National Cancer Institute®
Last Modified: May 1, 2002
UI - 11825664
AU - Lee SJ; Cho SH; Park SK; Kim SW; Park MS; Choi HY; Choi JY; Lee SY; Im
TI - HJ; Kim JY; Yoon KJ; Choi H; Shin SG; Park TW; Rothman N; Hirvonen A; Kang D Combined effect of glutathione S-transferase M1 and T1 genotypes on bladder cancer risk.
SO - Cancer Lett 2002 Mar 28;177(2):173-9
AD - Department of Internal Medicine, Hallym University College of Medicine, ChoonChun, South Korea.
To evaluate the association between genetic polymorphism of GSTM1, GSTT1 and development of bladder cancer, a hospital-based case-control study was conducted in South Korea. The study population consisted of 232 histologically confirmed male bladder cancer cases and 165 male controls enrolled from urology departments with no previous history of cancer or systemic diseases in Seoul during 1997-1999. The GSTM1 null genotype was significantly associated with bladder cancer (OR: 1.6, 95% CI: 1.0-2.4), whereas the association observed for GSTT1 null genotype did not reach statistical significance (OR: 1.3, 95% CI: 0.9-2.0). There was a statistically significant multiple interaction between GSTM1 and GSTT1 genotype for risk of bladder cancer (P=0.04); the risk associated with the concurrent lack of both of the genes (OR: 2.2, 95% CI: 1.2-4.3) was greater than the product of risk in men with GSTM1 null/GSTT1 present (OR: 1.3, 95% CI: 0.7-2.5) or GSTM1 present/GSTT1 null (OR: 1.1, 95% CI: 0.6-2.2) genotype combinations.
UI - 11971182
AU - Simon R; Struckmann K; Schraml P; Wagner U; Forster T; Moch H; Fijan A;
TI - Bruderer J; Wilber K; Mihatsch MJ; Gasser T; Sauter G Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer.
SO - Oncogene 2002 Apr 11;21(16):2476-83
AD - Institute for Pathology and Urologic Clinics, University of Basel, Schoenbeinstrasse 40, CH-4003 Basel, Switzerland.
The chromosomal region 12q13-q15 is recurrently amplified in bladder cancer. Putative target genes located in this region include MDM2, CDK4, and GLI. To evaluate the involvement of these genes in bladder cancer, we screened a tissue microarray (TMA) containing 2317 samples by fluorescence in situ hybridization (FISH). Amplification was found for MDM2 in 5.1%, for CDK4 in 1.1%, and for GLI in 0.4% of interpretable tumors. Among tumors having amplification of at least one of these 12q13-q15 genes, 76.6% had amplification of MDM2 alone and 6.4% had amplification of CDK4 alone. Coamplifications were seen of MDM2 and CDK4 in 10.6%, and of CDK4 and GLI in 6.4%. Neither coamplifications of all three genes nor isolated GLI amplifications were found. These data suggest a prominent role of MDM2 as a 12q13-q15 amplification target in bladder cancer. However, independent CDK4 amplifications do also occur suggesting either two non-overlapping amplification sites or else a minimal overlapping region between MDM2 and CDK4 perhaps containing another yet unknown oncogene. The frequency of amplification increased significantly from stage pTa to pT1-4 (P<0.04) and from low to high grade (P<0.005). These data are consistent with a high level of genetic instability in invasively growing and high-grade bladder tumors.
UI - 11820413
AU - Raitanen MP; Aine R; Kylmala T; Kallio J; Liukkonen T; Tammela T; The
TI - Finnbladder Group The dilemma of suspicious urine cytology in patients being followed for bladder cancer.
SO - Ann Chir Gynaecol 2001;90(4):256-9
AD - Division of Urology, Tampere University Hospital, Finland. email@example.com
BACKGROUND AND AIMS: Urine cytology is gold standard for clinical tests used in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Furthermore, a "suspicious" cytology report (class III) makes clinicians uncomfortable. In these cases, a more objective test, such as the BTA stat Test, may be useful in providing clarification. The aim of this study was to evaluate the dilemma of suspicious routine urine cytology and to determine whether the BTA stat Test provides diagnostic aid in this rare but controversial category. MATERIAL AND METHODS: 506 consecutive patients who were being followed for bladder cancer were included in the study. A voided urine sample was obtained prior to routine follow-up cystoscopy and split for culture and testing with the BTA stat Test. Clinical status of the disease was evaluated in patients with suspicious urine cytology, and the diagnostic aid of the BTA stat Test in these patients was determined. RESULTS: A total of 57 patients (11.3%) had urine cytology classified as suspicious. The BTA stat Test was positive in 29 (50.9%) and negative in 28 (49.1%) patients. Nineteen (33.3%) patients had recurrence at routine cystoscopy. Of the remaining 38 patients, 10 were further investigated due to a positive BTA stat Test. Two additional recurrences were detected bringing the total number of recurrences to 21 (36.8%), 48.3% (14/29) of the patients with positive and 25.0% (7/28) of the patients with negative BTA stat Test had recurrence (p = 0.069). Overall, 65.5% (19/29) of the patients with a positive BTA stat Test were found to have recurrence either at routine cystoscopy, at further investigations, or at the next cystoscopy compared to that of 35.7% (19/28) in those with negative testing (p = 0.024). The overall sensitivity of the BTA stat Test was 66.7%, and the specificity was 58.3%. CONCLUSIONS: At least a third of the patients under follow-up for bladder cancer with suspicious cytology had a recurrence, indicating that these patients are a risk group for recurrence. More importantly, a BTA stat Test result seems to provide some help in distinguishing those patients with very high risk for recurrence, for whom invasive further investigations should be conducted and a close follow-up policy maintained.
UI - 11820414
AU - Raitanen MP; Leppilahti M; Tuhkanen K; Forssel T; Nylund P; Tammela T;
TI - The FinnBladder Group Routine follow-up cystoscopy in detection of recurrence in patients being monitored for bladder cancer.
SO - Ann Chir Gynaecol 2001;90(4):261-5
AD - Department of Urology, Tampere University Hospital, Finland. firstname.lastname@example.org
BACKGROUND AND AIMS: Cystoscopy and urine cytology are the standard tools for monitoring superficial bladder cancer. The sensitivity of cystoscopy is, however, limited to the tumours that can be visualised, and the sensitivity of cytology is relatively low in low-stage/low-grade tumours. Therefore, new tumour markers have been developed. BTA stat has been reported to have high sensitivity in detecting both primary and recurrent bladder tumours, and may have the potential to detect tumours that cannot be visualised by routine cystoscopy including recurrences in upper tract. The objective of the study was to analyse the reliability of routine follow-up cystoscopy by further investigating patients with positive marker status, BTA stat Test and urine cytology, but negative cystoscopy. MATERIAL AND METHODS: 446 consecutive patients being followed for bladder cancer were analysed in a prospective multicenter study. A voided urine sample was obtained prior to cystoscopy and split for culture, cytology and BTA stat testing. In the case of positive marker status, BTA stat Test or urine cytology, but negative cystoscopy patients were further investigated by i.v. urography or renal ultrasound and random biopsies. The sensitivity of routine follow-up cystoscopy is reported. RESULTS: Of 446 patients 131 (29.4%) had a bladder cancer recurrence at routine cystoscopy. Of the remaining 315 patients not having recurrent tumour at cystoscopy, 56 patients (17.8%) had positive BTA stat Test result, 6 (1.9%) had positive cytology and 5 were positive by both tests. Nine recurrences that were missed at routine follow-up cystoscopy were detected by further investigations making the total number of bladder confined recurrent tumours 140 (140/446, 31.4%). Five of these 9 recurrences were high grade lesions (1 T1G3, 4 CIS), of which 4 were detected by positive cytology. The overall sensitivity of cystoscopy was 93.6%. CONCLUSIONS: We found that routine follow-up cystoscopy may miss over five percent of the recurrent tumours. Although cystoscopy remains the gold standard for bladder cancer follow-up, it is suggested that even with negative cystoscopy patients with positive marker status, BTA stat Test and especially urine cytology, should be considered at risk for coexisting, and in some case even high grade recurrence.
UI - 11859200
AU - Martin SA; Sears DL; Sebo TJ; Lohse CM; Cheville JC
TI - Smooth muscle neoplasms of the urinary bladder: a clinicopathologic comparison of leiomyoma and leiomyosarcoma.
SO - Am J Surg Pathol 2002 Mar;26(3):292-300
AD - Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
We report the clinicopathologic, immunohistochemical, and DNA ploidy findings of 18 leiomyosarcomas of the urinary bladder. In addition, we compare these malignant smooth muscle tumors with 10 cases of urinary bladder leiomyoma. The 14 male and four female patients with leiomyosarcoma ranged in age from 25 to 88 years (mean 64 years). The tumors ranged from 3.0 to 15.0 cm (mean 7.1 cm) in greatest dimension and were moderately to highly cellular, consisting of interlacing fascicles of spindled cells with mild to marked nuclear atypia. Coagulative tumor necrosis was identified in 14 cases (78%), and mitotic activity ranged from 1 to 42 mitotic figures (MF) per 10 high power fields (HPF) (mean 12 MF/10 HPF). Tumors were classified as either high-grade (12 cases) or low-grade (six cases) based on nuclear atypia, mitotic activity, and tumor necrosis. Actin positivity was present in 15 tumors (83%), and desmin immunoreactivity was present in seven tumors (39%). All cases were negative for epithelial markers and S-100. Proliferative activity, as assessed by MIB-1 staining, ranged from 0.1% to 51.4% (median 9.1%). Seven (39%) of the leiomyosarcomas were DNA aneuploid, eight (44%) were tetraploid, and three (17%) were diploid. Five patients underwent radical cystoprostatectomy, one radical cystectomy, seven had partial cystectomy, two underwent pelvic exenteration, and three patients had transurethral resection only. Follow-up information was available on all 18 cases and ranged from 2 to 68 months (mean 22 months). Of the 12 patients with high-grade tumors, six (50%) died of disease from 2 to 20 months (mean 7 months) after diagnosis and three patients (25%) are alive with metastatic tumor. Two of the six patients with low-grade leiomyosarcoma died of tumor, 61 and 68 months after diagnosis. There were five male and five female patients with leiomyoma ranging in age from 22 to 78 years (mean 61 years). The tumors ranged from 0.5 to 4.5 cm (mean 1.6 cm) in greatest dimension, were well circumscribed, and had low cellularity. Mitotic activity, necrosis, and cellular atypia were absent, and the tumors were strongly positive for both actin and desmin. MIB-1 staining ranged from 0% to 3.8% (median 0.8%). Seven (87.5%) of the leiomyomas were DNA diploid or near-diploid and one (12.5%) was DNA aneuploid. Six patients were treated with transurethral resection and four with partial cystectomy. All 10 patients were alive at the last follow-up (mean follow-up 75 months), and no tumor recurred or metastasized. Our study shows that low-grade leiomyosarcomas are capable of malignant behavior, and high-grade leiomyosarcomas appear to behave more aggressively than low-grade tumors. In addition, the diagnosis of urinary bladder leiomyoma should be reserved for noninfiltrative smooth muscle tumors lacking mitotic activity, cytologic atypia, and necrosis.
UI - 11920626
AU - Tada Y; Wada M; Migita T; Nagayama J; Hinoshita E; Mochida Y; Maehara Y;
TI - Tsuneyoshi M; Kuwano M; Naito S Increased expression of multidrug resistance-associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin.
SO - Int J Cancer 2002 Apr 1;98(4):630-5
AD - Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Overexpression of the P-glycoprotein/multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1) gene is closely associated with the clinical outcome of various malignancies, and it is involved in responses to some anticancer chemotherapeutic agents including doxorubicin. Six human MRP subfamily members (MRP2-7) with structural similarities to MRP1 have been identified. Recently, the relationships between MRP2 and MRP3 expression levels of some cancer cells and drug sensitivity to doxorubicin have been reported, but the relationship between the clinical samples and drug sensitivity remains unclear. We determined the expressions of the MDR1, MRP1, MRP2 and MRP3 gene in bladder cancer during the clinical course and sought to learn whether the expression was correlated with drug responses to doxorubicin. Doxorubicin, used in chemotherapeutic treatment including intravesical and systemic chemotherapy, is an important anticancer agent for the treatment of bladder cancer. We used quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for our study, and the sensitivity to doxorubicin in bladder cancer was determined using the in vitro succinate dehydrogenase inhibition test. Using 47 clinical samples of bladder cancer, we confirmed the significant correlation of MDR1, MRP1 and MRP3 mRNA levels with resistance to doxorubicin. We showed that the expression of MDR1, MRP1, MRP2 and MRP3 in recurrent tumors and residual tumors after chemotherapeutic treatment was higher than that in untreated primary tumors. In particular, the MDR1 expression in residual tumors was 5.7-fold higher than that in untreated primary tumors. Copyright 2002 Wiley-Liss, Inc.
UI - 11872026
AU - Saad A; Hanbury DC; McNicholas TA; Boustead GB; Morgan S; Woodman AC
TI - A study comparing various noninvasive methods of detecting bladder cancer in urine.
SO - BJU Int 2002 Mar;89(4):369-73
AD - Department of Urology, Lister Hospital, Stevenage, UK. email@example.com
OBJECTIVES: To compare the nuclear matrix protein (NMP)-22 assay, bladder tumour specific antigen (BTAstat) test, telomerase activity (using the telomeric repeat amplification protocol assay, TRAP) and a haemoglobin dipstick test for their ability to replace voided urine cytology (VUC) for detecting bladder cancer. PATIENTS AND METHODS: The study included 120 urological patients prospectively recruited and assessed before surgery. A single freshly voided urine sample (approximate 100 mL) was collected from each patient and aliquoted for each test. All assays were conducted according to the manufactures' guidelines; 79 patients were tested for telomerase activity. The results were then compared with VUC and the diagnosis confirmed by cystoscopy and histology. RESULTS: Fifty-two patients had histologically confirmed transitional cell carcinoma. The overall sensitivity for BTAstat, NMP22, telomerase, VUC and dipstick testing was 63%, 81%, 84%, 48% and 50%, respectively. Combining the results for telomerase and NMP22 gave a sensitivity of 100%. For G1 tumours the respective sensitivities were 23%, 62%, 56%, 23% and 15%, for G2 tumours, 68%, 86%, 92%, 50% and 41% and for G3 tumours 88%, 88%, 100%, 71% and 82%. For pTa tumours the respective detection rates were 48%, 70%, 84%, 39% and 30%, for pT1 tumours 80%, 90%, 90%, 50% and 50%, for pT2/pTis tumours, 100/100%, 100/100%, 100/100%, 88/100% and 88/83%. The overall specificity for the respective tests was 82%, 87%, 93%, 87% and 54%; combining the results of NMP22 and telomerase activity increased the specificity to 96%. CONCLUSIONS: There was significantly better detection than VUC when using the NMP22 and TRAP assay, especially for well-differentiated (P < 0.001 and 0.0027, respectively) and superficial tumours (P < 0.001 and 0.034, respectively). Combining the results of NMP22 and telomerase activity yielded values comparable with cystoscopy.
UI - 11710636
AU - Helpap B
TI - Nonepithelial neoplasms of the urinary bladder.
SO - Virchows Arch 2001 Oct;439(4):497-503
AD - Department of Pathology, Hegau-Klinikum Singen, University of Freiburg, Germany. firstname.lastname@example.org
Nonepithelial tumors are rare in the urinary bladder, but their exact classification is very important in the differential diagnosis between these tumors and epithelial lesions. In the new WHO classification and in the third series of the Armed Forces Institute of Pathology (AFIP) "Atlas of Tumor Pathology" on urinary bladder tumors, various mesenchymal tumors, mixed epithelial and mesenchymal tumors and myofibroblastic proliferations are summarized. In the following we will describe the histology, immunohistology, and cytogenetics of nonepithelial tumors and lesions.
UI - 11889593
AU - Helpap B; Kloppel G
TI - Neuroendocrine carcinomas of the prostate and urinary bladder: a diagnostic and therapeutic challenge.
SO - Virchows Arch 2002 Mar;440(3):241-8
AD - Department of Pathology, Academic Hospital of the University of Freiburg, Postfach 720, 78207 Singen, Germany. email@example.com
This review addresses the various morphological, immunohistochemical and cell kinetic aspects of pure and mixed neuroendocrine carcinomas of the prostate and urinary bladder and of carcinomas with focal neuroendocrine differentiation. It is important that neuroendocrine tumours of the prostate and urinary bladder be clearly distinguished from their nonneuroendocrine counterparts because of differences in treatment and prognosis. In the case of high-grade neuroendocrine carcinomas, early diagnosis and initiation of appropriate chemotherapy may increase survival and potentially induce complete remission in individual cases.
UI - 11996795
AU - Tsukamoto M; Matsuyama H; Oba K; Yoshihiro S; Takahashi M; Naito K
TI - Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):41-5
AD - Department of Urology, Yamaguchi University School of Medicine, Ube, Japan.
To investigate whether nonrandom aberrations of chromosomal numbers could predict tumor recurrence in patients with bladder cancer, archival urine cytology specimens (Giemsa-stained) from patients previously treated for transitional cell carcinoma of the urinary bladder were studied retrospectively by fluorescence in situ hybridization. A total of 48 patients (pTis, 6; pTa, 2: pT1, 32; and pT2-4, 8) were consecutively enrolled in this study, and numerical aberrations of chromosomes 9 and 17 were investigated. Cytology was diagnosed as negative for malignancy in 18 patients and positive in 30 patients. Twenty-seven of the 48 patients (56%) had one or more chromosomal aberrations. The frequency of numerical aberrations of chromosome 17 was correlated with increasing stage and grade, whereas loss of copies of chromosome 9 (monosomy) was frequently observed at a lower stage and grade. Chromosomal aberrations were detected in 9 (50%) of 18 patients with negative or equivocal cytology (class I, II, or III) by the Papanicolaou classification. Of eight patients with negative or equivocal cytology who developed tumor recurrence, four (50%) showed monosomy 9 and one (14%) showed a numerical aberration of chromosome 17. All six patients who showed monosomy of chromosome 9 developed tumor recurrence within 12 months, whereas four of the nine patients who did not show monosomy of this chromosome developed recurrence within 12 months (P<0.05, Fisher test). These results suggest that monosomy of chromosome 9 might be a prognostic marker for early tumor recurrence in patients with negative or equivocal cytology specimens.
UI - 11796234
AU - de Braud F; Maffezzini M; Vitale V; Bruzzi P; Gatta G; Hendry WF;
TI - Sternberg CN Bladder cancer.
SO - Crit Rev Oncol Hematol 2002 Jan;41(1):89-106
AD - START Project, European School of Oncology, Viale Beatrice d'Este 37, 20122 Milan, Italy.
Bladder cancer is the second most frequent tumour of the urogenital tract. Tobacco smoke has been shown to increase the risk of bladder cancer two- to fivefold as well as the exposure to metabolites of aniline dyes and other aromatic amines. Seventy-five per cent of bladder cancers are superficial at initial presentation, limited to the mucosa, submucosa, or lamina propria. Recurrence rates after initial treatment are 50-80%, with progression to muscle-invading tumour in 10-25%. In muscle-invading bladder cancers, there is a 50% risk of distant metastases. Surgery is the mainstay of standard treatment both in the form of transurethral endoscopic resection, mainly for superficial disease, and in the form of open ablative surgery with urinary diversion for muscle invasive disease. Endovesical administration of BCG has been employed after endoscopic resection as the most effective agent for both prophylaxis of disease recurrence and progression from superficial to invasive disease. The accepted treatment for muscle infiltrative disease is radical cystectomy. Response rates to combination chemotherapy regimens of up to 70% in patients with advanced metastatic disease have led to an investigation of its use for locally invasive disease in combination with conventional modalities of treatment.
UI - 11953885
AU - Turner KJ; Crew JP; Wykoff CC; Watson PH; Poulsom R; Pastorek J;
TI - Ratcliffe PJ; Cranston D; Harris AL The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer.
SO - Br J Cancer 2002 Apr 22;86(8):1276-82
AD - ICRF Molecular Oncology Laboratory and Angiogenesis Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Regulation by hypoxia may underlie the expression of vascular endothelial growth factor in bladder cancer. We have compared the distribution of vascular endothelial growth factor mRNA with a hypoxia marker, carbonic anhydrase 9 (CA IX). vascular endothelial growth factor mRNA was analysed by in situ hybridisation and CA IX by immunochemistry in 22 cases of bladder cancer. The relationship of microvessels to the distribution of CA IX was determined. In a separate series of 49 superficial tumours, CA IX immunostaining was compared with clinico-pathological outcome. In superficial and invasive disease there was overlap in the expression of vascular endothelial growth factor and CA IX, CA IX being more widespread. Both were expressed predominantly on the luminal surface, and surrounding areas of necrosis (invasive tumours). Expression of both factors was greater in superficial disease. Expression was absent within approximately 80 microm of microvessels. Unlike vascular endothelial growth factor, CA IX did not predict outcome in superficial disease. Differential responses to reoxygenation provide one explanation: vascular endothelial growth factor mRNA declined rapidly, while CA IX expression was sustained for >72 h. Expression of vascular endothelial growth factor mRNA in bladder tumours is consistent with hypoxic regulation and suggests differential regulation in superficial vs invasive disease. The expression of CA IX on the luminal surface justifies investigation of its utility as a therapeutic target/prognostic indicator. Copyright 2002 Cancer Research UK
UI - 11953886
AU - Dangles V; Lazar V; Validire P; Richon S; Wertheimer M; Laville V;
TI - Janneau JL; Barrois M; Bovin C; Poynard T; Vallancien G; Bellet D Gene expression profiles of bladder cancers: evidence for a striking effect of in vitro cell models on gene patterns.
SO - Br J Cancer 2002 Apr 22;86(8):1283-9
AD - Laboratoire d'Immunologie des Tumeurs, ESA 8067 CNRS, Faculte des Sciences Pharmaceutiques et Biologiques de Paris, Universite Paris V-Rene Descartes, 4 avenue de l'Observatoire, 75006 Paris, France.
In order to assess the effect of in vitro models on the expression of key genes known to be implicated in the development or progression of cancer, we quantified by real-time quantitative PCR the expression of 28 key genes in three bladder cancer tissue specimens and in their derived cell lines, studied either as one-dimensional single cell suspensions, two-dimensional monolayers or three-dimensional spheroids. Global analysis of gene expression profiles showed that in vitro models had a dramatic impact upon gene expression. Remarkably, quantitative differences in gene expression of 2-63-fold were observed in 24 out of 28 genes among the cell models. In addition, we observed that the in vitro model which most closely mimicked in vivo mRNA phenotype varied with both the gene and the patient. These results provide evidence that mRNA expression databases based on cancer cell lines, which are studied to provide a rationale for selection of therapy on the basis of molecular characteristics of a patient's tumour, must be carefully interpreted. Copyright 2002 Cancer Research UK
UI - 11992840
AU - Yang MH; Chen KK; Yen CC; Wang WS; Chang YH; Huang WJ; Fan FS; Chiou TJ;
TI - Liu JH; Chen PM Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan.
SO - Urology 2002 May;59(5):681-7
AD - Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
OBJECTIVES: Unusually high incidences of upper urinary tract urothelial carcinoma (UUT-UC) have been reported from the endemic area for "blackfoot disease" of southern Taiwan, and the arsenic-contaminated water was considered to be the reason for this prevalence. In this study, we determined the ratio of UC in different locations, the difference in clinical profiles for UUT-UC and urinary-bladder urothelial carcinoma (UB-UC), and the influence of tumor location on survival in a medical center of northern Taiwan. METHODS: A total of 535 patients with pathologically proven UC were reviewed retrospectively in this study, and clinical data were recorded from pathologic and chart reviews. Statistical analyses to determine the association between tumor location and clinical variables, and stratified survival analyses to determine the effect of tumor location on survival were performed. RESULTS: The incidence of UUT-UC was relatively high (the ratio of renal pelvis/ureter/urinary bladder was 1:2.08:6.72), even though most of the patients did not reside in the endemic "blackfoot disease" area. Young age, female sex, higher T stage, and elevated pretreatment serum lactate dehydrogenase and creatinine level were significantly associated with UUT-UC after multivariate logistic regression analysis. Tumor location influenced survival in patients with early-stage disease or favorable prognostic factors. CONCLUSIONS: Factors other than arsenic water contamination may contribute to the unusually high incidence of UUT-UC in the non-"blackfoot disease" area in Taiwan. UUT-UC carried a more aggressively clinical behavior than UB-UC; tumor location influences patient survival markedly in patients with early-stage disease or favorable prognostic factors.
UI - 11389545
AU - Veltri RW; Partin AW; Miller MC
TI - Quantitative nuclear grade (QNG): a new image analysis-based biomarker of clinically relevant nuclear structure alterations.
SO - J Cell Biochem Suppl 2000;Suppl 35():151-7
AD - Research & Development, UroCor, Inc., 840 Research Parkway, Oklahoma City, OK 73104, USA. firstname.lastname@example.org
This review addresses the potential clinical value of using quantitative nuclear morphometry information derived from computer-assisted image analysis for cancer detection and predicting outcomes such as tumor stage, recurrence, and progression. Today's imaging technology uses sophisticated hardware platforms coupled with powerful and user-friendly software packages that are commercially available as complete image analysis systems. There are many different mathematically derived nuclear morphometric descriptors (NMD's) (i.e. texture features) that can be calculated by these image analysis systems, but for the most part, these NMD's quantify nuclear size, shape, DNA content (ploidy), and chromatin organization (i.e. texture, both Markovian and non-Markovian) parameters. We have utilized commercially available image analysis systems and the NMD's calculated by these systems to create a mathematical solution, termed quantitative nuclear grade (QNG), for making clinical, diagnostic, and prognostic outcome predictions in both prostate and bladder cancer. A separate computational model is calculated for each outcome of interest using well-characterized and robust training, testing, and validation patient sample sets that adequately represent the selected population and clinical dilemma. A specific QNG solution may be calculated either by non-parametric statistical methods or non-linear mathematics employed by artificial neural networks (ANNs). The QNG solution, a measure of genomic instability, provides a unique independent variable to be used alone or to be included in an algorithm to assess a specific clinical outcome. This approach of customization of the nuclear morphometric descriptor (NMD) information through the calculation of a QNG solution mathematically adjusts for redundancy of features and reduces the complexity of the inputs used to create decision support tools for patient disease management. J. Cell. Biochem. Suppl. 35:151-157, 2000. Copyright 2001 Wiley-Liss, Inc.
UI - 11839665
AU - Chan MW; Chan LW; Tang NL; Tong JH; Lo KW; Lee TL; Cheung HY; Wong WS;
TI - Chan PS; Lai FM; To KF Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients.
SO - Clin Cancer Res 2002 Feb;8(2):464-70
AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
PURPOSE: We aimed to investigate the methylation pattern in bladder cancer and assess the diagnostic potential of such epigenetic changes in urine. EXPERIMENTAL DESIGN: The methylation status of 7 genes (RARbeta, DAPK, E-cadherin, p16, p15, GSTP1, and MGMT) in 98 cases of bladder transitional cell carcinoma and 4 cases of carcinoma in situ was analyzed by methylation-specific PCR. Twenty-two cases had paired voided urine samples for analysis. RESULTS: In transitional cell carcinoma tumor tissues, aberrant methylation was frequently detected in RARbeta (87.8%), DAPK (58.2%), E-cadherin (63.3%), and p16 (26.5%), whereas methylation of p15 (13.3%), GSTP1 (5.1%), and MGMT (5.1%) is not common. No association between methylation status and grading or muscle invasiveness was demonstrated. In 22 paired voided urine samples of bladder cancer, methylation of DAPK, RARbeta, E-cadherin, and p16 could be detected in 45.5%, 68.2%, 59.1%, and 13.6% of the cases, respectively. The sensitivity of methylation analysis (90.9%) was higher than that of urine cytology (45.5%) for cancer detection. Methylation of RARbeta(50%), DAPK (75%), and E-cadherin (50%) was also detected in carcinoma in situ. In 7 normal urothelium samples and 17 normal urine controls, no aberrant methylation was detected except for RARbeta methylation in 3 normal urothelium samples (42.9%) and 4 normal urine samples (23.5%), respectively. CONCLUSIONS: Our results demonstrated a distinct methylation pattern in bladder cancer with frequent methylation of RARbeta, DAPK, E-cadherin, and p16. Detection of gene methylation in routine voided urine using selected markers appeared to be more sensitive than conventional urine cytology.
UI - 11839666
AU - Onita T; Ji PG; Xuan JW; Sakai H; Kanetake H; Maxwell PH; Fong GH;
TI - Gabril MY; Moussa M; Chin JL Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer.
SO - Clin Cancer Res 2002 Feb;8(2):471-80
AD - Department of Surgery, University of Western Ontario, London, Ontario, N6A 4G5 Canada.
Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor-2alpha (HIF-2alpha) is a member of the basic helix-loop-helix/PAS domain protein family and is considered to be an endothelial-specific, hypoxia-inducible transcription factor. Because hypoxia is a fundamental element of tumor biology determining clinical outcome, we performed an immunohistochemical study of EPAS-1 expression in a cohort of bladder cancer cases and assessed the possible correlation of EPAS-1 expression with tumor hypoxia and growth. In the 67 cases (37 radical cystectomy and 30 transurethral resection) studied, overexpression of EPAS-1/HIF-2alpha protein was not found in cancer cells or in normal tissues but was mostly found in stroma around cancer cells, and strong positive staining was noted in perinecrotic regions. The perinecrotic/tumorous expression of EPAS-1/HIF-2alpha was correlated statistically with higher histological grade (P < 0.001), advanced pathological T stage (P < 0.001), and presence of necrosis (P < 0.001). A parallel immunohistochemical analysis of a marker gene of vascular endothelial growth factor demonstrated its positive correlation with tumor grade, stage, and EPAS-1/HIF-2alpha overexpression, supporting the correlation of EPAS-1/HIF-2alpha up-regulation with tumor angiogenesis. To further clarify the relationship between hypoxia and vascularity in the perinecrotic/tumorous area with EPAS-1/HIF-2alpha expression, tissue microvessel density (MVD) was assessed. No significant correlation (P = 0.442) was found between EPAS-1/HIF-2alpha expression and MVD if the 67 tumors of different stages were all included. However, EPAS-1/HIF-2alpha-positive cases had lower MVD than EPAS-1/HIF-2alpha-negative cases (P = 0.001) if only invasive cancer cases were analyzed. In addition, in all EPAS-1/HIF-2alpha-positive staining cases, EPAS-1/HIF-2alpha-positive foci had lower MVD than EPAS-1/HIF-2alpha-negative foci (P < 0.001). Finally, using serial sections, the location of EPAS-1/HIF 2alpha expression was identified mainly in tumor-associated macrophage (TAM) as well as in some fibroblast cells. Focal TAM infiltration was identified at a higher level in EPAS-1-positive cases than EPAS-1-negative cases (P < 0.001). This is the first clinical report suggesting that hypoxia-induced, perinecrotic EPAS-1/HIF-2alpha expression is correlated with tumor progression and angiogenesis at higher grade and stage through focal TAM infiltration in invasive bladder cancer.
UI - 11920732
AU - Edwards J; Duncan P; Going JJ; Watters AD; Grigor KM; Bartlett JM
TI - Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder.
SO - J Pathol 2002 Apr;196(4):380-5
AD - University Department of Surgery, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.
Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence. Copyright 2002 John Wiley & Sons, Ltd.
UI - 11890237
AU - Herr HW
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 MS; Perkins AC; Price MR; Scholfield DP; Bishop MC
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. email@example.com
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 HM; Manyak MJ; Becht E
TI - 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. firstname.lastname@example.org
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 - 11912378
AU - Holmang S; Johansson SL
TI - Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression.
SO - J Urol 2002 Apr;167(4):1634-7
AD - Department of Urology, Sahlgrenska University Hospital, Goteborg, Sweden.
PURPOSE: We studied the relationship of first cystoscopy findings with recurrence and progression rates in a large, population based series of patients with bladder cancer. MATERIALS AND METHODS: All 463 patients with an initial diagnosis of stage Ta-T1 bladder cancer in western Sweden in 1987 to 1988 were followed at least 5 years. The 355 patients who were treated with transurethral resection only until repeat cystoscopy or longer were selected for this report. RESULTS: Negative first cystoscopy findings were associated with significantly decreased recurrence and progression rates for all grades, and for stage Ta and T1 tumors. However, some patients with initial high grade carcinoma (WHO 2 to 3) had stage progression despite negative first cystoscopy. On multivariate analyses first cystoscopy findings and papillary urothelial neoplasm of low malignant potential versus grades 1 to 3 but not stage and the number of tumors had prognostic significance for time to recurrence. Only first cystoscopy findings and grade had prognostic significance for time to stage progression. CONCLUSIONS: Our data support other groups who recommend a less intense cystoscopy followup schedule in patients with negative cystoscopy findings 3 months after initial transurethral bladder resection. We recommend that patients with initial papillary urothelial neoplasm of low malignant potential and low grade carcinoma (WHO 1) with negative first cystoscopy findings undergo repeat cystoscopy at month 12. In our opinion followup should not be less intense in patients with high grade carcinoma (WHO 2-3), even in those with stage pTa disease.
UI - 11836583
AU - Junker K; Kania K; Fiedler W; Hartmann A; Schubert J; Werner W
TI - Molecular genetic evaluation of fluorescence diagnosis in bladder cancer.
SO - Int J Oncol 2002 Mar;20(3):647-53
AD - Department of Urology, Friedrich-Schiller-University, D-07743 Jena, Germany. email@example.com
Fluorescence diagnosis of superficial bladder cancer using 5-aminolevulinic acid (ALA) is a highly sensitive technique (95%). However, the specificity is only 60-70% due to false-positive results after histopathological examination. We hypothesized that the biopsies in fluorescence endoscopy could represent early preneoplastic lesions not detectable by histopathology. In order to evaluate the specificity of fluorescence endoscopy at the molecular genetic level we performed comparative genomic hybridization (CGH) and investigated telomerase activity of ALA-positive tissue samples. For CGH, DNA was isolated from 5-10 frozen sections. Tumor and normal (control) DNAs were amplified by DOP-PCR and labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridization and detection were carried out according to standard protocols. Telomerase activity was analyzed using a non-radioactive system (TRAP-assay). In 33 out of 118 bladder cancer cases (28%) detected by conventional cystoscopy, additional suspicious areas were found using ALA. CGH revealed genetic changes in 27% of samples with non-malignant histological diagnoses. Telomerase activity was found in 59% of these samples. Tumor samples showed genetic alterations in 84% and in 69% telomerase activity occurred. The type of genetic alterations in the normal biopsies was identical to the tumors. Based on these molecular data, the portion of false-positive results obtained by fluorescence diagnosis is lower than defined by histopathology alone. Genetic alterations and activation of telomerase activity are early events of tumor development in bladder cancer occurring earlier than histological features of neoplasia. The clinical importance of fluorescence diagnosis and the possible reduction of the recurrence rate have to be shown in ongoing clinical studies.
UI - 11956100
AU - Velicescu M; Weisenberger DJ; Gonzales FA; Tsai YC; Nguyen CT; Jones PA
TI - Cell division is required for de novo methylation of CpG islands in bladder cancer cells.
SO - Cancer Res 2002 Apr 15;62(8):2378-84
AD - Urologic Cancer Research Laboratory, Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9181, USA.
Cell division is essential for tumor development and progression. Methylation-mediated silencing caused by aberrant de novo methylation of CpG islands located in the promoter regions of growth regulatory genes occurs frequently in human cancers. We investigated the relationship between cell division and de novo methylation to determine whether de novo methylation can occur in the absence of cell division in cancer cells. We treated T24 bladder carcinoma cells with 5-Aza-2'-deoxycytidine to induce a transient demethylation and then compared the timing and kinetics of remethylation of the p16 gene locus under conditions of either G(0)-G(1) growth arrest induced by serum starvation and confluence or continuous cell proliferation in complete medium. Variable levels of remethylation were de