Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

Isoform-independent promotion of contractility and proliferation, and suppression of survival by with no lysine/K kinases in prostate stromal cells.

With no lysine/K kinases (WNKs) promote vasocontraction and vascular smooth muscle cell proliferation. In the prostate, smooth muscle contraction and growth may be critical for the development and medical treatment of voiding symptoms in benign prostatic hyperplasia. Here, we examined the effects of isoform-specific WNK silencing and of the WNK inhibitor WNK463 on growth-related functions and contraction in prostate stromal cells, and in human prostate tissues. Impacts of WNK silencing by transfection of cultured stromal cells with isoform-specific siRNAs were qualitatively and quantitatively similar for each WNK isoform. Effects of silencing were largest on cell death (3-5 fold increase in annexin V-positive/7-AAD-positive cells), on proliferation rate, Ki-67 mRNA expression and actin organization (reduced around two-thirds). Contraction in matrix contraction assays and viability were reduced to a lower degree (approximately half), but again to a similar extent for each WNK isoform. Effects of silencing were quantitatively and qualitatively reproduced by 10 µM WNK463, while 1 µM still induced cell death and breakdown in actin organization, without affecting proliferation or viability. Using 500 nM and 10 µM, WNK463 partly inhibited neurogenic and U46619-induced contractions of human prostate tissues (around half), while inhibition of α1-adrenergic contractions (around half) was limited to 10 µM. All four WNK isoforms suppress cell death and promote proliferation in prostate stromal cells. WNK-driven contraction of stromal cells appears possible, even though to a limited extent. Outcomes of isoform-specific WNK silencing can be fully reproduced by WNK463, including inhibition of smooth muscle contraction in human prostate tissues, but require high concentrations.

Enhanced prostatic Esr1+ luminal epithelial cells in the absence of SRD5A2.

Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a Srd5a2-/- mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)+ LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.

Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Performance of large language models on benign prostatic hyperplasia frequently asked questions.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition, yet it is challenging for the average BPH patient to find credible and accurate information about BPH. Our goal is to evaluate and compare the accuracy and reproducibility of large language models (LLMs), including ChatGPT-3.5, ChatGPT-4, and the New Bing Chat in responding to a BPH frequently asked questions (FAQs) questionnaire. METHODS: A total of 45 questions related to BPH were categorized into basic and professional knowledge. Three LLM-ChatGPT-3.5, ChatGPT-4, and New Bing Chat-were utilized to generate responses to these questions. Responses were graded as comprehensive, correct but inadequate, mixed with incorrect/outdated data, or completely incorrect. Reproducibility was assessed by generating two responses for each question. All responses were reviewed and judged by experienced urologists. RESULTS: All three LLMs exhibited high accuracy in generating responses to questions, with accuracy rates ranging from 86.7% to 100%. However, there was no statistically significant difference in response accuracy among the three (p > 0.017 for all comparisons). Additionally, the accuracy of the LLMs' responses to the basic knowledge questions was roughly equivalent to that of the specialized knowledge questions, showing a difference of less than 3.5% (GPT-3.5: 90% vs. 86.7%; GPT-4: 96.7% vs. 95.6%; New Bing: 96.7% vs. 93.3%). Furthermore, all three LLMs demonstrated high reproducibility, with rates ranging from 93.3% to 97.8%. CONCLUSIONS: ChatGPT-3.5, ChatGPT-4, and New Bing Chat offer accurate and reproducible responses to BPH-related questions, establishing them as valuable resources for enhancing health literacy and supporting BPH patients in conjunction with healthcare professionals.

Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Minimally invasive surgical therapies for benign prostatic hyperplasia in the geriatric population: A systematic review.

BACKGROUND: Geriatric patients, prone to adverse events (AEs) and low compliance with drugs, may benefit from minimally invasive surgical therapies (MISTs) for managing benign prostatic hyperplasia (BPH). We evaluated the efficacy, safety, and procedural characteristics of MISTs in geriatric patients with BPH. METHODS: PubMed/MEDLINE database was systematically searched for relevant articles through October 1, 2023. Eligible studies focused on geriatric patients (≥65 years) with BPH who were treated with MISTs and evaluated follow-up surgical, micturition, and/or sexual outcomes. Studies were included if there was separate reporting for age subgroups ≥65 years, or if the mean age minus standard deviation was ≥65 years, or if the first quartile was ≥65 years. RESULTS: Out of 292 screened studies, 32 (N = 3972 patients) met inclusion criteria and assessed prostatic artery embolization (PAE), Rezum, GreenLight, holmium laser enucleation of the prostate (HoLEP), thulium laser enucleation of the prostate (ThuLEP), diode laser enucleation of the prostate (DiLEP), and Aquablation. Except for Rezum, all MISTs required a planned overnight stay. While PAE and Rezum could be performed under local anesthesia, the other MISTs needed general or spinal anesthesia. Postoperative catheterization duration was longest for PAE (median 14 days) and Rezum (21 days) and shortest for GreenLight (1.9 days). At 12 months postoperatively, all MISTs exhibited significant percent changes in International Prostate Symptom Score (median -69.9%) and quality of life (median -72.5%). Clavien-Dindo Grade 1 AEs ranged widely, with PAE (5.8%-36.8%), Rezum (0%-62.1%), and GreenLight (0%-67.6%) having the largest range, and HoLEP (0%-9.5%), ThuLEP (2%-6.9%), and DiLEP (5%-17.5%) having the smallest. PAE, Rezum, DiLEP, and Aquablation reported no significant changes in the International Index of Erectile Function. CONCLUSIONS: Although all the MISTs reviewed in this study effectively treat BPH in geriatric patients, differences in procedural characteristics and safety profiles across MISTs were considerable. Physicians should use shared decision-making processes, considering risks and patient characteristics, when choosing a suitable treatment option for their patients.

Do Prostate Imaging-Reporting and Data System (PIRADS) lesions predict holmium laser enucleation of prostate outcomes?

INTRODUCTION AND OBJECTIVES: Prostate magnetic resonance imaging (MRI) is used for prostate cancer (PCa) screening and risk stratification and is helpful for surgical planning for patients undergoing holmium laser enucleation of the prostate (HoLEP). There are few studies investigating the correlation between MRI Prostate Imaging-Reporting and Data System (PIRADS) lesion characteristics and HoLEP pathology and outcomes. METHODS: We performed retrospective review of patients who underwent HoLEP between January 2021 and August 2023 by a single surgeon. Preoperative, intraoperative, and postoperative characteristics and outcomes were analyzed for all patients who had a documented preoperative prostate MRI. RESULTS: There were 334 patients without a pre-existing diagnosis of PCa and with a preoperative prostate MRI, of which 140 (42%) had at least one PIRADS lesion. There was a total of 203 PIRADS lesions: 91 (45%) in the peripheral zone (PZ), 106 (52%) in the transition zone (TZ), and 6 (2%) not specified. Incidental PCa was noted in 44 (13%) patients at time of HoLEP. Presence or location of lesion was not significantly associated with rate or grade of incidental PCa on pathology. Greater number of lesions and lesion size correlated with longer procedure times. Lesion number, size, or grade were not found to correlate with cancer grade or rate of cancer. CONCLUSIONS: Grade, presence, location, size, and number of PIRADS lesions on preoperative prostate MRI for patients with an appropriate prior PCa workup were not significantly associated with incidental PCa or higher PCa grade on HoLEP pathology.

Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

A prospective, randomized, open-label, parallel trial comparing the efficacy of α-blocker or 5α-reductase inhibitor withdrawal to continued combination therapy on the maintenance of lower urinary tract symptoms in men with benign prostatic hyperplasia.

BACKGROUND: It is uncertain how long combination therapy should be continued in patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). We investigated the withdrawal effects of α1-adrenergic receptor blocker (AB) or 5α-reductase inhibitor (5ARI) following successful combination therapy. METHODS: This prospective, randomized, open-label, parallel trial enrolled 222 patients with BPH/LUTS who showed at least a seven-point improvement in International Prostate Symptom Score-total (IPSS-T) and a ≥ 20% reduction in prostate volume (PV) following the initiation of combination therapy. Patients were randomized in a 1:1:1 ratio into continued-combination, AB-withdrawal, and 5ARI-withdrawal groups. IPSS, overactive bladder symptom score, EuroQol-five-dimensional questionnaire (EQ-5D-5L), EuroQol-visual analog scale (EQ-VAS), prostate volume (PV), maximal flow rate, postvoid residual urine (PVR), and prostate-specific antigen level were assessed every 6 months for 24 months. The predictors of IPSS-T deterioration were evaluated. RESULTS: At Month 24, IPSS-T deterioration (≥2 point) was observed in 20/72 (27.8%) and 19/72 (26.4%) patients in the AB- and 5ARI-withdrawal groups, respectively. Among them, 4/72 (5.6%) and 4/70 (5.7%) patients required readdition of the withdrawn drug (p = 0.868). In the continued combination group, EQ-VAS improved at Month 24 compared to baseline (p = 0.028). At Month 24, the AB-withdrawal group showed improvements in EQ-5D-5L, EQ-VAS, and PVR (all p < 0.005), while the 5ARI-withdrawal group showed improvement in IPSS-S (p = 0.011). Diabetes mellitus was associated with IPSS-T deterioration at Month 24 (p = 0.020). CONCLUSIONS: In patients with BPH/LUTS who are reluctant to continue combination therapy, AB or 5ARI withdrawal may be offered in men with improvement in IPSS-T by at least seven points and reduction in PV by at least 20%.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

Link between circadian rhythm and benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS).

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common urologic disease in aging males, affecting 50% of men over 50 and up to 80% of men over 80 years old. Its negative impact on health-related quality of life implores further investigation into its risk factors and strategies for effective management. Although the exact molecular mechanisms underlying pathophysiological onset of BPH are poorly defined, the current hypothesized contributors to BPH and lower urinary tract symptoms (LUTS) include aging, inflammation, metabolic syndrome, and hormonal changes. These processes are indirectly influenced by circadian rhythm disruption. In this article, we review the recent evidence on the potential association of light changes/circadian rhythm disruption and the onset of BPH and impact on treatment. METHODS: A narrative literature review was conducted using PubMed and Google Scholar to identify supporting evidence. The articles referenced ranged from 1975 to 2023. RESULTS: A clear relationship between BPH/LUTS and circadian rhythm disruption is yet to be established. However, common mediators influence both diseases, including proinflammatory states, metabolic syndrome, and hormonal regulation that can be asserted to circadian disruption. Some studies have identified a possible relationship between general LUTS and sleep disturbance, but little research has been done on the medical management of these diseases and how circadian rhythm disruption further affects treatment outcomes. CONCLUSIONS: There is evidence to implicate a relationship between BPH/LUTS and circadian rhythm disruptions. However, there is scarce literature on potential specific link in medical management of the disease and treatment outcomes with circadian rhythm disruption. Further study is warranted to provide BPH patients with insights into circadian rhythm directed appropriate interventions.

Modern predictors and management of incidental prostate cancer at holmium enucleation of prostate.

BACKGROUND: To evaluate contemporary preoperative risk factors and subsequent postoperative management of incidental prostate cancer (iPCa) and incidental clinically significant prostate cancer (icsPCa, Grade Group [GG] ≥ 2 PCa). METHODS: A retrospective cohort of 811 men undergoing Holmium enucleation of the prostate (HoLEP) (January 2021-July 2022) were identified. Advanced preoperative testing was defined as prostate health index (PHI), prostate MRI, and/or negative preoperative biopsy. Descriptive statistics (Whitney-Mann U test, Chi-squared test) and multivariable logistic regression were performed. RESULTS: iPCa and icsPCa detection rates were 12.8% (104/811) and 4.4% (36/811), respectively. Advanced preoperative testing (406/811, 50%) was associated with younger age and higher (prostate specific antigen) PSA, prostate volume, and PSA density. On multivariable analysis, PHI ≥ 55 was associated with iPCa (OR 6.91, 95% CI 1.85-26.3, p = 0.004), and % free PSA (%fPSA) was associated with icsPCa (OR 0.83, 95% CI 0.67, 0.94, p = 0.01). GG1 disease comprised the majority of iPCa (65%, 68/104) with median 1% involvement. iPCa patients were followed with active surveillance (median follow up 9.3 months), with higher risk patients receiving prostate MRI and confirmatory biopsy. Three patients proceeded to radical prostatectomy or radiation. CONCLUSIONS: In the era of MRI and advanced biomarkers, the majority of iPCa following HoLEP is low volume GG1 suitable for active surveillance. A tentative follow-up strategy is proposed. Patients with PHI ≥ 55 or low %fPSA, even with negative prostate MRI, can consider preoperative prostate biopsy before HoLEP.

Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1-/-) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay. RESULTS: In vivo, Itln-1-/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation. CONCLUSION: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia.

OBJECTIVE: Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients. METHODS: The robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification. RESULTS: The alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers. CONCLUSIONS: This study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

Identification and functional activity of Nik related kinase (NRK) in benign hyperplastic prostate.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in elder men. The current study aims to identify differentially expressed genes (DEGs) in hyperplastic prostate and to explore the role of Nik related kinase (NRK) in BPH. METHODS: Four datasets including three bulk and one single cell RNA-seq (scRNA-seq) were obtained to perform integrated bioinformatics. Cell clusters and specific metabolism pathways were analyzed. The localization, expression and functional activity of NRK was investigated via RT-PCR, western-blot, immunohistochemical staining, flow cytometry, wound healing assay, transwell assay and CCK-8 assay. RESULTS: A total of 17 DEGs were identified by merging three bulk RNA-seq datasets. The findings of integrated single-cell analysis showed that NRK remarkably upregulated in fibroblasts and SM cells of hyperplasia prostate. Meanwhile, NRK was upregulated in BPH samples and localized almost in stroma. The expression level of NRK was significantly correlated with IPSS and Qmax of BPH patients. Silencing of NRK inhibited stromal cell proliferation, migration, fibrosis and EMT process, promoted apoptosis and induced cell cycle arrest, while overexpression of NRK in prostate epithelial cells showed opposite results. Meanwhile, induced fibrosis and EMT process were rescued by knockdown of NRK. Furthermore, expression level of NRK was positively correlated with that of α-SMA, collagen-I and N-cadherin, negatively correlated with that of E-cadherin. CONCLUSION: Our novel data identified NRK was upregulated in hyperplastic prostate and associated with prostatic stromal cell proliferation, apoptosis, cell cycle, migration, fibrosis and EMT process. NRK may play important roles in the development of BPH and may be a promising therapeutic target for BPH/LUTS.

Serum Testosterone and Dihydrotestosterone and Incidence and Progression of Lower Urinary Tract Symptoms: Results From the REDUCE Study.

PURPOSE: Though the pathogenesis of benign prostatic hyperplasia is unclear, it was previously believed that increasing androgen levels contributed, though not all data support this idea. We tested if elevated serum testosterone or dihydrotestosterone were risk factors for lower urinary tract symptoms incidence in asymptomatic men and for lower urinary tract symptoms progression in symptomatic men. MATERIALS AND METHODS: A post hoc analysis of REDUCE was performed in 3009 asymptomatic men and in 2145 symptomatic men. REDUCE was a randomized trial of dutasteride for prostate cancer prevention in men with an elevated prostate-specific antigen and negative prestudy biopsy. We estimated multivariable adjusted hazard ratios and 95% confidence intervals using Cox models to test the association between quintiles of serum testosterone and dihydrotestosterone at baseline and lower urinary tract symptoms incidence and progression and tested for interaction by treatment arm (dutasteride vs placebo). RESULTS: In asymptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms incidence (P = .9, P = .4). In symptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms progression (P = .9, P = .7). Results were similar in both placebo and dutasteride arms (all P interaction ≥ .3). CONCLUSIONS: In REDUCE, higher serum testosterone and higher serum dihydrotestosterone were not associated with either lower urinary tract symptoms incidence in asymptomatic men or lower urinary tract symptoms progression in symptomatic men. These data do not support the hypothesis that serum androgens in middle-aged men are associated with lower urinary tract symptoms.

Efficacy and Safety of Vibegron for Persistent Symptoms of Overactive Bladder in Men Being Pharmacologically Treated for Benign Prostatic Hyperplasia: Results From the Phase 3 Randomized Controlled COURAGE Trial.

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Development of the UroARC Surgical Calculator: A Novel Risk Calculator for Older Adults Undergoing Surgery for Bladder Outlet Obstruction.

PURPOSE: Bladder outlet obstruction (BOO) is common in older adults. Many older adults who pursue surgery have additional vulnerabilities affecting surgical risk, including frailty. A clinical tool that builds on frailty to predict surgical outcomes for the spectrum of BOO procedures would be helpful to aid in surgical decision-making but does not currently exist. MATERIALS AND METHODS: Medicare beneficiaries undergoing BOO surgery from 2014 to 2016 were identified and analyzed using the Medicare MedPAR, Outpatient, and Carrier files. Eight different BOO surgery categories were created. Baseline frailty was calculated for each beneficiary using the Claims-Based Frailty Index (CFI). All 93 variables in the CFI and the 17 variables in the Charlson Comorbidity Index were individually entered into stepwise logistic regression models to determine variables most highly predictive of complications. Similar and duplicative variables were combined into categories. Calibration curves and tests of model fit, including C statistics, Brier scores, and Spiegelhalter P values, were calculated to ensure the prognostic accuracy for postoperative complications. RESULTS: In total, 212,543 beneficiaries were identified. Approximately 42.5% were prefrail (0.15 ≤ CFI < 0.25), 8.7% were mildly frail (0.25 ≤ CFI < 0.35), and 1.2% were moderately-to-severely frail (CFI ≥0.35). Using stepwise logistic regression, 13 distinct prognostic variable categories were identified as the most reliable predictors of postoperative outcomes. Most models demonstrated excellent model discrimination and calibration with high C statistic and Spiegelhalter P values, respectively, and high accuracy with low Brier scores. Calibration curves for each outcome demonstrated excellent model fit. CONCLUSIONS: This novel risk assessment tool may help guide surgical prognostication among this vulnerable population.

Intravoxel incoherent motion and diffusion kurtosis imaging and their machine-learning-based texture analysis for detection and assessment of prostate cancer severity at 3 T.

OBJECTIVES: To evaluate the role of combined intravoxel incoherent motion and diffusion kurtosis imaging (IVIM-DKI) and their machine-learning-based texture analysis for the detection and assessment of severity in prostate cancer (PCa). MATERIALS AND METHODS: Eighty-eight patients underwent MRI on a 3 T scanner after giving informed consent. IVIM-DKI data were acquired using 13 b values (0-2000 s/mm2) and analyzed using the IVIM-DKI model with the total variation (TV) method. PCa patients were categorized into two groups: clinically insignificant prostate cancer (CISPCa) (Gleason grade ≤ 6) and clinically significant prostate cancer (CSPCa) (Gleason grade ≥ 7). One-way analysis-of-variance, t test, and receiver operating characteristic analysis was performed to measure the discriminative ability to detect PCa using IVIM-DKI parameters. A chi-square test was used to select important texture features of apparent diffusion coefficient (ADC) and IVIM-DKI parameters. These selected texture features were used in an artificial neural network for PCa detection. RESULTS: ADC and diffusion coefficient (D) were significantly lower (p < 0.001), and kurtosis (k) was significantly higher (p < 0.001), in PCa as compared with benign prostatic hyperplasia (BPH) and normal peripheral zone (PZ). ADC, D, and k showed high areas under the curves (AUCs) of 0.92, 0.89, and 0.88, respectively, in PCa detection. ADC and D were significantly lower (p < 0.05) as compared with CISPCa versus CSPCa. D for detecting CSPCa was high, with an AUC of 0.63. A negative correlation of ADC and D with GS (ADC, ρ = -0.33; D, ρ = -0.35, p < 0.05) and a positive correlation of k with GS (ρ = 0.22, p < 0.05) were observed. Combined IVIM-DKI texture showed high AUC of 0.83 for classification of PCa, BPH, and normal PZ. CONCLUSION: D, f, and k computed using the IVIM-DKI model with the TV method were able to differentiate PCa from BPH and normal PZ. Texture features of combined IVIM-DKI parameters showed high accuracy and AUC in PCa detection.