Urine Detection of Survivin and Diagnosis of Bladder Cancer PRELIMINARY COMMUNICATION

PRELIMINARY
COMMUNICATION
Urine Detection of Survivin
and Diagnosis of Bladder Cancer
Shannon D. Smith, MD
Marcia A. Wheeler, MS
Janet Plescia, BS
John W. Colberg, MD
Robert M. Weiss, MD
Dario C. Altieri, MD
D
EREGULATED EXPRESSION OF
inhibitors of apoptosis is
thought to contribute to cancer by abnormally extending cell viability, favoring the accumulation of mutations, and promoting
resistance to therapy.1 A novel modulator of the cell death/viability balance in
cancer was recently identified as survivin,2 a member of the inhibitor of apoptosis gene family.3 Undetectable in
most normal adult tissues, survivin becomes the top fourth transcript expressed in common human cancers,2,4 in
which it correlates with unfavorable disease and abbreviated overall survival.5-9
Urothelial (transitional cell) carcinoma of the bladder is the fourth most
common cancer in men and the eighth
most common cancer in women in the
United States, accounting for more than
54000 new cases and 11200 deaths every year. Recurrences of bladder cancer
occur in up to 80% of patients and constitute a formidable obstacle to longlasting remissions, frequently anticipating muscle invasion, and disseminated
disease.10 Despite considerable efforts
to develop safe, reliable, noninvasive
screening strategies for bladder cancer,
the identification of a single predictive/
prognostic marker of the disease has remained elusive.11 Consistent with a proposed role of deregulated apoptosis in
urothelial cancer,12,13 survivin was found
in 78% of bladder cancers, but not in nor324
Context Dysregulation of apoptosis may favor onset and progression of cancer and
influence response to therapy. Survivin is an inhibitor of apoptosis that is selectively
overexpressed in common human cancers, but not in normal tissues, and that correlates with aggressive disease and unfavorable outcomes.
Objective To investigate the potential suitability of survivin detection in urine as a
novel predictive/prognostic molecular marker of bladder cancer.
Design, Setting, and Patients Survey of urine specimens from 5 groups:
healthy volunteers (n = 17) and patients with nonneoplastic urinary tract disease
(n = 30), genitourinary cancer (n = 30), new-onset or recurrent bladder cancer
(n = 46), or treated bladder cancer (n = 35), recruited from 2 New England urology
clinics.
Main Outcome Measures Detectable survivin levels, analyzed by a novel detection system and confirmed by Western blot and reverse transcriptase polymerase chain
reaction (RT-PCR), in urine samples of the 5 participant groups.
Results Survivin was detected in the urine samples of all 46 patients with new or
recurrent bladder cancer using a novel detection system (31 of 31) and RT-PCR (15 of
15) methods. Survivin was not detected in the urine samples of 32 of 35 patients treated
for bladder cancer and having negative cystoscopy results. None of the healthy volunteers or patients with prostate, kidney, vaginal, or cervical cancer had detectable
survivin in urine samples. Of the 30 patients with nonneoplastic urinary tract disease,
survivin was detected in 3 patients who had bladder abnormalities noted using cystoscopy and in 1 patient with an increased prostate-specific antigen level. Patients with
low-grade bladder cancer had significantly lower urine survivin levels than patients
with carcinoma in situ (P = .002).
Conclusions Highly sensitive and specific determination of urine survivin appears
to provide a simple, noninvasive diagnostic test to identify patients with new or recurrent bladder cancer.
mal urothelium, and its expression correlated with accelerated recurrences.14
Because of its expression in cancer but
not in normal tissues, we investigated the
potential suitability of urine survivin as
a new molecular marker for detection of
bladder cancer.
METHODS
Urine Specimens
One hundred fifty-eight urine specimens were collected at the urology clinics at Yale-New Haven Hospital and at
the Veterans Affairs, New England Health
Care Systems, West Haven, Connecticut, Division. Random clean-catch or
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JAMA. 2001;285:324-328
straight catheter urine samples were
obtained from individuals who were categorized into 5 different groups: group
1 included healthy volunteers with a
mean (SD) age of 47.6 (20.8) years who
were not taking any medication (n=17);
group 2 patients had a mean (SD) age of
60.0 (18.1) years with diagnosis of nonAuthor Affiliations: Departments of Surgery (Drs
Smith, Colberg, and Weiss, and Ms Wheeler) and Pathology (Ms Plescia and Dr Altieri), Boyer Center for
Molecular Medicine, Yale University School of Medicine, New Haven, Conn.
Corresponding Author and Reprints: Dario C. Altieri, MD, Yale University School of Medicine,
BCMM436B, 295 Congress Ave, New Haven, CT
06536 (e-mail: dario.altieri@yale.edu).
©2001 American Medical Association. All rights reserved.
SURVIVIN AND BLADDER CANCER
neoplastic urinary tract disease or hematuria (n = 30); group 3 patients had a
mean (SD) age of 71.5 (9.9) years with
diagnosis of genitourinary cancer,
excluding bladder cancer (n=30); group
4 patients had a mean (SD) age of 69.7
(8.7) years with diagnosis of new-onset
or recurrent bladder cancer (n=46); and
group 5 patients had a mean (SD) age of
76.1 (8.9) years and were undergoing
treatment or had already received treatment for bladder cancer and had negative cytoscopic findings on the day of
urine collection (n=35). Treatment measures in group 5 included intravesical
bacillus Calmette-Guerin, thiotepa, transurethral resection, partial cystectomy, and
radiation. Group 4 included patients who,
after urine collection, underwent similar treatment measures and/or salvage
cystectomy or radical cystectomy.
Urine Detection of Survivin
Urine specimens were filtered onto a nitrocellulose membrane using a microfiltration apparatus in a module providing a 48-wells-lot format. The blot was
analyzed for the presence of survivin using a polyclonal antibody. The protocol
is as follows: urine was collected and
stored at −80°C until analysis. On the day
of analysis, urine samples were centrifuged at 20000g for 20 minutes. Meanwhile, the Bio-Dot microfiltration apparatus was assembled with a 0.2-µm
nitrocellulose membrane (Bio-Rad Laboratories, Hercules, Calif) and moistened in 20-mmol Tris-buffered saline
(pH, 7.5). Then, the urine supernatant
(300 µL), along with increasing concentrations of Escherichia coli–expressed recombinant survivin15 as a standard
(0.001-1.0 µg/mL) in 300 µL of Trisbuffered saline, were filtered onto the
membrane. After filtration, the membrane was dried then blocked in 5% dried
milk plus 0.01% sodium azide in phosphate-buffered saline (PBS) (pH, 7.4) for
12 hours at 4°C. After washing in PBSTween 20 (0.25%), the membrane was
incubated with 2 µg/mL of a rabbit antibody to survivin16 for 3 hours at 22°C,
washed in PBS-Tween, and incubated
with a 1:1000 dilution of horseradish peroxidase-conjugated donkey antirabbit
IgG (Amersham Biotech, Piscataway, NJ)
for 1 hour at 22°C. After washes in PBS
twice for 10 minutes, PBS-Tween twice
for 5 minutes, and PBS twice for 5 minutes, binding of the primary antibody was
detected by enhanced chemiluminescence (Amersham Biotech) and autoradiography. Bands were quantitated by
densitometry and a weighted survivin
score was calculated on the basis of the
antibody reactivity with increasing concentrations of recombinant survivin as
follows: 0 for not detectable; 1 for 0.0010.25 µg/mL; 2 for 0.25 to 1 µg/mL; and
3 for more than 1 µg/mL. Each urine
specimen was analyzed at least twice on
2 different occasions and comparable results were obtained.
Western Blot
Urine specimens (100 mL) were centrifuged at 1200g for 10 minutes at
22°C, and the cell pellet was washed
twice in Tris-buffered saline and made
soluble in 0.5% Triton X-100 (Sigma,
St Louis, Mo) in the presence of protease inhibitors for 30 minutes at 4°C.
Samples were separated by SDS gel (BioRad Laboratories) electrophoresis,
transferred to nylon membranes (Millipore Corp, Bedford, Mass), and further incubated with 1 µg/mL of an antibody to survivin 1 6 followed by
horseradish peroxidase–conjugated
goat antirabbit IgG and chemiluminescence.
Reverse Transcriptase Polymerase
Chain Reaction
Fifty milliliters of clean-catch urine was
obtained from 15 patients with new or
recurrent urothelial cancer, 2 patients
with treated bladder cancer, 1 patient
with prostate cancer, 1 patient with nonneoplastic urinary tract disease, and 1
healthy volunteer. Total RNA was isolated from urine pellets using the Trizol reagent (Life Technologies Inc,
Gaithersburg, Md). Single-strand
complementary DNA (cDNA) was synthesized by random priming of 1-5 µg
total RNA using 1 µL of RT (Gibco BRL,
Life Technologies Inc) for 1 hour at
43°C. After heating at 70°C for 15 minutes, a first amplification reaction was
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carried out with survivin primers 59CTGCCTGGCAGCCCTTTCTCAA-39 (forward) and 59AATAAACCCTGGAAGTGGTGCA-39 (reverse)
with denaturation at 94°C for 15 seconds, annealing at 53°C for 15 seconds, and extension at 72°C for 1 minute
for 20 cycles, followed by incubation at
72°C for 5 minutes. A 463-base pair fragment of the survivin cDNA was subjected to a second round of amplification with nested survivin primers 59CCGCATCTCTACATTCAAGAAC-39
(forward) and 59-CTTGGCTCTTTCTCTGTCC-39 (reverse), with denaturation at 94°C for 30 seconds, annealing at 60°C for 30 seconds, and
extension at 72°C for 45 seconds for 30
cycles, followed by incubation at 72°C
for 5 minutes. The amplified survivin
cDNA of 279 base pair was separated on
a 2.0% solution of agarose gel and visualized by ethidium bromide staining.
Control reactions were amplified using
b-actin–specific primers 59-AGCGGGAAATCGTGCGTG-39 (forward) and
59-CAGGGTACATGGTGGTGCC-39
(reverse) with generation of a 309–
base pair fragment.
Statistical Analysis
The relationship between urine survivin and patients’ diagnosis was analyzed by a x2 test. Nonparametric statistical analysis was used to compare the
weighted urine survivin score with the
grading classification system performed at the Yale-New Haven Hospital. The calculation of predictive accuracy is not appropriate for this study
since the diagnosis was known at the
time of urine collection.
RESULTS
A representative experiment of detection of urine survivin using the BioDot test is shown in FIGURE 1. Determination of urine survivin with the BioDot method was carried out in 138 of
the 158 specimens collected for this
study (TABLE 1). Twenty additional
urine samples were analyzed for survivin expression by reverse transcriptase polymerase chain reaction (RTPCR) to independently evaluate the
(Reprinted) JAMA, January 17, 2001—Vol 285, No. 3
325
SURVIVIN AND BLADDER CANCER
specificity of the new method. Survivin
was not detected in urine of the 16 volunteers, 6 patients with benign pros-
tatic hyperplasia, 2 with interstitial cystitis, 3 with renal calculi, 6 with urinary
tract infection, or 6 with other nonneoplastic urinary tract disease (Table 1).
Urine survivin was detected in 3 of 5 patients with cryptogenic hematuria
(weighted survivin score, 2), who presented with a history of retention and
dysuria post-transurethral prostate resection, and revealed a trabeculated, irregularly thickened bladder, by cystoscopy (see “Comment” section). One
patient with increased prostatespecific antigen levels but without diagnosis of prostate cancer was positive
for urine survivin (Table 1). This patient also had a trabeculated, thickened
bladder, by cystoscopy. Survivin was not
detected in urine specimens of 19 patients with prostate, 8 with renal, 1 with
vaginal, or 1 with cervical cancer (Table
1). In contrast, urine survivin was detected in all 31 patients with new-onset
or recurrent bladder cancer (Table 1).
Histopathologic grading (grades I
through IV) of the 31 patients in group
4 analyzed for urine survivin by the
novel method included 13 patients with
grade II, 7 patients with grade III, and
Figure 1. Urine Detection of Survivin
Patient Group
Survivin,
µg/mL
0
RCC
TCC
TCC/R
TCC/R
Control
0.001
PC
TCC
TCC/R
TCC/R
Control
0.005
PC
TCC
TCC/R
TCC/R
Control
0.01
PC
TCC
TCC/R
TCC/R
Control
0.05
PC
TCC
TCC/R
TCC/R
Control
0.25
PSA
TCC/R
TCC/T
TCC/R
Control
1
BPH
TCC
TCC/R
TCC/R
Control
Control
BPH
RCC
PC
TCC
TCC/R
TCC/T
Healthy Volunteers (Group 1)
Benign Prostatic Hyperplasia (Group 2)
Renal Cell Carcinoma (Group 3)
Prostate Cancer (Group 3)
Bladder Cancer (Group 4)
Bladder Cancer In Remission (Group 5)
Bladder Cancer Receiving Treatment (Group 5)
Increasing concentrations of recombinant survivin or
urine specimens from the indicated patient groups were
applied to a slot-blot apparatus. The membrane was
incubated with an antibody to survivin followed by
horseradish peroxidase–conjugated goat antirabbit IgG.
Bands were visualized by chemiluminescence and quantitated by densitometry.
Table 1. Survivin Detection in 138 Urine Specimens Using a Novel Detection Method
Urine Specimens
Group 1 (control healthy volunteers)
Group 2
(nonneoplastic urinary tract diseases)
Total No.
of Patients
16
No. of Patients
Survivin-Negative
16
No. of Patients
Survivin-Positive
0
29
Hematuria
5
2
3
Urinary tract infection
6
6
0
Benign prostatic hyperplasia
6
6
0
Increased prostate specific antigen
1
0
1
Interstitial cystitis
2
2
0
Renal calculi
3
3
0
6
29
6
0
19
19
0
Renal
8
8
0
Vaginal
1
1
0
1
31†
33
1
0
30
0
31
3§
Other*
Group 3
(genitourinary cancers except bladder)
Prostate
Cervical
Group 4 (new or recurrent bladder cancer)
Group 5 (treated bladder cancer)‡
*Includes 1 patient with papillary necrosis, 2 with prostatitis, 1 with vesicoureteral reflux, and 2 with renal transplant
with elevated creatinine.
†Includes 1 patient with urothelial cancer of the ureter.
‡Patients had normal cystoscopy results.
§Two of these patients were treated with transurethral resection of the bladder tumor, and 1 with fulguration. One of
these patients had urine cytology positive for bladder cancer.
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5 patients with grade IV tumors. Carcinoma in situ was found in association
with the papillary and invasive carcinomas of 5 patients and in association with
high-grade urothelial cancer of the ureter in 1 patient. Thirty of 33 patients in
group 5 analyzed by the novel system
had no detectable urine survivin (Table
1). Five of these 30 patients were receiving bacillus Calmette-Guerin and
had completed 3 to 5 treatments, the
other 25 were status posttreatment with
negative cystoscopy findings. Three patients in group 5 with initial diagnosis
of grade II noninvasive bladder cancer
had positive test results for urine survivin after undergoing negative cystoscopic examination. One of the 3 patients had urine cytology positive for
bladder cancer. Two of the 3 patients
were treated with transurethral resection of the bladder tumor and 1 was
treated with fulguration.
When normalized for a weighted
mean (SD) survivin score, patients with
carcinoma in situ had considerably
higher survivin score (2.5 [0.5]; n=6)
than patients with grade II bladder cancer (1.3 [0.6]; n=13). The correlation
between weighted survivin score and
histopathology or grading of the various bladder cancer cases is shown in
TABLE 2 and TABLE 3, respectively. By
Western blot, a single survivin band of
16.5 kd was detected in the urine cell
pellet from a patient with bladder canTable 2. Correlation Between Weighted
Urine Survivin Score and Bladder Cancer
Histopathology*
Histopathology
Not determined
Noninvasive
papillary
carcinoma
No detrusor
muscle
invasion
Muscle invasion
Carcinoma in situ
No. of
Cases
Tested
3
Mean (SD)
Survivin
Score
1.7 (1.2)
4
1 (0)
12
1.6 (0.8)
6
6
1.7 (0.8)
2.5 (0.5)†
*The weighted survivin score was calculated using a standard curve with increasing concentrations of recombinant survivin as follows: 0, not detectable; 1, 0.001 to 0.25
µg/mL; 2, 0.25 to 1 µg/mL; and 3, more than 1 µg/mL.
†Significantly greater than either grade II or noninvasive
papillary carcinoma (P,.02).
©2001 American Medical Association. All rights reserved.
SURVIVIN AND BLADDER CANCER
COMMENT
In this study, we describe a simple, antibody-based test to identify the ap-
optosis inhibitor survivin2,4 in urine of
patients with bladder cancer. Survivin
was found in urine samples of all 46 patients with new or recurrent bladder
cancer, but not in any of the 17 healthy
volunteers, or in any of the 30 patients with other urologic cancers, and
only in 4 of 30 patients with nonneoplastic genitourinary disorders. Importantly, of the 3 patients with hematuria who tested positive for urine
survivin, 1 had a positive cytology result for bladder cancer and another was
diagnosed with bladder cancer within
6 months of survivin detection. Moreover, 32 of 35 patients treated for bladder cancer and achieving cystoscopic
remission had negative test results for
urine survivin. There is a positive correlation between a weighted urine survivin score and more advanced histopathologic tumor grading.
For its overexpression in cancer but
not in normal tissues,2,4 and its unfavorable predictive and/or prognostic
significance in various malignancies,5-9 survivin may constitute a useful molecular marker in cancer. This
may be particularly relevant in bladder cancer,11,17 in which simple and
noninvasive diagnostic means to monitor response to therapy and simplify follow-up protocols are urgently needed.
Although regarded as the criterion standard,18 urine cytology has low sensi-
tivity (30%-40%) in bladder cancer, and
fails to detect superficial, low-grade lesions. In this context, several urine
Table 3. Correlation Between Weighted
Urine Survivin Score and Bladder Cancer
Grading*
Grade
II
III
IV
IV
No. of
Cases Tested
Mean (SD) Survivin
Score
13
7
5
1
1.3 (0.6)
1.5 (0.8)
2 (1)
3†
*The weighted survivin score was calculated using a standard curve with increasing concentrations of recombinant survivin as follows: 0, not detectable; 1, 0.001 to 0.25
µg/mL; 2, 0.25 to 1 µg/mL; and 3, more than 1 µg/mL.
Histopathological analysis was carried out using the
Broader cytologic grading system for the classification of
papillary transitional cell tumors, grades I through IV.
†One of the 6 patients with associated carcinoma in situ
had urothelial cancer of the ureter (grade IV; survivin
score, 3).
Figure 2. Western Blot of Urine Survivin
TCC
Relative Molecular Weight, ×10 –3
cer but not in that from a healthy volunteer (FIGURE 2).
To independently evaluate the results obtained with the new method, 15
additional patients with new or recurrent bladder cancer were analyzed for
urine survivin by RT-PCR. A 279-base
pair survivin cDNA was amplified from
urine cell pellets of all the 15 new patients with bladder cancer (FIGURE 3
and data not shown). In contrast, urine
cell pellets from 5 additional individuals, 1 with urinary tract infection, 2 with
treated bladder cancer and negative cystoscopy results, 1 with prostate cancer, and 1 from a volunteer, had no survivin cDNA (Figure 3). In control
experiments, a 309–base pair b-actin–
cDNA fragment was indistinguishably
amplified from urine of controls and patients with bladder cancer (Figure 3).
Histopathologic cases of bladder cancer analyzed by RT-PCR included 5 patients with grade II tumors, 1 patient
with grade III, 6 patients with grade IV,
and 3 patients with carcinoma in situ.
These experiments suggest that exfoliated cancer cells may passively
release survivin in the extracellular
milieu (ie, urine) during tumor progression.
Control
30
21
14.5
Urine cell pellets from a healthy volunteer and a group
4 patient with bladder cancer (TCC) were electrophoresed, transferred to nylon membranes, and immunoblotted with an antibody to survivin followed by chemiluminescence.
Figure 3. Reverse Transcriptase Polymerase Chain Reaction Amplification of Survivin Messenger RNA in Urine Specimens
TCC
Control
Molecular Weight, Base Pair
M
TCC
M
400
300
200
M
Survivin
Control
M
400
300
β-Actin
200
Total RNA was extracted from urine cell pellets and reverse-transcribed by random priming. Amplification reactions were carried out with survivin-specific nested primers (279 bp) or b-actin–specific primers (309 bp). M indicates molecular weight markers in base pair; TCC, analysis of 5 representative patients with new or recurrent
bladder cancer (group 4).
©2001 American Medical Association. All rights reserved.
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327
SURVIVIN AND BLADDER CANCER
markers including bladder tumor antigen, nuclear matrix protein, telomerase activity, hyaluronic acid/hyaluronidase, and fibrin degradation products
have been characterized for their potential diagnostic/predictive value in
bladder cancer.19,20
In this patient series, the sensitivity
of the urine survivin test for new or recurrent bladder cancer was 100%, and
its specificity for other neoplastic and
nonneoplastic genitourinary tract diseases was 95% (P,.02). However, the
overall specificity of the test is likely to
vary depending on which patient population is the focus of clinical interest.
A screening test for group 1 individuals will have a false-positive rate of essentially zero, whereas patients with
clinical symptoms in groups 2 and 3 will
likely have a combined false-positive
rate of 5% to 10%. However, similarly
to the 2 patients with hematuria described above, these individuals should
Author Contributions: Dr Smith participated in study
concept and design, acquisition of data, analysis and
interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, provided statistical expertise, obtained
funding, and provided administrative, technical, or material support.
Ms Wheeler participated in study concept and design,
acquisition of data, analysis and interpretation of data,
drafting of the manuscript, critical revision of the manuscript for important intellectual content, and provided
administrative, technical, or material support.
Ms Plescia participated in study concept and design,
acquisition of data, analysis and interpretation of data,
critical revision of the manuscript for important intellectual content, and provided administrative, technical, or material support.
Dr Colberg participated in study concept and design
and acquisition of data.
Dr Weiss participated in study concept and design, acquisition of data, analysis and interpretation of data,
critical revision of the manuscript for important intellectual content, obtained funding, provided administrative, technical, or material support, and supervised conduct of the study.
Dr Altieri participated in study concept and design,
analysis and interpretation of data, drafting of the
manuscript, and obtained funding.
Funding/Support: Our work was supported by National Institutes of Health grants DK02499 (Dr Smith);
DK47548 and DK38311 (Dr Weiss); and CA78810 and
CA82130 (Dr Altieri).
Acknowledgment: We thank all the patients for their
participation in the study. We also thank Bernard Lytton, MD, Harris Foster, Jr, MD, Hubert Swana, MD,
Greg Barme, MD, Ithaar Derweesh, MD, and Luke Cho,
MD, and Sharyn Jones, PCA, Kathy Olsen, RN, and
Claire Puklin, RN, for devoting their time for sample
collection and their practical perspective of patient care.
8. Monzo M, Rosell R, Felip E, et al. A novel antiapoptosis gene: re-expression of survivin messenger
RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol. 1999;17:2100-2104.
9. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo
T, Tanigawa N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res. 1998;58:5071-5074.
10. Dawson C, Whitfield H. ABC of urology: urological malignancies, II: urothelial tumors. BMJ. 1996;
312:1090-1094.
11. Stein JP, Grossfeld GD, Ginsberg DA, et al.
Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol. 1998;160:645659.
12. Gazzaniga P, Gradilone A, Vercillo R, et al. Bcl2/bax mRNA expression ratio as prognostic factor in
low-grade urinary bladder cancer. Int J Cancer. 1996;
69:100-104.
13. Lara PC, Perez S, Rey A, Santana C. Apoptosis in
carcinoma of the bladder: relation with radiation treatment results. Int J Radiat Oncol Biol Phys. 1999;43:
1015-1019.
14. Swana HS, Grossman D, Anthony JN, Weiss RM,
Altieri DC. Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. N Engl
J Med. 1999;341:452-453.
15. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998;396:580-584.
16. Grossman D, McNiff JM, Li F, Altieri DC. Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol. 1999;
113:1076-1081.
17. Ozen H. Bladder cancer. Curr Opin Oncol. 1998;
10:273-278.
18. Brown FM. Urine cytology: it is still the gold standard for screening? Urol Clin North Am. 2000;27:2537.
19. Ramakumar S, Bhuiyan J, Besse JA, et al. Comparison of screening methods in the detection of bladder cancer. J Urol. 1999;161:388-394.
20. Lokeshwar VB, Obek C, Pham HT, et al. Urinary
hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade. J Urol.
2000;163:348-356.
be closely followed up because they may
subsequently develop bladder cancer.
Because of its high specificity, the urine
survivin test may be useful to complement cytology and/or other diagnostics markers19,20 to better monitor bladder cancer patients and identify early
recurrences or de novo neoplasms.
Other potential advantages of the urine
survivin test include its simplicity, suitability as a point-of-service procedure, and its cost-effectiveness, using
1-step detection with a single antibody to survivin that has now become
commercially available. Analysis of a
larger patient series may establish the
general suitability of urine survivin detection for monitoring response to
therapy and follow-up protocols in
bladder cancer.
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