***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose Cytokeratin 20 ( CK20 ) and insulin-like growth factor 2 ( IGF2 ) were previously proposed to be elevated in clinical sample s from patients with bladder cancer ( BCa ) . A two cohort design validation study was used to assess the relevance for BCa detection by transcript quantitation of both markers in urine sample s. Their diagnostic value was assessed in comparison with voided urine cytology ( VUC ) . Methods RNA isolation was carried out using cellular sediments of urine sample s from 196/103 histologically positive BCa patients , as well as 97/50 control subjects for the test ( TC ) and validation cohort ( VC ) , respectively .  Urinary transcript levels of CK20 and IGF2 were determined by qPCR . Results Relative transcript levels were significantly elevated 3.4/11-fold for CK20 and 188/64-fold for IGF2 ( p < 0.001 ) in urine sediments of BCa patients compared to controls in the TC and VC , respectively . In a combined analysis , the result ing sensitivity ( SN ) ( SNTC : 77.9 ; SNVC : 90.3 % ) and specificity ( SP ) ( SPTC : 88.0 ; SPVC : 84.0 % ) were similar to that of VUC . The sensitivity of VUC in combination with CK20 and IGF2 was considerably increased ( SNTC : 94.6 ; SNVC : 93.2 % ) while specificity was reduced ( SPTC : 72.0 ; SPVC : 82.0 % ) compared to VUC alone in the test and validation cohort . Conclusions Transcript levels of IGF2 and CK20 enabled the detection of BCa with a diagnostic performance similar to VUC . Combined analysis of voided urine cytology together with altered transcript levels of CK20 and IGF2 enhanced sensitivity , but did not improve overall test performance Abstract Objective : The aim of this study was to determine the diagnostic accuracy of UBC ® Rapid – a urine-based marker for bladder cancer – in patients with bladder cancer and controls , and to compare the test results across risk groups . Material s and methods : This prospect i ve phase II study was conducted at four Swedish hospitals .  UBC Rapid was evaluated in four groups : A , newly diagnosed bladder cancer ( n = 94 ) ; B , follow-up of non-muscle-invasive bladder cancer ( n = 75 ) ; C , benign urinary tract diseases ( n = 51 ) ; and D , healthy controls ( n = 50 ) . Tumours were divided into high risk ( carcinoma in situ , TaG3 , T1 , T2 and T3 ) and low risk ( low malignant potential , TaG1 and TaG2 ) . Urine sample s were quantitatively analysed by UBC Rapid .  Sensitivity , specificity , positive predictive value ( PPV ) and negative predictive value ( NPV ) were calculated based on optimal cut-off ( receiver operator characteristics curve analysis ) . A linear regression compared the UBC Rapid results in the different risk groups . Results : The optimal cut-off was 8.1 μg/l . The median UBC Rapid values were 9.3 μg/l [ interquartile range ( IQR ) 30.9 ] and 4.3 μg/l ( IQR 7.8 ) in patients with positive and negative cystoscopy , respectively ( p < .001 ) . The value for group A was 15.6 μg/l ( IQR 37.9 ) , group B 5.6 μg/l ( IQR 8.6 ) , group C 5.1 μg/l ( IQR 9.0 ) and group D 3.3 μg/l ( IQR 7.1 ) . Sensitivity was 70.8 % , specificity 61.4 % , PPV 71.3 % and NPV 60.8 % . The high-risk group had significantly  higher UBC Rapid values than the low-risk group : 20.5 μg/l ( IQR 42.2 ) , sensitivity 79.2 % and specificity 61.4 % versus 7.0 μg/l ( IQR 9.9 ) , sensitivity 60.0 % and specificity 61.4 % ( p = .039 ) . Conclusions : The UBC Rapid urine-based marker for bladder cancer gave higher values in patients with positive than in those with negative cystoscopy . The diagnostic accuracy was better in patients with high-risk than in those with low-risk tumours , and was better during primary detection than during surveillance Purpose : Patients with nonmuscle invasive bladder cancer are followed with frequent cystoscopies . In this study FGFR3 , TERT and OTX1 were investigated as a diagnostic urinary marker combination during followup of patients with primary nonmuscle invasive bladder cancer . Material s and Methods : In this international , multicenter , prospect i ve study 977 patients with nonmuscle invasive bladder cancer were included . A total of 2,496 urine sample s were collected prior to cystoscopy during regular visits . Sensitivity was estimated to detect concomitant recurrences . Kaplan‐Meier curves were used to estimate the development of future recurrences after urinalysis and a negative cystoscopy . Results : Sensitivity of the assay combination for recurrence detection was 57 % in patients with primary low grade , nonmuscle invasive bladder cancer . However , sensitivity was 83 % for recurrences that were pT1 or muscle invasive bladder cancer . Of the cases 2 % progressed to muscle invasive bladder cancer . Sensitivity for recurrence detection in patients with primary high grade disease was 72 % and 7 % of them had progression to muscle invasive bladder cancer . When no concomitant tumor was found by cystoscopy , positive urine sample s were more frequently followed by a recurrence over time compared to a negative urine sample ( 58 % vs 36 % , p < 0.001 ) . High stage recurrences were identified within 1 year after a positive urine test and a negative cystoscopy . Conclusions : Recurrences in patients with primary nonmuscle invasive bladder cancer can be detected by a combination of urine assays . This study supports the value of urinalysis as an alternative diagnostic tool in patients presenting with low grade tumors and as a means to identify high stage tumors earlier BACKGROUND Early diagnosis of carcinoma of bladder remains a challenge . Survivin , a member of the inhibitor of apoptosis ( IAP ) protein family , is frequently activated in bladder carcinoma . The objective of this study was to investigate urinary survivin as a marker for diagnosis of urinary bladder . MATERIAL S AND METHODS We examined urinary survivin concentration in 28 healthy individuals , 46 positive controls and 117 cases of histologically proven TCC prior to transurethral resection  , using ELISA , and compared values with findings for urinary cytology . RESULTS Survivin was found to be significantly higher in the cancer group ( P<0.05 ) . A cut off value of 17.7 pg/ml was proposed , with an approximate sensitivity of 82.9 % and specificity of 81.1 % ( P<0.0001 ) , whereas urine cytology had a sensitivity of 66.7 % and a specificity of 96.0 % . CONCLUSIONS Urinary survivin can be used as a non-invasive diagnostic biomarker for TCC bladder , both for primary and recurrent disease Most bladder cancer ( BC ) patients need life-long , invasive and expensive monitoring and treatment , making it a serious burden on the health system . Thus , there is a pressing need for an accurate test to assist diagnosis and surveillance of BC as an alternative to cystoscopy . Mutations in human TERT , FGFR3 , PIK3CA , and RAS genes have been proposed as potential molecular markers in bladder tumor . Their concomitant presence in urine sample s has not been fully explored . We investigated a panel of mutations in DNA from exfoliated urinary cells of 255 BC patients at diagnosis . Forty-one mutations in TERT , FGFR3 , PIK3CA , and RAS were analyzed by SNaPshot assay in relation to clinical outcome . In 81 of these patients under surveillance , the same set of mutations was screened in additional 324 sample s prospect ively collected . The most common mutations detected in urine at diagnosis were in the TERT promoter . In non-invasive BC , these mutations were related to high risk and grade ( p<0.0001 ) as well as progression to muscle-invasive disease ( p=0.01 ) , whereas FGFR3 mutations were observed in low- grade BC ( p=0.02 ) and patients with recurrences ( p=0.05 ) . Stronger associations were observed for combined TERT and FGFR3 mutations and number of recurrences ( OR : 4.54 95 % CI : 1.23 - 16.79 , p=0.02 ) . Analyses of the area under the curve for combinations of mutations detected at diagnosis and follow-up showed an accuracy of prediction of recurrence of 0.80 ( 95 % CI : 0.71 - 0.89 ) . Mutations in urine of BC patients may represent reliable biomarkers . In particular , TERT and FGFR3 mutations have a good accuracy of recurrence prediction PURPOSE Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine sample s. In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIAL S AND METHODS We performed a case-control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( IL-8 , MMP-9 and 10 , PAI-1 , VEGF , ANG , CA9 and APOE ) was assessed by enzyme-linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0.88 ( 95 % CI 0.84 - 0.93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine sample s and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays Purpose Recently , a proteomic study of sera from patients with bladder cancer identified S100A8 and S100A9 as tumor-associated proteins . The present cross-sectional study investigates whether calprotectin , the heterodimer of S100A8/S100A9 may serve as a urinary biomarker for the detection of urothelial bladder cancer . Methods  Urinary calprotectin concentrations were assessed in a population of 181 subjects including 46 cases of bladder cancer . 41 cases of renal cell cancer , 54 cases of prostate cancer , and 40 healthy subjects served as control .  Acute kidney injury , urinary tract infection , previous BCG-treatment and secondary transurethral resection of the bladder tumor were defined as exclusion criteria . Assessment was performed by enzyme-linked immunosorbent assay and immunohistochemistry detecting calprotectin . Results Median calprotectin concentrations ( ng/ml ) were significantly higher in patients with bladder cancer than in healthy controls ( 522.3 vs. 51.0 , p < 0.001 ) , renal cell cancer ( 90.4 , p < 0.001 ) , and prostate cancer ( 71.8 , p < 0.001 ) . In urothelial carcinoma prominent immunostaining occurred in a subset of tumor cells and in infiltrating myeloid cells . Receiver operating characteristic analysis provided an area under the curve of 0.88 for the differentiation of bladder cancer and healthy control . A cut-off value of 140 ng/ml ( determined by Youden ’s index ) result ed in sensitivity and specificity values of 80.4 and 92.5 % . Low grade tumors were associated with significantly lower calprotectin concentrations than high grade tumors ( 351.9 vs. 1635.2 ng/ml , p = 0.004 ) . Conclusions Urothelial malignancies are associated with highly increased concentrations of calprotecin in the urine . In absence of renal failure and pyuria , calprotectin constitutes a promising biomarker for the detection of bladder cancer OBJECTIVE To assess the diagnostic and prognostic performance of a noninvasive FGFR3 mutation analysis . After transurethral resection ( TUR ) of noninvasive bladder transitional cell carcinoma ( B-TCC ) , recurrence occurs in 70 % of patients , thus justifying cystoscopic surveillance . MATERIAL S AND METHODS A prospect i ve multic 
    Output:
    
Multi-target biomarker panels had a better diagnostic accuracy compared to single biomarker targets .
Urinary cytology with urinary biomarkers improved the diagnostic ability of the biomarker .
The sensitivity and specificity of biomarkers were higher for primary diagnosis compared to patients in the surveillance setting .
Few biomarkers achieve a high sensitivity and negative predictive value .