The Prostate

ObjectivesBenign Prostatic Hyperplasia (BPH) is the non-cancerous enlargement of the prostate accompanied by lower urinary tract symptoms, affecting 50% of men by the age of 501,2. Advanced highly symptomatic BPH exhibits large epithelial glandular nodules with microglandular/atypical adenomatous hyperplasia, but how these features form is unknown3. Our lab has reported that the common parasite Toxoplasma gondii can infect the prostate and induce glandular nodule formation in mice3. The objective of this study is to determine if T. gondii exposure in humans correlates to BPH and nodule formation and if it induces urinary dysfunction concurrent in the mouse model. MethodsWe assessed Toxoplasma exposure by serum ELISA in patients with BPH and non-BPH donor controls, and compared seropositivity rates between the groups. We further assessed the histopathology of these patients for the presence of inflammation and epithelial glandular nodule formation and compared Toxoplasma positive and negative samples. We determined voiding function in Toxoplasma-infected mice between 14 and 60 days of infection with void spot with Void Whizzard software. ResultsMen diagnosed with BPH are more likely to be seropositive for Toxoplasma than age-matched undiagnosed donor controls. In addition, BPH patients that are seropositive for Toxoplasma are more likely to exhibit glandular nodule formation with microglandular / adenomous hyperplasia than seronegative BPH patients. In animal studies, Toxoplasma infection results in abnormal void patterns concurrent with microglandular hyperplasia and nodule formation. ConclusionsThese results suggest that Toxoplasma may be contributing to BPH pathology and lower urinary tract dysfunction in both humans and mice, opening new insights into the development of this important disease. The results also serve to further characterize this model of prostatic hyperplasia and define it as a potential urinary dysfunction model.

BackgroundHomozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental DesignWe used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. ResultsIPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with [≥]pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. ConclusionsSubclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.

BackgroundIdentifying metabolites associated with prostate cancer (PC) aggressiveness may elucidate mechanisms underlying disease severity. Doing so for plasma and formalin-fixed, paraffin-embedded (FFPE) tissue could accelerate discovery. In this cross-sectional pilot study, we generated hypotheses for further exploration by assessing associations between plasma metabolites and Gleason score in individuals with PC and evaluating correlations between plasma and FFPE metabolite levels. MethodsWe examined plasma and FFPE samples from 10 individuals with Gleason score 7 (six 3+4, four 4+3) and nine individuals with Gleason score 9 (six 4+5, three 5+4) tumors from a convenience sample of 19 men with PC. We measured the relative abundance of polar metabolites at the time of radical prostatectomy. We used linear models of log2 fold changes to examine plasma metabolite levels relative to pathologic tumor grade. Relationships among metabolite levels measured in plasma and FFPE tumor tissue within individuals across metabolites were examined using Pearson correlations. ResultsAmong 18 plasma metabolites selected a priori because of prior associations with PC aggressiveness, serine (p=0.0051) and ornithine (p=0.036) levels were higher in individuals with Gleason 9 than Gleason 7 PC. After multiple testing correction, however, no associations were statistically significant. The median correlation between levels in plasma and FFPE tumor tissue was 0.45 (range: 0.40-0.53) for the 94 metabolites measured in both biospecimens. ConclusionsPlasma serine and ornithine demonstrated the largest differences between individuals with Gleason 7 and Gleason 9 PC. Metabolite levels in FFPE prostate tissue samples were moderately correlated with plasma levels. Future studies in larger samples are needed to further explore the hypotheses generated by this study.

ObjectiveTo demonstrate the proof of principle that machine learning (ML) can be used to quantify Gleason Pattern (GP) 4 on digitized biopsy slides using multiple measurement approaches, allowing direct comparison of their prognostic performance. MethodsWe assembled a convenience sample of 726 patients with grade group 2-4 prostate cancer on systematic biopsy who underwent radical prostatectomy between 2014 and 2023. Digitized biopsy slides were analyzed using a machine-learning algorithm (PAIGE-AI) to quantify GP4 using multiple measurement approaches, particularly with respect to how gaps between cancer foci ("interfocal stroma") were handled. GP4 extent was quantified using linear measurements or a pixel-based area metric. Discrimination of each GP4 quantification approach, along with Grade Group (GG), was assessed for adverse radical prostatectomy pathology and biochemical recurrence. ResultsWe identified 15 different quantification approaches and observed differences between their discrimination. The highest discrimination was in the pixel-countingmethod (AUC 0.648). GP4 quantification outperformed GG for predicting adverse pathology (AUC 0.627 vs 0.608). Amount of GP3 was non-predictive once GP4 was known. These findings were consistent for BCR. ConclusionsWe were able to measure slides using 15 distinct measurement approaches and replicated prior findings using ML to quantify GP4. Our findings support the use of ML as a research tool to compare different GP4 quantification approaches. We intend to use our method on larger cohorts to determine with which measurement approach best predicts oncologic outcome.

Background and objectiveChronic comorbidities like diabetes mellitus can influence cancer incidence and progression. However, their impact on pathological and molecular tumor characteristics, and dissemination, especially in prostate cancer (PCa), is not fully understood. Here, we investigated differences in the PCa molecular landscape with coexisting diabetes type 2 and its link to tumor dissemination. MethodsDAmico intermediate- or high-risk PCa patients (n=145), with type 2 diabetes or no diabetes, were analyzed for clinico-pathological features, circulating tumor cell (CTC) presence, yields and phenotypes in tumor-draining vein (TDVB) and peripheral blood (PB), primary tumor characteristics, and selected plasma biomarkers. Key findings and limitationsDiabetes type 2 was found in 20/13.8% patients and associated with more advanced clinical outcomes, i.e. pathological tumor stage (p=0.011) and lymph node involvement (p=0.020). Among patients diagnosed before age 65, diabetes and PCa showed a borderline association with shorter time-to-biochemical recurrence (p=0.032). Diabetic PCa patients had significantly higher total CTC counts in TDVB but not in PB, indicating enhanced tumor cell dissemination from primary tumor (PT). PTs from diabetic PCa patients displayed a borderline association with higher ALDH1 expression (p=0.054) and significantly lower vascular vessel density (p=0.008). Similarly, in patients under 65, PTs from diabetic PCa patients expressed genes linked to decreased angiogenesis. Plasma analyses revealed elevated GDF15 levels in PB (p<0.001), increased TRAP5 concentrations in TDVB (p=0.001), and reduced osteonectin levels in TDVB (p=0.026) in diabetic PCa patients. The studys limitation is the relatively small cohort, especially those with coexisting diabetes type 2. Conclusion and clinical implicationsDiabetes in PCa patients associates with advanced tumor stage, enhanced tumor cell dissemination, impaired vascularization, and distinct circulating biomarker alterations. Vascular alterations from diabetes, with systemic factors, especially in PCa patients under 65, may increase tumor dissemination in PCa. However, exact mechanisms need investigation in larger cohorts of patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/720986v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1f5047forg.highwire.dtl.DTLVardef@fa3f43org.highwire.dtl.DTLVardef@14f7765org.highwire.dtl.DTLVardef@27a12d_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundCyclin-dependent kinases drive the progression through the cell cycle and thereby form classical targets for cancer therapy. In prostate cancer (PC), the first line of therapy typically targets androgen receptor (AR), but it frequently leads to development of incurable form of the disease, castration-resistant PC (CRPC). Here, we sought to understand if CRPC cells are selectively addicted to a specific cell cycle kinase. MethodsWe used PC and CRPC patient data to evaluate transcriptional changes and modeled the responses in vitro using multiple models of PC, CRPC and normal cells. Development of a CDK2 inhibitor-resistant CRPC cell line, and a compound screen were used to identify chronic and acute vulnerabilities to augment the efficacy of our candidate therapy in multiple PC, CRPC and also normal cells, to assure selectivity. ResultsWe show that the emergence of CRPC is associated with significant upregulation of cyclins that positively regulate cyclin-dependent kinase 2 (CDK2) and downregulation of CDK4 cyclins. Accordingly, CDK2-specific inhibitors and its knock down efficiently reduce proliferation of PC and CRPC cells. CDK2 inhibitor-resistant CRPC model displayed transcriptional rewiring of cell cycle regulators, characterized by a shift towards CDK4/6-dependency and increased AR-signaling. Combinatorial drug screen discovered both antagonistic and additive combinations, and we show that AR inhibitors selectively augment the efficacy of CDK2 inhibitors against PC and CRPC cells, but the combination is not toxic to normal cells. ConclusionWe discovered that CRPC cells are addicted to high CDK2 activity and show that combination of CDK2 inhibitors with the currently used anti-CRPC therapies selectively augment their efficacy.

BackgroundRisk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa. MethodsPRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRSPSA). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis. ResultsIn the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.06-1.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation. ConclusionsAmong men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.

ImportanceMetastatic prostate cancer (PCa) incidence has increased in U.S. men, partly due to changes in prostate-specific antigen (PSA) screening recommendations. However, few studies have examined contemporary PSA screening practices in large U.S. healthcare systems. ObjectiveDescribe and examine contemporary PSA testing practices associated with metastatic PCa incidence. DesignCohort study. SettingVeterans Health Administration. ParticipantsVeterans diagnosed with prostate needle biopsy (PNBx) between 2015 and 2023 with follow-up through 2024, excluding those with a history of PCa. ExposuresPSA tests were retrieved from the VA corporate data warehouse and categorized by age at first VA PSA (<50, 50-59, [&ge;]60 years) and by longest interval between consecutive VA PSA tests in the 5 years before PNBx ([&le;]24 , >24 months). Clinical, laboratory, pathological, demographic, and Census Block Group-level socioeconomic status data were obtained from the VA Multi-OMICS Analysis Platform for Prostate Cancer (VA-MAPP) database. Main Outcomes and MeasuresMultivariable Cox models estimated hazard ratios (HR) from time of first VA PSA to first PNBx, evaluated risk of metastatic (regional or distant) versus localized PCa, or benign diagnosis, adjusted for sociodemographic and clinical covariates. Data were analyzed between July 1, 2023 and November 6, 2025. ResultsThere were 103,067 participants of whom 20% were <50 years old at first PSA, 31% non-Hispanic Black, 57% non-Hispanic White, and 13% other racial and ethnic groups. Of these, 22% had first PSA value [&le;]1, 51% had a screening interval [&le;]24 months, and 4% were diagnosed with metastatic PCa at time of PNBx. Compared to men aged <50 years at first PSA, those 50-59 (aHR 1.08, 95% CI: 1.06-1.11) and [&ge;]60 years (aHR 1.79, 95% CI: 1.74-1.84) had higher metastatic PCa. Men with longer screening intervals had higher metastatic PCa (aHR 1.09, 95% CI: 1.07-1.11). Men aged <50 years with shorter screening intervals had lower metastatic PCa (aHR: 0.10, 95% CI: 0.09-0.12) compared to men aged [&ge;]60 years with longer screening intervals. Conclusions and RelevanceFew male veterans were observed to have the most favorable combinations of age, PSA value, and PSA screening interval in relation to metastatic PCa, suggesting potential for further screening optimization.

The PRESERVE trial (NCT04972097) is a prospective, single-arm pivotal IDE study evaluating focal irreversible electroporation (IRE) using the NanoKnife System for intermediate-risk prostate cancer. Men with Gleason Grade Group 2-3 disease underwent focal IRE and were followed for durability of oncologic control and safety. At 24 months, 68 patients completed follow-up with no new treatment failures identified. PSA levels were below baseline in 97% of patients, and one clinically triggered biopsy was negative for cancer. No new device- or procedure-related adverse events occurred beyond 12 months. These findings demonstrate durable efficacy and sustained safety of focal IRE.

Aims Active surveillance (AS) allows selected men with localized prostate cancer to defer curative therapy and reduce treatment morbidity. Conversion from AS to treatment is commonly triggered by Gleason grade group (GGG) upgrading on confirmatory biopsy. We developed and validated a digital pathology artificial intelligence (DPAI) biomarker to predict GGG upgrading in AS-eligible patients. Materials & Methods The DPAI model was trained using histopathology image features from diagnostic biopsies of 998 patients and validated in an independent cohort of 296 patients meeting criteria for AS. Logistic regression estimated the probability of confirmatory-biopsy GGG increase, and feature selection identified the most predictive variables. Results AI-GUR (Artificial Intelligence-Gleason Upgrade Risk) predicted GGG reclassification at confirmatory biopsy (OR 1.60; p=0.0003), and provided information beyond conventional stratification (risk group, CAPRA) and cribriform morphology (all p<0.01). Predicted risks were similar across time from diagnosis (~10-15% to ~85% at 1, 1.5, or 2 years; p for time=0.50), consistent with initial biopsy mischaracterization rather than time-dependent progression. Conclusions AI-GUR provides individualized estimates of confirmatory-biopsy GGG upgrading for AS candidates. Using DPAI may improve shared decision-making by complementing standard clinicopathologic tools and molecular testing using the same biopsy specimen, while informing the likelihood of grade upgrade at confirmation.

BackgroundMen with aggressive, localized prostate cancer (PC) undergo definitive radiotherapy (RT) with androgen deprivation therapy (ADT). The prospective, phase II ARIEL trial evaluates a quantitative MRI biomarker, Restriction Spectrum Imaging restriction score (RSIrs), at three time points (before treatment, after ADT and after RT) for treatment response assessment. RSIrs highlights intracellular restricted diffusion and is correlated with high-grade PC. DesignParticipants are men with unfavorable-intermediate-risk or high-risk localized PC undergoing definitive RT with neoadjuvant and concurrent ADT, and MRI-RSI acquisitions at three time points: before therapy, after neoadjuvant ADT but before RT, and after RT. The primary aim is to evaluate performance of RSIrs for identifying patients who will experience early biochemical recurrence. Change in RSIrs within visible tumors after ADT and RT is the primary independent variable. Results97 patients met inclusion criteria and received [&ge;]1 MRI. On central review, visible PI-RADS lesions were identified in 88 patients: 80 patients had one lesion, and 8 patients had two lesions. After neoadjuvant ADT, 40% of lesions were not clearly visible. Those still visible had shrank by median 55.8% (IQR: 42.8-69.0%), much more than the prostate volume decrease of 21.5% (11.9-31.6%). RSIrs maximum within visible lesions decreased from mean 329 (SD:185) pre-ADT to 209 (SD:125) pre-RT (p<0.01), and to 107 (SD:61) post-RT (p<0.01). Conventional apparent diffusion coefficient (ADC) changes were less consistent. Follow-up is ongoing to assess whether imaging response is related to future recurrence risk. ConclusionARIEL has completed accrual and preliminary results demonstrate changes in RSIrs after treatment, which may indicate tumor response. Primary results will be presented when the primary endpoint is reached. With neoadjuvant ADT, both pre- and post-ADT MRI are likely necessary for accurate focal RT boost targeting. Concurrent commencement of ADT and RT simplifies workflows and facilitates accurate gross tumor volume delineation.

Introduction Aquablation for surgical treatment of benign prostatic enlargement (BPE) causing bladder outflow obstruction (BOO) has demonstrated good functional outcomes, even for large glands, with high rates of ejaculatory preservation reported. This is a protocol for a study that aims to review real-world outcomes of ejaculatory preservation or restoration post-Aquablation in an unselected cohort and compare to published clinical trial outcomes. Methods Retrospective data will be collected from a prospectively maintained consecutive case series of patients who underwent Aquablation, in a single UK centre. The primary outcome is ejaculatory function subjectively reported by men post-operatively, and classified as: antegrade ejaculation, retrograde/low volume ejaculation, anejaculation or not sexually active. Secondary outcomes are International Prostate Symptom Severity (IPSS), Quality of Life (QoL) Score, post-void residual (PVR), and incontinence. Descriptive and comparative statistical tests will be performed. Conclusions This study will review real-world ejaculatory function and clinical outcomes following robotic Aquablation for prostatic bladder outflow obstruction and compare this to published clinical trial outcomes.

Suppressor of cytokine signaling 1 (SOCS1) negative regulates inflammatory cytokine production and attenuates oncogenic growth factor signaling pathways. Reduced SOCS1 protein expression in human prostate cancer correlates with greater disease severity. To define the physiological functions of SOCS1 functions in the prostate, we conditionally ablated Socs1 in prostate epithelial cells of C57BL/6 mice. These Socs1{Delta}PE mice exhibited normal prostate development, maturation and lobular architecture. However, adult Socs1{Delta}PEmice developed progressive epithelial hyperplasia and inflammatory cell infiltration that were temporally and spatially distinct. SOCS1-deficient prostate showed increased epithelial cell proliferation and elevated oxidative stress markers, and prostate organoids recapitulated this hyperplasia phenotype. Diet-induced obesity exacerbated both hyperplasia and inflammation in SOCS1-deficient prostate. Upon transurethral infection with uropathogenic Escherichia coli UPEC1677 expressing the genotoxin colibactin, Socs1{Delta}PE mice developed invasive prostate cancer with complete loss of lobular architecture, whereas control mice developed hyperplasia and pre-neoplastic lesions. In vitro, SOCS1-deficient prostate organoid-derived epithelial cells exhibited increased DNA damage following exposure to UPEC1677. Deletion of the colibactin biosynthetic gene clbP in UPEC1677 abolished its ability to induce DNA damage in SOCS1-deficient cells and to drive prostate cancer in vivo. Proteomic analysis of prostate organoids revealed dysregulation of basal and luminal epithelial lineage markers and signaling pathway proteins that could promote neoplasia in SOCS1-deficient cells. Collectively, these findings establish an essential, epithelial cell-intrinsic role for SOCS1 in maintaining prostate tissue homeostasis by restraining proliferation, regulating lineage plasticity, limiting inflammation and oxidative stress, and conferring protection against genotoxic injury and neoplastic transformation.

BackgroundNo randomized clinical trial comparing the most established new modalities of treatment for patients with localized prostate cancer has been published, and there is scarce comparative effectiveness research assessing Patient-Reported Outcome Measures (PROMs). Objectiveto compare the impact of active surveillance, robot-assisted radical prostatectomy (RARP), Intensity-modulated radiotherapy (IMRT), and real-time brachytherapy on patients, through PROMs, from pre-treatment to five years after diagnosis of localized prostate cancer. MethodsProspective observational study (ClinicalTrials.gov, NCT05523856) of 566 male patients diagnosed in 2014 to 2021 with clinically localized prostate cancer (50-75 years old; stage cT1 or cT2, N0/Nx and M0/Mx; Gleason [&le;] 6 or 7 (if 3 + 4 with T1c); and PSA [&le;] 10 ng/ml) and followed until 2019-2026. The Expanded Prostate Cancer Index Composite (EPIC-26) measures urinary incontinence, urinary irritative/obstructive symptoms, sexual, bowel and hormonal domains. EPIC-26 was centrally administered via telephone interviews before treatment and then annually after treatment. Generalized estimating equation (GEE) models were constructed with overlap propensity score-based weights and adjusted by age and clinical tumor stage. ResultsWeighted results of adjusted GEE models showed significant declines for sexual health during the 5yr in all treatment groups (ranging from -19.8 to -27.6), but this worsening appeared earlier in those of active treatment (RARP, IMRT and brachytherapy) than in active surveillance. The RARP group presented the greatest deterioration in urinary incontinence (-28.5 vs -11.7 in active surveillance), while the greatest impairment in bowel symptoms was observed in both radiotherapy groups (around -3 vs +0.3 in active surveillance). ConclusionOur findings provide detailed novel evidence, measured over 5 yr, on the long-term impact of disease and treatment on patients with localized prostate cancer. While all treatment groups showed large sexual deterioration overtime, important differences in urinary incontinence (highest after RARP) and bowel symptoms (after IMRT and brachytherapy) persisted. These findings can inform patients during shared decision-making on the alignment between localized prostate cancer treatment choices and their priorities.

Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to identify new therapies for advanced disease. Aberrant glycosylation is common in prostate cancer and plays a functional role in disease progression. The sialyl-Tn antigen (sTn) has been widely studied in cancer, yet its involvement in prostate cancer remains relatively unexplored. Here, we utilise a novel anti-sTn antibody (L2A5) to comprehensively monitor sTn expression levels in clinical prostate cancer tissues encompassing normal, benign, primary, metastatic castrate-resistant prostate cancer (CRPC), and patient-derived xenografts (PDXs). We show that while sTn is detected at low or negligible levels in normal prostate tissues, it is expressed in 44% of prostate tumours, and prostate cancer patients with high sTn levels have significantly poorer survival times. Analysis of metastatic therapy resistant prostate-derived tumours growing in liver and bone, shows sTn is expressed in 37.5% of cases. Furthermore, we show sTn is expressed in nearly half of PDXs tested, supporting the use of PDX models as tools for testing anti-sTn therapeutic strategies. These findings identify sTn as potential prognostic biomarker and therapeutic target in prostate cancer and lay the groundwork for the development of sTn-targeted precision therapies for advanced disease.

Background: Prostate cancer is the second most common cancer in men worldwide. The Prostate Specific Antigen (PSA) blood test is widely used for prostate cancer detection but suffers from high false-positive rates (up to 80%). Genetic risk scores (GRS/PRS) have a similar performance to PSA testing in predicting prostate cancer risk. Method: GRS269 for prostate cancer was derived using 269 known risk variants and applied to UK Biobank participants. We assessed whether GRS269 improved power to predict prostate cancer diagnosis on top of age and pre-prostatectomy PSA level among 17,380 cases. Longitudinal PSA measurements were processed as median, first, last (most recent), and random PSA. All models were adjusted for age. Results: Across all PSA measures, the integrated model combining GRS269, PSA, and age consistently outperformed models using GRS269 or PSA alone. The highest predictive performance was observed using the last PSA value combined with GRS269 (AUC = 0.82, 95% CI: 0.81-0.82), compared to GRS269 alone (AUC = 0.70, 95% CI: 0.68-0.72) or PSA alone (AUC = 0.73, 95% CI: 0.70-0.75). Conclusion: Combining genetic risk with PSA and age improves prostate cancer risk prediction in a population setting. These findings highlight the potential clinical implications of integrating GRS will enhance early prostate cancer prediction pathways in primary care.

Background: Previous recommendations on screening for prostate cancer relied on ongoing trials of screening with prostate-specific antigen (PSA), which may have lacked sufficient follow-up duration to fully examine effects on mortality and overdiagnosis. Findings which consider absolute effects by age and screening intensity, along with newer guidance for assessing evidence certainty, may lead to different interpretations. Adding magnetic resonance imaging (MRI) to PSA-based screening has been raised as a way to reduce false positives (FPs) and overdiagnosis. Methods: We systematically searched MEDLINE, Embase, and Central from 2014 to January 28, 2026, for randomized controlled trials (RCTs) and prospective observational studies of: (i) screening versus no screening and (ii) sequential screening with MRI for those with a positive PSA test versus PSA alone among men not known to be at high risk for prostate cancer. Studies on screening with PSA or digital rectal examination (DRE) published pre-2014 were identified from existing systematic reviews and reference lists. Studies on FPs and complications from biopsies after PSA screening did not require a control group. Paired reviewers screened titles/abstracts (assisted with artificial intelligence) and full texts, assessed risk of bias, and extracted data, by age when available. We pooled data when suitable using random-effects models, investigated heterogeneity, and assessed the certainty of evidence using GRADE with conclusions of effects based on decision thresholds based on absolute effect sizes. Results: Across both questions, we included 15 RCTs (N=856,000; 8 sites of ERSPC considered separate trials) and 8 observational studies (N=56,122). At 20 years, among 1000 men who underwent repeated PSA-based screening every 2-4 years starting from age 55-69 (mean 62), there is likely a reduction in prostate-cancer mortality ([&ge;]2 fewer) and metastatic cancer incidence ([&ge;]6 fewer), at the expense of prostate-cancer overdiagnosis ([&ge;]24 cases) and FPs ([&ge;]150 cases) (all moderate certainty). If screening starts at age 50-54 or age 55, the benefits are probably smaller (e.g., 1 vs. 2 fewer prostate-cancer related deaths) with similar harms. Adding DRE or screening with PSA annually does not add benefit. One round of PSA screening or starting screening later at age 70-74 may not offer any important benefit or harm (low to moderate certainty), and any benefit from screening primarily with DRE was not shown. Compared with PSA alone, sequential screening with PSA followed by MRI reduces FPs ([&ge;]33 fewer) and overdiagnosis (via [&ge;]10 fewer diagnoses of clinically insignificant [e.g., Gleason 6] cancers without impacting detection of clinically significant cancers) (moderate to high certainty), though findings were limited to one round of screening without long-term follow-up or measurement of mortality. Interpretation: This review provides clinicians and other interest holders with anticipated absolute effects by age, and assessments of certainty across critical and important outcomes and with approximately two decades of follow-up. Findings apply to a general population and may differ for specific groups. Results for most critical outcomes, both benefits and harms, exceeded thresholds for clinically important effect sizes, thereby demonstrating the complexity of guideline developers' and patients' decision-making regarding screening trade-offs. Findings about adding MRI for those with a positive PSA test were limited and would require additional consideration of costs, infrastructure, expertise, and equity. Protocol registration: PROSPERO - CRD420250651056.

Bladder outlet obstruction leads to pathological remodeling and emergence of lower urinary tract symptoms. Although relief of obstruction is associated with symptomatic improvement, it is not universally successful, reflecting persistent alterations in the bladder. Reliable surrogate biomarkers of obstruction are lacking, particularly early in the disease course before irreversible damage to the bladder may have occurred. In this study, re-analysis of publicly available transcriptomic datasets from diverse rodent models of obstruction identified tissue transcripts including Cthrc1, Grem1, Ltbp2 and Msn that were induced in response to injury. Candidate markers were validated experimentally in an independent model of neurogenic obstruction demonstrating time-dependent changes. Candidate markers were also attenuated with either surgical removal of obstruction or treatment with anticholinergic medication or inosine. Integrated analysis of tissue transcriptomics data and tissue and urine proteomics data from a model of neurogenic obstruction revealed significant concordance between markers observed in tissue and urine. Urinary proteomics analysis identified a statistically significant increase in MSN in patients with neurogenic bladder compared to unaffected controls. These findings identify tissue and urine biomarkers of both non-neurogenic and neurogenic obstruction that may reflect early changes in obstructive uropathy that could be monitored in a non-invasive manner.

Few studies with pre-diagnostic samples have estimated associations between circulating metabolites and risk of advanced prostate cancer. We performed untargeted metabolomic profiling of pre-diagnostic blood samples from 212 advanced prostate cancer cases (stage [&ge;]T3b or lethal during follow-up) and 212 matched controls from the Health Professionals Follow-up Study. 243 metabolites were assayed using liquid chromatography-tandem mass spectrometry (Broad Institute) and met quality control standards. We used multivariable conditional logistic regression to generate odds ratios (OR) and 95% confidence intervals (95%CI) for associations between individual metabolites and risk of advanced prostate cancer, and conducted metabolite set enrichment tests to identify metabolite classes enriched in advanced prostate cancer. Subgroup analyses were conducted by body mass index (BMI) and time between blood draw and diagnosis. Levels of 16 lipid species were nominally associated with advanced prostate cancer at p<0.05, though none were statistically significant after multiple testing correction. The strongest signals were for C56:1 triacylglycerol (TAG; OR: 1.34, 95%CI: 1.07-1.67) and C38:4 diacylglycerol (DAG; OR: 1.27, 95%CI: 1.04-1.55). Enrichment analyses revealed six metabolite classes associated with advanced prostate cancer after multiple testing adjustment, the top four of which were DAGs and TAGs: DAGs overall (P=3.4E-07), unsaturated DAGs (P=5.9E-07), unsaturated TAGs (P=2.3E-06), and TAGs overall (P=2.4E-06). 43 metabolites were nominally associated with advanced prostate cancer among individuals with BMI <25 kg/m2; only three demonstrated nominal associations in individuals with BMI [&ge;]25 kg/m2. These findings suggest associations between circulating pre-diagnostic lipid levels and aggressive prostate cancer risk, particularly in lean individuals.

BackgroundDespite extensive cataloging of carcinogenic exposures by the International Agency for Research on Cancer (IARC) and pharmacogenomic variation by resources such as PharmVar and CPIC, few platforms unify exposure, metabolic activation and detoxification, DNA damage, and genetic annotation within a single interactive visualization framework. This gap limits systematic evaluation of gene-environment interactions in cancer risk assessment. MethodsWe developed the Carcino-Genomic Knowledge Graph, ExposoGraph, an interactive knowledge-graph platform for carcinogen metabolism and DNA damage pathways. The reference graph integrates curated data and annotations from IARC, KEGG, PharmVar, CPIC, CTD, and supporting literature/resources. The current reference graph contains 96 nodes across 5 entity types (Carcinogens, Enzymes, Metabolites, DNA Adducts, and Pathways) and 102 edges across 6 relationship types (activates, detoxifies, transports, forms adduct, repairs, and pathway). ResultsThe first-generation reference graph captures metabolic activation and detoxification pathways for 9 carcinogen classes spanning 15 index carcinogens. It represents 36 enzymes across Phase I activation (n=14), Phase II conjugation and detoxification (n=14), Phase III transport (n=3), and DNA repair (n=5). Interactive exploration supports carcinogen-class filtering, node- and edge-type filtering, metadata-based search, and detailed hover/detail views with provenance and pharmacogenomic annotations. The androgen branch highlights cross-pathway connectivity by linking androgen metabolism to estrogen quinone formation and DNA adduct generation through CYP19A1-mediated aromatization and downstream catechol estrogen chemistry. In the optional androgen-focused extension, additional receptor, tissue, and variant context further connects this branch to androgen receptor signaling and genotype-specific annotations. ConclusionsExposoGraph provides a first-generation integrated, interactive framework linking carcinogenic exposures to metabolic fates and genetic modulators. The platform supports hypothesis generation for gene-environment interaction studies and may inform future individualized risk modeling, while remaining a research-use framework rather than a clinically validated risk-assessment tool.