy. PATIENTS AND METHODS: The notes of patients born before 1964 with exstrophy were reviewed retrospectively. The patients were divided into two groups; 42 were thought to be at high risk of developing neoplasia because they had (at some time) had mixing of urine and faeces in a colorectal reservoir, whereas 61 had never been exposed to such a mixture and were thought to have a low risk of neoplasia. RESULTS: At a minimum of 35 years of follow-up, complete data were available for 61 patients; 42 were lost to follow-up, of whom 14 were at high risk and 28 at low risk of neoplasia. In the high-risk group, there were three with colonic carcinoma (two of whom presented before 1980 and died), one with carcinoma in situ of the colon, 10 with benign colonic neoplasms and three with bladder cancer (two of whom died). In the low-risk group, there was one patient with bladder cancer (who died) and one with a clear cell carcinoma of the kidney. Three of the four patients with bladder cancer had undergone cystectomy before 5 years of age. Assuming that all the lost patients are alive and free of neoplasia, the risk of neoplasia in adults born with exstrophy is 17.5%. The main risk is in those who have been exposed to mixing of urine and faeces in a colorectal reservoir (38%). Even in low-risk patients the risk of malignant neoplasia is 3.3% at a median (range) age of 42 (40-44) years, which is 27 times higher than that of the age-matched general population. CONCLUSIONS: Annual colonoscopy of patients deemed at high risk of colorectal neoplasia appears to be an effective screen for colorectal carcinoma, by identifying a premalignant stage, as there were no deaths after this was introduced. Despite bladder closure or diversion surgery within the first few years of life, patients with exstrophy have an almost 700-fold greater incidence of carcinoma of the bladder than the age-matched general population. Early cystectomy is not protective.
UI - 10873084
AU - Sier CF; Casetta G; Verheijen JH; Tizzani A; Agape V; Kos J; Blasi F;
TI - Hanemaaijer R Enhanced urinary gelatinase activities (matrix metalloproteinases 2 and 9) are associated with early-stage bladder carcinoma: a comparison with clinically used tumor markers.
SO - Clin Cancer Res 2000 Jun;6(6):2333-40
AD - Department of Molecular Pathology and Medicine DIBIT, San Raffaele Scientific Institute, Milan, Italy.
Matrix metalloproteinases (MMPs) are involved in tumor growth and metastasis, promoting the migration and invasion of cells. In this study, the amount of MMP-2 and MMP-9 activity was measured in urine from superficial bladder carcinoma patients (pTa, pT1) to evaluate their possible diagnostic value. The active and total amount of MMP-2 and MMP-9, respectively, in urine from tumor patients were compared with the levels in urine from age- and gender-matched healthy volunteers. Both MMP-2 and MMP-9 activity levels were significantly enhanced in urine from patients with high invasive cancers (pT2, PT3), whereas in urine from healthy controls no