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      Screening for urinary bladder cancer with the use of nuclear matrix protein (NMP) 22: is it feasible?

      abstract
      1 , 2 , , 2 , 3
      Tobacco Induced Diseases
      BioMed Central
      11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID)
      9-11 December 2013

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          Abstract

          Background Tobacco use accounts for the majority of urinary bladder cancer (UBC) cases both in men and women. It is widely accepted that smokers have increased risk of UBC [1-4]. An early diagnosis of UBC is crucial because patients with superficial UBC have much better prognosis than those with invasive UBC [1-5]. During the past years a variety of urine based markers have been introduced for screening of UBC. Nuclear matrix protein 22 (NMP22) is a nuclear protein that is accountable for chromatid regulation and cell separation during replication. The detection of NMP22 has been used from many clinical studies to evaluate the possibility of UBC screening [2-8]. The purpose of this review is to access the current literature in order to determine the usefulness of NMP22 in screening of UBC. Materials and methods A thorough search was conducted in MEDLINE using the terms urinary bladder cancer OR urinary bladder neoplasm, NMP22 and screening. The following inclusion criteria were adopted: i. studies that NMP22 was measured in high risk patients without UBC and ii. studies that NMP22 was compared between patients with known history of UBC and a control group without history of UBC. We excluded studies that NMP22 was used only for the surveillance of UBC. Results 185 English-language articles were retrieved and 38 were included in this study. Average total sensitivity of NMP22 was 73.44 ± 15.11% and average total specificity 72.82 ± 16.27%. Positive predictive value (PPV) was 37.12 ± 26.11% and negative predictive value (NPV) was 87.47 ± 10.60%. Two studies did not report total specificity or sensitivity rates. The majority of the reports concluded than NMP22 cannot be used for screening non-invasive UBC but benefits the screening for high grade UBC in symptomatic patients. However there is no study in the literature that indicates that NMP22 detection approaches level 1 of evidence in screening for UBC. Based on the fact that the prevalence of UBC in asymptomatic high risk patients without history of UBC is low (4.0%), the diagnostic value of mass screening programs in asymptomatic patients is questionable. Conclusions Detection of NMP22 is a non-invasive test that can be easily applied and gives diagnostic answers very quickly especially for tobacco-induced high grade tumors. NMP22 detection cannot replace cystoscopy. It is essential, more studies to be conducted with careful selection of patients, in order to find out, if NMP22 or a combination with other markers are useful for diagnosing UBC [1-5].

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          Most cited references6

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          Detection of bladder cancer using a point-of-care proteomic assay.

          A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory. To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer. Twenty-three academic, private practice, and veterans' facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner. Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ. The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test results available during the patient visit.
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            Comparison of screening methods in the detection of bladder cancer.

            We prospectively evaluate and compare the sensitivity and specificity of urine cytology, BTA stat, NMP22, fibrin/fibrinogen degradation products (FDP), telomerase, chemiluminescent hemoglobin and hemoglobin dipstick to detect bladder cancer. Single voided specimens were obtained from 57 patients with bladder cancer, and 139 without evidence of bladder malignancy on cystoscopy or a negative biopsy of indeterminate lesions. A cytology report was available for 125 patients and interpreted independently. BTA stat, NMP22 and FDP were analyzed according to manufacturer specifications. The telomerase assay was performed on cells collected from urine by centrifugation in preparation for polymerase chain reaction based amplification using the telomeric repeat amplification protocol assay. The chemiluminescent screening assay for hemoglobin in urine uses the pseudoperoxidase activity of hemoglobin on hydrogen peroxide and subsequent oxidation of 7-dimethylaminonaphthalene-1,2-dicarbonic acid hydrazide to generate chemiluminescence emission. Hemoglobin dipstick was interpreted as positive if the hemoglobin content in the urine was trace or greater. Overall sensitivity with urine cytology, BTA stat, NMP22, FDP, telomerase, chemiluminescent hemoglobin and the hemoglobin dipstick was 44, 74, 53, 52, 70, 67 and 47%, respectively. Specificity with cytology, telomerase and FDP was high (95, 99 and 91%, respectively) but BTA stat, NMP22 (optimized), chemiluminescent hemoglobin (optimized) and the hemoglobin dipstick demonstrated lower specificity of 73, 60, 63 and 84%, respectively. Stepwise logistic regression analysis revealed that for all tumors, and within each tumor grade and stage telomerase had the strongest association with bladder cancer among all tests (69% overall concordance). Telomerase was also positive in 91% of the patients (10 of 11) with carcinoma in situ. Urinary telomerase had the highest combination of sensitivity and specificity (70 and 99%, respectively) for bladder cancer screening in these patients. It was the strongest predictor with superior accuracy in patients with grade 1 and noninvasive tumors (pTa), and extremely useful in patients with carcinoma in situ. Telomerase appears to be promising and outperformed cytology, BTA stat, NMP22, FDP, chemiluminescent hemoglobin and hemoglobin dipstick in the prediction of bladder cancer.
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              Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer.

              We assessed variability in the diagnostic performance of NMP22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS transitional cell carcinoma of the bladder in a large international cohort. NMP22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1 and/or CIS transitional cell carcinoma at 12 participating institutions. Patient characteristics varied considerably among institutions. Overall 1,045 patients (36.4%) had recurrent transitional cell carcinoma (range across institutions 13.6% to 54.3%). Median NMP22 was 5.5 U/ml (range across institutions 2.5 to 18.8). Of the patients 33.5% had grade III tumors (range across institutions 20.6% to 54.0%) and 22.4% had muscle invasive tumors (range across institutions 3.2% to 38.2%). Area under the ROC curve for bladder TCC detection was 0.735 (95% CI 0.715 to 0.755, range across institutions 0.676 to 0.889). The manufacturer recommended cutoff of 10 U/ml detected 57% of cases with a 19% false-positive rate. AUC for grade III and stage T2 or greater disease was 0.806 (95% CI 0.780 to 831) and 0.864 (95% CI 0.839 to 0.890), respectively. For each NMP22 cutoff NMP22 had higher sensitivity for detecting grade III and stage T2 or greater bladder transitional cell carcinoma than for detecting any cancer. No optimal cutoffs for detecting any or aggressive bladder transitional cell carcinoma could be derived based on NMP22 values. There is a substantial degree of heterogeneity in the diagnostic performance of NMP22 applied to populations from different institutions. There is no clearly defined NMP22 cutoff but there is a continuum of risk for recurrence and progression.
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                Author and article information

                Contributors
                Conference
                Tob Induc Dis
                Tob Induc Dis
                Tobacco Induced Diseases
                BioMed Central
                2070-7266
                1617-9625
                2014
                6 June 2014
                : 12
                : Suppl 1
                : A6
                Affiliations
                [1 ]Medical school, National and Kapodistrian University of Athens, Athens, 115 27, Greece
                [2 ]Society of Junior Doctors, Athens,15123, Greece
                [3 ]Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA
                Article
                1617-9625-12-S1-A6
                10.1186/1617-9625-12-S1-A6
                4101296
                f53f733a-5272-4d94-9477-bb9773bff6b8
                Copyright © 2014 Stefanopoulos and Economopoulos; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID)
                Athens, Greece
                9-11 December 2013
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                Meeting Abstract

                Respiratory medicine
                Respiratory medicine

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