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A PDF file containing Supplementary case reports

Summary of downsampling study

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single-cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy-number changes in those populations, and measures of the proportion of cells with clonal copy-number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathologic measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant because primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single-cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.Significance: Genomic analysis of multiple individual cells harvested from prostate biopsies provides an indepth view of cell populations comprising a prostate neoplasm, yielding novel genomic measures with the potential to improve the accuracy of diagnosis and prognosis in prostate cancer. Cancer Res; 78(2); 348–58. ©2017 AACR.

OBJECTIVE To provide insights into the long-term impact of radical retro-pubic prostatectomy (ORRP) on lower urinary tract symptoms (LUTS) which are age and prostate dependent and adversely impact quality of life. METHODS 1995 men undergoing ORRP enrolled in a prospective longitudinal outcomes study. The American Urological Association Symptom Index was self-administered before ORRP and at predetermined time-points after surgery. A multivariate generalized linear model was used to evaluate the association of time since ORRP with American Urological Association symptom score (AUASS). McNemar's test and paired sample t-tests were used to assess whether the proportion of men with clinically significant LUTS (CSLUTS) defined by an AUASS >7 or mean AUASS differed significantly between the time-dependent assessments, respectively. RESULTS The 15-year mean adjusted AUASS was similar to baseline (7.00 vs 6.85, P = .66). Throughout the 15 years of follow-up, the proportion of men with CSLUTS was lower than baseline with the exception of the 3 month and 15 year assessments. Among men with baseline clinically insignificant LUTS (CILUTS), the mean adjusted AUASS at 15 years was significantly greater than baseline (6.09 vs 3.19, P < .001). Among men with baseline CSLUTS, ORRP led to a significant decrease in mean adjusted AUASS between baseline and 15 years (13.26 vs 8.67, P < .001). CONCLUSION ORRP favorably affects the long-term natural history of LUTS. The long-term economic and quality of life benefits of ORRP on LUTS should inform the risks and benefits of RP for treatment of localized prostate cancer.

OBJECTIVE To provide insights into the role of multiparametric magnetic resonance imaging (mpMRI) in predicting oncological control following 2 focal ablation (FA) templates for selective cases of prostate cancer. MATERIALS AND METHODS A total of 59 radical prostatectomies were performed between 2012 and 2016 on cases that fulfilled criteria for FA. The Gleason score (GS), extent of Gleason pattern (GP) 4, maximum linear cross-sectional length (MLCSL), and location of tumor foci were recorded and related to scale on corresponding 3-mm transverse slice prostate maps. Gleason pattern 4 extra-focal disease (GP4EFD) was defined as prostate cancer with any GP 4 not detected by mpMRI and transrectal ultrasound systematic biopsy observed outside a specified ablation zone. The location of these GP4EFD relative to the MRI lesion (MRI-L) (contralateral or ipsilateral) was recorded and used to predict oncological control following a hypothetical margin and ipsilateral hemi-ablation templates. RESULTS Overall, 15 of 59 (25.4%) of the prostate specimens had at least 1 GP4EFD. Of the total 20 GP4EFD, 7 of 20 (35%) were ipsilateral and 13 of 20 (65%) were contralateral to the MRI-L. Of the GP4EFD, 16 of 20 (80%), 2 of 20 (10%), and 2 of 20 (10%) were GS 3 + 4, GS 4 + 3, and GS 4 + 4, respectively. Of these GP4EFD, 10 of 20 (50%) exhibited an MLCSL

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single-cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy-number changes in those populations, and measures of the proportion of cells with clonal copy-number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathologic measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant because primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single-cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions. Significance: Genomic analysis of multiple individual cells harvested from prostate biopsies provides an indepth view of cell populations comprising a prostate neoplasm, yielding novel genomic measures with the potential to improve the accuracy of diagnosis and prognosis in prostate cancer. Cancer Res; 78(2); 348–58. ©2017 AACR.

OBJECTIVE To determine if multiparametric (mp) magnetic resonance imaging (MRI) can identify significant apical disease, thereby informing decisions regarding preservation of the membranous urethra. MATERIALS AND METHODS Men undergoing radical prostatectomy (RP) between January 2012 and June 2016, who underwent a 12-core transrectal ultrasonography-guided systematic biopsy (SB), preoperative 3-Tesla MRI, and sectioning of the prostate specimen with tumour foci mapping, were extracted from a single surgeon's prospective longitudinal outcomes database. Apical SB and mpMRI lesion results were compared with regard to their ability to predict aggressive tumours in the prostatic apex (PA), defined as prostate cancer grade group >1. RESULTS Of the 100 men who met the eligibility criteria, 43 (43%) exhibited aggressive prostate cancer in the distal 5 mm of the apex. A Likert score >2 in the apical one-third of the prostate was found to be more reliable than any cancer found on apical SB at detecting aggressive cancer in the apex. On multivariate regression analysis, which included Likert score in the apex, age, prostate-specific antigen (PSA) level, prostate size and presence of any cancer on apical biopsy, only Likert score (P = 0.005) and PSA level (P = 0.025) were significant and independent predictors of aggressive cancer in the distal apex. CONCLUSION The results of the study showed that MRI was superior to SB at identifying aggressive prostate cancer within the distal PA and may be useful for planning the extent of apical preservation during RP.

Objective To determine how ipsilateral (ipsi) and contralateral (contra) systematic biopsies (SB) impact detection of clinically significant vs insignificant prostate cancer (PCa) in men with unilateral magnetic resonance imaging (MRI) lesion undergoing MRI-ultrasound fusion-targeted biopsy (MRF-TB). Materials and Methods A total of 211 cases with 1 unilateral MRI lesion were subjected to SB and MRF-TB. Biopsy tissue cores from the MRF-TB, ipsi-SB, and contra-SB were analyzed separately. Results A direct relationship was observed between MRI suspicion score and (1) detection of any cancer, (2) Gleason 6 PCa, and (3) Gleason >6 PCa. MRF-TB alone, MRF-TB + ipsi-SB, and MRF-TB + contra-SB detected 64.1%, 89.1%, and 76.1% of all PCa, respectively; 53.5%, 81.4%, and 69.8% of Gleason 6 PCa, respectively; and 73.5%, 96.0%, and 81.6% of Gleason >6 PCa, respectively. MRF-TB + ipsi-SB detected 96% of clinically significant PCa and avoided detection of 18.6% of clinically insignificant PCa. MRF-TB + contra-SB detected 81.6% of clinically significant PCa and avoided detection of 30.2% of clinically insignificant PCa. Conclusion Our study suggests that ipsi-SB should be added to MRF-TB, as detection of clinically significant PCa increases with only a modest increase in clinically insignificant PCa detection. Contra-SB in this setting may be deferred because it primarily detects clinically insignificant PCa.

Objectives To examine the characteristics and management of earlier (within 5 years) vs later (after 5 years) biochemical recurrence (BCR) after radical prostatectomy (RP). Materials and Methods Between October 2000 and October 2009, 1597 men underwent open retropubic RP. BCRs were managed using salvage radiation therapy (SRT), androgen deprivation therapy (ADT) or active surveillance (AS). BCR-free survival was assessed using Kaplan–Meier analysis. Factors predicting earlier or later BCR and BCR after SRT were assessed using logistic regression and Cox proportional hazard models, respectively. Results The probabilities of developing BCR within 5 years and 10 years were 12.3% (95% confidence interval [CI] 10.7–13.9) and 18.4% (95% CI 16.2–20.6), respectively. On multivariate analysis, prostate-specific antigen doubling time, positive surgical margins and pathological Gleason score significantly differentiated earlier from later BCR. Overall, 74.5, 12.7 and 12.7% of men developing BCR underwent SRT, ADT or AS, respectively. A significantly greater proportion of men in the earlier BCR group underwent SRT (80.8 vs 59%) and ADT (14.6 vs 8.2%), and a significantly greater proportion of men in the later BCR group underwent AS (32.8 vs 4.6%; P

We examined the time dependent rates of urinary continence following open retropubic radical prostatectomy.A total of 1,995 men treated with radical prostatectomy were enrolled in a prospective longitudinal outcomes study. The UCLA-PCI-UFS (UCLA-Prostate Cancer Index-Urinary Function Index) was administered at baseline, and 3, 6, 12, 24, 96, 120 and 180 months after open retropubic radical prostatectomy. Urinary continence was defined by 1 pad or less in 24 hours. Two multiple regression models were constructed to evaluate the association of time since open retropubic radical prostatectomy with the UCLA-PCI-UFI score and urinary continence.The decrease in urinary continence rates between baseline and 15 years (99.6% vs 87.2%, p0.001), and 2 and 15 years (95.3% vs 87.2%, p = 0.021) were statistically significant. Urinary continence rates were consistently higher in the younger group at all time points.A significant decrease in urinary continence rates was observed between baseline and 2 years, and between 2 and 15 years in the entire cohort. Urinary continence rates in age matched men in the general population who were followed longitudinally for 15 years were comparable to those in our study population. This suggests that while open retropubic radical prostatectomy causes primarily sphincteric urinary incontinence, it may be protective for subsequent benign prostatic hyperplasia mediated urinary incontinence.

Background There is no consensus regarding how to assess oncological control following focal ablation of prostate cancer. Objective To assess quality of life and in-field recurrence following focal laser ablation (FLA). Design, setting, and participants Of 34 men participating in a prospective outcomes study following FLA, 32 underwent prostate-specific antigen (PSA) testing and magnetic resonance imaging (MRI) at 6 mo and 2 yr. All underwent assessment of urinary and sexual function at 1 yr. Intervention FLA and MRI-targeted biopsy of the ablation zone. Outcome measurements and statistical analysis The American Urological Association Symptom Score and the Sexual Health Inventory for Men at baseline and 12 mo were compared using a two-sided Wilcoxon signed-rank test with a significance level of p = 0.05. The percentage of positive and negative in-field biopsies was calculated for suspicious and nonsuspicious post-ablation MRI scans. Results and limitations FLA was associated with no adverse impact on urinary or sexual function. For men with suspicious MRI (MRI+) findings, in-field disease recurrence of intermediate and low risk disease was detected in 75% and 25% of cases, respectively. For men with nonsuspicious MRI (MRI−) findings, in-field disease recurrence of intermediate- and low-risk disease was detected in 22.4% and 50% of cases, respectively. The change in PSA from baseline did not discriminate cases with MRI− findings with and without cancer at 2 yr. Conclusions MRI reliably identifies in-field recurrence of only intermediate-risk prostate cancer at 2 yr after FLA. A biopsy of the ablation zone must be performed for MRI+ findings. The decision to perform an ablation-zone biopsy for men with MRI− scans should be influenced by whether detection of low-risk disease would influence management. Patient summary Our study provides compelling evidence that men should undergo interval magnetic resonance imaging to assess the probability of intermediate-risk disease in the ablation zone following focal laser ablation of localized prostate cancer.

We determined the natural history of pathologically benign cancer suspicious regions on multiparametric magnetic resonance imaging following targeted biopsy.Between January 2012 and September 2014, 330 men underwent prostate multiparametric magnetic resonance imaging. A total of 533 cancer suspicious regions were identified and scored on a Likert scale of 1 to 5 based on suspicion for malignancy with 5 indicating the highest suspicion level. Following multiparametric magnetic resonance imaging all men underwent magnetic resonance imaging-ultrasound fusion targeted prostate biopsy using ProFuse software and the ei-Nav|Artemis system (innoMedicus, Cham, Switzerland), and a computer generated 12-core random biopsy. We analyzed a cohort of 34 men with a total of 51 cancer suspicious regions who had benign prostate biopsies and underwent repeat multiparametric magnetic resonance imaging and prostate specific antigen testing at 1 year. Changes in the greatest linear measurement, the suspicion score and serum prostate specific antigen were ascertained.During 1 year the suspicion score distribution and the mean greatest linear measurement of the cancer suspicious regions decreased significantly (p 0.0001) while mean prostate specific antigen did not significantly change (p = 0.632). Two (3.9%), 15 (29.4%) and 34 cancer suspicious regions (66.7%) showed an increase, no change and decrease in suspicion score, respectively. No (0%), 21 (42.0%) and 29 cancer suspicious regions (58.0%) showed an increase of 20% or greater, no change and a decrease of 20% or greater in greatest linear measurement, respectively. Of the 2 cancer suspicious regions exhibiting an increased suspicion score neither showed a prostate specific antigen increase of 0.5 ng/ml or greater.Our study provides compelling evidence that few benign cancer suspicious regions increase in suspicion score and/or the greatest linear measurement within 1 year independent of the baseline suspicion score. Therefore, routinely repeating multiparametric magnetic resonance imaging at 1 year in men with pathologically benign cancer suspicious regions should be discouraged since it is unlikely to influence management decisions.

We examined the effect of previous transurethral resection of the prostate (TURP) on multiple oncologic and continence outcomes after robotic-assisted radical prostatectomy (RARP). We performed a retrospective cohort study of a total of 2693 patients from 2007 to 2014 who underwent RARP. Patients were stratified into 49 patients who had previous TURP prior to RARP (group 1) and 2644 patients who had no TURP prior to RARP (group 2). We collected operative variables including estimated blood loss, operative time, and positive surgical margin (PSM) rates. Urinary continence, defined as 0 pads per day (PPD), and social continence, defined as 1-PPD, were also assessed. American Urological Association Symptoms Score (AUASS), overall ability to function sexually, and Expanded Prostate Cancer Index Composite (EPIC) questionnaire were evaluated at 3 and 12 months after RARP. Weakness of urinary stream (EPIC #4d) at 12 months imposed a greater problem for group 1 patients with prior TURP compared to group 2 patients without prior TURP (p = 0.012). PSM was not statistically significant between the two groups (p = 0.110). Group 1 patients had a greater PSM rate (30.61 %) as compared to group 2 (20.95 %). PSM locations in group 1 patients showed the most common locations at the posterior and apex. The difference between the two groups for AUASS, overall sexual function, estimated blood loss, operative time, urinary continence, and social continence was not statistically significant. We examined the effect of previous TURP on postoperative RARP continence and oncologic outcomes. This data can be used to counsel those with prior TURP before RARP.

BackgroundSerum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients.MethodsA total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT)

using ex vivo 3 Tesla or 7 Tesla magnetic field strengths from fresh prostatectomy specimens (n1⁄415) obtained from either organ donor or PCa patients under Institutional Review Board approval. To achieve the closest correspondence between histopathological components and MRI images in terms of resolution and sectioning planes, multiple high resolution imaging protocols (ranging from few minutes to overnight) were tested. Ductograms were generated as part of image post-processing. Specimens were subsequently submitted for histopathological evaluation. RESULTS: A total of 7 imaging protocols were tested (Table 1). Ex vivo 7 Tesla MRI identified normal components of prostate glands including ducts, blood vessels, concretions, and stroma at a spatial resolution of 60 X 60 X 60 mm3 to 107 X 107 X 500 mm3. A 7 Tesla spin echo image from a whole gland at a spatial resolution of 100 X 107 X 750 mm3 shown that the visible structures clearly approached the microscopic scale highlighting the microanatomy of intraprostatic tissue (Figure 1). Malignant glands and nests of tumor cells identified at 60 X 60 X 90 mm3 were highly comparable to low magnification (x2) histopathology. Ductograms enhanced the differentiation between benign and malignant glands. CONCLUSIONS: We demonstrated that critical histopathological features of the prostate gland can be identified with high resolution ex vivo MRI examination and offer promise that MR microscopy of PCa will ultimately be possible in vivo. Source of Funding: None

Objective To provide insight into the impact of radical prostatectomy (RP) on prostate cancer–specific mortality (PCSM) in a primarily prostate-specific antigen screen–detected cohort of men with localized prostate cancer (PCa). Methods Between 2000 and 2013, 1864 men consented to participate in a prospective longitudinal outcomes study after RP for localized PCa by a single surgeon. Men lost to follow-up were queried to the National Death Index to acquire mortality data. Results From our cohort of 1864 men (median age 59 years, median preoperative prostate-specific antigen 5.0, median follow-up 9.1 years), Kaplan-Meier analysis demonstrated 10-year all-cause mortality and PCSM of 4.6% and 1.4%, respectively. Ten-year PCSM for low, intermediate, and high D'Amico risk were 0.9%, 1.0%, and 7.4%, respectively (P

Background: The presence of lymph nodes (LN) within the prostatic anterior fat pad (PAFP) has been reported in several recent reports. These PAFP LNs rarely harbor metastatic disease, and the characteristics of patients with PAFP LN metastasis are not well-described in the literature. Our previous study suggested that metastatic disease to the PAFP LN was associated with less severe oncologic outcomes than those that involve the pelvic lymph node (PLN). Therefore, the objective of this study is to assess the oncologic outcome of prostate cancer (PCa) patients with PAFP LN metastasis in a larger patient population. Methods: Data were analyzed on 8800 patients from eleven international centers in three countries. Eighty-eight patients were found to have metastatic disease to the PAFP LNs (PAFP+) and 206 men had isolated metastasis to the pelvic LNs (PLN+). Clinicopathologic features were compared using ANOVA and Chi square tests. The Kaplan-Meier method was used to calculate the time to biochemical recurrence (BCR). Results: Of the eighty-eight patients with PAFP LN metastasis, sixty-three (71.6 %) were up-staged based on the pathologic analysis of PAFP and eight (9.1 %) had a low-risk disease. Patients with LNs present in the PAFP had a higher incidence of biopsy Gleason score (GS) 8–10, pathologic N1 disease, and positive surgical margin in prostatectomy specimens than those with no LNs detected in the PAFP. Men who were PAFP+ with or without PLN involvement had more aggressive pathologic features than those with PLN disease only. However, there was no significant difference in BCR-free survival regardless of adjuvant therapy. In 300 patients who underwent PAFP LN mapping, 65 LNs were detected. It was also found that 44 out of 65 (67.7 %) nodes were located in the middle portion of the PAFP. Conclusions: There was no significant difference in the rate of BCR between the PAFP LN+ and PLN+ groups. The PAFP likely represents a landing zone that is different from the PLNs for PCa metastasis. Therefore, the removal and pathologic analysis of PAFP should be adopted as a standard procedure in all patients undergoing radical prostatectomy.

cancer significant association with finding upstaging/upgrading at RP specimens in this subset of patients. Positive Surgical Margin (PSM) was noted in 66(16%) patients, and the PSM rate was significantly higher in patients who were upstaged in the RP specimens. The mean follow-up of the study population was 28 months and the predicted Biochemical Recurrence Free survival at 5 years was 92% and 88% in the patients who were not and were upstaged/upgraded at RP specimens respectively CONCLUSIONS: Percentage of positive cores appears to predict pathological upstaging/upgrading at radical prostatectomy in patients subjected to Active Surveillance

Item does not contain fulltext From April 2013 to July 2014, 25 consecutive men participated in a longitudinal outcomes study following in-bore magnetic resonance imaging (MRI)-guided focal laser ablation (FLA) of prostate cancer (PCa). Eligibility criteria were clinical stage T1c and T2a disease; prostate-specific antigen (PSA)