The stanford prostate cancer calculator: Development and external validation of online nomograms incorporating PIRADS scores to predict clinically significant prostate cancer.

BACKGROUND: While multiparametric MRI (mpMRI) has high sensitivity for detection of clinically significant prostate cancer (CSC), false positives and negatives remain common. Calculators that combine mpMRI with clinical variables can improve cancer risk assessment, while providing more accurate predictions for individual patients. We sought to create and externally validate nomograms incorporating Prostate Imaging Reporting and Data System (PIRADS) scores and clinical data to predict the presence of CSC in men of all biopsy backgrounds. METHODS: Data from 2125 men undergoing mpMRI and MR fusion biopsy from 2014 to 2018 at Stanford, Yale, and UAB were prospectively collected. Clinical data included age, race, PSA, biopsy status, PIRADS scores, and prostate volume. A nomogram predicting detection of CSC on targeted or systematic biopsy was created. RESULTS: Biopsy history, Prostate Specific Antigen (PSA) density, PIRADS score of 4 or 5, Caucasian race, and age were significant independent predictors. Our nomogram-the Stanford Prostate Cancer Calculator (SPCC)-combined these factors in a logistic regression to provide stronger predictive accuracy than PSA density or PIRADS alone. Validation of the SPCC using data from Yale and UAB yielded robust AUC values. CONCLUSIONS: The SPCC combines pre-biopsy mpMRI with clinical data to more accurately predict the probability of CSC in men of all biopsy backgrounds. The SPCC demonstrates strong external generalizability with successful validation in two separate institutions. The calculator is available as a free web-based tool that can direct real-time clinical decision-making.

Utility of PSA Density in Predicting Upgraded Gleason Score in Men on Active Surveillance With Negative MRI.

OBJECTIVES: To determine whether PSA density (PSAD), can sub-stratify risk of biopsy upgrade among men on active surveillance (AS) with normal baseline MRI. METHODS: We identified a cohort of patients with low and favorable intermediate-risk prostate cancer on AS at two large academic centers from February 2013 - December 2017. Analysis was restricted to patients with GG1 cancer on initial biopsy and a negative baseline or surveillance mpMRI, defined by the absence of PI-RADS 2 or greater lesions. We assessed ability of PSA, prostate volume and PSAD to predict upgrading on confirmatory biopsy. RESULTS: We identified 98 patients on AS with negative baseline or surveillance mpMRI. Median PSA at diagnosis was 5.8 ng/mL and median PSAD was 0.08 ng/mL/mL. Fourteen men (14.3%) experienced Gleason upgrade at confirmatory biopsy. Patients who were upgraded had higher PSA (7.9 vs 5.4 ng/mL, P = .04), PSAD (0.20 vs 0.07 ng/mL/mL, P < .001), and lower prostate volumes (42.5 vs 65.8 mL, P = .01). On multivariate analysis, PSAD was associated with pathologic upgrade (OR 2.23 per 0.1-increase, P = .007). A PSAD cutoff at 0.08 generated a NPV of 98% for detection of pathologic upgrade. CONCLUSION: PSAD reliably discriminated the risk of Gleason upgrade at confirmatory biopsy among men with low-grade prostate cancer with negative MRI. PSAD could be clinically implemented to reduce the intensity of surveillance for a subset of patients.

Applying the PRECISION approach in biopsy naïve and previously negative prostate biopsy patients.

OBJECTIVES: The PRECISION trial provides level 1 evidence supporting prebiopsy multiparametric magnetic resonance imaging (mpMRI) followed by targeted biopsy only when mpMRI is abnormal [1]. This approach reduced over-detection of low-grade cancer while increasing detection of clinically significant cancer (CSC). Still, important questions remain regarding the reproducibility of these findings outside of a clinical trial and quantifying missed CSC diagnoses using this approach. To address these issues, we retrospectively applied the PRECISION strategy in men who each underwent prebiopsy mpMRI followed by systematic and targeted biopsy. METHODS AND MATERIALS: Clinical, imaging, and pathology data were prospectively collected from 358 biopsy naïve men and 202 men with previous negative biopsies. To apply the PRECISION approach, a retrospective analysis was done comparing the cancer yield from 2 diagnostic strategies: (1) mpMRI followed by targeted biopsy alone for men with Prostate Imaging Reporting and Data System ≥ 3 lesions and (2) systematic biopsy alone for all men. Primary outcomes were biopsies avoided and the proportion of CSC cancer (Grade Group 2-5) and non-CSC (Grade Group 1). RESULTS: In biopsy naïve patients, the mpMRI diagnostic strategy would have avoided 19% of biopsies while detecting 2.5% more CSC (P= 0.480) and 12% less non-CSC (P< 0.001). Thirteen percent (n= 9) of men with normal mpMRI had CSC on systematic biopsy. For previous negative biopsy patients, the mpMRI diagnostic strategy avoided 21% of biopsies, while detecting 1.5% more CSC (P= 0.737) and 13% less non-CSC (P< 0.001). Seven percent (n= 3) of men with normal mpMRI had CSC on systematic biopsy. CONCLUSIONS: Our results provide external validation of the PRECISION finding that mpMRI followed by targeted biopsy of suspicious lesions reduces biopsies and over-diagnosis of low-grade cancer. Unlike PRECISION, we did not find increased diagnosis of CSC. This was true in both biopsy naïve and previously negative biopsy cohorts. We have incorporated this information into shared decision making, which has led some men to choose to avoid biopsy. However, we continue to recommend targeted and systematic biopsy in men with abnormal MRI.

Teaching Urologists "How to Read Multi-Parametric Prostate MRIs Using PIRADSv2": Results of an iBook Pilot Study.

OBJECTIVE: To create an online resource that teaches urologists how to interpret prostate multiparametric magnetic resonance imaging (mpMRI). As prostate mpMRI becomes widely adopted for cancer diagnosis and targeted biopsy, it is increasingly important that urologists are comfortable and experienced in assessing the images. The purpose of this study was to create an online mpMRI ibook and measure its effect on instilling proficiency among urology residents. METHODS: We created a case-based ibook aimed at teaching clinicians how to identify and score prostate lesions on mpMRI using the Prostate Imaging-Reporting and Data System (PIRADS) v2. Residents completed a 43-question pretest before gaining access to the ibook for 1 month. The test asks participants to identify and score visible lesions using interactive mpMRI images. After a formal review of the material, they completed a post-test. Participants also rated their diagnostic confidence on a scale of 1-10 before and after reviewing the ibook. The change in performance and confidence scores for each resident was compared using Wilcoxon signed-rank test. RESULTS: Eleven urology residents completed the pretest, review session and post-test. The mean test score rose from 37% (median 40%) to 57% (median 58%) after reviewing the ibook. Improvement was significant (P= .0039). Confidence scores also improved (P = .001). CONCLUSION: We created an interactive ibook that teaches urologists how to evaluate prostate mpMRIs and demonstrated improved performance in interpretation among urology residents. This effective module can be incorporated into resident education on a national level and offered as a self-teaching resource for practicing urologists.

Prostate Magnetic Resonance Imaging Interpretation Varies Substantially Across Radiologists.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) interpreted by experts is a powerful tool for diagnosing prostate cancer. However, the generalizability of published results across radiologists of varying expertise has not been verified. OBJECTIVE: To assess variability in mpMRI reporting and diagnostic accuracy across radiologists of varying experience in routine clinical care. DESIGN, SETTING, AND PARTICIPANTS: Men who underwent mpMRI and MR-fusion biopsy between 2014-2016. Each MRI scan was read by one of nine radiologists using the Prostate Imaging Reporting and Data System (PIRADS) and was not re-read before biopsy. Biopsy histopathology was the reference standard. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were the PIRADS score distribution and diagnostic accuracy across nine radiologists. We evaluated the association between age, prostate-specific antigen, PIRADS score, and radiologist in predicting clinically significant cancer (Gleason ≥7) using multivariable logistic regression. We conducted sensitivity analyses for case volume and changes in accuracy over time. RESULTS AND LIMITATIONS: We analyzed data for 409 subjects with 503 MRI lesions. While the number of lesions (mean 1.2 lesions/patient) did not differ across radiologists, substantial variation existed in PIRADS distribution and cancer yield. The significant cancer detection rate was 3-27% for PIRADS 3 lesions, 23-65% for PIRADS 4, and 40-80% for PIRADS 5 across radiologists. Some 13-60% of men with a PIRADS score of <3 on MRI harbored clinically significant cancer. The area under the receiver operating characteristic curve varied from 0.69 to 0.81 for detection of clinically significant cancer. PIRADS score (p<0.0001) and radiologist (p=0.042) were independently associated with cancer in multivariable analysis. Neither individual radiologist volume nor study period impacted the results. MRI scans were not retrospectively re-read by all radiologists, precluding measurement of inter-observer agreement. CONCLUSIONS: We observed considerable variability in PIRADS score assignment and significant cancer yield across radiologists. We advise internal evaluation of mpMRI accuracy before widespread adoption. PATIENT SUMMARY: We evaluated the interpretation of multiparametric magnetic resonance imaging of the prostate in routine clinical care. Diagnostic accuracy depends on the Prostate Imaging Reporting and Data System score and the radiologist.

Performance of multiparametric MRI appears better when measured in patients who undergo radical prostatectomy.

Utilization of pre-biopsy multiparametric MRI (mpMRI) is increasing. To optimize the usefulness of mpMRI, physicians should accurately quote patients a numerical risk of cancer based on their MRI. The Prostate Imaging Reporting and Data System (PIRADS) standardizes interpretation of mpMRI; however, reported rates of clinically significant prostate cancer (CSC) stratified by PIRADS score vary widely. While some publications use radical prostatectomy (RP) specimens as gold standard, others use biopsy. We hypothesized that much of the variation in CSC stems from differences in cancer prevalence in RP cohorts (100% prevalence) vs biopsy cohorts. To quantify the impact of this selection bias on cancer yield according to PIRADS score, we analyzed data from 614 men with 854 lesions who underwent targeted biopsy from 2014 to 2018. Of these, 125 men underwent RP. We compared the PIRADS detection rates of CSC (Gleason ≥7) on targeted biopsy between the biopsy-only and RP cohorts. For all PIRADS scores, CSC yield was much greater in patients who underwent RP. For example, CSC was found in 30% of PIRADS 3 lesions in men who underwent RP vs 7.6% in men who underwent biopsy. Our results show that mpMRI performance appears to be better in men who undergo RP compared with those who only receive biopsy. Physicians should understand the effect of this selection bias and its magnitude when discussing mpMRI results with patients considering biopsy, and take great caution in quoting CSC yields from publications using RP as gold standard.

Genomewide view of gene silencing by small interfering RNAs.

RNA interference (RNAi) is an evolutionarily conserved mechanism in plant and animal cells that directs the degradation of messenger RNAs homologous to short double-stranded RNAs termed small interfering RNA (siRNA). The ability of siRNA to direct gene silencing in mammalian cells has raised the possibility that siRNA might be used to investigate gene function in a high throughput fashion or to modulate gene expression in human diseases. The specificity of siRNA-mediated silencing, a critical consideration in these applications, has not been addressed on a genomewide scale. Here we show that siRNA-induced gene silencing of transient or stably expressed mRNA is highly gene-specific and does not produce secondary effects detectable by genomewide expression profiling. A test for transitive RNAi, extension of the RNAi effect to sequences 5' of the target region that has been observed in Caenorhabditis elegans, was unable to detect this phenomenon in human cells.