The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

Enhanced clinical decisions for management of benign prostatic hyperplasia using patient-reported outcomes: protocol for a prospective observational study.

BACKGROUND: Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) significantly impact quality of life among older men. Despite the prevalent use of the American Urological Association Symptom Index (AUA-SI) for BPH, this measure overlooks key symptoms such as pain and incontinence, underscoring the need for more comprehensive patient-reported outcome (PRO) tools. This study aims to integrate enhanced PROs into routine clinical practice to better capture the spectrum of LUTS, thereby improving clinical outcomes and patient care. METHODS: This prospective observational study will recruit men with LUTS secondary to BPH aged ≥ 50 years from urology clinics. Participants will be stratified into medical and surgical management groups, with PRO assessments scheduled at regular intervals to monitor LUTS and other health outcomes. The study will employ the LURN Symptom Index (SI)-29 alongside the traditional AUA-SI and other non-urologic PROs to evaluate a broad range of symptoms. Data on comorbidities, symptom severity, and treatment efficacy will be collected through a combination of electronic health records and PROs. Analyses will focus on the predictive power of these tools in relation to symptom trajectories and treatment responses. Aims are to: (1) integrate routine clinical tests with PRO assessment to enhance screening, diagnosis, and management of patients with BPH; (2) examine psychometric properties of the LURN SIs, including test-retest reliability and establishment of clinically meaningful differences; and (3) create care-coordination recommendations to facilitate management of persistent symptoms and common comorbidities measured by PROs. DISCUSSION: By employing comprehensive PRO measures, this study expects to refine symptom assessment and enhance treatment monitoring, potentially leading to improved personalized care strategies. The integration of these tools into clinical settings could revolutionize the management of LUTS/BPH by providing more nuanced insights into patient experiences and outcomes. The findings could have significant implications for clinical practices, potentially leading to updates in clinical guidelines and better health management strategies for men with LUTS/BPH. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov (NCT05898932).

The 10-item LURN Symptom Index (LURN SI-10) Detects Additional Symptoms and Shows Convergent Validity With the IPSS in Men Presenting With Lower Urinary Tract Symptoms.

OBJECTIVE: To determine how the LURN-SI-10, a novel questionnaire developed by the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), compares with the International Prostate Symptom Score (IPSS) in men with lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). Specifically, to assess convergent validity and determine how frequently the LURN-SI-10 identifies symptoms not captured by the IPSS. MATERIALS AND METHODS: Men presenting with BPH/LUTS were prospectively administered LURN-SI-10 and IPSS questionnaires. Urinary incontinence (UI) including post-void dribbling (PVD), urgency urinary incontinence (UUI), stress urinary incontinence (SUI), as well as bladder pain were considered present if the patient reported "about half the time or more" on LURN-SI-10. Correlations between LURN-SI-10 and IPSS were assessed as continuous and categorical variables. Multivariable linear regression analysis was performed to determine associations with symptom scores. RESULTS: LURN-SI-10 and IPSS were highly correlated in men with BPH/LUTS (r = 0.82, n = 429), as were respective bother and quality of life scores (ρ = 0.74). The LURN-SI-10 identified additional symptoms including PVD (24%), UUI (13%), SUI (2%), and pain (8%). Men with any UUI, SUI, or PVD had on average a 7.6-point higher LURN-SI-10 score than those without UI (P<.001) and 8.0-point higher IPSS score than those without UI (P<.001). CONCLUSION: The LURN-SI-10 correlates strongly with the IPSS, but the LURN-SI-10 identifies additional important symptomatology in men with LUTS. This additional information may improve the evaluation and treatment of men with BPH/LUTS. Further prospective studies of the LURN-SI-10 is warranted.

The 17-gene Genomic Prostate Score assay as a predictor of biochemical recurrence in men with intermediate and high-risk prostate cancer.

The validated 17-gene Oncotype DX Genomic Prostate Score® (GPS™) assay risk-stratifies prostate-cancer patients with localized disease. The assay has primarily been utilized in lower risk patients deciding between active surveillance versus definitive therapy. In this retrospective cohort study, we analyze the association of the GPS result with time to biochemical recurrence post-prostatectomy in patients with National Comprehensive Cancer Network® (NCCN) intermediate and higher risk prostate cancer. The 141 patients included in the study were from the NorthShore University HealthSystem diagnosed 2014-2019 with NCCN intermediate (n = 109) or higher risk (n = 32) prostate cancer, treated with radical prostatectomy 2015-2019. The association of GPS result with time to biochemical recurrence was evaluated using univariable and multivariable Cox proportional hazards models in 120 patients with unfavorable intermediate or higher risk. Median (interquartile range) follow-up time was 28 (20 to 38) months. The GPS result was significantly associated with time to biochemical recurrence as both a continuous and dichotomous variable in univariable (hazard ratio [HR] per 20 GPS units 2.36, 95% CI 1.45-3.80, p < 0.001; HR for GPS result 41-100 vs 0-40 3.28, 95% CI 1.61-7.19, p < 0.001) and in multivariable models accounting for NCCN risk group (HR per 20 GPS units 2.14, 95% CI 1.31-3.46, p = 0.003; HR for GPS result 41-100 vs 0-40 3.00, 95% CI 1.43-6.72, p = 0.003) or biopsy Gleason Score and diagnostic PSA or PSA density. These results indicate that the GPS assay was a strong predictor of biochemical recurrence after radical prostatectomy in this unfavorable intermediate and higher risk prostate cancer patient population.

TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease.

Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.

How I do it: Aquablation in very large prostates (> 150 mL).

Aquablation has been well-studied in prostates sizes up to 150 mL. Recently, American Urological Association guidelines distinguish surgical interventions for men with large prostates (80 mL-150 mL) and now very large prostates (> 150 mL). Readers will gain an understanding of how to use Aquablation in the very large prostate size category.

Men with lower urinary tract symptoms secondary to BPH undergoing Aquablation with very large prostates (> 150 mL).

INTRODUCTION: The AUA guidelines for benign prostatic hyperplasia distinguish treatments based upon prostate volume (PV), particularly for very large prostates (> 150 mL). While the clinical outcomes and benefits of Aquablation have been studied for men with average and large prostates, it is unknown whether this technology can be used for very large prostates. MATERIALS AND METHODS: Men with PV > 150 mL undergoing Aquablation were identified retrospectively from four North American hospitals. The surgical times and clinical outcomes of men with very large prostates (> 150 mL) were compared to data from men with average PV ≤ 80 mL (WATER study) and large PV 80 mL-150 mL (WATER II study). RESULTS: The average PV of men who underwent Aquablation with very large prostates was 209 mL ± 56 (n = 34, range 151-362 mL), large PV 107 mL ± 20 (n = 101, range 80-150 mL) and average PV 54 mL ± 16 (n = 116, range 30-80 mL). For men with PV > 150 mL, baseline IPSS was 19 ± 6. With a mean follow up of 7 ± 9 months, the IPSS improved to 7 ± 5 (p < 0.001). Peak urinary flow rate, Qmax, improved from 7 ± 4 mL/s to 19 ± 5 mL/s (p<0.001). Compared to the two other PV groups, there were no differences in terms of improvements in IPSS, quality of life, or uroflowmetry. There were no reports of transfusions (0%) in the cohort of men with very large prostates. CONCLUSIONS: In the present study, we demonstrate that Aquablation is effective and safe in prostates greater than 150 mL while showing consistent outcomes compared to average and large prostates sizes.

Prevalence and Characteristics of Urinary Incontinence in a Treatment Seeking Male Prospective Cohort: Results from the LURN Study.

PURPOSE: Male urinary incontinence is thought to be infrequent. We sought to describe the prevalence of urinary incontinence in a male treatment seeking cohort enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network). MATERIALS AND METHODS: Study inclusion and exclusion criteria, including men with prostate cancer or neurogenic bladder, were previously reported. LURN participants prospectively completed questionnaires regarding lower urinary tract symptoms and other clinical variables. Men were grouped based on incontinence type, including 1) no urinary incontinence, 2) post-void dribbling only and 3) urinary incontinence. Comparisons were made using ANOVA and multivariable regression. RESULTS: Of the 477 men 24% reported no urinary incontinence, 44% reported post-void dribbling only and 32% reported urinary incontinence. African American men and those with sleep apnea were more likely to be in the urinary incontinence group than in the no urinary incontinence group (OR 3.2, p = 0.02 and OR 2.73, p = 0.003, respectively). Urinary incontinence was associated with significantly higher bother compared to men without leakage (p <0.001). Compared to men without urinary incontinence and men with only post-void dribbling those with urinary incontinence were significantly more likely to report higher scores (more severe symptoms) on the PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires regarding bowel issues, depression and anxiety than men without urinary incontinence (p <0.01). CONCLUSIONS: Urinary incontinence is common among treatment seeking men. This is concerning because the guideline recommended questionnaires to assess male lower urinary tract symptoms do not query for urinary incontinence. Thus, clinicians may be missing an opportunity to intervene and improve patient care. This provides a substantial rationale for a new or updated symptom questionnaire which provides a more comprehensive symptom assessment.

Regulation of Latent Membrane Protein 1 Signaling through Interaction with Cytoskeletal Proteins.

UNLABELLED: Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) induces constitutive signaling in EBV-infected cells to ensure the survival of the latently infected cells. LMP1 is localized to lipid raft domains to induce signaling. In the present study, a genome-wide screen based on bimolecular fluorescence complementation (BiFC) was performed to identify LMP1-binding proteins. Several actin cytoskeleton-associated proteins were identified in the screen. Overexpression of these proteins affected LMP1-induced signaling. BiFC between the identified proteins and LMP1 was localized to lipid raft domains and was dependent on LMP1-induced signaling. Proximity biotinylation assays with LMP1 induced biotinylation of the actin-associated proteins, which were shifted in molecular mass. Together, the findings of this study suggest that the association of LMP1 with lipid rafts is mediated at least in part through interactions with the actin cytoskeleton. IMPORTANCE: LMP1 signaling requires oligomerization, lipid raft partitioning, and binding to cellular adaptors. The current study utilized a genome-wide screen to identify several actin-associated proteins as candidate LMP1-binding proteins. The interaction between LMP1 and these proteins was localized to lipid rafts and dependent on LMP1 signaling. This suggests that the association of LMP1 with lipid rafts is mediated through interactions with actin-associated proteins.

Identification of transmembrane protein 134 as a novel LMP1-binding protein by using bimolecular fluorescence complementation and an enhanced retroviral mutagen.

Latent membrane protein 1 (LMP1) of Epstein-Barr virus induces constitutive signaling in infected cells. LMP1 signaling requires oligomerization of LMP1 via its transmembrane domain, localization to lipid rafts in the membrane, and association of the LMP1 cytoplasmic domain to adaptor proteins, such as the tumor necrosis factor receptor-associated factors (TRAFs). Protein complementation is a novel technique to examine protein-protein interaction through the assembly of functional fluorescent proteins or enzymes from inactive fragments. A previous study in our lab demonstrated the use of bimolecular fluorescence complementation (BiFC) to study the assembly of the LMP1 signaling complexes within the plasma membrane of mammalian cells. In the present study, LMP1 was used as bait in a genome-wide BiFC screen with an enhanced retroviral mutagen to identify new LMP1-binding proteins. Our screen identified a novel LMP1-binding protein, transmembrane protein 134 (Tmem134). Tmem134 is a candidate oncogene that is amplified in breast cancer cell lines. Binding, colocalization, and cofractionation between LMP1 and Tmem134 were confirmed. Finally, Tmem134 affected LMP1-induced NF-κB induction. Together, these data suggest that BiFC is a unique and novel platform to identify proteins recruited to the LMP1-signaling complex.

Characterization of the latent membrane protein 1 signaling complex of Epstein-Barr virus in the membrane of mammalian cells with bimolecular fluorescence complementation.

BACKGROUND: Bimolecular fluorescence complementation (BiFC) is a novel technique to examine protein-protein interaction through the assembly of fluorescent proteins. In the present study, BiFC was used to study the assembly of the Epstein-Barr virus latent membrane protein 1 (LMP1) signaling complex within the membrane of mammalian cells. LMP1 signaling requires oligomerization, localization to lipid rafts, and association of the cytoplasmic domain to adaptor proteins, such as the tumor necrosis factor receptor associated factors (TRAFs). METHODS: LMP1-TRAF and LMP1-LMP1 interactions were assayed by BiFC using fluorescence microscopy and flow cytometry. Function of LMP1 BiFC contructs were confirmed by transformation assays and nuclear factor- κB (NF-κB) reporter assays. RESULTS: BiFC was observed between LMP1 and TRAF2 or TRAF3 and mutation of the LMP1 signaling domains reduced complementation. Fluorescence was observed in previously described LMP1 signaling locations. Oligomerization of LMP1 with itself induced complementation and BiFC. LMP1-BiFC constructs were fully functional in rodent fibroblast transformation assays and activation of NF-κB reporter activity. The BiFC domain partially suppressed some LMP1 mutant phenotypes. CONCLUSIONS: Together these data suggest that BiFC is a unique and novel platform to identify and characterize proteins recruited to the LMP1-signaling complex.