Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

Budgetary Impact of Including the Urinary Genomic Marker Cxbladder Detect in the Evaluation of Microhematuria Patients.

INTRODUCTION: Current AUA guidelines mandate a risk-stratified approach for the evaluation of microhematuria. Urine genomic tests with high negative predictive value could further reduce unnecessary diagnostic testing and morbidity, but the economic impact is unknown. This study modeled the financial impact of Cxbladder Detect on microhematuria evaluations. METHODS: A decision tree analysis was constructed by Coreva Scientific comparing 1-year costs of the standard microhematuria evaluation using the AUA guidelines vs an algorithm incorporating Cxbladder Detect. Cxbladder Detect-positive patients had cystoscopy and imaging, whereas patients with negative tests were reevaluated in 6 months. Patients with positive diagnostic testing underwent cystoscopy, and positive cystoscopies led to transurethral resection of bladder tumor. Test performance was based on published literature, and costs were based on Medicare allowable fees. RESULTS: Using the decision tree model, the average savings of using Cxbladder Detect was $559 compared with the standard of care, with an average reduction of 0.38 procedures per patient. Probabilistic analysis showed statistical significance with a median reduction in the total cost of $498 per patient (95% CrI [-1356, -2]) and a significant median reduction in diagnostic procedures per patient of 0.36 (95% CrI [-0.52, -0.16]) without impact on the number of cancers diagnosed. CONCLUSIONS: This model-based study demonstrates the potential economic value of using a Cxbladder-driven protocol for microhematuria evaluations.

Bladder EpiCheck urine test in the follow-up of NMIBC: a cost analysis.

PURPOSE: In the Netherlands yearly more than 5000 patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). With a specificity of 88.0% and a negative predictive value (NPV) for high grade NMIBC of 99.3%, the Bladder EpiCheck (BE) urine test may be used in NMIBC to reduce the burden of follow-up cystoscopies. METHODS: In this study a cost analysis of the BE follow-up strategy in the Dutch healthcare system was performed. In half of the follow-up appointments, BE was used as a rule-in for cystoscopy. In addition, the possible delay in recurrence detection was estimated. A cost calculation tool was developed using Microsoft Excel. RESULTS: The BE strategy results in an estimated cost reduction of 8%, 4% and 9% in low, intermediate and high risk patients, respectively. In the Netherlands this may result in a cost reduction of approximately 1.6 million euro per year. The estimated delay in the detection of recurrent disease would be 3.9, 1.7 and 1.3 months in low, intermediate and high risk NMIBC patients respectively. CONCLUSION: To conclude, the BE can be used to reduce the costs of NMIBC follow-up, with a small delay in diagnosis of recurrent disease.

Assessment of Xpert Bladder Cancer Monitor test performance for the detection of recurrence during non-muscle invasive bladder cancer follow-up.

PURPOSE: To assess the performance of the Xpert Bladder Cancer (BC) Monitor during the follow-up of patients with non-muscle invasive bladder cancer (NMIBC). METHODS: Patients with previously diagnosed NMIBC and followed up in clinical practice settings in two French urology departments between September 2017 and July 2019 were consecutively enrolled in this prospective observational study. Patients with a positive cystoscopy or computed tomography urogram underwent subsequent transurethral resection of the bladder, and/or biopsy, and the specimens were pathologically assessed. Cytology and Xpert BC Monitor tests were performed on urine samples. Xpert BC Monitor performance was assessed versus cystoscopy for disease-negative patients or versus histology for disease-positive patients, and was compared to that of cytology. RESULTS: Overall, 500 patients with a median age of 70.0 years were included. NMIBC recurrence was diagnosed in 44 cases (8.8%). Overall sensitivity, specificity, and negative predictive values (NPVs) were 72.7% (32/44), 73.7% (330/448) and 96.5% (330/342) for the Xpert BC Monitor, and 7.7% (2/26), 97.8% (310/317) and 92.8% (310/334) for cytology, respectively. The Xpert BC Monitor detected 92.3% (12/13) of the high-grade tumours and ruled out their presence in 99.7% (330/331) of cases. Analysis of the areas under the receiver operating characteristic curves demonstrated the superior performance of the Xpert BC Monitor over that of cytology. CONCLUSION: Xpert BC Monitor performance was superior to that of cytology in the follow-up of NMIBC. The exclusion of aggressive tumours with a very high NPV (99.7%) supports the use of this urinary test in daily practice.

Prospective assessment of two-gene urinary test with multiparametric magnetic resonance imaging of the prostate for men undergoing primary prostate biopsy.

PURPOSE: To evaluate the diagnostic accuracy of SelectMDx and its association with multiparametric magnetic resonance (mpMRI) in predicting prostate cancer (PCa) and clinically significant PCa (csPCa) on prostate biopsies among men scheduled for initial prostate biopsy. METHODS: In this single-center prospective study, 52 men scheduled for initial prostate biopsy, based on elevated total PSA level (> 3 ng/ml) or abnormal digital rectal examination, were consecutively included. All subjects underwent SelectMDx, PSA determination and mpMRI. RESULTS: SelectMDx score was positive in 94.1 and 100% of PCa and csPCa, respectively, and in only 8.6% of negative cases at biopsy. The probability for a csPCa at the SelectMDx score was significantly (p = 0.002) higher in csPCa (median value 52.0%) than in all PCa (median value 30.0%). SelectMDx showed slightly lower sensitivity (94.1 versus 100.0%) but higher specificity (91.4%) than total PSA (17.1%), and the same sensitivity but higher specificity than mpMRI (80.0%) in predicting PCa at biopsy. The association of SelectMDx plus mpMRI rather than PSA density (PSAD) plus mpMRI showed higher specificity (both 91.4%) compared to the association of PSA plus mpMRI (85.7%). In terms of csPCa predictive value, SelectMDx showed higher specificity (73.3%) than PSA (13.3%) and mpMRI (64.4%); as for the association of SelectMDx plus mpMRI (75.6%) versus PSA plus mpMRI (68.9%), the association of PSAD plus mpMRI showed the highest specificity (80.0%). CONCLUSION: Our results of SelectMDx can be confirmed as significant but their impact on clinical practice together with a cost-effectiveness evaluation should be investigated in a larger prospective multicenter analysis.

Stochastic microsensors for the assessment of DNA damage in cancer.

Three stochastic microsensors based on graphite powder modified with three different oleamides: N-(2-piperidin-1-ylethyl)oleamide, N-(3,4-dihydroxyphenethyl)oleamide and N-(2-morpholinoethyl)oleamide, were designed, characterized, and used to assess DNA damage in cancer by assaying two biomarkers namely 8-nitroguanine and 8-hydroxy-2'-deoxyguanosine. The two biomarkers were determined from urine and whole blood samples. The characterization of the microsensors was done at two pHs 7.40 and 3.00. The best microsensor for the simultaneous determination of biomarkers in whole blood and urine samples was the one based on the graphite paste modified with N-(3,4-dihydroxyphenethyl)oleamide. The results indicated that the proposed microsensors can be reliably used for pattern recognition and quantitative determination of 8-nitroguanine and 8-hydroxy-2'-deoxyguanosine in whole blood and urine, and accordingly, for the assessment of DNA damage in cancer patients.

Urine as a biological modality for colorectal cancer detection.

Introduction: The increasing incidence of colorectal cancer (CRC) in young adults warrants early and preferably noninvasive diagnostic modalities. Although the current stool-based assays have had good performance indicators for CRC detection, the overall poor uptake remains a challenging issue. However, alternative blood and urine markers are emerging.Areas covered: This paper discusses the various urinary biomarkers available for the detection of CRC. The more commonly encountered drawbacks are the small number of studies and the size of the study population. We discuss the role of microRNA and ProstaglandinE2 in CRC detection. The emergence of new, low-cost technologies, specifically in the detection of volatile organic compounds (VOCs), presents a promising future. We postulate possible mechanisms for the origin of these VOCs in urine and their role in carcinogenesis.Expert opinion: Urinary biomarkers provide an alternative option to the stool-based screening tests. MicroRNA and ProstaglandinE2 have shown utility in CRC detection. Evidence so far suggests that VOCs could also be a potential biomarker for the detection of CRC. In addition to its interaction within the colon lumen, this altered 'VOC signature' might also play a role in carcinogenesis. Low-cost technology may enable such diagnostic methods to be utilized at the point of care.

Assessment of clinical performance of an ultrasensitive nanowire assay for detecting human papillomavirus DNA in urine.

OBJECTIVE: To evaluate whether HPV DNA in urine has potential advantages as an alternative biomarker for HPV-based cervical cancer screening. METHODS: Among patients with Cobas HPV test results, a total of 67 HPV-positive (n = 42) and -negative (n = 25) women who agreed to participate in this study were willing to provide paired cervical and urine samples, and we observed concordance between sample types from each patient in identifying HPV genotypes using the nanowire assay. RESULTS: We detected high-risk strains of HPV DNA in unprocessed urine specimens using polyethyleneimine-conjugated nanowires (PEI-NWs). Concordance for high-risk HPV (hrHPV) between paired urine and cervical samples was 90.4% (κ = 0.90; 95% CI: 0.80-100.00). The virological sensitivity and specificity for detection of HPV DNA from a small urine sample (200 µL) were 81.3% (κ = 0.83; 95% CI: 62.1-100.0) and 98.0% (κ = 0.83; 95% CI: 94.2-100.0) for HPV16 group, 100.0% (κ = 0.65; 95% CI: 100.0-100.0) and 95.3% (κ = 0.65; 95% CI: 90.1-100.0) for HPV18 group, and 96.4% (κ = 0.97; 95% CI: 89.6-100.0) and 100.0% (κ = 0.97; 95% CI: 100.0-100.0) for other hrHPV group, respectively. CONCLUSIONS: The nanowire assay demonstrated excellent ability to identify HPV DNA from urine specimens. We observed an excellent agreement in the detection of high-risk HPV between paired urine and cervical samples, even with small urine sample volume.

Prognostic urinary miRNAs for the assessment of small renal masses.

BACKGROUND: Renal cell carcinoma (RCC) is often detected incidentally as a small renal mass (SRM; pT1a, ≤4 cm). It is clinically challenging to predict progression in patients with SRMs. This is largely due to the recent recognition of clinically progressive and non-progressive RCC-SRMs. It is critical to accurately stratify SRM patients according to risk to avoid unnecessary treatment. This is especially significant for elderly and infirm patients, where the risk of surgery outweighs mortality from SRMs. METHODS: We employed a qRT-PCR array-based approach and targeted qRT-PCR to identify and validate early, non-invasive diagnostic and prognostic biomarkers of RCC-SRMs. In total, we evaluated eighty urine samples, including 30 renal oncocytoma (≤4 cm) cases, 26 progressive and 24 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases. RESULTS: We identified nine urinary miRNAs which displayed significantly elevated expression in ccRCC-SRMs (pT1a; ≤4 cm) relative to renal oncocytoma (≤4 cm). Additionally, miR-328-3p displayed significantly down-regulated expression in progressive relative to non-progressive ccRCC-SRMs. Patients with elevated miR-328-3p expression had significantly longer overall survival (HR = 0.29, 95% CI = 0.08-1.03, p = 0.042) compared to patients with low miR-328-3p expression. We also found no significant association between miR-328-3p expression levels and gender, age, laterality, tumor size, or grade, suggesting that miR-328-3p is an independent prognostic biomarker. CONCLUSIONS: Our in-depth miRNA profiling approach identified novel biomarkers for early-stage ccRCC-SRMs. Pretreatment characterization of urinary miRNAs may provide insight into early RCC progression and could potentially aid clinical decision-making, improving patient management and reducing overtreatment.

Urinary peptide panel for prognostic assessment of bladder cancer relapse.

Non-invasive tools stratifying bladder cancer (BC) patients according to the risk of relapse are urgently needed to guide clinical intervention. As a follow-up to the previously published study on CE-MS-based urinary biomarkers for BC detection and recurrence monitoring, we expanded the investigation towards BC patients with longitudinal data. Profiling datasets of BC patients with follow-up information regarding the relapse status were investigated. The peptidomics dataset (n = 98) was split into training and test set. Cox regression was utilized for feature selection in the training set. Investigation of the entire training set at the single peptide level revealed 36 peptides being strong independent prognostic markers of disease relapse. Those features were further integrated into a Random Forest-based model evaluating the risk of relapse for BC patients. Performance of the model was assessed in the test cohort, showing high significance in BC relapse prognosis [HR = 5.76, p-value = 0.0001, c-index = 0.64]. Urinary peptide profiles integrated into a prognostic model allow for quantitative risk assessment of BC relapse highlighting the need for its incorporation in prospective studies to establish its value in the clinical management of BC.

Patients choose certainty over burden in bladder cancer surveillance.

BACKGROUND: Due to the high risk of recurrence of non-muscle invasive bladder cancer, all patients undergo regular cystoscopic surveillance for early detection. As cystoscopy is invasive, costly and increases the burden of the disease considerably, there is significant ongoing research and development into non-invasive urinary biomarker substitutes. This study aims to assess the level of sensitivity required before patients accept a new urinary biomarker. METHODS: We studied the preferences for a hypothetical diagnostic urinary biomarker and compared this to usual care (cystoscopy) at different levels of sensitivity among 437 patients with bladder cancer (354 men and 83 women) from the UK Bladder Cancer Prognosis Programme. A standard gamble approach was used to estimate the minimally acceptable sensitivity (MAS) of the new biomarker. Additionally, non-parametric statistical analyses were performed to investigate the association between surveillance preference and various patient characteristics. RESULTS: Almost half of patients (183, 43%) would not replace cystoscopy with a urinary biomarker unless it was 100% sensitive. The median MAS was 99.9999%, and nearly 85% of patients demanded a sensitivity of at least 99% before preferring a urinary biomarker test over cystoscopy. These results were consistent across all patient characteristics and demographic categories. CONCLUSIONS: Our results indicate that patients demand urinary biomarkers as sensitive as cystoscopy before they would be willing to forego cystoscopy for bladder cancer surveillance.

Assessment of microsatellite instability for screening bladder cancer in high-risk population.

AIMS: This study aims to determine the diagnostic efficacy of microsatellite markers for screening bladder cancer in population at high risk. MATERIALS AND METHODS: A population of 200 people was screened for bladder cancer using a set of microsatellite markers. Urine samples were obtained from four different types of population groups - Group 1 (healthy population group), Group 2 (current smokers with a smoking history of more than 10 years), Group 3 (bladder cancer group), and Group 4 (bladder cancer group who were former smokers with a history of more than 10 years). Polymerase chain reaction (PCR) was performed to amplify microsatellite sequences at D9S63, D9S156, and D9S283. PCR products were separated on 1.8% agarose gel and were scanned using ultraviolet transilluminator. RESULTS: In Group 2 (high-risk population group, mainly current smokers with a history of more than 10 years), microsatellite alterations were found in 36 out of 50 people. We observed microsatellite alterations in 38 out of 50 people in Group 3 (bladder cancer group) and in 39 out of 50 people in Group 4 (bladder cancer group, mainly former smokers with a history of more than 10 years). The sensitivity of this test in Group 2, Group 3, and Group 4 was found to be 72%, 76% and 78%, respectively. The specificity of this test in each group was found to be 90%. CONCLUSION: Using these set of microsatellite markers, medium sensitivity and high specificity were reported for this test. The current findings suggest that a set of microsatellite markers (D9S63, D9S156, and D9S283) can be used to detect bladder cancer in high-risk population.

The role of prostate cancer antigen 3 (PCA3) in prostate cancer detection.

INTRODUCTION: The prostate cancer antigen 3 (PCA3) score has been the first urine assay to obtain the Food and Drug Administration approval for guiding decisions regarding additional biopsies. Different aspects of this urinary assay (diagnostic performance, prognostic value, cost/benefit balance, integration with other molecular and imaging modalities) have now been well evaluated. Areas covered: This expert review will summarize current achievements and future perspectives provided by this urine biomarker. Expert commentary: The clinical benefit of the PCA3 score, in addition to the other established factors has been demonstrated before regarding biopsy decision making in men with persistent risk of prostate cancer. Its potential prognostic value also suggests its usefulness in selecting low risk patients for active surveillance protocols, however future daily-practice changing studies are needed. Economics assessment and additional value compared with other biomolecular and imaging modalities are still under investigation.

Cost-Effectiveness of Urinary Biomarker Panel in Prostate Cancer Risk Assessment.

PURPOSE: SelectMDx (MDxHealth®) is a panel of urinary biomarkers used in conjunction with traditional risk factors to individualize risk prediction for clinically significant prostate cancer. In this study we sought to characterize the effectiveness of SelectMDx in a population of American men with elevated prostate specific antigen. MATERIALS AND METHODS: We developed a Markov decision analytical model to simulate the chain of events and downstream outcomes associated with ultrasound guided prostate biopsy and a strategy in which the biomarker panel is implemented prior to biopsy. The primary outcome was health outcomes, measured in QALYs (quality-adjusted life years). The secondary outcome was health care costs from the Medicare payer perspective. Multiple 1-way sensitivity analyses were performed to characterize model robustness. RESULTS: The expected mean QALYs per patient under the current standard was 10.796 at a cost of $11,060 during an 18-year horizon. Incorporating the urinary biomarker panel resulted in an expected mean of 10.841 QALYs per patient and a mean cost of $9,366, representing an average of 0.045 QALYs gained at a cost savings of $1,694 per patient. When extrapolating these data to a conservative estimate of 311,879 men per year undergoing biopsy, one would expect that the biomarker panel would result in an incremental 14,035 QALYs gained at a cost savings of $528,323,026 in each yearly cohort. The biomarker panel strategy dominated the current standard across a wide range of sensitivity analyses. CONCLUSIONS: Routine use of the SelectMDx urinary biomarker panel to guide biopsy decision making improved health outcomes and lowered costs in American men at risk for prostate cancer. This strategy may optimize the value of prostate cancer risk assessment in an era of increasing financial accountability.

Preliminary Evaluation of the Diagnostic Usefulness of Uroplakin 2 with an Assessment of the Antioxidant Potential of Patients with Bladder Cancer.

BACKGROUND: Urothelial carcinoma is the most common type of bladder cancer (BC). It makes up more than 90% of all bladder cancers. Uroplakins are tissue-specific, glycoproteins, playing a role in the construction and function of urothelium. The emergence of uroplakins in the urine and/or plasma may be of potential importance in the early detection of BC. In our study, the diagnostic value of plasma and urine uroplakin 2 (UP2) concentration in bladder cancer was investigated, with an assessment of the antioxidant potential of BC patients. The correlation between UP2, total antioxidant capacity (TAC), and concentration of glutathione (GSH) was also examined. MATERIALS AND METHODS: This study included 61 BC patients and 33 healthy controls. UP2 concentration was estimated by the immunoenzymatic method (ELISA). TAC and GSH were determined in spectrophotometrically methods. RESULTS: UP2 concentration in BC patients was significantly higher (p≤0.001) both in plasma and in urine compared to the control groups (C). TAC concentration in urine (p≤0.001) and GSH concentration in plasma (p=0.047) were significantly lower in BC group compared to the C group. The high specificity and sensitivity for UPK2 in plasma (76%, 80%, respectively) and urine (88%, 84%, respectively) were observed. Positive correlations were observed between concentration of UP2 in plasma and TAC concentration in urine and between UP2 concentration in plasma and GSH concentration in the same material. CONCLUSION: The study showed the early diagnostic value of urine and plasma UP2 in BC. There was a decrease in UP2 concentration in the urine of patients with the development of BC. The decrease of antioxidant systems (TAC, GSH) indicates their relationship with the BC process. Based on the obtained results, it is justified to continue the study in a larger group of patients with BC.

Cytokeratin 20 immunocytochemistry on urine sediments: A potential low-cost adjunct to cytology in the diagnosis of low-grade urothelial carcinoma.

BACKGROUND: Urine cytology is the corner-stone for the diagnosis of urothelial neoplasia; however, a substantial proportion of low-grade carcinomas are reported as inconclusive owing to scant cellularity and subtle cytological features. Biomarkers applied on urine sediment smears of such patients are likely to be clinically relevant. Access to Food and Drug Administration approved urinary biomarkers in resource limited setting is poor. Detection of cytokeratin 20 (CK20) in urine sediments, although still a research tool, is a promising marker as immunocytochemistry is performed regularly in several Indian laboratories. OBJECTIVE: We tested the clinical utility of CK20 immunocytochemistry as a potential low-cost adjunct to urine cytology in diagnosis of low-grade urothelial carcinoma. One hundred and fifty fresh, voided urine specimens from 42 cases of biopsy proven urothelial neoplasia (14 high grade, 28 combined low-grade [n=26]) and low malignant potential [n=2]), and 20 non-neoplastic lesions were included in the study sample. RESULTS: Confident diagnosis of malignancy was possible in five (17.8%) low-grade malignancies. Thirteen of 16 (81.3%) low-grade malignancies with inconclusive cytology showed positive CK20 expression. This reduced the proportion of low-grade cases with inconclusive cytology from 57.1% to 10.7% (P=.021). In addition, we could correctly classify one case of bladder lithiasis with false positive urine cytology. Discrepant CK20 staining (positive) was seen in one patient with acute cystitis. CONCLUSIONS: CK20 expression in non-umbrella cells is a robust marker of urinary bladder carcinoma. It has potential clinical utility for identification of low-grade urothelial malignancy with inconclusive cytological diagnosis.

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

IMPORTANCE: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. OBJECTIVE: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. INTERVENTIONS/EXPOSURES: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. MAIN OUTCOMES AND MEASURES: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. RESULTS: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. CONCLUSIONS AND RELEVANCE: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.

Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.

OBJECTIVE: To assess the cost-effectiveness of a new urinary biomarker-based risk score (SelectMDx; MDxHealth, Inc., Irvine, CA, USA) to identify patients for transrectal ultrasonography (TRUS)-guided biopsy and to compare this with the current standard of care (SOC), using only prostate-specific antigen (PSA) to select for TRUS-guided biopsy. MATERIALS AND METHODS: A decision tree and Markov model were developed to evaluate the cost-effectiveness of SelectMDx as a reflex test vs SOC in men with a PSA level of >3 ng/mL. Transition probabilities, utilities and costs were derived from the literature and expert opinion. Cost-effectiveness was expressed in quality-adjusted life years (QALYs) and healthcare costs of both diagnostic strategies, simulating the course of patients over a time horizon representing 18 years. Deterministic sensitivity analyses were performed to address uncertainty in assumptions. RESULTS: A diagnostic strategy including SelectMDx with a cut-off chosen at a sensitivity of 95.7% for high-grade prostate cancer resulted in savings of €128 and a gain of 0.025 QALY per patient compared to the SOC strategy. The sensitivity analyses showed that the disutility assigned to active surveillance had a high impact on the QALYs gained and the disutility attributed to TRUS-guided biopsy only slightly influenced the outcome of the model. CONCLUSION: Based on the currently available evidence, the reduction of over diagnosis and overtreatment due to the use of the SelectMDx test in men with PSA levels of >3 ng/mL may lead to a reduction in total costs per patient and a gain in QALYs.

High-speed biosensing strategy for non-invasive profiling of multiple cancer fusion genes in urine.

Aberrant chromosal rearrangements, such as the multiple variants of TMPRSS2:ERG fusion gene mutations in prostate cancer (PCa), are promising diagnostic and prognostic biomarkers due to their specific expression in cancerous tissue only. Additionally, TMPRSS2:ERG variants are detectable in urine to provide non-invasive PCa diagnostic sampling as an attractive surrogate for needle biopsies. Therefore, rapid and simplistic assays for identifying multiple urinary TMPRSS2:ERG variants are potentially useful to aid in early cancer detection, immediate patient risk stratification, and prompt personalized treatment. However, current strategies for simultaneous detection of multiple gene fusions are limited by tedious and prolonged experimental protocols, thus limiting their use as rapid clinical screening tools. Herein, we report a simple and rapid gene fusion strategy which expliots the specificity of DNA ligase and the speed of isothermal amplification to simultaneously detect multiple fusion gene RNAs within a short sample-to-answer timeframe of 60min. The method has a low detection limit of 2 amol (1000 copies), and was successfully applied for non-invasive fusion gene profiling in patient urine samples with subsequent validation by a PCR-based gold standard approach.