Prostate最新文献

Introduction: Using serum metabolomics in Community-Based Participatory Research (CBPR) with underserved populations presents challenges due to the invasive nature of venipuncture, which limits longitudinal sample collection in community settings. In this pilot study, we compared saliva and serum metabolomics in patients with prostate cancer to evaluate saliva's potential in biomarker research and identified metabolic changes associated with androgen deprivation therapy (ADT).

Methods: Blood and saliva were collected from 20 eugonadal patients with prostate cancer and 20 patients receiving ADT. Untargeted metabolomics of metabolites was performed, and glucocorticoids were quantified using targeted metabolomics. Data were analyzed using MassHunter, METLIN database, and MetaboAnalyst.

Results: Across all samples, 1198 metabolites were identified. Comparing ADT to eugonadal serum and integrating fold change (FC > 2 or FC < 0.5) and significance (adjusted p < 0.1), we identified 14 upregulated and 20 downregulated metabolites. Comparing ADT to eugonadal saliva, we identified 14 upregulated and 28 downregulated metabolites. Targeted metabolomics confirmed correlations between serum and salivary cortisol and salivary and serum cortisone (r = 0.61 and 0.62, p < 0.001), underscoring the potential of saliva glucocorticoids as biomarkers for stress-related metabolic alterations and suggesting that saliva reflects the systemic metabolomic profile.

Conclusion: ADT-associated metabolomic changes are detectable in saliva. Targeted analysis suggests that salivary glucocorticoids may serve as biomarkers of metabolism and stress in community-based studies. Our findings support saliva as a non-invasive alternative to serum for biomarker research, facilitating community-based investigations and advancing public health efforts.

Background: Among the approved therapies for metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone and docetaxel are administered concomitantly with corticosteroids. This study evaluated the association between corticosteroid use and risk of adverse events among patients with mHSPC.

Methods: We conducted an observational cohort study among patients ≥ 65 years of age who were enrolled in Medicare parts A, B, or D, and initiated treatment for mHSPC. The primary exposure was corticosteroids between June 1, 2017-December 31, 2023. Primary outcomes were nine composite adverse event outcomes. Exploratory outcomes were all-cause death, all-cause hospitalization, and adverse event-related hospitalization. Conventional Cox models were used to model corticosteroid exposure as a binary time-varying covariate, and weighted cumulative exposure models were used to account for varying doses, durations, and timing of corticosteroid exposure.

Results: Of 24,857 patients, 12,839 (52%) received at least one dose of corticosteroids during the follow-up period. Compared with patients who were not exposed to at least one ≥ 5 mg prednisone-equivalent dose of corticosteroids, patients exposed to corticosteroids during follow-up were at significantly higher risk of all adverse event types, except ophthalmic events, and had a 34% higher risk of all-cause death (adjusted hazard ratio: 1.34; 95% confidence interval: 1.27-1.42). Risks increased with prolonged corticosteroid exposure and with higher daily doses.

Conclusions: Our findings suggest that patients exposed to corticosteroids are at increased risk of adverse events, hospitalization, and death. As not all mHSPC treatments require concomitant use of corticosteroids, these findings may help to inform treatment decision-making.

Background: The progression of prostate cancer (PCa) to a castration-resistant state (CRPC) remains a major clinical challenge. Resistance to second-generation androgen receptor (AR) antagonists like enzalutamide often involves the reactivation of AR signaling, frequently through intratumoral androgen synthesis. The molecular drivers that regulate this adaptive resistance mechanism are not fully understood. GPR133 (also known as ADGRD1) is an adhesion G protein-coupled receptor with emerging roles in various cancers, but its function in prostate cancer is unknown. While androgen signaling is classically mediated by the nuclear AR, GPR133 has recently been identified as a novel membrane androgen receptor, though its functional relationship with the AR pathway in prostate cancer is unknown.

Methods: We analyzed GPR133 expression in patient-derived PCa tissues and its correlation with clinical outcomes using publicly available datasets and our patients' samples. We employed gain- and loss-of-function approaches in vitro to test whether GPR133 specifically mediates resistance to enzalutamide. RNA sequencing was used to identify downstream pathways regulated by GPR133. The role of the downstream effector HSD3B1 was assessed using siRNA-mediated silencing. The therapeutic implications of GPR133 expression were validated in vivo using xenograft mouse models.

Results: GPR133 expression is significantly downregulated in prostate cancer tissue compared to benign tissue and is further decreased in CRPC. Low GPR133 expression correlates with poorer disease-free survival. Silencing GPR133 conferred robust resistance to enzalutamide in vitro and in vivo. Conversely, overexpression of GPR133 could further sensitize cancer cells to enzalutamide. Mechanistically, loss of GPR133 transcriptionally upregulated key enzymes in the steroid hormone biosynthesis pathway, most notably HSD3B1. This upregulation led to elevated intracellular testosterone levels and sustained androgen receptor (AR) signaling, characterized by the persistent expression of AR target genes despite enzalutamide treatment. Silencing HSD3B1 reversed the enzalutamide resistance induced by GPR133 knockdown.

Conclusions: Our findings identify GPR133 as a novel tumor suppressor in prostate cancer. Loss of GPR133 expression is a key event in the progression to CRPC that promotes therapeutic resistance by activating the intratumoral androgen synthesis pathway. GPR133 may serve as a valuable prognostic biomarker and a potential therapeutic target for advanced prostate cancer.

Background: Smoking is a modifiable risk factor for prostate cancer (PCa) diagnosis, recurrence, and mortality. While the mutagenic effects of tobacco are well-documented, the immunological consequences of smoking within the tumor microenvironment (TME) are poorly understood. This study investigates how smoking reshapes the PCa immune landscape and how the associated changes could potentially be associated with patient survival.

Methods: Tumor tissues from smoker and nonsmoker prostate cancer patients were subjected to multiplex gene expression analysis of immune cell types using the nanoString nCounter® PanCancer immune profiling panel to examine the effect of smoking behavior on the immune landscape. Gene expression data were also analyzed using Enrichr to identify differentially activated pathways in smoker versus nonsmoker patients. Further, we surveyed public databases to examine the association between top differentially-expressed genes and altered immune cell abundance with patient survival.

Results: Current-smokers exhibited significantly higher infiltration of tumor-associated macrophages (TAMs) (p = 0.036) and regulatory T cells (Tregs) (p = 0.045), compared to nonsmokers, with a trend for lower mast cell infiltration (p = 0.055). A significant positive correlation (r = 0.42; p = 0.036) was observed between TAMs with Tregs in all samples, with a stronger correlation in current-smokers (r = 0.88; p = 0.008) than nonsmokers (r = 0.26; p = 0.403). A total of 89 DEGs were identified between current-smokers and nonsmokers, associated with upregulation of immunosuppressive pathways including "primary immunodeficiency" and "PD-L1 expression and PD-1 checkpoint," and downregulation of "antigen-processing and -presentation" and "NF-kappa-B signaling" pathways. Key upregulated genes, MAGEA3, POU2AF1, and SEMG1, correlated with immune suppression markers and poorer PCa patient survival. Concomitant high TAM and Treg infiltration also significantly correlated with reduced overall survival (p = 0.04). No significant differences were observed between current-smokers and former-smokers, who exhibited patterns similar to nonsmokers.

Conclusions: These findings suggest that active smoking creates an immunosuppressive TME, potentially facilitating rapid tumor growth and aggressive progression. Smoking cessation may reverse these changes, highlighting the clinical significance of smoking behavior in disease outcomes.

Background: Plasticity of cancer, including epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) self-renewal, and microenvironmental adaptation, drives metastasis, therapy resistance, and poor outcomes in prostate cancer (PCa). Ion channels and extrachromosomal DNA (ecDNA) have emerged as key drivers of such adaptive processes by influencing signaling, metabolism, and immune interactions.

Methods: We evaluated available evidence on ion channel biology, ecDNA dynamics, and their roles in tumor plasticity and drug resistance in PCa. Further, we analyzed two publicly accessible single-cell RNA-sequencing (scRNA-seq) datasets (primary PCa and castration-resistant PCa) to determine ion channel and transporter expression profiles in tumor and stromal cell populations.

Results: Our analysis showed cell type-specific expression of many ion channels, including KCNJ10, CACNA1H, and CLIC1, and identification of six transporters (SLC25A1, SLC25A10, SLC25A33, SLC25A42, SLC29A2, SLC7A11) strongly enriched in luminal tumor cells. The discovered genes regulate mitochondrial metabolism, redox homeostasis, nucleotide biosynthesis, immune modulation, and resistance to ferroptosis, all contributing to tumor growth. ecDNA facilitates oncogene amplification (e.g., MYC, EGFR), induction of EMT, and immune evasion, driving intratumoral heterogeneity and therapy-resistant clones.

Conclusions: Ion channels and ecDNA are central to the disease progression and treatment resistance of PCa through regulation of EMT, CSC phenotype, and tumor microenvironment (TME) interactions. Targeting the drivers-through ion channel modulators, ferroptosis induction, and ecDNA-targeting interventions (BET/HDAC inhibitors, CRISPR-based methods) offers a promising way to overcome resistance. Integration of multi-omics, and combination treatments will be key to construct precision medicine strategies and improve clinical outcomes in advanced PCa.

Background: To implement "MeinLUKS," an automated e-health follow-up system within the EPIC MyChart portal after radical prostatectomy (RP), and to examine factors influencing portal adoption, as well as functional and oncological outcome differences between users and non-users.

Methods: We retrospectively analyzed men undergoing RP at a tertiary center (January/2022-October/2023). Patients were classified as "users" if they submitted follow-up data via MeinLUKS or "non-users" if monitored through referring physicians. Sociodemographic, clinical, functional, and oncological outcomes were retrieved from institutional registries and included standardized patient-reported outcome measures. Both groups were invited to structured telephone interviews addressing barriers and facilitators of adoption.

Results: Of 274 patients, 128 (47%) used MeinLUKS and 146 (53%) relied on traditional follow-up. Users were younger, more educated, and often urban residents, while oncological characteristics were comparable. Median time to no pad use was not different (11 vs. 28 days, p = 0.3) with similar long-term continence (79% vs. 73% pad-free, p = 0.3). Patient reported sexual function recovery was better among users (56% vs. 36%, p = 0.01). MeinLUKS automatically flagged two biochemical recurrences and unreported complications not identified in routine care. Among 91 interviewees, users emphasized organizational benefits and digital competence, while non-users cited poor onboarding, limited physician advocacy, and interface complexity. Limitations include single-center, retrospective design and non-randomized comparisons.

Conclusions: Automated e-health follow-up improved data completeness, reduced workforce demands, and detected clinically relevant events missed in routine care. Optimizing onboarding, clinician engagement, and usability may increase adoption and enhance quality and efficiency in prostate cancer survivorship care.

Background: Chronic inflammation is commonly observed in benign prostatic hyperplasia (BPH) tissue and may contribute to lower urinary tract symptoms (LUTS) as well as disease progression. This study evaluated the efficacy of combining a standardized extract of Serenoa repens (Sr) with alfuzosin versus alfuzosin monotherapy in men with LUTS due to BPH.

Methods: In this prospective Phase III, randomized, multicenter, real-world study, 300 treatment-naïve men with moderate-to-severe LUTS (IPSS > 7) and prostate volume > 30 cc were enrolled. Patients received either alfuzosin 10 mg/day or alfuzosin 10 mg plus HESr 320 mg/day for 12 months. Primary endpoints included changes in IPSS and uroflowmetry (Q_max). Secondary endpoints included quality of life (IPSS-Q8), storage symptoms (IPSS-Q2 and Q4), nocturia (IPSS-Q7), erectile function (IIEF-5), and ejaculatory function (MSHQ-Ej). Outcomes were analyzed using mixed-model ANOVA with post hoc Tukey's tests. Statistical analysis was performed using JMP Pro 14 (SAS Institute Inc.). The protocol was approved by our Ethical Committee Lazio Area 1, Protocol 0949/2023, Rif 7385 on December 12, 2023.

Results: Both treatments significantly improved total IPSS over time (p < 0.0001). Across all time points, combination therapy was associated with consistently lower IPSS scores, demonstrating a significant time-by-treatment interaction (p = 0.007). Nocturia improved significantly over time (p < 0.0001); the combination group showed greater benefit from Month 3 onward (p = 0.006), though the main treatment effect was not statistically significant (p = 0.076). Q_max improved in both groups (p < 0.0001), with a significant time-treatment interaction (p = 0.006), but no significant main effect of treatment type (p = 0.113). A mild but significant decline in IIEF-5 was observed in both groups over time. Treatment adherence exceeded 86% in both arms.

Conclusions: The combination of HESr and alfuzosin was significantly more effective than alfuzosin monotherapy in relieving LUTS, with greater benefits from Month 3 onward. Q_max and nocturia also showed greater, although mild, improvements with combination therapy. Sexual function outcomes were comparable between groups. High adherence and real-world applicability support the clinical value of this combination in managing BPH-related LUTS.

Background: The management of mCSPC has improved with the addition of docetaxel and androgen receptor pathway inhibitors (ARPi) to androgen deprivation therapy. However, patient outcomes remain heterogeneous, highlighting the need for practical prognostic models. The Bellmunt risk score, based on ECOG status, hemoglobin, and liver metastases, was developed for urothelial carcinoma, but its role in mCSPC is unclear.

Methods: This retrospective study analyzed 182 mCSPC patients treated with first-line docetaxel or ARPi from 2010 to 2024. Patients were stratified into low- and high-risk groups by the Bellmunt score. Overall survival (OS) was assessed with Kaplan-Meier and Cox models. Subgroup and interaction analyses were performed to evaluate the consistency of the Bellmunt risk score's prognostic value across treatment modalities. The Bellmunt, CHAARTED, and LATITUDE criteria were compared using the concordance index (C-index).

Results: Patients with a low Bellmunt risk score had significantly longer OS than high-risk patients (median OS: 44.4 vs. 14.1 months; p < 0.001). This prognostic effect was consistent in both ARPi and docetaxel subgroups, with no significant interaction between treatment type and Bellmunt score (p-interaction = 0.185). In multivariate analysis, the Bellmunt score remained an independent predictor of OS (HR: 3.13; 95% CI: 1.16-8.43; p = 0.024). The Bellmunt score showed better discriminative ability for OS (C-index: 0.67) than CHAARTED (0.62) and LATITUDE (0.64) criteria. However, the absolute differences in C-index values were modest, and the analysis was restricted to patients with complete data, potentially introducing selection bias.

Conclusion: The Bellmunt risk score appears to offer a practical approach to risk stratification in mCSPC, with promising prognostic value across treatment types. However, its incremental clinical utility over existing criteria is limited, and its role in guiding therapy remains unestablished. These exploratory findings warrant prospective validation.

Background: Survival differs markedly between men with metastatic prostate cancer (mPC) confined to lymph nodes (LNM) versus bone (BM). We examined whether site-specific genomic alterations-and their combinations-explain this disparity and could inform intensity-modulated follow-up or therapy.

Methods: Clinical and targeted-sequencing data for 1011 men with mPC in the cBioPortal for Cancer Genomics registry were analyzed (LNM-only = 622; BM-only = 389). Genes altered in > 5% of tumors (two-sided p < 0.05) were assessed individually and in every possible multigene cluster for associations with overall survival (OS). Survival was evaluated with Kaplan-Meier curves and the difference in restricted mean survival time (dRMST) to pinpoint the first significant curve divergence. Synthetic-lethal (SL) interactions were explored via the SLOAD database.

Results: In total, 18 of 184 profiled genes (9.8%) exceeded the 5% alteration threshold. FOXA1 was enriched in BM, whereas TMPRSS2, ERG, PTEN, ZFHX3, CDK12, and KMT2C were enriched in LNM (p < 0.05). Among 9143 tested gene clusters, 65 were associated with inferior OS; 48 occurred in the LNM subgroup, 17 in the combined cohort, and none in the BM alone. High-risk clusters showed first OS divergence 10-60 months after diagnosis of metastasis. SLOAD identified 615 putative SL pairs involving these genes.

Conclusions: We identified 65 site-specific multigene clusters-chiefly in lymph node-only mPC-that underlie the survival gap between nodal and bone metastases. These signatures suggest a 10-60-month interval that may lend itself for intensity-modulated follow-up. We also discovered hundreds of synthetic-lethal gene-alteration pairs, opening future research opportunities in combinatorial therapeutic targeting.