Clinical utility of a non-invasive urine test for risk assessing patients with no obvious benign cause of hematuria: a physician-patient real world data analysis.

BACKGROUND: The non-invasive Cxbladder urine test system has demonstrated clinical utility in ruling out urothelial carcinoma (UC) in patients with asymptomatic microscopic hematuria (AMH), suggesting that the number of invasive diagnostic tests, including cystoscopy, used in this patient population may be reduced by Cxbladder testing prior to conducting a full urological work-up. The aim of this study was to demonstrate the enhanced clinical utility of communicating objective information on diagnostic decisions made by individual physicians on individual patients with AMH. METHODS: Three hundred ninety-six physician-patient decisions were generated from twelve participant physicians evaluating real world case notes from the same 33 patients presenting with AMH. Each physician reviewed and recommended diagnostic tests and procedures based on each patient's referral data and then re-evaluated their clinical recommendation following disclosure of the non-invasive Cxbladder urine test result. Changes assessed were the total number of requested diagnostic procedures and the number of invasive procedures, including cystoscopy, following addition of information from Cxbladder in the Triage and Triage and Detect modalities. RESULTS: Physicians made significant changes to their diagnostic behavior for patients with AMH when presented with Cxbladder test results, including a reduction in the number of total and invasive procedures including cystoscopy for individuals identified as having a low probability of UC. The intensity of investigation was targeted and increased, including use of total procedures and cystoscopy, for patients identified by Cxbladder tests as having a high probability of UC: urologists increased the level of investigation for both total procedures and invasive procedures. The outcome resulted in patients with a high risk of UC receiving appropriate guideline-recommended invasive diagnostic tests. Patients who tested negative were offered fewer and significantly less invasive procedures. This change in physician behavior results in an increased clinical and patient utility, lower risk of missed UC and invasive test-related harm incidents. CONCLUSIONS: This study demonstrated the potential for increased clinical resolution and significantly enhanced patient management, when physicians consider Cxbladder test results in their clinical evaluation. The change in physician behavior led to more appropriate diagnostic procedure selection and resource allocation to the benefit of both patients and healthcare systems.

A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria.

PURPOSE: We investigated whether the RNA assay uRNA® and its derivative Cxbladder® have greater sensitivity for the detection of bladder cancer than cytology, NMP22™ BladderChek™ and NMP22™ ELISA, and whether they are useful in risk stratification. MATERIALS AND METHODS: A total of 485 patients presenting with gross hematuria but without a history of urothelial cancer were recruited prospectively from 11 urology clinics in Australasia. Voided urine samples were obtained before cystoscopy. The sensitivity and specificity of the RNA tests were compared to cytology and the NMP22 assays using cystoscopy as the reference. The ability of Cxbladder to distinguish between low grade, stage Ta urothelial carcinoma and more advanced urothelial carcinoma was also determined. RESULTS: uRNA detected 41 of 66 urothelial carcinoma cases (62.1% sensitivity, 95% CI 49.3-73.8) compared with NMP22 ELISA (50.0%, 95% CI 37.4-62.6), BladderChek (37.9%, 95% CI 26.2-50.7) and cytology (56.1%, 95% CI 43.8-68.3). Cxbladder, which was developed on the study data, detected 82%, including 97% of the high grade tumors and 100% of tumors stage 1 or greater. The cutoffs for uRNA and Cxbladder were prespecified to give a specificity of 85%. The specificity of cytology was 94.5% (95% CI 91.9-96.5), NMP22 ELISA 88.0%, (95% CI 84.6-91.0) and BladderChek 96.4% (95% CI 94.2-98.0). Cxbladder distinguished between low grade Ta tumors and other detected urothelial carcinoma with a sensitivity of 91% and a specificity of 90%. CONCLUSIONS: uRNA and Cxbladder showed improved sensitivity for the detection of urothelial carcinoma compared to the NMP22 assays. Stratification with Cxbladder provides a potential method to prioritize patients for the management of waiting lists.

Differential trafficking of AMPA and NMDA receptors during long-term potentiation in awake adult animals.

Despite a wealth of evidence in vitro that AMPA receptors are inserted into the postsynaptic membrane during long-term potentiation (LTP), it remains unclear whether this occurs in vivo at physiological concentrations of receptors. To address the issue of whether native AMPA or NMDA receptors undergo such trafficking during LTP in the adult brain, we examined the synaptic and surface expression of glutamate receptor subunits during the early induction phase of LTP in the dentate gyrus of awake adult rats. Induction of LTP was accompanied by a rapid NMDA receptor-dependent increase in surface expression of glutamate receptor 1-3 (GluR1-3) subunits. However, in the postsynaptic density fraction only GluR1 accumulated. GluR2/3-containing AMPA receptors, in contrast, were targeted exclusively to extrasynaptic sites in a protein synthesis-dependent manner. NMDA receptor subunits exhibited a delayed accumulation, both at the membrane surface and in postsynaptic densities, that was dependent on protein synthesis. These data suggest that trafficking of native GluR1-containing AMPA receptors to synapses is important for early-phase LTP in awake adult animals, and that this increase is followed homeostatically by a protein synthesis-dependent trafficking of NMDA receptors.

Clinical Utility of Cxbladder for the Diagnosis of Urothelial Carcinoma.

INTRODUCTION: This study aimed to demonstrate the clinical utility of non-invasive multigene Cxbladder urine tests in reducing the overall number of diagnostic tests and invasive procedures used in the clinical evaluation of patients presenting with microhematuria, a key symptom of urothelial carcinoma (UC). There is a belief that using non-invasive molecular diagnostic tests in patients with hematuria may lead to patients undergoing unnecessary and costly invasive procedures that can cause adverse events and decrease patient quality of life. The objective of this study was to determine whether or not this was the case, using Cxbladder. METHODS: Data from 396 patient-by-urologist interactions generated 792 decision points from a standardized cohort of 33 patients evaluated by 12 urologists. Participant physicians recommended a selection of tests and procedures based on referral data, then reviewed and amended their recommendations in the context of diagnostic information from Cxbladder used in the Triage and Triage and Detect clinical modalities. RESULTS: All urologists changed their diagnostic behavior in at least one patient case with the addition of Cxbladder results. The total number of diagnostic procedures was reduced by 5% and 25% following disclosure of results from Cxbladder in the Triage and the Triage and Detect modalities, respectively. The total number of requested invasive procedures was reduced from 425 at referral to 379 (-11%) and 292 (-31%) following disclosure of Cxbladder information in the Triage and Triage and Detect modalities, respectively. CONCLUSIONS: Urologists made compelling changes to their clinical decision-making when they were provided with Cxbladder results for patients presenting with hematuria. Cxbladder provides an increase in clinical utility by focusing the use of invasive diagnostic procedures to appropriate patients, reducing both the total number and number of invasive procedures used in the clinical management of patients with hematuria, thereby improving the diagnostic experience and outcomes for patients. FUNDING: Pacific Edge Ltd.

Clinical comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma.

OBJECTIVE: Patients with urothelial carcinoma (UC) undergo rigorous surveillance for recurrence. Noninvasive urine tests are not currently recommended by guideline panels owing to insufficient clinical benefit. The objective of this study was to prospectively compare the performance of the Cxbladder Monitor test to other commonly available urine markers and cytology for surveillance of patients with UC. METHODS AND MATERIALS: A total of 1,036 urine samples were collected from 803 patients undergoing surveillance for UC. Of these, 1,016 samples were directly assessed using cytology, NMP22 Bladderchek and NMP22 enzyme-linked immunosorbent assay (ELISA), and the clinically validated Cxbladder Monitor test. An exploratory analysis was also performed comparing data from 157 samples where UroVysion fluorescence in situ hybridization analysis was performed locally. RESULTS: The sensitivity of Cxbladder Monitor (0.91) significantly outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The negative predictive value of Cxbladder Monitor was also superior at 0.96 compared with cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). All false-negative results (n = 14) observed using Cxbladder Monitor were also negative for cytology, NMP22 ELISA, and NMP22 BladderChek. In the more limited set, UroVysion fluorescence in situ hybridization also had inferior sensitivity (0.33) and negative predictive value (0.92). CONCLUSIONS: The Cxbladder Monitor test significantly outperforms current Food and Drug Administration-approved urine-based monitoring tests, as well as cytology, in a large representative population undergoing surveillance for recurrent UC. This supports using Cxbladder Monitor as a confirmatory negative adjunct to cystoscopy or to justify postponing cystoscopic investigations in patients with a low risk of recurrence.

Aging alters long-term potentiation--related gene networks and impairs synaptic protein synthesis in the rat hippocampus.

During aging, memory retention and persistence of long-term potentiation (LTP) are impaired, suggesting an aging-related deterioration in mechanisms regulating information storage. Late-phase LTP requires synthesis of proteins at synapses as well as integrated regulation of gene networks. Because aging diminishes the persistence of LTP, primarily by affecting the transition between early and late phases, we assessed whether this was reflected in perturbation of gene networks. Using DNA microarray analysis, we compared LTP-associated gene expression in young (5 months), middle-aged (15 months), and old (22 months) male Sprague-Dawley rats. As expected, we found no significant difference in LTP measured 20 minutes postinduction; however, we found that overall more genes were regulated in the young group. Bioinformatics predicted not only dysregulation of activator protein-1 and nuclear factor kB transcription factor activity and epigenetic modifications but also dysregulation of protein synthesis. Notably, we confirmed an age-related impairment in metabotropic and ionotropic receptor-mediated synaptic protein synthesis. Together, these results demonstrate that LTP-specific gene expression is altered with aging and suggest that dysregulation of synaptic protein synthesis also contributes to the age-dependent reduction in LTP persistence.