髙原 健

Few studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO-IO and IO-tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoint was objective response rate. Efficacy was compared between IO-IO and IO-TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO-IO and IO-TKI. In bone metastases (n = 80), OS tended to favor IO-TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO-TKI (P = 0.011). IO-TKI may be a more appropriate first-line option than IO-IO for mRCC with bone or liver metastases, while efficacy is similar for other sites.

BASCKGROUND: Immune checkpoint inhibitor (ICI)-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC). Proton-pump inhibitors (PPIs), frequently used to treat gastrointestinal conditions, have been implicated in modulating ICI efficacy, potentially through gut microbiome dysbiosis. However, the impact of PPIs on ICI-based therapies for mRCC remains unclear. METHODS: This multicenter retrospective cohort study analyzed 427 patients with mRCC classified as intermediate or poor risk according to the IMDC criteria treated with first-line IO-IO (ipilimumab plus nivolumab) or IO-TKI (ICI plus tyrosine kinase inhibitor) therapies. Patients were stratified by PPI use during the 30 days before and including the day of ICI initiation. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between PPI users and nonusers. RESULTS: PPI use was significantly associated with shorter OS in patients receiving IO-IO therapy (median OS, 23.34 months vs. not reached; P = .002), but not in those receiving IO-TKI therapy (P = .909). Multivariate analysis confirmed PPIs as an independent prognostic factor for OS in the IO-IO group (HR, 1.647; 95% CI, 1.007-2.693; P = .046). No significant differences in PFS or ORR were observed between PPI users and nonusers in either group, although the complete response rate was notably lower in PPI users treated with IO-IO (1.6% vs. 10.3%; P = .025). CONCLUSIONS: PPI use was associated with inferior survival in mRCC patients receiving IO-IO therapy, potentially through microbiome modulation and other immunologic or clinical mechanisms; however, these findings are based on retrospective data and should be regarded as hypothesis-generating. Caution is advised when prescribing PPIs to patients undergoing ICI-based therapy, particularly IO-IO regimens, and prospective studies are needed to confirm whether avoiding unnecessary PPI use can improve clinical outcomes.

OBJECTIVES: Evidence on upfront androgen receptor signaling inhibitor (ARSI) plus androgen deprivation therapy (ADT) in the older population with metastatic castration-sensitive prostate cancer (mCSPC) is scarce. We aimed to compare the oncological outcomes of ARSI plus ADT (upfront doublet therapy) and conventional ADT in mCSPC patients aged ≥ 75 years in a real-world clinical practice. METHODS: Subjects were mCSPC patients aged ≥ 75 years who received upfront doublet therapy (upfront doublet group) or ADT, either alone or in combination with bicalutamide (conventional ADT group) as a first-line systemic therapy. Castration-resistant prostate cancer-free survival (CRPC-FS), overall survival (OS), and cancer-specific survival (CSS) were analyzed. Propensity score matching (PSM) was used to adjust the clinicopathological features. RESULTS: After PSM, a total of 200 mCSPC patients, 100 in the upfront doublet group and 100 in the conventional ADT group, were included. In the PSM population, median CRPC-FS was 30.8 months in the upfront doublet group and 12.1 months in the conventional ADT group (p < 0.05). Median OS was N.A. in the upfront doublet group and 45.2 months in the conventional ADT group (p < 0.05). Median CSS was also statistically different between the two groups (N.A. vs. 61.6 months; p < 0.05). In subgroup analyses, the upfront doublet group showed improved oncological outcomes in high-volume disease compared with the conventional ADT group, but not in low-volume disease. CONCLUSIONS: The oncological benefits of upfront doublet therapy are not diminished in mCSPC patients, even in the older population; but these benefits are limited when restricted to low-volume disease.

OBJECTIVES: We aimed to evaluate overall survival (OS) and determine the optimal timing of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI)-based therapy. METHODS: This retrospective study reviewed medical records of 447 patients with mRCC treated with ICI at multiple Japanese institutions between January 2018 and August 2023. From this cohort, 178 patients with lymph node or distant metastases received either cytoreductive nephrectomy (CN group; n = 72) or ICI therapy without cytoreductive nephrectomy (non-CN group; n = 106) as first-line treatment. RESULTS: Median progression-free survival was 15.7 months, and median overall survival was 58.1 months. CN significantly improved OS, with the CN group's median OS not reached, compared to 29.6 months in the non-CN group (p = 0.01). Deferred CN also showed improved survival outcomes. Poor prognostic factors for immediate CN included International Metastatic Renal Cell Carcinoma Database Consortium poor risk, sarcomatoid differentiation, and a high neutrophil-to-lymphocyte ratio. CONCLUSIONS: We developed a prognostic model to guide patient selection for CN, emphasizing the need for personalized treatment strategies.

BACKGROUND: Despite durable benefits of ipilimumab and nivolumab in metastatic renal cell carcinoma (mRCC), early progressive disease (PD), defined as disease progression within 3 months, occurs, and its predictors remain unclear. We aimed to investigate the clinical factors associated with early PD in patients with mRCC treated with this regimen. METHODS: A retrospective analysis of a multi-institutional database identified 193 patients with mRCC treated with ipilimumab plus nivolumab. Logistic regression analyses assessed associations between clinical factors and early PD. RESULTS: During a median follow-up of 17 months, patients had median overall (OS) and progression-free survival (PFS) of 35 and 14 months, respectively. Objective response and PD rates were 49.9% and 24.9%, respectively. Patients with early PD had significantly worse OS than those with non-early PD (10 vs. 42 months; P = 0.0002). Multivariate analyses identified bone metastasis and performance status (PS) as independent indicators of early PD (P = 0.03 and 0.01, respectively). Early PD rates varied by metastatic site (lung, 19.3%; bone, 31.2%; brain, 10%; and liver, 30%). Patients with clear-cell RCC had a median OS of 48 months and PFS of 22 months. The identified variables of early PD were consistent across all patient populations evaluated. CONCLUSIONS: Bone metastasis and PS predict early PD in patients with mRCC treated with ipilimumab plus nivolumab, with antitumor effect of the regimen varying by metastatic site. Clarifying the characteristics of early PD may guide clinical decision-making in treatment selection.

OBJECTIVES: We evaluated the association between initial prostate-specific antigen (iPSA) levels and prognosis in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC) and extensive bone metastases treated with androgen receptor signaling inhibitors (ARSI). SUBJECTS AND METHODS: This retrospective study included 276 de novo high-risk mHSPC patients with extensive bone metastases (extent of disease [EOD] score ≥ 2) who received ARSI as first-line therapy. The data were collected from institutions participating in the ULTRA Japan Study group. Patient data were collected from institutions affiliated with the ULTRAJ group. Patients were stratified into quartiles based on iPSA levels, and a cutoff value of 200 ng/mL was used for subgroup analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and Cox proportional hazards regression models. A restricted cubic spline analysis was conducted to evaluate the nonlinear association between iPSA levels and OS. RESULTS: Kaplan-Meier analysis demonstrated significant associations between iPSA quartiles and OS (p = 0.030), with the lowest survival observed in the lowest iPSA group (Q1: < 200 ng/mL). A spline-based analysis suggested an inverted J-shaped association between iPSA and OS, with the lowest hazard ratio observed at 1664 ng/mL. Patients with iPSA < 200 ng/mL exhibited significantly shorter OS than those with higher levels (p = 0.015), while no significant difference in PFS was observed (p = 0.869). CONCLUSIONS: Initial PSA levels were associated with prognosis in high-risk mHSPC with extensive bone metastases. Although patients with relatively low iPSA had significantly shorter OS, those exhibited no significant difference in PFS, suggesting that patients with low iPSA could benefit from ARSI as the 1st line treatment.

OBJECTIVES: Immune checkpoint inhibitor (ICI)-based combination therapies are first-line treatments for locally advanced or metastatic renal cell carcinoma (mRCC). However, second-line treatment efficacy remains uncertain due to limited large randomized trials. This study evaluated real-world oncological outcomes after second-line treatments in patients who received combination ICIs as first-line treatment. METHODS: Among 467 patients who received ICI combination therapy as first-line treatment for mRCC between January 2018 and January 2024, those who received cabozantinib (Cabo) or axitinib (Axi) as second-line treatment were included in this study. The patient characteristics at the initiation of second-line treatment, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Prognostic factors associated with OS after the initiation of second-line treatment were evaluated. RESULTS: The Cabo and Axi groups included 87 and 45 patients, respectively. Median OS and PFS after the initiation of secondary treatment were 32 and 9 months in the Cabo group (p = 0.269), and 33 and 12 months in the Axi group (p = 0.399). Multivariable analysis identified serum C-reactive protein (CRP) ≥ 0.6 mg/dL and estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 at the start of secondary treatment as independent predictors of OS. Stratification by these factors revealed a significant OS difference (p < 0.001). CONCLUSIONS: Oncological outcomes after the initiation of secondary treatment did not differ significantly between the Cabo and Axi groups. An eGFR < 40 mL/min/1.73 m2 and CRP ≥ 0.6 mg/dL at the start of Cabo or Axi treatment were independent OS predictors after secondary treatment.

BACKGROUND: The treatment strategy for urothelial carcinoma has advanced with the development of enfortumab vedotin (EV); however, a comparative analysis of its therapeutic efficacy between upper urinary tract urothelial carcinoma (UTUC) and bladder cancer (BCa) has yet to be established. We aimed to compare the effects of EV after pembrolizumab treatment between the patients with UTUC and BCa. METHODS: We included the patients with advanced UC patients who received EV after pembrolizumab in this retrospective study. We investigated the impact of various clinical variables including age, primary site of disease (UTUC vs. BCa), Liver metastasis, lung metastasis, prior number of regimens before EV treatment, and ECOG PS, which influenced on prognosis and efficacy of EV treatment. RESULTS: A total of 63 male and 23 female patients were included in our study. The number of UTUC and BCa patients were 33 and 53, respectively. The UTUC cohort had a significantly older patient population and a greater incidence of lung metastases compared to the BCa group. The prognosis of UTUC patients were not significantly different from BCa patients. However, UTUC was determined as significant factor to predict better overall response rate than BCa in multiple logistic regression analysis. CONCLUSIONS: UTUC patients showed significantly better response to EV treatment than BCa patients.

BACKGROUND/AIM: Immune-related adverse events (irAEs) are associated with improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immuno-oncology therapy. However, various irAEs occur during such therapy. In this study, we analyzed the association between irAEs and prognosis of patients with mRCC treated with nivolumab and ipilimumab. PATIENTS AND METHODS: We retrospectively collected data from 193 patients with mRCC who were treated with nivolumab and ipilimumab as first-line treatment between September 2018 and February 2023 at multiple institutions. We performed Cox proportional hazards analysis for progression-free (PFS) and overall (OS) survival to identify specific irAEs associated with prognosis. RESULTS: Among the 153 eligible patients (median age=68 years; range=27-86 years, the median PFS was 7.8 months (95% confidence interval=6.0-12.5 months), and the median OS was 34.0 months (95% confidence interval=23.9 months - not reached). The most common irAEs were endocrine disorder (28.8%), rash (18.3%), pulmonary disorder (10.5%), and liver dysfunction (9.8%). In the multivariate analysis, endocrine disorder-related irAEs were identified as prognostic factors for significantly better PFS and OS. Additionally, rash-related irAEs were significant prognostic factors, specifically for better OS (p<0.05). CONCLUSION: Both rash and endocrine disorder-related irAEs were predictors of survival outcomes in patients with mRCC treated with nivolumab and ipilimumab. Optimal management of these irAEs is essential for improving prognosis.

Immune checkpoint inhibitors (ICIs) are a key component of first-line treatment for metastatic renal cell carcinoma (mRCC). However, predicting treatment-related adverse events (TRAEs) remains challenging. This study investigated the utility of eosinophil-related biomarkers as predictors of Common Terminology Criteria for Adverse Events grade ≥ 3 TRAEs in mRCC patients undergoing ICI combination therapy. In this retrospective analysis across 21 hospitals in Japan, we examined 180 patients treated with ICI/ICI therapy and 216 patients treated with ICI/tyrosine kinase inhibitor (TKI) therapy. Grade ≥ 3 TRAEs occurred in 39.4% and 31.9% of patients in the ICI/ICI and ICI/TKI groups, respectively. An elevated eosinophil proportion of ≥ 2.0% (odds ratio [OR]: 2.36; 95% CI [confidence interval] 1.23-4.54, p = 0.01) and a low neutrophil/eosinophil ratio (NER) of ≤ 40.0 (OR: 2.78, 95% CI 1.39-5.53, p = 0.004) were significant predictors of severe TRAEs in the ICI/ICI group. However, no significant associations were found in the ICI/TKI group. These findings may help identify patients who suffer from grade ≥ 3 TRAEs and help determine individualized treatment strategies in patients with mRCC.

The composition of the distal ileum microbiota and the impact of fecal exposure during intracorporeal urinary diversion (ICUD) on gastrointestinal (GI) complications remain unclear. This study included 146 patients with bladder cancer who underwent ICUD without bowel preparation and received only a single day of antibiotic prophylaxis. Fecal samples were collected directly from the distal ileum during surgery, and ascitic fluid was obtained postoperatively from abdominal drains. Among the patients, 129 (88.3%) had minimal microbial growth in ileal feces, while 17 (11.7%) showed significant colonization. The most commonly identified organisms were Streptococcus, Enterococcus, Enterobacter, Klebsiella, and Candida. The incidence of GI complications was significantly higher in patients with positive ileal fecal cultures compared to those with no detectable growth (39.4% vs. 7.7%, P < 0.001), and even more pronounced in patients with positive ascitic cultures (72.5% vs. 11.3%, P < 0.001). Multivariate analysis identified positive ascitic cultures as an independent predictor of GI complications. Additionally, frailty was significantly associated with the presence of microbial growth in ascitic fluid. These findings suggest that, although the distal ileal microbiota is largely suppressed under short-term antibiotic prophylaxis, the presence of intra-abdominal bacteria or fungi is strongly linked to postoperative GI complications, including ileus. Frailty may contribute to microbial dysbiosis and the persistence of intra-abdominal pathogens, particularly Enterococcus and Enterobacter species.

PURPOSE: The purpose of this study is to determine the utility of the CANLPH score as a predictive biomarker for patients with advanced and metastatic renal cell carcinoma (a/mRCC). By validating its prognostic value, this study aims to contribute to more personalized treatment strategies for a/mRCC. METHODS: In a multicenter retrospective study by the JK-FOOT consortium, we analyzed data from 309 a/mRCC patients undergoing ICI-based therapy. The CANLPH score-a composite marker of C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), and platelet to hemoglobin ratio (PHR)-for its prognostic accuracy in predicting cancer-specific survival (CSS). Advanced statistical methods, including receiver operating characteristic (ROC) curve analysis, Cox proportional-hazard regression, and Harrell's concordance index (C-index), were employed to assess its predictive capacity against established factors. RESULTS: The median follow-up period was 17 months, revealing two-year and five-year overall survival rates of 76.8% and 62.4%, respectively, with CSS rates at 78.3% and 66.2%. The CANLPH score well stratified survival outcomes of ICI-based treatment for RCC patients (HR 5.71; P < 0.0001). C-index analysis demonstrated that the CANLPH score had the highest predictive potency for CSS among models, including IMDC score. Multivariate analysis confirmed the CANLPH score (HR, 5.59; P = 0.0007) and Karnofsky performance status (HR, 2.59; P = 0.0032) as independent prognostic factors for CSS. CONCLUSIONS: The CANLPH score emerges as a critical tool in the a/mRCC therapeutic landscape, enabling precise prediction of patient outcomes with ICI-based therapies. Limitations include the retrospective design and the single national cohort. Prospective validation studies are warranted.

OBJECTIVE: This study aimed to establish a robust predictive model for biochemical recurrence (BCR) in patients with prostate cancer who underwent robot-Assisted Radical Prostatectomy. MATERIAL AND METHODS: A cohort of 1700 patients who underwent robot-assisted radical prostatectomy (RARP) for prostate cancer between August 2009 and December 2022 was included. BCR was defined as two consecutive PSA levels exceeding 0.2 ng/mL post-radical prostatectomy. Cox proportional hazards regression identified predictive variables for BCR. Subsequently, pathologic T stage, PSA level, positive surgical margin, extraprostatic extension, and seminal vesicle involvement were retained. A nomogram was constructed using R software to predict BCR. The model was evaluated using the C-index and calibration curves. RESULTS: A total of 161 instances of BCR were observed during a median follow-up of 61.0 months (range, 12-162 months). The 5-year BCR-free survival rate for the cohort was 25 %. Univariate analysis demonstrated significant associations between BCR and PSA, clinical T stage, biopsy Gleason score, D'Amico risk classification, pathologic T stage, pathologic Gleason score, extraprostatic extension, seminal vesicle invasion, and positive surgical margins. Multivariate analysis identified high PSA ≥20 ng/mL (HR: 1.93; p = 0.034), pathologic T stage 3-4 (HR: 1.89; p < 0.001), pathologic Gleason score 8-10 (HR: 5.43; p < 0.001), extraprostatic extension (HR: 1.41; p < 0.001), seminal vesicle involvement (HR: 1.92; p = 0.018), and positive surgical margin (HR: 2.73; p < 0.001) as independent predictors of BCR. The new model exhibited a C-index of 0.743 (95 % confidence interval: 0.741-0.745). CONCLUSION: The developed nomogram accurately predicts the likelihood of BCR-free status within 3 years following RARP. This allows for tailored follow-up strategies, optimizing resource allocation, and holds significant clinical utility, warranting broader implementation and further research.

Prostate cancer (PCa) is one of the most common cancers among men worldwide, and robot-assisted radical prostatectomy (RARP) is a widely used treatment for localized PCa. Achieving pentafecta outcomes, which include continence, potency, cancer control, free surgical margins, and no major complications, is a critical measure of surgical success and long-term prognosis. However, predicting these outcomes remains challenging. In this retrospective, single-center study, we analyzed data from 1,752 patients who underwent RARP for localized prostate adenocarcinoma between August 2009 and April 2023. The pentafecta outcome was achieved in 290 patients (16.6%). Multivariate analysis revealed that bilateral nerve sparing significantly increased the likelihood of achieving the pentafecta outcome (odds ratio 10.36, 95% CI: 5.75-18.66; p < 0.001). Preoperative potency and bilateral nerve sparing were also identified as key predictors. Nomograms were developed using preoperative and postoperative variables, including age, PSA level, biopsy Gleason score, clinical stage, pathological tumor stage, tumor grade, nerve sparing, and preoperative potency. Internal validation of the nomograms was performed using bootstrapping methods, demonstrating robust predictive performance. These nomograms provide valuable tools for personalized surgical planning and patient counseling and may be applicable to broader populations, given the inclusion of universally recognized predictive factors and rigorous validation. This study presents the development and validation of nomograms to predict pentafecta outcomes before and after RARP. These nomograms provide valuable tools for clinicians to estimate the likelihood of achieving postoperative pentafecta outcomes. Incorporating these nomograms into clinical practice may improve patient counseling and shared decision-making.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have improved survival in metastatic renal cell carcinoma (mRCC), with nivolumab (NIVO) plus ipilimumab (IPI) showing benefits in intermediate- and poor-risk patients. Despite first-line efficacy, progression is common, requiring second-line therapies. Tyrosine kinase inhibitors (TKIs) are commonly administered after ICIs; however, the relationship between progression-free survival (PFS) in first- and second-line settings is not well defined. This study examined the correlation of PFS in patients with mRCC treated with ICIs followed by TKIs. PATIENTS AND METHODS: This retrospective multicenter study analyzed 66 patients with mRCC who received NIVO + IPI as first-line therapy and subsequent TKIs between September 2018 and February 2023. Patients were stratified according to the International Metastatic RCC Database Consortium (IMDC) risk classification. RESULTS: Median PFS for second-line TKIs was 6.9 months, and overall survival was 17.7 months. While no significant correlation was observed between first- and second-line PFS in the overall cohort or the IMDC intermediate-risk subgroup, a significant positive correlation was found in the poor-risk group (Spearman's rho=0.677, p=0.002). CONCLUSION: Treatment outcomes in poor-risk patients may exhibit a predictable response pattern across therapy lines, potentially informing personalized treatment strategies.

BACKGROUND/AIM: Cancer-induced pain (CIP) exacerbates patient's quality of life. However, it is unknown whether CIP is associated with survival in urothelial carcinoma (UC) patients treated with enfortumab vedotin (EV). This study retrospectively investigated the prognostic significance of CIP in EV-treated UC patients. PATIENTS AND METHODS: We analyzed clinical data from patients with locally advanced or metastatic UC who received EV treatment, assessing various factors such as age, metastasis site, ECOG Performance Status (PS), and CIP status prior to treatment. CIP was determined based on clinical records cancer-related pain or the use of analgesics for pain management. RESULTS: A total of 114 patients (78 males and 36 females) were included in the study. The group with CIP included significantly higher number of patients with bone metastasis. Progression-free survival of the patients with CIP was not significantly different from those without CIP. However, the patients with CIP showed worse overall survival (OS) than those without CIP. Cox proportional regression analysis showed that CIP, liver metastasis, and ECOG PS were significant predictors of poorer OS. CONCLUSION: CIP before the treatment of EV was a significant predictor of reduced OS in patients with UC. Early management of CIP or initiation of EV therapy before CIP development may improve survival outcomes.

BACKGROUND: Metastatic nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with poor prognosis. The clinical characteristics and prognostic factors of immuno-oncology (IO) combination therapy for nccRCC are not well known. This study analyzed patients with metastatic nccRCC treated with IO combination therapy. METHODS: We retrospectively collected data from 447 patients with metastatic RCC treated with IO-based combination therapy as first-line treatment between September 2018 and July 2023 in a Japanese multicenter study. The primary endpoints were objective response rate, progression-free survival (PFS), and overall survival (OS), comparing groups treated with IO-IO and IO-tyrosine kinase inhibitor (TKI) therapies. RESULTS: Seventy-five patients with metastatic nccRCC were eligible for analysis: 39 were classified into the IO-IO group and 36 into the IO-TKI group. Median PFS was 5.4 months (95% CI: 1.6-9.1) for the IO-IO group and 5.6 (95% CI: 3.4-12.0) for the IO + TKI group. Median OS was 24.2 months (95% CI: 7.5-NA) for the IO-IO group and 23.4 (95% CI: 18.8-NA) for the IO + TKI group, with no significant difference. In univariate analysis, International Metastatic Renal Cell Carcinoma Database Consortium scores, Karnofsky performance status, neutrophil-to-lymphocyte ratio, and the presence of liver metastases were significantly associated with OS, whereas in multivariate analysis, only the presence of liver metastases was significantly associated with OS (P = .035). CONCLUSIONS: There was no significant difference in OS or PFS between IO-IO and IO-TKI combination therapy as first-line treatment for patients with nccRCC. Liver metastasis is a poor prognostic factor for such patients.