The Prostate

Prostate cancer (PC) remains a significant health concern as the second leading cause of cancer-related death in American men. Androgen deprivation therapies represent the standard of care for patients with PC, regardless of disease stage. Gonadotropin-releasing hormone (GnRH) antagonists, such as Degarelix, are commonly used hormone therapies for PC and work by suppressing testosterone production. Previous studies indicate a prostate involution-regeneration cycle following surgical castration and testosterone addback. However, whether a similar response occurs following pharmacologic androgen deprivation with agents such as Degarelix remains poorly understood. In particular, the temporal dynamics of prostate involution and subsequent regeneration after chemical castration have not been systematically defined. Our study utilizes immunocompetent mouse models to evaluate the systemic and temporal effects of Degarelix treatment and determine its efficacy in suppressing PC tumor growth. We show that continuous Degarelix treatment significantly suppressed systemic testosterone levels in mice, whereas testosterone levels returned to physiological baseline following Degarelix withdrawal. Gross anatomical, H&E, and Trichrome analyses demonstrated that Degarelix induced castration resulted in prostate involution, characterized by reduced gland size and increased stromal remodeling. This phenotype was reversed after Degarelix withdrawal, highlighting the reversibility of pharmacological androgen deprivation. Immunofluorescence staining revealed changes in basal and luminal epithelial cell populations within the prostatic gland, indicating changes in prostate glandular architecture following Degarelix induced castration and subsequent regeneration. Next, we evaluated the impact of chemical castration on PC tumor growth. Although Degarelix initially suppressed tumor growth, this response was not sustained through the study endpoint, suggesting the emergence of acquired resistance to androgen deprivation. These findings establish this immunocompetent model as a physiologically relevant platform for dissecting the mechanisms that drive therapeutic resistance and tumor progression following androgen deprivation. Our findings highlight the effectiveness of chemical castration with Degarelix and establish a robust model to study both therapeutic responses and the emergence of castration resistance in PC.

Background: Chronic inflammation is the most common histological feature in Benign Prostatic Hyperplasia (BPH), and T cells are a key component of immune infiltrate. Advanced BPH is commonly associated with the formation of nodules, but it remains unclear whether a link exists among T cell infiltration, nodular development, and BPH progression. Using a Toxoplasma gondii (T. gondii) model and human specimens, we characterize the subtypes of T cells present during prostatic hyperplasia and their association with nodular development of the prostate. Methods: Male CBA/j mice were intraperitoneally infected with T. gondii parasites, and flow cytometry was performed on the prostate to quantify the number of CD4+ and CD8+ T cells. Histology was used to score microglandular hyperplasia (MGH), and immunofluorescence was used to quantify and examine the locality of CD4+ and CD8+ T cells and compared that to human BPH tissue. Results: We found that infecting male mice with T. gondii resulted in an increase of both CD4+ and CD8+ T cells in the prostate acutely and that CD8+ cells remained sustained at chronically. We also established the presence of glandular nodule formation at this timepoint through hematoxylin and eosin (H&E) staining. Immunofluorescence revealed that CD8+ cells were found proximal to forming glandular nodules relative to non-nodular glands. We also found more CD8+ cells localized to non-nodular glands in nodular BPH tissue versus non-nodular BPH tissue. Finally, we discovered a higher prevalence of CD8+ cells in T. gondii IgG+ patients than in IgG- patients. All T. gondii IgG+ patients exhibited nodular BPH, whereas all but one IgG- patient exhibited non-nodular BPH. Conclusions: This study is the first to investigate the presence and location of CD4+ and CD8+ T cells within nodular and non-nodular BPH glands. We found an association of the presence of CD8+ T cells with nodular progression. This association held true in human prostate tissue. Translationally, CD8+ T cells may enhance nodular BPH progression, and T. gondii infection may promote this CD8+ T cell-mediated response.

Background: Biochemical recurrence (BCR) occurs in 20-40% of men after radical prostatectomy. Existing postoperative recurrence risk tools based on PSA and pathology are clinically useful but show only moderate and variable discrimination, highlighting the need for biomarkers that improve risk stratification and consequent treatment decisions. We hypothesized that the prostate microenvironment, including both the tumor and non-cancerous adjacent tissue, may contain prognostic features associated with adverse postoperative PSA outcomes. Methods: We assembled a cohort of matched tumor-adjacent benign and tumor prostate tissue from 243 men across three institutions to establish a discovery cohort (n=123; 43 postoperative PSA events, 35%) and validation cohort (n=120; 46 events, 38%). For primary binary analyses, a postoperative PSA event included BCR, defined as two consecutive postoperative PSA values >=0.2 ng/mL, or PSA persistence. We performed RNA sequencing of matched tumor-adjacent benign and tumor tissues, quantified immune signatures, and developed an integrated model combining the adjacent-tissue B-cell signature, preoperative PSA, and radical prostatectomy Gleason score (BRIGADE). CAPRA-S-adjusted Cox analyses excluding recurrence-time-0 cases evaluated time to BCR, and CD19 multiplex immunofluorescence provided tissue-level confirmation (n=10). Results: In prostatectomy specimens, tumors from patients without a postoperative PSA event were enriched for B-cell transcriptional programs, whereas tumors from event-positive patients showed elevated proliferation signatures. B-cell-related transcriptional programs were correlated between tumor and adjacent tissue. Tumor-adjacent benign B-cell scores were higher in no-event cases and discriminated postoperative PSA-event status in PCBN discovery (AUC 0.63) and BM validation (AUC 0.81) cohorts, outperforming numerous other immune-related signatures. In CAPRA-S-adjusted Cox sensitivity analyses excluding recurrence-time-0 cases, higher adjacent-tissue B-cell activity was associated with reduced recurrence risk in PCBN (HR 0.42, 95% CI 0.19-0.94; BH-adjusted p=0.035) and BM (HR 0.54, 95% CI 0.30-0.95; BH-adjusted p=0.034). Tissue-based validation showed that CD19+ B-cell density in adjacent benign tissue was higher in no-event than event-positive patients (median 0.1145 vs 0.0471; p=0.008). BRIGADE achieved an AUC of 0.68 in cross-validation and 0.83 in independent validation, compared to AUCs of 0.54-0.63 and 0.44-0.78 for the tested clinical predictors, respectively. At the fixed classification threshold, the validation-cohort odds ratio for BRIGADE was 2.75. The adjacent B-cell score remained associated with lower odds of a postoperative PSA event after adjustment for PSA and Gleason score. Conclusions: B-cell infiltration in tumor-adjacent benign prostate tissue may complement existing clinicopathologic models for stratifying adverse postoperative PSA outcomes and subsequent BCR after radical prostatectomy. The transcriptomic signal was recapitulated by CD19-based tissue staining, supporting further development of a pathology-based assay.

Background. Progression of prostate cancer under androgen receptor (AR) pathway-targeted therapy spans a phenotypic spectrum, from tumors that sustain AR pathway output to tumors that become independent of AR signaling. Experimental models that occupy the intermediate portion of this spectrum, in which AR is still expressed but pathway output is reduced, are comparatively scarce. Methods. LNCaP cells expressing a triple-modality reporter (LNCaP-TR) were injected into nude mice by the intracardiac route, and a bone lesion that arose in the middle spine of one animal was recovered and propagated as LNCaP-TR-BoM. The subline and its parental line were compared by two-dimensional and three-dimensional culture assays, RNA-seq, qRT-PCR, and immunoblotting. AR pathway output was assessed using KLK3 expression under AR antagonist treatment. Public prostate cancer datasets provided clinical context. A CRISPR-Cas9 EPHA3-edited derivative was evaluated in aggregation and spheroid assays. Results. Relative to parental LNCaP-TR, LNCaP-TR-BoM formed more numerous and larger cell aggregates in monolayer culture and larger, less circular spheroids in both suspension and Matrigel three-dimensional culture. AR mRNA was modestly reduced and AR protein remained readily detectable, whereas KLK3 mRNA and protein were reduced disproportionately more than those of AR. Residual KLK3 expression remained suppressible by AR inhibitors enzalutamide and darolutamide. Transcriptome-based pseudotime placed LNCaP-TR-BoM between the parental line and the androgen-refractory LNCaP-RF variant. Subsequent differential gene expression (DGE) and pathway enrichment analysis revealed that LNCaP-TR-BoM exhibits transcriptomic rewiring concordant with that of clinical mCRPC, thus evidencing LNCaP-TR-BoM as a potentially clinically relevant model cell line. Finally, EPHA3 showed the largest fold change among the most significant differentially expressed genes in LNCaP-TR-BoM compared with the parental line. Therefore, EPHA3 was explored to demonstrate the utility of the LNCaP-TR-BoM cell line as a discovery system for genes that potentially drive the malignancy of bone-metastatic prostate cancer at the intermediate AR-attenuated progression stage. An EPHA3-silenced derivative of LNCaP-TR-BoM lacking detectable EPHA3 protein formed smaller aggregates and smaller, more circular spheroids, suggesting EPHA3 may play a role in driving the malignancy of AR-intermediate bone-metastatic prostate cancer. This finding provides support for the potential utility of the LNCaP-TR-BoM cell line as a discovery system for genes relevant to driving AR-intermediate bone-metastatic prostate cancer. Conclusions. LNCaP-TR-BoM is a bone lesion-derived prostate cancer cell line in which AR expression is retained but AR pathway output is attenuated, accompanied by an mCRPC-concordant transcriptomic shift and altered multicellular organization. It provides a paired discovery system for candidate genes such as EPHA3.

Background: The incremental value of PSMA PET/CT over multiparametric MRI (mpMRI) for selecting patients for prostate cancer focal therapy is undefined. Unlike lesion-detection studies, we evaluated whether PSMA PET/CT, mpMRI, and their combination correctly determine focal therapy eligibility when validated against whole-mount histopathology (WMHP). Methods: We retrospectively analyzed patients undergoing radical prostatectomy (RP) at UCLA (2017-2024) with preoperative PSMA PET/CT and mpMRI, biopsy grade group (GG) [&le;]3, unilateral disease, and prostate-specific antigen <20 ng/mL. Two blinded readers per modality assessed extraprostatic extension (EPE), seminal vesicle invasion (SVI), bilateral disease, and multifocality; a third adjudicated discordances. Eligibility required absence of all four. On WMHP, ineligibility was EPE, SVI, multifocal or bilateral disease with a contralateral or secondary GG[&ge;]2 nodule, or any GG>3 focus at RP. Modalities were compared by McNemar tests. Results: Of 112 patients, 77 (69%) were ineligible on WMHP, including 19 (17%) with a GG>3 focus at RP. Sensitivity and specificity were 53% and 54% for PET and 70% and 49% for mpMRI. Combined imaging improved sensitivity to 83% (P<0.001 vs PET; P=0.002 vs MRI) but reduced specificity to 26%. Per 100 patients at this prevalence, this would correctly identify approximately 9 additional ineligible patients while falsely excluding approximately 7 true candidates. mpMRI was more sensitive than PET for EPE (77% vs 32%, P<0.001), whereas PET was more specific (90% vs 58%, P<0.001). Combined imaging improved detection of multifocal (44% vs 23%, P=0.001) and bilateral disease (45% vs 23%, P=0.002) versus MRI alone. Conclusions: Adding PSMA PET/CT to mpMRI significantly improves sensitivity for exclusionary features, reflecting complementary molecular and anatomic information. However, combined imaging still misses a substantial proportion of adverse pathology, so imaging alone should not determine eligibility.

Purpose: Biochemical recurrence (BCR) after radical prostatectomy (RP) presents heterogeneous recurrence patterns and variable outcomes following salvage radiotherapy (sRT). We evaluated clinicopathologic determinants of PSMA-PET/CT detection, anatomical recurrence distribution, and biochemical disease-free survival (bDFS) following PSMA-PET-guided sRT. Methods: This retrospective single-institution study included 140 patients with BCR after RP who underwent Ga-PSMA-PET/CT prior to sRT with or without androgen deprivation therapy. PSMA-PET-positive findings were categorized as prostate bed only (PBO) or pelvic nodal involvement with or without the prostate bed (PLNI). Receiver operating characteristic (ROC) analysis, logistic regression, and Cox proportional hazards models were employed. Results: PSMA-PET detected locoregional recurrence in 77/140 patients (55%). On multivariable analysis, PSA at recurrence (OR=2.07; p=0.003) and age (OR=1.07; p=0.016) were the sole independent predictors of PSMA-PET positivity. ROC analysis yielded AUC=0.74 (optimal threshold of 0.58 ng/mL). Among PSMA-positive patients, PBO was associated with a longer time to BCR (tBCR) (37.5 versus 15 months; p=0.006). Seminal vesicle invasion (SVI) and pT-stage predicted PLNI on univariable analysis. Among 124 of 140 evaluable patients (median follow-up 31 months), estimated bDFS at 24, 36, and 60 months was 89.7%, 80.2%, and 54.1%, respectively. SVI (HR=2.39; p=0.031), EPE (HR=2.82; p=0.012), pT-stage (HR=1.64; p=0.021), and pN-stage (HR=1.83; p=0.045) were associated with increased failure on univariable Cox regression, though none retained independent significance. Conclusion: PSA burden and age independently predicted PSMA-PET detection. Recurrence patterns reflected disease behavior, as PBO was associated with longer tBCR. Adverse pathologic features were associated with pelvic nodal disease and reduced biochemical control; none remained independently predictive.

Background: Prostate cancer (PCa) is the most common urological malignancy globally and remains a major cause of cancer mortality among men. In Hong Kong, a comprehensive evaluation of disease burden, real-world treatment patterns, and outcomes across clinically relevant PCa subgroups is essential for identifying unmet needs and optimising care delivery. Objectives: This study aims to characterise the burden of PCa and patterns of care in Hong Kong by (1) estimating annual patient load (2) describing treatment patterns, and (3) evaluating real-world outcomes among patients receiving systemic therapy (chemotherapy or novel hormonal agents [NHA]) and novel agents (immunotherapy, poly ADP-ribose polymerase [PARP] inhibitors, radiation therapy). Methods: We conducted a population-based retrospective cohort study using electronic medical records from the Hong Kong Hospital Authority (HA). The cohort included patients diagnosed with PCa between January 1, 2012 and December 31, 2024. Subgroup analyses included patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) and were further stratified by the treatment received. Descriptive analyses summarised annual patient load and treatment patterns over 2018 to 2022. We evaluated treatment outcomes from 2012 to 2024, including overall survival, progression-free survival, number of hospitalisations, and main adverse events. Results: From 2018 to 2022, prevalence increased for prostate cancer (12,014 to15,610), mHSPC (1,188 to 1,779), and mCRPC (167 to 290), while annual mCRPC incidence rose from 125 to 274. There was an increasing number of prevalent and new users of the investigated novel treatment, including first-/second-/third-line therapy for mCRPC. Compared with patients treated with NHAs, chemotherapy showed a numerically higher rate of hospitalisations, bone treatment initiation and higher hematologic toxicity. Conclusions: This population-based retrospective study provides Hong Kong-specific evidence on PCa burden, real-world management, and outcomes across key subgroups, thereby supporting policy planning, formulary evaluation, and targeted strategies to address unmet clinical needs. Funding: This work was supported by a grant from Novartis.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is increasingly used to characterize newly diagnosed prostate cancer on the assumption that uptake highlights aggressive disease. However, maximum standardized uptake value (SUVmax) varies widely across localized tumors. Recent genomic assessments have suggested SUVmax reflects tumor biology even when accounting for other tumor indices. Here, we examined highly annotated pathologic, imaging and clinical correlates of intraprostatic SUVmax at the level of individual tumor foci in a prospective multimodal cohort. Methods: Exploratory lesion-level analysis of the radical prostatectomy arm of a single-center prospective diagnostic-accuracy trial (NCT04461509). Patients underwent simultaneous 18F-DCFPyL PSMA PET, multiparametric magnetic resonance imaging (MRI) and high-resolution MRI before prostatectomy, with central blinded pathology and imaging review. Grade Group (GG) [&ge;]2 foci measuring [&ge;]10 mm were eligible. The primary outcome was focus-level SUVmax. Correlates spanning histology, tumor microenvironment, MRI and clinical indices were examined by Spearman correlation and rank-based group comparison, followed by separate linear regressions of log(1+SUVmax) each adjusted for GG and tumor size. A digital-pathology sensitivity analysis quantified immune, stromal and tumor pixel-area fractions on hematoxylin and eosin (H&E) sections from a subset of foci using a trained QuPath classifier. Results: Twenty-seven patients contributed 34 tumor foci, of which 21 (61.8%) were GG2. Median SUVmax was 5.7 (interquartile range [IQR] 3.9 - 12.1; range 0.0 - 57.9). SUVmax rose across the cribriform/intraductal carcinoma (Crib/IDC) gradient (median 3.9, 4.8 and 10.2 for absent, focal and extensive; p = 0.010), correlated with % Gleason pattern 4 ({rho} = +0.47, p = 0.005) and correlated inversely with stromal content ({rho} = - 0.40, p = 0.020). Grade Group (p = 0.115), Prostate Imaging Reporting and Data System (PI-RADS) 4 versus 5 (p = 0.705), standard apparent diffusion coefficient (ADC) ({rho} = - 0.27, p = 0.130), baseline prostate-specific antigen (PSA) ({rho} = +0.04, p = 0.816) and PSA density ({rho} = - 0.02, p = 0.918) were not associated with SUVmax. In separate models of log(1+SUVmax) adjusted for Grade Group and tumor size, % Gleason pattern 4 remained associated with uptake (standardized {beta} = +0.76, 95% CI +0.11 to +1.41), Crib/IDC ({beta} = +0.36, - 0.03 to +0.74), and stromal content ({beta} = - 0.30, - 0.62 to +0.02). On 18 slides re-quantified by pixel classifier, no pixel-based compartment fraction correlated with SUVmax (immune {rho} = - 0.06, stroma {rho} = +0.02, tumor {rho} = - 0.04; all p > 0.5). Conclusions: In this prospective lesion-level cohort, intraprostatic PSMA SUVmax was associated with increased Gleason pattern 4 and cribriform/intraductal burden but not with other common risk indices. SUVmax therefore appears to carry information additive to conventional risk factors. Further investigations examining the tumor biology that reflects SUVmax are warranted.

Background: Biochemical recurrence (BCR) occurs in up to 40% of men following radical prostatectomy (RP). Current risk models rely primarily on clinicopathologic variables and may not fully capture the biological heterogeneity associated with recurrence. The Decipher Genomic Classifier (DGC), prostate-specific membrane antigen positron emission tomography (PSMA-PET), and multiparametric magnetic resonance imaging (mpMRI) provide complementary prognostic information that may improve prediction. Objective: To develop and evaluate machine learning (ML) models integrating DGC, PSMA-PET, and mpMRI for preoperative prediction of BCR following RP. Methods: This retrospective study included patients with available preoperative DGC, PSMA-PET, mpMRI, and clinicopathologic data. Logistic regression (LR), random forest (RF), and XGBoost models were developed using single- and multimodality feature combinations. Early- and intermediate-fusion strategies were evaluated. Performance was assessed using an area under the receiver operating characteristic curve (AUC) and accuracy. Clinical utility was evaluated using decision curve analysis. Results: XGBoost consistently outperformed LR and RF. DGC achieved the highest single-modality performance (AUC 0.94, accuracy 86.7%). Among multimodal models, DGC combined with PSMA-PET using intermediate fusion achieved the best overall performance (AUC 0.93, accuracy 87.0%). Addition of mpMRI reduced performance (AUC 0.85, accuracy 83.0%). Decision curve analysis demonstrated positive net benefit across clinically relevant thresholds. Conclusion: XGBoost-based multimodal fusion improved preoperative BCR prediction following RP. DGC was the strongest individual predictor, while integration with PSMA-PET provided the best overall performance, supporting the potential of radiogenomic ML models for personalized risk stratification.

Advanced prostate cancer exhibits profound cellular and molecular heterogeneity, frequently becoming resistant to androgen receptor (AR) targeting through lineage plasticity and neuroendocrine differentiation. Immunotherapies have shown limited efficacy in prostate cancer, largely due to its immunosuppressive tumour microenvironment. Hypersialylation contributes to immune evasion by engaging sialic acid-binding immunoglobulin-like lectins (Siglecs) on immune cells, forming glyco-immune checkpoints. Although this pathway represents a promising therapeutic target, the distribution of Siglec ligands across diverse prostate cancer phenotypes and their response to standard-of-care hormone therapy remain poorly understood. Here, we utilised high-affinity engineered sialoglycan-binding reagents (HYDRA) to perform comprehensive immunohistochemical profiling of Siglec-7 and Siglec-9 ligands across a panel of 40 Washington Carcinoma of the Prostate (LuCaP) patient-derived xenograft (PDX) models. Ligand expression was evaluated in relation to AR status and neuroendocrine phenotype. To determine the impact of androgen deprivation on the tumour glycome, ligand expression was compared between matched PDX lines grown in intact and castrated mice. Our findings reveal widespread but heterogeneous expression of Siglec-7 and Siglec-9 ligands across the LuCaP cohort. Expression levels were comparable between AR-positive adenocarcinoma models and AR-negative neuroendocrine variants, demonstrating that this glyco-immune checkpoint is maintained across distinct prostate cancer lineages. Under castration conditions, glycan remodelling occurred in a model-dependent manner. A subset of PDX models exhibited reduced Siglec ligand expression following castration, suggesting partial AR dependence. In contrast, other models displayed increased ligand expression, consistent with adaptive immune evasion in response to therapeutic stress, while a third group remained largely unchanged. Collectively, our study demonstrates that the Siglec-7/9 glyco-immune checkpoint axis is broadly maintained across the spectrum of prostate cancer lineage plasticity but is dynamically remodelled by androgen deprivation in a patient-specific manner. These findings support the sialoglycan-Siglec axis as a lineage-independent immunotherapeutic target and suggest that strategies aimed at disrupting Siglec-mediated immune suppression, such as tumour desialylation, may be most effective when combined with androgen deprivation therapy to enhance anti-tumour immunity.

Prostate cancer progression is accompanied by dynamic remodeling of malignant cell states, whose metastatic potential and regulatory programs remain poorly defined. Here, we integrated single-cell, spatial, bulk transcriptomic, epigenomic, and experimental data to characterize malignant cell state transitions and identify candidate regulators associated with metastatic progression. A distinct intermediate state exhibits increased copy-number alterations, stemness, proliferation, and MYC activity, together with the highest transcriptional similarity to metastatic tumor cells, and is therefore designated as a metastasis-initiating-like (MIC-like) state. Transcriptional and regulon dynamics along the malignant cell state trajectory highlight FEV as a prominent candidate associated with the MIC-like state, with concordant expression and regulon activity patterns. Functionally, FEV is associated with a hybrid epithelial-mesenchymal phenotype, and its perturbation disrupts this phenotype, accompanied by reduced epithelial and mesenchymal features as well as impaired prostate cancer cell migration and invasion. Beyond this tumor-intrinsic feature, FEV is also associated with reduced cytotoxicity and interferon responses in the tumor microenvironment through its regulation of MIF-family genes. In addition to its potential roles in tumor cell plasticity and immune remodeling, FEV shows a reciprocal association with androgen signaling and distinct expression patterns across treatment response groups, highlighting its potential relevance in therapeutic contexts.

Purpose To assess whether follow-up MRI, biopsy status, and timing of cribriform disease detection predict active surveillance (AS) failure in a contemporary transatlantic cohort. Materials and Methods. Retrospective MRI-driven AS cohort of 619 men at two academic centers (UK/USA), 2012-2024. Primary outcome: AS failure (disease-specific mortality, metastasis, grade group [GG] [&ge;]4 progression, or post-treatment biochemical recurrence). Key exposures: final MRI and biopsy status, timing of cribriform [&ge;]GG2 detection. Cumulative incidence was derived; independent predictors used multivariable Fine-Gray models. Results. Over median follow-up of 6.4 years, 39/619 men (6%) experienced AS failure. Cribriform [&ge;]GG2 was detected in 82/619 (13%) on follow-up biopsy versus 24/619 (4%) at baseline, comparably in baseline GG1 (10%) and non-cribriform GG2 (9%), and only in MRI-visible tumors. Three-year AS failure after final biopsy was 31% in men with cribriform [&ge;]GG2 versus 0-2% with stable or non-cribriform disease; 44% of failures had stable MRI. On Fine-Gray analysis, cribriform [&ge;]GG2 was the only independent predictor of AS failure in re-biopsied men (SHR 30; 95% CI 5.2-167; P<0.001); no type of MRI progression category was independently predictive. Among 595 men cribriform-negative at baseline, 6-year AS failure after a second biopsy was 34% if cribriform [&ge;]GG2 was detected versus 7% if still cribriform-negative. Conclusions. Cribriform status at follow-up biopsy independently predicts AS failure, whereas MRI progression does not. The three-fold higher cribriform prevalence at follow-up likely reflects baseline sampling error. Because newly detected cribriform tumours were exclusively MRI-visible, early repeat biopsy of patients with MRI-visible disease may considerably improve risk stratification.

Objectives: To estimate the absolute benefit of adding and prolonging androgen deprivation therapy (ADT) to radiation therapy (RT) for men with localized prostate cancer by integrating cancer-specific risk, other-cause mortality (OCM) risk, and relative treatment efficacy. Subjects and Methods: Individualized risks were estimated by integrating cause-specific hazard estimates from a validated staging system (STAR-CAP) with those from a validated non-cancer mortality model (OCCAM). ADT treatment efficacy was then incorporated using published hazard ratio estimates from the MARCAP meta-analysis. Model utility was illustrated using the Prostate, Lung, Colon, and Ovarian (PLCO) cancer screening trial cohort (n=5468 prostate cancer patients with complete covariates). The primary outcome was the estimated 10-year absolute risk reduction (ARR) in distant metastasis (DM) from adding short-term ADT (STADT) to RT or extending STADT to long term ADT (LTADT). Results: Within PLCO, model estimated risk of DM at 10 years ranged from <1% to 56% under guideline concordant care and OCM risk ranged from 3% to 80% independent of treatment. For patients with NCCN unfavorable intermediate-risk (n=1814), adding STADT to RT reduced estimated 10 year DM risk by a median of 4%, but the ARR estimates for individuals ranged from <1% to almost 15%. Similar variation was seen within NCCN high-risk patients (n=1289) with a median ARR of 9% [Range: 0.4%-17.2%] when prolonging ADT treatment. Moreover, 25% of NCCN unfavorable intermediate-risk patients have less than a 2.4% ARR while 25% of NCCN high-risk patients experience less than a 5% ARR. Conclusion: An integrated model accounting for both prostate cancer aggressiveness and comorbidities demonstrates substantial heterogeneity in the estimated absolute benefit of ADT within conventional risk groups. This approach provides individualized estimates to support treatment discussions; external validation is needed before clinical implementation.

Active surveillance (AS) delays or avoids unnecessary treatment-related side effects for early localised non-aggressive prostate cancer (PCa) through monitoring with regular prostate-specific antigen (PSA) testing, digital rectal examination (DRE), magnetic resonance imaging (MRI) and prostate biopsy. Whilst baseline MRI has prognostic value and is increasingly used for disease monitoring, molecular biomarkers could be an adjunct to refine risk stratification and disease prognostication [2]. Unlike tissue-based genomic classifiers such as Decipher (Veracyte) and Prolaris CCP (Myriad), blood-based molecular testing for example cell-free RNA (cfRNA) offers minimally invasive real-time monitoring. Moreover, cfRNA may yield genetic information shed from different cell populations within the tumour microenvironment, as well as the host circulation, expanding the opportunities for biomarker discovery. Here, we test the feasibility of whole transcriptome profiling of cfRNAs from the blood of PCa patients under AS, exploring differences between patients with stable disease (SD), and progression to radical prostatectomy (RP).

Background: A 2019 report from our institution described a multilayer artificial neural network (ANN) for predicting prostate cancer at biopsy in 334 patients, trained with TensorFlow 1.x and evaluated at three fixed step counts without separating hyperparameter selection from test evaluation. We re-analyzed an expanded cohort from the same institution using contemporary machine-learning practice. Methods: We pooled all available biopsy episodes from the same institutional database (n = 526; 524 after excluding one non-binary outcome code and one record with missing digital rectal examination [DRE] data), retaining the same seven predictors used in the original report (age, prior biopsy history, PSA, prostate volume, DRE, and MRI diffusion-weighted imaging findings in the peripheral and transition zones). Because 27 patients contributed more than one biopsy episode, we used patient-ID-grouped, stratified k-fold cross-validation (StratifiedGroupKFold; scikit-learn 1.8.0) with 3 and 5 folds, repeated over 10 random partitions, to avoid leakage between folds. Four classifiers were compared: L2-regularized logistic regression, gradient boosting, random forest, and a shallow (single hidden layer) multilayer perceptron. Two outcomes were modeled: detection of any prostate cancer, and detection of clinically significant prostate cancer (Gleason score [&ge;] 7). Results: Any-cancer prevalence was 55.7% (292/524) and Gleason score [&ge;] 7 prevalence was 39.7% (208/524). With repeated 5-fold cross-validation, gradient boosting gave the highest discrimination for any prostate cancer (mean AUC 0.826, 95% CI 0.823-0.830) and for Gleason score [&ge;] 7 (mean AUC 0.855, 95% CI 0.852-0.859), closely followed by random forest and logistic regression (AUC 0.81-0.85). The shallow multilayer perceptron performed worse and less consistently than the other three models (any-cancer AUC 0.671; Gleason score [&ge;] 7 AUC 0.742) and than the deeper five-hidden-layer ANN reported in 2019. Results with 3-fold cross-validation were essentially unchanged. Conclusions: In an expanded cohort, regularized logistic regression, gradient boosting, and random forest all discriminated prostate cancer at biopsy at least as well as the previously reported multilayer ANN, using far simpler models and a methodology that separates hyperparameter tuning from performance estimation. A shallow neural network offered no advantage over these simpler alternatives in this sample size. This is a preprint; the study has not undergone external peer review.

A subset of untreated primary prostate cancer (PCa) contain substantial focal T-cell infiltrates, but whether these reflect antitumor responses that could potentially be enhanced by immune checkpoint blockade (ICB) remains unclear. We used immunohistochemistry, immunofluorescence, whole-slide spatial analysis, bulk RNA sequencing, and immune-cell deconvolution to characterize immune infiltrates in untreated primary PCa. Absolute CD8 T-cell density generally increased with total CD3 T-cell density, but the CD8/CD3 ratio decreased as overall T-cell density increased, indicating a preferential increase in CD4 T cells. Highly infiltrated tumors also had lower GZMB abundance relative to CD8 T-cell abundance. Multiplex analysis showed trends toward greater TIM3 and LAG3 expression among PD1CD8 T cells and increased regulatory T-cell features in highly infiltrated tumors. TIGIT cell density and the TIGIT/CD3 ratio increased with T-cell infiltration, whereas PD1/CD3 was not associated with overall CD3 T-cell density. Both TIGIT/CD3 and PD1/CD3 ratios were enriched within lymphoid aggregates compared with matched tumor and benign regions, consistent with these structures being checkpoint-rich immune niches. Transcriptomic analyses supported a shift in relative immune composition toward CD4 T cells and selective increases in immune checkpoints. Together these findings suggest that effective immune responses in a subset of primary PCa with increased T-cell infiltration are being repressed by several mechanisms and may respond to therapies targeting specific immunosuppressive mechanisms.

Prostate cancer remains one of the most common cancers among men globally. While significant strides have been made in diagnosis and treatment, understanding the complex genetic and epigenetic underpinnings of the disease remains crucial for guiding intervention and developing more personalized and effective therapies. The importance of DNA methylation in prostate cancer has been known for some time, but important facets of the modulation of the epigenome during carcinogenesis remain obscure, partly because the bulk of cancer methylation data have been produced using microarray technologies. Here we utilise the TruSeq methyl capture method (EPICseq) to profile the, previously defined, UK Prostate ICGC cohort of well-annotated primary prostate cancers. To this we add methylation sequencing of benign tissue from the same men. These data allow us to identify differentially methylated regions distinguishing cancerous and non-cancerous prostate tissue, while identifying numerous genes whose methylation profiles can perform that task as well as distinguishing between classes of prostate cancer. We describe a describe a methylation-based control mechanism for prostate-cancer-associated SNPs, and show that this seems a likely mechanism of action for a SNP near the MMP7 gene. We describe three novel molecular signatures that arise from different aspects of the biology of prostate cancer revealed by sequencing. Each is shown to be an independent classifier of cancers into groups with different expected times to relapse. These consist of patterns in driver gene methylation, strand-specific methylation, and signal arising in mitochondrial reads. We show that these signatures, combined with existing molecular tools, provide a powerful predictor of time to recurrence. By substantially enhancing understanding of prostate cancer risk, detection, and prognosis, we pave the way for the development of clinical practices that will benefit patients and improve outcomes.

Importance Public prostate cancer data may appear under different repository identifiers or releases while representing overlapping patients, specimens, or sample records. The implications for reported analytic independence require assessment at both resource and publication levels. Objective To characterize supported nonindependence among selected public prostate cancer resources and assess reported overlap control in publications using related resources. Design Cross-sectional methodological audit. Resource records were reconciled through September 2, 2026; recovery of retained sources and adjudication continued through September 8, 2026. Language-model extraction and targeted original-source checks informed deterministic classification. The authors manually verified all positive findings, including supplementary materials, in September 2026. Setting Public prostate cancer repositories and Europe PMC and PubMed retrieval, with a publication cutoff of August 15, 2026. Participants A nonrepresentative frame of 189 repository study records and 108 publication/version records contributing 230 publication-resource-pair records. Exposures Analytic use of both endpoints of a confirmed resource relation in the same linked claim. Main Outcomes and Measures Supported identity levels and resolvable patient-identifier counts; reported overlap control when linked analyses required independent records. Unresolved evidence was retained separately. Published results were not reanalyzed. Results The audit identified 101 supported resource pairs: 97 with direct patient, specimen, or sample-record identity, 1 with component containment, and 3 with study/source nonindependence. Among 108 publication/version records, 8 (6 journal articles and 2 preprint versions) used related resources in analyses requiring independence without reporting applicable overlap controls. Another 3 reported applicable controls, 16 retained reporting gaps, and 81 fell outside the qualifying use or relation criteria. One of the 8 had 45 shared sample identifiers in two validation sheets, corroborating sample-record reuse but not donor identity. No global independent-patient total or prevalence estimate was established. Conclusions and Relevance Resource nonindependence coexisted with absent claim-specific control reporting, with direct sample-record corroboration in one publication. The findings support provenance-aware use and explicit reporting, without establishing effects on published results.

Docetaxel is a major therapeutic option for advanced prostate cancer, but the development of acquired resistance substantially limits its clinical efficacy. Although multiple mechanisms have been implicated in docetaxel resistance, the upstream regulatory pathways coordinating these phenotypes remain incompletely understood. Here, we investigated the role of serine/arginine-rich protein kinase 1 (SRPK1), a key regulator of pre-mRNA splicing, in acquired docetaxel resistance in prostate cancer. Docetaxel-resistant PC3 cells showed increased SRPK1 expression at both the protein and RNA levels. Genetic depletion or pharmacological inhibition of SRPK1 substantially restored docetaxel sensitivity, whereas ectopic SRPK1 expression in parental PC3 cells increased resistance. Mechanistically, SRPK1 inhibition reduced expression of {beta}III-tubulin and restored docetaxel-induced microtubule bundling. SRPK1 inhibition also increased apoptosis in resistant cells, accompanied by increased cleavage of caspase-8, caspase-9 and PARP. In parallel, SRPK1 inhibition restored E-cadherin expression and reduced the enhanced migratory phenotype of resistant cells. At the signalling and RNA-processing levels, docetaxel-resistant cells exhibited increased EGFR expression and increased phosphorylation of the SRPK1 substrate SRSF1. SRSF1 depletion partially restored docetaxel sensitivity, supporting an EGFR-SRPK1-SRSF1 pathway in resistance. Importantly, inhibition of SRPK1 or depletion of SRSF1 altered the splicing of apoptosis- and microtubule-associated genes, increasing the pro-apoptotic Bcl-xS and MCL-1S isoforms and shifting tau splicing towards 3R at the expense of 4R. Collectively, these findings identify SRPK1 as a central regulator of multiple phenotypic and molecular features of docetaxel resistance in prostate cancer. Targeting SRPK1-dependent splicing may therefore represent a strategy to re-sensitize resistant prostate cancer cells to docetaxel.

Background: Prostate cancer enzalutamide treatment is approved at a standard dose of 160 mg daily. Concerns for real-world patients -- older and more fragile than those enrolled in clinical trials -- have prompted consideration of initiating treatment with lower doses, but the long-term efficacy of this approach remains unknown. We evaluate the long-term survival and longevity in patients treated with standard versus upfront low-dose enzalutamide. Methods: Retrospective analysis of 151 patients treated with enzalutamide (102 receiving 160 mg; 49 receiving [&le;]80 mg) between 2014--2021 at the Centre Hospitalier Universitaire de Martinique, with complete follow-up through end of life (98.7% completeness of follow-up). Primary outcomes were overall survival (OS), progression-free survival (PFS), and longevity (attained age). Results: Doses [&le;]80 mg were associated with longer median OS (36.3 vs. 20.7 months), improved restricted mean OS (difference of 0.7 years, p=0.05), and enhanced longevity (median 82.5 vs. 78.3 years, p=0.004). PSA response rate at 12 weeks was higher with lower-dose (71.4% vs. 48.8%, p=0.016). In multivariable models adjusted for prognostic factors, [&le;]40 mg compared with 160 mg was non-inferior regarding OS (HR=0.61, 95% CI 0.36--1.06), superior regarding PFS (HR=0.59, 95% CI 0.35--0.99), and superior regarding longevity (HR=0.48, 95% CI 0.28--0.84). Bone metastasis, poor performance status, PSA response, time to PSA nadir, and disease duration were independent predictors of outcomes. A post-hoc analysis revealed a strong association between dose and physician-prescribing profiles, ranging from "endorse-lowest-dose" to "never-deviate-from-full-dose". Conclusions: Lower doses of enzalutamide were non-inferior to full-dose. Dose-adapted strategies warrant further investigation.