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OBJECTIVES: The glucocorticoid receptor beta (GRβ) not only inhibits the function of the glucocorticoid receptor but also possesses unique transcriptional activity. Whereas the role of GRβ varies among different cancer types, its significance in bladder cancer remains unclear. This study aimed to investigate the clinical significance of GRβ expression in bladder cancer. METHODS: Immunohistochemical analysis was performed on tissue samples obtained from 106 patients who underwent surgery for bladder cancer. The immunoreactivity of GRβ was evaluated using the labeling index (0%-100%). The association between GRβ expression and clinical parameters obtained from medical records was analyzed. RESULTS: GRβ expression was significantly lower in muscle-invasive bladder cancer (≥ pT2) compared with non-muscle-invasive cases (≤ pT1) (p = 0.0177). Furthermore, patients who experienced intravesical recurrence after surgery exhibited significantly lower GRβ expression (p = 0.0179). CONCLUSIONS: These findings suggest that GRβ may serve as a potential biomarker for predicting the progression and recurrence of bladder cancer.

DOI： 10.1111/iju.70254

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INTRODUCTION: This study aimed to investigate the real-world usage patterns and persistence rates of mirabegron and vibegron in the treatment of overactive bladder (OAB). METHODS: A retrospective review was conducted on patients who received either mirabegron or vibegron as their initial treatment for OAB between August 2022 and December 2024. Two types of persistence rates were assessed: (1) the individual persistence for each drug (persistence rate I) and (2) the overall β3-adrenergic agonist persistence among patients who switched between mirabegron and vibegron (persistence rate II). RESULTS: In total, 192 patients were included, with 128 (66.7%) receiving mirabegron and 64 (33.3%) receiving vibegron. Mirabegron was more commonly prescribed to male patients. The median persistence rate I was 11 months for mirabegron (95% CI, 6-16) and was not reached for vibegron (95% CI, 9 months to not estimable) (p = 0.071). Among those who discontinued treatment, 40.7% of mirabegron users and 17.6% of vibegron users switched to the alternative β3 agonist. The median persistence rate II was 16 months for mirabegron (95% CI, 8-20) and not reached for vibegron (95% CI, 9 months to not estimable) (p = 0.352). CONCLUSION: The higher discontinuation rate of mirabegron may reflect the availability of vibegron as an alternative treatment option. The complementary use of both β3 agonists could play a key role in optimizing OAB management.

DOI： 10.1111/iju.70309

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BACKGROUND/AIM: The impact of neoadjuvant chemohormonal therapy (NCHT) on biochemical recurrence-free survival (BRFS) in patients with very-high risk localized prostate cancer remains uncertain, particularly because previous studies have included heterogeneous populations with locally advanced disease. This retrospective study evaluated the clinical significance of NCHT in patients with strictly defined T2-T3a very-high risk disease. PATIENTS AND METHODS: A total of 49 patients treated between 2017 and 2024 were analyzed; 25 received NCHT consisting of androgen deprivation therapy and estramustine phosphate, while 24 underwent radical prostatectomy without NCHT. All patients received robot-assisted radical prostatectomy with extended lymph node dissection. RESULTS: Baseline characteristics and pathological outcomes were comparable between the two groups, with a median follow-up period of 19 months in the NCHT group and 29 months in the non-NCHT group. Kaplan-Meier analysis demonstrated no significant difference in BRFS between the groups (p=0.397). In multivariable Cox analysis, primary Gleason pattern 5 was the only independent predictor of BRFS (hazard ratio=3.72; 95% confidence interval=1.19-11.58), whereas NCHT did not confer an oncological benefit. CONCLUSION: These findings suggest that for patients with very-high risk prostate cancer limited to T2-T3a disease, NCHT does not improve biochemical recurrence outcomes, and tumor biology-particularly primary Gleason pattern 5-plays a more decisive role in prognosis than neoadjuvant systemic intensification. While cytotoxic therapy combined with androgen deprivation remains of investigational interest, its utility in organ-confined but biologically aggressive prostate cancer appears limited based on current evidence. Further large-scale, prospective studies are warranted to clarify the optimal patient selection for neoadjuvant approaches.

DOI： 10.21873/invivo.14264

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BACKGROUND/AIM: The therapeutic efficacy of Immuno-Oncology combination therapy based on the number of metastatic organs in renal cancer has yet to be examined. Therefore, we herein compared the efficacy of dual immune checkpoint blockade (IO-IO) and combination of immunotherapy with tyrosine kinase inhibitors (IO-TKI) strategies in metastatic renal cell carcinoma (mRCC), with a focus on how the number of metastatic organs affects clinical outcomes. PATIENTS AND METHODS: This retrospective study included 147 patients with mRCC treated with systemic therapies between August 2015 and July 2023. A multivariable Cox proportional hazards model was used to examine the relationships between clinical parameters and survival. To examine whether the effects of the number of metastatic organs on survival varied between treatment regimens, interaction terms were evaluated. RESULTS: In the multivariate Cox regression analysis, IMDC poor risk [hazard ratio (HR)=1.95; 95% confidence interval (CI)=1.19-3.18] and the presence of three or more metastatic organs in the IO-TKI group (HR=3.72; 95% CI=1.35-10.23) were identified as independent predictors of progression-free survival (PFS). In the IO-TKI group, patients with <3 metastatic organs had longer PFS than those with ≥3 metastatic organs. No significant difference in PFS was observed between <3 and ≥3 metastatic organs in the IO-IO group. This differential effect of the metastatic burden was confirmed by a significant interaction between the treatment group and number of metastatic organs (p for interaction=0.001). CONCLUSION: The number of metastatic organs affects the efficacy of IO-TKI but has no effect on the efficacy of IO-IO treatment. We recommend considering the number of metastatic organs as an additional prognostic factor to optimize treatment selection for patients with mRCC.

DOI： 10.21873/cdp.10513

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There is a great unmet medical need for development of molecularly characterizing modalities to assist in the complex classification of rare kidney cancers, some of which are diagnosed as unclassified renal cell carcinoma (unclassified RCC) due to complex histology. Here we show utility of the comparative transcriptome atlas as an assistive modality for complex classification of rare kidney cancers. Whereas whole genome sequencing (WGS) of 52 rare kidney cancers identifies very few clinically significant variants in a subset of cases, unsupervised clustering results of RNA-seq data from 219 renal tumors including 140 rare kidney cancers are largely consistent with the histological classification based on WHO2022 classification. Additionally, the comparative transcriptome atlas may provide an opportunity to define the molecular characteristics of unclassified RCC and might predict patient outcome. These findings support the comparative transcriptome atlas as an assistive modality for complex classification of rare kidney cancers.

DOI： 10.1038/s41467-025-65303-z

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Fatty acid-binding protein 4 (FABP4) is an important adipokine associated with inflammatory responses and metabolic regulation. Although a high-fat diet (HF) and/or HF-mediated obesity have been clearly linked to the progression of prostate cancer, with FABP4 potentially playing a critical role in this relationship, the mechanisms by which FABP4 facilitates this interaction remain unclear. After generating FABP4 knockout (FABP4-/-) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, it was found that FABP4-/- TRAMP mice presented significantly ameliorated prostate tumorigenesis and tumor progression along with decreased body weight, protumorigenic cytokine secretion, and pan-amino acid synthesis when compared to TRAMP mice under the HF condition. Additionally, treatment with BMS309403-a chemical inhibitor of FABP4-was observed to abrogate the HF-mediated TRAMP tumor progression, along with reductions in body weight and cytokine production. Thus, FABP4 plays an essential role in the progression of HF-mediated prostate cancer through the modulation of metabolic and inflammatory pathways, providing a potential therapeutic target for prostate cancer.

DOI： 10.3390/ijms262110621

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BACKGROUND: Insulin-like growth factor (IGF) binding protein-2 (IGFBP2) is a secretory protein that modulate the activity of IGFs. It is highly expressed in various cancers such as prostate cancer (PCa), in which it may play a controversial role in tumor progression, however, the molecular mechanisms of IGFBP2 in PCa progression remain unclear. METHODS: In this study, we examined the expression pattern and role of IGFBP2 in PCa cells and the stroma during prostate tumor cell progression. RESULTS: IGFBP2 was highly expressed in LNCaP cells and prostate stromal fibroblasts (PrSC) and was mainly secreted by PrSCs. Tumor cell growth and invasiveness were not directly affected by treatment with IGFBP2 siRNAs (siIGFBP2) or recombinant IGFBP2 (rIGFBP2). However, decreased expression of IGFBP2 significantly increased PrSC activation and the secretion of pro-tumorigenic cytokines IL-6, IL-8, IP10, and CCL5 through upregulation of TGF-β, which subsequently enhanced prostate tumor cell progression. Clinically, low expression of stromal IGFBP2 was associated with a high reactive prostate stroma, advanced PCa progression, and increased IGFBP2 levels in the serum. CONCLUSION: Here, we provide mechanistic evidence that IGFBP2 act as a critical regulatory factor in the activation of prostate stromal microenvironment and contributes to aggressive PCa progression.

DOI： 10.1186/s12964-025-02414-6

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OBJECTIVES: To evaluate the effects of renal impairment at the time of second-line tyrosine kinase inhibitor (TKI) therapy initiation and rapid renal function decline during first-line immuno-oncology (IO) combination therapy on metastatic renal cell carcinoma (mRCC) patients treated with second-line TKIs. METHODS: This multicenter retrospective study included 243 mRCC patients treated with first-line IO combination therapy, followed by second-line TKI therapy. Patients were divided into three groups using the estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) at the time of second-line TKI therapy initiation: eGFR ≥ 60, 30 ≤ eGFR < 60, and eGFR < 30. The eGFR slope during first-line IO combination therapy was calculated using eGFR measurements when initiating first-line and second-line therapies. Multivariable Cox proportional hazards regression analyses were performed to evaluate the effects of renal impairment and eGFR slope on progression-free survival (PFS) and overall survival (OS). RESULTS: The incidence rates of any grade and grade ≥ 3 adverse events were not significantly different among the three groups. Univariable analyses indicated that eGFR slope was not significantly associated with PFS or OS. Multivariable analyses suggested that moderate (30 ≤ eGFR < 60 mL/min/1.73 m2) and severe (eGFR < 30 mL/min/1.73 m2) renal impairment had no effects on shorter PFS, whereas severe renal impairment was independently and significantly associated with shorter OS. CONCLUSIONS: TKIs can be safely used as a second-line treatment after first-line IO combination therapy in mRCC patients with renal impairment without sacrificing oncological outcomes, except for in patients with severe renal impairment.

DOI： 10.1111/iju.70172

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In 2002, the renal cancer T classification was revised by dividing T1 into T1a and T1b at a 4 cm cutoff. However, local treatment using minimally invasive procedures resulted in better outcomes for tumors smaller than 3 cm, leading the European Association of Urology guideline committee to propose a 3 cm cutoff for T1a/b. Nonetheless, the impact of changing the T1 cutoff on robot-assisted partial nephrectomy (RALPN) has not been fully investigated. This study included 300 out of 335 patients with clinical stage T1 disease who underwent RALPN at our institution between November 2013 and April 2024. We evaluated the discriminative performance of clinical outcomes in each group using tumor diameter cutoffs of 4 and 3 cm. Using a 3 cm cutoff, patients with tumors ≥ 3 cm showed a greater decline in estimated glomerular filtration rate (eGFR) (e.g., the change from baseline to 1-year follow-up) ( - 9.6% vs.  - 4.9%, p = 0.003) and a higher incidence of overall complications (25% vs. 15%, p = 0.040) compared to those with smaller tumors. With a 4 cm cutoff, differences in eGFR decline ( - 7.8% vs.  - 6.7%, p = 0.134) and overall complications (27% vs. 17%, p = 0.100) were not significant. The 3 cm cutoff more accurately predicted overall complications with a higher area under the curve (0.575 vs. 0.451, p = 0.037). A 3 cm cutoff for the T classification of kidney cancer may more accurately predict postoperative renal function and the risk of complications.

DOI： 10.1007/s11701-025-02775-7

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OBJECTIVES: Oncological outcomes in patients with urothelial carcinoma treated with avelumab maintenance therapy or conventional platinum-based first-line chemotherapy were compared in real-world practice. METHODS: Outcomes in patients with advanced urothelial carcinoma treated with platinum-based first-line chemotherapy without avelumab (chemo group, n = 300) or avelumab maintenance therapy (avelumab group, n = 85) between March 2004 and September 2024 were retrospectively evaluated. Overall survival (OS) in the chemo and avelumab groups was stratified by the number of cycles of first-line chemotherapy. The primary outcome was OS among patients without progressive disease (non-PD) at the cycle-4 assessment (the standard-switch cohort). The secondary outcome was OS among patients with non-PD at the cycles-2 to 3 assessment (the early-switch cohort). RESULTS: In the standard-switch cohort (non-PD at cycle 4), the chemo and avelumab groups comprised 122 and 47 patients, respectively; median OS was significantly longer with avelumab than with chemo (70 vs. 26 months; p = 0.015). In the early-switch cohort (non-PD at cycles 2-3), the chemo and avelumab groups comprised 104 and 35 patients, respectively; median OS was significantly longer with avelumab than with chemo (33 vs. 13 months; p = 0.002). A multivariable Cox regression analysis revealed that avelumab administration was significantly associated with a reduced risk of OS (hazard ratio, 0.37; p < 0.001). The retrospective design is a limitation of this study. CONCLUSION: Avelumab maintenance appeared to improve outcomes across cycles 2-3 and ≥ 4, though residual confounding cannot be excluded.

DOI： 10.1002/cam4.71241

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OBJECTIVES: Combination therapy of nivolumab-plus-ipilimumab has been approved for advanced or metastatic renal cell carcinoma in Japan, but large-scale clinical data targeting Japanese patients is limited. To evaluate the early outcomes and factors related to early progression and response. METHODS: J-ENCORE is an ongoing multicenter, prospective, observational study of the effectiveness and safety of nivolumab-plus-ipilimumab for patients in Japan with advanced or metastatic renal cell carcinoma. The objective response rate, duration of response, progression-free survival, overall survival, incidence of adverse events, and factors related to early progression within 3 months, and response were assessed. RESULTS: We included 274 patients (median age: 68 years, 24.8% aged ≥ 75 years, 78.8% male). The median follow-up was 23.4 months. The objective response rate was 36.8%. Among responders, 63.3% had progression-free survival > 12 months. The median progression-free survival was 9.9 months; the 12-month overall survival was 76.3%. Of the patients, 77.0% experienced treatment-related adverse events, 42.3% experienced grade 3-4 events, and 1.1% experienced treatment-related death. Early progression was associated with female sex, poor risk status, liver metastasis, high baseline C-reactive protein levels, and high neutrophil-to-lymphocyte ratios. Responders were less likely to have bone metastases. Limitations include the observational nature of the study and a relatively short follow-up period. CONCLUSIONS: This is the first prospective, real-world study to demonstrate the effectiveness and safety of nivolumab-plus-ipilimumab in Japan, with the results comparable to those of CheckMate 214. These findings support the use of nivolumab-plus-ipilimumab, although further studies with longer follow-up on nivolumab-plus-ipilimumab are needed. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT04043975; University Hospital Medical Information Network-Clinical Trial Registration: UMIN000036772.

DOI： 10.1111/iju.70076

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Enfortumab Vedotin Ineligible criTeriA (EVITA) were proposed for the selection of patients to receive enfortumab vedotin (EV) and pembrolizumab treatment. However, the usefulness of these criteria has not been fully verified. We retrospectively analyzed data from 301 patients with unresectable or metastatic urothelial carcinoma who underwent first-line chemotherapy and 135 patients with EV monotherapy in real-world practice. We evaluated the numbers of patients fulfilling the modified EVITA (mEVITA; excluding ocular abnormalities) and the relationship of the mEVITA to the safety and efficacy in patients with EV monotherapy. Of the 301 patients who received first-line chemotherapy, 4.3% (n = 13) met the mEVITA criteria. The primary factor contributing to mEVITA ≥ 2 was renal dysfunction. Of the 135 patients who underwent subsequent EV therapy, the number of the mEVITA had no influence on the frequency of all-grade and grade ≥ 3 adverse events. However, the mEVITA ≥ 2 was significantly associated with temporary EV interruption. Oncological outcomes were not associated with the number of the mEVITA. In conclusion, 4.3% and 14.8% of patients met the mEVITA criteria at the time of first-line and subsequent EV therapy, respectively. Having mEVITA ≥ 2 may be associated with temporary interruption of EV therapy.

DOI： 10.1038/s41598-025-09806-1

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PURPOSE: Adjuvant pembrolizumab improved disease-free survival (DFS) and overall survival (OS) versus placebo in participants with renal cell carcinoma (RCC) at increased risk of recurrence after nephrectomy in the global phase 3 KEYNOTE-564 study. This post hoc subgroup analysis evaluated the efficacy and safety of adjuvant pembrolizumab in East Asian (Japan, South Korea, Taiwan) participants enrolled in KEYNOTE-564. MATERIALS AND METHODS: Eligible participants were randomly assigned 1:1 to receive adjuvant pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≤17 cycles. The primary endpoint was DFS by investigator assessment. OS was a key secondary endpoint. Safety was a secondary endpoint. RESULTS: The East Asian subgroup included 126 participants (pembrolizumab, n=58; placebo, n=68). Median follow-up was 62.1 months (range 49.6‒73.0). Hazard ratio for DFS with pembrolizumab versus placebo was 0.70 (95% confidence interval 0.41‒1.20). Median DFS was not reached with pembrolizumab versus 58.8 months with placebo; estimated 48-month rate was 61.3% versus 51.2%. Hazard ratio for OS was 0.47 (95% confidence interval 0.15‒1.49). Median OS was not reached with pembrolizumab and placebo; estimated 48-month rate was 94.8% versus 91.2%. Treatment-related adverse events occurred in 70.7% of participants (29.3% grade 3‒4) receiving pembrolizumab and 36.8% of participants (0.0% grade 3‒4) receiving placebo. No pembrolizumab-related deaths occurred. CONCLUSION: In the KEYNOTE-564 East Asian subgroup, adjuvant pembrolizumab provided DFS and OS benefits versus placebo and had a safety profile consistent with the global results. These results further support pembrolizumab as adjuvant treatment for East Asian patients with RCC at increased risk of recurrence after nephrectomy.

DOI： 10.4143/crt.2025.365

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OBJECTIVE: We aimed to investigate the impact of skin adverse events (AEs) of enfortumab vedotin (EV) on prognosis in patients with locally advanced or metastatic urothelial carcinoma in real-world practice. METHODS: This study analyzed data from 115 patients with locally advanced or metastatic urothelial carcinoma. We evaluated the association between EV dose and skin AEs in these patients. The impact of skin AEs on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and Cox regression analysis. RESULTS: The median PFS and OS were 8.1 and 14.5 months, respectively. EV dose reduction was observed in 68 (59.1%) patients. An estimated dose amount in the first, second, and seventh cycles was 95%, 85%, and 81%, respectively. We observed skin AEs in 69 (60%) cases, and they were observed within 1 month in 53 (76.8%) of cases. Patients with skin AEs had significantly longer PFS and OS compared to those without skin AEs. Multivariable Cox regression analysis showed a significant association of skin AEs with prolonged PFS and OS. CONCLUSIONS: Skin AEs were significantly associated with prolonged prognosis compared to those without skin AEs, although EV dose reduction was required in 59.1% of patients. Careful dose adjustment of EV may be crucial for long-term use and optimizing oncological outcomes.

DOI： 10.1111/iju.70030

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INTRODUCTION: Effectiveness and safety of second-line tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) for whom first-line immuno-oncology (I-O) combination therapy was discontinued because of adverse events (AEs) remain to be determined. PATIENTS AND METHODS: Clinicopathological data were retrospectively collected from 34 institutions between August 2018 and January 2022 for 243 patients with mRCC who received second-line TKIs after first-line I-O combination therapy. Two patients who requested discontinuation of first-line I-O combination therapy were excluded. Oncological outcomes and safety were compared between patients who discontinued first-line I-O combination therapy because of progressive disease (Group PD) and AEs (Group AE). First- and second-line overall survival (OS) were defined as the time from the start of first- and second-line therapy to death, respectively. Propensity score matching was applied to adjust prognostic factors between the 2 groups. RESULTS: There were 179 patients in Group PD and 62 patients in Group AE. Objective response rate and disease control rate were similar between the 2 groups. Progression-free survival (PFS), second-line OS, and first-line OS were significantly longer in Group AE than in Group PD (median 13.6 months vs. 8.5 months, P = 0.005; median not reached [NR] vs. 19.5 months, P = .005; median NR vs. 30.8 months, P = .012, respectively). After propensity score matching, PFS and second-line OS were still significantly longer and first-line OS tended to be longer in Group AE than in Group PD. There were no significant differences in the occurrence of AEs of any grade, including severe grades of 3 or greater, between the 2 groups. CONCLUSION: Second-line TKIs are safe and at least as effective in patients with mRCC who discontinued first-line I-O combination therapy because of AEs as they are in patients who discontinued because of PD.

DOI： 10.1016/j.clgc.2025.102322

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OBJECTIVE: To validate multiple prognostic models in metastatic renal cell carcinoma patients who received second-line axitinib following first-line nivolumab plus ipilimumab therapy. METHODS: Five prognostic models (ACL, albumin, C-reactive protein, and lactate dehydrogenase; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; ATP, axitinib treatment prediction; JMRC, Japanese metastatic renal cancer) to predict overall survival (OS) were validated and compared using data from 86 metastatic renal cell carcinoma patients who received second-line axitinib therapy following first-line nivolumab plus ipilimumab therapy at 34 hospitals affiliated with the Japan Urologic Oncology Group. RESULTS: The Karnofsky performance status, time from initial diagnosis to first-line therapy, and hemoglobin, platelet, albumin, and C-reactive protein levels correlated with OS in univariate Cox regression analyses. Among these factors, only albumin had a significant impact on OS in the multivariate analysis. The integrated area under the curve (AUC) of the ACL, IMDC, MSKCC, ATP, and JMRC models were 0.78, 0.76, 0.76, 0.69, and 0.70, respectively. The ACL model showed a higher value than the others in the time-dependent AUC. CONCLUSIONS: The accuracy of the five prognostic models (ACL, IMDC, MSKCC, ATP, and JMRC) created in the pre-immuno-oncology (IO) treatment cohort was maintained in the second-line axitinib group after nivolumab plus ipilimumab therapy. The ACL model demonstrated moderate accuracy in predicting OS with the fewest number of clinical variables.

DOI： 10.1093/jjco/hyaf018

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Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

DOI： 10.1111/cas.16326

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BACKGROUND: Immune-combinations have recently become the standard first-line treatment for patients with metastatic renal cell carcinoma (mRCC). This study evaluated the applicability of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model in predicting outcomes for patients treated with either immune-oncologic drug doublet (IO-IO) or immune-oncologic drug tyrosine kinase inhibitor combinations (IO-TKI). A secondary objective to compare the effectiveness of IO-IO versus IO-TKI within the IMDC risk groups over a short follow-up period. METHODS: A retrospective analysis was conducted on 172 patients with mRCC treated with first-line immunotherapy combinations. Progression free survival (PFS), time to treatment failure 2 (TTF2), and overall survival (OS) were compared between IMDC risk categories. Model fit was assessed using the c-index. The inverse probability of treatment weighting (IPTW) method was used to adjust and compare outcomes between IO-IO and IO-TKI, except for IMDC favorable risk patients due to the small number of IO-IO cases. RESULTS: The IMDC risk model demonstrated a c-index of 0.684 (OS) for entire cohort, 0.600 (PFS), 0.596 (TTF2), and 0.624 (OS) for IO-IO, and 0.667 (PFS), 0.702 (TTF2), and 0.751 (OS) for IO-TKI. In the IMDC intermediate and poor risk groups after IPTW adjustment, PFS (HR 0.72), TTF2 (HR 0.67), and OS (HR 0.74) did not significantly differ between IO-IO and IO-TKI. Specifically, in the IMDC intermediate risk group, PFS (HR 0.79), TTF2 (HR 0.69), and OS (HR 0.65) were longer in IO-TKI, though the differences were not statistically significant. In the IMDC poor risk group, PFS (HR 0.76), TTF2 (HR 0.77), and OS (HR 1.03) were comparable. CONCLUSIONS: The impact of IMDC risk model on survival was modest in IO-IO, while remained statistically substantial in IO-TKI. Survival outcomes did not significantly differ between IO-IO and IO-TKI during the short follow-up period.

DOI： 10.1186/s12885-025-13504-6

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BACKGROUND: To develop and validate a prognostic risk model for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with upfront abiraterone acetate (ABI). METHODS: This retrospective multicenter study involved 233 high-risk mHSPC patients who received upfront ABI, developed by three academic centers. The model was externally validated with an independent cohort of 282 patients. To identify independent prognostic factors for second progression-free survival (PFS2) and develop the best-fitted model, Cox proportional hazards regression, followed by the Akaike information criterion, was used. Patients were categorized into three groups based on their risk scores. PFS2 and overall survival (OS) were evaluated according to the risk groups in the discovery and validation cohorts. RESULTS: The median age was 72 (range 51-89) years, with a median follow-up duration of 27 months. Independent factors linked to PFS2 included an Eastern Cooperative Oncology Group performance status ≥2, a primary Gleason score of 5, an extent of disease score of ≥3 or liver metastasis, and lactate dehydrogenase >220 U/L. Median PFS2 for favorable-, intermediate-, and poor-risk groups were not reached, 43 months, and 16 months, respectively. The median OS was 29 months in the poor-risk group, whereas it was not reached in the favorable- and intermediate-risk groups. The 2-year OS rates in the favorable-, intermediate- and poor-risk groups were 94.5%, 80.1%, and 60.3%, respectively. The validation cohort confirmed the risk model's relationship with PFS2 and OS. The median PFS2 and OS in the high-risk group were 21 months and 32 months, respectively. CONCLUSIONS: Our prognostic model, including five clinical factors, is useful for patient care and treatment selection in high-risk mHSPC patients treated with ADT plus ABI. The developed model could provide more accurate information, guide treatment decisions, or classify patients in future clinical trials.

DOI： 10.1002/pros.24802

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OBJECTIVE: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. METHODS: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. RESULTS: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p  = .045 and p =  0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p  = .025 and p =  0.036, respectively). CONCLUSIONS: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

DOI： 10.1080/15384047.2024.2312602

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DOI： 10.1111/iju.15578

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Recent advances in medical and nursing care have improved the prognosis of patients with severe motor and intellectual disabilities (SMID). However,there has been a proportionate increase in the incidence of malignant tumor-related deaths in this population owing to their prolonged survival. In this study,we reviewed the clinical characteristics of four bladder cancers in young SMID patients treated at our hospital. In all patients,a diagnosis of a bladder tumor was made after a referral from the family medical department to the urology department ; the median time from the first symptom to the diagnosis was 12.5 months (range : 0-17 months). In clinical staging,two patients had non-invasive cancer,while the other two had invasive bladder cancer (one patient with cN1). Radical cystectomy with ileal conduit was performed in three patients (pathological stages were pTa with CIS,pT3aN1,and pT3bN0),and transurethral bladder tumor ablation was performed in the fourth one. The median postoperative follow-up period was 134 months (range : 20-182 months). Three patients survived afterward,while one patient died due to other causes. These findings suggest that young SMID patients tend to have a more severe form of bladder cancer compared to the general young population. Therefore,complaints of gross hematuria and urinary symptoms in young patients with SMID need appropriate evaluation in cooperation with the family department for an early diagnosis.

DOI： 10.14989/ActaUrolJap_70_8_227

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Arterio-ureteral fistulas (AUFs), which are relatively rare but potentially life-threatening, require prompt diagnosis and treatment. We reported a case of AUFs following robot-assisted laparoscopic radical cystectomy (RARC) with extended pelvic lymph node dissection and ileal conduit urinary diversion for muscle-invasive bladder cancer, which resulted in massive hemorrhage. Urine leaked from the anastomosis between the ureter, and the end of the ileal conduit was infected, which resulted in an AUF between the pseudoaneurysm of the right common iliac artery and the ureter. The AUF was managed successfully by vascular intervention with an arterial stent graft.

DOI： 10.1111/ases.13348

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BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival. METHODS: This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68 years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival. RESULTS: On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002). CONCLUSION: A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC.

DOI： 10.1007/s10147-024-02538-8

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OBJECTIVES: This study aimed to assess the prognostic outcomes in mRCC patients receiving second-line TKI following first-line IO combination therapy. METHODS: This study retrospectively included 243 mRCC patients receiving second-line TKI after first-line IO combination therapy: nivolumab plus ipilimumab (n = 189, IO-IO group) and either pembrolizumab plus axitinib or avelumab plus axitinib (n = 54, IO-TKI group). Oncological outcomes between the two groups were compared, and prognostication systems were developed for these patients. RESULTS: In the IO-IO and IO-TKI groups, the objective response rates to second-line TKI were 34.4% and 25.9% (p = 0.26), the median PFS periods were 9.7 and 7.1 months (p = 0.79), and the median OS periods after the introduction of second-line TKI were 23.1 and 33.5 months (p = 0.93), respectively. Among the several factors examined, non-CCRCC, high CRP, and low albumin levels were identified as independent predictors of both poor PFS and OS by multivariate analyses. It was possible to precisely classify the patients into 3 risk groups regarding both PFS and OS according to the positive numbers of the independent prognostic factors. Furthermore, the c-indices of this study were superior to those of previous systems as follows: 0.75, 0.64, and 0.61 for PFS prediction and 0.76, 0.70, and 0.65 for OS prediction by the present, IMDC, and MSKCC systems, respectively. CONCLUSIONS: There were no significant differences in the prognostic outcomes after introducing second-line TKI between the IO-IO and IO-TKI groups, and the histopathology, CRP and albumin levels had independent impacts on the prognosis in mRCC patients receiving second-line TKI, irrespective of first-line IO combination therapies.

DOI： 10.1111/iju.15396

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Robot-assisted partial nephrectomy (RAPN) has been shown to be a safe and effective method for treatment of small renal tumors, including clinical T1b renal cell carcinoma (RCC); however, the impact of RAPN for cT1b renal tumors on renal function is not well understood. In this retrospective study, 50 patients who underwent RAPN for cT1b renal tumors were evaluated for pre- and post-operative renal function and perioperative clinical factors. Renal function was assessed using the estimated glomerular filtration rate (eGFR) at baseline and on postoperative days (POD) 1, 7, 30, and 180.A significant renal functional decline was defined as ≥ 15% reduction in eGFR at POD180 compared with eGFR at baseline. Logistic regression analyses were used to identify risk factors for renal function decline, including age, sex, RENAL nephrometry score, operative time, and estimated blood loss. The median patient age was 62 years, and the median tumor diameter and RENAL nephrometry score were 44 mm (IQR 43-50) and 8 (IQR 7-9), respectively. Of these patients, 16 (36%) showed a significant renal functional decline at POD 180. In the multivariate analysis, the L component of the RENAL nephrometry score and an estimated blood loss of 200 mL or more were identified as significant risk factors for renal functional decline. These findings suggest that the preoperatively definable L component of the RENAL nephrometry score and intraoperative blood loss, which may be modifiable factors, play significant roles in post-RAPN renal function decline.

DOI： 10.1007/s11701-024-01848-3

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PURPOSE: The International Bladder Cancer Group designated the subgroup that is resistant to Bacillus Calmette-Guérin (BCG) but does not meet the criteria for BCG-unresponsive NMIBC as "BCG-exposed high-risk NMIBC" to guide optimal trial design. We aimed to investigate the treatment patterns and prognoses of patients with BCG-exposed NMIBC. METHODS: We conducted a retrospective chart review of 3283 patients who received intravesical BCG therapy for NMIBC at 14 participating institutions between January 2000 and December 2019. Patients meeting the criteria for BCG-exposed and BCG-unresponsive NMIBC, as defined by the Food and Drug Administration and International Bladder Cancer Group, were selected. To compare treatment patterns and outcomes, high-risk recurrence occurring more than 24 months after the last dose of BCG was defined as "BCG-treated NMIBC." In addition, we compared prognoses between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. RESULTS: Of 3283 patients, 108 (3.3%), 150 (4.6%), and 391 (11.9%) were classified as having BCG-exposed, unresponsive, and treated NMIBC, respectively. BCG-exposed NMIBC demonstrated intermediate survival curves for intravesical recurrence-free and progression-free survival, falling between those of BCG-unresponsive and treated NMIBC. Among patients with BCG-exposed NMIBC, 48 (44.4%) received BCG rechallenge, which was the most commonly performed treatment, and 19 (17.6%) underwent early cystectomy. No significant differences were observed between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. CONCLUSIONS: The newly proposed definition of BCG-exposed NMIBC may serve as a valuable disease subgroup for distinguishing significant gray areas, except in cases of BCG-unresponsive NMIBC.

DOI： 10.1007/s00345-024-04834-4

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OBJECTIVE: Several guidelines recommended that second transurethral resection should be performed in patients with diagnosis of high-risk non-muscle-invasive bladder cancer. However, therapeutic benefits of second transurethral resection before bacillus Calmette-Guérin intravesical instillation were conflicting amongst previous studies. We investigated the prognostic impact of second transurethral resection before bacillus Calmette-Guérin instillation in high-risk non-muscle-invasive bladder cancer patients. METHODS: This retrospective study included 3104 non-muscle-invasive bladder cancer patients who received bacillus Calmette-Guérin instillations between 2000 and 2019 at 31 collaborative institutions. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors of intravesical recurrence, disease progression, cancer-specific mortality and overall mortality. RESULTS: In the entire population, patients undergoing second transurethral resection (33%, 1026/3104) had a lower risk of intravesical recurrence on univariate analysis (hazard ratio 0.85, 95% confidence interval 0.73-0.98, P = 0.027), although it did not remain significant on multivariate analysis (hazard ratio 0.90, 95% confidence interval 0.76-1.07, P = 0.24). Subgroup analysis revealed that, in pT1 patients (n = 1487), second transurethral resection was significantly correlated with a lower risk of intravesical recurrence on multivariate analysis (hazard ratio 0.80, 95% confidence interval 0.64-1.00, P = 0.048), but lower risks of disease progression (hazard ratio 0.75, 95% confidence interval 0.56-1.00, P = 0.049), cancer-specific mortality (hazard ratio 0.54, 95% confidence interval 0.35-0.85, P = 0.007) and overall mortality (hazard ratio 0.73, 95% confidence interval 0.55-0.97, P = 0.027) on univariate analysis. CONCLUSIONS: Second transurethral resection confers accurate pathological staging and could be used to safely select good candidates for intravesical bacillus Calmette-Guérin instillation. We further confirm that second transurethral resection could confer an oncological benefit in pT1 bladder cancer patients treated by bacillus Calmette-Guérin instillation, and so strongly recommend second transurethral resection in this patient population.

DOI： 10.1093/jjco/hyad155

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Immuno-oncology (IO) combination therapy is utilized as a first-line systemic treatment for advanced renal cell carcinoma. However, evidence supporting the use of cabozantinib after IO combination therapy is lacking. We retrospectively analyzed patients who received second-line cabozantinib after IO combination therapy using the Japanese Urological Oncology Group (JUOG) database. In total, 254 patients were enrolled in the JUOG global study, and 118 patients who received second-line cabozantinib comprised the study cohort. The objective response rate, disease control rate, second-line cabozantinib progression-free survival (PFS), and overall survival from second-line for overall were 32%, 75%, 10.5 months, and not reached, respectively, for first-line IO-IO therapy were 37%, 77%, 11.1 months, and not reached, respectively, versus 24%, 71%, 8.3 months, and not reached, respectively, for first-line IO-tyrosine kinase inhibitor therapy. In univariate and multivariate analyses, discontinuation of first-line treatment because of progressive disease and liver metastasis were independent risk factors for PFS. All-grade adverse events occurred in 72% of patients, and grade 3 or higher adverse events occurred in 28% of patients. Second line-cabozantinib after first-line IO combination therapy for advanced renal cell carcinoma was expected to be effective after either IO-IO or IO-TKI treatment and feasible in real-world practice.

DOI： 10.1038/s41598-023-48087-4

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OBJECTIVES: To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population. METHODS: In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database. RESULTS: In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups. CONCLUSIONS: The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population.

DOI： 10.1002/cam4.6591

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BACKGROUND: Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years. METHODS: We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455-1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737-3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877). CONCLUSIONS: The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates.

DOI： 10.1007/s10147-023-02394-y

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BACKGROUND: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). METHODS: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. RESULTS: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. CONCLUSION: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials.

DOI： 10.1007/s10147-023-02401-2

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BACKGROUND: We report a case of diffuse large B-cell lymphoma that progressed rapidly after androgen deprivation therapy for prostate cancer in a patient with a history of IgG4-related disease. Estrogen has been reported to be a possible cause of acute exacerbations of malignant lymphoma only in mouse models. Therefore, its clinical significance has not been clarified. CASE PRESENTATION: This case report describes a 75-year-old man with prostate cancer who had IgG4-related disease. Hormone therapy was initiated to treat prostate cancer, but he developed dyspnea and back pain. A diagnosis was made of diffuse large B-cell lymphoma. Immunohistochemistry was positive for estrogen receptor β, which led us to suspect rapid progression of diffuse large B-cell lymphoma due to estrogen suppression by gonadotropin-releasing hormone antagonists. Hormone therapy was discontinued, and the patient received R-CHOP therapy. Subsequently, the lymphoma masses shrunk, and the patient obtained remission. CONCLUSION: This case is the first report of clinical significance regarding the crucial role of estrogen and estrogen receptor β in malignant lymphoma in a patient with IgG4-related disease. Our report aims to raise awareness of the need to carefully select treatment options for prostate cancer patients with IgG4-related disease or lymphoma.

DOI： 10.1007/s00432-023-05292-y

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A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure.

DOI： 10.3390/curroncol30090587

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OBJECTIVES: To examine the long-term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real-world settings. METHODS: This was a multicenter, retrospective, observational study, with a 36-month follow-up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). RESULTS: Of the 208 patients, 36.5% received nivolumab monotherapy as second-line, 30.8% as third-line, and 31.7% as fourth- or later-line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36-month OS rate of 54.3% (second-line, 57.4%; third-line, 52.6%; fourth- or later-line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first-line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor-tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. CONCLUSIONS: This 36-month real-world follow-up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long-term effectiveness of sequential therapy from first-line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis.

DOI： 10.1111/iju.15206

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BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first-line therapy. METHODS: This multi-institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune-related adverse events and progression-free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated. RESULTS: The median observation period was 16 months (interquartile range, 5-27). The median age at NIVO+IPI initiation was 68 years in the male-dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315-8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075-16.949, p = 0.039) was an independent risk factor for PRD. CONCLUSIONS: PRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first-line therapy and might indicate that a candidate will not benefit from NIVO+IPI.

DOI： 10.1002/cam4.6306

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DOI： 10.1007/s10147-023-02331-z

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Upper urinary tract urothelial carcinoma (UTUC) after intravesical bacillus Calmette-Guerin (BCG) therapy is rare, and its incidence, clinical impact, and risk factors are not fully understood. To elucidate the clinical implications of UTUC after intravesical BCG therapy, this retrospective cohort study used data collected between January 2000 and December 2019. A total of 3226 patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) and treated with intravesical BCG therapy were enrolled (JUOG-UC 1901). UTUC impact was evaluated by comparing intravesical recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) rates. The predictors of UTUC after BCG treatment were assessed. Of these patients, 2873 with a medical history that checked UTUC were analyzed. UTUC was detected in 175 patients (6.1%) during the follow-up period. Patients with UTUC had worse survival rates than those without UTUC. Multivariate analyses revealed that tumor multiplicity (odds ratio [OR], 1.681; 95% confidence interval [CI], 1.005-2.812; p = 0.048), Connaught strain (OR, 2.211; 95% CI, 1.380-3.543; p = 0.001), and intravesical recurrence (OR, 5.097; 95% CI, 3.225-8.056; p < 0.001) were associated with UTUC after BCG therapy. In conclusion, patients with subsequent UTUC had worse RFS, CSS, and OS than those without UTUC. Multiple bladder tumors, treatment for Connaught strain, and intravesical recurrence after BCG therapy may be predictive factors for subsequent UTUC diagnosis.

DOI： 10.3390/cancers15072002

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A 66-year-old male was diagnosed with cT4N0M1b small-cell neuroendocrine carcinoma of the prostate. Four months after the administration of combined androgen blockade, multiple novel metastatic regions in the lung and liver and progression of bone metastasis were observed. The patient was referred to our hospital because of biochemical and radiographic progression after four cycles of docetaxel as a first-line therapy for castration-resistant prostate cancer. Transurethral resection of the prostate and hepatic biopsy revealed small-cell carcinoma with positive expression of neuroendocrine markers. The FoundationOne CDx next-generation sequencing test revealed several pathogenic variants, including BRCA2 (W1692fs*3), KEAP1 (R320W), and TP53 (C2385) mutation. After four cycles of chemotherapy with carboplatin plus etoposide (CE), the metastatic regions regressed markedly. The prostate-specific antigen (PSA) and neuron-specific enolase (NSE) level decreased by 96.9% and 91.6%, respectively. However, 2 months after the completion of four cycles of CE, elevation of tumor marker levels, and re-growth of the metastatic regions were observed. Although olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), achieved a 45.2% decrease in NSE, the patient rejected to continue therapy because of G2 adverse events. After receiving an additional two cycles of CE and one cycle of cabazitaxel, the patient died because of cancer progression 24 months after the initial treatment for prostate cancer. Here, we present a case of BRCA2-altered small-cell neuroendocrine prostate cancer treated with both platinum-containing chemotherapy and PARPi. Both therapies achieved an initial response; however, durable responses were not obtained. Additional discussion regarding the optimal treatment strategy for BRCA-altered small-cell/neuroendocrine prostate cancer is required.

DOI： 10.1159/000531134

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Language：Japanese   Publisher：World Journal of Surgical Oncology  

DOI： 10.1186/s12957-022-02669-0

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Language：Japanese   Publisher：Japanese journal of clinical oncology  

DOI： 10.1093/jjco/hyac141

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Language：Japanese   Publisher：International Journal of Molecular Sciences  

DOI： 10.3390/ijms231911742

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Language：Japanese   Publisher：Urology  

DOI： 10.1016/j.urology.2022.05.034

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Language：Japanese  

DOI： 10.14989/ActaUrolJap_68_8_265

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Language：Japanese   Publisher：Genes  

DOI： 10.3390/genes13071204

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Language：Japanese   Publisher：Japanese Journal of Clinical Oncology  

DOI： 10.1093/jjco/hyac047

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Language：Japanese   Publisher：Human Molecular Genetics  

DOI： 10.1093/hmg/ddab345

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OBJECTIVE: To evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: We retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune-related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression-free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting-adjusted Cox regression analysis. RESULTS: Of the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non-PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting-adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non-PPI users, whereas Abs use was not associated with poorer outcomes. CONCLUSION: The concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.

DOI： 10.1002/bco2.118

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Language：Japanese   Publisher：International Journal of Molecular Sciences  

DOI： 10.3390/ijms23042214

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OBJECTIVES: We retrospectively investigated if robot-assisted laparoscopic partial nephrectomy (RAPN) contributes to a decrease in resected parenchymal volume (RPV), an increase in postoperative parenchymal volume (PPV), and an improvement of postoperative renal function when compared with conventional laparoscopic partial nephrectomy (LPN) using a three-dimensional image analysis system. METHODS: Patients who underwent LPN (n = 37) and RAPN (n = 66) from November 2013 to November 2018 were included in this study. All patients had a tumor diameter of 4 cm or less. Patients with an anatomical or functional single kidney were excluded. RPV and PPV were measured using SYNAPSE VINCENT®. The surgical outcomes were compared between the two groups. RESULTS: Warm ischemic time in the RAPN group was significantly shorter than that in the LPN group (p < 0.001). The ratio of RPV to tumor volume (RPV/TV) in the RAPN group was significantly lower than that in the LPN group (p = 0.016). PPV in the RAPN group was significantly higher than that in the LPN group (p = 0.049). The decreased estimated glomerular filtration rate in the RAPN group was significantly lower than that in the LPN group on days 1, 7, 30, 90, and 180 after surgery. CONCLUSIONS: Postoperative renal function in the RAPN group was significantly better than that in the LPN group in both the short and long term. In addition to a short warm ischemia time, the decreased RPV/TV and increased PPV may have contributed to the improvement of postoperative renal function.

DOI： 10.1111/ases.12966

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab.

DOI： 10.1111/cas.15488

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Language：Japanese   Publisher：Japan Association of Endocrine Surgeons・Japanese Society of Thyroid Surgery  

DOI： 10.11226/jaesjsts.39.1_44

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Language：Japanese   Publisher：IJU Case Reports  

DOI： 10.1002/iju5.12531

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Language：Japanese   Publisher：International Journal of Clinical Oncology  

DOI： 10.1007/s10147-021-02091-8

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Language：Japanese   Publishing type：Research paper (scientific journal)  

It remains unknown whether the early response to vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) management in malignancies links to long-term survival. The objective of this study was to investigate the survival rates and predictive factors of early response in patients with metastatic renal cell carcinoma (mRCC) managed by VEGFR-TKIs. From Jan. 2008 to Oct. 2018, 496 patients were treated with VEGFR-TKIs as first-line treatment at the eight Japanese hospitals (Michinoku RCC). Early cessation was defined as VEGFR-TKIs being given up within 3 months after their initiation. The number of patients in early cessation VEGFR-TKIs (Cohort I) was 173 (34.9%), and in long-term use (Cohort II) was 323 (65.1%). The cancer-specific survival (CSS) and overall survival (OS) were better in Cohort II. IMDC Poor-risk was at risk of early cessation of a first-line VEGFR-TKI. Axitinib was the most preferred drug for long-term treatment. On closer examination, both Cohort I and II were divided into two groups, the patients ceased VEGFR-TKI due to adverse events (Group A [67 from Cohort I] and Group C [51 from Cohort II]) and disease progression (Group B [106 from Cohort I] and Group D [272 from Cohort II]). Despite that the cessation was adverse events, CSS and OS in Group A were worse than both Group C and D. Axitinib was administered with the safer profile. IMDC Poor risk was the risk factor for the early disease progression. Managing early adverse events may contribute to a better prognosis in mRCC patients treated VEGFR-TKIs.

DOI： 10.1002/cam4.5268

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Language：Japanese   Publisher：European Journal of Clinical Pharmacology  

DOI： 10.1007/s00228-022-03420-0

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Language：Japanese   Publisher：European Urology Focus  

DOI： 10.1016/j.euf.2022.06.002

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Language：Japanese   Publisher：MedComm  

DOI： 10.1002/mco2.89

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Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). METHODS: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. RESULTS: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. CONCLUSIONS: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

DOI： 10.1186/s12885-021-07966-7

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Language：Japanese  

A 46-year-old woman was referred to our hospital with a left-sided renal tumor pointed out by ultrasonography at the time of a medical checkup.Computed tomography revealed a mass measuring 88×77×68 mm on the upper pole of the left kidney. She was diagnosed with cT2aN0M0 clear cell renal cell carcinoma. Laparoscopic left nephrectomy was performed uneventfully. Histopathological diagnosis was clear cell renal cell carcinoma, G2, v1, pT2. Four months after surgery, lung metastases appeared, and systemic therapy was given sequentially as follows ; sunitinib for 2 months, nivolumab for 8 months, axitinib for 17 months, and pazopanib for 2 months.However, metastases progressed, and a re-administration of nivolumab was planned. The nivolumab re-treatment resulted in a marked reduction in multiple lung metastases despite the previous failure by nivolumab treatment. There are few reports on the therapeutic effect of re-administration of nivolumab. We report a case of successful treatment by re-administration of nivolumab.

DOI： 10.14989/ActaUrolJap_67_12_525

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Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O. METHODS: The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (<6 or ≥6 months) and discontinuation reason of prior I-O (progression or adverse events), and TT regimen (sunitinib or axitinib). We also analyzed PFS2 of prior I-O and OS from first-line therapy. RESULTS: The ORR and median PFS of TT after NIVO and NIVO+IPI among the subgroups was 17-36% and 20-44%, and 7.1-11.6 months and 16.3-not reached (NR), respectively. The median OS of TT after NIVO was longer in patients with longer TTF of NIVO and treated with axitinib. Conversely, median OS of TT after NIVO+IPI was similar among subgroups. The median PFS2 of NIVO and NIVO+IPI was 36.7 and 32.0 months, respectively. The median OS from first-line therapy was 70.5 months for patients treated with NIVO and NR with NIVO+IPI. The safety profile of each TT after each I-O was similar to previous reports. CONCLUSIONS: The efficacy of TT after NIVO or NIVO+IPI was favorable regardless of the TTF and discontinuation reason of prior I-O, and TT regimen.

DOI： 10.1093/jjco/hyab114

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Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. METHODS: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. RESULTS: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9-46.8), not reached (63.5 to not estimable), 46.8 months (37.1-52.9), and 10.4 months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. CONCLUSION: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

DOI： 10.1007/s10147-021-01979-9

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Benign ureteroenteric anastomosis strictures (UESs) are one of many critical complications that may cause irreversible disability following robot-assisted radical cystectomy (RARC). Previous studies have shown that the incidence rates of UES after RARC can reach 25.3%, with RARC having higher UES incidence rates compared to open radical cystectomy. Various known and unknown factors are involved in the occurrence of UES. To minimize the incidence of UES after RARC, our group has standardized the procedure and technique for intracorporeal urinary diversion by applying the following five strategies: (1) wide delicate dissection of the ureter and preservation of the periureteral tissues; (2) gentle handling of the ureter and security of periureteral tissues at the anastomotic site; (3) use of indocyanine green to confirm good blood supply; (4) standardization of the ample ureteral spatulation length for Wallace ureteroenteric anastomosis through objective measurements; and (5) development of an institutional standardized procedure manual. This review focused on the incidence, etiology, prevention, and management of UES after RARC to bring attention to the incidence of this complication while also proposing standardized surgical procedures to minimize its incidence after RARC.

DOI： 10.3390/curroncol28050348

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences.

DOI： 10.1002/cam4.4130

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.

DOI： 10.1016/j.transproceed.2021.02.010

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Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation. METHODS: We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated. RESULTS: HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy. CONCLUSION: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.

DOI： 10.1002/cac2.12137

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Language：Japanese   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear. METHODS: Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs. RESULTS: Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3-4 events in 51% of patients, and no treatment-related deaths occurred. CONCLUSIONS: TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.

DOI： 10.1093/jjco/hyaa266

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Language：Japanese   Publisher：International Journal of Clinical Oncology  

DOI： 10.1007/s10147-020-01797-5

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Language：Japanese   Publisher：International Journal of Urology  

DOI： 10.1111/iju.14759

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.

DOI： 10.1007/s00262-021-03032-0

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Language：Japanese   Publisher：日本泌尿器内視鏡学会  

<p> 今回我々はロボット支援腹腔鏡下腎尿管全摘除術 (RNU) の初期経験を得た.</p><p> 対象は2019年7月から2020年7月にda Vinci Si (4例) またはXi (2例) サージカルシステムでRNUを受けた6症例. 全例男性で患側は左4例, 右2例, cT3の3例を含む4例で術前化学療法を施行した. 完全側臥位, 軽度ジャックナイフ体位, 6または7ポート, 経腹膜アプローチで手術を施行した. 術中, 体位変換やペイシェントカートの移動は行わなかった.</p><p> 手術時間の中央値は308分, 推定出血量の中央値は63 mLで輸血や開腹手術移行は無かった. pT3の左尿管癌症例1例で摘出標本断端が陽性であった. 周術期合併症はClavien-dindo分類でGrade Ⅱの乳糜腹水, 下痢を1例ずつ認めた.</p><p> RNUは手術手技の標準化とより多くの症例を対象とした長期追跡調査が必要であるが, UTUC症例に対する新たな治療選択肢となり得る.</p>

DOI： 10.11302/jsejje.34.318

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Language：Japanese   Publishing type：Research paper (scientific journal)  

OBJECTIVES: This study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN). METHODS: A total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. RESULTS: Of the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0-2) than that in the high-score (3-6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score. CONCLUSIONS: The REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.

DOI： 10.1016/j.urolonc.2021.08.015

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Language：Japanese   Publisher：Japanese Society of Endourology  

<p><b>Purpose :</b> We examined whether suturing renorrhaphy increased the parenchymal reduction volume by CT in robot-assisted partial nephrectomy (RAPN).</p><p><b>Materials and Method :</b> We analyzed 69 patients with a renal mass <4 cm in diameter who underwent RAPN between November 2013 and November 2018 at Akita University Hospital. The data of 26 patients who underwent suturing renorrhaphy and those of 43 patients who underwent medullary hemostatic suturing alone were retrospectively compared.</p><p><b>Results :</b> The tumor diameter and RENAL score were not significantly different between the groups. The median operative time, warm ischemic time, and blood loss were not significantly different between the groups. Also, the median parenchymal reduction volume, decreasing rate of eGFR, and incidence rate of high-grade postoperative complications were not significantly different between the groups.</p><p><b>Conclusion :</b> The addition of suturing renorrhaphy to RAPN neither significantly increased the parenchymal reduction volume nor significantly decreased the kidney function when compared with the non-renorrhaphy technique.</p>

DOI： 10.11302/jsejje.34.130

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Language：Japanese   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To assess the clinical benefit of pembrolizumab as second-line therapy for advanced urothelial carcinoma. METHODS: We retrospectively compared the effects of pembrolizumab with those of conventional chemotherapy on the prognosis of patients with advanced urothelial carcinoma at six hospitals between January 2004 and August 2020. We compared the oncological outcomes between the patients treated with pembrolizumab and those treated with conventional chemotherapy using Kaplan-Meier curve analysis and multivariate Cox regression analysis with the inverse probability of treatment weighting method. RESULTS: The numbers of patients in the pembrolizumab and chemotherapy groups were 121 and 67, respectively. Patients in the pembrolizumab group were significantly older (median 72 vs 66 years, P = 0.001), and had poor Eastern Cooperative Oncology Group performance status (median 1 vs 0, P = 0.001). The unadjusted Kaplan-Meier curve analysis showed no significant differences in the median overall survival from the first-line chemotherapy (24.7 months vs 16.3 months, P = 0.159). Inverse probability of treatment weighting-adjusted multivariate Cox proportional hazards analyses showed a significant difference between the pembrolizumab and chemotherapy groups in overall survival (P = 0.003, hazard ratio 0.63). CONCLUSIONS: Despite the non-negligible age difference between the trial and our clinical practice, our study supports the benefit of second-line pembrolizumab over chemotherapy in real-world practice.

DOI： 10.1111/iju.14601

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Language：Japanese   Publisher：Journal of Clinical Pathology  

DOI： 10.1136/jclinpath-2020-206548

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald χ2 statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25-85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1-72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7-4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4-11.0 and 1.1-8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients.

DOI： 10.1038/s41598-020-77135-6

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Language：Japanese   Publisher：Health Science Reports  

DOI： 10.1002/hsr2.197

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Language：Japanese   Publisher：International Journal of Urology  

DOI： 10.1111/iju.14363

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Language：Japanese   Publisher：Transplant Immunology  

DOI： 10.1016/j.trim.2020.101330

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Language：Japanese   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: The in vivo effect of abiraterone on bone mineral density (BMD) in addition to androgen deprivation therapy was examined using a murine model. MATERIALS AND METHODS: The mice were separated into the following groups: control, abiraterone, castration, and castration+abiraterone. The percentage change in the ratio of bone to tissue volume (BV/TV), number of osteoblasts and osteoclasts, and the serum level of bone markers were compared on day 21. RESULTS: The BV/TV ratio of the abiraterone, castration, and castration+abiraterone groups was lower than that of the control group. However, the change in the BV/TV ratio in the castration+abiraterone group was not significantly different from that in the castration group. There was no significant difference in the serum TRAP5b level and the number of osteoclasts and osteoblasts between the castration+abiraterone and the castration groups. CONCLUSION: The addition of abiraterone to castration did not affect BMD in the murine model.

DOI： 10.21873/invivo.12167

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Language：Japanese   Publisher：International Journal of Medical Robotics and Computer Assisted Surgery  

DOI： 10.1002/rcs.2117

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Language：Japanese   Publisher：Hinyokika kiyo. Acta urologica Japonica  

DOI： 10.14989/ActaUrolJap_66_10_351

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Language：Japanese   Publishing type：Research paper (scientific journal)  

This case report documents seminal vesicle cystadenoma with concurrent prostate cancer in a 49-yearold man evaluated at follow-up for a high prostate-specific antigen level (12 ng/ml). Transrectal ultrasound-guided prostate biopsy was performed for adenocarcinoma of the prostate (Gleason score 3+4= 7). Staging computed tomography showed a 6.6×5.5×5.0 cm cystic tumorof the seminal vesicle. A possible diagnosis of primary malignant tumor of the seminal vesicle with concurrent organ-confined prostate cancer was considered. However, seminal vesicle tumor biopsy was not performed because the patient underwent open radical prostatectomy with the resection of the seminal vesicle tumor. Histopathologic examination of the seminal vesicle and the prostate revealed cystadenoma (Gleason score 4+3=7) and adenocarcinoma (stage pT2cN0). Neither recurrence of the cystadenoma nor biochemical recurrence of the prostate cancer was observed 5 years and 6 months after the surgery.

DOI： 10.14989/actauroljap_66_10_351

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Language：Japanese   Publisher：Neurourology and Urodynamics  

DOI： 10.1002/nau.24427

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Language：Japanese   Publisher：International Journal of Clinical Oncology  

DOI： 10.1007/s10147-020-01693-y

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Language：Japanese   Publisher：International Journal of Clinical Oncology  

DOI： 10.1007/s10147-020-01692-z

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Language：Japanese   Publisher：Pharmacological Reports  

DOI： 10.1007/s43440-020-00090-6

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Language：Japanese   Publisher：Urology Case Reports  

DOI： 10.1016/j.eucr.2020.101138

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Language：Japanese   Publisher：iScience  

DOI： 10.1016/j.isci.2020.100998

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Language：Japanese   Publisher：BMC Cancer  

DOI： 10.1186/s12885-020-06844-y

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Language：Japanese   Publisher：Cancer Science  

DOI： 10.1111/cas.14294

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Language：Japanese   Publisher：Acta Urologica Japonica  

DOI： 10.14989/ActaUrolJap_66_l_l

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Language：Japanese  

The initial results robot-assisted pyeloplasty (RAP) performed on 6 patients were compared with those of laparoscopic pyeloplasty (LP) for ureteropelvic junction obstruction performed on 26 patients in a Japanese regional center. The median operating time, estimated blood loss, time to oral intake, time to start walking, and hospital stay were not significantly different between the groups. There was no difference in the rate of complications of Clavien-Dindo≥grade III between the two groups. Although the number of entered patients was small, the results indicated that RAP is feasible with favorable outcome.

DOI： 10.14989/actauroljap_66_1_1

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Language：Japanese  

The initial results robot-assisted pyeloplasty (RAP) performed on 6 patients were compared with those of laparoscopic pyeloplasty (LP) for ureteropelvic junction obstruction performed on 26 patients in a Japanese regional center. The median operating time, estimated blood loss, time to oral intake, time to start walking, and hospital stay were not significantly different between the groups. There was no difference in the rate of complications of Clavien-Dindo≥grade III between the two groups. Although the number of entered patients was small, the results indicated that RAP is feasible with favorable outcome.

DOI： 10.14989/ActaUrolJap_66_1_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>症例は56歳、女性。妊娠中毒症を契機として腎機能が低下し、41歳時に血液透析導入。夫婦間生体腎移植を希望し当科受診。DSA陽性でnMFI値が高く術前にRituximab 200 mg/bodyを1回投与、新鮮凍結血漿を用いた血漿交換を4回施行した。2019年7月にABO血液型適合生体腎移植術を施行。移植後は軽度の脳梗塞を発症するも後遺症無く回復。全身状態、移植腎機能とも良好で明らかな拒絶反応を認めず、当初の予定通り退院した。腎移植後8カ月が経過した2020年3月初旬から微熱が持続し、その後38度台の発熱となり近医受診。発熱以外の自覚症状は無く細菌尿を認めたため尿路感染症として抗生物質投与で解熱するも投薬終了後に再び発熱したため当科受診。細菌尿及びCMVアンチゲネミアの陽性化を認め抗生物質及びVGCV投与を開始。速やかに解熱するも抗生物質投与が終了すると再び発熱。全身CTで右肺に境界明瞭な類円形の腫瘤像を2つ認め、精査加療目的に当科入院。呼吸器内科にコンサルトするもあらゆるマーカーが陰性。気管支鏡検査でBALを行うも確定診断に至らず退院。抗生物質投与期間中のみ解熱が得られていた。フォローの胸部レントゲン写真で右肺腫瘤陰影の増大を認め再度気管支鏡検査でBALを行い、最終的に肺アスペルギルス症の診断を得た。</p>

DOI： 10.11386/jst.55.Supplement_388_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>腎移植後患者は、透析や制限の多い治療から解放されることより、他の腎代替療法である血液透析・腹膜透析を選択した患者よりも社会復帰率が高いと言われている。当院では、2018年1月から2018年12月に当院で生体腎移植を受けて１年後もフォローされていた患者18名（うち１名は学生）のうち、16名が移植前から就労しており、15名が復職および再就職、復学している。しかし、中には移植前より透析による時間的制限で就労が困難だった患者、入院のため職を失った患者、移植後に社会復帰をしても職場の理解が得られずに退職した患者などがいる。腎移植後に社会復帰をしやすくするために①移植前や退院前に仕事や就学状況について情報収集を行い、主治医とも相談しながら病状に応じたアセスメントを行うこと②社会復帰後に関わる方に、腎移植後の外来通院間隔や治療、仕事や学業において注意すべき点などについて理解してもらうこと③一度社会復帰した後に、何か問題が生じて本人が援助を希望した場合にも相談の上で介入していくことが必要と考える。また、社会復帰支援はレシピエント移植コーディネーターのみでは行うことができず、他職種との協力が必要なケースも多い。今回、当院の腎移植後患者のうち、本人・家族より社会復帰について相談があり、MSWと連携して支援を行った事例を用いながら考察し、報告する。</p>

DOI： 10.11386/jst.55.Supplement_333_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>腎移植後患者は、透析や制限の多い治療から解放されることより、他の腎代替療法である血液透析・腹膜透析を選択した患者よりも社会復帰率が高いと言われている。当院では、2018年1月から2018年12月に当院で生体腎移植を受けて１年後もフォローされていた患者18名（うち１名は学生）のうち、16名が移植前から就労しており、15名が復職および再就職、復学している。しかし、中には移植前より透析による時間的制限で就労が困難だった患者、入院のため職を失った患者、移植後に社会復帰をしても職場の理解が得られずに退職した患者などがいる。腎移植後に社会復帰をしやすくするために①移植前や退院前に仕事や就学状況について情報収集を行い、主治医とも相談しながら病状に応じたアセスメントを行うこと②社会復帰後に関わる方に、腎移植後の外来通院間隔や治療、仕事や学業において注意すべき点などについて理解してもらうこと③一度社会復帰した後に、何か問題が生じて本人が援助を希望した場合にも相談の上で介入していくことが必要と考える。また、社会復帰支援はレシピエント移植コーディネーターのみでは行うことができず、他職種との協力が必要なケースも多い。今回、当院の腎移植後患者のうち、本人・家族より社会復帰について相談があり、MSWと連携して支援を行った事例を用いながら考察し、報告する。</p>

DOI： 10.11386/jst.55.supplement_333_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【目的】移植腎間質線維化／尿細管萎縮（IF/TA）は移植腎廃絶の大きな要因である。当院では2013年10月から、エベロリムス（EVR）を移植2週後からadd onしTac及びMMFを減量するプロトコルを採用。移植成績やIF/TAについて従来プロトコルと比較・検討した。【対象と方法】対象は2011年1月から2017年12月までに当院で腎移植を施行した104例。画像解析装置（WinROOF2015）を用いて移植腎皮質線維化の間質占有率（IFR）を測定し、0hr生検標本でのIFRを基準として移植1年時点でのその増生率を算出。両群間で移植成績を比較・検討し、移植腎間質線維増生の危険因子について解析。【結果】移植1年時点での拒絶発症率、移植腎機能、生着率は両群で差を認めなかったが、EVR群ではウイルス感染が有意に高かった（p=0.001）。IFR増生率はリツキシマブ非投与群（p=0.037）、CYP3A5 non-expresser群（p=0.027）、ウイルス感染あり群（p=0.019）、EVR非投与群（p < 0.001）で有意に高く、多変量解析ではEVR非投与群（p< 0.001）はIFR増生率の独立した危険因子であった。【結論】EVR併用プロトコルは従来プロトコルよりIFR増生率が有意に少なく、EVRは移植腎間質の線維増生を抑制する可能性がある。</p>

DOI： 10.11386/jst.55.Supplement_357_2

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【目的】移植腎間質線維化／尿細管萎縮（IF/TA）は移植腎廃絶の大きな要因である。当院では2013年10月から、エベロリムス（EVR）を移植2週後からadd onしTac及びMMFを減量するプロトコルを採用。移植成績やIF/TAについて従来プロトコルと比較・検討した。【対象と方法】対象は2011年1月から2017年12月までに当院で腎移植を施行した104例。画像解析装置（WinROOF2015）を用いて移植腎皮質線維化の間質占有率（IFR）を測定し、0hr生検標本でのIFRを基準として移植1年時点でのその増生率を算出。両群間で移植成績を比較・検討し、移植腎間質線維増生の危険因子について解析。【結果】移植1年時点での拒絶発症率、移植腎機能、生着率は両群で差を認めなかったが、EVR群ではウイルス感染が有意に高かった（p=0.001）。IFR増生率はリツキシマブ非投与群（p=0.037）、CYP3A5 non-expresser群（p=0.027）、ウイルス感染あり群（p=0.019）、EVR非投与群（p < 0.001）で有意に高く、多変量解析ではEVR非投与群（p< 0.001）はIFR増生率の独立した危険因子であった。【結論】EVR併用プロトコルは従来プロトコルよりIFR増生率が有意に少なく、EVRは移植腎間質の線維増生を抑制する可能性がある。</p>

DOI： 10.11386/jst.55.supplement_357_2

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【背景】Rituximab時代でのABO血液型不適合腎移植（ABOI-KT）における抗血液型抗体価のリバウンド現象の臨床的意義は明らかとされていない。【対象・方法】2005年11月から2019年3月までに当院でRituximab投与後にABOI-KTを施行した70例を対象とした。術直前の目標抗体価をIgG/IgMとも32倍以下に設定し、抗体除去療法は1～４回施行した。抗体除去療法後に抗体価がbaselineまで再上昇した場合、リバウンド現象有りと定義した。【結果】リバウンド現象は20例（29％；リバウンド群）で認められ、また移植後1ヶ月以内のABMR発症例は10例（14％）であった。リバウンド現象はbaseline抗体価64倍以上例（p = 0.001）と抗A抗体例(p = 0.016)で有意に発生頻度が高かった。Baselineや移植直前の抗体価とABMＲとの関連性は認められなかったが、リバウンド群では7例（35％）にABMRがみられ、非リバウンド群（50例）と比較して有意にその頻度が高く（p = 0.004）、多変量解析ではリバウンド現象がABMRの独立した危険因子であった（ｐ= 0.003）。【結語】リバウンド現象はABMR発症の危険因子であり、ABOI-KTでは目標抗体価の達成の可否のみならず、リバウンド現象の有無にも注目すべきと考える。</p>

DOI： 10.11386/jst.55.Supplement_309_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【背景】Rituximab時代でのABO血液型不適合腎移植（ABOI-KT）における抗血液型抗体価のリバウンド現象の臨床的意義は明らかとされていない。【対象・方法】2005年11月から2019年3月までに当院でRituximab投与後にABOI-KTを施行した70例を対象とした。術直前の目標抗体価をIgG/IgMとも32倍以下に設定し、抗体除去療法は1～４回施行した。抗体除去療法後に抗体価がbaselineまで再上昇した場合、リバウンド現象有りと定義した。【結果】リバウンド現象は20例（29％；リバウンド群）で認められ、また移植後1ヶ月以内のABMR発症例は10例（14％）であった。リバウンド現象はbaseline抗体価64倍以上例（p = 0.001）と抗A抗体例(p = 0.016)で有意に発生頻度が高かった。Baselineや移植直前の抗体価とABMＲとの関連性は認められなかったが、リバウンド群では7例（35％）にABMRがみられ、非リバウンド群（50例）と比較して有意にその頻度が高く（p = 0.004）、多変量解析ではリバウンド現象がABMRの独立した危険因子であった（ｐ= 0.003）。【結語】リバウンド現象はABMR発症の危険因子であり、ABOI-KTでは目標抗体価の達成の可否のみならず、リバウンド現象の有無にも注目すべきと考える。</p>

DOI： 10.11386/jst.55.supplement_309_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【緒言】高齢者では免疫応答が低下するため過剰免疫抑制に注意が必要とされる。【方法】2009年11月から2019年4月に当院で腎移植を受けたレシピエントを、移植時年齢55歳未満（若年群：97例）、55歳以上65歳未満（中年群：54例）、65歳以上（高齢群：27例）に分け、薬物動態を比較し臨床結果を後方視的に検討した。免疫抑制法はTAC、MMF、PSL、Bxで導入し2013年10月以降は移植2週後からEVRを追加した。免疫学的ハイリスク症例ではリツキシマブ投与や抗体除去を行った。高齢を理由に免疫抑制プロトコルの変更は行わなかった。【結果】夫婦間移植の割合は若年群で有意に低かった。各群間でリツキシマブ使用例や拒絶治療例の割合、移植後1年までの各免疫抑制薬の薬物動態、移植後5年までのeGFRに有意差を認めなかった。観察期間中に感染症で入院を要した症例は各群で26%、18%、14%発癌は2%、8%、11%に認められ、いずれも有意差はなかった。移植後5年正着率はそれぞれ95%、82%、87%であったがdeath censoredでは95%、96%、100%であった。【結語】65歳以上の腎移植レシピエントでは薬物動態が若年者と同等にもかかわらず、免疫抑制療法に伴う有害事象や拒絶反応の発症率が若年者と同程度であり、免疫抑制薬の過度な減量には注意が必要である。</p>

DOI： 10.11386/jst.55.Supplement_362_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【緒言】高齢者では免疫応答が低下するため過剰免疫抑制に注意が必要とされる。【方法】2009年11月から2019年4月に当院で腎移植を受けたレシピエントを、移植時年齢55歳未満（若年群：97例）、55歳以上65歳未満（中年群：54例）、65歳以上（高齢群：27例）に分け、薬物動態を比較し臨床結果を後方視的に検討した。免疫抑制法はTAC、MMF、PSL、Bxで導入し2013年10月以降は移植2週後からEVRを追加した。免疫学的ハイリスク症例ではリツキシマブ投与や抗体除去を行った。高齢を理由に免疫抑制プロトコルの変更は行わなかった。【結果】夫婦間移植の割合は若年群で有意に低かった。各群間でリツキシマブ使用例や拒絶治療例の割合、移植後1年までの各免疫抑制薬の薬物動態、移植後5年までのeGFRに有意差を認めなかった。観察期間中に感染症で入院を要した症例は各群で26%、18%、14%発癌は2%、8%、11%に認められ、いずれも有意差はなかった。移植後5年正着率はそれぞれ95%、82%、87%であったがdeath censoredでは95%、96%、100%であった。【結語】65歳以上の腎移植レシピエントでは薬物動態が若年者と同等にもかかわらず、免疫抑制療法に伴う有害事象や拒絶反応の発症率が若年者と同程度であり、免疫抑制薬の過度な減量には注意が必要である。</p>

DOI： 10.11386/jst.55.supplement_362_1

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Language：Japanese   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy. METHODS: We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score-based inverse probability of treatment weighting method to adjust for group imbalances. RESULTS: The median (range) age of the patients was 65 (59-73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting-adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups. CONCLUSIONS: Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.

DOI： 10.1111/iju.14466

PubMed

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【目的】mTOR阻害薬エベロリムス (EVR) の副作用に脂質異常症があるが、機序解明に繋がる臨床データは少ない。今回LDLコレステロールとその上昇に関与するPCSK9濃度に及ぼすEVRの影響と、mTORC1及びPCSK9遺伝子多型の影響について検討した。【方法】腎移植患者53名を対象に、患者背景、EVR血中濃度、PCSK9濃度を調査した。さらにmTORC1及びPCSK9遺伝子多型との関連を解析した。【結果】EVR投与後のPCSK9濃度は投与前に比べ有意に高く(214 vs 295ng/mL、P=0.004)、EVR AUC0-12とPCSK9濃度変化率との間に有意な相関が認められた (r=0.316、P=0.021)。加えてEVR投与後のPCSK9濃度変化率がmTORC1 rs2295080Gアレル保有患者で有意に高かった(P=0.006)。一方、PCSK9遺伝子多型およびLDLコレステロール濃度変化率は、PCSK9濃度変化率と相関しなかった。多変量解析よりmTORC1 rs2295080Gアレル保有患者、EVR AUC0-12、及び女性においてEVR投与後のPCSK9変化率の上昇に独立性が認められた。【考察】EVR誘発脂質異常症はPCSK9を介した機序が示唆された。さらにLDLコレステロール上昇は、PCSK9上昇と同時に起こるのではなく、その後徐々に上昇すると考える。</p>

DOI： 10.11386/jst.55.supplement_369_2

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>生体腎移植は待機手術として行われる。設定された手術日にピークを合わせて様々なリスクを低減化し、考え得る最善の状態で手術に臨むことが基本である。しかし、先行的腎移植（PEKT）では移植までの期間が短いためリスク評価や必要に応じた治療が不十分となる恐れがある。特に貧血は短期間での治療が困難であり周術期に輸血を施行せざるを得ない症例も多い。実際、当科の症例を見てみると2004年7月から2015年12月までの期間でPEKT群（33例）では非PEKT群（171例）と比較して当科初診時のHbが有意に低値であった。ほぼ同時期の生体腎移植症例163例の検討では102例（62.6%）で濃厚赤血球製剤が輸血されていた。背景因子の比較では、輸血施行群で非施行群と比較して有意に女性が多く（p=0.03）、腎移植前日のHb値が低値（p＜0.001）であった。幸い、免疫学的ハイリスク症例を除くと両群間でde novo DSA産生やABMRの頻度に有意差は見られなかったものの、輸血は行わないに越したことはなく、術前Hb値がより高値であれば輸血を要しなかった症例も多いと思われた。周術期の輸血回避のため、腎移植、特にPEKT施行時には術前にエリスロポエチン製剤や鉄剤などを充分に投与しHb値を上昇させておく必要がある。</p>

DOI： 10.11386/jst.55.supplement_255_2

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>【目的】mTOR阻害薬エベロリムス (EVR) の副作用に脂質異常症があるが、機序解明に繋がる臨床データは少ない。今回LDLコレステロールとその上昇に関与するPCSK9濃度に及ぼすEVRの影響と、mTORC1及びPCSK9遺伝子多型の影響について検討した。【方法】腎移植患者53名を対象に、患者背景、EVR血中濃度、PCSK9濃度を調査した。さらにmTORC1及びPCSK9遺伝子多型との関連を解析した。【結果】EVR投与後のPCSK9濃度は投与前に比べ有意に高く(214 vs 295ng/mL、P=0.004)、EVR AUC0-12とPCSK9濃度変化率との間に有意な相関が認められた (r=0.316、P=0.021)。加えてEVR投与後のPCSK9濃度変化率がmTORC1 rs2295080Gアレル保有患者で有意に高かった(P=0.006)。一方、PCSK9遺伝子多型およびLDLコレステロール濃度変化率は、PCSK9濃度変化率と相関しなかった。多変量解析よりmTORC1 rs2295080Gアレル保有患者、EVR AUC0-12、及び女性においてEVR投与後のPCSK9変化率の上昇に独立性が認められた。【考察】EVR誘発脂質異常症はPCSK9を介した機序が示唆された。さらにLDLコレステロール上昇は、PCSK9上昇と同時に起こるのではなく、その後徐々に上昇すると考える。</p>

DOI： 10.11386/jst.55.Supplement_369_2

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>症例は56歳、女性。妊娠中毒症を契機として腎機能が低下し、41歳時に血液透析導入。夫婦間生体腎移植を希望し当科受診。DSA陽性でnMFI値が高く術前にRituximab 200 mg/bodyを1回投与、新鮮凍結血漿を用いた血漿交換を4回施行した。2019年7月にABO血液型適合生体腎移植術を施行。移植後は軽度の脳梗塞を発症するも後遺症無く回復。全身状態、移植腎機能とも良好で明らかな拒絶反応を認めず、当初の予定通り退院した。腎移植後8カ月が経過した2020年3月初旬から微熱が持続し、その後38度台の発熱となり近医受診。発熱以外の自覚症状は無く細菌尿を認めたため尿路感染症として抗生物質投与で解熱するも投薬終了後に再び発熱したため当科受診。細菌尿及びCMVアンチゲネミアの陽性化を認め抗生物質及びVGCV投与を開始。速やかに解熱するも抗生物質投与が終了すると再び発熱。全身CTで右肺に境界明瞭な類円形の腫瘤像を2つ認め、精査加療目的に当科入院。呼吸器内科にコンサルトするもあらゆるマーカーが陰性。気管支鏡検査でBALを行うも確定診断に至らず退院。抗生物質投与期間中のみ解熱が得られていた。フォローの胸部レントゲン写真で右肺腫瘤陰影の増大を認め再度気管支鏡検査でBALを行い、最終的に肺アスペルギルス症の診断を得た。</p>

DOI： 10.11386/jst.55.supplement_388_1

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Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>生体腎移植は待機手術として行われる。設定された手術日にピークを合わせて様々なリスクを低減化し、考え得る最善の状態で手術に臨むことが基本である。しかし、先行的腎移植（PEKT）では移植までの期間が短いためリスク評価や必要に応じた治療が不十分となる恐れがある。特に貧血は短期間での治療が困難であり周術期に輸血を施行せざるを得ない症例も多い。実際、当科の症例を見てみると2004年7月から2015年12月までの期間でPEKT群（33例）では非PEKT群（171例）と比較して当科初診時のHbが有意に低値であった。ほぼ同時期の生体腎移植症例163例の検討では102例（62.6%）で濃厚赤血球製剤が輸血されていた。背景因子の比較では、輸血施行群で非施行群と比較して有意に女性が多く（p=0.03）、腎移植前日のHb値が低値（p＜0.001）であった。幸い、免疫学的ハイリスク症例を除くと両群間でde novo DSA産生やABMRの頻度に有意差は見られなかったものの、輸血は行わないに越したことはなく、術前Hb値がより高値であれば輸血を要しなかった症例も多いと思われた。周術期の輸血回避のため、腎移植、特にPEKT施行時には術前にエリスロポエチン製剤や鉄剤などを充分に投与しHb値を上昇させておく必要がある。</p>

DOI： 10.11386/jst.55.Supplement_255_2

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Language：Japanese   Publisher：Clinical and Experimental Nephrology  

DOI： 10.1007/s10157-019-01780-z

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Language：Japanese   Publisher：International Immunopharmacology  

DOI： 10.1016/j.intimp.2019.105881

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Language：Japanese   Publisher：Clinical Genitourinary Cancer  

DOI： 10.1016/j.clgc.2019.07.006

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Language：Japanese  

A 36-year-old female was referred to our hospital for a giant abdominal mass found by ultrasound examination. A computed tomographic scan showed a large retroperitoneal mass measuring 11 cm in diameter suspected to be liver invasion, a right atrial and inferior vena cava (IVC) tumor thrombus with obstruction of hepatic vein junction of IVC, and small lung metastases. She was diagnosed with cT4N0M1 adrenocortical carcinoma (ACC) by a needle biopsy and radiographic examination. Right adrenalectomy and thrombectomy were successfully performed without cardiac arrest and without liver dissection. The operative time was 485 minutes, and the estimated blood loss was 7, 533 ml. No major peri- or postoperative complications were observed. For the residual lung mass, a first line combination chemotherapy with etoposide, doxorubicin, cisplatin and mitotane followed by a second line chemotherapy with gemcitabine and capecitabine were administered. She has been alive with disease for 45 months under mitotane treatment against residual lung metastases. In conclusion, extended surgery could be successfully performed for advanced ACC with right atrium and IVC tumor thrombus. Although careful planning is needed for successful surgery, combination therapy with extended surgery and subsequent systematic chemotherapy may provide a substantial benefit in patients with advanced ACC.

DOI： 10.14989/actauroljap_65_10_397

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Language：Japanese   Publisher：Acta Urologica Japonica  

DOI： 10.14989/ActaUrolJap_65_10_397

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Language：Japanese  

A 68-year-old man was referred to our hospital with a right-sided renal tumor identified by ultrasonography at the time of his medical check-up. Computed tomography revealed a well-circumscribed but distorted mass measuring 64×45×57 mm in the right kidney with para-aortic lymph node swelling. Laparoscopic right nephrectomy with para-aortic lymphadenectomy was performed. Histopathological diagnosis was mucinous tubular and spindle cell carcinoma (MTSCC) (pT3a) without lymph node metastasis (pN0). Postoperatively, metastases were identified in the lungs, and the vertebral and iliac bones. The patient was treated with axitinib. The lung nodule progressed and left sacrum metastases appeared even after treatment with axitinib. Therefore, nivolumab was administered as second-line treatment. The metastases in the lungs, as well as vertebral and iliac bone showed complete response to this therapy. MTSCC of the kidney is a rare low-grade renal cell carcinoma without any established systemic therapy for metastatic or unresectable lesions. We report a case of metastatic MTSCC in a patient who showed a favorable response to nivolumab treatment. This is the first report to describe successful treatment of metastatic MTSCC with anti-programmed cell death 1 antibody.

DOI： 10.14989/actauroljap_65_9_363

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Language：Japanese   Publisher：Molecular and Clinical Oncology  

DOI： 10.3892/mco.2019.1887

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Language：Japanese   Publisher：Acta Urologica Japonica  

DOI： 10.14989/ActaUrolJap_65_9_363

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Language：Japanese   Publisher：Frontiers in Endocrinology  

DOI： 10.3389/fendo.2019.00572

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Language：Japanese  

We report a case of idiopathic penile pyoderma gangrenosum that was successfully treated with corticosteroid treatment without penectomy. A 67-year-o1d man with induration and tenderness of the penile shaft visited a local hospital. A penile abscess was suspected on magnetic resonance imaging, and needle biopsy did not reveal malignancy. After the tension of the penile shaft had worsened, he was referred to our hospital where surgical drainage and re-biopsy were performed. Microbiological cultures revealed no growth, and pathological examination revealed no evidence of malignancy. Despite drainage, the abscess recurred on postoperative day 18. With a working diagnosis of penile pyoderma gangrenosum, we initiated prednisolone 30 mg once daily followed by taper and performed a second surgical drainage, leaving the wound open to heal by secondary intention. Wound discharge declined gradually, and no recurrence of abscess has yet been observed. Pyoderma gangrenosum is clinically diagnosed when subcutaneous chronic inflammatory findings are present without concurrent bacterial infection. Corpus cavernosum abscess presenting as the initial symptom of pyoderma gangrenosum is rare. Most cases of recurrent corpus cavernosum abscess eventually result in total penectomy. In this case, we successfully avoided penectomy by suspecting pyoderma gangrenous and initiating prednisolone treatment appropriately.

DOI： 10.14989/actauroljap_65_6_219

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Language：Japanese   Publisher：Acta Urologica Japonica  

DOI： 10.14989/ActaUrolJap_65_6_219

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Language：Japanese   Publisher：Clinical Genitourinary Cancer  

DOI： 10.1016/j.clgc.2018.09.019

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Language：Japanese   Publisher：日本泌尿器内視鏡学会  

<p> 独立した腹腔鏡手術の術者となるためには, 術前決定事項として, アプローチ (経腹膜か経後腹膜か), ポートの留置部位, デバイス選択, などを自ら判断, 決定できることに加え, 術中はさらに解剖学的な理解と判断, 剥離, 止血, 脈管処理等を安全に実行する技術が要求される. 腹腔鏡技術向上のため筆者は, ①ドライボックスを用いた反復練習, ②指導医の手術を真似る, ③自らの手術を振り返る, ④他施設の手術を見る, という4項目を実践した. 一方, 教わる立場から, 教える側には①指導医間の指導内容の統一, ②手技の言語化, ③自ら判断し実践させる, という3項目が重要であると考える. 一度, 自分の型を身につけ手術を完遂できるようになると, 自分の型以外にも型があることに気づき, 型の違いを知ることで理解はさらに深まる.</p>

DOI： 10.11302/jsejje.32.21

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Language：Japanese   Publisher：株式会社医学書院  

DOI： 10.11477/mf.1413206392

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Language：Japanese   Publisher：Japanese Journal of Clinical Oncology  

DOI： 10.1093/jjco/hyy092

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Language：Japanese   Publisher：BMC Urology  

DOI： 10.1186/s12894-018-0353-4

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Language：Japanese   Publisher：International Immunopharmacology  

DOI： 10.1016/j.intimp.2018.03.004

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Language：Japanese   Publisher：Oncotarget  

DOI： 10.18632/oncotarget.25423

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Axitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration (C0, C2, C4, C8, and C12; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed. Axitinib C0 and AUC0-12 in patients with UGT1A1 poor metabolisers (*6/*6, *6/*28, and *28/*28; n = 10) were significantly higher than those in patients with UGT1A1 extensive metabolisers (*1/*1, *1/*6,*1/*28, and *27/*28; n = 36) (23.6 vs. 7.8 ng/mL, p = 0.030, and 441.3 vs. 217.1 ng h/mL, p = 0.007). The cutoff levels of C0 to predict ≥ G2 hypothyroidism and ≥ G2 anorexia were 6.6 and 7.1 ng/mL, respectively (p = 0.005 and p = 0.035). The overall survival (OS) in patients with C0 > 5 ng/mL was significantly better than that in patients with C0 < 5 ng/mL (p = 0.022). Genetic polymorphisms in UGT1A1 were significantly associated with the plasma axitinib level. The plasma axitinib level was significantly associated with the frequency of AEs and OS in patients with mRCC. No direct relationship was observed between UGT1A1 genotypes and the frequency of AEs or OS.

DOI： 10.1007/s12032-018-1113-8

PubMed

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Language：Japanese   Publisher：International Journal of Molecular Sciences  

DOI： 10.3390/ijms19030882

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Language：Japanese   Publisher：Transplantation Proceedings  

DOI： 10.1016/j.transproceed.2017.06.021

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Language：Japanese   Publisher：Clinical and Experimental Nephrology  

DOI： 10.1007/s10157-016-1375-4

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Language：Japanese   Publisher：American Journal of Nephrology  

DOI： 10.1159/000479983

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Language：Japanese   Publisher：Cancer Letters  

DOI： 10.1016/j.canlet.2017.03.034

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Language：Japanese  

DOI： 10.11477/mf.1413206022

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Language：Japanese   Publisher：Oncology Reports  

DOI： 10.3892/or.2017.5552

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Language：Japanese   Publisher：株式会社医学書院  

DOI： 10.11477/mf.1413205992

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Language：Japanese   Publisher：PLoS ONE  

DOI： 10.1371/journal.pone.0171615

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Language：Japanese   Publisher：Anti-Cancer Drugs  

DOI： 10.1097/CAD.0000000000000425

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Language：Japanese   Publisher：Surgical Laparoscopy, Endoscopy and Percutaneous Techniques  

DOI： 10.1097/SLE.0000000000000433

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Language：Japanese   Publisher：Xenobiotica  

DOI： 10.1080/00498254.2016.1235742

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Language：Japanese   Publisher：Oncotarget  

DOI： 10.18632/oncotarget.22908

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