Prostate最新文献

Background: Dogs spontaneously develop prostate carcinoma (PC) and share prostate gland anatomy, physiology, and size to men. Over the last 15 years, we have developed and refined a canine model of focal PC to evaluate therapeutic-diagnostic (theranostic) interventions. A comprehensive description of the pathology and synthesis of the various studies has not been performed. The goal of this manuscript was to describe the canine model tumor pathology within the framework of its methodological development to help guide future translational PC research.

Methods: In published and unpublished studies, we previously inoculated prostate glands of immunosuppressed, intact beagle dogs (n = 56) with a canine PC cell line (Ace-1) transduced with human or canine genes for targeted theranostics. Gross tumor assessment and histology were performed in all cases. Molecular tumor and microenvironmental pathology was investigated using digital image analysis, immunohistochemistry, laser-capture microdissection, and quantitative real-time PCR.

Results: The model reliably (85.7% engraftment rate) formed prostatic tumors resembling intermediate and high-grade localized PC, with poorly differentiated morphology, stromal invasion, and peripheral growth. Soft tissue metastasis occurred in 13/48 (27.1%) dogs. Most dogs formed multifocal prostatic tumors with occasional tumors outside the prostate gland. Tumor location influenced growth behavior and the microenvironment. Allografts were histologically classified as intraglandular intraprostatic, invasive intraprostatic, capsular, or extraprostatic. Compared to intraprostatic tumors, capsular/extraprostatic tumors had increased proliferation (Ki-67 index), epithelial-to-mesenchymal transition, and microenvironmental alterations that included increased collagenous stroma, fibroplasia, and reduced immune cell infiltration.

Conclusions: The canine model of PC captured important pathologic features of men undergoing curative-intent therapy alongside model- and species-specific characteristics of interest to researchers. Beyond defining pathology, the results highlighted applications of the canine model in studying the tumor microenvironment and advancing preclinical, anti-cancer strategies in a large animal species.

Background: There is a complex relationship between body weight and survival in prostate cancer. While increased BMI is associated with increased prostate cancer incidence and death, obesity is associated with improved survival in metastatic castrate-resistant prostate cancer (mCRPC). However, little is known about the effect of weight change before the treatment of mCRPC on survival. We assessed the association between BMI, weight loss before treatment, PSA levels, and overall survival in mCRPC.

Methods: Veterans treated with abiraterone or enzalutamide for de novo mCRPC from May 2011 to June 2017 were identified within the VHA. BMI and weight loss in the year before treatment were determined. Kruskal-Wallis, χ² tests, ANOVA, Kaplan-Meier, and Cox proportional hazard modeling tests were used to assess the association between BMI, weight loss, PSA at the start of treatment, and overall survival, with covariates including age, race, and Charlson Comorbidity Index.

Results: We identified 8857 veterans treated for mCRPC with weight loss values available and 8438 patients with BMI values available. There was shorter survival in veterans with weight loss > 10% of body weight (median = 9.8 months, n = 1332) compared with 5%-10% loss (median = 16.1 months, n = 1619) and stable weight (median = 25.1 months, n = 5906). Mean PSA levels increased (106.3, 160.0, 267.8) as BMI decreased (BMI > 30, BMI 25-30, BMI < 25), respectively. As weight loss increased (stable weight vs. weight loss 5%-10% vs. weight loss > 10%), mean PSA levels increased (112.2, 205.8, 405.9), respectively. Compared with a stable weight, both losing 5%-10% of weight (HR: 1.30, 95% CI: 1.22-1.38) and losing > 10% of weight (HR: 1.98, 95% CI: 1.85-2.12) are independently associated with increased mortality. Analyses in subgroups revealed BMI > 30 with stable weight to be the most favorable group in terms of survival, while BMI < 25 with > 10% weight loss had the highest mortality risk (HR: 2.63, 95% CI: 2.39-2.89).

Conclusion: Weight loss the year before treatment is associated with increased mortality and higher PSA levels in patients with mCRPC. The effect of weight loss is independent of BMI, where we found that lower BMI is associated with increased mortality and higher PSA levels in patients with mCRPC. This risk increases with the magnitude of weight loss, with lower BMI categories compounding the risk. Both weight loss and BMI should be incorporated into survival models to improve prognostication in mCRPC.

Background: Prostate cancer (PCa) diagnosis is often hindered by the need to detect clinically significant disease (csPCa) while minimizing unnecessary biopsies. The Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI) are promising tools to address these challenges.

Objective: To develop and internally validate a predictive model for PCa and csPCa by combining PHI and mpMRI in a high-risk population.

Methods: This retrospective study included 179 patients who underwent prostate biopsy between 2019 and 2023. Inclusion criteria comprised elevated PSA (> 3 ng/mL), suspicious digital rectal examination and/or family history, PHI values, and pre-biopsy mpMRI. Logistic regression models were developed, and model performance was assessed using C-statistics, calibration plots, and decision curve analysis (DCA).

Results: PCa was diagnosed in 40.2% of patients, and csPCa in 34.7% of them. A multivariate model including PHI, prostate volume, and mpMRI achieved an AUC of 0.81 for PCa. For csPCa, the best model combined PHI and prostate volume (AUC 0.76). In the PI-RADS 3 subgroup, PHI showed high discriminatory performance (AUC 0.81), surpassing PSA density (PSA-D). The DCA showed a superior net benefit of the multivariable models compared to single-parameter strategies.

Conclusion: Integrating PHI and mpMRI improves PCa diagnostic accuracy and clinical decision-making, especially in ambiguous cases such as PI-RADS 3 lesions, and reduces unnecessary biopsies in clinical practice.

Background: Salvage radiotherapy (RT) is a standard treatment for non-metastatic prostate cancer recurrence after radical prostatectomy (RP), yet the efficacy of concurrent hormone therapy remains debated. This systematic review and meta-analysis evaluates the impact of adding hormone therapy to adjuvant or salvage RT on key survival outcomes.

Methods: We searched PubMed, Scopus, Web of Science, and clinical trial registries for randomized phase 2 or 3 trials comparing RT alone versus RT with hormone therapy (anti-androgens or androgen deprivation therapy) in patients undergoing RP. A random-effects meta-analysis with the inverse variance method was performed for overall survival (OS), metastasis-free survival (MFS), and progression-free survival (PFS) after extracting the corresponding hazard ratios (HR) and 95% confidence intervals (CI).

Results: Four trials with generally low risk of bias were identified. Pooled HRs were 0.85 (95% CI: 0.72-0.99) for OS, 0.82 (95% CI: 0.70-0.96) for MFS, and 0.58 (95% CI: 0.51-0.66) for PFS, favoring hormone therapy. Following a sensitivity analysis that excluded the results of one of the four trials, the significance for OS was no longer observed.

Conclusion: Hormone therapy with post-RP RT significantly improves OS, MFS, and PFS in prostate cancer patients. Although the benefit in OS appears less robust, these findings support the significant role of hormone therapy in delaying disease progression. PROSPERO Registration Number: CRD42024597336.

Background: Cuproptosis holds significant potential for optimizing cancer therapeutic strategies. However, the molecular mechanism by which lipoic acid synthase (LIAS) regulates cuproptosis in prostate cancer (PC) remains unclear.

Methods: The GEPIA online tool and PC cell lines were used to analyze the expression of LIAS in PC. Cuproptosis characteristics were assessed using Cu²⁺ detection kits, Western blot (LIAS/FDX1), and immunofluorescence (DLAT oligomerization). Cell viability and proliferation capacity were determined by CCK-8 and colony formation assays. qPCR was used to detect p53 pathway gene expression. Glycolytic activity was analyzed by measuring extracellular acidification rate (ECAR), glucose uptake, and ATP levels. The regulatory relationship was validated using glycolytic inhibitors within the cuproptosis model.

Results: LIAS expression was significantly downregulated in both PC and cuproptosis models. Overexpression of LIAS enhanced cuproptosis effects and suppressed the viability and proliferative capacity of cancer cells. Further analysis revealed that LIAS suppressed glycolysis by activating the p53 pathway, manifested by decreased extracellular acidification rate (ECAR), reduced glucose uptake, and diminished ATP levels. Notably, inhibition of glycolysis promoted cuproptosis, thereby impeding tumor progression.

Conclusion: LIAS promotes cuproptosis and inhibits cancer cell proliferation in PC by activating the p53 signaling pathway to suppress glycolytic activity. These findings indicate that LIAS represents a potential therapeutic target for intervening in PC, and regulation of the glycolysis-cuproptosis axis may serve as an effective strategy for improving PC progression.

Purpose: As the incidence of prostate cancer rises in Asian countries, notable disparities in life expectancy, economic status, and education levels are observed. This study aimed to use the Human Development Index (HDI), which reflects these factors, to explore differences in prostate cancer diagnosis, staging, and initial treatment across various Asian nations and areas, and uncover the impact of socioeconomic factors on patient outcomes.

Methods: We analyzed patients diagnosed with prostate cancer between January 2016 and December 2018 who were enrolled in the Asian Prostate Cancer Study Group (A-CaP). Patients were grouped into three HDI categories (medium, high, very high). A statistical comparison was conducted to evaluate differences in diagnostic methods and initial treatments across 12 Asian countries and areas based on HDI classification.

Results: In total, 35,776 prostate cancer patients were included. Patients in the very high HDI group had lower PSA levels, fewer ISUP Grade 5 cases, and reduced metastatic disease (M1) compared to the other groups. Advanced diagnostic modalities (e.g., CT, MRI, and bone scintigraphy) were more commonly used in the very high HDI group. Imaging modalities were less frequently used in medium HDI countries with low PSA, and in high HDI countries with high PSA. Regarding treatment, patients in very high HDI countries and areas were more likely to receive radiation therapy or active surveillance. Surgical treatment was more common for metastatic patients in high and medium HDI countries and areas.

Conclusion: This study highlights significant differences in prostate cancer management across 12 Asian countries and areas, emphasizing the influence of HDI on diagnostic and treatment outcomes.

Background: EAU guidelines recommend salvage radical prostatectomy (sRP) only in highly selected patients with recurrent prostate cancer in experienced centers.

Methods: The Junior ERUS/Young Academic Urologist Working Group on Robot-Assisted Surgery conducted a multicentric project to investigate biochemical recurrence-free (BCR), metastases-free (MFS), and overall survival (OS) outcomes in robotic sRP patients stratified according to EAU criteria.

Results: Of 180 patients, 49% fulfilled EAU criteria. Patients not fulfilling EAU criteria more frequently underwent focal therapy as primary treatment (53% vs. 33%) and exhibited significantly higher rates of pT3-4 (70% vs. 48%), positive surgical margins (48% vs. 24%), and pathological Gleason score 8-10 (72% vs. 48%, all p < 0.01), with no differences in postoperative complications. Rates of PSA persistence were significantly higher in patients not fulfilling EAU criteria (16% vs. 0%, p < 0.001). Regarding BCR, patients not fulfilling EAU criteria harbored significantly worse BCR-free survival (hazard ratio (HR): 1.96, p = 0.046) with 24- and 48-month BCR-free survival rates of 81.7% and 73.9% vs. 65.0% and 58.5% for patients fulfilling EAU criteria. After multivariable adjustment, patients not fulfilling EAU criteria harbored higher risk of BCR (HR: 2.94, p = 0.045). Regarding MFS and OS outcomes, no significant differences were observed in the comparison between both groups. Incorporating presalvage surgery features into a new classification yielded better discrimination for BCR analysis, but were comparable to EAU criteria for MFS and OS outcomes.

Conclusions: The majority of patients do not fulfill EAU criteria, and even more so after focal therapy. These patients harbor worse BCR rates after robotic sRP. However, within our short-term follow-up, no differences in MFS and OS were observed.

Objective: Androgen deprivation therapy (ADT) was the frontline treatment for patients with prostate cancer ineligible for radical prostatectomy. However, the development of resistance to ADT significantly limits its clinical efficacy.

Methods: Using a genome-wide CRISPR/Cas9 knockout (GeCKO) library screen combined with single-cell RNA sequencing (scRNA-seq) analysis, we identified key genes involved in ADT resistance.

Results: Macrophage migration inhibitory factor (MIF) was identified as a critical mediator of ADT resistance. Inhibition of MIF significantly overcomes ADT resistance. Moreover, we found that the androgen receptor (AR), but not its splice variant AR-V7, negatively regulates MIF expression. Consequently, inhibition of the AR signaling pathway via ADT results in the upregulation of MIF expression. Elevated expression of MIF promotes prostate cancer cell proliferation by upregulating AMPD2 expression.

Conclusions: Our findings demonstrate that ADT induces MIF upregulation, which in turn drives prostate cancer cell proliferation via upregulating AMPD2 expression, eventually contributing to the development of resistance to ADT.