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ABSTRACT & COMMENTARY
Synopsis: Bladder cancer is a common tumor, particularly in older individuals. Urine cytology is currently used as a screen for some high-risk individuals, but the assay lacks sensitivity. In this report, the detection of a newly described inhibitor of apoptosis (survivin) was found to be a highly sensitive indicator of active bladder cancer. Further study is needed, but it is likely that the assessment of urinary survivin will become a commonly used screening tool for the early detection and management of bladder cancer.
Source: Smith SD, et al. JAMA 2001;285:324-328.
Urine cytology is currently a standard for screening high-risk individuals for bladder cancer, but its sensitivity is estimated to be only 30-40%.1 Survivin is a recently described modulator of apoptosis2 that has been found to be over-expressed in a wide range of tumors, including those of urinary endothelium origin.3,4 Smith and colleagues from Yale University School of Medicine addressed the potential use of a urinary survivin assay as a predictive/prognostic molecular marker of bladder cancer.
Five distinct groups of volunteers provided 158 urine samples for this analysis. Group 1 (n = 17) were normal, healthy controls; group 2 (n = 30) were individuals with nonneoplastic urinary tract disorders (including hematuria, infection, renal stones, etc.); group 3 (n = 30) were those with genitourinary tumors other than bladder cancer (including renal, vaginal, and prostatic); group 4 (n = 46) were those with newly diagnosed bladder cancer or those with newly discovered recurrent bladder cancer (samples taken before treatment); and group 5 (n = 35) were those receiving therapy for active disease, but with negative cystoscopic examination on the day of sampling. Urines were tested for the presence of survivin by a modified immunoassay and the results were confirmed by Western Blot and reverse transcriptase polymerase chain reaction (RT-PCR).
Survivin was detected in 100% of the urine samples from the 46 patients with new or recurrent bladder cancer but was not detected in the urine of any of the healthy volunteers or in any of those with prostate, renal, vaginal, or cervical cancer. However, of the 30 patients with non-neoplastic urinary tract disease, four patients tested positive for survivin. Of these, three had bladder abnormalities noted by cystoscopy and one had an elevated PSA level.
Smith et al conclude that the appearance of survivin in the urine was a highly sensitive and specific marker of new or recurrent bladder cancer.
COMMENT by william B. Ershler, MD
Disordered cell death (apoptosis) is currently considered a contributing factor in the development of many cancers. Survivin is one member of a gene family that inhibits apoptosis,2 and its presence has been shown to be common in cancer cells and correlate with prognosis.5 Accordingly, in one series, survivin was found in 78% of bladder cancers, but not in normal urothelium, and its expression correlated with accelerated recurrences.
The importance of survivin in the urine was clearly demonstrated in this report. All patients with active bladder cancer had detectable levels, whereas 32 of 35 treated patients were found to be negative. Furthermore, no survivin was detected in the urine of normal controls and when it was detected in four of 30 individuals with non-neoplastic urinary tract conditions, it was associated with an abnormal appearing bladder by cystoscopy in three and a high PSA in the fourth. Thus, the assay is both highly sensitive and specific for bladder pathology. In fact, its potential use far exceeds the current standard—urine cytology and, if these results are confirmed, it will be a significant clinical advance for bladder cancer screening.
Although the antibody used in this study to detect survivin is commercially available, standardization of the detection assay needs to be established. This, no doubt, will happen soon. Thereafter, clinician investigators will need to develop and test protocols that will ultimately determine the overall clinical use of the assay. It would seem from this work, however, that there is great potential for the measurement of urinary survivin as both a screening tool and an indicator of treatment efficacy in the management of bladder cancer.
1. Brown FM. Urol Clin N Amer 2000;27:25-37.
2. Ambrosini G, et al. Nat Med 1997;3:917-921.
3. Velculescu VE, et al. Nat Genet 1999;23:387-388.
4. Dawson C, et al. BMJ 1996;312:1090-1094.
5. Swana HS, et al. N Engl J Med 1999;341:452-453.