Pilot study of positive airway pressure usage, patient journey and program engagement for users of a digital obstructive sleep apnea program.

Purpose: This single-arm, decentralized pilot study assessed patient journey, positive airway pressure (PAP) usage and program satisfaction for users of an entirely virtual telemedicine program for obstructive sleep apnea (OSA) diagnosis and management. This analysis focuses specifically on the subset of participants in the program who were diagnosed with OSA and prescribed PAP therapy. Methods: The Verily Clinical Studies Platform was used for virtual screening, consent, and enrolling eligible patients from North Carolina and Texas. After completing the virtual OSA diagnosis process, participants diagnosed with OSA and prescribed PAP therapy downloaded the program's mobile app. The app featured tools such as educational content, live coaching support, and motivational enhancement. Results: Of the patients included in this analysis (N = 105), the majority were female (58%), and white (90%). The mean time from first televisit to PAP initiation was 29.2 (SD 12.8) days and f 68 out of the 105 patients (65%) reached 90-day adherence. On average, patients used their PAP device for 4.4 h per day, and 5.4 h on days used. Engagement with the app was associated with higher rates of PAP adherence. Adherent individuals used the mobile app 52 out of the 90 days on average, compared to non-adherent individuals who used the app on 35 out of the 90 days on average (p = 0.0003). Conclusions: All of the 105 patients in this program diagnosed with OSA and prescribed PAP therapy were able to efficiently complete the entire OSA diagnostic pathway. The majority of these individuals also were able to adhere to their prescribed PAP therapy and had clinically meaningful PAP usage rates over the 90 days of therapy. Future studies might further evaluate the impact of this type of end-to-end virtual program on longer-term adherence and clinical outcomes over time. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04599803?term=NCT04599803&draw=2&rank=1, identifier NCT04599803.

Assessment of Patient Journey Metrics for Users of a Digital Obstructive Sleep Apnea Program: Single-Arm Feasibility Pilot Study.

BACKGROUND: Despite the importance of diagnosis and treatment, obstructive sleep apnea (OSA) remains a vastly underdiagnosed condition; this is partially due to current OSA identification methods and a complex and fragmented diagnostic pathway. OBJECTIVE: This prospective, single-arm, multistate feasibility pilot study aimed to understand the journey in a nonreferred sample of participants through the fully remote OSA screening and diagnostic and treatment pathway, using the Primasun Sleep Apnea Program (formally, Verily Sleep Apnea Program). METHODS: Participants were recruited online from North Carolina and Texas to participate in the study entirely virtually. Eligible participants were invited to schedule a video telemedicine appointment with a board-certified sleep physician who could order a home sleep apnea test (HSAT) to be delivered to the participant's home. The results were interpreted by the sleep physician and communicated to the participant during a second video telemedicine appointment. The participants who were diagnosed with OSA during the study and prescribed a positive airway pressure (PAP) device were instructed to download an app that provides educational and support-related content and access to personalized coaching support during the study's 90-day PAP usage period. Surveys were deployed throughout the study to assess baseline characteristics, prior knowledge of sleep apnea, and satisfaction with the program. RESULTS: For the 157 individuals who were ordered an HSAT, it took a mean of 7.4 (SD 2.6) days and median 7.1 days (IQR 2.0) to receive their HSAT after they completed their first televisit appointment. For the 114 individuals who were diagnosed with OSA, it took a mean of 13.9 (SD 9.6) days and median 11.7 days (IQR 10.1) from receiving their HSAT to being diagnosed with OSA during their follow-up televisit appointment. Overall, the mean and median time from the first televisit appointment to receiving an OSA diagnosis was 21.4 (SD 9.6) days and 18.9 days (IQR 9.2), respectively. For those who were prescribed PAP therapy, it took a mean of 8.1 (SD 9.3) days and median 6.0 days (IQR 4.0) from OSA diagnosis to PAP therapy initiation. CONCLUSIONS: These results demonstrate the possibility of a highly efficient, patient-centered pathway for OSA workup and treatment. Such findings support pathways that could increase access to care, reduce loss to follow-up, and reduce health burden and overall cost. The program's ability to efficiently diagnose patients who otherwise may have not been diagnosed with OSA is important, especially during a pandemic, as the United States shifted to remote care models and may sustain this direction. The potential economic and clinical impact of the program's short and efficient journey time and low attrition rate should be further examined in future analyses. Future research also should examine how a fast and positive diagnosis experience impacts success rates for PAP therapy initiation and adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04599803; https://clinicaltrials.gov/ct2/show/NCT04599803.

The accuracy of a portable sleep monitor to diagnose obstructive sleep apnea in adolescent patients.

STUDY OBJECTIVES: The efficacy of portable-monitor (PM) sleep testing in children is not well understood. While most studies have evaluated PM in a lab setting, the utility of PM in the home environment is relatively unknown. We sought to determine whether home PM accurately diagnoses obstructive sleep apnea in adolescents and to assess patient satisfaction with home PM sleep testing. METHODS: We evaluated adolescents (age 12-18 years) with suspected obstructive sleep apnea using a PM device. In addition to in-laboratory polysomnography (PSG), all participants had PM testing performed twice, once in their home and once concurrent to in-laboratory PSG. PM was compared to PSG using 2 primary outcomes: the apnea-hypopnea index and oxygen desaturation index. All participants were approached for interview to evaluate their experience with PM sleep testing. RESULTS: Twenty adolescents participated. Bland-Altman analysis comparing the apnea-hypopnea index and oxygen desaturation index determined by home or in-laboratory PM to in-laboratory PSG revealed mostly agreement; however, some deviations were observed when either parameter was markedly increased. While PM testing tended to underestimate the apnea-hypopnea index, the diagnostic agreement between home PM and PSG was 80% (by the White-Westbrook method). Most preferred PM to PSG and found PM easy to very easy to set up. CONCLUSIONS: In a small cohort of adolescents, our study supports the application of home PM in the diagnosis of suspected obstructive sleep apnea. Until studies implementing PM using larger cohorts become readily available, the findings from this preliminary study could contribute to adolescents receiving sleep apnea therapy more promptly. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT03748771. At the time of issue publication, this registration is not publicly available because the trial includes a device that is not approved or cleared for use in pediatric populations. Once the device is FDA cleared, the registration will become public.

Where to Next for Optimizing Adherence in Large-Scale Trials of Continuous Positive Airway Pressure?

Large-scale randomized trials of positive airway pressure (PAP) efficacy have been largely negative but PAP adherence was notably suboptimal across the trials. To address this limitation, evidence-based PAP adherence protocols embedded within the larger trial protocol are recommended. The complexity of such protocols depends on adequacy of resources, including funding and inclusion of behavioral scientist experts on the scientific team, and trial-specific considerations (eg, target population) and methods. Recommendations for optimizing PAP adherence in large-scale trials are set forth that address rigor and reproducibility.

Adaptive servo-ventilation reduces atrial fibrillation burden in patients with heart failure and sleep apnea.

BACKGROUND: Patients with heart failure and sleep apnea are at increased risk for developing arrhythmias. Whether treatment of sleep apnea reduces arrhythmias is unknown. OBJECTIVE: The purpose of this study was to determine whether adaptive servo-ventilation (ASV) with optimal medical therapy (OMT) reduces atrial fibrillation (AF) and/or ventricular tachycardia/ventricular fibrillation (VT/VF) burden compared to OMT alone. METHODS: We conducted a prospective substudy of patients with pacemakers/defibrillators in the Cardiovascular Improvements with Minute Ventilation-Targeted ASV Therapy in Heart Failure (CAT-HF) trial. Change in arrhythmia burden was compared using a mixed model analysis to account for multiple measurements per patient. RESULTS: Among 35 randomized patients eligible and analyzed (19 ASV, 16 OMT only) in the AF cohort, mean age was 64 ± 12 years, 23% were women (n = 8), 49% had previous AF (n = 17), 89% had reduced ejection fraction (n = 31), and mean apnea hypopnea index was 41 ± 17 events per hour. Baseline characteristics were similar between groups. Change in AF burden from baseline to follow-up was -15.8% ± 36.5% with ASV vs +23.7% ± 36.2% with OMT (P = .034). There was no significant change in the AF cohort in the mean number of VT/VF events: +3.3 ± 14.9 events with ASV vs -0.3 ± 7.3 events with OMT (P = .58). Five subjects had appropriate therapies for VT/VF in the ASV arm vs 6 subjects in the OMT arm. CONCLUSION: This study provides proof of concept that treatment of sleep apnea with ASV leads to reduction in AF burden compared with OMT alone, without an increase in VT/VF events. This hypothesis should be tested in a large outcomes trial.

Treatment of sleep-disordered breathing in heart failure impacts cardiac remodeling: Insights from the CAT-HF Trial.

BACKGROUND: Sleep-disordered breathing (SDB), including central and obstructive sleep apnea, is a marker of poor prognosis in heart failure (HF) and may worsen cardiac dysfunction over time. Treatment of SDB with adaptive servoventilation (ASV) may reverse pathologic cardiac remodeling in HF patients. METHODS: The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) trial randomized patients with acute decompensated HF and confirmed SDB to either optimal medical therapy (OMT) or treatment with ASV and OMT. Patients with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) were included. Echocardiograms, performed at baseline and 6 months, assessed cardiac size and function and evaluated cardiac remodeling over time. The CAT-HF trial was stopped early in response to the SERVE-HF trial, which found increased mortality among HFrEF patients with central sleep apnea treated with ASV. RESULTS: Of the 126 patients enrolled prior to trial cessation, 95 had both baseline and 6-month echocardiograms (77 HFrEF and 18 HFpEF). Among HFrEF patients, both treatment arms demonstrated a significant increase in EF: +4.3% in the ASV group (.0004) and +4.6% in OMT alone (P = .007) and a significant decrease in LV end-systolic volume index: -9.4 mL/m2 in the ASV group (P = .01) and -8.6 mL/m2 in OMT alone (P = .003). Reductions in left atrial (LA) volume and E/e' were greater in the ASV arm, whereas patients receiving OMT alone demonstrated more improvement in right ventricular function. HFpEF patients treated with ASV also had a decrease in LA size that was greater than those receiving OMT alone. Although there were significant intragroup changes within the ASV + OMT and OMT-alone groups, there were no significant intergroup differences at 6 months. CONCLUSIONS: Significant reverse LV remodeling was seen among HFrEF patients with SDB regardless of treatment allocation. Substantial reductions in LA volume among HFrEF and HFpEF patients receiving ASV suggest that ASV treatment may also improve diastolic function and warrant further investigation.

Cardiovascular Outcomes With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure: The CAT-HF Trial.

BACKGROUND: Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality. OBJECTIVES: The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to-severe sleep apnea. METHODS: Eligible patients hospitalized with HF and moderate-to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6-min walk distance) at 6 months. RESULTS: 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p < 0.0001). The primary endpoint did not differ significantly between the ASV and control groups (p = 0.92 Wilcoxon). Changes in composite endpoint components were not significantly different between ASV and control. There was no significant interaction between treatment and ejection fraction (p = 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fraction (p = 0.036). CONCLUSIONS: In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874).

Lessons learned from a clinical trial: Design, rationale, and insights from The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Sero-Ventilation (ASV) Therapy in Heart Failure (CAT-HF) Study.

OBJECTIVE: The CAT-HF Study was designed to evaluate the safety and efficacy of minute ventilation-targeted adaptive servo-ventilation (MV-ASV) during sleep in addition to optimized medical therapy (active therapy) versus optimized medical therapy alone (usual care) at 6 months, initiated in patients after hospitalization for acute decompensated heart failure (ADHF). This paper outlines the rationale, design and information learned at the time of study discontinuation. BACKGROUND: Sleep disordered breathing (SDB) is common in heart failure patients and is associated with worse outcomes in this patient population. Based on a belief that MV-ASV was safe in stable HF patients, CAT-HF was designed to examine whether MV-ASV improved outcomes in hospitalized HF patients During the course of CAT-HF, new results from SERVE-HF indicated that ASV therapy may be harmful in patients with left ventricular ejection fractions (LVEF)≤45% and central sleep apnea, a subgroup of patients enrolled in CAT-HF. METHODS: CAT-HF was a prospective, randomized, controlled, multicenter clinical trial (NCT: 01953874) in HF patients with either reduced or preserved ejection fraction and an Apnea-Hypopnea Index ≥15 events per hour randomized to usual care or active treatment in a 1:1 ratio. 215 patients were intended to be randomized following a hospitalization for ADHF. At the time of discontinuation, 126 patients were randomized. The primary endpoint is a global rank composite endpoint of death, CV hospitalizations, and Six minute walk distance (6MWD). Secondary endpoints will include changes in functional parameters, biomarkers, quality of life (QOL), sleep, and breathing. CONCLUSIONS: The CAT-HF study was designed to assess the efficacy and safety of MV ASV treatment in patients after hospitalization for ADHF, but was stopped early due to safety concerns in HF patients with (LVEF)≤45% and predominant central sleep apnea.

Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA.

More than 1,000,000 men undergo prostate biopsy each year in the United States, most for "elevated" serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.

Prostate cancer gene 3 score predicts prostate biopsy outcome in men receiving dutasteride for prevention of prostate cancer: results from the REDUCE trial.

OBJECTIVES: To examine the ability of the urinary prostate cancer gene 3 (PCA3) assay to predict biopsy-detected cancers in men receiving dutasteride in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study cohort. METHODS: Urine and serum samples from 930 men in the active arm were acquired at years 2 and 4 of the biopsy visits. In addition to univariate logistic regression and receiver operating characteristic analysis, multivariate analysis for association with biopsy outcome was performed for PCA3 score in the presence of serum prostate-specific antigen (PSA), age, prostate volume, and family history of prostate cancer. RESULTS: At year 2, the univariate PCA3 score area under the receiver operating characteristic curve (AUC) was 0.668 versus 0.603 for PSA. At year 4, the PCA3 assay significantly predicted the biopsy outcome (AUC 0.628, 95% confidence interval 0.556-0.700), and the PSA level was not predictive (AUC 0.556, 95% confidence interval 0.469-0.642). The year 2 multivariate model yielded an AUC of 0.712. Removing the PCA3 score decreased the AUC to 0.660 (P = .0166 vs the full model). The median PCA3 scores in the dutasteride arm were not different from those in the 1072 men in the placebo arm (16.2 and 17.2 at year 2, P = .1755; and 18.8 and 18.1 at year 4, P = .2340, respectively). However, the PSA values were reduced >50% in the dutasteride arm at both visits (both P < .0001 vs placebo). At a PCA3 score cutoff of 35, the sensitivity and specificity were equivalent between the 2 arms. CONCLUSIONS: In the present study, the PCA3 assay outperformed PSA for cancer detection in men undergoing dutasteride treatment and improved the diagnostic accuracy when combined with the PSA level and other clinical variables. In addition, no adjustment in PCA3 score was needed to yield equivalent clinical performance between the dutasteride and placebo arms. These findings are particularly important in light of the potential role of dutasteride for prostate cancer chemoprevention.

PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial.

PURPOSE: We determined the performance of PCA3 alone and in the presence of other covariates as an indicator of contemporaneous and future prostate biopsy results in a population with previous negative biopsy and increased serum prostate specific antigen. MATERIALS AND METHODS: Urine PCA3 scores were determined before year 2 and year 4 biopsies from patients in the placebo arm of the REDUCE trial, a prostate cancer risk reduction study evaluating men with moderately increased serum prostate specific antigen results and negative biopsy at baseline. PCA3, serum prostate specific antigen and percent free prostate specific antigen results were correlated with biopsy outcome via univariate logistic regression and ROC analyses. Multivariate logistic regression was also performed including these biomarkers together with prostate volume, age and family history. RESULTS: PCA3 scores were measurable from 1,072 of 1,140 subjects (94% informative rate). PCA3 scores were associated with positive biopsy rate (p <0.0001) and correlated with biopsy Gleason score (p = 0.0017). PCA3 AUC of 0.693 was greater than serum prostate specific antigen (0.612, p = 0.0077 vs PCA3). The multivariate logistic regression model yielded an AUC of 0.753 and exclusion of PCA3 from the model decreased AUC to 0.717 (p = 0.0009). PCA3 at year 2 was a significant predictor of year 4 biopsy outcome (AUC 0.634, p = 0.0002), whereas serum prostate specific antigen and free prostate specific antigen were not predictive (p = 0.3281 and 0.6782, respectively). CONCLUSIONS: PCA3 clinical performance was validated in the largest repeat biopsy study to date. Increased PCA3 scores indicated increased risk of contemporaneous cancers and predicted future biopsy outcomes. Use of PCA3 in combination with serum prostate specific antigen and other risk factors significantly increased diagnostic accuracy.

Evaluation of the ETS-related gene mRNA in urine for the detection of prostate cancer.

PURPOSE: Prevalent gene fusions in prostate cancer involve androgen-regulated promoters (primarily TMPRSS2) and ETS transcription factors (predominantly ETS-regulated gene (ERG)], which result in tumor selective overexpression of ERG in two thirds of patients. Because diverse genomic fusion events lead to ERG overexpression in prostate cancer, we reasoned that it may be more practical to capture such alterations using an assay targeting ERG sequences retained in such gene fusions. This study evaluates the potential of an assay quantitating ERG mRNA in post-digital rectal exam (DRE) urine for improving prostate cancer detection. EXPERIMENTAL DESIGN: Patients scheduled to undergo transrectal ultrasound-guided needle biopsy of the prostate were prospectively enrolled. On the day of biopsy, patients provided a urine sample immediately following a DRE. Urine ERG mRNA was measured and normalized to urine prostate-specific antigen (PSA) mRNA using the DTS 400 system. Demographic traits, clinical characteristics and biopsy results were analyzed for association with urine ERG score. RESULTS: The study was conducted on 237 patients. Prostate cancer was shown on biopsy in 40.9% of study subjects. A higher urine ERG score associated significantly with malignancy on biopsy (P = 0.0145), but not with clinical stage or Gleason score. Urine ERG score performed best in Caucasians and in men with a PSA of

PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume.

PURPOSE: PCA3 is a prostate specific, nonprotein coding RNA that is over expressed in prostate cancer. Recent studies showed the diagnostic potential of a urine based PCA3 for predicting biopsy outcome. We assessed the relationship between urine PCA3 and pathological features in whole mount radical prostatectomy specimens. MATERIALS AND METHODS: Post-digital rectal examination urine specimens were obtained from 72 men with prostate cancer before radical prostatectomy. PCA3 and PSA mRNA were measured. The ratio of PCA3 to PSA mRNA was recorded as a PCA3 score and correlated with data on each prostate specimen. RESULTS: Patients with extracapsular extension had a significantly higher median PCA3 score than patients without extracapsular extension (48.8 vs 18.7, p = 0.02). PCA3 score significantly correlated with total tumor volume (r = 0.38, p <0.01). On multivariate analysis PCA3 score was an independent predictor of extracapsular extension (p = 0.01) and total tumor volume less than 0.5 cc (p = 0.04). At a cutoff PCA3 score of 47 extracapsular extension was predicted with 94% specificity and an 80% positive predictive value. When combined with serum PSA and biopsy Gleason score, the ROC AUC for predicting extracapsular extension was 0.90. CONCLUSIONS: PCA3 detected in the post-digital rectal examination urine of patients with prostate cancer correlated with pathological findings. Therefore, it could provide prognostic information. To our knowledge this is the first report of a molecular urine assay that predicts extracapsular extension.

Predicting prostate cancer risk through incorporation of prostate cancer gene 3.

PURPOSE: The online Prostate Cancer Prevention Trial risk calculator combines prostate specific antigen, digital rectal examination, family and biopsy history, age and race to determine the risk of prostate cancer. In this report we incorporate the biomarker prostate cancer gene 3 into the Prostate Cancer Prevention Trial risk calculator. MATERIALS AND METHODS: Methodology was developed to incorporate new markers for prostate cancer into the Prostate Cancer Prevention Trial risk calculator based on likelihood ratios calculated from separate case control or cohort studies. The methodology was applied to incorporate the marker prostate cancer gene 3 into the risk calculator based on a cohort of 521 men who underwent prostate biopsy with measurements of urinary prostate cancer gene 3, serum prostate specific antigen, digital rectal examination and biopsy history. External validation of the updated risk calculator was performed on a cohort of 443 European patients, and compared to Prostate Cancer Prevention Trial risks, prostate specific antigen and prostate cancer gene 3 by area underneath the receiver operating characteristic curve, sensitivity and specificity. RESULTS: The AUC of posterior risks (AUC 0.696, 95% CI 0.641-0.750) was higher than that of prostate specific antigen (AUC 0.607, 95% CI 0.546-0.668, p = 0.001) and Prostate Cancer Prevention Trial risks (AUC 0.653, 95% CI 0.593-0.714, p <0.05). Although it was higher it was not statistically significantly different from that of prostate cancer gene 3 (AUC 0.665, 95% CI 0.610-0.721, p >0.05). Sensitivities of posterior risks were higher than those of prostate cancer gene 3, prostate specific antigen and Prostate Cancer Prevention Trial risks. CONCLUSIONS: New markers for prostate cancer can be incorporated into the Prostate Cancer Prevention Trial risk calculator by a novel approach. Incorporation of prostate cancer gene 3 improved the diagnostic accuracy of the Prostate Cancer Prevention Trial risk calculator.

PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance.

PURPOSE: Prostate cancer gene 3 (PCA3) has shown promise as a molecular marker in prostate cancer detection. We assessed the association of urinary PCA3 score with prostatectomy tumor volume and other clinical and pathological features. MATERIALS AND METHODS: Urine specimens were collected after digital rectal examination from 59 men scheduled for prostate biopsy and 83 men scheduled for radical prostatectomy. Prostatectomy findings were evaluable for 96 men. PCA3 and prostate specific antigen mRNAs were quantified with Gen-Probe DTS 400 System. The PCA3 score was defined as the ratio of PCA3 mRNA/prostate specific antigen mRNA x10(3). RESULTS: The PCA3 score in men with negative biopsies (30) and positive biopsies (29) were significantly different (median 21.1 and 31.0, respectively, p = 0.029). The PCA3 score was significantly correlated with total tumor volume in prostatectomy specimens (r = 0.269, p = 0.008), and was also associated with prostatectomy Gleason score (6 vs 7 or greater, p = 0.005) but not with other clinical and pathological features. The PCA3 score was significantly different when comparing low volume/low grade cancer (dominant tumor volume less than 0.5 cc, Gleason score 6) and significant cancer (p = 0.007). On multivariate analysis PCA3 was the best predictor of total tumor volume in prostatectomy (p = 0.001). Receiver operating characteristic curve analysis showed that the PCA3 score could discriminate low volume cancer (total tumor volume less than 0.5 cc) well with area under the curve of 0.757. CONCLUSIONS: The PCA3 score appears to stratify men based on prostatectomy tumor volume and Gleason score, and may have clinical applicability in selecting men who have low volume/low grade cancer.

PCA3: a molecular urine assay for predicting prostate biopsy outcome.

PURPOSE: A urinary assay for PCA3, an mRNA that is highly over expressed in prostate cancer cells, has shown usefulness as a diagnostic test for this common malignancy. We further characterized PCA3 performance in different groups of men and determined whether the PCA3 score could synergize with other clinical information to predict biopsy outcome. MATERIALS AND METHODS: Prospectively urine was collected following standardized digital rectal examination in 570 men immediately before prostate biopsy. Urinary PCA3 mRNA levels were quantified and then normalized to the amount of prostate derived RNA to generate a PCA3 score. RESULTS: The percent of biopsy positive men identified increased directly with the PCA3 score. PCA3 assay performance was equivalent in the first vs previous negative biopsy groups with an area under the ROC curve of 0.70 and 0.68, respectively. Unlike serum prostate specific antigen the PCA3 score did not increase with prostate volume. PCA3 assay sensitivity and specificity were equivalent at serum prostate specific antigen less than 4, 4 to 10 and more than 10 ng/ml. A logistic regression algorithm using PCA3, serum prostate specific antigen, prostate volume and digital rectal examination result increased the AUC from 0.69 for PCA3 alone to 0.75 (p = 0.0002). CONCLUSIONS: PCA3 is independent of prostate volume, serum prostate specific antigen level and the number of prior biopsies. The quantitative PCA3 score correlated with the probability of positive biopsy. Logistic regression results suggest that the PCA3 score could be incorporated into a nomogram for improved prediction of biopsy outcome. The results of this study provide further evidence that PCA3 is a useful adjunct to current methods for prostate cancer diagnosis.

A multicenter evaluation of the PCA3 molecular urine test: pre-analytical effects, analytical performance, and diagnostic accuracy.

BACKGROUND: Measurement of prostate cancer gene 3 (PCA3) mRNA normalized to prostate-specific antigen (PSA) mRNA in urine has been proposed as a marker for prostate cancer. METHODS: We investigated pre-analytical effects, analytical performance, and diagnostic accuracy of a quantitative assay for PCA3. RESULTS: Urine specimens collected without prostate manipulation demonstrated low informative rates. However, specimens collected following digital rectal examinations of 3 or 8 strokes per prostate lobe demonstrated informative rates >94%. Across all urine specimen types, median PCA3 results did not show statistically significant differences (P>0.8). Measurements of controls of known mRNA content demonstrated percent recoveries of 100+/-15% for both PCA3 and PSA mRNAs. PCA3 mRNA total, intra-assay, inter-assay, and inter-site CVs were < or =17.1%, < or =14.0%, < or =9.9%, and < or =3.2%, respectively. Corresponding CVs for PSA mRNA assay were < or =11.5%, < or =8.6%, < or =7.9%, and < or =8.3%. Blinded assay of urines from 72 men with known prostate biopsy outcomes yielded areas under the curve from receiver-operating characteristic analysis of 0.7 at both research sites. Deming regression of individual PCA3 results between sites yielded slope=0.94, intercept=0.48, R=0.9677 (P<0.0001). CONCLUSIONS: The PCA3 assay is insensitive to pre-analytical factors, performs well analytically and correctly classifies a high percent of subjects with known prostate cancer status across research sites.

PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy.

OBJECTIVES: Men with elevated serum prostate-specific antigen (PSA) levels and negative prostate biopsy findings present a dilemma because of the lack of an accurate diagnostic test. We evaluated the potential utility of the investigational prostate cancer gene 3 (PCA3) urine assay to predict the repeat biopsy outcome. METHODS: Urine was collected after digital rectal examination (three strokes per lobe) from 233 men with serum PSA levels persistently 2.5 ng/mL or greater and at least one previous negative biopsy. The specimens were collected from April 2004 to January 2006. The PCA3 scores were determined using a highly sensitive quantitative assay with transcription-mediated amplification. The ability of the PCA3 score to predict the biopsy outcome was assessed and compared with the serum PSA levels. RESULTS: The RNA yield was adequate for analysis in the urine samples from 226 of 233 men (ie, the informative specimen rate was 97%). Repeat biopsy revealed prostate cancer in 60 (27%) of the of 226 remaining subjects. Receiver operating characteristic curve analysis yielded an area under the curve of 0.68 for the PCA3 score. In contrast, the area under the curve for serum PSA was 0.52. Using a PCA3 score cutoff of 35, the assay sensitivity was 58% and specificity 72%, with an odds ratio of 3.6. At PCA3 scores of less than 5, only 12% of men had prostate cancer on repeat biopsy; at PCA3 scores greater than 100, the risk of positive biopsy was 50%. CONCLUSIONS: In men undergoing repeat prostate biopsy to rule out cancer, the urinary PCA3 score was superior to serum PSA determination for predicting the biopsy outcome. The high specificity and informative rate suggest that the PCA3 assay could have an important role in prostate cancer diagnosis.

APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer.

BACKGROUND: Prostate cancer gene 3 (PCA3) encodes a prostate-specific mRNA that has shown promise as a prostate cancer diagnostic tool. This report describes the characterization of a prototype quantitative PCA3-based test for whole urine. METHODS: Whole-urine specimens were collected after digital rectal examination from 3 groups: men scheduled for prostate biopsy (n = 70), healthy men (<45 years of age with no known prostate cancer risk factors; n = 52), and men who had undergone radical prostatectomy (n = 21). PCA3 and prostate-specific antigen (PSA) mRNAs were isolated, amplified, and quantified by use of Gen-Probe DTS400 Systems. Prostate biopsy results were correlated with the PCA3/PSA mRNA ratio, and PSA mRNA concentrations were used to normalize PCA3 signals and confirm the yield of prostate-specific RNA. Assay precision, specimen stability, and mRNA yield were also evaluated. RESULTS: The specimen informative rate (fraction of specimens yielding sufficient RNA for analysis) was 98.2%. In this clinical research study, ROC curve analysis of prebiopsy specimens yielded an area under the curve of 0.746; sensitivity was 69% and specificity 79%. Serum PSA assay specificity was 28% for this same group. PCA3 and PSA mRNAs were undetectable in postprostatectomy specimens except for one man with recurrent prostate cancer. Assay interrun CVs were < or =12%. Both mRNAs were stable in processed urine up to 5 days at 4 degrees C and after 5 freeze-thaw cycles. CONCLUSION: The APTIMA PCA3 assay combines simple specimen processing with precise assays and existing instruments and could add specificity to the current algorithm for prostate cancer diagnosis.