Prostate最新文献

Background: This study evaluated factors associated with clinical failure and toxicity in patients with low-, intermediate-, and high-risk prostate cancer treated with low-dose-rate brachytherapy (LDR-BT) alone or combined with external beam radiation therapy (EBRT).

Methods: Seven hundred thirteen patients (low risk: n = 323; intermediate-risk: n = 390) underwent LDR-BT alone, whereas 534 patients (intermediate-risk: n = 225; high risk: n = 309) underwent LDR-BT combined with EBRT. The Fine-Gray hazard model was used to identify factors associated with clinical failure, and the Youden index was employed to determine BED cut-off values for Grade 3 or higher toxicity.

Results: In patients treated with LDR-BT alone, BED thresholds of ≥ 180 Gy2 (low-risk; hazard ratio [HR]: 0.38; 95% confidence interval [95% CI], 0.15-0.98, intermediate-risk; HR: 0.29; 95% CI, 0.12-0.70) was significantly associated with better clinical outcomes. Patients with Grade 3 or higher toxicity had significantly higher BEDs than those without toxicity (p = 0.008). A BED threshold of 200 Gy2 was identified as a cut-off value for toxicity risk. In patients treated with LDR-BT combined with EBRT, BED was not significantly associated with improved clinical failure-free rates. Patients experiencing Grade 3 or higher toxicity exhibited significantly higher BEDs than those without toxicity (p = 0.04). A BED cut-off of 220 Gy2 was determined for toxicity.

Conclusion: For patients undergoing LDR-BT alone, a BED of 180-200 Gy2 is optimal. For patients undergoing LDR-BT combined with EBRT, a BED of 200-220 Gy2 may be more appropriate.

Background: The USPSTF recommendation against PSA screening (RAPS) in 2012 resulted in unfavorable changes in prostate cancer (PCa) outcomes. However, the effect on cancer-specific mortality (CSM) in localized PCa has not been assessed.

Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2021), we identified patients treated with radiotherapy (RT) or radical prostatectomy (RP) for localized PCa. Time trends were examined using least-squares linear regression. Multivariable Cox regression was used to study the association between RAPS and PCa-mortality.

Results: Of 270,092 patients aged < 75 years, 191,621 (70.1%) were treated before and 78,471 (29.1%) in the RAPS era. CSM at 6 years of follow-up was 1.6% (95% confidence interval [CI]: 1.6, 1.7) before and 1.9% (95%CI: 1.8, 2.0) in the RAPS era (p < 0.001). In multivariable Cox models adjusted to patient characteristics, RAPS era independently predicted 1.2-fold higher CSM overall (95%CI: 1.1, 1.3; p < 0.001), 1.3-fold higher CSM in RP-patients (95%CI: 1.1, 1.4; p < 0.001), and 1.1-fold higher CSM in RT-patients (95%CI: 1.02, 1.2; p = 0.02) aged < 75 years. Of 33,688 patients aged ≥ 75 years, 12,485 (37.1%) were treated before and 21,203 (62.9%) in the RAPS era. CSM at 6 years of follow-up was 4.2% (95%CI: 3.8, 4.6) before and 4.8% (95%CI: 4.5, 5.1) in the RAPS era (p = 0.002). In multivariable Cox models adjusted to patient characteristics, RAPS era did not predict higher CSM overall, in RP-patients, or in RT-patients (all p ≥ 0.5) aged ≥ 75 years. Limitations include changes in early detection and disease management over time, which might have impacted CSM as well.

Conclusions: The USPSTF RAPS introduction resulted in a 1.2-fold higher CSM in localized PCa patients aged < 75 years, but not in patients aged ≥ 75 years. The time trend analysis suggested that this negative effect has become increasingly pronounced since the USPSTF RAPS.

Background: Long-term cancer control efficacy of robotic-assisted laparoscopic prostatectomy (RALP) in men with pathologically high-risk prostate cancer and prostate-specific antigen (PSA) persistence remains poorly addressed in the literature. Our aim was to evaluate long-term survival and additional treatment (AT) rates in these individuals.

Methods: We included 803 patients who underwent RALP for pathologically high-risk PCa (pT ≥ 3a, pN0-1 or GG ≥ 4) between 2001 and 2022 at a single tertiary referral center (Henry Ford Hospital, Detroit). Patients without adequate information about PSA persistence were excluded from the analysis (n = 128). Kaplan-Meier curves estimated AT free-survival (ATFS) and all-cause mortality (ACM) free-survival, whereas the competing risk method was used to estimate cancer-specific mortality (CSM) free-survival, after stratification according to PSA persistence. Competing risk and Cox regression models tested the impact of PSA persistence on three endpoints: AT rates, CSM, and ACM.

Results: Our final cohort consisted of 675 who underwent RALP for pathologically high-risk PCa, 187 (27.7%) of whom had PSA persistence. The median age at surgery was 64 years (IQR 59-68), and the median follow-up duration was 75 months (IQR 33-125). Patients with PSA persistence were more likely to have higher PSA values at surgery (8 vs. 7 ng/mL, p < 0.001), pT3b-4 PCa (62.5% vs. 39.9%, p < 0.001), pN1 PCa (55.6% vs. 35.7%, p < 0.001), and positive surgical margins (PSMs) (65.2% vs. 43.4%, p < 0.001). Moreover, patients in the PSA persistence group had higher proportion undergoing only hormone therapy (HT) (24.1% vs. 11.9%, p < 0.001) and radiotherapy (RT) plus HT (50.8% vs. 31.1%, p < 0.001), reporting higher median PSA values at RT (0.6 vs. 0.2 ng/mL, p < 0.001), compared to patients with undetectable PSA. At 10 years after RALP, CSM-FS and ACM-FS were 79.7% versus 90.3% (Gray-test p-value = 0.001) and 72.1% versus 79.6% (log-rank p-value = 0.013), for persistent versus undetectable PSA, respectively. The 10-year rates of ATFS were 6.6% versus 33.2% (log-rank p-value < 0.0001), for persistent versus undetectable PSA, respectively. At MVA, persistent PSA was associated with AT (HR: 3.05, p < 0.001), but not with CSM (HR: 1.49, p = 0.2) or ACM (HR: 1.09, p = 0.9).

Conclusion: Patients with pathologically high-risk PCa and PSA persistence after RALP, despite being at greater hazard of AT (HT and/or RT), did not have less favorable cancer control outcomes at 10 years than their counterparts with undetectable PSA levels. Our report provides the longest follow-up after RALP for this subset of patients, making it a valuable resource for counseling patients on the long-term oncologic outcomes of this procedure and postoperative adjuvant/salvage therapies.

Background: To independently assess data for recently reported genes-BIK, SAMHD1, FAM111A, and AOX1-in which rare variants have been associated with prostate cancer (PCa) risk and aggressiveness.

Methods: The study included 4448 PCa cases from Johns Hopkins School of Medicine and 103,221 population-based controls from the Genome Aggregation Database (gnomAD). Gene-based and variant-based association tests were performed within each major ancestry group using Fisher's exact test and Firth logistic regression. Bonferroni-corrected significance thresholds were applied to account for multiple testing.

Results and conclusion: In the NFE population, suggestive statistical evidence of association with PCa risk was found for two of the four genes, BIK and SAMHD1. The evidence was primarily driven by missense variants: BIK S87G and SAMHD1 Q465K and V112I. The effect sizes of these variants were stronger than, or comparable to, those of well-established PCa risk variants such as HOXB13 G84E and CHEK2 T367fs. A weak association signal was observed between AOX1 and PCa aggressiveness. Statistical power was limited for analyses in other ancestry groups, particularly for tests of PCa aggressiveness. Implication of BIK and SAMHD1 as PCa susceptibility genes represents a major breakthrough since the discovery of HOXB13 in 2012 and may have clinical utility for risk stratification and contribute to our understanding of the molecular etiology of PCa.

Purpose: Men with a history of testicular cancer are known to have an increased risk of developing prostate cancer. The objective of this study is to determine if testicular cancer survivors are predisposed to a higher incidence of aggressive prostate cancer later in life and greater risks of mortality.

Materials and methods: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with prostate cancer and either no prior cancer diagnosis or a previous diagnosis (≥ 5 years ago) of either testicular cancer or another cancer with a high survival rate (5-year survival > 70%). Cox regression models were used to determine the risk of mortality.

Results: Of the 392,238 prostate cancer patients, 423 had a history of testicular cancer, 31,428 had a history of another cancer, and 377,975 had no prior history of cancer. The mean ages of prostate cancer diagnosis were 62.53 +/- 8.23 years, 67.95 +/- 8.46 years, and 67.95 +/- 9.47, respectively (p < 0.001). Testicular cancer was associated with earlier mortality on survival analysis in multivariable analysis controlling for age of prostate cancer diagnosis, race, clinical T stage, PSA level at diagnosis, and Gleason score.

Conclusions: A history of testicular cancer may be associated with an increased risk of developing early prostate cancer and increased mortality. Confirmatory studies are warranted.

Background: Genomic instability is a key feature of cancer and plays a central role in tumor progression. One emerging metric for genomic instability is the fraction of genome altered (FGA), which quantifies the proportion of the genome affected by copy number alterations. Previous studies in various solid tumors have shown that high FGA is associated with aggressive disease and adverse clinical outcomes. However, the clinical significance of FGA in prostate cancer (PC) remains unclear. In this study, we investigated the role of FGA as a potential biomarker of tumor aggressiveness and a poor prognosis in PC using several large-scale public databases.

Methods: We analyzed the processed data from previous large-scale PC studies available through the cBioPortal database: MSK CHORD 2024 (n = 3211), MSK 2021 (n = 2069), MSK 2020 mCSPC (n = 424), SU2C/PCF mCRPC (n = 444), and AACR Project GENIE (n = 5306). Associations between FGA and clinical parameters such as T stage, Gleason score (GS), tumor volume, metastatic burden, pathological subtype, and treatment history were evaluated. Kaplan-Meier survival analysis was used to assess the prognostic value of FGA.

Results: High FGA was significantly associated with aggressive clinical features, including higher T stage, GS, metastatic burden, and neuroendocrine prostate cancer histology. FGA increased after most therapeutic interventions. Patients with high FGA had significantly poorer overall survival across nearly all treatment modalities. An oncoplot analysis revealed a higher frequency of somatic alterations in key driver genes, including AR, PTEN, and TP53, in high-FGA tumors.

Conclusions: FGA was closely associated with tumor aggressiveness, therapy-induced genomic instability, and a poor prognosis in PC. It may serve as a clinically relevant biomarker across diverse treatment contexts.

Background: Resistance to 5α-reductase inhibitors (5ARIs) represents a significant therapeutic challenge in benign prostatic hyperplasia (BPH) clinical management. While the c-Kit-mediated signaling has been implicated in various pathological conditions, its role in BPH and 5ARI resistance remains undefined.

Methods: Patient-derived organoids (PDOs) were established from BPH specimens and characterized through immunofluorescence, immunohistochemistry, and RT-qPCR analysis. Transcriptomic profiling was performed to identify differentially expressed genes between 5ARI-sensitive and resistant samples. The functional significance of c-Kit-mediated signaling was evaluated using selective inhibitor ISCK03. Further analysis identified cellular targets of c-Kit inhibition, and downstream signaling mechanisms were characterized through pathway analysis.

Results: RNA sequencing revealed differentially expressed genes between 5ARI-sensitive and resistant BPH PDOs, with significant enrichment in KIT and related genes. Enhanced c-Kit expression was confirmed in 5ARI-resistant specimens through multiple methodologies. Selective c-Kit inhibition with ISCK03 specifically suppressed 5ARI-resistant PDOs proliferation while sparing sensitive ones. Tests utilizing single-cell-derived organoids identified basal epithelial cells as primary targets of c-Kit inhibition. Mechanistic studies demonstrated that c-Kit maintains 5ARI resistance through the PI3K/AKT and Wnt/β-catenin signaling axis, with c-Kit inhibition significantly downregulating this pathway.

Conclusions: c-Kit-mediated signaling is associated with 5ARI resistance in BPH, potentially through modulation of PI3K/AKT and Wnt/β-catenin pathways. These findings highlight c-Kit as a potential therapeutic target for overcoming 5ARI resistance.