Transcriptomic Heterogeneity of Expansile Cribriform and Other Gleason Pattern 4 Prostate Cancer Subtypes.

BACKGROUND: Prostate cancers featuring an expansile cribriform (EC) pattern are associated with worse clinical outcomes following radical prostatectomy (RP). However, studies of the genomic characteristics of Gleason pattern 4 subtypes are limited. OBJECTIVE: To explore transcriptomic characteristics and heterogeneity within Gleason pattern 4 subtypes (fused/poorly formed, glomeruloid, small cribriform, EC/intraductal carcinoma [IDC]) and the association with biochemical recurrence (BCR)-free survival. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study including 165 men with grade group 2-4 prostate cancer who underwent RP at a single academic institution (2016-2020) and Decipher testing of the RP specimen. Patients with Gleason pattern 5 were excluded. IDC and EC patterns were grouped. Median follow-up was 2.5 yr after RP for patients without BCR. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Prompted by heterogeneity within pattern 4 subtypes identified via exploratory analyses, we investigated transcriptomic consensus clusters using partitioning around medoids and hallmark gene set scores. The primary clinical outcome was BCR, defined as two consecutive prostate-specific antigen measurements >0.2 ng/ml at least 8 wk after RP, or any additional treatment. Multivariable Cox proportional-hazards models were used to determine factors associated with BCR-free survival. RESULTS AND LIMITATIONS: In this cohort, 99/165 patients (60%) had EC and 67 experienced BCR. Exploratory analyses and clustering demonstrated transcriptomic heterogeneity within each Gleason pattern 4 subtype. In the multivariable model controlled for pattern 4 subtype, margin status, Cancer of the Prostate Risk Assessment Post-Surgical score, and Decipher score, a newly identified steroid hormone-driven cluster (hazard ratio 2.35 95% confidence interval 1.01-5.47) was associated with worse BCR-free survival. The study is limited by intermediate follow-up, no validation cohort, and lack of accounting for intratumoral and intraprostatic heterogeneity. CONCLUSIONS: Transcriptomic heterogeneity was present within and across each Gleason pattern 4 subtype, demonstrating there is additional biologic diversity not captured by histologic subtypes. This heterogeneity can be used to develop novel signatures and to classify transcriptomic subtypes, which may help in refining risk stratification following RP to further guide decision-making on adjuvant and salvage treatments. PATIENT SUMMARY: We studied prostatectomy specimens and found that tumors with similar microscopic appearance can have genetic differences that may help to predict outcomes after prostatectomy for prostate cancer. Our results demonstrate that further gene expression analysis of prostate cancer subtypes may improve risk stratification after prostatectomy. Future studies are needed to develop novel gene expression signatures and validate these findings in independent sets of patients.

Gleason Grade 1 Prostate Cancer Volume at Biopsy Is Associated With Upgrading but Not Adverse Pathology or Recurrence After Radical Prostatectomy: Results From a Large Institutional Cohort.

PURPOSE: Clinical guidelines suggest that for low-grade, clinically localized prostate cancer, patients with higher volume of disease at diagnosis may benefit from definitive therapy, although the data remain unclear. Our objective was to determine associations between low-grade prostate cancer volume and outcomes in men managed with primary radical prostatectomy. MATERIALS AND METHODS: Men with cT1-2N0/xM0/x prostate cancer, prostate specific antigen at diagnosis <10 ng/mL, and Gleason grade group 1 pathology on diagnostic biopsy managed with primary radical prostatectomy were included. Outcomes were pathological upgrade at radical prostatectomy (≥Gleason grade group 2), University of California, San Francisco adverse pathology at radical prostatectomy (≥Gleason grade group 3, pT3/4, or pN1), alternate adverse pathology at radical prostatectomy (≥Gleason grade group 3, ≥pT3b, or pN1), and recurrence (biochemical failure with 2 prostate specific antigen ≥0.2 ng/mL or salvage treatment). Multivariable logistic regression models were used to estimate associations between percentage of positive cores and risk of upgrade and adverse pathology at radical prostatectomy. Multivariable Cox proportional hazards regression models were used to estimate associations between percentage of positive cores and hazard of recurrence after radical prostatectomy. RESULTS: A total of 1,029 men met inclusion criteria. Multivariable logistic regression models demonstrated significant associations between percentage of positive cores and pathological upgrade (OR 1.31, 95% CI 1.1-1.57, P < .01), but not University of California, San Francisco adverse pathology at radical prostatectomy (P = .84); percentage of positive cores was negatively associated with alternate adverse pathology (OR 0.67, 95% CI 0.48-0.93, P = .02). Multivariable Cox regression models demonstrated no association between percentage of positive cores and hazard of recurrence after radical prostatectomy (P = .11). CONCLUSIONS: In men with Gleason grade group 1 prostate cancer, tumor volume may be associated with upgrading at radical prostatectomy, but not more clinically significant outcomes of adverse pathology or recurrence.

Residual Benign Prostate Glandular Tissue after Radical Prostatectomy is Not Associated with the Development of Detectable Postoperative Serum Prostate Specific Antigen.

PURPOSE: To determine if benign glandular tissue at the surgical margin (BGM) is associated with detectable prostate specific antigen (PSA) and/or biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: Participants underwent RP for localized prostate cancer between 2004 and 2018. Regression analysis was used to identify demographic, clinical and surgical factors associated with the likelihood of BGM presence on surgical pathology. Oncologic outcomes included detectable PSA (>0.03 ng/ml), BCR (≥0.2 ng/ml) and progression to BCR or salvage treatment after detectable PSA. Life tables and Cox proportional hazards regression models were used to determine the association of BGM and risk of oncologic outcomes. RESULTS: A total of 1,082 men underwent RP for localized prostate cancer with BGM reported on surgical pathology and an undetectable postoperative PSA. BGM was present on 249 (23%) specimens. Younger age, bilateral nerve sparing surgery and robotic approach were associated with presence of BGM while malignancy at the surgical margin (MSM) was not. At 7 years after RP, 29% experienced detectable PSA and 11% had BCR. In the subgroup of men who reached detectable PSA, 79% had progression within 7 years. On multivariate Cox proportional hazards regression, BGM status was not independently associated with detectable PSA, BCR and/or progression from detectable PSA to BCR or salvage treatment. CONCLUSIONS: The presence of BGM at RP was not associated with increased risk of MSM, detectable PSA, BCR or progression after detectable PSA.

Patient Satisfaction in a Safety Net Urology Clinic.

INTRODUCTION: Patient satisfaction has become an important metric in medicine. In this study, we aim to identify modifiable factors contributing toward poor satisfaction amongst patients in a safety net urology clinic. We hypothesize that wait times and long distances traveled to clinic will have the largest contribution toward negative patient experiences. METHODS: We conducted a cross-sectional study of adult patients presenting to the urology clinic at Zuckerberg San Francisco General Hospital. Participants completed a survey using the RAND Patient Satisfaction Questionnaire-18 after their clinic visit. Associations among demographic factors, wait times, use of a translator and satisfaction were examined. RESULTS: Two hundred patients, 19 to 90 years old (median age 62), were enrolled. Overall, 65% of patients were satisfied with their experience in our clinic. Our results demonstrated a significant association among race, language and overall satisfaction scores (p=0.009 and p=0.003, respectively). Multivariable analysis showed that those who waited more than an hour to see a physician were less satisfied compared with those who waited less than 15 minutes (OR 0.25, 95% CI 0.08-0.74). Similarly, those who used a translator were less satisfied than those who did not use a translator (OR 0.29, 95% CI 0.08-1.01). CONCLUSIONS: In a safety net urology clinic, language differences and wait times may contribute to poor patient satisfaction. Future efforts toward improving language interpreter functionality and decreasing patient wait times will likely improve patient satisfaction.

MRI-Based Prostate-Specific Antigen Density Predicts Gleason Score Upgrade in an Active Surveillance Cohort.

OBJECTIVE. Elevated prostate-specific antigen density (PSAD) based on transrectal ultrasound (TRUS) measurements has been shown to be strongly associated with clinically significant disease and to predict progression on active surveillance (AS) for men with disease that is at a low stage or grade. We hypothesized that elevated MRI PSAD is similarly associated with increased risk of progression on subsequent biopsy. MATERIALS AND METHODS. In this retrospective study, men with Gleason score of 3+3 on diagnostic TRUS-guided biopsy who were managed with AS, had undergone MRI, and had at least one additional biopsy were included. MRI PSAD was calculated using prostate volume on MRI and prostate-specific antigen level temporally closest to the MRI. Multivariable logistics regression models were used to evaluate the association between MRI PSAD and predictors of upgrade on serial biopsy. RESULTS. A total of 166 patients were identified, of whom 74 (44.6%) were upgraded to a Gleason score of 7 or higher on subsequent biopsy. Lesions with Prostate Imaging Reporting and Data System (PI-RADS) scores of 4 and 5 more commonly had MRI PSAD of 0.15 ng/mL2 or higher (51.93% vs 22.22%, p = 0.01) than lesions with PI-RADS scores of 1-3. Median MRI PSAD was significantly higher in the upgraded group compared with the group that was not upgraded (0.15 ng/mL2 vs 0.11 ng/mL2, p = 0.01). MRI PSAD was significantly associated with increased odds of upgrading on subsequent biopsy (log transformation; odds ratio, 1.9 [95% CI, 1.2-2.8]; p = 0.01) after adjusting for age and length of follow-up. CONCLUSION. MRI PSAD was significantly associated with Gleason score upgrading on subsequent biopsy for men initially diagnosed with Gleason 3+3 disease. Although this result is intuitive, to our knowledge it has not been previously shown. As MRI utilization increases, MRI PSAD can aid in risk stratification for men managed with AS.

Socioeconomic Status in Non-directed and Voucher-based Living Kidney Donation.

BACKGROUND: Little has been reported about the socioeconomic status (SES) and demographics of non-directed (altruistic) and voucher-based donation. OBJECTIVE: To analyze common characteristics amongst altruistic donors in order to promote non-directed and voucher-based donation. DESIGN, SETTING, AND PARTICIPANTS: Information regarding altruistic donations from 2008 to 2015 and voucher-based donors was obtained from the National Kidney Registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: An SES index, created and validated by the Agency for Healthcare Research and Quality (AHRQ), was created by geocoding the donor's zip code and linking it to seven publicly available SES variables found in the 2010 United States Census data. RESULTS AND LIMITATIONS: In total, 267 non-directed and 3 voucher-based donations were identified. Non-directed donors were predominantly female (58%), with an average age of 45.6 yr (range, 21-72). The mean SES index score was 55.6 (SD=3.2), which corresponds to the 77th percentile of 1.5 million MediCare beneficiaries as reported by the AHRQ in 2008. Voucher-based donors were Caucasian males of high SES. The study was limited by the number of voucher-based donations. CONCLUSIONS: Non-directed and voucher-based donors are in the upper end of the economic spectrum. The voucher-based program has built within it the inherent capacity to remove disincentives to donation, which currently limit altruistic donation. PATIENT SUMMARY: We wanted to determine what types of people donated their kidneys altruistically, so that we could understand how to motivate more people to donate their kidneys. The voucher-based program was recently started and is a promising tool to motivate many people to donate kidneys by removing major disincentives to donation.

Female Sexual Dysfunction and the Placebo Effect: A Meta-analysis.

OBJECTIVE: To quantify the placebo effect of various pharmacologic modalities including neuromodulators, hormonal agents, and onabotulinum toxin A for female sexual dysfunction. DATA SOURCES: Using Meta-analyses Of Observational Studies in Epidemiology guidelines, we conducted a systematic review of PubMed, EMBASE, ClinicalTrials.gov, and the Cochrane Review databases. METHODS OF STUDY SELECTION: Eleven search terms, "female sexual dysfunction" "treatment" in combination with "hypoactive sexual desire," "arousal disorder," "sexual pain disorder," "genitourinary syndrome of menopause," "orgasmic disorder," "vulvovaginal atrophy," "vaginismus," "vaginal atrophy," "vulvodynia," and "vestibulitis," were used. Studies were included if their design was randomized, included a placebo arm, and used the Female Sexual Function Index as an outcome measure. TABULATION, INTEGRATION, AND RESULTS: The placebo effect on the Female Sexual Function Index was compared with each respective study's treatment effect using inverse-variance weighting in a random-effects analysis model. Six hundred five relevant articles were retrieved. Twenty-four randomized controlled trials included a placebo arm. Of these, eight studies used the Female Sexual Function Index. Across these studies, 1,723 women with clinical pretreatment female sexual dysfunction received placebo. Two thousand two hundred thirty-six women were in the treatment arm of the respective studies and received various pharmacologic interventions including flibanserin, bupropion, onabotulinum toxin A, intravaginal prasterone, intranasal oxytocin, ospemifene, and bremelanotide. Women receiving placebo improved 3.62 (95% CI 3.29-3.94) on the Female Sexual Function Index. The treatment arm had a corresponding increase of 5.35 (95% CI 4.13-6.57). CONCLUSION: This meta-analysis of Level I evidence demonstrates that 67.7% of the treatment effect for female sexual dysfunction is accounted for by placebo. Our findings suggest that the current treatments for female sexual dysfunction are, overall, minimally superior to placebo, which emphasizes the ongoing need for more efficacious treatment for female sexual dysfunction.

Low self-efficacy is associated with decreased emergency department use in underserved men with prostate cancer.

BACKGROUND: Self-efficacy has been strongly associated with health behavior and health maintenance. We examined the relationship between patient-provider self-efficacy and emergency department usage in low-income, underinsured, or uninsured patients with prostate cancer. METHODS: We prospectively analyzed quality of life, behavior, and self-efficacy data from men enrolled in a state-funded program providing free prostate cancer care. We summarized patient characteristics stratified by self-efficacy scores (high, mid, and low) and by emergency department visit (any vs. none). We conducted a multivariate repeated measures regression analysis with negative binomial distribution to calculate predicted counts of emergency department visits over time across the self-efficacy strata. RESULTS: Our cohort included 469 men with a maximum follow-up time of 84 months. Of these men, 70 had visited the emergency department during their enrollment for a total of 118 unique visits. The regression analysis demonstrated a decreasing number of emergency department visits over time for the low (P = 0.0633) and mid (P = 0.0450) self-efficacy groups but not for the high self-efficacy group (P = 0.1155). Pain (22.9%), urinary retention (18.6%), and fever (5.9%) were the most common reasons for emergency department visits. CONCLUSIONS: Patients with low and mid self-efficacy had a decreasing number of emergency department usage over time. Those with high self-efficacy did not follow these trends. Interventions to improve communication between patients and primary treatment teams could prove beneficial in avoiding excess emergency department use.