Aim This narrative review aims to describe established and emerging urinary biomarkers in the diagnosis and surveillance of non-muscle invasive bladder cancer. It provides a comprehensive account of classical, FDA-approved protein biomarkers and discusses their limitations. Further, we discuss the role that epigenetic, genetic, and exosomal markers can play to enhance sensitivity and specificity of the available tests. Background The initial diagnosis and surveillance of bladder cancer involves a combination of cystoscopy, upper urinary tract imaging, and urine cytology. Despite high specificity, cytology is limited by low sensitivity. There are currently 6 urinary assays approved by the FDA to enhance diagnosis and surveillance of bladder cancer. While these have improved diagnosis and surveillance when combined with cytology, these tests are still not sufficiently sensitive and false positives often occur in benign conditions which result in inflammation of the urinary tract. Advancements in laboratory techniques have produced significant advancements in epigenetic and genetic markers, as well as extracellular vesicles, with DNA- and RNA-based markers dominating the research in this area in recent years. Methods We identified relevant published data, using the PubMed/ Medline search engines as well as Google Scholar. We performed an online search using the terms “bladder cancer”, “non-muscle invasive bladder cancer” in combination with “urine biomarkers” and limited articles in English published up to February 2020. This review consolidated on all available narrative and systematic reviews published in the 5 years in this field, while also reviewing the original data of each clinical trial or observational study which led to the development of the biomarkers. Conclusion The development of laboratory techniques and understanding urine-based biomarkers in BC has fuelled the use of noninvasive liquid-based biomarkers to complement urine cytology. Nonetheless, none are sufficiently effective when used in isolation, and cytology remains the gold standard in many practices. Future efforts will be focused on using these markers in combination as a predictive signature, and moving on to validating them for use in everyday clinical practice.

/pdf/urinary-biomarkers-in-bladder-cancer-a-review-of-the-current-3pk254bst3.pdf

Urinary biomarkers in bladder cancer: A review of the current landscape and future directions.

Context Surgical margin status and preservation of the neurovascular bundles (NVB) are important prognostic indicators for oncological and functional outcomes of patients undergoing radical prostatectomy (RP). Intraoperative frozen section (IFS) has been used to evaluate margin status during surgery with the intention of reducing positive surgical margins (PSMs) and guiding safe preservation of the NVBs during RP, but its value is controversial. Objective To evaluate current literature comparing outcomes of men undergoing RP with IFS versus RP without IFS. Evidence acquisition Medline, Embase, and Cochrane Library searches for all relevant publications (PROSPERO ID CRD42019125940), including comparative studies reporting on men undergoing RP with and without IFS, were performed. Outcomes of interest were surgical margin status, long-term oncological outcomes, NVB status, and erectile function (EF) recovery. Data were narratively synthesised in light of methodological and clinical heterogeneity of included studies. Evidence synthesis After screening 834 publications, 10 nonrandomised retrospective comparative studies (including 16 897 patients) were retrieved. The technique of IFS differed considerably between studies. Eight studies reported a reduction in PSM rates (–1.4% to –14.5%) with IFS, though two studies report higher PSM rates (+0.4% and +10%) with IFS. Three studies reported on long-term oncological outcomes, and no difference was seen with IFS. Three studies reported on the performance of IFS systematically at the posterolateral margin of the prostate (neurovascular structure-adjacent frozen-section examination [NeuroSAFE] technique). In all these three studies, either NVB preservation or EF recovery was improved. All studies were deemed to be at either a serious or a moderate risk of bias. Conclusions No randomised controlled trials were identified, and significant heterogeneity existed with regard to many features of the studies included. Within the limitations of this review, the evidence suggests that IFS during RP can facilitate a modest reduction in PSM rates. There is evidence that IFS performed systematically at the posterolateral margin of the prostate can facilitate more NVB preservation. However, in the main, the lack of prospective, randomised, standardised research with long-term oncological and functional outcomes precludes strong conclusions and highlights the need for such studies. Patient summary The data of this review suggest that frozen section sampling of the prostate (ie, whilst the patient is still asleep) during prostate cancer surgery can reduce the likelihood of cancer being detected at the edge of the removed prostate. It also finds that a type of frozen section analysis (neurovascular structure-adjacent frozen-section examination [NeuroSAFE] technique) can help allow the nerves around the prostate to be left intact safely during surgery. However, the studies in this review are very different from one another and generally at a high risk of errors. Therefore, comparisons and conclusions must be made carefully.

Intraoperative Frozen Section for Margin Evaluation During Radical Prostatectomy: A Systematic Review.

Background Follow-up recommendations for patients with nonmuscle invasive bladder cancer (NMIBC) are largely based upon expert opinion. A growing body of evidence suggests that current follow-up strategies for bladder cancer patients with low and intermediate risk represent overdiagnosis and may lead to overtreatment. The goal of this study is to explore the options of a noninvasive follow-up in patients with pTa G1-2/low-grade NMIBC. Methods The risks and options for a urine marker-guided, noninvasive follow-up of patients with pTa G1-2/low-grade NMIBC were defined and the study design for a prospective randomized trial (UroFollow) was developed based upon the current literature. Results The investigators postulated that follow-up of patients with pTa G1-2/low-grade NMIBC requires a high sensitivity of urinary tumor markers. However, data from prospective studies with prediagnostic urine samples are scarce, even for approved markers, and cross-sectional studies with symptomatic patients overestimate the sensitivity. So far, cell-based markers (e.g., uCyt+ and UroVysion) in urine appeared to have higher sensitivities and specificities in low-grade NMIBC than urine cytology and markers analyzing soluble tumor-associated antigens. Marker panels are more sensitive than single-marker approaches at the expense of a lower specificity. Given a prospective randomized comparison with a marker sensitivity of 80% compared to usual care with cystoscopy, the sample size calculation yielded that 62 to 185 patients under study per arm are needed depending on different recurrence rates. Conclusions Based upon these findings the UroFollow trial has been designed as a prospective randomized study comparing a noninvasive marker-based (UroVysion, NMP22, urine cytology, and ultrasound) follow-up with the current standard of care over a period of 3 years.

Toward noninvasive follow-up of low-risk bladder cancer - Rationale and concept of the UroFollow trial.

Bladder cancer is a common urological cancer with a high recurrence rate that requires long-term follow-up, and early detection positively affects prognosis. To date, the initial diagnosis and follow-up for bladder cancer rely on cystoscopy, which is an invasive and expensive procedure. Therefore, urinary markers for the detection of bladder cancer have attracted research attention for decades to reduce unnecessary cystoscopies. Urine, which is in continuous contact with bladder cancer, is considered a suitable fluid for providing tumor information. Urinary cytology is the only widely used urinary marker in clinical practice; however, it has poor sensitivity for low-grade tumors; indicating the need for novel urinary markers. Considerable research has been conducted on this topic over the years, resulting in a complex landscape with a wide range of urinary markers, including protein-, exfoliated cell-, RNA-, DNA-, and extracellular vesicle-based markers. Although some of these markers have been approved by the U.S. Food and Drug Administration and are commercially available, their use in clinical practice is limited. To facilitate clinical application, potential urinary markers must withstand prospective clinical trials and be easy for patients and clinicians to understand and utilize in a clinical context. This review provides a comprehensive overview of currently available and recently reported promising urinary markers for bladder cancer. Additionally, the challenges and the prospects of these urinary markers for clinical implementation in bladder cancer treatment were discussed.

Urinary markers for bladder cancer diagnosis: A review of current status and future challenges.

Background To evaluate the clinical effectiveness of a novel CellDetect staining technique, compared with fluorescent in situ hybridization (FISH), and urine cytology, in the diagnosis of urothelial carcinoma (UC). Methods A total of 264 patients with suspicious UC were enrolled in this study. All tissue specimens were collected by biopsy or surgery. Urine specimen was obtained for examinations prior to the surgical procedure. CellDetect staining was carried out with CellDetect kit, and FISH was performed with UroVysion detection kit, according to the manufacturer's instructions. For urine cytology, all specimens were centrifuged using the cytospin method, and the slides were stained by standard Papanicolaou stain. Results In this study, there were 128 cases of UC and 136 cases of non-UC, with no significant difference in gender and age between the two groups. Results for sensitivity of CellDetect, FISH, and urine cytology were 82.8%, 83.6%, and 39.8%, respectively. The specificity of the three techniques were 88.2%, 90.4%, and 86.0%, respectively. The sensitivity of CellDetect and FISH are significantly superior compared to the conventional urine cytology; however, there was no significant difference in specificity among three staining techniques. In addition, the sensitivity of CellDetect in lower urinary tract UC, upper urinary tract UC, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC) were 83.3%, 81.8%, 83.5%, and 72.0%, respectively. The screening ability of CellDetect has no correlation with tumor location and the tumor stage. The sensitivity of CellDetect in low-grade UC and high-grade UC were 51.6 and 92.8%. Thus, screening ability of CellDetect in high-grade UC is significantly superior compared to that in low-grade UC. Conclusions CellDetect and FISH show equal value in diagnosing UC, both are superior to conventional urine cytology. Compared to FISH, CellDetect is cost effective, easy to operate, with extensive clinical application value to monitor recurrence of UC, and to screen indetectable UC.

/pdf/diagnostic-value-comparison-of-celldetect-fluorescent-in-4d1d9pq37r.pdf

Diagnostic value comparison of CellDetect, fluorescent in situ hybridization (FISH), and cytology in urothelial carcinoma.

Background CellDetect is a unique histochemical stain enabling color and morphological discrimination between malignant and benign cells based on differences in metabolic signature. Objective The objective of the present study was to validate the performance of this assay in a controlled, blinded, multicenter study. Design, setting, and participants The study, conducted in nine hospitals, included patients with documented history of bladder cancer, monitored for urothelial carcinoma (UCC) or scheduled for bladder cancer surgery. Outcome measurements and statistical analysis Cystoscopy and/or biopsy were used as a reference standard to determine sensitivity and specificity. Smears were stained by CellDetect and interpreted by two cytologists blinded to the patient's final diagnosis. The findings were compared with those of standard urine cytology and BTA stat. Results and limitations Two hundred and seventeen voided urine specimens were included. Ninety-six (44%) were positive by histology and 121 (56%) were negative by either cystoscopy or histology. The overall sensitivity of CellDetect was 84%. Notably, the sensitivity for detecting low-grade nonmuscle-invasive bladder cancer tumors was greater than this of BTA stat (78% vs 54%) and more than two-fold higher compared with standard cytology (33%, p ≤ 0.05). The specificity was 84% in patients undergoing routine surveillance by cystoscopy. At a median follow-up of 9 mo, 21% of the patients with positive CellDetect and negative reference standard developed UCC, which was significantly higher compared with the 5% of the true negative cases. Limitations include the lack of instrumental urine samples and the lack of patients with nongenitourinary cancers in the study population. Conclusions This study validates the performance of CellDetect as a urine-based assay to identify UCC in patients with history of bladder cancer. The high sensitivity was maintained across all cancer grades and stages without compromising the assay specificity. Further studies are required to test whether this novel stain can be incorporated in routine bladder cancer surveillance as a noninvasive alternative to cystoscopy. Patient summary Surveillance of bladder cancer requires frequent invasive procedures. In the present study, we validate the ability of a novel biomarker to accurately identify early-stage tumors in urine specimens for the noninvasive monitoring of patients with history of bladder cancer.

A Novel Urine-Based Assay for Bladder Cancer Diagnosis: Multi-Institutional Validation Study

Pd19-09 performance of a novel urine-based biomarker for the monitoring of bladder cancer recurrence

CellDetect Histochemical Stain for the Monitoring of Urothelial Carcinoma in Clinical Setting

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A Novel Urine-Based Assay for Bladder Cancer Diagnosis: Multi-Institutional Validation Study

Pd19-09 performance of a novel urine-based biomarker for the monitoring of bladder cancer recurrence

CellDetect Histochemical Stain for the Monitoring of Urothelial Carcinoma in Clinical Setting