Prostate

IntroductionMacrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia.MethodsSingle-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (ResultsBPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, accumulate with increased prostate volume. TREM2 high and MARCO high macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2high macrophages have a statistically significant increase in neutral lipid compared to TREM2low macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages.DiscussionThese data define two new BPH immune subpopulations, TREM2high and MARCOhigh macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

ObjectivesProstate imaging quality (PI-QUAL) was developed to standardise the evaluation of prostate MRI quality and has recently been updated to version 2. This study aims to assess inter-reader agreement for PI-QUAL v1 and v2 scores and investigates changes in MRI quality score categories.Materials and methodsThe study retrospectively analysed 350 multiparametric MRI (mpMRI) scans. Two expert uroradiologists independently assessed mpMRI quality using PI-QUAL v1 and v2 guidelines. Biparametric MRI (bpMRI) categorisation based on PI-QUAL v2 included only T2WI and diffusion-weighted imaging (DWI) results. Inter-reader agreement was determined using percentage agreement and kappa, and categorisation comparisons were made using the chi-square test.ResultsSubstantial inter-reader agreement was observed for the overall PI-QUAL v1 score (κ = 0.64) and moderate agreement for v2 mpMRI (κ = 0.54) and v2 bpMRI scores (κ = 0.57). Inter-reader agreements on individual sequences were similar between v1 and v2 (kappa for individual sequences: T2WI, 0.46 and 0.49; DWI, 0.66 and 0.70; DCE, 0.71 and 0.61). Quality levels shifted from predominantly "optimal" in v1 (65%) down to "acceptable" using v2 (55%); p ConclusionThis study shows consistent inter-reader agreement between PI-QUAL v1 and v2, encompassing overall and individual sequence categorisation. A notable shift from "optimal" to "acceptable" quality was demonstrated when moving from v1 to v2, with DCE tending improving quality from "inadequate" (bpMRI) to "acceptable" (mpMRI).Key pointsQuestion What are the agreement levels of image quality of prostate MRI by using PI-QUAL v1 and v2? Findings Inter-reader agreement based on PI-QUAL v1 and v2 is comparable. Dynamic contrast enhancement (DCE) enables an overall shift from inadequate quality (at bpMRI) to acceptable quality (mpMRI). Clinical relevance The inter-reader agreement on PI-QUAL v1 and v2 is equivalent. PI-QUAL v2 assesses prostate bpMRI as well as mpMRI quality. Transitioning from inadequate to acceptable between v2-bpMRI and v2-mpMRI highlights the role of DCE as an "image quality safety net."

The androgen receptor (AR) is central in prostate tissue identity and differentiation, and controls normal growth-suppressive, prostate-specific gene expression. It also drives prostate tumorigenesis when hijacked for oncogenic transcription. The execution of growth-suppressive AR transcriptional programs in prostate cancer (PCa) and the potential for reactivation remain unclear. Here, we use a genome-wide approach to modulate canonical androgen response element (ARE) motifs-the classic DNA binding elements for AR-to delineate distinct AR transcriptional programs. We find that activating these AREs promotes differentiation and growth-suppressive transcription, potentially leading to AR+ PCa cell death, while ARE repression is tolerated by PCa cells but deleterious to normal prostate cells. Gene signatures driven by ARE activity correlate with improved prognosis and luminal phenotypes in PCa patients. Canonical AREs maintain a normal, lineage-specific transcriptional program that can be reengaged in PCa cells, offering therapeutic potential and clinical relevance.

ObjectivesTo evaluate the effect of prostate volume on the risk of clinically significant prostate cancer (csPCa) across a range of PSA-density (PSAd) values, and to explore the relationship between PI-RADS category and PSAd in predicting csPCa.Materials and methodsWe retrospectively analyzed 2190 patients undergoing mpMRI for suspected PCa. Patients were classified as csPCa and clinically insignificant (negative and insignificant PCa). Logistic regression was performed to assess the csPCa risk at different PSAd cut-offs across different prostate volume subgroups ( 80 mL) and PI-RADS categories. The effect of prostate volume on PSAd performance was evaluated using ROC analysis. To assess robustness, we performed an 80:20 split-sample internal validation.Results747/2190 (34.1%) patients had PCa, including 571 (26.1%) with csPCa. Regardless of PSAd, csPCa risk exceeded 30% for PI-RADS 4 and 50% for PI-RADS 5. At a 10% csPCa risk threshold, the optimal PSAd cut-offs were 0.20 ng/mL² for PI-RADS 1-2 and 0.12 ng/mL² for PI-RADS 3. Logistic regression showed a significant inverse correlation between prostate volume and csPCa probability. Notably, 79% of csPCa patients with prostate volume ≤ 40 mL had a PSAd ≥ 0.15 ng/mL², compared to only 22.4% with volumes ≥ 60 mL. PSAd performed significantly worse for larger glands (≥ 60 mL), with AUCs of 0.70 versus 0.84 (≤ 40 mL) and 0.82 (40-60 mL), both p ConclusionThe optimal PSAd cut-offs for guiding biopsy decisions were 0.20 ng/mL² for PI-RADS 1-2 and 0.12 ng/mL² for PI-RADS 3. When using PSAd to guide biopsy decision for PI-RADS 1-3 patients with large prostates (> 60 mL), caution is warranted, as PSAd becomes significantly less accurate.Key pointsQuestion The optimal PSA-density thresholds for biopsy decisions in PI-RADS 1-3 patients remain uncertain, and data on the impact of prostate volume on its performance are limited. Findings Optimal PSA-density thresholds were 0.20 ng/mL² for PI-RADS 1-2 and 0.12 ng/mL² for PI-RADS 3. Diagnostic performance of PSA-density decreased significantly in men with larger glands (≥ 60 mL). Clinical relevance PSA-density cut-offs of 0.20 (PI-RADS 1-2) and 0.12 ng/mL² (PI-RADS 3) can guide biopsy decisions. In PI-RADS 1-3 patients with large prostate (≥ 60 mL), PSA-density becomes significantly less predictive, and low values may not reliably exclude csPCa.