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Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC. Full article

Autophagy-associated readouts in localized prostate cancer cannot be interpreted based on LC3, p62/SQSTM1, or LC3 puncta alone. In line with the concept of autophagy as a stress-response system, this review proposes a flux-aware, organelle-centered framework for assigning biological meaning to autophagy-related changes under disease-relevant stress. The framework integrates oxidative burden, lysosomal competence, selective autophagy, mitophagy, ferritinophagy, p62/SQSTM1-NRF2 signaling, ferroptosis-aware controls, and disease-stage context to distinguish four interpretive states: homeostatic quality control, adaptive tumor survival, blocked clearance, and stress-overload vulnerability. Flavonoid-associated responses are used as stress-test examples because they expose recurrent limitations in the field, including supraphysiologic exposures, limited metabolite realism, static-marker inflation, and insufficient assessment of lysosomal function. However, the framework is not restricted to dietary compounds; it applies to metabolic, pharmacological, inflammatory, androgen-related, radiation-associated, or therapy-induced perturbations in which autophagy-associated markers are altered without resolution of flux or organelle function. By linking autophagosome formation, cargo turnover, lysosomal acidification, redox buffering, and phenotype-level endpoints, this review defines a practical evidence hierarchy for interpreting autophagy in localized prostate cancer and for prioritizing translational vulnerabilities arising from organelle crosstalk. This contribution is primarily conceptual and is operationalized methodologically through flux-based evaluation criteria and translationally through disease-window-specific study-design recommendations. Full article

One of the most commonly diagnosed malignancies in men worldwide, prostate cancer (PCa) is the subject of much study across various treatment approaches and medical specialties. Currently, 5-year survival rates exceed 90%, and research efforts have increasingly shifted towards approaches that improve quality of life, minimizing the likelihood and severity of morbidities associated with treatment. Focal cryoablation is an approach that has been steadily gaining traction in recent years, both for its reduced risk of morbidity and greater potential for salvage therapy, relative to standard treatment. The goal of this work is to discuss the safety and efficacy of focal cryoablation for prostate cancers and define it in context among other treatment approaches. Publications describing approaches to, results from, and the science behind PCa cryoablation were reviewed and collated, describing the current landscape. Additional comparisons were made against analogous approaches, including radiation, surgical resection, hormone therapy, and other ablation modalities. Currently available literature characterizes prostate cryoablation as an effective and well-tolerated approach for treating primary and recurrent PCa, although the data are limited by heterogeneous evidence, lack of standardized endpoints, and an absence of robust randomized comparisons. Cryoablation for prostate cancer continues to evolve, offering a minimally invasive treatment option for both primary and salvage prostate cancer patients, although additional long-term studies are needed. Full article

Prostate club-like cells have emerged as a recurrent but conceptually unsettled epithelial population across normal prostate, benign remodeling, inflammatory lesions, and prostate cancer. Although the term derives from airway biology, current evidence suggests that, in the prostate, these cells are better viewed as context-dependent noncanonical epithelial states than as a definitive lineage. Single-cell, spatial transcriptomic, and integrative studies place club-like cells most consistently in the prostatic urethra and proximal ducts under near-homeostatic conditions, whereas related programs reappear in benign prostatic hyperplasia, proliferative inflammatory atrophy, and tumor-associated niches. Across these contexts, club-like states intersect with androgen perturbation, inflammatory remodeling, epithelial plasticity, and treatment adaptation. Molecularly, they are defined less by a single marker than by a partially overlapping secretory, stress-associated, and remodeling-related gene program, with variable relationships to urethral luminal, intermediate, and progenitor-like epithelial states. This review synthesizes current evidence on the definition, distribution, molecular identity, functional implications, and disease relevance of prostate club-like cells. We argue that their main significance lies in clarifying prostate epithelial heterogeneity and state transitions, while key priorities include harmonized nomenclature, longitudinal sampling, spatial validation, and functional perturbation. Full article

Background and Clinical Significance: Many diagnostic radiopharmaceuticals are excreted in the urine. This can pose a diagnostic challenge when urine-containing structures are in atypical locations, particularly in review of planar imaging without anatomical details from cross-sectional imaging. This case highlights a challenging ^99mTc-methylene diphosphonate (^99mTc-MDP) bone scan in a patient with an inguinal hernia containing a portion of the urinary bladder. Subsequently, we review diagnostic challenges on conventional and molecular imaging following surgical repair of the inguinal hernia. Case Presentation: A 79-year-old man with prostate cancer underwent initial staging prior to prostatectomy with ^99mTc-MDP bone scintigraphy. Anterior and posterior images showed focal uptake overlying the pubic symphysis. Lateral views showed that the activity was extraosseous. Follow-up CT urography showed a bladder hernia as the cause of the abnormality on bone scan. Prostatectomy and inguinal hernia repair were performed as a combination case. Four years postoperatively, follow-up ⁶⁸Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) showed no recurrence. The CT component of the exam showed an intermediate-density focus at the right inguinal hernia repair site, corresponding to a plugoma related to a polypropylene mesh plug, and a hyperattenuating Gore-Tex mesh repair of the left inguinal hernia. Conclusions: This case highlights the importance of lateral projections in resolving scintigraphic pitfalls and recognizing mesh-related imaging appearances to prevent misinterpretation. Full article

Background: Robot-assisted radical prostatectomy (RARP) is the predominant surgical approach for localized prostate cancer in high-volume centers worldwide. However, comprehensive real-world data describing complete institutional transition from open to robotic surgery remain limited. This study evaluated perioperative and early oncological outcomes of a contemporary RARP cohort and characterized the transition from open radical prostatectomy (ORP) to RARP in a European center. Methods: We analyzed 520 consecutive patients who underwent RARP between January 2023 and December 2025. Perioperative, pathological, and biochemical outcomes were assessed. Biochemical recurrence was defined as prostate-specific antigen ≥0.2 ng/mL. Institutional data from 2011 to 2025 were reviewed to evaluate procedural trends and the transition from ORP to RARP. Surgeon-specific and institutional learning curves were analyzed using operative time and linear regression models. Results: Following the introduction of robotic surgery in 2018, annual RARP volume increased from 37 procedures to 205 in 2025. Since 2023, RARP accounted for more than 99% of all radical prostatectomies. Median operative time decreased from 185 min in 2023 to 165 min in 2025, with consistent downward trends observed across all surgeons. Linear regression confirmed progressive improvement in operative efficiency, with learning rates ranging from −0.22 to −0.92 min per case. Estimated blood loss was minimal, no patients required transfusion, and major complications occurred in four patients (0.8%). Hospital stay decreased from 2 days to predominantly 1 day. During follow-up, 36 patients developed biochemical recurrence or PSA persistence. Biochemical recurrence-free survival differed significantly according to pathological stage (log-rank p < 0.001), with 24-month estimates of 93.7%, 91.5%, and 82.1% for pT2, pT3a, and pT3b disease, respectively. Conclusions: RARP provides favorable perioperative safety, minimal morbidity, and favorable early oncological outcomes in a high-volume setting. The complete institutional transition from ORP to RARP, together with demonstrated surgeon-specific and institutional learning effects, supports the feasibility and safety of implementing RARP as the institutional standard within a structured robotic program. Full article

Precision medicine in prostate cancer (PCa) is increasingly best understood as a continuum linking risk-adapted detection, multimodal diagnosis and phenotyping, and implementation-ready decision pathways. Contemporary clinical guidelines emphasize structured diagnostic strategies, appropriate use of advanced imaging, and selective deployment of biomarkers when results can alter management. Upstream risk enrichment using polygenic risk scores and multivariable prediction models may improve the yield of clinically significant disease while mitigating harms related to overdiagnosis. At the point of suspicion, magnetic resonance imaging-first pathways and reflex biomarker testing provide practical tools to reduce unnecessary biopsy while maintaining safeguards for the detection of clinically important disease. Beyond diagnosis, prostate-specific membrane antigen positron emission tomography refines disease-state phenotyping in initial staging, biochemical recurrence, and limited-burden presentations, while standardized acquisition and reporting improve reproducibility and multidisciplinary communication. Germline and tumor-based molecular profiling should be operationalized as a longitudinal care process with clear consent, turnaround targets, and test-to-action rules that define what each result enables at specific decision nodes. Finally, longitudinal monitoring approaches, including liquid biopsy and artificial intelligence-enabled pathology, are evolving rapidly and require transparent reporting and rigorous risk-of-bias appraisal before broad clinical adoption. This narrative review synthesizes key evidence across the precision continuum and outlines a decision-node-based, test-to-action framework for maximizing clinical benefit, maintaining quality, and ensuring equitable access. Full article

Prostate cancer (PCa) remains a major global health concern, with a subset of patients progressing to aggressive disease despite advances in diagnosis and treatment. Epithelial–mesenchymal transition (EMT) plays a pivotal role in tumor invasion, metastasis, and immune evasion; however, its cellular heterogeneity and clinical relevance in PCa remain incompletely understood. We analyzed single-cell transcriptomic data to characterize EMT dynamics in malignant epithelial cells. Malignant cells were identified based on aberrant copy number variation patterns, and EMT activity was quantified using AUCell. Gene expression profiling and gene set enrichment analysis identified key EMT-associated genes. By integrating bulk transcriptomic data with LASSO regression analysis, we identified five pivotal genes and constructed an EMT infiltration scoring model. The model demonstrated robust predictive performance in an external Gene Expression Omnibus validation cohort and effectively predicted early biochemical recurrence. Further analyses revealed significant associations between EMT scores, clinicopathological features, immune cell infiltration, genomic instability, and tumor immune dysfunction and exclusion scores. Pathway enrichment analysis highlighted distinct molecular characteristics between high- and low-score groups. Additionally, molecular docking using AutoDock identified potential targeted therapeutic agents for key EMT genes. Overall, this study systematically delineates EMT heterogeneity at the single-cell level and establishes a robust EMT infiltration model for prognostic prediction and therapeutic guidance in PCa, providing novel insights for precision risk stratification and individualized treatment strategies. Full article

Background: Prostate cancer (PCa) is biologically heterogeneous, requiring management strategies that balance oncologic benefit with preservation of quality of life. Prostate-specific membrane antigen (PSMA) has emerged as a key theranostic biomarker enabling highly sensitive molecular imaging and targeted therapy. Purpose: The present manuscript aims to summarize the clinical role of PSMA-PET/CT in PCa across staging, treatment selection, and response assessment, with a special focus on its contribution to personalized management. Key Findings: PSMA-PET/CT demonstrates superior accuracy compared with conventional imaging, frequently leading to stage migration and changes in therapeutic strategy. It improves detection of metastatic and recurrent disease, guides selection for systemic and PSMA-targeted therapies, and supports metastasis-directed treatment in oligometastatic settings, potentially delaying androgen-deprivation therapy and preserving quality of life. Additionally, PSMA-PET enhances intra-prostatic lesion delineation for focal therapies and radiotherapy planning. Limitations include reduced sensitivity for very small lesions, possible false positives, variability among tracers, and issues related to access and standardization. Conclusions: PSMA-PET/CT is a cornerstone of precision imaging in PCa, enabling more individualized treatment decisions across the disease continuum. Ongoing studies will further define its long-term clinical impact and integration into routine care. Full article

Background/Objectives: Prostate cancer (PCa) remains a prevalent malignancy among men, often complicated by recurrence and unfavorable clinical outcomes. Consequently, precise risk stratification and timely clinical intervention are paramount. Initially, we delineated distinct expression profiles of histone modification regulators via unsupervised clustering, identifying PCa subtypes with divergent survival probabilities and biological phenotypes. Subsequently, we sought to develop a prognostic gene signature, derived from the transcriptomic variations among these regulator-defined subtypes, to predict outcomes in PCa patients following radical prostatectomy (RP). Methods: Clinical and transcriptomic data from PCa cohorts were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories for comprehensive analysis. Subtypes driven by histone modification regulators were established using unsupervised consensus clustering, followed by in-depth characterization of their molecular features and associated pathways. A risk-scoring model was then developed to evaluate its prognostic efficacy in this patient population. Results: Stratification based on histone modification regulators yielded four distinct PCa subtypes exhibiting heterogeneous survival outcomes, functional pathways, and genomic mutational landscapes. Following rigorous feature selection, a 21-gene risk signature (HIS_score)—comprising MXD3, CCDC28B, COL11A2, SLC39A5, GPT, DNASE1L2, PIF1, KRTAP5-9, TTLL10, KRTAP5-1, KRTAP5-10, HAGHL, MSLNL, AMH, NKAIN4, CCDC114, SLC9A3, SULT1E1, ALB, SLC6A14, and RPE65—was constructed. Survival analyses demonstrated that patients assigned to the high HIS_score cohort experienced significantly worse clinical outcomes compared to their low-score counterparts. Furthermore, we integrated this signature into a novel clinical nomogram to facilitate individualized prognostic assessments. Conclusions: Derived from transcriptomic disparities between extreme epigenetic subtypes, the HIS_score and its associated nomogram serve as robust prognostic instruments. These tools effectively encapsulate the downstream transcriptional sequelae of histone modification dysregulation, offering clinicians a valuable framework to accurately predict post-RP outcomes and expedite the formulation of personalized therapeutic strategies. Full article

Background/Introduction: Prostate cancer (PCa) is the most commonly diagnosed malignancy among men and remains a major cause of cancer-related mortality worldwide. We aimed to evaluate whether radiomic features extracted from normal endocrine organs, combined with clinical variables, could predict clinical progression in patients with PSMA-negative prostate cancer. Materials and Methods: In this retrospective study, 101 men with biochemically recurrent prostate cancer and negative [¹⁸F]DCFPyL PET/CT scans were included. Radiomic features were extracted from the adrenal glands, thyroid, the hypothalamus–pituitary complex, and testes. Post-imaging variables were excluded to prevent temporal data leakage. Models were developed using a stratified train/test split framework with preprocessing and feature selection performed exclusively within the training subset prior to evaluation on the held-out test set. Performance was evaluated using AUC, accuracy, sensitivity, specificity, and Brier score, while bootstrap confidence intervals and DeLong analysis were used for statistical assessment. Results: Multimodal fusion models integrating CT radiomics, PET radiomics, and clinical variables demonstrated the strongest predictive performance. The highest-performing model combined TESTIS_CT and TESTIS_PET radiomics with clinical variables, achieving an AUC of 0.758 (95% CI: 0.653–0.849). Clinical-only models remained highly competitive, with the best configuration achieving an AUC of 0.727 (95% CI: 0.618–0.833). PET + clinical and CT + clinical models achieved AUC values of up to 0.733 and 0.729, respectively, while imaging-only models demonstrated substantially lower discrimination. Although endocrine organ radiomics numerically improved predictive performance and specificity, DeLong analysis demonstrated no statistically significant improvement beyond clinical variables alone. Discussion: These findings suggest that endocrine organ radiomics may provide complementary system-level imaging biomarkers reflecting tumor–host interactions in PSMA-negative prostate cancer. However, their incremental clinical value remains modest. Conclusions: Endocrine organ radiomics combined with clinical variables demonstrated promising predictive performance in PSMA-negative prostate cancer, particularly in multimodal fusion models. Nevertheless, the added value beyond clinical variables alone was not statistically significant and requires validation in larger independent cohorts. Full article

Prostate cancer (PCa) is predominantly an acinar adenocarcinoma arising from the prostatic glandular epithelium, with tumor grade assessed using the International Society of Urological Pathology (ISUP) Grade Group classification, reflecting the degree of glandular differentiation and underlying molecular heterogeneity. PCa exhibits wide clinical behavior heterogeneity, ranging from indolent disease to aggressive forms with poor outcomes. Accurate prognostic assessment is, therefore, essential for guiding treatment selection and monitoring disease progression. This review examines recent advances in imaging and non-imaging biomarkers that contribute to improved risk stratification, treatment planning, and disease monitoring. Particular attention is given to multiparametric magnetic resonance imaging (mpMRI), whole-body magnetic resonance imaging (WB-MRI), positron emission tomography/computed tomography (PET/CT), positron emission tomography/magnetic resonance imaging (PET/MRI), computed tomography (CT), and transrectal ultrasound (TRUS), evaluated for their capacity not only to detect disease but also to predict recurrence, progression, and survival outcomes. In parallel, the prognostic role of non-imaging biomarkers is discussed, including the prostate-specific antigen (PSA), histopathological grading, biochemical and inflammatory biomarkers, as well as genomic classifiers and circulating tumor DNA (ctDNA). Emerging approaches such as radiomics, liquid-biopsy-derived molecular profiles, and artificial intelligence (AI)-based multimodal integration are highlighted for their potential to enhance individualized decision making. This review underscores the importance of combining imaging and molecular information to refine prognostic models and accelerate the translation of precision medicine in PCa. Full article

Biochemical recurrence (BCR) after radical prostatectomy (RP) remains a major clinical challenge. Although metabolic reprogramming drives prostate cancer (PCa) progression, its predictive value for BCR and its interplay with the tumor immune microenvironment (TIME) remain incompletely understood. By integrating weighted gene co-expression network analysis (WGCNA) with machine learning, we identified four metabolic-related hub genes (GDPD1, PLA2G7, PTGDS, and SRD5A2) and developed an XGBoost-Cox model that accurately stratified BCR risk (training 5-year AUC: 0.858; validation 5-year AUC: 0.745). SHAP analysis enhanced the model’s interpretability, while immunohistochemistry (IHC) validated differential protein expression of these targets across 32 clinical specimens. Furthermore, immune profiling demonstrated that these genes are closely linked to M2 macrophage-mediated immunosuppression and altered T-cell infiltration. To translate these biomarkers into therapeutic targets, we employed in silico screening, molecular docking, and molecular dynamics simulations, identifying (-)-epigallocatechin gallate (EGCG) as a promising multi-target candidate. Subsequent in vitro assays confirmed that EGCG binds stably to GDPD1, PTGDS, and SRD5A2, effectively suppressing malignant PCa phenotypes and prostate-specific antigen (PSA) secretion. In summary, we established a robust and interpretable model for predicting BCR after RP, and our in vitro validation suggests that EGCG holds promise as a therapeutic agent to delay PCa progression. Full article

Background: Pathological T0 (pT0) prostate cancer following radical prostatectomy is uncommon, and its prognostic significance remains unclear, particularly after neoadjuvant hormonal therapy (NHT). We investigated the incidence of pT0 disease in a multicenter Japanese cohort and described postoperative biochemical recurrence (BCR) outcomes. Methods: This retrospective study analyzed 3079 patients who underwent robot-assisted radical prostatectomy at nine Japanese centers between 2011 and 2021. Patients were classified as having pT0 or non-pT0 disease. Because only four pT0 cases occurred without NHT, these are summarized descriptively. Exploratory Kaplan–Meier and log-rank analyses of biochemical recurrence-free survival (BRFS) were performed for the NHT subgroup. Results: Twenty-seven pT0 cases (0.9%) were identified, and 85.2% were identified after NHT. Overall, 399 patients (13.0%) developed BCR. Among patients who did not undergo NHT, the 1- and 2-year BRFS rates were 100% and 100%, respectively, in the pT0 group and 92.4% and 88.1%, respectively, in the non-pT0 group. In the NHT subgroup, the corresponding rates were 92.9% and 92.7%, versus 91.8% and 85.5%, respectively (p = 0.651). Conclusions: pT0 disease after robot-assisted radical prostatectomy is rare and occurs predominantly after NHT. Given the possibility that late-onset recurrences may have been overlooked, the results of this trial should be understood as providing evidence from the short- to intermediate-term perspective. Full article

Purpose: Prostate cancer is one of the most common malignancies in men, yet current prognostic methods remain suboptimal. Emerging evidence indicates that microRNAs (miRNAs) play critical roles in prostate cancer progression. This study aimed to identify miRNAs associated with adverse clinical outcomes by comparing miRNA expression profiles between prostate tumors with unfavorable versus favorable prognostic features. Materials and Methods: High-throughput next-generation sequencing (NGS) was used to analyze miRNA expression in formalin-fixed, paraffin-embedded prostate cancer tissue samples. Patients were classified into favorable or unfavorable prognosis groups based on risk stratification scores, Gleason grade group, and biochemical recurrence. Differentially expressed miRNAs were identified using a fold-change threshold ≥2 and a false discovery rate (FDR) <0.05. Predicted target genes and pathway analyses were conducted to generate candidate regulatory hypotheses rather than confirm mechanistic relationships. Results: Several miRNAs were differentially expressed according to prognostic category. miR-206 was significantly downregulated in high-risk tumors compared with low-risk tumors. High-Gleason-grade tumors showed reduced expression of miR-7704 and miR-4454, while miR-25-3p and let-7f-5p were upregulated. In patients with early biochemical recurrence, miR-7704 and miR-10400-5p were downregulated relative to those with prolonged recurrence-free survival. Target prediction analysis identified CPEB3, HAND1, PTAR1, and SPRYD4 as shared candidate targets, with CPEB3 emerging as a prioritized candidate supported by consistency in external datasets rather than a confirmed molecular target. Conclusions: Distinct miRNA expression patterns correlate with prostate cancer aggressiveness and clinical outcomes. miR-206, miR-7704, miR-4454, miR-25-3p, and let-7f-5p represent candidate prognostic biomarkers. Their shared target CPEB3 should be interpreted as a prioritized candidate for future investigation. Given the very small sample size and the lack of qRT-PCR and functional validation, these findings should be considered preliminary and hypothesis-generating, requiring validation in larger independent cohorts and experimental studies. Full article