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Cystoscopy remains the "gold standard" for identifying bladder cancer, but has it's drawbacks: it is expensive, invasive and many people find it uncomfortable. A urine test is far easier to get patients to readily comply to.
Urine cytology, the most commonly used test for bladder cancer, microscopically identifies the presence of abnormal, malignant cells, which are shed into the urine in patients with bladder cancer. The method has high specificity (ie, few false-positives). However, it has low sensitivity (ie, many false-negatives, especially in superficial and low-grade tumors), results are not immediately available and are interpreter-dependent [subjective]. While quite accurate in detecting high-grade bladder cancer and carcinoma in situ, its ability to detect low-grade cancer is limited.
Therefore, urine-based marker tests are being developed to fill some of the remaining needs. These newer tests are more accurate in detecting low-grade bladder cancer, so they are especially useful in monitoring for recurrence, may significantly improve and simplify workup, diagnosis, and follow-up, and hopefully allow for detection of disease at an earlier stage, thus improving the chances of curative therapy.
A diagnostic test is one that predicts the presence of a disease. An ideal diagnostic test would always give the right answer, with a positive result in everyone with the disease and a negative result in everyone else - and would be quick, safe, simple, painless, reliable, and inexpensive, as well. Since no current diagnostic test is ideal, we need to evaluate each of them for their clinical usefulness. In practice, for any diagnostic test there is a trade-off between sensitivity and specificity. In cancer diagnosis, the need for this trade-off is rooted in the fact that cancer arises from our own tissues. It is not completely "foreign" to our systems like a virus or bacterium is.
It's important to remember that there are four possible results when a diagnostic test is run:
True positive - when the test is positive and the patient does have the disease
Here's another way of looking at this (often referred to as a "truth table"):
Calculating the disease sensitivity and specificity are ways of evaluating diagnostic tests, using the four possible results.
Sensitivity - is the ability of a test to correctly identify a positive specimen, and it tells you how good the test is at identifying the disease. Statistically, it's the proportion of patients with the disease who have a positive result, that is, the number of "true positives" out of all the situations where the disease is present.
For example, 100 patients with cancer are tested using a test that detects tumors. There are 80 positive results and 20 negative results. This means the test has a sensitivity of 80% - it correctly identified 80 of the 100 cancers - and it gave 20 false negative results.
Specificity - is the ability of a test to correctly identify a negative specimen, and it tells you how good the test is at identifying when the disease is absent. The statistical way of looking at this is the proportion of patients without the disease who have a negative test, that is, the number of "true negatives" out of all the situations where the disease is not present.
For example, 100 normal, healthy individuals are tested using a test that detects tumors. There are 80 positives and 20 negatives. This means the test has a specificity of 20% - it correctly identified 20 of the 100 negative specimens - and it gave 80 false positive results.
Both sensitivity and specificity are very important, and they can both be influenced by various factors, such as the characteristics of the population tested or the value used as a cut-off for the test (above which the test is positive and below which it is negative). A test with low sensitivity and many false negative results will fail to detect the tumor in a large portion of the patients being tested, while a test with low specificity with many false positive results may lead to unnecessary invasive or expensive procedures and cause undue alarm.
Many, but not all, patients report they would rather be "scared for nothing" than miss a tumor, and are therefore most interested in tests with high sensitivity.1
The original Bard BTA Test, which continues to be referred to in the literature from time to time, was a latex agglutination test detecting bladder tumor-associated analytes and is no longer distributed in the US. It is important to note that it has been replaced by two newer tests based on significantly improved technology with much better sensitivity and specificity.
Both of the new tests detect a human complement factor H-related protein (hCFHrp) which has been shown to be produced by several human bladder cancer cell lines, and by human bladder cancers, but not by other epithelial cell lines (Kinders, Clin Cancer Res 4:2511, 1998). It is thought that factor H acts to protect the tumor cell from the body's natural immune system (Corey, J Biol Chem 275:12917, 2000). Both the BTA stat and BTA TRAK tests can provide valuable but slightly different information for the bladder cancer patient and her doctor.
The BTA stat Test is a qualitative (positive or negative) test provided in a disposable format similar to a home pregnancy test. It uses five drops of urine and can be read in five minutes by the appearance of a colored line in the patient window, while a colored line appears in a "check" window to indicate the test is working properly. This test is cleared in the US for use by clinical laboratories, the physician or his staff right in the office, or even by the bladder cancer patient at home (with a physician's prescription). To date, it is the only tumor marker in the United States with this status. Besides being highly sensitive, fast, and easy to use, with a unique availability to be run by the physician and/or the patient, this test is significantly less costly than other diagnostic tests or cytology.
The BTA TRAK Assay is a quantitative immunoassay test and provides a numerical result of the hCFHrp level. Like the NMP22 test, urine must be sent to a reference laboratory where the test is performed by professional technologists. In addition to knowledge of the specific level, an advantage of the BTA TRAK test is the ability to monitor the rise or fall of hCFHrp.
Numerous clinical studies have been conducted with the new BTA tests. Most reports state findings in terms of "sensitivity" and "specificity." Briefly, sensitivity is the ability of the test to correctly identify a positive specimen, and specificity is the ability of the test to correctly identify a negative specimen.
BTA stat Test Studies
BTA TRAK Assay Studies
Another comparison study (Giannopoulos, Urology 55:871, 2000) published this year showed that the BTA stat Test was more sensitive than cytology in all stages and grades except G3, while NMP22 was more sensitive than cytology only in stage Ta and Grade 1 and 2. The BTA stat Test also had higher sensitivity than NMP22 in all stages and grades.
It is also important to note that in both of the BTA tests, and with NMP22 as well, results can be compromised if there is a urinary tract infection, inflammation, or kidney stones present, if there has been recent trauma to the bladder, or if the specimen is collected by catheter. The paper by Sharma, for example, shows the dramatic increase in specificity when these conditions are excluded from testing (Sharma, J Urol 162:53, 1999). As with any test, for the results to be most useful they should be interpreted in light of all the medical and clinical information available.
Clinical trials in both the US and Europe are continuing to broaden our understanding of the optimal use of the BTA products, and we await the publications of these results.1
More information about the BTA stat test can be found here: http://www.btastat.com
The BTA stat® Test is available for purchase with a prescription http://www.btastat.com/how_to_get_test.html
FISH - also on WebCafe: an expert P.F. Bassi, MD, reviews FISH
From the website of MD. Anderson Cancer Center
Fluorescence-in-situ-hybridization (FISH) for multiple centromeric probes has previously been shown to be a very sensitive test for diagnosing UC, however the test was limited by the requirement of multiple cytospins to evaluate 4 or more probe sets. Recently a new commercial test (VYSIS) for evaluating urinary cytology became available in which 4 probes are simultaneously evaluated on a per cell basis on a single cytospin. We performed a pilot study to test the efficacy of the new FISH test compared to standard urine cytology. This study showed that the multi-color FISH probe test was more sensitive than cytology, easily performed and yielded a high number of cells with numerical chromosomal aberrations.
Vysis® UroVysion Bladder Cancer Recurrence Kit (UroVysion Kit), takes a Cellular Genomics approach to disease management by detecting genomic changes (chromosome abnormalities) in bladder cells that are indicative of cancer. As few as four abnormal cells identified with the UroVysion Kit indicate the presence of cancer. For info about clinical studies, sensitivity and specificity of the Vysis kit, please click here
DiagnoCure’s ImmunoCyt™ Bladder Cancer Monitoring Test
ImmunoCyt™ is a 510(k) cleared, by the FDA, qualitative direct immuno-cytofluorescence assay, intended for use in conjunction with cytology to increase the overall sensitivity for the detection of tumor cells exfoliated in the urine of patients previously diagnosed with bladder cancer.
ImmunoCyt™ contains a cocktail of three monoclonal antibodies labeled with fluorescent markers. The cocktail of antibodies have been shown to react with a mucin glycoprotein as well as to be specific to a glycoform of CEA. The test detects cellular markers specific for bladder cancer in exfoliated cells isolated from urine sample. This non-invasive test, when coupled with urine cytology proves to be more sensitive than urine cytology alone or other currently available tumor markers.
The current standard method for non-invasive detection of bladder cancer is urinary cytology, which consists of identifying the presence of cancer cells in urine. Urinary cytology has high specificity but poor sensitivity, typically no greater than 30% to 45%. This sensitivity varies according to the stage and grade of the tumor.
ImmunoCytT™is carried out in parallel with cytology to improve cytology's sensitivity at detecting tumor cells in the urine of patients, especially those with low stage, low grade tumors. The concomitant use of classical cytology and ImmunoCytTM can substantially improve the detection of bladder cancer. As shown in the ImmunoCytTM performance analysis (cumulative data from eleven publications and presentations from 3,203 cases), a sensitivity of 88% has been obtained when both cytology and ImmunoCyt™ were used together http://www.diagnocure.com/anglais/section4/sec4.htm - DiagnoCure Inc. website, manufacturers of ImmunoCyt™.
A multicenter study in the United States, published in the Journal of Urology, concluded: ImmunoCyt™ enhances the sensitivity of cytology, which is a specific but not a sensitive method for detecting bladder cancer. The ability of this immunocytochemical test to detect low grade, superficial, small tumors makes it the most suitable available marker to test for monitoring strategies in patients with low risk bladder cancer. Performance of urine test in patients monitored for recurrence of bladder cancer: a multicenter study in the United States.
FDP has shown high sensitivity even for low-grade and non-invasive tumors, and its diagnostic ability could be superior to NMP22 according to a recent study (Nippon Hinyokika Gakkai Zasshi 2001 Jan;92(1):1-5 ] Oeda T, Manabe D Department of Urology, Onomichi Municipal Hospital.PMID: 11235137)
The FDP test detects the presence of fibrin and fibrinogen degradation products in urine. It is a simple test that can be performed in the office, and results are available in about 10 minutes. Fibrin and fibrinogen degradation products are protein fragments generated by the action of the fibrinolytic system on fibrin and fibrinogen. Plasma proteins leak from blood vessels in tumors into the surrounding tissue. Clotting factors rapidly convert the fibrinogen in the plasma into an extravascular fibrin clot, which is degraded by plasmin and activated by urokinase. The FDP test can detect these degradation products and is positive in two thirds of patients with bladder cancer. The FDP assay is more accurate than urine cytology and has high specificity (negative in 96% of healthy subjects). The FDP test was found to be superior to the BTA test in at least one study*.
Telomerase is another substance currently being assessed for its potential usefulness in diagnosing transitional cell cancer (TCC) and in monitoring for recurrence. It will soon be made available to doctors and patients. Telomerase is a ribonucleoprotein enzyme responsible for production of telomeres, which are DNA sequences that occupy the ends of chromosomes and protect their integrity during DNA replication and may be involved in the immortalization of a cancer cell 3
Comparison of screening methods in the detection of bladder cancer
Although the test is proven to identify low-grade tumors, it is not recommended for use in routine screening programs because of the low incidence of bladder cancer and should be aimed at high-risk subgroups, noted the authors, from Morgagni-Pierantoni Hospital, Forli. PubMed abstract
An online article in the Urology Times (www.urologytimes.com) reported over the JAMA article;
"It looks like we are looking at something with about 90% sensitivity and 90% specificity. That is about 10 points higher than any other test that is out there," said Dr. O'Donnell, who was not involved with this study.
The main advantages of the test, according to Dr. Calistri, are that it is noninvasive, can be performed under local anesthetic, and is significantly less expensive, at $20, than the approximately $100 for cystoscopy or $50 for urinary cytology.
"... [I]t could be a good marker for high-risk screening groups," Dr. Calistri told Urology Times. "Furthermore, it shows a high sensitivity for the diagnosis of low-grade tumors that can escape detection during cytological examination. Results are usually available in 2 to 3 days." article link
Hyaluronidase and hyaluronic acid
Hyaluronidase and hyaluronic acid are associated with induction of angiogenesis. Dr. Lokeswahr and colleagues at the U.of Miami S.O.M. have shown that Hyaluronic acid (HA), the urinary HAase levels of intermediate (G2) to high- grade (G3) bladder cancer patients are five- to seven-fold elevated as compared to those of normal individuals and patients with other genitourinary conditions or low-grade (G1) bladder cancer. The increase in urinary HAase levels is due to the secretion of a tumor-derived HAase which is elevated eight-fold in G2/G3 tumor tissues. The HAase in bladder tumor tissues is secreted by tumor epithelial cells and is associated with the invasive/metastatic potential of the tumor cells.5
You can read Dr. Lokeswahr's page at the U of Miami website: http://urology.med.miami.edu/urologic_research_research_projects.asp
2006: update on HA
The reserachers suggest that after more experience and follow-up using this assay in the clinical setting, it might be possible to predict not only the cases with residual tumor, but also those who require early radical surgery or those in whom this can be delayed.
In addition to being a good marker in the initial evaluation of bladder carcinoma thanks to its excellent sensitivity (83.1%) and specificity (90.1%) [according to the Lokeswahr studies referenced below], HA potential uses include follow-up, prognostic evaluation, preventing unnecessary interventions and/or to indicate cases where early radical intervention is necessary."10
Dec. 2005 - Using a prospectively determined cutoff, 67 of the 75 samples from patients with bladder cancer were positive for BLCA-4, resulting in an assay sensitivity of 89%. Also, 62 of the 65 samples from individuals without bladder cancer were negative for BLCA-4, resulting in an assay specificity of 95%.
Feb. 2004 BLCA-4, appears to be associated with a "field effect" of the disease, and in clinical trials is able to separate individuals with bladder cancer from those without the disease with high sensitivity and specificity. BLCA-4 is a bladder cancer marker that is highly specific and occurs early in the development of the disease. It appears to be a transcription factor that may play a role in the regulation of the gene expression in bladder cancer. BLCA-4 is a marker with significant clinical utility that may have an active role in the disease.
4. Comparison of screening methods in the detection of bladder cancer
5. Secretion of bladder tumor-derived hyaluronidase activity by invasive bladder tumor cells. Lokeshwar VB; Soloway MS; Block NLDepartment of Urology, University of Miami School of Medicine, Cancer Lett 1998 Sep 11;131(1):21-7 PMID: 9839616 UI: 99053351
6. http://www.ca-journal.org/frames/articles/articles_1999/49_131-134_frame.htm CA NEWS & VIEWS Highlights from the American Cancer Society's 41st Science Writers Seminar
7.Highly specific urine-based marker of bladder cancer Thu-Suong Van Lea, Raymond Millerb, Timothy Barderb, Marko Babjukc, Douglas M. Potterd and Robert H. Getzenberga,Department of Urology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PennsylvaniabEprogen Incorporated, Darien, IllinoiscCharles University, Prague, Czech RepublicDepartment of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania Urology Volume 66, Issue 6 , December 2005, Pages 1256-1260
V.B. Lokeshwar, C. Obek, H.T. Pham, D. Wei, M.J. Young and R.C. Duncan et al., Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade, J Urol 163 (2000) (1), pp. 348–356.
V.B. Lokeshwar and N.L. Block, HA-HAase urine test. A sensitive and specific method for detecting bladder cancer and evaluating its grade, Urol Clin North Am 27 (2000) (1), pp. 53–61.
10. Urinary Hyaluronan as a Marker for the Presence of Residual Transitional Cell Carcinoma of the Urinary Bladder Carlo C. Passerottia, b, Corresponding Author Contact Information, Alexandre Bonfima, João R.M. Martinsb, c, Marcos F. Dall’Oglioa, Lucia O. Sampaiob, Aline Mendesb, Valdemar Ortiza, Miguel Srougia, Carl P. Dietrichb, 1 and Helena B. Naderb ./ aDisciplina de Urologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil; bDisciplina de Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil; cDisciplina de Endocrinologia e Metabologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil ; European Urology Volume 49, Issue 1 , January 2006, Pages 71-75
|Last Updated ( Friday, 14 November 2008 )|