BACKGROUND:During puberty, androgen levels surge to drive development and maturation of the prostate, a male accessory reproductive organ. The objective of this study is to determine the dose dependent effect of the androgen on the mouse pubertal prostate development. METHODS:Male Blb/C mice were castrated, and various amounts of the androgen were implanted before puberty. The dosage-dependent effect of the androgen on pubertal prostate development was investigated. RESULTS:Mouse prostate development was initiated at the age of 30 days when testosterone reached 550 pg/mL and completed at the age of 60 days when testosterone reached 1,000 pg/mL. The minimal serum testosterone level (800 pg/mL) was required for full development of the prostate. Androgen implantation, before the start of puberty, resulted in a high serum testosterone level (1200 pg/mL), equivalent to that of the physiological adult level, that induced a prostatic epithelial hyperplasia phenotype with an enlarged prostate gland. The high levels of androgen increased epithelial cell proliferation and expression of the androgen receptor-target genes in the pubertal prostate. CONCLUSION:This research provides an important insight into the androgen's effect on prostate development through puberty.
BACKGROUND:On a population level, black patients have more prostate cancer (PC), particularly aggressive PC. Similarly, on initial biopsy, black race has been linked with higher PC and high-grade PC risk. Whether this extends to first repeat biopsy is unknown. We tested if black race predicts PC risk, grade, and biopsy compliance within a phase 3 PC prevention trial with study-mandated biopsies among patients with an initial negative prestudy biopsy. METHODS:Analysis of 7445 patients (2.4% black, 97.6% white) from REDUCE, a 4-year, double-blind, placebo-controlled trial testing dutasteride versus placebo on PC risk. Patients had a single, negative, prestudy biopsy, PSA 2.5-10 ng/mL, and study-mandated biopsies at 2 and 4-years. Multivariable logistic and multinomial regressions were used to test if self-reported race predicted PC, grade (low, Grade-Group 1 [GG1] vs. high, Grade-Group > 2 [GG2+]), and biopsy compliance. Given concerns about noncompliance affecting analyses, primary analyses for PC examined 2-year biopsy outcomes among patients who underwent biopsy. RESULTS:On multivariable analysis, black patients were less likely to receive the 2-year biopsy (OR: 0.53, 95%CI: 0.39-0.74), but had higher PC risk, which approached, but did not reach significance (OR 1.56, 95%CI: 0.98-2.46). When stratified by grade, on multivariable analysis, black race was unrelated to GG1 (RRR: 1.17, 95%CI: 0.65-2.12) but associated with GG2 + PC (RRR: 2.44, 95%CI: 1.29-4.64) at the 2-year biopsy. CONCLUSION:Among patients with a negative prestudy biopsy on a phase 3 trial, black patients had lower compliance with study-mandated biopsy but were 2.44 times more likely to have GG2 + PC on the 2-year biopsy versus white patients. These data extend population and initial biopsy data to first repeat biopsy, strongly supporting that black race is linked with aggressive PC. Given differential biopsy compliance may be greater in the real-world, these data suggest population data may underestimate true racial disparities in PC risk and aggressiveness.
BACKGROUND:Biochemical recurrence (BCR) following radical prostatectomy (RP) occurs in 20%-40% of patients with localized prostate cancer. Neoadjuvant PROSTVAC has been shown to enhance T-cell infiltration into the tumor immune microenvironment, but whether these immunologic changes translate into improved long-term oncologic outcomes remains unknown. PATIENTS AND METHODS:This secondary analysis evaluated 26 patients from a Phase II neoadjuvant PROSTVAC trial who underwent RP. Patients received recombinant vaccinia-PSA-TRICOM priming followed by three fowlpox-PSA-TRICOM boosts before surgery. Tumor immune responses (CD4 + /CD8 + T-cell infiltration) and peripheral antigen-specific T-cell responses to PSA, MUC-1, and brachyury were previously assessed. Primary outcomes included BCR-free survival (BCR-FS) and metastatic progression at extended follow-up. RESULTS:From May 2014 to June 2017, 26 patients were enrolled, received neoadjuvant PROSTVAC, and subsequently underwent RP. Eighteen (69.2%) patients had NCCN® unfavorable-intermediate, high, or very high-risk disease at baseline. At a median follow-up of 8.9 years (range 7.0-10.1), BCR occurred in six patients (23.1%), and none developed metastatic disease. Comparing pre- and post-PROSTVAC peripheral antigen-specific T-cell responses, patients with PSA-specific immune responses had 100% 8-year BCR-FS, compared with 70.0% in nonresponders (p = 0.247). Those with any tumor-associated antigen response demonstrated 85.7% versus 66.7% 8-year BCR-FS (p = 0.149). Patients with CD4+ or CD8 + T-cell responses at the tumor site or invasive margin had 86.2% versus 58.9% 8-year BCR-FS (p = 0.257). CONCLUSION:Neoadjuvant PROSTVAC may have oncologic activity in localized prostate cancer, as we observed a longer BCR-FS in immune responders and no metastatic progression in a small cohort. Further investigation of the biological mechanism by which therapeutic immunotherapy may establish durable antitumor immunity in localized prostate cancer is warranted.
BACKGROUND:To evaluate and compare the efficacy of a simplified diagnostic and individualized comprehensive treatment strategy based on the "prostate-pelvic syndrome (PPS)" theory versus the traditional National Institutes of Health (NIH) conventional classification-based protocol for type III prostatitis in men under 40 years. METHODS:In this prospective randomized controlled trial, 222 patients (18-39 years) with type III prostatitis were randomly assigned to individualized comprehensive therapy guided by simplified PPS-based diagnosis (n = 112) or traditional NIH conventional classification-based therapy (n = 110) for 6 weeks. Randomization was performed using a computer-generated sequence with allocation concealment via sealed opaque envelopes. The primary endpoint was the change in the NIH-chronic prostatitis symptom Index (NIH-CPSI) total score and the response rate (≥ 6-point decrease). Secondary endpoints included changes in prostate volume (PV), NIH-CPSI subdomain scores, and the proportion of patients with sexual dysfunction (SD). Univariate and multivariate analyses identified factors influencing treatment response. RESULTS:A total of 212 patients completed follow-up (108 PPS and 104 NIH). Baseline characteristics were comparable between groups (p > 0.05). After treatment, the median decrease in NIH-CPSI total score was significantly greater in the PPS group than in the NIH group (p = 0.003), and the response rate was higher (79.6% versus 61.5%, p = 0.004). The intergroup difference was primarily driven by the quality-of-life domain (p = 0.003), while pain and voiding domain changes did not differ significantly between groups. Multivariate analysis identified PPS-based treatment [odds ratio (OR) = 2.227, 95% onfidence intervals (CI): 1.143-4.337] and baseline factors, including SD (OR = 0.334, 95% CI: 0.165-0.673), sedentariness (OR = 3.554, 95% CI: 1.652-7.642), and PV ≥ 20 mL (OR = 4.850, 95% CI: 1.870-12.575), as independent predictors of response. CONCLUSION:In men under 40 years with type III prostatitis, individualized comprehensive therapy guided by simplified PPS-based diagnosis was associated with greater symptom improvement-particularly in quality of life-compared with the traditional NIH conventional classification-based protocol. The findings suggest that a comprehensive, symptom-directed treatment strategy may outperform a more restricted classification-based regimen, though the contribution of the simplified diagnostic pathway-eliminating lower urinary tract pathogen localization and invasive expressed prostatic secretion testing-per se requires further study. TRIAL REGISTRATION:MR-34-24-035332; https://www.medicalresearch.org.cn.
BACKGROUND:Benign prostatic hyperplasia (BPH) is the most common disease in aging males. BPH growth is androgen-dependent, and it appears that androgens preferentially stimulate the growth of BPH as compared to normal prostate. The mechanism of preferential androgen stimulation of BPH growth is not clear. Our previous studies suggest that primary BPH stromal cells, but not the paired normal adjacent prostate (NAP) stromal cells from the same patients, could stimulate prostatic epithelial cell proliferation in 3D co-culture. However, whether androgen regulation of prostatic stromal cells is altered in BPH nodules is not clear. METHODS:Paired BPH and NAP primary stromal cells were prepared from the same patients. Early passage paired BPH and NAP primary cells were treated with androgens and/or antiandrogens for RNA-seq analysis. RNA-seq data were analyzed using principal component analysis (PCA) and functional enrichment analysis. Conditioned medium of the paired BPH and NAP primary cells in the presence or absence of androgens were used in three-dimensional (3D) culture of benign prostatic epithelial cells. RESULTS:RNA-seq data analysis suggests that androgen-induced gene expression in BPH primary stromal cells is heightened compared to paired NAP stromal cells. AR activation in BPH stromal cells appears to enhance cellular motility, vascular and extracellular matrix remodeling, and paracrine signaling, while simultaneously modulating cell cycle and metabolic processes. Compared to regular BPH stromal conditioned medium, conditioned medium of androgen-stimulated BPH stromal cells further enhanced prostatic epithelial cell proliferation in 3D culture. In contrast, medium of NAP stromal cell culture conditioned in the presence of androgen had no significant effect on prostatic epithelial cell proliferation in 3D culture. CONCLUSIONS:Our findings suggest that androgen stimulation of prostatic epithelial cell growth via paracrine prostatic stromal signaling is enhanced in BPH and is associated with heightened androgen-responsiveness of BPH stromal cells.
BACKGROUND:Intraprostatic uptake patterns on 18F-PET/PSMA, such as those defined by the PRIMARY score, have been associated with clinically significant prostate cancer. However, the value of the peripheral focal intense uptake pattern (IFPUP), as a predictor of histologic upgrading after radical prostatectomy remains unclear. OBJECTIVE:To determine whether the IFPUP is associated with histological upgrading in specimens obtained from radical prostatectomy in patients with prostate cancer. METHODS:We performed a retrospective cohort study including patients with localized prostate cancer who underwent PET/PSMA prior to radical prostatectomy between 2022 and 2024. Clinical, imaging, and pathology data were collected. IFPUP was defined as SUVmax ≥ 11.4. Histologic upgrading was defined as an increase in ISUP grade from biopsy to prostatectomy. Associations were evaluated using multivariable logistic regression; diagnostic performance was assessed by AUROC, sensitivity, specificity, and predictive values. RESULTS:Thirty-four patients were included (median age 68 years, median PSA 12 ng/mL). Histologic upgrading occurred in 47.1% (16/34). IFPUP was observed in 33% and was significantly associated with upgrading (56% vs. 12%, p = 0.008). On multivariable analysis, IFPUP remained an independent predictor (OR 16.63, 95% CI 1.42-195.6, p = 0.025). Diagnostic performance of IFPUP included AUROC 0.722 (95% CI 0.574-0.870), sensitivity 56%, specificity 88%, positive predictive value 82%, and negative predictive value 68%. CONCLUSIONS:The presence of IFPUP on PET/PSMA is an independent predictor of histologic upgrading in localized prostate cancer. Its high specificity and positive predictive value suggest clinical utility as a complementary preoperative biomarker for risk stratification, warranting validation in larger cohorts.
BACKGROUND:Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is reshaping nodal staging in prostate cancer by detecting regional lymph node metastases with greater accuracy than conventional imaging. This has created a new cohort of patients with N1M0 disease detectable only on advanced imaging, raising important questions regarding prognosis, treatment intensification and the applicability of historical management paradigms derived from conventional imaging. The aim of this review is to consider de novo N1M0 management on PSMA-PET and current evidence. METHODS:A comprehensive review of the literature was performed using Medline, PubMed and Web of Science. Search terms included combinations of "N1M0", "prostate cancer", "PSMA", "PET", "lymph node" and "metastasis". English-language studies and relevant reference lists were reviewed, with interpretation focused on diagnostic performance, stage migration and management implications of PSMA-PET-detected nodal disease. RESULTS:PSMA-PET outperforms conventional imaging for nodal staging, improving diagnostic confidence and frequently altering management. However, sensitivity for small-volume nodal disease remains imperfect, limiting exclusion of microscopic metastases. Emerging data suggest PSMA-PET drives stage migration whilst influencing use of surgery, radiotherapy and systemic therapy to better tailor treatment fields. However, high-level prospective evidence demonstrating improved long-term oncological outcomes remains limited. CONCLUSIONS:PSMA-PET is a practice-changing staging modality in N1M0 prostate cancer, but whether earlier detection and treatment escalation translate into meaningful survival benefit remains uncertain.
BACKGROUND:Upfront treatment intensification with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor has become a standard approach for metastatic hormone-sensitive prostate cancer (mHSPC). However, prognosis remains poor for some patients despite second-generation androgen receptor antagonist-based doublet therapy. Although triplet therapy with darolutamide and docetaxel is available, its added clinical value over apalutamide- or enzalutamide-based doublet therapy in real-world practice remains unclear. Gleason pattern 5 (GP5) reflects aggressive tumor biology and may be relevant for treatment selection. We evaluated whether triplet therapy was associated with longer castration-resistant prostate cancer-free survival (CRPC-FS) than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC, with a particular focus on effect modification by GP5 status. METHODS:This retrospective multicenter cohort study used the ULTRA-J multicenter collaborative database in Japan. We included systemic treatment-naïve patients with mHSPC who received either doublet therapy with ADT plus apalutamide or enzalutamide, or triplet therapy with ADT, darolutamide, and docetaxel, between February 2018 and October 2024. The final analytic cohort consisted of 294 patients. Overlap weighting was used to reduce treatment-selection bias. The primary endpoint was CRPC-FS, and overall survival (OS) was assessed as a supportive endpoint. Progression-free survival 2 (PFS2) and post-CRPC docetaxel use were evaluated as exploratory post-progression outcomes. RESULTS:The median follow-up duration estimated using the reverse Kaplan-Meier method was 18.0 months in the doublet group and 11.0 months in the triplet group. In the overlap weighting-adjusted overall cohort, triplet therapy was associated with longer CRPC-FS than doublet therapy (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.13-0.64; p = 0.002). A significant interaction was observed for GP5 status (p for interaction = 0.037). In the GP5-positive subgroup, triplet therapy was associated with longer CRPC-FS than doublet therapy (HR, 0.16; 95% CI, 0.06-0.42; p < 0.001), whereas no clear advantage of triplet therapy was observed in the GP5-negative subgroup (HR, 1.85; 95% CI, 0.29-11.94; p = 0.52). No clear difference in OS was observed at the current follow-up. CONCLUSIONS:Triplet therapy was associated with longer CRPC-FS than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC. This association appeared more evident in patients with GP5-positive disease. Given the shorter follow-up in the triplet group, limited event numbers in subgroup and PFS2 analyses, and the nonrandomized nature of post-CRPC treatment sequencing, these findings should be interpreted as hypothesis-generating.
BACKGROUND:[-2]proPSA(p2PSA)-related indices have demonstrated diagnostic value for detecting prostate cancer (PC) in males with modest increases in prostate-specific antigen levels (PSA) of < 10 ng/mL. However, the "leak point" of p2PSA level in the blood circulation before developing screen-detectable PC remains uncertain. Therefore, this study evaluated the ability of p2PSA-related indices in the years before considering conventional biopsy indications. METHODS:This case-control study analyzed database and serum bank information from a population-based screening cohort in Gunma Prefecture. The case group included 58 males diagnosed with PC due to increased PSA (4-10 ng/mL) followed serially for 5 years. The control group comprised 58 males without PC based on biopsy who were matched to the case group by adjusted PSA levels (± 2 ng/mL) and age (± 5 years) at the time of biopsy. p2PSA, free PSA, and PSA were measured from frozen serum samples from 0 to 5 years before biopsy. RESULTS:p2PSA-to-free PSA ratio (%p2PSA) and prostate health index (phi) were significantly higher in the case group than in the control group from five, three, and 3 years before biopsy, respectively. The areas under the receiver operating characteristic curve for predicting PC were 0.437 for PSA, 0.637 for phi, 0.663 for %p2PSA, and 0.618 for free PSA-to PSA ratio (%fPSA) at 3 years before biopsy. CONCLUSIONS:p2PSA-related indices showed group-level differences between future PC cases and matched controls before PSA exceeded conventional cut-offs. These findings should be regarded as hypothesis-generating and require validation in prospective studies before clinical application to risk-stratified screening.
OBJECTIVE:Incidental prostate cancer (PCa) patients are currently stratified to either cT1a vs. cT1b stage, depending on tumor volume (< 5% vs. > 5%) in the resected tissue. We tested for other models that could improve cancer-specific survival (CSS) predictions. METHODS:Incidental (cT1a/cT1b) PCa patients were retrospectively identified within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015). Kaplan-Meier plots illustrated CSS at 5 years of follow-up. Combination of variables resulted in three distinct stratification models based on cT1a vs. cT1b and Gleason score sum (GS). Multivariable Cox regression models that predicted CSS were used for area under the curve (AUC) quantification after 20-fold cross validation. RESULTS:We identified a total of 5155 incidental PCa patients. CSS at 5 years was 98% for cT1a vs. 90% for cT1b (p < 0.0001). CSS at 5 years for combination of cT1a and GS 6 patients was 99% vs. 92% for patients with either cT1b or GS ≥ 7 (p < 0.0001). Finally, for patients with GS < 8, CSS at 5 years was 98% vs. 72% for patients with GS ≥ 8 (p < 0.0001). The multivariable adjusted AUC was 0.83 vs. 0.82 vs. 0.88, for each model, respectively. CONCLUSION:Of all tested stratification models, the consideration of GS stratified between < 8 and ≥ 8 resulted in the best survival discrimination, as well as highest accuracy after cross-validation. In consequence, the use of this model (GS < 8 vs. ≥ 8) appears better suited than the standard cT1a vs. cT1b substaging, when CSS represents the endpoint of interest.
BACKGROUND:Hot flashes are common and often debilitating side effects of castration therapy; a cornerstone in the treatment of metastatic prostate cancer (PCa) as well as in localized or locally advanced PCa when combined with radiotherapy. The evidence for relieving vasomotor symptoms is limited. This systematic review presents both pharmacological and non-pharmacological interventions for treating hot flashes in men with PCa undergoing castration therapy, primarily androgen deprivation therapy (ADT). METHODS:a systematic literature search was conducted in PubMed using ("hot flash*" OR "hot flush*" OR "vasomotor*") AND ("prostate") as keywords. Studies with intervention for hot flashes due to castration therapy, estimation of treatment response (e.g., reduction in frequency or impact on quality of life) and patients with PCa (any stage) were eligible. RESULTS:Of 469 papers, 35 were included in the review. The included studies evaluated cyproterone acetate, estrogen or estrogen derivatives, progesterone derivatives, selective serotonin reuptake inhibitors (SSRIs), gabapentin, oxybutynin, and clonidine, as well as non-pharmacological interventions such as acupuncture, cognitive behavioral therapy (CBT), and dietary supplements (e.g., Dong Quai/Angelica Sinensis, Serelys Homme, soy protein, and Salvia officinalis). Across all blinded pharmacological interventions, the relative reduction in hot flash frequency ranged from -21% to -84%, and the placebo effect was between -19% and -30%. CONCLUSION:Hormonal agents such as cyproterone acetate and estrogen appear to be the most effective treatments, although they are associated with side effects. Non-pharmacological options like acupuncture and CBT may offer some benefit, while dietary supplements seem to be ineffective. Future studies are needed also to evaluate newer treatments, such as fezolinetant, in this patient population.
BACKGROUND:The modified Glasgow Prognostic Score (mGPS) and systemic immune-inflammation index (SII) are useful prognostic markers for various malignancies. This study aimed to evaluate their prognostic significance in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel (CBZ). METHODS:We retrospectively reviewed the data of 344 patients with mCRPC who initiated CBZ treatment at Kobe University Hospital and affiliated institutions. The optimal SII cutoff value for predicting overall survival (OS) was determined using the maximally selected rank statistics (Maxstat) method. The prognostic significance of the mGPS and SII was assessed using Cox proportional hazards models. RESULTS:The median OS of the entire cohort was 15.9 months. The optimal SII cutoff value determined using the Maxstat method was 850.6. A multivariate analysis demonstrated that an mGPS ≥ 1 and an SII ≥ 850.6 were independent predictors of poorer OS, with hazard ratios of 2.10 (95% confidence interval [CI], 1.55-2.85; p < 0.001) and 1.58 (95% CI, 1.13-2.21; p = 0.008), respectively. Notably, among patients with an mGPS of 0, further stratification using the SII cutoff (mGPS 0/SII-low vs. mGPS 0/SII-high) significantly discriminated OS rates. CONCLUSION:mGPS and SII are significant prognostic biomarkers in patients with mCRPC treated with CBZ. Their combined assessment may provide improved risk stratification and support clinical decision-making in this population group.
BACKGROUND:The Phoenix definition is widely used to define biochemical recurrence (BCR) after radiation therapy for prostate cancer; however, a definitive definition of cure remains unclear. This study aimed to identify factors associated with late BCR after low-dose-rate brachytherapy (LDR-BT), defined as BCR occurring ≥ 5 years after treatment among patients who remained recurrence-free during the first 5 years, using machine-learning methods. METHODS:We retrospectively analyzed 1419 patients who underwent LDR-BT between 2004 and 2019. Of these, 52 (3.7%) experienced BCR within 5 years, and 244 patients did not have ≥ 5 years of follow-up because of death or loss to follow-up. The remaining 1123 patients were recurrence-free at 5 years and formed the analysis cohort for late BCR (≥ 5 years). Random survival forest (RSF) and survival decision-tree analyses were applied to identify predictive factors, and recurrence-free survival was estimated using the Kaplan-Meier method. RESULTS:The 10-year BCR-free survival rate was 94.8%. RSF identified the 5-year prostate-specific antigen (PSA) value, PSA doubling time (PSA-DT) at 5 years, primary Gleason pattern, and NCCN risk classification as the most important predictors. Optimal cutoff values were 0.93 ng/mL for PSA at 5 years and 5.3 years for PSA-DT. Patients with lower PSA or longer PSA-DT had significantly higher 10-year recurrence-free rates than those at higher risk (97.3% vs. 11.1% and 99.0% vs. 68.1%, respectively; p < 0.001). CONCLUSIONS:PSA level and PSA-DT at 5 years were strong predictors of late BCR after LDR-BT. These findings suggest that follow-up intervals may be safely extended for low-risk patients, thereby reducing the burden of hospital visits and healthcare costs.
BACKGROUND:To determine whether systematic biopsy can be safely omitted in selected patients undergoing antibiotic-free transperineal cognitive MRI-targeted prostate biopsy under local anesthesia, and to identify clinical and imaging parameters associated with cognitive biopsy superiority. METHODS:This retrospective study included patients who underwent antibiotic-free transperineal prostate biopsy under local anesthesia. All patients had multiparametric prostate MRI (mpMRI) visible lesions and received both systematic and cognitive MRI-targeted biopsy. Targeted cores were obtained from all PI-RADS 4-5 lesions and from PI-RADS 3 lesions only when PSA density was ≥ 0.10 ng/mL/cm3. Cognitive biopsy non-inferiority was defined as an ISUP Grade Group equal to or higher than that obtained from systematic cores in the same patients. PSA density, MRI lesion size, and PI-RADS category were incorporated into a multivariable model to predict when systematic sampling would not add diagnostic value. RESULTS:The multivariable model incorporating PSA density, MRI lesion size, and PI-RADS category demonstrated good discriminatory performance (AUC 0.881, sensitivity 92.6%, specificity 84.8%). In patients meeting all predefined model criteria, cognitive biopsy achieved concordant or superior grading in 95.2% of cases, whereas in those not meeting these criteria, systematic biopsy provided higher-grade detection in all cases within this subgroup. CONCLUSIONS:In carefully selected patients with elevated PSA density, larger mpMRI visible lesions, and high PI-RADS scores, transperineal cognitive MRI-targeted biopsy may support the selective omission of systematic cores without compromising diagnostic reliability. In contrast, systematic sampling remains indispensable in lower-risk profiles, underscoring the value of a risk-adapted biopsy strategy.
Background Benign prostatic hyperplasia (BPH) leads to prostate enlargement and lower urinary tract symptoms that can resist treatment. A histologic hallmark of BPH is glandular epithelial hyperplasia with new ductal branching morphogenesis. The stromal inductive factors driving tissue morphogenesis may provide new therapeutic targets, but are incompletely known due in part to a paucity of cell culture model systems. We thus sought to create a reliable cell culture assay for human prostatic branching morphogenesis.Methods Various combinations of input cells, cell densities and cell culture medium were trialed. A robust solution comprised embedding BHPrE1 immortalized human prostatic epithelial cells in Matrigel, together with an inductive source of BPH stromal fibroblasts or their conditioned medium. Resultant spheroids were measured and budding/branching morphogenesis evaluated by brightfield microscopy and optionally immunofluorescence. Candidate paracrine signaling pathways were interrogated using small molecule inhibitors and neutralizing antibodies.Results We have detailed a simple, robust cell culture assay for human prostatic epithelial branching morphogenesis. Preliminary application of the assay to investigate signaling pathways previously implicated in developmental budding/branching morphogenesis identified functions of epidermal growth factor (EGF), insulin-like growth factors (IGFs), and bone morphogenetic proteins (BMPs) in stimulating prostatic spheroid growth. However, only BMP inhibition blocked prostatic epithelial budding/branching morphogenesis.Conclusions We have described a straightforward cell culture assay for human prostatic budding/branching morphogenesis that in particular spotlights IGFs and BMPs as candidate therapeutic targets in BPH. Additional preclinical testing is warranted.
BACKGROUND AND OBJECTIVE:Metastatic hormone-sensitive prostate cancer (mHSPC) exhibits heterogeneous progression patterns, with early progression to metastatic castration-resistant prostate cancer (mCRPC) within 12 months indicating aggressive tumor biology and poor prognosis. Current risk stratification tools (CHAARTED, LATITUDE) offer limited individualized prediction. Machine learning approaches are increasingly applied to predict prostate cancer progression, but most models show modest performance (AUC 0.68-0.72), limited external validation, or require genomic variables unavailable in routine practice. This study aimed to develop and externally validate a novel RINH algorithm for predicting early mCRPC progression (≤ 12 months) using exclusively clinical variables, positioning it as a superior alternative to conventional ML classifiers. METHODS:This multicenter study enrolled 412 patients with de novo mHSPC from seven Spanish academic centers using mixed retrospective-prospective data collection. Twenty clinical variables were recorded, including demographics, PSA, ISUP grade, metastatic localization, CHAARTED/LATITUDE classifications, and treatment modalities. Following RINH-based outlier exclusion (55 patients), 357 patients (29 with early progression, 8.1%) were used to train six ML algorithms: RINH, Logistic Regression, Linear Discriminant, Support Vector Machine, Random Forest, and Subspace Discriminant. A two-tiered validation strategy integrated stratified fivefold cross-validation across all centers and formal external validation using center 1 (n = 121, 19 events) for training and centers 2-7 (n = 207, 10 events) for independent testing. Performance metrics included AUC, sensitivity, specificity, accuracy, and F1-score. KEY FINDINGS AND LIMITATIONS:Artificial intelligence and machine learning (ML) are transforming oncology, promising personalized risk stratification beyond traditional clinical criteria. In metastatic hormone-sensitive prostate cancer (mHSPC), early progression to castration resistance (mCRPC) within 12 months signals aggressive biology and poor prognosis, yet current tools (CHAARTED, LATITUDE) offer limited individualized prediction. Multiple ML models have been proposed with variable success: most achieve modest performance (AUC 0.68-0.72), lack robust external validation, or rely on genomic variables inaccessible in routine practice. We propose a novel approach using the Rivality Index Neighborhood (RINH) algorithm, demonstrating superior predictive capacity in an initial multicenter validation with exclusively clinical variables. This study provides rigorous multicenter external validation, advancing toward implementable precision oncology tools. CONCLUSIONS AND CLINICAL IMPLICATIONS:The RINH algorithm achieves superior predictive performance for early mCRPC progression using exclusively clinical variables, representing a significant advance toward implementable risk stratification. However, low reliability scores in external validation underscore that excellent performance metrics alone do not guarantee stability. Before clinical deployment, validation in substantially larger cohorts with higher progression events is essential. If validated, this model could enable personalized, risk-adapted therapeutic strategies, refining patient selection for treatment intensification or de-escalation.
INTRODUCTION:Temporal trends of metastatic prostate cancer (mPCa) in the prostate-specific membrane antigen positron emission tomography (PSMA PET) era in the United States are not known. METHODS:In the Surveillance, Epidemiology, and End Results (SEER) database (2018-2022), all PCa patients were identified. Estimated annual percentage change (EAPC) and multivariable logistic regression (MLR) models tested the effect of the PSMA PET era (2021-2022) on mPCa rate and its substages (M1a, M1b, M1c) rates. RESULTS:Overall, 236,723 PCa patients were identified. Of those, 20,450 (8.6%) harbored mPCa. mPCa rate increased from 7.9% in 2018 to 9.4% in 2022 (EAPC: +4.7%, p = 0.019). In MLR model, PSMA PET era independently predicted 1.1-fold (p < 0.001) increase in mPCa. Within mPCa patients, 1,564 (8.0%), 14,806 (72.0%), and 4,080 (20.0%) harbored M1a, M1b, and M1c substages. M1a and M1b substages rates increased in PSMA PET era (M1a: from 6.3% in 2018 to 9.1% in 2022, EAPC: +9.3%, p = 0.009; M1b: from 70.3% in 2018 to 74.7% in 2022, EAPC: +1.7%, p = 0.043), but not M1c (from 23.3% in 2018 to 16.2% in 2022, EAPC: -8.7%, p = 0.036). In MLR models, PSMA PET era independently predicted 1.3-fold increase (p < 0.001) in M1a, 1.2-fold increase (p < 0.001) in M1b, but 0.7-fold (p < 0.001) decrease in M1c. CONCLUSION:The introduction of PSMA PET resulted in an increase in the proportion of mPCa patients in the United States. Within those, M1a and M1b substages increased, but M1c decreased. These observations suggest a stage migration phenomenon, where low burden mPCa (M1a and M1b) is diagnosed more frequently at the expense of high burden mPCa (M1c).
Purpose This study aims to investigate the effects of holmium laser enucleation of the prostate (HoLEP) with proactive preservation of one lateral lobe (PLL-HoLEP) on urinary function and sexual function in patients with benign prostatic hyperplasia (BPH). Methods From April 2024 to April 2025, 71 patients who underwent PLL-HoLEP (Group A) were studied based on inclusion and exclusion criteria. Meanwhile, 140 patients who underwent traditional HoLEP from September 2022 to March 2024 were selected as the control group (Group B). After propensity score matching (PSM) was performed, the baseline characteristics of the two groups were balanced. Subsequently, differences in clinical outcomes between the groups were compared. We compared preoperative and postoperative complications, international prostate symptom score (IPSS), quality of life (QoL), maximum urine flow rate (Q(max)), postvoid residual urine (PVR), International Index of Erectile Function (IIEF-5), QMSHQ EjF, and QMSHQ EjS between the two groups, and conducted follow-up evaluations of surgical outcomes and sexual function. Results Fifty-four pairs of patients were successfully matched by PSM. Operative time, resected prostate weight, hemoglobin decrease, and incidence of transient incontinence and retrograde ejaculation in Group A were lower than those in Group B. There were significant differences in IPSS, QoL, Q(max), and PVR between preoperative and 1 month postoperative periods in two groups (p < 0.05). However, there were no statistically significant differences in IPSS, QoL, Q(max), and PVR between the two groups at one and 6 months postoperatively (p > 0.05). Significant differences in IIEF-5, QMSHQ EjF, and QMSHQ EjS scores were observed between the two groups during the 6-month postoperative follow-up of sexual function (p < 0.05), with Group A showing better outcomes. Conclusion For patients who satisfy the inclusion and exclusion criteria, PLL-HoLEP can reduce the incidence of transient urinary incontinence and retrograde ejaculation and more effectively preserve the sexual function of patients with BPH.
BACKGROUND:For patients with unfavorable intermediate or high risk localized prostate cancer receiving definitive radiotherapy, androgen deprivation therapy reduces recurrence and improves survival but is underutilized due to toxicity concerns. Patients who forgo initial ADT may later require salvage ADT. Robust real world risk estimates can guide counseling. PATIENTS AND METHODS:We conducted a retrospective cohort study using SEER-Medicare. Men aged 66 years diagnosed from 2010 to 2021 and treated with external beam radiotherapy were included. Exposure was concurrent ADT with radiotherapy versus radiotherapy alone. Salvage ADT was defined as initiation after the initial treatment period. We estimated cumulative incidence of salvage ADT accounting for death as a competing risk and used Fine-Gray models to obtain adjusted sub-distribution hazard ratios, controlling for demographics, tumor characteristics, and facility factors. RESULTS:Among 5,092 patients with unfavorable intermediate-risk disease, 61.17% received concurrent ADT with definitive RT. Among 6,970 patients with high-risk disease, 89.60% received concurrent ADT with definitive RT. At 5 years, the adjusted cumulative incidence of salvage ADT was 3.53% (RT with ADT) versus 6.07% (RT alone) for unfavorable intermediate-risk, and 5.92% vs 19.17% for high-risk patients. On multivariable analysis, concurrent ADT with definitive RT was associated with a lower risk of salvage ADT in both the unfavorable intermediate-risk group (SHR, 0.56; 95% CI,A 0.45-0.70; p < 0.01) and the high-risk group (SHR, 0.26; 95% CI, 0.21-0.31; p < 0.01). Higher PSA was also associated with increased risk for salvage ADT for both risk groups, and higher Gleason score was also associated with increased salvage ADT in high-risk patients. CONCLUSIONS:Omission of initial ADT during RT is associated with an increased risk of salvage ADT in unfavorable intermediate-risk and high-risk prostate cancer. These real-world, population-based estimates help inform patient counseling and facilitate personalized treatment decisions.
