Masahiro Yashi

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC); however, validating body composition-related biomarkers for their efficacy remains incomplete. We evaluated the association between body composition-related markers and the prognosis of patients with mRCC who received ICI-based first-line therapies. Patients and Methods: We retrospectively investigated 60 patients with mRCC who underwent ICI-based therapy as their first-line treatment between 2019 and 2023. Body composition variables, including skeletal muscle, subcutaneous fat, and visceral fat indices, were calculated using baseline computed tomography scans. Sarcopenia was defined according to sex-specific cut-off values of the skeletal mass index. The associations between body composition indices and objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Patients with sarcopenia had lower ORR and DCR than those without sarcopenia (33.3% vs. 61.1%, p = 0.0436 and 52.4% vs. 94.4%, p = 0.0024, respectively). Patients with sarcopenia had a significantly shorter median PFS (14 months vs. not reached, p = 0.0020) and OS (21 months vs. not reached, p = 0.0023) than patients without sarcopenia did. Sarcopenia was a significant predictor of PFS (hazard ratio [HR], 4.31; 95% confidence interval [CI], 1.65–14.8; p = 0.0018) and OS (HR, 5.44; 95% CI, 1.83–23.4; p = 0.0013) along with poor IMDC risk. No association was found between the subcutaneous, visceral, and total fat indices and the therapeutic effect of ICI-based therapy. Conclusions: Sarcopenia was associated with a lower response and shorter survival rates in patients with mRCC who received first-line ICI-based therapy.

Background: The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration‐resistant prostate cancer (CRPC) progression. The neuromediator, gastrin‐releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin‐releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis‐targeted (ARAT) agents.Methods: One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first‐line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate‐specific antigen (PSA) response and survival estimates.Results: In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: −34.5% vs. low ProGRP: −85.7% p = .033). PSA progression‐free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA‐PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA‐PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003).Conclusions: Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA‐ and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Objectives: To avoid misunderstandings based on the failure to demonstrate oncological benefit from extended pelvic lymph node dissection (PLND) during radical prostatectomy in a recent randomized controlled trial. We evaluated early survival outcome in contemporary patients with limited to high-risk prostate cancer (PCa) using propensity score (PS)-matched analysis.Materials and Methods: Three-hundred and forty-seven patients with high-risk PCa were enrolled. They were determined to have a lymph node (LN) involvement probability of greater than 5%. Biochemical recurrence (BCR)-free survival was compared between two groups divided by adherence with extended template and timeframe related to improving PLND procedure.Results: The mean LN yield was 23.4 and 2.7, and the positive LN rate was 19.3 and 2.0% in the extended PLND and other groups, respectively. In the entire unmatched cohort, the estimated curve was 13.1% superior in 3-year BCR-free survival for the extended PLND group. The PS-matched cohort was converged in each LN yield group to 99 patients, and the difference in the 3-year BCR-free survival widened to 22.2% (hazard ratio 0.46, 95% confidence interval 0.27-0.80; p=0.005). The statistical difference was consistent in standard high-risk PCa, and was a significant trend in very high-risk PCa. In the analysis of two groups divided by timeframe, the difference in the BCR-free survival was a significant trend.Conclusion: The results possibly demonstrate the therapeutic role of extended PLND in high-risk PCa. Statistical demonstration of benefits depends on the quality of extended PLND and whether the study cohort is the optimal composition of cancer risk.

Background: A recent randomized controlled trial failed to demonstrate oncological benefit from extended pelvic lymph node dissection (PLND) during radical prostatectomy, while subgroup analysis suggested a potential benefit in high grade prostate cancer (PCa). We evaluated early survival outcome in contemporary PCa patients using propensity score (PS)-matched analysis.Methods: Three hundred and seventy-eight patients with high-risk PCa were enrolled. They were determined to have a lymph node (LN) involvement probability of greater than 5%. The National Comprehensive Cancer Network classification and Johns Hopkins University criteria were used as risk stratification. Clinical stage was determined by assessing digital rectal examination and multiparametric magnetic resonance imaging. Biochemical recurrence (BCR)-free survival was compared between the two groups divided by the threshold of LN yield, which was set at 15.Results: The mean LN yield was 23.9 and 3.4, and the positive LN rate was 20.1% and 2.0% in the sufficient and insufficient LN yield groups, respectively. In the entire unmatched cohort, the estimated curve was 15.6% superior in 3-year BCR-free survival for sufficient LN yield (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.40-0.94; p=0.025). The PS-matched cohort was converged in each LN yield group to 117 patients, and the difference in the 3-year BCR-free survival widened to 24.8% (HR 0.43, 95% CI 0.26-0.74; p=0.002). In the PS-matched analyses of subgroups, the statistical difference was consistent in both standard high-risk PCa (HR 0.43, 95% CI 0.20-0.93; p=0.033) and very high-risk PCa (HR 0.45, 95% CI 0.21-0.96; p=0.040). Conclusions: Our results possibly demonstrate the therapeutic role of PLND in high-risk PCa. The benefit of PLND depends on the surgeon complying with the extended template and removing a sufficient number of LNs in selected patients with an optimal risk-range.

Many urologic surgeons refer to biopsy core details for decision making in cases of localized prostate cancer (PCa) to determine whether an extended resection and/or lymph node dissection should be performed. Furthermore, recent reports emphasize the predictive value of prostate-specific antigen density (PSAD) for further risk stratification, not only for low-risk PCa, but also for intermediate- and high-risk PCa. This study focused on these parameters and compared respective predictive impact on oncologic outcomes in Japanese PCa patients. Two-hundred and fifty patients with intermediate- and high-risk PCa according to the National Comprehensive Cancer Network (NCCN) classification, that underwent robot-assisted radical prostatectomy at a single institution, and with observation periods of longer than 6 months were enrolled. None of the patients received hormonal treatments including antiandrogens, luteinizing hormone-releasing hormone analogues, or 5-alpha reductase inhibitors preoperatively. PSAD and biopsy core details, including the percentage of positive cores and the maximum percentage of cancer extent in each positive core, were analyzed in association with unfavorable pathologic results of prostatectomy specimens, and further with biochemical recurrence. The cut-off values of potential predictive factors were set through receiver-operating characteristic curve analyses. In the entire cohort, a higher PSAD, the percentage of positive cores, and maximum percentage of cancer extent in each positive core were independently associated with advanced tumor stage ≥ pT3 and an increased index tumor volume > 0.718 ml. NCCN classification showed an association with a tumor stage ≥ pT3 and a Gleason score ≥8, and the attribution of biochemical recurrence was also sustained. In each NCCN risk group, these preoperative factors showed various associations with unfavorable pathological results. In the intermediate-risk group, the percentage of positive cores showed an independent predictive value for biochemical recurrence. In the high-risk group, PSAD showed an independent predictive value. PSAD and biopsy core details have different performance characteristics for the prediction of oncologic outcomes in each NCCN risk group. Despite the need for further confirmation of the results with a larger cohort and longer observation, these factors are important as preoperative predictors in addition to the NCCN classification for a urologic surgeon to choose a surgical strategy.

The relationship between the clinicopathological features and molecular changes associated with standardized uptake value (SUV) determined by Positron emission tomography (PET) with [18F] fluorodeoxyglucose (18F-FDG PET) in human renal cell carcinoma (RCC) has not been elucidated. On the other hand, overactivation of the phosphatidylinositol 3’kinase (PI3K), serine/threonine kinase Akt, and mammalian target of rapamycin (mTOR) pathway has been detected in a variety of human cancers, including RCC. So far, little is known about the relationship between the SUV and these proteins in human RCC. Thus, it is important to study the relevance of SUV with clinicopathological features in human RCCs from a molecular point of view. Seventy-seven consecutive patients with RCC who underwent nephrectomy and pretreatment determination of the maximum SUV (SUVmax) by 18F-FDG PET were analyzed. We investigated the relationship between the SUVmax, phosphorylated-Akt (Ser-473) (pAkt(Ser-473)), phosphorylated-Akt (Thr-308) (pAkt(Thr-308), and phosphorylated-S6 ribosomal protein (Ser-235/236) (pS6) protein levels in the primary tumor and various clinicopathological features. The average SUVmax of the primary tumor was 6.9 (1.5 to 40.3). A higher SUVmax was correlated with higher expression of pAkt(Ser-473), pAkt (Thr-308), and pS6 protein in the primary tumor. A higher SUVmax and increased expression of pAkt (Ser-473), pAkt (Thr-308), and pS6 of the primary tumor was associated with less tumor differentiation, a higher pT stage, regional lymph node involvement, microscopic vascular invasion, and distant metastasis, as well as with early relapse following radical nephrectomy in patients who had localized or locally advanced RCC without distant metastasis (cTanyNanyM0) and with shorter overall survival in all patients. A higher SUVmax on 18F-FDG PET is associated with elevated tumor levels of pAkt and pS6 protein and with aggressive behavior and metastatic potential of RCC, as well as with early relapse following radical nephrectomy and shorter overall survival. These findings suggest that SUVmax may be useful for predicting the biological characteristics of RCC.

Background: Activation of Rho, one of the small GTPases, and its major downstream target Rho-kinase (ROCK) promotes the development and metastasis of cancer. We previously showed that elevation of Rho and ROCK expression was associated with tumor invasion, metastasis, and an unfavorable prognosis in patients with urothelial cancer of the bladder or upper urinary tract. Methods: We investigated the effects of a ROCK inhibitor on the growth, migration, and apoptosis of bladder cancer cells. We also examined phosphorylation of RhoA (RhoA activity) by measuring its GTP-bound active form and assessed the expression of ROCK to explore the underlying molecular mechanisms. Results: Lysophosphatidic acid (LPA) and geranylgeraniol (GGOH) induced an increase of cell proliferation and migration in association with promotion of RhoA activity and upregulation of ROCK expression. The ROCK inhibitor fasudil (HA-1077) suppressed cell proliferation and migration, and also induced apoptosis in a dose-dependent manner. HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity. Conclusions: These findings suggest that ROCK could be a potential molecular target for the treatment of urothelial cancer.