Effects of protein restriction on insulin-like growth factor (IGF)-1 in men with prostate cancer: results from a randomized clinical trial.

BACKGROUND: Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer. METHODS: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m2) men with localized prostate cancer, aged 43-72 years, were randomized (1:1) with permuted blocks to 4-6 weeks of customized isocaloric PR diets (0.8 g protein/kg lean body mass) or their usual diet. Biomarkers influencing cancer biology, including serum IGF-1 and its binding proteins were measured longitudinally. RESULTS: Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration. CONCLUSION: These findings demonstrate that protein restriction without calorie restriction does not reduce serum IGF-1 concentration or increase IGFBP-1 and IGFBP-3 in men with localized prostate cancer. Further research is needed to identify dietary interventions for safely and effectively reducing IGF-1 in this patient group.

Prostate-Specific Membrane Antigen-Targeted Imaging and Its Correlation with HOXB13 Expression.

Homeobox 13 (HOXB13) is an oncogenic transcription factor that directly regulates expression of folate hydrolase 1, which encodes prostate-specific membrane antigen (PSMA). HOXB13 is expressed in primary and metastatic prostate cancers (PCs) and promotes androgen-independent PC growth. Since HOXB13 promotes resistance to androgen receptor (AR)-targeted therapies and regulates the expression of folate hydrolase 1, we investigated whether SUVs on PSMA PET would correlate with HOXB13 expression. Methods: We analyzed 2 independent PC patient cohorts who underwent PSMA PET/CT for initial staging or for biochemical recurrence. In the discovery cohort, we examined the relationship between HOXB13, PSMA, and AR messenger RNA (mRNA) expression in prostate biopsy specimens from 179 patients who underwent PSMA PET/CT with 18F-piflufolastat. In the validation cohort, we confirmed the relationship between HOXB13, PSMA, and AR by comparing protein expression in prostatectomy and lymph node (LN) sections from 19 patients enrolled in 18F-rhPSMA-7.3 PET clinical trials. Correlation and association analyses were also used to confirm the relationship between the markers, LN positivity, and PSMA PET SUVs. Results: We observed a significant correlation between PSMA and HOXB13 mRNA (P < 0.01). The association between HOXB13 and 18F-piflufolastat SUVs was also significant (SUVmax, P = 0.0005; SUVpeak, P = 0.0006). Likewise, the PSMA SUVmax was significantly associated with the expression of HOXB13 protein in the 18F-rhPSMA-7.3 PET cohort (P = 0.008). Treatment-naïve patients with LN metastases demonstrated elevated HOXB13 and PSMA levels in their tumors as well as higher PSMA tracer uptake and low AR expression. Conclusion: Our findings demonstrate that HOXB13 correlates with PSMA expression and PSMA PET SUVs at the mRNA and protein levels. Our study suggests that the PSMA PET findings may reflect oncogenic HOXB13 transcriptional activity in PC, thus potentially serving as an imaging biomarker for more aggressive disease.

Symptomatic Benign Prostatic Hyperplasia with Suppressed Epigenetic Regulator HOXB13 Shows a Lower Incidence of Prostate Cancer Development.

Our objective was to identify variations in gene expression that could help elucidate the pathways for the development of prostate cancer (PCa) in men with Benign Prostatic Hyperplasia (BPH). We included 98 men with BPH, a positive prostate MRI (Prostate Imaging Reporting and Data System; PIRADS ≥ 4), and a negative biopsy from November 2014 to January 2018. RNA sequencing (RNA-Seq) was performed on tissue cores from the MRI lesion and a geographically distant region (two regions per patient). All patients were followed for at least three years to identify who went on to develop PCa. We compared the gene expressions of those who did not develop PCa ("BPH-only") vs. those who did ("BPH/PCa"). Then, we identified the subset of men with BPH who had the highest American Urological Association (AUA) symptom scores ("symptomatic BPH") and compared their gene expression to the BPH/PCa group. At a median follow-up of 47.5 months, 15 men had developed PCa while 83 did not. We compared gene expressions of 14 men with symptomatic BPH (AUAss ≥ 18) vs. 15 with BPH/PCa. We found two clusters of genes, suggesting the two groups had distinctive molecular features. Differential analysis revealed genes that were upregulated in BPH-only and downregulated in BPH/PCa, and vice versa. Symptomatic BPH men had upregulation of T-cell activation markers (TCR, CD3, ZAP70, IL-2 and IFN-γ and chemokine receptors, CXCL9/10) expression. In contrast, men with BPH/PCa had upregulation of NKX3-1 and HOXB13 transcription factors associated with luminal epithelial progenitors but depleted of immune cells, suggesting a cell-autonomous role in immune evasion. Symptomatic BPH with immune-enriched landscapes may support anti-tumor immunity. RNA sequencing of benign prostate biopsy tissue showing upregulation of NKX3-1 and HOXB13 with the absence of T-cells might help in identifying men at higher risk of future PCa development, which may be useful in determining ongoing PCa screening.

Novel non-MRI imaging techniques for primary diagnosis of prostate cancer: micro-ultrasound, contrast-enhanced ultrasound, elastography, multiparametric ultrasound, and PSMA PET/CT.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) provides enhanced diagnostic accuracy in the detection of prostate cancer, but is not devoid of limitations. Given the recent evolution of non-MRI imaging techniques, this critical review of the literature aimed at summarizing the available evidence on ultrasound-based and nuclear medicine imaging technologies in the initial diagnosis of PCa. METHODS: Three databases (PubMed®, Web of Science™, and Scopus®) were queried for studies examining their diagnostic performance in the primary diagnosis of PCa, weighted against a histological confirmation of PCa diagnosis, using a free-text protocol. Retrospective and prospective studies, both comparative and non-comparative, systematic reviews (SR) and meta-analysis (MA) were included. Based on authors' expert opinion, studies were selected, data extracted, and results qualitatively described. RESULTS: Micro-ultrasound (micro-US) appears as an appealing diagnostic strategy given its high accuracy in detection of PCa, apparently non-inferior to mpMRI. The use of multiparametric US (mpUS) likely gives an advantage in terms of effectiveness coming from the combination of different modalities, especially when certain modalities are combined. Prostate-specific membrane antigen (PSMA) PET/CT may represent a whole-body, one-step approach for appropriate diagnosis and staging of PCa. The direct relationship between lesions avidity of radiotracers and histopathologic and prognostic features, and its valid diagnostic performance represents appealing characteristics. However, intrinsic limits of each of these techniques exist and further research is needed before definitively considering them reliable tools for accurate PCa diagnosis. Other novel technologies, such as elastography and multiparametric US, currently relies on a limited number of studies, and therefore evidence about them remains preliminary. CONCLUSION: Evidence on the role of non-MRI imaging options in the primary diagnosis of PCa is steadily building up. This testifies a growing interest towards novel technologies that might allow overcoming some of the limitations of current gold standard MRI imaging.

Impact of 18F-fluciclovine PET/CT on plans for androgen deprivation therapy in patients with biochemical recurrence of prostate cancer: data analysis from two prospective clinical trials.

INTRODUCTION: Despite early detection and primary therapy improvements, biochemical recurrence (BCR) of prostate cancer remains common. The advent of highly sensitive molecular imaging has facilitated identification of men with limited metastatic disease burden that might be more optimally treated with metastases-directed therapy than with androgen deprivation therapy (ADT). The LOCATE (NCT02680041) and FALCON (NCT02578940) trials assessed the impact of 18F-fluciclovine PET/CT on the management of patients with BCR after curative-intent primary therapy. We performed a secondary analysis of LOCATE and FALCON data to characterize sites of recurrence and management decisions for BCR patients who had an intended management plan including ADT prior to undergoing 18F-fluciclovine PET/CT. METHODS: Data from 317 LOCATE/FALCON patients who underwent 18F-fluciclovine PET/CT were analyzed and those with a prescan plan for ADT (± another treatment) were selected. 18F-Fluciclovine detection rates were determined at the patient level and for the prostate/prostate bed region, pelvic and extra-pelvic lymph nodes (LN), soft tissues, and bones. The patients' pre- and postscan treatment plans were compared and were stratified by imaging results. RESULTS: A total of 146 patients had a prescan plan for ADT (60 as monotherapy and 86 in combination with another modality). 18F-Fluciclovine detected lesions in 85 of 146 (58%) patients planned for ADT. Detection rates in the prostate/bed, pelvic LN, extra-pelvic LN, soft tissues and bone were 30%, 25%, 13%, 2.1%, and 13%, respectively. Twenty-five (17%) patients had positivity confined to the prostate/bed, 21 (14%) had 18F-fluciclovine-positive pelvic LN (±prostate/bed) but no other involvement and 39 (27%) had involvement outside the prostate/bed and pelvic LN. Postscan, 93 of 146 (64%) patients had a management change, 55 (59%) of which were to abort ADT. Only 25% of the patients originally planned for ADT monotherapy still had an unaltered plan for ADT monotherapy postscan. Patients with a postscan plan for ADT monotherapy had the most disseminated disease. Disease in the prostate/bed only was most common in those whose plan was altered to abort ADT. CONCLUSIONS: 18F-Fluciclovine-PET/CT influenced management plans for the majority of patients with a prescan plan for ADT. Plans were commonly amended to target salvage therapy for lesions identified with 18F-fluciclovine PET/CT, and consequently likely spared/delayed patients the morbidity associated with ADT.

Should men undergo MRI before prostate biopsy - CON.

Prostate magnetic resonance imaging (MRI) is increasingly used prior to biopsy in response to the overdiagnosis and overtreatment of prostate cancer (CaP) associated with prostate-specific antigen (PSA) based screening. However, technical limitations in the conventional diffusion-weighted imaging (DWI) sequences as well as the high degree of radiologist-to-radiologist variability in interpreting prostate MRI result in inadequate accuracy. Specifically, the insufficient negative predictive value (NPV) of prostate MRI (76%-87%) does not allow biopsy to be omitted in the negative MRI setting. Additionally, the variable, and relatively low positive predictive value (PPV) of MRI (27%-44%) provides only an incremental improvement in risk prediction compared to readily available clinical tools such as the Prostate Cancer Prevention Trial risk calculator. This small benefit is likely confined to the minority of patients with positive MRI findings in a typically under-sampled region of the prostate (e.g., anterior lesions), which may be obviated by newer biopsy approaches and tools such as transperineal prostate biopsy and micro-ultrasound technology. With these considerations in mind, pre-biopsy prostate MRI in its current form is unlikely to provide a clinically significant benefit, and should not be considered as routine practice until its accuracy is sufficiently improved.

Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract, we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology. EXPERIMENTAL DESIGN: We identified tumor-specific acK13-HOXB13 signal enriched super enhancer (SE)-regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity, and CRPC tumor growth by employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids, we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth. RESULTS: acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA, Angiopoietins) genes early in prostate cancer development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE-regulated targets is insensitive to enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide, and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b. CONCLUSIONS: In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13-ACK1 axis regulated prostate cancers.

Liquid biomarkers for early detection of prostate cancer and summary of available data for their use in African-American men.

BACKGROUND: Several liquid biomarker tests have been developed to account for the limitations of prostate specific antigen (PSA) screening prior to prostate biopsy. African ancestry is an established risk factor for prostate cancer (PCa) and must be particularly considered when evaluating patients with liquid biomarkers. While multiple tests have been developed over decades of exploration, recent advances can help patients and physicians incorporate data into a broader clinical context. METHODS: We sought to review currently available liquid biomarker tests in a practical, clinically directed fashion with particular focus on performance in men with African ancestry. We reviewed discovery and validation studies and highlight important considerations for each test. RESULTS: We discuss the advantages and limitations of percent free PSA, Prostate Health Index, Progensa® PCA3, ExoDx® Prostate Test, SelectMDx®, 4Kscore® Test, and Mi-Prostate Score and summarize salient studies on their use. A literature review of evidence specifically for men with African ancestry was conducted and available studies were summarized. CONCLUSIONS: Liquid biomarkers can be useful tools for aiding in risk stratification prior to prostate biopsy. Use of such tests should be individualized based on a thorough knowledge of supporting evidence and the goals of the patient and physician. Further study should prioritize evaluation of such biomarkers in men with African ancestry.

The impact of smoking on sexual function.

OBJECTIVES: To evaluate the hypothesis that there is an improvement in sexual function following smoking cessation (as smoking is a well-established risk factor for sexual dysfunction), we analysed the association between cigarette smoking and smoking cessation with sexual function among participants of the REduction by DUtasteride of prostate Cancer Events (REDUCE) study. SUBJECTS AND METHODS: We analysed baseline data of 6754 men, aged 50-75 years divided into: lifelong non-smokers, former smokers, and current smokers. We examined total testosterone (TT, normal range ≥10 nmol/L) and sexual function variables: self-reported sexual activity, low libido, and erectile dysfunction (ED). Differences between current vs non-smokers and former vs current smokers were analysed using the chi-square test, linear and logistic regressions. RESULTS: A total of 3069 (45.4%) men were non-smokers, 2673 (39.6%) former smokers, and 1012 (15%) current smokers. Current smokers were significantly younger than former and non-smokers (mean age 61.6, 63.2, and 62.7 years, respectively), leaner (mean body mass index 27.0, 27.7, and 27.2 kg/m2 , respectively), and had less hypertension (32.4%, 41.6%, and 36.8%, respectively; all P < 0.01). In uni- and multivariable analysis, current smokers had higher mean TT than non-smokers (485.4 vs 451.2 nmol/L, P < 0.001), higher prevalence of low libido (25.6% vs 21.0%, P = 0.002) and ED (31.6% vs 26.0%, P < 0.001) with comparable sexual activity (81.7% vs 82.8%, P = 0.420). In multivariable analysis, former smokers had statistically significantly less prevalence of low libido (odds ratio [OR] 0.8, P = 0.013) and ED (OR 0.8, P = 0.006) compared to current smokers. CONCLUSION: Cigarette smoking was associated with worse sexual health compared to non-smokers, while former smokers had better erectile function and libido than current smokers. Smoking cessation may improve male sexual health and counselling on smoking cessation may be considered at the time of sexual health evaluations.

Survival Outcomes in Men with Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Treated with Prostate-Only versus Whole Pelvic Radiation Therapy.

PURPOSE: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy. Treatment is frequently intensified by electively treating the pelvic lymph nodes (LNs) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy. MATERIALS AND METHODS: National Cancer Database records of men diagnosed between 2008-2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±androgen deprivation therapy (72-86.4 Gy) with (15,175) or without (13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression. RESULTS: Of the men, 53% received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (p <0.001). WPRT trended toward improved OS in all men with UIR-PCa and HR-PCa (HR: 0.95 [95% CI: 0.90-1.006], p=0.055). WPRT correlated with improved OS in men with Gleason 9 and 10 disease (HR: 0.87 [0.78-0.98], p=0.02) or risk of LN involvement ≥10% (HR: 0.93 [0.87-0.99], p=0.03). CONCLUSIONS: Men with higher LN risk scores and Gleason grade benefited from WPRT. These results complement the recent POP-RT randomized trial in mostly positron emission tomography/computerized tomography-staged patients, demonstrating that a more heterogeneous population of men staged without functional imaging benefits from WPRT.

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

PURPOSE: Our goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study. MATERIALS AND METHODS: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications. RESULTS: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain. CONCLUSIONS: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Does the sequence of high-dose rate brachytherapy boost and IMRT for prostate cancer impact early toxicity outcomes? Results from a single institution analysis.

BACKGROUND: We present the first report comparing early toxicity outcomes with high-dose rate brachytherapy (HDR-BT) boost upfront versus intensity modulated RT (IMRT) upfront combined with androgen deprivation therapy (ADT) as definitive management for intermediate risk or higher prostate cancer. METHODS AND MATERIALS: We reviewed all non-metastatic prostate cancer patients who received HDR-BT boost from 2014 to 2019. HDR-BT boost was offered to patients with intermediate-risk disease or higher. ADT use and IMRT target volume was based on NCCN risk group. IMRT dose was typically 45 Gy in 25 fractions to the prostate and seminal vesicles ± pelvic lymph nodes. HDR-BT dose was 15 Gy in 1 fraction, delivered approximately 3 weeks before or after IMRT. The sequence was based on physician preference. Biochemical recurrence was defined per ASTRO definition. Gastrointestinal (GI) and Genitourinary (GU) toxicity was graded per CTCAE v5.0. Pearson Chi-squared test and Wilcoxon tests were used to compare toxicity rates. P-value < 0.05 was significant. RESULTS: Fifty-eight received HDR-BT upfront (majority 2014-2016) and 57 IMRT upfront (majority 2017-2018). Median follow-up was 26.0 months. The two cohorts were well-balanced for baseline patient/disease characteristics and treatment factors. There were differences in treatment sequence based on the year in which patients received treatment. Overall, rates of grade 3 or higher GI or GU toxicity were <1%. There was no significant difference in acute or late GI or GU toxicity between the two groups. CONCLUSION: We found no significant difference in GI/GU toxicity in intermediate-risk or higher prostate cancer patients receiving HDR-BT boost upfront versus IMRT upfront combined with ADT. These findings suggest that either approach may be reasonable. Longer follow-up is needed to evaluate late toxicity and long-term disease control.

Prostate Cancer Incidence and Mortality Following a Negative Biopsy in a Population Undergoing PSA Screening.

OBJECTIVE: Transrectal ultrasound guided biopsy for diagnostic workup for prostate cancer (PCa) has a substantial false negative rate. We sought to estimate PCa incidence and mortality following negative biopsy in a cohort of men undergoing prostate cancer screening. SUBJECTS AND METHODS: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial randomized participants 55-74 years to an intervention vs control arm. Intervention arm men received annual prostate-specific antigen (PSA) tests for 6 years and digital rectal exams (DRE) for 4 years. We examined the cohort of men with a positive PSA (> 4 ng/mL) or DRE screen followed within one year by a negative biopsy. PCa incidence and mortality rates from time of first negative biopsy were analyzed as a function of PSA level at diagnosis and other factors. Cumulative incidence and mortality rates accounting for competing risk were estimated. Multivariate proportional hazards regression was utilized to estimate hazard ratios (HRs) of PCa outcomes by PSA level, controlling for age and race. RESULTS: The negative biopsy cohort included 2855 men. Median (25th/75th) age at biopsy was 65 (61/69) years; biopsies occurred between 1994 and 2006. Median (25/75th) follow-up was 13.2 (6.5/16.8) years for incidence and 16.6 (12.3/19.2) years for mortality. 740 PCa cases were diagnosed, with 33 PCa deaths. Overall 20-year cumulative PCa incidence and mortality rates were 26.4% (95% CI: 24.8-28.1) and 1.2% (95% CI: 0.9-1.7), respectively. HRs for PCa incidence and mortality increased significantly with increasing PSA. CONCLUSION: The mortality rate from PCa through 20 years following a negative biopsy is low.

Smoking Is Associated With Basal Cell Hyperplasia on Prostate Biopsy Specimens.

OBJECTIVES: To the best of our knowledge, no study has analyzed the association between cigarette smoking and prostate basal cell proliferation. Therefore, we sought to evaluate whether smoking status is associated with the presence of basal cell hyperplasia (BCH). METHODS: We performed a retrospective analysis of 8,196 men aged 50 to 75 years with prostate-specific antigen values between 2.5 µg/mL and 10 µg/mL and prior negative biopsy who were enrolled in the (REDUCE) trial. Cigarette smoking status was divided into current, former, or never categories at enrollment. The association between smoking and baseline BCH was evaluated, with logistic regression in univariable and multivariable analysis. RESULTS: A total of 1,233 (15.1%) men were current smokers, 3,206 (39.1%) were former smokers, and 3,575 (45.8%) were never smokers. In univariable analysis, current smoking was associated with higher baseline BCH occurrence compared with never (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14-3.10) and former smokers (OR, 1.77; 95% CI, 1.06-2.95). Similar results were found after adjusting for patient characteristics (current vs never smokers: OR, 1.92; 95% CI, 1.14-3.26; current vs former smokers: OR, 1.71; 95% CI, 1.01-2.91). CONCLUSIONS: Among men undergoing prostate biopsy, all of whom had a negative biopsy result, current smoking at enrollment was independently associated with BCH in standard peripheral zone prostate biopsies.

Single-cell Spatial Proteomic Revelations on the Multiparametric MRI Heterogeneity of Clinically Significant Prostate Cancer.

PURPOSE: Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear. EXPERIMENTAL DESIGN: We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence-based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics. RESULTS: More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy. CONCLUSIONS: Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.

Dutasteride Improves Nocturia but Does Not Lead to Better Sleep: Results from the REDUCE Clinical Trial.

PURPOSE: In men, complaints of nocturia causing poor sleep are often attributed to benign prostatic hyperplasia and treated with benign prostatic hyperplasia medications. We assessed whether treating lower urinary tract symptoms with dutasteride altered either nocturia or sleep quality using data from REDUCE. MATERIALS AND METHODS: REDUCE was a 4-year randomized, multicenter trial comparing dutasteride 0.5 mg/day vs placebo for prostate cancer chemoprevention. Study participants were men considered at increased risk for prostate cancer. Eligibility included age 50-75 years, prostate specific antigen 2.5-10 ng/ml, and 1 negative prostate biopsy. At baseline, 2 years and 4 years, men completed the International Prostate Symptom Score and Medical Outcomes Study Sleep Scale, a 6-item scale assessing sleep. To test differences in nocturia and Medical Outcomes Study Sleep Scale over time, we used linear mixed models adjusted for baseline confounders. Subanalyses were conducted in men symptomatic from lower urinary tract symptoms, nocturia, poor sleep, or combinations thereof. RESULTS: Of 6,914 men with complete baseline data, 80% and 59% were assessed at 2 and 4-year followup, respectively. Baseline characteristics were balanced between treatment arms. Dutasteride improved nocturia at 2 (-0.15, 95% CI -0.21, -0.09) and 4 years (-0.24, 95% CI -0.31, -0.18) but did not improve sleep. When limited to men symptomatic from lower urinary tract symptoms, nocturia, poor sleep or combinations thereof, results mirrored findings from the full cohort. CONCLUSIONS: In men with poor sleep who complain of nocturia, treatment of lower urinary tract symptoms with dutasteride modestly improves nocturia but has no effect on sleep. These results suggest men with poor sleep who complain of nocturia may not benefit from oral benign prostatic hyperplasia treatment.

Factors associated with higher prostate biopsy yield: when is software-assisted fusion MRI-targeting necessary?

OBJECTIVE: To evaluate the addition of software-assisted fusion magnetic resonance imaging (MRI) targeted biopsy to systematic biopsy and determine clinical and imaging factors associated with improved prostate cancer (PCa) detection. METHODS: We analyzed 454 patients who had prostate MRI and underwent combined systematic and software-assisted fusion MRI-targeted biopsy at 2 academic centers between July 2015 and December 2017. For our analysis, we compared the Gleason grade group of cores obtained systematically to cores obtained using MRI-targeting. Using multivariable analysis, we examined clinical and imaging factors associated with higher grade group disease in MRI-targeted cores. RESULTS: Software assisted fusion MRI-targeted biopsy detected higher grade group disease in 18.3% of patients. Factors associated with higher grade group disease in MRI-targeted cores included anterior MRI lesion location (odds ratio [OR] 3.15, P< 0.01) and multiple lesions on MRI (OR 2.47, P = 0.01). Increasing prostate volume per cubic centimeter was noted to be negatively associated (OR 0.98, P = 0.02). Notably, factors not found to be associated with improved detection included PIRADS classification 5 compared to 3 (OR 2.47, P = 0.08), PIRADS classification 4 compared to 3 (OR 1.37, P = 0.50), previous negative biopsy (OR 1.48, P = 0.29), inclusion on an active surveillance protocol (OR 1.36, P = 0.48), transitional zone lesion location (OR 0.72, P = 0.45), and institution at which biopsy was performed (OR 1.81, P = 0.16). CONCLUSION: Adding software-assisted fusion MRI-targeting to systematic prostate biopsy offers benefit for men with an anterior and multiple MRI lesions. In absence of these factors, systematic biopsy alone or with cognitive fusion may be considered.