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No practical predictive biomarkers exist to date for the response to androgen receptor-axis targeted (ARAT) therapies in metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether prostate-specific antigen (PSA) kinetics in primary androgen-deprivation therapy for advanced hormone-sensitive prostate cancer may be associated with the response to ARAT agents in mCRPC. This study assessed 102 patients with mCRPC treated with enzalutamide or abiraterone to evaluate the associations between clinical outcomes and PSA kinetics, including the ratio of initial to nadir PSA (I/N PSA) level in primary combined androgen blockade. The PSA response was defined as a ≥50% decrease at 3 months from baseline in patients with mCRPC. In patients treated with enzalutamide, the optimal cut-off I/N PSA value for PSA response was 531 ng/ml (sensitivity=66.7%, specificity=88.2%, area under the curve=0.73, using a receiver operating characteristic curve). The PSA response was 83.3% and 25.0% in the high and low I/N PSA groups, respectively. The median overall survival and radiographic progression-free survival from enzalutamide initiation were longer for the high compared to the low I/N PSA group. Multivariate analysis revealed I/N PSA (hazard ratio=0.275, p=0.026) as an independent risk factor for overall survival in the patients treated with enzalutamide. In contrast, I/N PSA showed no predictive ability for PSA response in patients treated with abiraterone. In patients with mCRPC, I/N PSA can be a practical predictive biomarker for response to the ARAT agent enzalutamide.

We examined the prognostic use of the 3-month prostate-specific antigen (PSA3m) level after androgen-deprivation therapy in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). The present study included 145 patients with mHSPC who received primary androgen-deprivation therapy. The optimal cutoff PSA3m value for prediction of 5-year overall survival was 2.56 ng/ml (area under the receiver operating characteristics curve=0.67) using a time-dependent receiver operating characteristic (survival ROC) curve. In patients with CHAARTED low-volume and LATITUDE low-risk disease, the median overall survival was longer for patients with low PSA3m than that for those with high PSA3m. Multivariate analysis revealed PSA3m (hazard ratio=1.99; p=0.006) and age ≥80 years as independent risk factors for overall survival in patients with mHSPC. PSA3m can be a useful prognostic biomarker to avoid excessive upfront combination therapy, particularly in elderly patients with low-volume and low-risk mHSPC.

We found that FOXO1‐shRNA sublines or FOXO1‐positive cells co–treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p‐FOXO1) in cisplatin‐resistant sublines established by long‐term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle‐invasive bladder cancer undergoing cisplatin‐based neoadjuvant therapy further showed a strong trend to associate between p‐FOXO1 positivity and unfavorable response to chemotherapy.

Background/Aim: No practical biomarkers predict the response to enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). The present study aimed to evaluate the prognostic value of the initial-to-nadir prostate-specific antigen (PSA) ratio (I/N PSA) in primary hormone therapy for metastatic hormone-naïve prostate cancer associated with the response to first-line enzalutamide in mCRPC. Patients and Methods: Twenty-eight patients with mCRPC received first-line enzalutamide to determine the associations between I/N PSA in combined androgen blockade and clinical outcomes. The PSA response was defined as ≥90% decline from baseline in patients with mCRPC. Results: The optimal cutoff I/N PSA value for PSA response was 1,219 (sensitivity=71.4%, specificity=92.9%, area under the receiver operating characteristic curve=0.85). The PSA response was 90.9% in the high I/N PSA group and 23.5% in the low I/N PSA group. The median overall survival, prostate cancer-specific survival, and radiographic progression-free survival after initiation of enzalutamide were statistically greater for the high I/N PSA group than the low group. Multivariable analysis showed that I/N PSA was an independent predictor of overall survival (hazard ratio=0.23; p=0.026). Conclusion: In chemotherapy-naïve patients with mCRPC, I/N PSA was a predictive and prognostic biomarker for first-line enzalutamide. The I/N PSA can enable optimization of individual treatment in real-world clinical practice.

Neuroendocrine prostate cancer (NEPC) is generally an aggressive form of prostate cancer that can arise de novo or develop as a castration-resistant mechanism. While first-line platinum-based chemotherapy is effective against NEPC, its limited response duration and subsequent treatments pose significant clinical challenges. Standard second-line treatments have not been established due to the limited data available. The aim of this review was to reveal the current status of second-line therapy for NEPC. A literature search was conducted using PubMed and Web of Science and a total of 13 articles were included in this review. Prospective and retrospective studies demonstrated that treatment outcome of second-line therapy using platinum with etoposide or docetaxel was unfavorable and progression-free survival was 3 months or shorter. Amrubicin and irinotecan were also frequently used as second-line therapy, however, efficacy of these agents was modest and response duration was less than 6 months. NEPC patients with homologous recombination repair gene alterations may benefit from treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. Ongoing clinical studies investigate various agents, including immune checkpoint inhibitors, molecularly targeted agents, and PARP inhibitors. With the increasing recognition and active biopsy of NEPC lesions, the number of NEPC patients is anticipated to rise. Accumulating more knowledge and experience is crucial in developing novel treatment strategies to combat this disease.

The biological significance of sodium–glucose cotransporter 2 (SGLT2) in clear cell renal cell carcinoma (ccRCC) has yet to be elucidated. In this study, we aimed to determine the role of SGLT2 in ccRCC tumor progression. The human ccRCC line KMRC-1, which contains a von Hippel–Lindau (VHL) gene mutation, was used to assess the effects of the SGLT2 inhibitor (SGLT2i) dapagliflozin on proliferation and migration in media containing different glucose concentrations (25, 12.5, or 5 mM). Dapagliflozin significantly reduced cell proliferation and migration in 25 mM glucose medium. Similarly, SGLT2 knockdown involving short hairpin RNA lentiviral transfection significantly decreased cell viability, migration, and colony formation compared with the control subline in 25 mM glucose medium. Moreover, tumor progression was inhibited in the media with low glucose concentrations. Remarkably, 2 µM dapagliflozin inhibited the progression of ccRCC at concentrations as low as 5 mM (normoglycemic model) glucose medium as well as 25 mM (severe glycemia model) glucose medium. In addition, dapagliflozin treatment significantly enhanced the apoptosis of ccRCC cells. Our findings demonstrate that SGLT2 impacts the progression of ccRCC with the VHL mutation. In light of the above findings, SGLT2is, which exert the dual effects of SGLT2 blockade and glycemic control, may represent a novel therapeutic agent, particularly in patients with ccRCC who suffer from concurrent diabetes mellitus. To the best of our knowledge, this is the first preclinical study demonstrating the impact of SGLT2 inhibition on the progression of ccRCC with the VHL mutation.

Background/Aim: This study retrospectively investigated the impact of enfortumab vedotin (EV) monotherapy on the oncological outcome, safety profile, and health-related quality of life (HRQoL) in patients with metastatic urothelial carcinoma. Patients and Methods: We assessed 26 consecutive patients who had received EV monotherapy after failure of platinum-based chemotherapy and immune checkpoint blockade therapy at our single institution from December 2021 to January 2023. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and EORTC QLQ-C30 as an HRQoL instrument were evaluated. Results: The ORR and DCR were 57.7% and 80.8%, respectively. EV was effective regardless of the patient and tumor characteristics, including the efficacy of previous systemic therapy, performance status, number of Bellmunt risk factors, and presence of variant histology. With a median follow-up time of 7.5 months, the median durations of PFS and OS were 5.4 months and 10.3 months, respectively. Grade ≥3 AEs included neutropenia (15.4%), fatigue (7.7%), appetite loss (7.7%), rash (3.8%), febrile neutropenia (3.8%), hyperglycemia (3.8%), and interstitial pneumonia (3.8%). AEs resulting in withdrawal of EV, interruption of EV, and dose reduction occurred in two (7.7%), nine (34.6%), and 13 patients (50.0%), respectively. The EORTC QLQ-C30 scores from baseline to post-EV introduction remained stable. Conclusion: EV monotherapy demonstrated promising anti-tumor activity and tolerability in patients with metastatic urothelial carcinoma.

This study aimed to clarify the impact of proton pump inhibitors (PPIs) on oncological outcomes in patients who received pembrolizumab for advanced urothelial carcinoma (UC). Forty advanced UC patients treated with pembrolizumab were retrospectively reviewed and divided into two groups (PPI: 15 patients; without PPI: 25 patients). Tumor response and survival were compared between these groups. The factors associated with survival were also investigated. The objective response rate was significantly lower in the group with PPIs compared with the group without PPIs. Both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the group with PPIs than in the group without PPIs. The use of PPIs was a significant predictor of poor PFS and OS in multivariate analysis. The use of PPIs was negatively associated with tumor response and survival in patients with advanced UC treated with pembrolizumab.

This study retrospectively investigated the impact of squamous differentiation on the prognosis of patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). Among the 244 consecutive patients who underwent RNU at our Institution from May 2005 to October 2019, 224 were analysed. Metastasis-free (MFS) and overall (OS) survival rates were evaluated using Kaplan-Meier analysis and Cox regression analysis. With a median follow-up time of 58 months, the groups with pure UTUC (n=197) and UTUC with squamous differentiation (n=27) had 5-year MFS rates of 65.2% and 40.9% (p=0.005) and 5-year OS rates of 74.4% and 49.0% (p=0.002), respectively. Multivariate analyses revealed that the presence of squamous differentiation was significantly associated with poor MFS (hazard ratio=1.88; p=0.027) and OS (hazard ratio=1.70; p=0.048). Squamous differentiation in UTUC appears to be an independent predictor of poor prognosis after RNU for UTUC.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3 . Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.