Masayoshi Nagata

Background: Inflammation-based biomarkers may refine prognostic stratification in patients with metastatic renal cell carcinoma (mRCC). This study evaluated the prognostic value of the pretreatment C-reactive protein-to-albumin ratio (CAR) and systemic immune-inflammation index (SII) in patients with mRCC receiving first-line systemic therapy. Methods: We retrospectively analyzed 117 patients who received first-line systemic therapy between January 2001 and April 2022. Pretreatment CAR and SII were evaluated as readily available blood-based inflammatory biomarkers. Overall survival (OS) was defined as the primary outcome, and progression-free survival (PFS) was defined as the secondary outcome. Exploratory cutoffs were CAR 0.0731 and SII 533.81. Results: High CAR and high SII were independently associated with shorter OS after adjustment for IMDC risk classification and nephrectomy status. The adjusted HRs were 2.36 for high CAR (95% CI, 1.30–4.27; p = 0.005) and 2.58 for high SII (95% CI, 1.42–4.69; p = 0.002). Patients with concurrent elevation of both CAR and SII had the shortest OS compared with those with neither marker elevated (HR, 6.39; 95% CI, 2.76–14.77; p < 0.001). Adding CAR and SII to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) improved the optimism-corrected C-index for OS from 0.641 to 0.733. Conclusions: Pretreatment CAR and SII were associated with OS in patients with mRCC receiving first-line systemic therapy. These readily available biomarkers may help refine OS risk assessment when used alongside established clinical factors, but external validation is required before clinical implementation.

Introduction: Avelumab maintenance therapy was approved in Japan for curatively unresectable urothelial carcinoma (UC) without progression after prior platinum‐based chemotherapy (PBC) based on results from the JAVELIN Bladder 100 phase 3 trial. We report post hoc analyses of post‐marketing surveillance (PMS) data in subgroups defined by age, prior PBC regimen, and best overall response (BOR) to prior PBC. Methods: Patients with curatively unresectable UC who received ≥ 1 dose of avelumab maintenance in Japan between February and December 2021 were evaluated. The primary objective was to evaluate safety based on prespecified adverse drug reactions (ADRs). The secondary objective was to evaluate effectiveness, including time to treatment failure (TTF; discontinuation for any reason) and overall survival (OS). Results: The analysis population included 453 patients. In patients aged ≤ 64 ( n = 75), 65 to 74 ( n = 198), or ≥ 75 ( n = 180) years, prespecified ADRs occurred in 17 (22.7%), 69 (34.9%), and 58 (32.2%); median TTF was 4.8, 4.4, and 4.9 months; and 12‐month OS rates were 77.6%, 82.7%, and 72.6%, respectively. In patients with prior cisplatin + gemcitabine ( n = 267), carboplatin + gemcitabine ( n = 163), or dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin ( n = 9) treatment, prespecified ADRs occurred in 93 (34.8%), 45 (27.6%), and 3 (33.3%); median TTF was 4.6, 4.6, and 5.1 months; and 12‐month OS rates were 79.6%, 73.8%, and 88.9%, respectively. In patients with prior complete response ( n = 47), partial response ( n = 242), or stable disease ( n = 149), prespecified ADRs occurred in 16 (34.0%), 79 (32.6%), and 45 (30.2%); median TTF was 5.2, 4.6, and 4.6 months; and 12‐month OS rates were 89.4%, 76.3%, and 75.8%, respectively. Discussion: In this PMS population, safety and effectiveness were observed with avelumab maintenance therapy across subgroups defined by age, prior PBC regimen, or BOR to prior PBC. Findings support the favorable benefit–risk profile of avelumab maintenance in clinical practice. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR: UMIN 43435)

Background: Robot-assisted partial nephrectomy (RAPN) is a standard approach for localized renal cell carcinoma (RCC), emphasizing renal functional preservation. The Minimum Layer Resection (MLR) method, guided by 3D virtual partial nephrectomy (3DvPN) planning, was developed to balance oncological safety with parenchymal preservation. This study evaluated functional and oncological outcomes of RAPN with MLR and identified predictors of renal functional decline. Methods: We retrospectively analyzed 237 patients (after screening 312 cases) who underwent RAPN between 2012 and 2022 with ≥36-month follow-up. 3DvPN planning was used to guide MLR when feasible; both MLR and non-MLR were available and applied throughout the study period according to predefined indications. The primary endpoint was the percentage of estimated glomerular filtration rate (eGFR) preservation at 36 months; a ≥10% decline was clinically significant. Secondary endpoints included perioperative outcomes, acute kidney injury (AKI), and oncological outcomes such as margin involvement and recurrence. Results: The median age was 60 years, tumor size 29 mm, and warm ischemia time 21 min, with selective or superselective clamping achieved in 62.8% of cases. Postoperative AKI occurred in 25.0% (no patient required dialysis). At 3 years, the median eGFR preservation rate was 84.4%, and 28.5% of patients experienced a ≥10% decline. Independent predictors of short-term decline (14 days) were BMI > 25 kg/m², AKI, and WIT > 25 min, whereas long-term decline (36 months) was associated with tumor size > 30 mm and WIT > 25 min. Margin involvement was 1.7%, recurrence 3.8%, and major complications (Clavien–Dindo ≥IV) occurred in 1.7%. Conclusions: In conclusion, RAPN with the MLR technique under 3DvPN guidance demonstrated favorable perioperative outcomes, acceptable oncologic safety, and good mid-term renal functional preservation (up to 36 months). The approach provides a reproducible surgical strategy that maximizes parenchymal preservation while maintaining negative surgical margins. Prospective multicenter studies with longer follow-up are warranted to confirm long-term durability and to define the role of MLR in routine practice.

Background: This study aimed to develop and evaluate machine learning (ML) models to predict biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP). Methods: We retrospectively analyzed clinical data from 1125 patients who underwent RARP between July 2013 and December 2023. The dataset was divided into a training set (70%) and a testing set (30%) using a stratified sampling strategy. Five ML models were developed using the training set. Model performance was evaluated on the testing set using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 scores. Additionally, model interpretability was assessed using SHapley Additive exPlanations (SHAP) values to determine the contribution of individual features. Results: Among the five ML models, the LightGBM model achieved the best prediction ability with an AUC of 0.881 (95%CI: 0.840–0.922) in the testing set. For model interpretability, SHAP values explained the contribution of individual features to the model, revealing that pathological T stage (pT), positive surgical margin (PSM), prostate-specific antigen (PSA) nadir, initial PSA, systematic prostate biopsy positive rate, seminal vesicle invasion (SVI), pathological International Society of Urological Pathology Grade Group (pGG), and perineural invasion (PI) were the key contributors to the predictive performance. Conclusions: We developed and validated ML models to predict BCR following RARP and identified that the LightGBM model with 8 variables achieved promising performance and demonstrated a high level of clinical applicability.

Objectives: We attempt to assess whether prostate-specific antigen decline rate in the first month (PSADR1M = postoperative PSA in the first month/initial PSA) acts as a predictor for biochemical recurrence (BCR) and to evaluate other preoperative and postoperative variables that may predict BCR following robot-assisted laparoscopic prostatectomy (RARP). Method: Based on the D’Amico risk classification system, 777 patients who underwent RARP for localized prostate cancer were classified into a low/intermediate-risk group (n = 435) and a high-risk group (n = 342). The predictors of BCR were identified by univariate and multivariate logistic regression analyses. The area under the curve (AUC) and optimal cutoff values of PSADR1M were determined by receiver operating characteristic (ROC) analysis. Kaplan–Meier curves for biochemical recurrence-free survival (BRFS) rates were stratified by optimal cutoff values of PSADR1M. Results: Effective predictors of BCR in the entire cohort included pT3 (p < 0.001), pathological Grade Group (pGG3, pGG4+5) compared to pGG1+2 (p < 0.001, p = 0.017), positive surgical margins (PSM) (p < 0.001), seminal vesicle invasion (SVI) (p = 0.006), and PSADR1M ≥ 0.62% (p < 0.001). ROC analysis showed that PSADR1M as a predictor for BCR had an AUC of 0.762 for the whole cohort, and 0.821 for the high-risk group, respectively. The optimal cutoff values of PSADR1M were 0.62% in the whole cohort, and 0.68% in high-risk group. Conclusions: As an effective predictor of BCR, PSADR1M can assess the tumor status of prostate cancer patients intuitively and effectively after RARP, especially in the high-risk group.

PURPOSE: Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes. METHODS: Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients. CONCLUSION: In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.

Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients’ clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers—higher hemoglobin at baseline and achieving negative reversion of CTCs—were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC.

Enzalutamide is a second-generation androgen-receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker after enzalutamide administration. A retrospective subgroup analysis and prognostic survey of 43 patients with mCRPC and bone metastases, treated in Juntendo University-affiliated hospitals from 2015–2022, were conducted. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months post-treatment. Relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with CTCs at baseline. Furthermore, patients showing negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positive continuation. Two biomarkers–higher hemoglobin at baseline and achieving negative-reversion of CTCs–were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in treatment of mCRPC.

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRβ (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.