Evaluation of a New Survivin ELISA and UBC® Rapid for the Detection of Bladder Cancer in Urine

Gleichenhagen, Jan; Arndt, Christian; Casjens, Swaantje; Meinig, Carmen; Gerullis, Holger; Raiko, Irina; Brüning, Thomas; Ecke, Thorsten; Johnen, Georg

doi:10.3390/ijms19010226

Cited by 32 publications

(34 citation statements)

References 56 publications

(85 reference statements)

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“…The need for quantitative urinary markers like UBC ® Rapid Test had also been published before [11]. The results of this study are showing again high values for UBC ® Rapid Test especially for patients with high-grade bladder cancer [9,12,13,14]. Following from a previously published study with a high number of samples, the results of this study show that this test could be useful for combination in a diagnostic panel for patients of the high-risk group for bladder cancer.…”

Section: Discussionsupporting

confidence: 52%

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UBC® Rapid Test—A Urinary Point-of-Care (POC) Assay for Diagnosis of Bladder Cancer with a focus on Non-Muscle Invasive High-Grade Tumors: Results of a Multicenter-Study

Ecke

Weiss

Stephan

et al. 2018

IJMS

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Objectives: UBC® Rapid Test measures soluble fragments of cytokeratins 8 and 18 in urine. We present results of a multicenter study using an updated version of UBC® Rapid Test in bladder cancer patients, patients with urinary bladder cancer positive history, and healthy controls. Material and Methods: In total 530 urine samples have been included in this study. Clinical urine samples were used from 242 patients with tumors of the urinary bladder (134 non-muscle-invasive low-grade tumors (NMI-LG), 48 non-muscle-invasive high-grade tumors (NMI-HG), and 60 muscle-invasive high-grade tumors (MI-HG)), 62 patients with non-evidence of disease (NED), and 226 healthy controls. Urine samples were analyzed by the UBC® Rapid point-of-care (POC) assay and evaluated by Concile Omega 100 POC Reader. All statistical analyses have been performed using R version 3.2.3. Results: Elevated levels of UBC® Rapid Test in urine are higher in patients with bladder cancer in comparison to the control group (p < 0.001). The sensitivity for the whole bladder cancer cohort was 53.3% (positive predictive value (PPV) 90.2%, negative predictive value (NPV) 65.2%) and was 38.8% (PPV 78.8%, NPV 72.1%) for non-muscle-invasive low-grade bladder cancer; 75.0% (PPV 72.0%, NPV 94.7%) for non-muscle-invasive high-grade bladder cancer and 68.3% (PPV 74.6%, NPV 91.8%) for muscle-invasive high-grade bladder cancer. The specificity for the statistical calculations was 93.8%. The cut-off value (10 µg/L) was evaluated for the whole patient cohort. The area under the curve of the quantitative UBC® Rapid Test using the optimal threshold obtained by receiver operating characteristics (ROC) analysis was 0.774. Elevated values of UBC® Rapid Test in urine are higher in patients with high-grade bladder cancer in comparison to low-grade tumors and the healthy control group. Conclusions: UBC® Rapid Test has potential to be a clinically valuable urinary protein biomarker for detection of high-grade bladder cancer patients and could be added in the management of NMI-HG tumors. UBC® Rapid results generated in both study centers in the present multicenter study are very similar and reproducible. Furthermore UBC® Rapid Test is standardized and calibrated and thus independent of used batch of test as well as study site.

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Section: Discussionsupporting

confidence: 52%

“…Furthermore, it could also be interesting to include a combination of different tumor markers into BCa diagnostics. How to combine UBC ® Rapid with other markers has been shown by Gleichenhagen et al [13]. In this study a combination of UBC ® Rapid and survivin increased the sensitivity to 66% with a specificity of 95%.…”

Section: Discussionsupporting

confidence: 49%

UBC® Rapid Test—A Urinary Point-of-Care (POC) Assay for Diagnosis of Bladder Cancer with a focus on Non-Muscle Invasive High-Grade Tumors: Results of a Multicenter-Study

Ecke

Weiss

Stephan

et al. 2018

IJMS

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“…These cytokeratins are located in the cytoskeleton of epithelial cells and tend to be overexpressed in urothelial tumor types including bladder cancer ( 17 – 19 ). Based on this, several trials have been performed to investigate the efficacy of the UBC ® Rapid Test in the detection and follow-up of bladder cancer ( 20 – 22 ). However, differences in the design and enrollment of these studies have resulted in inconsistent conclusions, so its diagnostic accuracy remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic accuracy of the UBC� Rapid Test for bladder cancer: A meta‑analysis

Cui

Chen

et al. 2018

Oncol Lett

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Bladder cancer is one of the most common cancer types globally. The UBC® Rapid Test is a potential novel diagnostic method for bladder cancer, but studies into its accuracy have produced inconsistent results. Thus, the present meta-analysis was conducted in order to determine the overall accuracy of the UBC® Rapid Test in detecting bladder cancer. A comprehensive literature search was conducted using MEDLINE, Embase, Cochrane Library, Web of Science, Chinese WanFang and the China National Knowledge Infrastructure databases for relevant studies. Quality assessment of diagnostic accuracy studies 2 was used to assess the quality of each included study. The diagnostic accuracy of the UBC® Rapid Test was evaluated by pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and the area under the curve (AUC). In addition, Deeks' funnel plot was used to evaluate potential publication bias. Eight studies were included in the quantitative meta-analysis. The results were as follows: Sensitivity 0.59 [95% confidence interval (CI), 0.55–0.62], specificity 0.76 (95% CI, 0.72–0.80), PLR 2.55 (95% CI, 1.75–3.70), NLR 0.56 (95% CI, 0.46–0.67), DOR 4.88 (95% CI, 2.82–8.45) and AUC 0.70 (95% CI, 0.67–0.74). According to the present results, the UBC® rapid test is highly accurate in the diagnosis of bladder cancer, however, further studies with better-designed and larger samples are required in order to support the results of the present study.

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“…Survivin antibody was provided by the Department of Molecular Medicine at the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance in Bochum, Germany. A detailed description of recombinant survivin and antibody production as well as the analytical specificity of the survivin antibody can be found at Gleichenhagen et al [ 36 ]. We used this method for survivin in a regular immunohistochemistry procedure.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we are one of the first centers who evaluated this survivin antibody by immunohistochemistry. Reproducibility of the new survivin antibody as a component of an ELISA was investigated and published by Gleichenhagen et al [ 36 ]. The experiments for immunostaining for survivin have been performed and evaluated at University Hospital Charité Berlin (Germany).…”

Section: Methodsmentioning

confidence: 99%

Prognostic Role of Survivin and Macrophage Infiltration Quantified on Protein and mRNA Level in Molecular Subtypes Determined by RT-qPCR of KRT5, KRT20, and ERBB2 in Muscle-Invasive Bladder Cancer Treated by Adjuvant Chemotherapy

Ecke

Kiani

Schlomm

et al. 2020

IJMS

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Objectives: Bladder cancer is a heterogeneous malignancy. Therefore, it is difficult to find single predictive markers. Moreover, most studies focus on either the immunohistochemical or molecular assessment of tumor tissues by next-generation sequencing (NGS) or PCR, while a combination of immunohistochemistry (IHC) and PCR for tumor marker assessment might have the strongest impact to predict outcome and select optimal therapies in real-world application. We investigated the role of proliferation survivin/BIRC5 and macrophage infiltration (CD68, MAC387, CLEVER-1) on the basis of molecular subtypes of bladder cancer (KRT5, KRT20, ERBB2) to predict outcomes of adjuvant treated muscle-invasive bladder cancer patients with regard to progression-free survival (PFS) and disease-specific survival (DSS). Materials and Methods: We used tissue microarrays (TMA) from n = 50 patients (38 males, 12 female) with muscle-invasive bladder cancer. All patients had been treated with radical cystectomy followed by adjuvant triple chemotherapy. Median follow-up time was 60.5 months. CD68, CLEVER-1, MAC387, and survivin protein were detected by immunostaining and subsequent visual inspection. BIRC5, KRT5, KRT20, ERBB2, and CD68 mRNAs were detected by standardized RT-qPCR after tissue dot RNA extraction using a novel stamp technology. All these markers were evaluated in three different centers of excellence. Results: Nuclear staining rather than cytoplasmic staining of survivin predicted DSS as a single marker with high levels of survivin being associated with better PFS and DSS upon adjuvant chemotherapy (p = 0.0138 and p = 0.001, respectively). These results were validated by the quantitation of BIRC5 mRNA by PCR (p = 0.0004 and p = 0.0508, respectively). Interestingly, nuclear staining of survivin protein was positively associated with BIRC5 mRNA, while cytoplasmic staining was inversely related, indicating that the translocation of survivin protein into the nucleus occurred at a discrete, higher level of its mRNA. Combining survivin/BIRC5 levels based on molecular subtype being assessed by KRT20 expression improved the predictive value, with tumors having low survivin/BIRC5 and KRT20 mRNA levels having the best survival (75% vs. 20% vs. 10% 5-year DSS, p = 0.0005), and these values were independent of grading, node status, and tumor stage in multivariate analysis (p = 0.0167). Macrophage infiltration dominated in basal tumors and was inversely related with the luminal subtype marker gene expression. The presence of macrophages in survivin-positive or ERBB2-positive tumors was associated with worse DSS. Conclusions: For muscle-invasive bladder cancer patients, the proliferative activity as determined by the nuclear staining of survivin or RT-qPCR on the basis of molecular subtype characteristics outperforms single marker detections and single technology approaches. Infiltration by macrophages detected by IHC or PCR is associated with worse outcome in defined subsets of tumors. The limitations of this study are the retrospective nature and the limited number of patients. However, the number of molecular markers has been restricted and based on predefined assumptions, which resulted in the dissection of muscle-invasive disease into tumor–biological axes of high prognostic relevance, which warrant further investigation and validation.

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Evaluation of a New Survivin ELISA and UBC® Rapid for the Detection of Bladder Cancer in Urine

Cited by 32 publications

References 56 publications

UBC® Rapid Test—A Urinary Point-of-Care (POC) Assay for Diagnosis of Bladder Cancer with a focus on Non-Muscle Invasive High-Grade Tumors: Results of a Multicenter-Study

UBC® Rapid Test—A Urinary Point-of-Care (POC) Assay for Diagnosis of Bladder Cancer with a focus on Non-Muscle Invasive High-Grade Tumors: Results of a Multicenter-Study

Diagnostic accuracy of the UBC� Rapid Test for bladder cancer: A meta‑analysis

Prognostic Role of Survivin and Macrophage Infiltration Quantified on Protein and mRNA Level in Molecular Subtypes Determined by RT-qPCR of KRT5, KRT20, and ERBB2 in Muscle-Invasive Bladder Cancer Treated by Adjuvant Chemotherapy

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