Sonia Gaur

Prospective Evaluation of PI-RADS™ Version 2 Using the International Society of Urological Pathology Prostate Cancer Grade Group System

Purpose: The PI‐RADS™ (Prostate Imaging Reporting and Data System), version 2 scoring system, introduced in 2015, is based on expert consensus. In the same time frame ISUP (International Society of Urological Pathology) introduced a new pathological scoring system for prostate cancer. Our goal was to prospectively evaluate the cancer detection rates for each PI‐RADS, version 2 category and compare them to ISUP group scores in patients undergoing systematic biopsy and magnetic resonance imaging‐transrectal ultrasound fusion guided biopsy. Materials and Methods: A total of 339 treatment naïve patients prospectively underwent multiparametric magnetic resonance imaging evaluated with PI‐RADS, version 2 with subsequent systematic and fusion guided biopsy from May 2015 to May 2016. ISUP scores were applied to pathological specimens. An ISUP score of 2 or greater (ie Gleason 3 + 4 or greater) was defined as clinically significant prostate cancer. Cancer detection rates were determined for each PI‐RADS, version 2 category as well as for the T2 weighted PI‐RADS, version 2 categories in the peripheral zone. Results: The cancer detection rate for PI‐RADS, version 2 categories 1, 2, 3, 4 and 5 was 25%, 20.2%, 24.8%, 39.1% and 86.9% for all prostate cancer, and 0%, 9.6%, 12%, 22.1% and 72.4% for clinically significant prostate cancer, respectively. On T2‐weighted magnetic resonance imaging the cancer detection rate in the peripheral zone was significantly higher for PI‐RADS, version 2 category 4 than for overall PI‐RADS, version 2 category 4 in the peripheral zone (all prostate cancer 36.6% vs 48.1%, p = 0.001, and clinically significant prostate cancer 22.9% vs 32.6%, p = 0.002). Conclusions: The cancer detection rate increases with higher PI‐RADS, version 2 categories.

What Are We Missing? False-Negative Cancers at Multiparametric MR Imaging of the Prostate

Purpose To characterize clinically important prostate cancers missed at multiparametric (MP) magnetic resonance (MR) imaging. Materials and Methods The local institutional review board approved this HIPAA-compliant retrospective single-center study, which included 100 consecutive patients who had undergone MP MR imaging and subsequent radical prostatectomy. A genitourinary pathologist blinded to MP MR findings outlined prostate cancers on whole-mount pathology slices. Two readers correlated mapped lesions with reports of prospectively read MP MR images. Readers were blinded to histopathology results during prospective reading. At histopathologic examination, 80 clinically unimportant lesions (<5 mm; Gleason score, 3+3) were excluded. The same two readers, who were not blinded to histopathologic findings, retrospectively reviewed cancers missed at MP MR imaging and assigned a Prostate Imaging Reporting and Data System (PI-RADS) version 2 score to better understand false-negative lesion characteristics. Descriptive statistics were used to define patient characteristics, including age, prostate-specific antigen (PSA) level, PSA density, race, digital rectal examination results, and biopsy results before MR imaging. Student t test was used to determine any demographic differences between patients with false-negative MP MR imaging findings and those with correct prospective identification of all lesions. Results Of the 162 lesions, 136 (84%) were correctly identified with MP MR imaging. Size of eight lesions was underestimated. Among the 26 (16%) lesions missed at MP MR imaging, Gleason score was 3+4 in 17 (65%), 4+3 in one (4%), 4+4 in seven (27%), and 4+5 in one (4%). Retrospective PI-RADS version 2 scores were assigned (PI-RADS 1, n = 8; PI-RADS 2, n = 7; PI-RADS 3, n = 6; and PI-RADS 4, n = 5). On a per-patient basis, MP MR imaging depicted clinically important prostate cancer in 99 of 100 patients. At least one clinically important tumor was missed in 26 (26%) patients, and lesion size was underestimated in eight (8%). Conclusion Clinically important lesions can be missed or their size can be underestimated at MP MR imaging. Of missed lesions, 58% were not seen or were characterized as benign findings at second-look analysis. Recognition of the limitations of MP MR imaging is important, and new approaches to reduce this false-negative rate are needed.

Changes in prostate cancer detection rate of MRI-TRUS fusion vs systematic biopsy over time: evidence of a learning curve

Background:To determine the effect of urologist and radiologist learning curves and changes in MRI-TRUS fusion platform during 9 years of NCI’s experience with multiparametric magnetic resonance imaging (mpMRI)/TRUS fusion biopsy.Methods:A prospectively maintained database of patients undergoing mpMRI followed by fusion biopsy (Fbx) and systematic biopsy (Sbx) from 2007 to 2016 was reviewed. The patients were stratified based on the timing of first biopsy. Cohort 1 (7/2007−12/2010) accounted for learning curve. Cohort 2 (1/2011–5/2013) and cohort 3 (5/2013–4/2016) included patients biopsied prior to and after debut of a new software platform, respectively. Clinically significant (CS) disease was defined as Gleason 7 (3+4) or higher. McNemar’s test compared cancer detection rates (CDRs) of Sbx and Fbx between time periods.Results:1528 patients were included in the study with 230, 537 and 761 patients included in three respective cohorts. Median age (interquartile range) was 61.0 (±9.0), 62.0 (±7.3), and 64.0 (±11.0) years in three cohorts, respectively (P<0.001). Fbx and Sbx had comparable CS CDR in cohort 1 (24.8 vs 22.2%, P=0.377). Fbx detected significantly more CS disease compared to Sbx in the following two periods (cohort 2: 31.5 vs 25.0%, P=0.001; cohort 3: 36.4 vs 30.3%, P<0.001) and detected significantly less low risk disease in the same period (cohort 2: 14.5 vs 19.6%, P<0.001; cohort 3: 12.6 vs 16.7%, P<0.001). Even after multivariate adjustment with age, PSA, race, clinical stage and MRI suspicion score, Fbx CS cancer detection increased in successive cohorts (cohort 2: OR 2.23, P=0.043; cohort 3: OR 2.92, P=0.007).Conclusions:In the past 9 years, there has been significant improvement in the accuracy of Fbx. Our results show that after an early learning period, Fbx detected higher rates of CS cancer and lower rates of clinically insignificant cancer than Sbx. Software advances allowed for even greater detection of CS disease.

A Magnetic Resonance Imaging–Based Prediction Model for Prostate Biopsy Risk Stratification

Importance Multiparametric magnetic resonance imaging (MRI) in conjunction with MRI–transrectal ultrasound (TRUS) fusion-guided biopsies have improved the detection of prostate cancer. It is unclear whether MRI itself adds additional value to multivariable prediction models based on clinical parameters. Objective To determine whether an MRI-based prediction model can reduce unnecessary biopsies in patients with suspected prostate cancer. Design, Setting, and Participants Patients underwent MRI, MRI-TRUS fusion-guided biopsy, and 12-core systematic biopsy in 1 session. The development cohort used to derive the prediction model consisted of 400 patients from 1 institution enrolled between May 14, 2015, and August 31, 2016, and the validation cohort included 251 patients from 2 independent institutions who underwent biopsies between April 1, 2013, and June 30, 2016, at 1 institution and between July 1, 2015, and October 31, 2016, at the other institution. The MRI model included MRI-derived parameters in addition to clinical variables. Area under the curve of receiver operating characteristic curves and decision curve analysis were performed. Main Outcomes and Measures Risk of clinically significant prostate cancer on biopsy, defined as a Gleason score of 3 + 4 or higher in at least 1 biopsy core. Results Overall, 193 (48.3%) of the 400 patients in the development cohort (mean [SD] age at biopsy, 64.3 [7.1] years) and 96 (38.2%) of the 251 patients in the validation cohort (mean [SD] age at biopsy, 64.9 [7.2] years) had clinically significant prostate cancer, defined as a Gleason score greater than or equal to 3 + 4. By applying the model to the external validation cohort, the area under the curve increased from 64% to 84% compared with the baseline model (P < .001). At a risk threshold of 20%, the MRI model had a lower false-positive rate than the baseline model (46% [95% CI, 32%-66%] vs 92% [95% CI, 70%-100%]), with only a small reduction in the true-positive rate (89% [95% CI, 85%-96%] vs 99% [95% CI, 89%-100%]). Eighteen of 100 fewer biopsies could have been performed, with no increase in the number of patients with missed clinically significant prostate cancers. Conclusions and Relevance The inclusion of MRI-derived parameters in a risk model could reduce the number of unnecessary biopsies while maintaining a high rate of diagnosis of clinically significant prostate cancers.

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

Background: Lens degeneration in Fpr1−/− mice prompted us to search for functional FPR1 expression directly on lens epithelial cells. Results: FPR1 is functionally expressed on human lens epithelial cells but has atypical properties compared with hematopoietic cell FPR1. Conclusion: Lens epithelial cell FPR1 may be involved in development and maintenance of the lens. Significance: This is the first link between non-hematopoietic expression of FPR1 and an ophthalmologic phenotype. Formyl peptide receptor 1 (FPR1) is a G protein-coupled chemoattractant receptor expressed mainly on leukocytes. Surprisingly, aging Fpr1−/− mice develop spontaneous lens degeneration without inflammation or infection (J.-L. Gao et al., manuscript in preparation). Therefore, we hypothesized that FPR1 is functionally expressed directly on lens epithelial cells, the only cell type in the lens. Consistent with this, the human fetal lens epithelial cell line FHL 124 expressed FPR1 mRNA and was strongly FPR1 protein-positive by Western blot and FACS. Competition binding using FPR1 ligands N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys (Nle = Norleucine), formylmethionylleucylphenylalanine, and peptide W revealed the same profile for FHL 124 cells, neutrophils, and FPR1-transfected HEK 293 cells. Saturation binding with fluorescein-labeled N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys revealed ∼2500 specific binding sites on FHL-124 cells (KD ∼ 0.5 nm) versus ∼40,000 sites on neutrophils (KD = 3.2 nm). Moreover, formylmethionylleucylphenylalanine induced pertussis toxin-sensitive Ca2+ flux in FHL 124 cells, consistent with classic Gi-mediated FPR1 signaling. FHL 124 cell FPR1 was atypical in that it resisted agonist-induced internalization. Expression of FPR1 was additionally supported by detection of the intact full-length open reading frame in sequenced cDNA from FHL 124 cells. Thus, FHL-124 cells express functional FPR1, which is consistent with a direct functional role for FPR1 in the lens, as suggested by the phenotype of Fpr1 knock-out mice.

Risk of Upgrading from Prostate Biopsy to Radical Prostatectomy Pathology—Does Saturation Biopsy of Index Lesion during Multiparametric Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy Help?

Purpose: We sought to determine whether saturation of the index lesion during magnetic resonance imaging‐transrectal ultrasound fusion guided biopsy would decrease the rate of pathological upgrading from biopsy to radical prostatectomy. Materials and Methods: We analyzed a prospectively maintained, single institution database for patients who underwent fusion and systematic biopsy followed by radical prostatectomy in 2010 to 2016. Index lesion was defined as the lesion with largest diameter on T2‐weighted magnetic resonance imaging. In patients with a saturated index lesion transrectal fusion biopsy targets were obtained at 6 mm intervals along the long axis of the index lesion. In patients with a nonsaturated index lesion only 1 target was obtained from the lesion. Gleason 6, 7 and 8‐10 were defined as low, intermediate and high risk, respectively. Results: Included in the study were 208 consecutive patients, including 86 with a saturated and 122 with a nonsaturated lesion. Median patient age was 62.0 years (IQR 10.0) and median prostate specific antigen was 7.1 ng/ml (IQR 8.0). The median number of biopsy cores per index lesion was higher in the saturated lesion group (4 vs 2, p <0.001). The risk category upgrade rate from systematic only, fusion only, and combined fusion and systematic biopsy results to prostatectomy was 40.9%, 23.6% and 13.8%, respectively. The risk category upgrade from combined fusion and systematic biopsy results was lower in the saturated than in the nonsaturated lesion group (7% vs 18%, p = 0.021). There was no difference in the upgrade rate based on systematic biopsy between the 2 groups. However, fusion biopsy results were significantly less upgraded in the saturated lesion group (Gleason upgrade 20.9% vs 36.9%, p = 0.014 and risk category upgrade 14% vs 30.3%, p = 0.006). Conclusions: Our results demonstrate that saturation of the index lesion significantly decreases the risk of upgrading on radical prostatectomy by minimizing the impact of tumor heterogeneity.

Imaging the High-risk Prostate Cancer Patient: Current and Future Approaches to Staging

Imaging is critically important for the diagnosis, staging, and management of men with high-risk prostate cancer. Conventional imaging modalities have been employed for local and metastatic staging with limited performance. Sodium fluoride positron emission tomography is recommended when there is high suspicion of bone metastases despite a negative or indeterminate bone scan. Magnetic resonance imaging has advantages in local staging but its value depends on the extent of disease. Whole-body positron emission tomography/magnetic resonance imaging could provide both local and distant staging. None of the existing positron emission tomography agents are recommended in practice guidelines; however, among them, prostate-specific membrane antigen-based tracers seem to hold the most promise based on sensitivity and specificity.

Prospective comparison of PI-RADS version 2 and qualitative in-house categorization system in detection of prostate cancer: Prospective Comparison of PI-RADSv2

Prostate Imaging‐Reporting and Data System v. 2 (PI‐RADSv2) provides standardized nomenclature for interpretation of prostate multiparametric MRI (mpMRI). Inclusion of additional features for categorization may provide benefit to stratification of disease.

A Decomposable Model for the Detection of Prostate Cancer in Multi-parametric MRI.

Institutions that specialize in prostate MRI acquire different MR sequences owing to variability in scanning procedure and scanner hardware. We propose a novel prostate cancer detector that can operate in the absence of MR imaging sequences. Our novel prostate cancer detector first trains a forest of random ferns on all MR sequences and then decomposes these random ferns into a sum of MR sequence-specific random ferns enabling predictions to be made in the absence of one or more of these MR sequences. To accomplish this, we first show that a sum of random ferns can be exactly represented by another random fern and then we propose a method to approximately decompose an arbitrary random fern into a sum of random ferns. We show that our decomposed detector can maintain good performance when some MR sequences are omitted.

Prostate MR Imaging for Posttreatment Evaluation and Recurrence

Prostate multiparametric MR imaging (mpMRI) plays an important role in local evaluation after treatment of prostate cancer. After radical prostatectomy, radiation therapy, and focal therapy, mpMRI can be used to visualize normal post-treatment changes and to diagnose locally recurrent disease. An understanding of the various treatments and expected changes is essential for complete and accurate post-treatment mpMRI interpretation.