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Abramson Cancer CenterNCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of Bladder Cancer - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
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.
2
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.
3
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.
4
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.
5
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.
6
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.
7
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. mskacel@pol.net
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.
8
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.
9
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.
10
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.
11
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. mutting@imb-jena.de
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.
12
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.
13
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.
msimms@gertrude42.freeserve.co.uk
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.
14
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. poulakis@em.uni-frankfurt.de
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.
15
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. george-hemstreet@ouhsc.edu
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.
16
UI - 11584067
AU - Nersesyan AK
TI -
Re: Biomarker risk assessment and bladder cancer detection in a cohort
exposed to benzidine.
SO - J Natl Cancer Inst 2001 Oct 3;93(19):1492-3
17
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. em1lobea@uco.es
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.
18
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.
19
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.
20
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.dekok@ckcl.azn.nl
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.
21
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.
22
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
23
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.
24
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.
25
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.
26
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.
27
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.
28
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
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