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.

Long-term complications and health-related quality of life outcomes after radical prostatectomy with or without subsequent radiation treatment for prostate cancer.

BACKGROUND: To report objective long-term complications and health related quality of life (HRQOL) outcomes after radical prostatectomy (RP) with and without radiation therapy (RT) for prostate cancer (CaP). METHODS: We analyzed patients diagnosed with CaP who underwent RP from the UCSF Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry between 1995 and 2020. Cox proportional hazards were used to assess risk of postoperative complications which included cystitis, gastrointestinal (GI) toxicity, incontinence requiring a surgical procedure, ureteral injury and urinary stricture. Repeated measures mixed models were used to assess the effects of radiation and complications on patient-reported urinary, bowel, and sexual function after surgery. RESULTS: Of 6,258 men who underwent RP, cumulative incidence of EBRT was 9.1% at 5 years after surgery. Patients who received postoperative radiation were at increased risk for onset of cystitis (HR 5.60, 95% CI 3.40-9.22, P < 0.01). Receipt of RT was not associated with other complications. In repeated measures analysis, postoperative RT was associated with worsening general health scores, adjusting for complications of incontinence, urinary stricture, GI toxicity or ureteral injury, independent of whether patients had those complications. CONCLUSIONS: RT after RP was associated with an increase in the risk of cystitis and worse general health in the long term. Other complications and HRQOL outcomes did not demonstrate differences by whether patients had RT or not. While post-operative RT is the only curative option for CaP after RP, patients and providers should be aware of the increased risks when making treatment decisions.

The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer.

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease. SIGNIFICANCE: Comprehensive characterization of the five subtypes of metastatic castration-resistant prostate cancer identified transcription factors that drive each subtype and showed that the double-negative subtype has the worst prognosis.

The Long-term Incidence and Quality of Life Outcomes Associated With Treatment-Related Toxicities of External Beam Radiotherapy for Prostate Cancer.

OBJECTIVE: To assess the long-term incidence of treatment-related toxicities and quality of life (QOL) outcomes associated with toxicity after external beam radiotherapy (EBRT) for prostate cancer. METHODS: We identified all men who had EBRT between 1994 and 2017 from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a longitudinal, nationwide prostate cancer registry. CaPSURE was queried for patient-reported and International Classification of Diseases-9/10 and Current Procedural Terminology codes. The Medical Outcomes Studies Short Form 36 and the University of California, Los Angeles Prostate Cancer Index were used to provide measures of general health, sexual, urinary, and bowel function. Repeated measures mixed models were used to determine QOL change after onset of toxicity. RESULTS: From a total of 15,332, 1744 (11.4%) men had EBRT. The median follow-up was 7.9years (interquartile range [IQR] 4.3-12.7). The median time to onset of any toxicity including urinary pad usage in 265 (15.4% at 8years) men was 4.3years (IQR 1.8-8.0). The most frequent toxicity was hemorrhagic cystitis (104, 5.9% at 8years) after a median of 3.7years (1.3-7.8), gastrointestinal (48, 2.7% at 8years) after a median of 4.2years (IQR 1.3-7.8), followed by urethral stricture (47, 2.4% at 8years) after a median of 3.7years (IQR 1.9-9.1). Repeated measures mixed models found that onset of hemorrhagic cystitis was associated with change in general health over time. CONCLUSION: EBRT for prostate cancer is associated with distinct treatment-related toxicities which can occur many years after treatment and can affect QOL. These results may help men understand the long-term implications of treatment decisions.

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.

Medium Term Outcomes of Focal Cryoablation for Intermediate and High Risk Prostate Cancer: MRI and PSA are Not Predictive of Residual or Recurrent Disease.

OBJECTIVE: To understand oncologic outcomes of focal cryoablation for prostate cancer and efficacy MRI and PSA to predict residual disease and recurrence. METHODS: We retrospectively analyzed patients who underwent focal cryotherapy at a single institution. Inclusion criteria included clinically localized biopsy-proven cancer that was clearly visible on MRI or ultrasound. The primary outcomes were failure-free survival (FFS) defined as no transition to radical, whole-gland or systemic therapy and biochemical recurrence (Phoenix PSA nadir +2 increases), and secondary outcomes included changes in the Gleason grade group (GG) and MRI findings. RESULTS: 75 patients completed post cryotherapy biopsy with a median follow-up of 1.89 [IQR 1.19-2.77] years. Failure free survival was met by 96.2% of patients at 2 year follow up and of those who did not meet this outcome, 3 had metastasis, 1 had a salvage prostatectomy and 5 underwent radiation. On the treated side of the prostate, 7 (9.5%) of patients had residual ≥GG2 disease compared to 7 (9.5%) patients on the untreated side. Out of the 12 patients who had residual ≥GG2 disease at follow up biopsy (either on treated or untreated side of the prostate), 11 (91.7%) had PI-RADS 1-3 on follow up MRI. Using a multivariate cox proportional hazards model, Phoenix criteria for recurrence (PSA nadir +2) was not predictive for FFS. CONCLUSIONS: Focal cryotherapy is effective for treating focal lesions of prostate cancer, but patients require continued surveillance. MRI and PSA are not reflective of residual disease on follow up biopsy.

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.

Post-operative complications following feminizing genitoplasty in moderate to severe genital atypia: Results from a multicenter, observational prospective cohort study.

Disorders/differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. While there remains controversy around the traditionally binary concept of sex, most patients with DSD are reared either male or female depending on their genetic sex, gonadal sex, genital phenotype and status of their internal genital tract. This study uses prospective data from 12 institutions across the United States that specialize in DSD care. We focused on patients raised female. Eligible patients had moderate to severe genital atypia (defined as Prader score >2), were ≤2 years of age at entry, and had no prior genitoplasty. The aim of this study is to describe early post operative complications for young patients undergoing modern approaches to feminizing genitoplasty. Of the 91 participants in the cohort, 57 (62%) were reared female. The majority had congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (n = 52), 1 had ovo-testicular syndrome, 2 had mixed gonadal dysgenesis and 2 had partial androgen insensitivity syndrome (PAIS). Of the 50 participants who received early genitoplasty, 43 (86%) had follow-up at 6-12 months post-surgery. Thirty-two participants (64%) received a clitoroplasty, 31 (62%) partial urogenital mobilization and 4 (8%) total urogenital sinus mobilization. Eighteen percent (9/50) experienced post-surgical complications with 7 (14%) being rated as Clavien-Dindo grade III. Both parents and surgeons reported improved satisfaction with genital appearance of participants following surgery compared to baseline. This information on post-operative complications associated with contemporary approaches to feminizing genitoplasty performed in young children will help guide families when making decisions about whether or not to proceed with surgery for female patients with moderate to severe genital atypia.

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.

The Impact of Partnership Status and Social Support on Health Related Quality of Life Outcomes in Men with Prostate Cancer.

INTRODUCTION: We examined the relationship between partnership status and social support and its effect on longitudinal health related quality of life outcomes in underserved, low income men with prostate cancer. METHODS: We prospectively analyzed quality of life outcomes across partnership status and the social support of each patient enrolled in a state funded program for free prostate cancer treatment. The UCLA Prostate Cancer Index Short Form was used to quantify urinary, sexual and bowel habits in the 2 domains of bother and function. Physical health and mental health were measured with the RAND Medical Outcomes Study Short Form. We compared 4 levels of partnership and social support dyads with a repeated measures analysis while controlling for patient characteristics. RESULTS: A total of 223 men were eligible for inclusion in the study. Of the 70 patients with a partner 54 (77%) listed their partner as their only support member and the remaining 16 listed their partner and 1 or 2 children as their support group. There were few differences in the major quality of life domains of urinary, bowel and bladder function and bother. Physical and mental health scores did not differ by partnership status or social support. CONCLUSIONS: While we hypothesized that being partnered and having increased social support would have a positive effect on quality of life, we did not find this association in our longitudinal analysis. We propose that patterns of confiding in others and integration of a nurse case manager are highly gender based, and may provide possible explanations for our findings.

Use of Polyethylene Glycol Electrolyte Solution Expedites Return of Bowel Function and Facilitates Early Discharge after Kidney Transplantation.

BACKGROUND: Delay in the return of bowel function often prolongs hospitalization after kidney transplantation, leading to increased patient morbidity and health care costs. Polyethylene glycol (PEG) solution has been observed to aid the return of bowel function in postoperative patients undergoing abdominal surgery. STUDY DESIGN: Using a 2-arm, single-surgeon, nonrandomized study, we compared the addition of PEG along with early resumption of diet with a control group using only early resumption of diet in kidney transplantation patients. RESULTS: There were 51 subjects in the control group and 47 subjects in the PEG intervention group. The primary outcomes measure, time to bowel movement, was significantly shorter than the control group by an entire day (2.9 ± 1.1 days vs 4.0 ± 1.3 days; p < 0.001). In propensity score analysis, patients receiving PEG had bowel movements sooner (-1.06 ± 0.25 days; p < 0.001) and decreased lengths of stay (-1.16 ± 0.27 days; p < 0.001). CONCLUSIONS: Polyethylene glycol significantly reduced time to return of bowel function and postoperative length of stay. By adding PEG to the postoperative protocol, we can help to reduce costs of hospitalization and improve overall outcomes in renal transplantation patients.

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.