Urologic Oncology-seminars and Original Investigations最新文献

Introduction: Until recently, the widespread use of genetic markers in prostate cancer (PCa) has been limited by the complexities and cost of genomic data analysis. Artificial intelligence (AI), due to its ability to process large volumes of unstructured data, holds the potential to play a transformative role in the future of medical genetics.

Methods: We conducted a systematic literature review using the Medline citation database and the Google Scholar search engine to evaluate the feasibility of AI applications in PCa diagnostics and disease progression prediction. We selected articles that presented data on the use of AI to identify genetic markers and/or their association with clinical data in patients with confirmed or suspected prostate cancer, without applying any time restriction. In total, 15 articles were included in the final analysis.

Results: Studies investigating the application of AI in prostate cancer diagnosis have demonstrated that machine learning (ML) methods can be effectively used to identify novel cancer-related genes from genetic databases. Additionally, ML algorithms have shown potential in predicting clinical risk in PCa. By analyzing miRNAs, mRNAs, lncRNAs, and patterns of gene upregulation and alteration, AI has been able to predict adverse clinical outcomes such as metastatic progression, biochemical recurrence following radical prostatectomy, reduced survival, and elevated serum PSA levels. Moreover, AI tools have been utilized to predict genitourinary complications after radiation therapy through genome-wide data analysis, to identify cell line phenotypes resistant to antiandrogen therapy and to detect novel signaling pathways that may be targeted by emerging systemic treatments.

Conclusion: AI-based methods appear to be promising tools for the identification of new genetic biomarkers in PCa, offering potential for improvements in disease detection, prognosis, and prediction of treatment response, including the identification of actionable therapeutic targets. However, their clinical implementation remains limited due to a lack of clinical validation and practical benefit uncertainties.

Introduction: The human telomerase reverse transcriptase (hTERT) upregulation is a common feature in many cancers. While telomerase activity is often linked to gene expression, the relationship between promoter methylation and hTERT levels can be complex. This study aimed to investigate the association between hTERT promoter hypermethylation and its expression for prognosis and pathogenesis of bladder cancer.

Methods: A total of 50 histologically confirmed bladder cancer tissue samples and matched adjacent normal controls were evaluated in a single-center prospective study. Promoter methylation was assessed by methylation-specific PCR (MS-PCR) targeting the CpG-rich hTERT promoter region, while protein expression was analyzed by immunohistochemistry using standardized scoring criteria. For validation, TCGA-BLCA data were analyzed for TERT mRNA expression, promoter methylation (TSS1500 and gene body regions), copy-number alterations (CNA), and survival outcomes. Correlation analyses and Kaplan-Meier plots were used for integrative assessment.

Results: Promoter hypermethylation of hTERT was detected in 90% of bladder cancers, with 80% showing high hTERT protein expression. A strong positive association between promoter hypermethylation and high protein expression was observed (P = 0.04). This was corroborated by TCGA data showing a significant upregulation of TERT mRNA in bladder tumors. The expression of hTERT was at its strongest at stage IV, though this trend was not significant in the larger TCGA cohort (P = 0.256) The large-scale survival analysis revealed no significant association between TERT expression with OS (P = 0.76), PFS (0.95), DFS (P = 0.88) and pan-cancer analysis. TERT amplification was linked to markedly higher expression levels, but weak correlation between methylation and expression at selected CpG loci and methylation at TSS1500 or gene body regions and expression CONCLUSION: Our findings demonstrate that hTERT promoter hypermethylation is paradoxically associated with increased protein expression in bladder cancer, possibly through disruption of repressor binding within the THOR region. Although hTERT expression lacks prognostic value, its consistent upregulation suggests potential use as a screening biomarker and supports exploration of telomerase-targeted therapeutic strategies.

Background: Germline genetic testing and genetic counseling have become integral aspects of prostate cancer management. In 2018, the National Comprehensive Cancer Network (NCCN) broadened testing recommendations to identify more at-risk individuals based on tumor characteristics and family cancer history. We assessed genetic counseling referrals and outcomes in relation to this expansion in a large safety-net population.

Methods: We analyzed cases of prostate adenocarcinoma diagnosed in 2016 to 2023 at JPS Health Network (JPS), a safety-net provider in Texas. Demographic and clinical data including genetic counseling referrals and testing results were obtained from cancer registries and electronic health records. Statistical analysis was performed using logistic regression model.

Results: Among 543 patients, 46% were Black, 27% were Hispanic, and 40% had metastatic disease. Overall, 132 patients (24%) were referred for genetic counseling, of whom 102 (77%) completed the visits. Rates of referrals increased from 4% in 2017 to 9% in 2019 to 28% in 2023. A multivariate logistic regression determined that patients with stage 3 or 4 cancers were more likely than stage 1 to be referred (P = 0.02 and P < 0.01 respectively). Genetic testing was completed for 78 patients (76%) with 8 (10%) having 9 positive results in BRCA1 (n = 1), BRCA2 (n = 1), CHEK2 (n = 3), MSH2 (n = 2), PALB2 (n = 1), and PMS2 (n = 1).

Conclusion: Following guideline changes, genetic testing referrals for patients with prostate cancer increased approximately 7-fold in a safety-net setting. Over three-fourths of referred patients completed testing and 10% had positive results, demonstrating the feasibility and importance of genetic testing in underserved populations.

Background and objective: The preferred management of clinical stage I (CS1) germ cell tumor (GCT) is surveillance. Standard surveillance imaging protocols expose young patients to potential radiation-related consequences and have financial implications. We evaluated the safety of omitting routine pelvic imaging.

Methods: Patients with CS1 GCT electing surveillance at 3 major referral centers were included. "Pelvis only" recurrence was defined as those detectable solely on pelvic imaging below the bifurcation of common iliac vessels. Any inguinal recurrence detected on pelvic imaging was considered an "inguinal recurrence." Standard surveillance imaging protocols were used to estimate radiation dose reduction and cost saving per patient.

Results: A total of 285 patients were included. Forty-three patients (15%) had pelvic/inguinal nodal recurrence and 16/43 (37%) were detectable by imaging alone. However, in 11/16 (69%), pelvic/inguinal nodal disease was either visible on CT abdomen cuts (3) or there was simultaneous retroperitoneal recurrence (8). Only 5/285 (1.7%) patients had pelvis/inguinal recurrence only detectable on CT pelvis. Only 3/220 (1.3%) patients with no prior cryptorchidism or inguinal/scrotal surgery had pelvis only recurrence. The estimated reduction in radiation dose ranged between 2.31 and 3.46 mSv over 5 years with cost savings of 700 to 800 USD per patient. A limitation of the study includes variability in imaging protocols amongst the centers.

Conclusion: Isolated pelvic/inguinal recurrence in CS1 GCT is rare and routine pelvic imaging appears to have limited value. Omitting CT pelvis could also reduce radiation exposure and offers cost-saving.

Background: Our aim was to examine a diverse patient population to identify any sociodemographic factors, specifically lack of health care coverage, that may worsen aggressiveness of disease on presentation and negatively impact outcomes in testicular germ cell tumors (TGCT).

Methods: Patients who were diagnosed and treated for TGCT at both a SNH (Safety-Net Hospital) and TCH (Tertiary Care Hospital) covered by the same institution and physicians were retrospectively reviewed to assess any disparities in outcomes. We evaluated whether insurance coverage affected the severity of disease on presentation based on International Germ Cell Collaborative Group (IGCCCG) prognostic classification.

Results: Between January 2009 and December 2020, 144 patients were considered underinsured compared to 82 patients that were fully insured. Underinsured patients were more likely to be treated at SNH (85.4% vs. 7.3% P < 0.01), more likely to be Hispanic (73.6% vs. 17.1%, P < 0.01) and more likely to present with advanced disease (P = 0.01). IGCCG risk at presentation was worse for underinsured vs. insured including 19 patients (23.8%) vs. 3 patients (8.1%) with intermediate risk disease and 22 patients (27.5%) vs. 5 patients (13.5%) with poor risk disease (P < 0.01). Although recurrence after first line chemotherapy was similar between underinsured and insured (P = 0.38), the CSS outcomes were worse in those patients without insurance (P = 0.02). Patients with worse presentation of disease (IGCCCG risk group) also demonstrated worse CSS outcomes (P < 0.01).

Conclusions: Insurance status can be associated with a worse prognostic disease presentation of TGCT and may have implications on treatment options and survival. These findings underscore the necessity of community outreach and educational interventions targeting populations in SNHs to improve earlier access to care or increase availability of salvage options in rare cases to mitigate these disparities.

Background: Doublet therapy of androgen deprivation therapy (ADT) with androgen receptor signaling inhibitor (ARSI) or triplet therapy of ADT with docetaxel and ARSI represent possible treatment options in patients with metastatic castration-sensitive prostate cancer (mCSCaP). However, real-world data comparing these 2 treatments are lacking. Our objective was to compare prostate-specific antigen (PSA) kinetics between doublet and triplet therapy in patients with mCSCaP.

Methods: We retrospectively analyzed systemic treatment-naïve mCSCaP patients treated in Japan between 2018 and 2024. The patients received either doublet or triplet therapy. PSA nadir (≤ 0.02 ng/ml) and PSA response rates (≥ 90%, ≥ 99% reduction from baseline at 3 months) were assessed. Propensity score matching (2:1 ratio) was used to balance patient characteristics.

Results: After matching 768 patients with mCSCaP, 188 patients were included in the doublet and 94 in the triplet therapy groups. At 12 months, the proportion of patients achieving PSA ≤ 0.02 ng/ml was significantly higher in the triplet group than in the doublet group (P < 0.05), particularly among those with high-volume disease. PSA response ≥ 99% at 3 months was comparable between the 2 groups (P = 0.08). Treatment related adverse events (TRAEs) of grade ≥ 3 were more frequent with triplet therapy.

Conclusions: Triplet therapy may offer superior PSA decline in patients with high-volume disease, however, this benefit comes at the cost of increased toxicity. Treatment choice should consider disease volume and patient tolerability.

Background: The relative clinical value of disitamab vedotin (RC48) monotherapy versus its combination with a programmed cell death protein 1 (PD-1) inhibitor remains unclear in previously treated patients with locally advanced or metastatic urothelial carcinoma (LA/mUC). Identifying patients who truly benefit from immunotherapy intensification is therefore critical to guide personalized treatment and avoid overtreatment.

Patients and methods: We conducted a retrospective analysis to compare the clinical outcomes of RC48 monotherapy versus its combination with a PD-1 inhibitor in pretreated patients with LA/mUC. To address potential confounders, multiple imputation and inverse probability of treatment weighting (IPTW) were employed. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety assessment.

Results: The median follow-up for the 195 patients was 10.3 months. No significant difference in OS was observed between combination therapy and monotherapy (median OS, 16.7 vs. 22.0 months; HR 1.09; 95% confidence intervals [95% CI], 0.67-1.78; P = 0.73). PFS, ORR, and DCR did not differ significantly between groups. In exploratory analyses, patients with HER2-positive and PD-L1-negative tumors showed improved outcomes with combination therapy (OS HR 0.28; 95% CI, 0.09-0.86; P = 0.03; PFS HR 0.46; 95% CI, 0.24-0.89; P = 0.02). PFS benefit was also observed in those with nondivergently differentiated histology (HR 0.66; 95% CI, 0.44-0.98; P = 0.04).

Conclusion: While RC48 combined with a PD-1 inhibitor did not confer survival advantage in the overall population, patients with HER2-positive and PD-L1-negative tumors, as well as those without divergent histologic differentiation, may derive additional benefit from combination therapy. Safety findings were consistent with prior experience.