Translational andrology and urology最新文献

Background: Olaparib has demonstrated therapeutic potential in treating metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations, especially BRCA2. However, resistance to PARP inhibition remains a significant clinical hurdle. Recent evidence suggests frequent activation of fibroblast growth factor receptor 1 (FGFR1) signaling in mCRPC, yet its impact on DNA repair regulation is poorly understood. This study aimed to investigate whether FGFR1 signaling modulates BRCA2 expression and contributes to PARP inhibitor resistance.

Methods: We performed integrative transcriptomic analyses of multiple mCRPC datasets to examine the correlation between FGFR1 and BRCA2 expression. Functional assays including genetic knockdown, pharmacological inhibition, and overexpression studies were conducted in DU145 and PC3 cells. In vitro and in vivo models were employed to evaluate the impact of FGFR1 modulation on olaparib sensitivity, apoptosis, and proliferation. Gene set enrichment analysis (GSEA) was used to identify FGFR1-associated pathways. Western blotting and pathway inhibition experiments were used to dissect the underlying mechanism.

Results: In this study, integrative transcriptomic analyses of multiple mCRPC datasets revealed a strong positive correlation between FGFR1 and BRCA2 expression. Functional assays in DU145 cells, which exhibit high FGFR1 and BRCA2 levels, demonstrated that genetic knockdown or pharmacological inhibition of FGFR1 (via PD173074) markedly reduced BRCA2 expression. FGFR1 inhibition significantly enhanced olaparib sensitivity by promoting apoptosis and suppressing cell proliferation both in vitro and in vivo. Gene set enrichment analyses stratified by BRCA2 levels converged on MAPK as the predominant FGFR1-downstream pathway linked to BRCA2. Mechanistically, FGFR1 functions as an upstream regulator of BRCA2, contributing to sustained HRR activity and attenuated response to PARP inhibition. Complementarily, transient FGFR1 overexpression in PC3 elevated phosphorylated-ERK and BRCA2, whereas MAPK inhibition blunted phosphorylated-ERK and attenuated BRCA2 induction, supporting an FGFR1-MAPK/ERK-BRCA2 axis.

Conclusions: Together, these data reveal an FGFR1-driven, MAPK-dependent mechanism that sustains BRCA2 and attenuates PARP-inhibitor activity, nominate FGFR1 status as a candidate biomarker of PARP-inhibitor responsiveness, and support biomarker-guided co-targeting of FGFR1 and PARP in BRCA2-dependent mCRPC.

Background and objective: Although devastating complications of the bladder outlet resulting from prostate cancer (PC) treatments are relatively uncommon, they do exist. These complications deteriorate patients' quality of life (QoL), and with the combination of increased incidence of PC and patient longevity after treatment, awareness of adverse outcomes in recent years have increased. This review discusses the incidence, risk factors, diagnostic work-up, and management options for devastated bladder outlet (DBO), resulting from PC treatment complications, requiring urinary diversion (UD).

Methods: A systematic literature search was conducted via OvidSP covering 1946 to present. The selection was limited to English language studies.

Key content and findings: DBO can be a consequence of the treatment of benign conditions, but more frequently from complications of pelvic cancer treatments and especially multimodal PC treatments. Patients with a combination of complications, typically recalcitrant bladder outlet obstruction, urinary incontinence, urinary fistula, and/or severe bladder dysfunction end up in a situation we can call DBO. Initially patients will be offered conservative treatment or reconstruction. However, in the worst circumstances, such as prior radiotherapy, failed reconstruction, DBO with end-stage bladders, or patient's severe comorbidities, reconstruction may neither be realistic nor justified. UD with or without cystectomy may be the best option for these patients. Outcomes and repercussions on QoL vary extensively with management options. Meticulous preoperative diagnostic evaluation and thorough patient counseling are paramount in selecting the right treatment strategy for each individual patient. There are a wide range of UD options including a suprapubic catheter to more sophisticated solutions like augmentation cystoplasty with continent catheterizable channel and many others.

Conclusions: There is a non-negligible risk of DBO after treatment of PC, especially following multimodal treatment. In the worst circumstances, management with UD may be necessary. Possible UD options are discussed.

Background: Erectile dysfunction (ED) has been linked to cardiovascular disease (CVD), but the associations are inconsistent and causal relationships remain unclear. We combined National Health and Nutrition Examination Survey (NHANES) data with Mendelian randomization (MR) to investigate the association and potential causal effects of ED on CVD.

Methods: ED in the NHANES and MR analyses was defined based on questionnaire responses, self-reported diagnosis, physician diagnosis, or use of ED medication. Based on the NHANES survey stratified by erectile status, we performed univariate analysis and logistic regression to assess the association between ED and CVD. Then MR analysis was performed to explore the causal relationship between ED and CVD. Exposure and outcome data were obtained from publicly available large-scale genome-wide association studies (GWAS). Inverse variance weighted (IVW) was used as the primary method to analyze causal relationships. All results are expressed as odds ratio (OR) and 95% confidence interval (CI).

Results: A total of 3,624 participants were included in the observational study according to erectile function status. In the weighted cohort, 36.80% reported some degree of ED, with 12.33% sometimes able to achieve an erection and 6.09% never able to achieve an erection. After fully adjusting for covariates, never able to get and keep an erection was associated with increased risk of stroke (OR: 2.42; 95% CI: 1.20-4.91; P=0.03). MR analysis confirmed a genetic causal association between ED and large artery stroke (OR: 1.06; 95% CI: 1.00-1.11; P<0.05) and small vessel stroke (OR: 1.06; 95% CI: 1.04-1.09; P<0.001).

Conclusions: Evidence from both NHANES and MR confirmed that ED was associated with increased risk of stroke.

Background: Prostate adenocarcinoma (PCa) imposes a significant global health burden. Radiotherapy is a primary local treatment for non-surgically managed patients; however, reliable tools to predict which individuals will derive a survival benefit are lacking. This study aimed to develop a risk stratification model to evaluate survival benefits of radiotherapy in non-surgically treated PCa patients and identify subgroups likely to benefit from radiotherapy.

Methods: Data from 100,155 non-surgically treated PCa patients [2004-2015] were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. All-subsets regression and multivariate Cox regression were used to construct nomograms for overall survival (OS) and cancer-specific survival (CSS), quantifying survival risk and stratifying patients into low- and high-risk groups. Subgroup analyses based on risk stratification were conducted to assess the value of radiotherapy.

Results: In the whole cohort, radiotherapy significantly improved 5-year OS (84.2% vs. 76.6%, P<0.001) and CSS (84.2% vs. 76.6%, P<0.001). After risk stratification, high-risk patients receiving radiotherapy exhibited 10.1% and 10.2% improvements in 5-year OS and CSS, respectively (both P<0.05). In contrast, low-risk patients demonstrated no CSS benefit (P>0.05) and reduced OS [hazard ratio (HR): 1.07, 95% confidence interval (CI): 1.02-1.13, P=0.01] following radiotherapy. In non-metastatic stage patients, the nomograms retained good discrimination and the pattern of radiotherapy benefit was consistent with the main analysis.

Conclusions: The developed nomograms effectively identify patients likely to benefit from radiotherapy. High-risk patients experience significant OS and CSS benefits, while radiotherapy is not recommended for low-risk patients.

Background: Prostate cancer (PCa) is a common malignant tumor in older men, and bone metastasis is its most frequent form. Once bone metastasis occurs, survival drops sharply. The Gleason score is the standard tool for judging how aggressive the cancer is; men with high-risk disease face higher chances of treatment failure and death. Therefore, early detection and prediction of bone metastasis and high Gleason scores by magnetic resonance imaging (MRI) are clinically important. In this study, we analyzed clinical and MRI data from 168 PCa patients to evaluate the role of clinical features and MRI-based radiomics in predicting bone metastasis and high-grade Gleason scores.

Methods: This retrospective study included 168 patients with pathologically confirmed PCa from Zhongshan Hospital of Traditional Chinese Medicine. Clinical and pathological data, as well as MRI images, were collected. Radiomics and clinical features were extracted and divided into training and testing sets using a random ratio. Feature selection was performed using t-tests and least absolute shrinkage and selection operator (LASSO) regression to reduce dimensionality and identify effective features. Machine learning algorithms were constructed based on two datasets: one combining clinical information with radiomics features, and the other using radiomics features alone. Model performance was assessed using metrics such as accuracy, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results: Patients with bone metastasis and high-grade Gleason Scores had significantly higher levels of total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) compared to those without bone metastasis and with low-grade Gleason scores (P<0.05). In the testing set, the best-performing model for predicting bone metastasis was the Extreme Gradient Boosting (XGBoost) model that used clinical features combined with radiomics features, with an AUC of 0.875, which was superior to the AUC of 0.732 for radiomics features alone. For predicting high-grade Gleason scores, the XGBoost model using clinical features combined with radiomics features also performed best, with an AUC of 0.830, outperforming the AUC of 0.778 for radiomics features alone. The most significant clinical feature identified was fPSA, while the most significant radiomics features were log-sigma-5-0-mm-3D_glszm_ZoneEntropy for bone metastasis and wavelet-HLH_gldm_HighGrayLevelEmphasis for high-grade Gleason scores respectively.

Conclusions: We proposed a predictive model that integrated clinical features and radiomics features obtained from prostate MRI, offering a non-invasive and radiation-free approach to predict bone metastasis and high-grade Gleason scores in PCa.

Background: In female patients undergoing cystectomy where orthotopic bladder reconstruction is not an option, urethrectomy is typically performed. Unlike in males, female urethrectomy carries a risk of damaging clitoral structures and nerves, potentially contributing to post-cystectomy sexual dysfunction. This study evaluates overall survival in women undergoing cystectomy with versus without urethrectomy.

Methods: A retrospective review of electronic medical records from 2000 to 2023 was conducted. Radical cystectomy specimens were reviewed for surgical details, tumor characteristics, urethral involvement, and urethrectomy status. Institutional criteria required urethrectomy in patients receiving neobladder reconstruction.

Results: Among 347 women who underwent cystectomy, 298 received urethrectomy and 49 did not. The mean age was 65.4 years. Urethral involvement was present in 15 cases (7%). One patient with a neobladder and positive urethral margin remained disease-free at 5 years. At the last follow-up, 54.2% of patients with urethrectomy and 61.2% without urethrectomy showed no evidence of disease. A total of 76 patients (26.5%) were alive with disease, 62 (20.8%) in the urethrectomy group and 14 (28.6%) in the non-urethrectomy group. Kaplan-Meier analysis showed mean overall survival of 246.9 months with urethrectomy vs. 173.9 months without. Propensity score matching (2:1) included 70 urethrectomy and 35 non-urethrectomy patients. Kaplan-Meier and Cox regression analyses showed no significant survival difference (P=0.07).

Conclusions: Urethra-sparing cystectomy in women may be oncologically safe when no urethral involvement is present and should be considered to preserve sexual function.

Background: Early age at menarche (AAM) has been linked to adverse metabolic trajectories that may influence bladder function, but the association between AAM and overactive bladder (OAB), and the mediating role of body mass index (BMI), remains unclear. This study aimed to examine the association of AAM with OAB risk, quantify BMI mediation, and evaluate causality using Mendelian randomization (MR).

Methods: We analyzed data from 9,647 women in the National Health and Nutrition Examination Survey (NHANES, 2011-2018). OAB was defined by an Overactive Bladder Symptom Score (OABSS) ≥3. Multivariable logistic regression and restricted cubic spline (RCS) analyses evaluated the AAM-OAB relationship, adjusting for demographic, clinical, and lifestyle confounders. Mediation analysis quantified BMI's role. MR analysis, using 156 single-nucleotide polymorphisms (SNPs) from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database, validated causality.

Results: Each one-year increase in AAM was associated with a 5% reduced OAB risk [odds ratio (OR): 0.95, 95% confidence interval (CI): 0.93-0.98, P<0.001]. Compared to the earliest AAM quartile (Q1), Q2 (OR: 0.86, 95% CI: 0.77-0.97, P=0.01) and Q4 (OR: 0.81, 95% CI: 0.70-0.93, P=0.003) showed lower OAB risk. RCS analysis confirmed a linear inverse relationship (P-non-linear =0.107). BMI mediated 30.89% of the AAM-OAB association (indirect effect: -0.004, 95% CI: -0.005 to -0.004, P<2×10-16). MR analysis supported causality (OR: 0.998, 95% CI: 0.996-0.999, P=0.008), with no pleiotropy (MR-Egger intercept P=0.87).

Conclusions: Early AAM increases OAB risk, partially mediated by BMI, with causal evidence from MR. Screening for early AAM and managing weight may reduce OAB risk.

Background: Elderly patients (≥70 years) with bladder cancer undergoing radical cystectomy (RC) represent a vulnerable population with heterogeneous outcomes. Traditional pathological lymph node (pN) staging has limitations. This study evaluated the prognostic value of lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) compared to pN and developed a novel nomogram for this demographic.

Methods: Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database [2004-2015], 1,018 elderly bladder cancer patients post-RC were identified and randomly split into training (n=712) and internal validation (n=306) cohorts. An independent external cohort (n=260) was included. Predictive performance of pN, LNR, and LODDS was assessed using time-dependent area under the curve (AUC) and concordance index (C-index). Prognostic factors were identified via least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression. A nomogram predicting 1-, 3-, and 5-year overall survival (OS) was constructed and validated.

Results: LODDS demonstrated superior prognostic discrimination compared to pN and LNR across all cohorts (training C-index: LODDS 0.602 vs. pN 0.573 vs. LNR 0.579). The final nomogram incorporated race, tumor stage (T stage), metastasis stage (M stage), chemotherapy status, and LODDS. It showed robust performance: training C-index =0.647 [95% confidence interval (CI): 0.622-0.672], internal validation C-index 0.650 (95% CI: 0.611-0.690), and external validation C-index =0.729 (95% CI: 0.687-0.770). Calibration curves indicated strong agreement between predicted and observed survival. LODDS maintained superior stratification within the ≥80-year subgroup. Risk stratification based on the nomogram significantly differentiated survival outcomes (log-rank P<0.001).

Conclusions: LODDS provides enhanced prognostic stratification over pN and LNR in elderly bladder cancer patients post-RC. The developed and validated LODDS-based nomogram offers a practical tool for individualized survival prediction, aiding clinical decision-making in this growing population.

Background: Epididymitis with abscess formation is a rare but clinically significant condition associated with worse prognosis in the course of epididymitis. This study explores the predictive value of haematological parameters in adult patients with epididymitis and abscess formation.

Methods: Adult patients with epididymitis from January 2000 to December 2024 in Hong Kong were identified using the Hong Kong Clinical Data Analysis and Reporting System (CDARS). The patients were divided into two groups: those with epididymitis and those with abscess formation. Their characteristics and haematological parameters were collected and analyzed between the groups.

Results: A total of 4,652 patients were analysed (4,567 with epididymitis and 85 with epididymitis associated with abscess formation). Patients with epididymitis and abscess formation faced significantly higher risks of undergoing epididymectomy or orchiectomy compared to those with epididymitis alone (34/85 versus 65/4,567, P<0.001). Mean platelet volume (MPV) was identified as an independent predictor for epididymitis with abscess formation [odds ratio (OR): 1.886, 95% confidence interval (CI): 1.570-2.267], with a cut-off value of 8.80 fL. When combined with age and diabetes mellitus, the area under the receiver operating characteristic curve (AUC) was 0.828 (95% CI: 0.788-0.868), demonstrating a sensitivity of 68.2% and a specificity of 82.2%.

Conclusions: This study demonstrated that MPV is an independent predictor of epididymitis with abscess formation. Clinicians should pay closer attention to MPV in epididymitis patients who are older and have diabetes mellitus.

Background: Due to the heavy medical workload of medical staff and the complicated procedure of medical science popularization, there are certain difficulties and resistance in medical science popularization. The main objective of this study was to evaluate the feasibility of generative artificial intelligence (AI) models in the medical science popularization of urological diseases.

Methods: ChatGPT 4.0 was used to generate relevant content on the pathogenesis, clinical manifestations, diagnosis and treatment of different urological diseases, and the generated content was evaluated and analyzed in multiple dimensions including scientificity, recency, comprehensiveness, understandability, conciseness and interest. The unreasonable contents of ChatGPT 4.0 were revised. Then all the revised contents were evaluated again from the six dimensions and compared with the initial evaluation.

Results: ChatGPT 4.0 generated content scored high in scientificity, recency, and comprehensiveness, while scoring relatively low in understandability, conciseness, and interest. There was no significant difference in the scores of the generated content in different diseases. There was no significant difference in the scores of pathogenesis, clinical manifestations, diagnosis and treatment. Manual revision could significantly improve the comprehensiveness and conciseness of the generated content.

Conclusions: Generative AI tools such as ChatGPT may assist urologists in popularizing knowledge of urological diseases, and the generated content needs to be manually reviewed to ensure the accuracy and readability of the content.