INTRODUCTION: Upper tract urothelial carcinoma with neuroendocrine differentiation (UC-NE) is extremely rare and generally associated with aggressive behavior and poor prognosis. Optimal treatment strategies remain unclear, particularly regarding the role of nectin-4-targeted therapy. CASE PRESENTATION: A 61-year-old man was diagnosed with UC-NE of the renal pelvis. Laparoscopic nephroureterectomy revealed invasive UC-NE with lymphatic invasion (pT1, G2) and carcinoma in situ of the ureter (pTis, G1). Immunohistochemistry showed strong nectin-4 expression in the urothelial component but only weak to moderate expression in the neuroendocrine component. Ten months after surgery, para-aortic and bilateral pelvic lymph node recurrence developed. Treatment with enfortumab vedotin (EV) plus pembrolizumab achieved a complete response after 3 cycles, and remission was maintained with continued therapy. CONCLUSION: This case suggests that EV plus pembrolizumab may be effective for UC-NE and highlights the importance of evaluating nectin-4 and the tumor immune microenvironment when considering treatment strategies for this rare subtype.

BACKGROUND: Doublet therapy of androgen deprivation therapy (ADT) with androgen receptor signaling inhibitor (ARSI) or triplet therapy of ADT with docetaxel and ARSI represent possible treatment options in patients with metastatic castration-sensitive prostate cancer (mCSCaP). However, real-world data comparing these 2 treatments are lacking. Our objective was to compare prostate-specific antigen (PSA) kinetics between doublet and triplet therapy in patients with mCSCaP. METHODS: We retrospectively analyzed systemic treatment-naïve mCSCaP patients treated in Japan between 2018 and 2024. The patients received either doublet or triplet therapy. PSA nadir (≤ 0.02 ng/ml) and PSA response rates (≥ 90%, ≥ 99% reduction from baseline at 3 months) were assessed. Propensity score matching (2:1 ratio) was used to balance patient characteristics. RESULTS: After matching 768 patients with mCSCaP, 188 patients were included in the doublet and 94 in the triplet therapy groups. At 12 months, the proportion of patients achieving PSA ≤ 0.02 ng/ml was significantly higher in the triplet group than in the doublet group (P < 0.05), particularly among those with high-volume disease. PSA response ≥ 99% at 3 months was comparable between the 2 groups (P = 0.08). Treatment related adverse events (TRAEs) of grade ≥ 3 were more frequent with triplet therapy. CONCLUSIONS: Triplet therapy may offer superior PSA decline in patients with high-volume disease, however, this benefit comes at the cost of increased toxicity. Treatment choice should consider disease volume and patient tolerability.

BACKGROUND/AIM: Enfortumab vedotin (EV) is an antibody-drug conjugate approved for metastatic urothelial carcinoma (mUC); however, clinical data in elderly patients are limited. Given the increasing use of EV as a first-line or subsequent treatment, assessing its safety and efficacy in older populations is crucial. PATIENTS AND METHODS: This retrospective, multi-institutional study evaluated the safety and efficacy of EV in patients aged ≥80 years with platinum-refractory mUC. Clinical outcomes were compared with those in patients aged <80 years. Propensity score matching (PSM) was used to minimize selection bias. RESULTS: Among 129 patients included, 25 (19%) were aged ≥80 years. Median follow-up was 7.7 months. There were no significant differences in overall survival (OS: 14.7 vs. 8.9 months, p=0.411), progression-free survival (PFS: 10.2 vs. 6.5 months, p=0.972), or objective response rate (ORR: 56% vs. 46%, p=0.248) between older and younger patients. Rates of treatment discontinuation and dose reduction were comparable between patients aged ≥80 and those aged <80 years, with no statistically significant differences (8% vs. 13%, p=0.529; 28% vs. 21%, p=0.438). CONCLUSION: EV demonstrated comparable efficacy and tolerability in patients aged ≥80 years relative to younger counterparts. These findings support the safe and effective use of EV in elderly patients with mUC and highlight the need for further prospective studies in this population.

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

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

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

Urothelial carcinoma (UC), which includes bladder carcinoma (accounting for 90-95% of cases) and upper urinary tract carcinoma (comprising 5-10%), is one of the most prevalent malignancies worldwide. For several decades, platinum-based chemotherapy has been the primary treatment modality for this disease. However, recent advancements have significantly transformed the therapeutic landscape for patients with UC. This transformation has been facilitated by the introduction of various treatment options, including immune checkpoint inhibitors targeting PD-L1 or PD-1, antibody-drug conjugates that target nectin-4 or trophoblast cell surface antigen 2 expressed on cancer cells, and fibroblast growth factor receptor (FGFR) inhibitors specifically indicated for Patients with UC with FGFR3 mutations. Although these novel therapies have demonstrated marked survival benefits for patients with locally advanced or metastatic UC, their efficacy can vary depending on the specific molecular profile present on cancer cells. In this review, we summarize the molecular classifications of UC and the corresponding treatment landscape associated with these classifications.

Radiotherapy (RT) for prostate cancer increases the risk of bladder cancer. The genomic landscape of bladder cancer following RT for prostate cancer and its differentiation from bladder cancers that develop without a history of pelvic RT remains unclear. We examined gene mutations in bladder cancers that developed following RT and those that developed without prior RT. Fourteen patients who developed primary bladder cancer following brachytherapy were categorized into radiation-associated bladder tumor (RA-BT) group, whereas 33 patients diagnosed with primary bladder cancer without a history of pelvic RT were classified into the bladder tumor (BT) group. The frequency of TERT promoter mutations was 35.7% and 63.6% in the RA-BT and BT groups, respectively (p = 0.112). Among the other characteristic mutations, FGFR3 and TP53 were frequently observed in both groups (FGFR3: RA-BT vs. BT, 14.3 vs. 42.4%; TP53: RA-BT vs. BT, 50 vs. 33.3%). Rare mutations in bladder cancer were more frequently observed in the RA-BT group, including ADGRB3 (28.6%), CBL (21.4%), TGM7 (21.4%), and BTK (14.3%). There were significantly more C → T substitutions in the RA-BT group than in the BT group. In our study, the genetic mutations in the RA-BT group had distinct features from those in the BT group.

BACKGROUND: Urinary extracellular vesicles (uEVs), directly secreted from bladder cancer (BCa) cells, harbor potential for biomarker discovery. METHODS: We performed proteomic analysis to explore and validate uEV-based diagnostic markers for BCa, with a focus on cytoplasmic EV proteins. Among the 1960 proteins identified by shotgun proteomics (tandem mass tag-labeled liquid chromatography-tandem mass spectrometry [LC-MS/MS]) of uEVs from seven patients with BCa and four healthy individuals, 17 cytoplasmic EV proteins were significantly elevated in the patients' urine (fold change > 1.5; p < 0.05). These 17 proteins were subsequently validated using targeted proteomics (selected reaction monitoring/multiple reaction monitoring) using urine samples from 49 and 48 patients with and without BCa, respectively, including those with non-BCa hematuria. RESULTS: Ten measurable EV proteins remained significantly elevated in the urine of patients with BCa, with EV-EIF2S1 demonstrating the best diagnostic performance (area under the receiver operating characteristic [ROC] curve [AUC] [ROCAUC]: 0.83). Additionally, EV-EIF2S1 distinguished patients with BCa from those without BCa and hematuria in a suitable manner (ROCAUC: 0.92). Functional analysis of EIF2S1 in the BCa cell lines (T24 and 5637) showed that EIF2S1 knockdown markedly inhibited cell proliferation and induced cell cycle arrest and apoptosis, suggesting its essentiality for BCa cell growth and survival. CONCLUSIONS: This study identified EV-EIF2S1 as a novel, uEV-based BCa diagnostic marker and demonstrated its functional significance in BCa cell growth and survival.

Robotic-assisted laparoscopic radical prostatectomy and intensity-modulated radiation therapy are the most common radical treatments for localized prostate cancer, and brachytherapy (BT) also plays a role in this field. Iodine-125 (I-125) low-dose rate (LDR) prostate BT is an established treatment. However, it remains controversial. Specifically, there are a variety of issues, such as indications for combined treatment with external beam radiotherapy and androgen deprivation therapy, prostate-specific antigen follow-up, the significance of postimplant biopsy, the usefulness of salvage BT and focal therapy, reduction of toxicities, and bladder cancer after BT. In this review, we summarize the recent developments in I-125 LDR BT.

Gut microbiota plays a crucial role in the development and progression of prostate cancer, with previous studies indicating that certain bacterial taxa are more abundant in castration-resistant prostate cancer (CRPC) compared to hormone-sensitive prostate cancer (HSPC). Notably, the composition of gut microbiota can vary significantly by geographic region, and Japanese individuals have a distinct microbial profile. However, research exploring these differences within Japanese populations remains limited. This study investigated the gut microbiota differences between Japanese men with HSPC and CRPC and further validated these findings using a transgenic mouse model. Rectal swab samples were collected from 140 Japanese men diagnosed with HSPC (n = 84) or CRPC (n = 56) between September 2020 and July 2022. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Additionally, Pten-KO mice, which model the progression from HSPC to CRPC, underwent similar microbiota analysis. Results revealed significant differences in gut microbiota composition between HSPC and CRPC patients. Specifically, the CRPC group showed a higher abundance of Firmicutes, including Gemella and Lactobacillus, compared to the HSPC group. These differences were mirrored in the mouse model, where CRPC mice also showed an increase in these bacteria. This study identifies distinct microbial differences between HSPC and CRPC in Japanese men, suggesting that Gemella and Lactobacillus may be associated with the progression to castration resistance in prostate cancer. These findings suggest that gut microbiota differences may be associated with prostate cancer progression. Further research is needed to explore the potential of targeting the microbiota as a therapeutic strategy.

BACKGROUND: The efficacy of abiraterone acetate varies among patients with high-risk metastatic castration-sensitive prostate cancer (mCSPC). Both androgen receptor (AR) and cytokeratin 18 (CK18) are markers of the luminal lineage of prostate cancer, and their expression levels have been suggested to affect the response to androgen deprivation therapy (ADT). This study aimed to predict the efficacy of abiraterone acetate in high-risk mCSPC via immunohistochemical staining of biopsy specimens obtained at the time of prostate cancer diagnosis. METHODS: We retrospectively analyzed 44 patients treated with abiraterone acetate in combination with ADT. AR and CK18 expression in prostate biopsy specimens were assessed using immunohistochemical staining. RESULTS: AR and CK18 staining was not significantly associated with overall survival (OS). However, low AR staining was significantly associated with a shorter time to castration-resistant prostate cancer (TTCRPC) compared with high AR staining (log-rank test, p = 0.018). Similarly, low CK18 staining was significantly associated with a shorter TTCRPC compared with high CK18 staining (log-rank test, p = 0.037). CONCLUSIONS: Immunohistochemical analysis of AR or CK18 expression in biopsy specimens may serve as a predictive biomarker of high-risk mCSPC treated with abiraterone acetate. TRIAL REGISTRATION: None.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) targeting Nectin-4, has been available as standard care for metastatic urothelial carcinoma (mUC) patients who have progressed after platinum-based chemotherapy and checkpoint inhibitors (CPIs). However, the association between body mass index (BMI) and clinical outcomes for EV remains unknown. METHODS: We analyzed the records of 123 mUC patients who received EV. The cohort was divided into low BMI (< 22, n = 65) and high BMI (≥ 22, n = 58) groups. Propensity score matching was performed to reduce clinical bias between the two groups. RESULTS: In the total cohort (n = 123), the objective response rate (ORR) and disease control rate (DCR) were 46% and 68%, respectively. The ORR was significantly higher in the higher BMI group (62%, n = 58) compared to the lower BMI group (32%, n = 65). Among the pair-matched cohort (n = 100), despite reducing potential bias, the ORR remained significantly higher in the higher BMI group than in the lower BMI group (64% vs. 32%, p = 0.002). Both overall survival (OS) and radiographic progression-free survival (r-PFS) were longer in the higher BMI group compared to the lower BMI group (median OS: not reached vs. 8 months, p = 0.035; median r-PFS: 10 vs. 4 months, p < 0.001). On multivariate analyses, a higher BMI (≥ 22) was an independent predictor for achieving objective response and favorable OS in mUC patients treated with EV. CONCLUSIONS: The findings of this study suggest a potential association between high BMI and improved tumor response to EV in mUC patients with disease progression after platinum-based chemotherapy and CPIs.

BACKGROUND: Differences in the effectiveness of second-generation androgen receptor axis-targeted agents (ARATs) in high-risk metastatic hormone-sensitive prostate cancer (mHSPC) remain unclear. This study aimed to identify the factors influencing the efficacy of ARATs in patients with high-risk mHSPC and compare their long-term effectiveness. METHODS: Four hundred and sixty-six patients with mHSPC treated with ARATs were retrospectively recruited from our hospital and affiliated hospitals of the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2024. Cox proportional hazards analysis was performed to identify prognostic factors for overall survival in patients with mHSPC. Propensity score matching was used to adjust for the differences in clinical backgrounds of the patients. RESULTS: Univariate and multivariable analyses revealed that Gleason pattern 5 and pretreatment ALP levels were notable prognostic factors for overall survival in patients with mHSPC treated with ARATs. In the subgroup of patients with high-risk mHSPC with Gleason pattern 5, apalutamide and enzalutamide showed significantly better outcomes in terms of PSA-PFS, PFS2, and overall survival compared to abiraterone acetate though selection bias and the small number of patients may be associated with the results in this study. Univariate and multivariable analyses suggested that ARATs selection (ABI vs. APA or ENZ) may serve as an independent predictor of overall survival in patients with high-risk mHSPC with Gleason pattern 5 treated with ARATs. CONCLUSION: Gleason pattern 5 may be a predictive factor for ARAT efficacy in patients with high-risk mHSPCs.

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

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

BACKGROUND: Androgen-receptor signaling inhibitors (ARSIs) become the new standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). It is unknown whether time to castration resistance (TTCR), when using the first-line ARSIs, offers predictive value in mHSPC. We sought to assess the clinical outcomes for mHSPC patients treated with first-line ARSIs focusing on the TTCR. METHODS: Data from the ULTRA-Japan study cohort from five academic institutes (496 mHSPC patients) were retrospectively analyzed. RESULTS: The median overall survival (OS) in the total cohort was 80 months with a median follow-up of 18 months. Of 496 patients, 332 (67%), 82 (16.5%), and 82 (16.5%) were treated with first-line abiraterone acetate + prednisone, enzalutamide, and apalutamide, respectively. During the follow-up, a total of 155 (31%) were diagnosed with mCRPC with a median TTCR of 10 months. In those 155 patients, TTCR > 12 months is an independent predictor of longer OS from the first-line ARSIs. Cox regression analysis of the TTCR from initiating first-line ARSI in 496 mHSPC patients revealed three variables as independent predictors of shorter TTCR, including Gleason's score (GS) ≥ 9, the extent of disease (EOD) ≥ 2, and the presence of liver metastasis. CONCLUSION: Our results indicate that mHSPC patients with those three features are likely to have primary resistance to first-line ARSIs (doublet therapy), thus requiring consideration of other options, such as the recent triplet approach.

BACKGROUND: Upfront androgen receptor signaling inhibitor (ARSI) along with androgen deprivation therapy is the current standard of care for metastatic castration-sensitive prostate cancer. However, evidence on second-line therapy after upfront ARSI is scarce. We aimed to evaluate the oncological outcome of ARSI versus docetaxel (DOC) after upfront ARSI therapy in a real-world clinical practice. METHODS: Subjects were metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed within 2 years of upfront ARSI therapy and received ARSI (ARSI group) or DOC (DOC group) as a second-line therapy. Second-line progression-free survival (second-line PFS), and second-line overall survival (second-line OS) were assessed. Propensity score matching (PSM) was used to adjust the clinicopathological features and treatment patterns. RESULTS: A total of 101 mCRPC patients, 68 in the ARSI group, and 33 in the DOC group, were included in this analysis. Median second-line PFS was 6.3 months in the ARSI group and 4.9 months in the DOC group (p = 0.21). Median second-line OS was 25.0 months in the ARSI group and 14.2 months in the DOC group (p = 0.06). Prostate-specific antigen nadir ≤ 0.2 ng/ml during upfront ARSI therapy was significantly associated with improved second-line PFS. After PSM, no significant difference in second-line PFS and second-line OS were observed between the two groups. CONCLUSION: ARSI or DOC has comparable oncologic outcomes in terms of second-line PFS and second-line OS. Further prospective research with longer follow-ups will be needed to identify the optimal treatment after upfront ARSI therapy.

BACKGROUND/AIM: The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However, limited data are available to determine whether the introduction of novel agents affected patient characteristics, treatment patterns, and outcomes compared with the period when these agents were not available. The objective of this study was to evaluate the impact of the introduction of novel mCRPC agents on patient characteristics, treatment patterns, and outcomes. PATIENTS AND METHODS: Two cohorts of Japanese patients diagnosed with mCRPC between 2009 and 2014 (Epoch 1) and 2015 and 2019 (Epoch 2) were retrospectively analyzed. RESULTS: A total of 125 treatment-naïve mCRPC patients, consisting of 42 patients in Epoch 1 and 83 patients in Epoch 2, were evaluated. We obtained the following results: (i) a dramatic shift in the first-line treatment from docetaxel to androgen receptor axis-targeted agents (ARATs), (ii) an age range expansion for first-line treatment, and (iii) an overall survival (OS) advantage in Eopch 2 compared to Epoch 1. Multivariate analysis in the overall population showed that Epoch 2 and low prostate-specific antigen (PSA) levels at the start of first-line treatment were independent prognostic factors for OS. CONCLUSION: In real-world mCRPC practice, the introduction of novel agents has improved the prognosis of mCRPC while allowing more patients to receive mCRPC treatment across a broad age range. In addition, low PSA levels at the start of first-line treatment were associated with improved OS, indicating the importance of starting mCRPC treatment while PSA levels are low.

Hypoxia is a common feature of solid tumors. However, the impact of hypoxia on immune cells within tumor environments remains underexplored. Carbonic anhydrase 9 (CA9) is a hypoxia-responsive tumor-associated enzyme. We previously noted that regardless of human CA9 (hCA9) expression, hCA9-expressing mouse renal cell carcinoma RENCA (RENCA/hCA9) presented as a "cold" tumor in syngeneic aged mice. This study delves into the mechanisms behind this observation. Gene microarray analyses showed that RENCA/hCA9 cells exhibited elevated mouse serpinB9, an inhibitor of granzyme B, relative to RENCA cells. Corroborating this, RENCA/hCA9 cells displayed heightened resistance to antigen-specific cytotoxic T cells compared with RENCA cells. Notably, siRNA-mediated serpinB9 knockdown reclaimed this sensitivity. In vivo tests showed that serpinB9 inhibitor administration slowed RENCA tumor growth, but this effect was reduced in RENCA/hCA9 tumors, even with adjunctive immune checkpoint blockade therapy. Further, inducing hypoxia or introducing the mouse CA9 gene upregulated serpinB9 expression, and siRNA-mediated knockdown of the mouse CA9 gene inhibited the hypoxia-induced induction of serpinB9 in the original RENCA cells. Supernatants from RENCA/hCA9 cultures had lower pH than those from RENCA, suggesting acidosis. This acidity enhanced serpinB9 expression and T cell apoptosis. Moreover, coculturing with RENCA/hCA9 cells more actively prompted T cell apoptosis than with RENCA cells. Collectively, these findings suggest hypoxia-associated CA9 not only boosts serpinB9 in cancer cells but also synergistically intensifies T cell apoptosis via acidosis, characterizing RENCA/hCA9 tumors as "cold."

BACKGROUND/AIM: Radium-223 treatment reduces the risk of death in patients with metastatic castration-resistant prostate cancer (CRPC). This study analyzed the prognostic factors in patients treated with radium-223 dichloride. PATIENTS AND METHODS: Patients who received radium-223 dichloride were retrospectively analyzed. Prostate-specific antigen (PSA) response and alkaline phosphatase (ALP) decline rates were analyzed. Overall survival (OS) was evaluated using Kaplan-Meier curves, and prognostic factors for OS were assessed using Cox proportional hazards analysis. RESULTS: Fifty-six patients were included in the study. The five-year OS rate in patients after diagnosis of CRPC was 62.2% [95% confidence interval (CI)=27.55-112.45], while the five-year OS rate in patients at the initiation of radium-223 treatment was 21.3% (95%CI=17.20-36.79). Six patients (11.1%) had a >50% PSA decline rate, and 10 (17.9%) had a >50% ALP decline rate. Cox proportional hazards analysis showed that PSA levels at the initiation of radium-223 treatment [hazard ratio (HR)=1.00; 95%CI=1.00-1.00; p=0.0054] and Gleason Pattern (GP) 5 (HR=5.42; 95%CI=1.08-27.27; p=0.0400) were associated with OS. Patients with GP 5 had a significantly poorer prognosis compared with patients with a GP ≤4. Early administration of radium-223 as a first- or second-line treatment was not associated with OS compared with late administration of radium-223 as a third-line or later treatment. CONCLUSION: GP 5 and high PSA levels at radium-223 initiation were associated with worse OS. Radium-223 as first- or second-line treatment was not associated with OS. Therefore, a treatment strategy for CRPC based on GP 5 is needed.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has significantly improved the prognosis of some patients with advanced urothelial carcinoma (UC), but it does not provide high therapeutic efficacy in all patients. Therefore, identifying predictive biomarkers is crucial in determining which patients are candidates for ICI treatment. This study aimed to identify the predictors of ICI treatment response in patients with platinum-refractory advanced UC treated with pembrolizumab. METHODS: Patients with platinum-refractory advanced UC who had received pembrolizumab at two hospitals in Japan were included. Univariate and multivariate analyses were performed to identify biomarkers for progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-one patients were evaluable for this analysis. Their median age was 75 years, and the vast majority of the patients were male (85.4%). The objective response rate was 29.3%, with a median overall survival (OS) of 17.8 months. On multivariate analysis, an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥ 2 (HR = 6.33, p = 0.03) and a baseline neutrophil-to-lymphocyte ratio (NLR) > 3 (HR = 2.79, p = 0.04) were significantly associated with poor OS. Antibiotic exposure did not have a significant impact on either PFS or OS. CONCLUSIONS: ECOG-PS ≥ 2 and baseline NLR > 3 were independent risk factors for OS in patients with platinum-refractory advanced UC treated with pembrolizumab. Antibiotic exposure was not a predictor of ICI treatment response.

INTRODUCTION: The histological types of urethral cancer are mainly squamous cell or transitional cell carcinoma. Neuroendocrine tumor is extremely a rare type of urethral cancer. CASE PRESENTATION: A 72-year-old man visited with an erythema at the external urethral meatus. After 3 months, a 1-cm reddish solid tumor was found on the external urethral meatus. He had a history of bladder cancer (pTa with carcinoma in situ), including the prostatic urethra, and underwent radical cystectomy with urethrectomy and ileal conduit construction 11 years ago. After 3 months, a 1-cm reddish solid tumor was found on the external urethral meatus. The pathological diagnosis was a neuroendocrine tumor. Partial penectomy was performed. CONCLUSION: Small cell neuroendocrine tumor could occur on urethral remnant after radical cystectomy with urethrectomy for urothelial cancer. Inspection of the penis and urethral meatus is important during regular follow-up of patients after radical cystectomy.

PURPOSE: To investigate the risk of bladder cancer (BCa) in patients treated with brachytherapy for prostate cancer (PCa). METHODS: We retrospectively analyzed 583 patients with PCa who underwent brachytherapy with or without external beam radiotherapy (EBRT). We analyzed the disease-free survival (DFS) of BCa in patients with PCa who underwent brachytherapy with or without EBRT. We performed multivariate Cox regression analyses of DFS using age, EBRT, and Brinkman index (BI) score (number of cigarettes smoked per day × number of years smoking) ≥ 200 as variables for BCa after brachytherapy. RESULTS: Fourteen patients (2.4%) developed BCa after brachytherapy with or without EBRT. The percentage of high-grade urothelial carcinoma (UC) was 63.6%. A total of 85.7% of patients had non-muscle invasive BCa, and 14.3% of patients had muscle invasive BCa. DFS was longer in brachytherapy monotherapy than in combination therapy (brachytherapy + EBRT). Multivariate Cox regression analysis showed that a BI score ≥ 200 (Hazard Ratio (HR 8.61; 95% Confidence Interval (CI) 1.12-65.98) and EBRT combination (HR 3.29; 95% CI 1.03-10.52) were significantly associated with BCa development in patients with PCa treated with brachytherapy. Furthermore, patients with BI score ≥ 200 and EBRT combination had a significantly higher risk of BCa compared with patients with BI score < 200 (HR Log-rank test P = 0.010). CONCLUSION: Most cases of BCa after brachytherapy with or without EBRT are high grade and invasive. We hypothesized that the EBRT combination might be a risk factor for BCa in patients with PCa who underwent brachytherapy.

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer's disease, rheumatoid arthritis, and colon cancer. The analysis of feces from patients with prostate cancer by 16S rRNA sequencing has uncovered various associations between altered gut microbiomes and prostate cancer. Gut dysbiosis caused by the leakage of gut bacterial metabolites, such as short-chain fatty acids and lipopolysaccharide results in prostate cancer growth. Gut microbiota also play a role in the metabolism of androgen which could affect castration-resistant prostate cancer. Moreover, men with high-risk prostate cancer share a specific gut microbiome and treatments such as androgen-deprivation therapy alter the gut microbiome in a manner that favors prostate cancer growth. Thus, implementing interventions aiming to modify lifestyle or altering the gut microbiome with prebiotics or probiotics may curtail the development of prostate cancer. From this perspective, the "Gut-Prostate Axis" plays a fundamental bidirectional role in prostate cancer biology and should be considered when screening and treating prostate cancer patients.

BACKGROUND/AIM: The treatment strategy for metastatic upper tract urothelial carcinoma (mUTUC) is currently based on the evidence from metastatic urinary bladder cancer (mUBC). However, some reports have shown that the outcomes of UTUC differ from those of UBC. Therefore, we retrospectively analyzed the prognosis of patients with mUBC and mUTUC treated with first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients who underwent platinum-based chemotherapy at the Kindai University Hospital and affiliated hospitals between January 2010 and December 2021 were included in the study. There were 56 patients with mUBC and 73 with mUTUC. Kaplan-Meier curves were used to estimate progression-free (PFS) and overall (OS) survival. Multivariate analyses were performed using Cox proportional hazards model to predict prognostic factors. RESULTS: The median PFS was 4.5 and 4.0 months for the mUBC and mUTUC groups, respectively (p=0.094). The median OS was 17.0 months for both groups (p=0.821). The multivariate analysis showed no prognostic factor for PFS. The multivariate analysis for OS showed that younger age at the initiation of chemotherapy and immune checkpoint inhibitor use after first-line therapy were significantly associated with better OS. CONCLUSION: Platinum-based chemotherapy had a similar effect on patients with mUTUC and mUBC.

BACKGROUND/AIM: Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, often discovered at an advanced stage at diagnosis. Nectin-4 is expressed in a broad range of patients with UTUC and is associated with poor progression-free survival. The receptors of the erythroblastosis oncogene B (ErbB) family are potential therapeutic targets for urothelial carcinoma. Herein, we aimed to investigate the relationship of nectin-4 and ErbB family receptors, namely epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in patients with UTUC. Targeted therapies for these receptors could be used in sequence or in combination for increasing treatment efficiency. PATIENTS AND METHODS: We performed immunohisto-chemical analysis for HER2, EGFR, and nectin-4 using tissue microarrays. A total of 98 UTUC patients were included in the study. We investigated the impact of EGFR and HER2 expression status on recurrence-free survival (RFS) and cancer-specific survival (CSS) of all patients. RESULTS: The percentages of patients positive for HER2, EGFR, and nectin-4 were 97%, 70%, and 65%, respectively. The co-expression rates of HER2-EGFR, HER2-nectin-4, and EGFR-nectin-4 were 69%, 64%, and 47%, respectively. The number of patients positive for all three receptors was 47%. Higher HER2 levels were significantly associated with worse CSS and RFS. Higher EGFR levels were associated with a worse CSS. CONCLUSION: HER2, EGFR, and nectin-4 were highly expressed in UTUC. Combination of HER2-, EGFR-, and nectin-4-targeted therapy may be an effective option for the treatment of patients with UTUC.

PURPOSE: There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period. METHODS: Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT. RESULTS: OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients. CONCLUSION: The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

During tumorigenesis, certain tissues are colonized by mutant clones with oncogenic driver mutations as precancer lesions. These mutations can facilitate clonal expansion and may contribute to malignant transformation. The molecular features of low-grade non-muscle invasive bladder cancer (NMIBC) and high-grade bladder cancer are so distinct that they are thought to follow different evolutionary tumorigenesis pathways. Although NMIBC accounts for most bladder tumors, the somatic mutation patterns in "precancer" urothelium of patients with NMIBC remain unclear. Here, we analyzed specimens of normal urothelium and bladder tumors from patients with low-grade and high-grade NMIBC and investigated the genomic evolution of the cancer. Somatic mutations were analyzed using 50 oncogene-targeted sequences and droplet digital polymerase chain reaction for TERT promoter mutations. Somatic mutations in TERT promoter, FGFR3, and CDKN2A were characteristically identified in the normal urothelium of patients with NMIBC. These mutations, consistently identified in both tumor and normal specimens, likely affect clonal expansion during the malignant transformation of NMIBC. Though larger samples and comprehensive study are warranted to confirm our results, the difference in mutational landscape of the precancerous urothelium of patients with bladder cancer could offer deeper understandings of genomic evolution in bladder tumorigenesis.

PURPOSE: In this study, we aimed to elucidate the pathophysiology of post-micturition dribble (PMD) through analyzing several variables including pressure flow study (PFS) findings and symptoms questionnaire. METHODS: We retrospectively analyzed male patients who visited our department between 2010 and 2020. We used modified international prostate symptom score (m-IPSS), which consists of eight sub-score related to lower urinary tract symptoms (Incomplete Emptying, Frequency, Intermittency, Urgency, Weak Stream, Straining, Nocturia, and PMD) and one question related to quality of life (QOL). Multivariate regression analysis was conducted to evaluate the relationship between PMD and the variables, including age, prostate volume (PV), body mass index, bladder outlet obstruction index (BOOI), bladder contractility index, and bladder voiding efficiency, which were obtained by PFS. RESULTS: A total of 143 male patients were analyzed. The patients with PMD showed significantly larger PV and higher BOOI, and worse IPSS total and QOL score than those without PMD. Multivariate regression analysis showed that large PV and BOOI were significantly associated with PMD. In Spearman's correlation analysis, PMD and each m-IPSS sub-score except nocturia had significant positive correlation. Furthermore, Spearman's correlation analysis showed that PMD and QOL had significant strong positive correlation. CONCLUSION: PMD was significantly associated with large PV and BOO evaluated by PFS. Furthermore, PMD significantly exacerbated QOL. The severity of PMD and the other m-IPSS sub-score except nocturia could have intercorrelation with each other.

Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non-metastatic castration-resistant prostate cancer (nmCRPC), but cross-resistance of androgen receptor-axis-targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non-steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response >50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression-free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large-scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients.

PURPOSE: The therapeutic landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically. Here, we provide the current status and future prospective of the management of mHSPC. METHODS: We reviewed recent literature of landmark studies on the managements of mHSPC. RESULTS: Upfront docetaxel or androgen receptor signaling inhibitor (ARSi) in addition to ADT has improved survival in mHSPC patients and has become the new standard of care. Triplet therapy with docetaxel, ARSi and ADT also improved survival. In the future, triplet therapy may become the standard of care. Oligometastatic mHSPC patients could benefit from local therapy. The inclusion of risk factors or the genetic biomarkers will provide the best treatment for individual mHSPC patients. CONCLUSION: Strong systemic therapy in the first-line treatment of mHSPC has been shown to improve survival and quality of life. Currently, several clinical trials are evaluating novel compounds such as PARP inhibitor, AKT inhibitor, and immune checkpoint inhibitor. The therapeutic landscape of mHSPC management will change dramatically.

Background: Several therapeutic agents are available for metastatic castration-resistant prostate cancer (CRPC). However, prognosis is still not well developed. The Gleason score (GS) is a prognostic factor available for patients with metastatic CRPC. GSs ranging from 6 to 10 and GSs ≥8 are usually categorized as single prognostic factors. In this study, we evaluated the prognosis of high-GS metastatic CRPC in Japanese men. Methods: Overall, 105 patients with metastatic CRPC with a GS ≥8 were retrospectively analyzed. Multivariate analyses of patient age, GS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) were performed using Cox proportional hazards analysis to predict overall survival (OS). Results: GS 8 had all Gleason patterns of 4+4. Thirty patients (28.6%) had GS of 8, and 75 (71.4%) had GS of 9 or 10. As a first-line treatment for metastatic CRPC, 42 patients (40%) received abiraterone, 35 (33.3%) received enzalutamide, and 26 (24.8%) received docetaxel. The 5-year OS in patients with GS of 8 was 65.0% [95% confidence interval (CI): 43.07-86.82%], while the 5-year OS in patients with GS of 9 or 10 was 37.0% (95% CI: 24.41-56.11%). There was a significant difference in OS between the GS 8 and GS 9-10 groups (log-rank test, P=0.038). Multivariate analysis showed that GS and ECOG-PS were significant prognostic factors for OS. Conclusions: Patients with metastatic CRPC with GS 9-10 had poor prognoses, suggesting the need for additional treatment options.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

Trophoblast cell surface antigen 2 (Trop-2, encoded by TACSTD2) is the target protein of sacituzumab govitecan, a novel antibody-drug conjugate for locally advanced or metastatic urothelial carcinoma. However, the expression status of Trop-2 in upper tract urothelial carcinoma (UTUC) remains unclear. We performed immunohistochemical analysis of 99 UTUC samples to evaluate the expression status of Trop-2 in patients with UTUC and analyze its association with clinical outcomes. Trop-2 was positive in 94 of the 99 UTUC samples, and high Trop-2 expression was associated with favorable progression-free survival (PFS) and cancer-specific survival (p = 0.0011, 0.0046). Multivariate analysis identified high Trop-2 expression as an independent predictor of favorable PFS (all cases, p = 0.045; high-risk group (pT3≤ or presence of lymphovascular invasion or lymph node metastasis), p = 0.014). Gene expression analysis using RNA sequencing data from 72 UTUC samples demonstrated the association between high TACSTD2 expression and favorable PFS (all cases, p = 0.069; high-risk group, p = 0.029). In conclusion, we demonstrated that Trop-2 is widely expressed in UTUC. Although high Trop-2 expression was a favorable prognostic factor in UTUC, its widespread expression suggests that sacituzumab govitecan may be effective for a wide range of UTUC.

Recently, combination therapy including immune checkpoint inhibition (ICI) has proven to be effective as first-line therapy for patients with metastatic renal cell carcinoma. Although the first-line combination therapies with ICI have shown clinical benefit, a number of patients require second-line treatment. We report a 60-year-old man with metastatic renal cell carcinoma who was treated with pazopanib soon after nivolumab plus ipilimumab combination therapy. He experienced Grade 3 disseminated intravascular coagulation (DIC). We suspect that this was caused by an interaction between pazopanib and nivolumab even though ICI therapy was discontinued. He was treated with thrombomodulin and platelet transfusion and recovered from DIC. Treatment with pazopanib was subsequently restarted. No evidence of DIC was observed thereafter. This severe adverse reaction may have been induced by an interaction between activated proinflammatory immune cells and cytokines from an exacerbated inflammatory state and pazopanib. This report highlights the need to perform careful monitoring of patients who receive molecular targeted therapy after ICI-based immunotherapy.

Renal cell carcinoma (RCC) is known to respond to immune checkpoint blockade (ICB) therapy, whereas there has been limited analysis of T-cell responses to RCC. In this study, we utilized human carbonic anhydrase 9 (hCA9) as a model neoantigen of mouse RENCA RCC. hCA9-expressing RENCA RCC (RENCA/hCA9) cells were rejected in young mice but grew in aged mice. CD8+ T cells were the primary effector cells involved in rejection in young mice, whereas CD4+ T cells participated at the early stage. Screening of a panel of hCA9-derived peptides revealed that mouse CD8+ T cells responded to hCA9288-296 peptide. Mouse CD4+ T cells responded to lysates of RENCA/hCA9, but not RENCA cells, and showed reactivity to hCA9 276-290, which shares three amino acids with hCA9 288-296 peptide. Immunohistochemistry analysis revealed that few T cells infiltrated RENCA/hCA9 tissues in aged mice. ICB therapy of anti-PD-1/anti-CTLA-4 antibodies promoted T-cell infiltration into tumor tissues, whereas no definite antitumor effect was observed. However, additional combination with cyclophosphamide or axitinib, a vascular endothelial growth factor receptor inhibitor, induced complete regression in half of the RENCA/hCA9-bearing aged mice with increased expression of PD-L1 in tumor tissues. These results indicate that hCA9 can be a useful model neoantigen to investigate antitumor T-cell responses in mice with RCC, and that RENCA/hCA9 in aged mice can serve as a non-inflamed 'cold' tumor model facilitating the development of effective combined immunotherapies for RCC.

症例は67歳男性で、数年前に左腎細胞癌に対して開腹下根治的左腎摘除術を施行し、病理診断はclear cell renal cell carcinoma、pT4、Fuhrman grade 2であった。単発の肺転移に対して胸腔鏡下右肺部分切除術を施行し、その後も二度単発の肺転移再発を認めたためそれぞれ肺部分切除術を施行した。その後、中縦隔に12mm大のリンパ節腫大と30mm大の脾転移を認め、脾転移出現後3ヵ月目には脾転移は60mm大まで増大した。スニチニブ投与12日目に38℃台の発熱がみられた。播種性血管内凝固症候群を合併するガス産生性脾膿瘍の診断にて、スニチニブを休薬の上、meropenem 1.5g/日とthrombomodulin 19200Uを開始した。入院5日目には、腹部単純CT画像で門脈ガス像は消失し脾内ガス像の減少も認めた。thrombomodulinの投与を終了し経過観察したが、38℃前半の発熱が持続し入院8日目に再度門脈ガス像が出現した。入院11日目に放射線科医師によりエコーガイド下経皮的脾臓ドレナージを施行した。その結果、排液培養からは嫌気性グラム陽性球菌(Anaerococcus属)が検出された。ドレナージを施行後は解熱傾向となり、入院15日目には肝内門脈内のガス像の消失を認めた。入院35日目ドレーンチューブを留置したまま、腹腔鏡下脾臓摘出術(術中高度癒着のため開腹へ移行)を施行した。病理学的所見より、内部に壊死組織を含む淡明細胞癌の脾転移と診断した。術後2日目より飲水・食事再開し、術後経過は良好であり術後7日目に退院となった。

A 67-year-old man underwent open radical left nephrectomy for left renal cell carcinoma [pT4N0M1 (right lower lobe of lung)] and thoracoscopic partial right lung resection for lung metastasis. The patient subsequently developed a solitary lung metastasis at 10 months and then at 26 months postoperatively. He underwent partial lung resection on each occasion. During the 28 months postoperatively, he was found to have a 12 mm middle mediastinal lymph node metastasis and a 30 mm splenic metastasis, which gradually increased in size. Three months after discovery, sunitinib was initiated at 37.5 mg 2 weeks on/1 week off. Twelve days later, the patient presented with complaints of fever. A gas-producing splenic abscess was diagnosed and he was admitted on the same day. His condition improved with antibiotics and splenic drainage. On day 35 of hospitalization, he underwent laparoscopic splenectomy. The patient's postoperative clinical course was uneventful and he was discharged 7 days after the surgery.

This study aimed to compare the effects of abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy (ADT) with those of combined androgen blockade (CAB) therapy in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study retrospectively identified 163 patients with high-risk mHSPC at Kindai University and affiliated hospitals between January 2014 and December 2020. Kaplan-Meier analysis was used to summarize progression-free survival (PFS) and overall survival (OS). Multivariate Cox proportional hazard modeling was used to identify the prognostic factors in the overall cohort. Propensity score matching was used to adjust the clinical characteristics, and log-rank test was applied to these propensity score-matched cohorts. Seventy-four patients who received AAP with ADT and 89 patients who received CAB were included in this study. The median follow-up duration was 27 months (range, 2-89 months). The median PFS and OS were not reached by the AAP+ADT group and 15 and 79 months, respectively, in the CAB group. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score and AAP+ADT were significant prognostic factors for PFS, whereas ECOG PS score, visceral metastasis, and AAP+ADT were significant prognostic factors for OS. The 2-year PFS was 76.1% in the AAP+ADT group and 38.6% in the CAB group (P < 0.0001), and the 2-year OS was 90.2% in the AAP+ADT group and 84.8% in the CAB group (P = 0.015). In conclusion, AAP+ADT had better PFS and OS than CAB in patients with high-risk mHSPC.

Purpose: This study aimed to elucidate the relationship of psoas muscle atrophy and visceral obesity with lower urinary tract symptoms in geriatric female patients. Patients and Methods: We retrospectively reviewed the medical records of female patients aged ≥65 years. The psoas muscle index was defined, using computed tomography, as the cross-sectional area of the psoas muscle at the third lumbar vertebral level divided by the body surface area. We also measured visceral fat area at the umbilical level using computed tomography. We used logistic regression analysis to examine the relationships between the International Prostate Symptom Score (total score, voiding subscore, and storage subscore) and variables, such as age, body mass index, psoas muscle index, and visceral fat area. The International Prostate Symptom Score was categorized as mild, moderate, or severe. Results: One hundred thirty-nine patients were included in our study. In the logistic regression analysis, we found statistically significant relationships between severe (versus mild-to-moderate) International Prostate Symptom Score storage subscore and variables, including low and high levels of psoas muscle index and visceral fat area, respectively. We could not find any significant relationships between the International Prostate Symptom Score total score and voiding subscore and the variables. Conclusion: Psoas muscle atrophy and visceral fat accumulation are potential risk factors for severe storage symptoms in female patients aged ≥65 years.

OBJECTIVES: We compared sexual function by the expanded prostate cancer index composite (sexual domains of EPIC), health-related quality of life (SF-8), and International Prostate Symptom Score (I-PSS) inpatients using tadalafil after prostate brachytherapy (PB). Forty-five patients who underwent PB between April 2011 and January 2014 were included in this study. Patients were divided into the tadalafil (20 mg,once/week or once/two weeks) treated and non-treated (NT) groups. Sexual function was assessed prior to PB treatment and followed up to 24 weeks after PB. SF-8, sexual domains of EPIC, IPSS and subjective symptoms were assessed pre-PB and at 4, 8, 16, and 24 weeks post-PB. Patients in the tadalafil group achieved higher sexual function scores compared to NT group at all time points. For SF8, the patients in the tadalafil group significantly improved in mental health by the eighth week, and significantly worsened in the NT group (8 w ; p = 0.04). The voiding domains of EPIC score were found to worsen significantly after 4 weeks from PB in both groups, but the score tended to improve over 24 weeks. There was no significant difference between two groups. The I-PSS total score was found to worsen significantly in both groups post-PB, but the tadalafil group had a tendency to worsen less. PB treatment of localized prostate cancer is preferred for the preservation of sexual function. Management of sexual dysfunction with tadalafil after PB does not worsen sexual functions. We concluded that tadalafil might be applicable to mental health care in the treatment of patients with a high interest in sexual function before PB.

The aim of our study was to identify risk factors that may influence outcomes for patients presenting with Fournier gangrene. Twelve patients hospitalized and treated between August 2007 and August 2013 were included in this study. Distinct features were noted after one or two weeks of hospitalization. We did not observe a significant correlation between death risk and the extent of necrosis in this patient set. However, the extent of necrosis tended to correlate with the duration of hospitalization in the survivors. We also compared the results of blood biochemical analyses between the surviving and non-surviving groups. A significant difference was noted in the levels of glucose (Glu) after two weeks. In the non-surviving group, Glu levels were increased. These findings suggest a relationship between glycemic control after the initiation of therapy and death. We also examined the results of blood biochemical analyses according to the duration of hospitalization. The lactate dehydrogenase (LDH) levels at admission and LDH levels after two weeks were significantly higher in the patients with a duration of hospitalization longer than the median duration of 61.5 days. These findings suggest a relationship between the duration of hospitalization and the extent of necrosis at diagnosis.

We report a case of a patient with a fistula between the right ureter and external iliac artery. The patient was a 75-year-old woman who had undergone abdominal radical hysterectomy for uterine cancer, and whole pelvis radiotherapy for right external iliac lymph node metastasis. Her post-operative course was complicated by hydronephrosis of the right kidney, which was treated by the insertion of a double-J stent. While removing the frequently obstructed double-J stent after percutaneous nephrostomy, arterial hemorrhage occurred from the external urethral meatus. Computed tomographic scan demonstrated right ureteral external iliac artery fistula formation located adjacent to the pseudoaneurysm. The patient was treated successfully with endovascular stent grafting and has showed no episode of hematuria since then.

Testicular tumors of ovarian epithelial types are rare, and their etiology is unknown. Moreover, a clear treatment policy has not become settled. Under the diagnosis of a testicular tumor, this patient underwent a high orchiectomy, and the pathology revealed testicular tumor of ovarian epithelial type. CA125 was elevated for three years post-operatively and a recurrence was discovered in the left inguinal region by positron emission tomography-computed tomography. Therefore, tumor extirpation was performed. The pathology result confirmed the recurrence of testicular tumor of ovarian epithelial type. After the surgery, the patient was given combined therapy with paclitaxel and carboplatin, which is a regimen of ovarian cancer, on a triweekly basis. After five courses of this therapy, the patient remains in remission.

We experienced a case of testicular cancer that was successfully treated by salvage chemotherapy comprised of methotrexate, actinomycin D and etoposide (MEA). A 25-year-old man was admitted to our hospital with a diagnosis of stage III B2 (JUA classification) testicular cancer. The patient had multiple lung metastases, and underwent a left orchiectomy. A histopathological examination revealed a choriocarcinoma, embryonal carcinoma, mature teratoma, and a yolk sac tumor. Tumor marker levels were elevated ; human chorionic gonadotropin β was 46 mIU/ml and alpha fetoprotein was 437 ng/ml. Although he was treated post-operatively with two courses of bleomycin, etoposide and cisplatin therapy, four courses of high-dose carboplatin, etoposide and iphosphamide (VIP) therapy, and two courses of CPT-11＋ cisplatin therapy, tumor maker levels remained elevated and lung metastases were stable. Accordingly, he received three courses of MEA therapy. MEA therapy is regimen used to treat gestational trophoblastic neoplasia. After MEA therapy, levels of the tumor markers normalized. He then underwent a partial resection of lung and enucleation of lung metastasis by the video assisted thoracoscopic surgery method. Histopathological examination of the lung metastasis revealed only necrotic tissue. Tumor recurrence has not been observed in the 14 months since the MEA therapy.

A 61-year-old man visited our department with the complaint ofa palpable hard mass in the penile shaft which showed a significant uptake on fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT). He had undergone a surgery for local invasive esophageal cancer and had received adjuvant chemotherapy. Open biopsy revealed metastases in the carvenous body and the glans of the penis from esophageal squamous cell carcinoma. He died from the cancer 5 months after the biopsy in spite of additional chemotherapy.

OBJECTIVES: This study examined the association between sleep disorders and lower urinary tract symptoms in patients who had visited urology departments. METHODS: This was an independent cross-sectional, observational study. Outpatients who had visited the urology departments at the Kinki University School of Medicine or the Sakai Hospital, Kinki University School of Medicine, between August 2011 and January 2012 were assessed using the Athens Insomnia Scale and the International Prostate Symptom Score. RESULTS: In total, 1174 patients (mean age, 65.7 ± 13.7 years), with 895 men (67.1 ± 13.2 years old) and 279 women (61.4 ± 14.6 years old), were included in the study. Approximately half of these patients were suspected of having a sleep disorder. With regard to the International Prostate Symptom Score subscores, a significant increase in the risk for suspected sleep disorders was observed among patients with a post-micturition symptom (the feeling of incomplete emptying) subscore of ≥1 (a 2.3-fold increase), a storage symptom (daytime frequency + urgency + nocturia) subscore of ≥5 (a 2.7-fold increase), a voiding symptom (intermittency + slow stream + hesitancy) subscore of ≥2 (a 2.6-fold increase), and a nocturia subscore of ≥2 (a 1.9-fold increase). CONCLUSION: The results demonstrated that the risk factors for sleep disorders could also include voiding, post-micturition, and storage symptoms, in addition to nocturia.

OBJECTIVES: This study was conducted to examine the therapeutic efficacy and anti-inflammatory effect of ramelteon in elderly patients with insomnia associated with lower urinary tract symptoms (LUTS), who visited our urology department. METHODS: The study included 115 patients (102 men, 13 women) who scored ≥4 on the Athens Insomnia Scale and who wished to receive treatment. The assessment scales for therapeutic efficacy included the International Prostate Symptom Score (IPSS) for LUTS and the Insomnia Severity Index (ISI) for sleep disorders. The high-sensitivity C-reactive protein (hs-CRP) test was used to an objective assessment. The patients were treated with ramelteon (8 mg/day) for an average of 10 weeks and were then reexamined using the questionnaires and hs-CRP test to evaluate therapeutic efficacy. RESULTS: IPSS total scores declined significantly from 11.39 ± 8.78 to 9.4 ± 7.72. ISI total scores improved significantly from 11.6 ± 5.2 to 9.2 ± 5.3 (P < 0.0001). The levels of hs-CRP decreased significantly from 0.082 (standard deviation [SD] upper limit, 0.222; SD lower limit, -0.059) to 0.06 (SD upper limit, 0.152; SD lower limit, -0.032). The ISI scores ≥ 10 (n = 51) showed a weak correlation with the hs-CRP levels. CONCLUSION: Ramelteon had a systemic anti-inflammatory effect and improved sleep disorders and LUTS, suggesting that it may be a useful treatment for patients with LUTS-associated insomnia.

A 70-year-old man with the complaint of macrohematuria and hematospermia was admitted to our hospital for further examination of a cystic formation of the right seminal vesicle, 3.6 cm in diameter, detected by magnetic resonance imaging(MRI). Cystoscopy revealed no remarkable change, but urine cytology was class III. The serum concentration of prostate specific antigen (PSA) was within the normal range of 1.83 ng/ml. Transperineal needle biopsy of the prostate and cystic tumor of the seminal vesicle revealed adenocarcinoma of the prostate and seminal vesicle, but immunostaining for PSA was negative, so we diagnosed the case as primary adenocarcinoma of the seminal vesicle. Bloody fluid of the cyst was obtained by transperineal aspiration, but no cancer cells were detected by cytological examination. Total prostatectomy was performed, and pathological findings was infiltration of prostate cancer into the seminal vesicle (pT3b) because immunostaining of the PSA was positive.

A 63-year-old man visited our hospital with body weight loss. Laboratory examination revealed a high serum level of carbohydrate antigen 19-9 (CA19-9) and LDH. There were no abnormal findings in the gastrointestinal tract. Enhanced abdominal computed tomography (CT) revealed a renal tumor, 5×3 cm in diameter, in the right lower pole and multiple lymph node swelling. The right renal tumor was not a typical renal cell carcinoma, so we considered the presence of bellini duct carcinoma and renal pelvis carcinoma, we performed right nephroureterectomy. Histopathological diagnosis was urothelial carcinoma with glandular differentiation of the renal pelvis. Post operation chemotherapy with GC (gemcitabine/cisplatin: 3-cycle), MVAC (methotrexate/vinblastine/doxorubicin/cisplatin: 1-cycle), TS-1 + CBDCA (tegafur-gimeracil-oteracil potassium/carboplatin: 3-cycle) was performed for lymph node metastasis, but he died of cachexia 18 months after operation.

本研究の初年度は、2020年からのCOVID19感染拡大の影響を受け、加えて当病院内において大規模クラスターが複数回発生したことも大きく影響し、サンプル収集に苦慮した。昨年2022年度は、ようやくCOVID19感染拡大が落ち着き、通常の癌治療が実行できるようになったことから、IO-drug治療前後の血液サンプルが目標の20例を達成し、同時に手術による腫瘍組織サンプルもストックすることができた。血液サンプルは、血漿とPBMCとして液体窒素に保存しており、腫瘍サンプルは凍結標本（-80℃）とパラフィンブロックとして保存している。CTL誘導能についてのアッセイをいきなり行うのではなく、腫瘍微小免疫環境と免疫療法の治療効果と何かしらの密接な関連性が存在するという観点から、まず、腫瘍組織を用いた腫瘍浸潤免疫担当細胞の師匠環境に関するパイロット研究を計画した。IOベース複合免疫療法により、効果があった数症例と全く効果のなかった数症例について、パイロットスタディとして、多重IHCによる腫瘍内浸潤細胞の免疫プロファイルについて検討してみた。具体的には、手術によって得られた腎癌組織の免疫関連分子に対するMulticolarIHC（多重染色）を施行し、免疫担当細胞の免疫学的機能について細胞表面マーカーなどの発現を検討し、種々の結果を得た。結果に基づきMulticolor FCMやMass cytometerを用いた免疫プロファイリングを施行する予定である。なお、後述しているが、腫瘍微小免疫環境と治療効果に関するパイロット研究の一部の結果は、2024年4月の日本泌尿器科学会総会でポスター発表する予定である。

我々はペプチドワクチン開発に着手し、5分子に対するワクチンを開発し、一部は特許申請を行い、2021年度に2つの特許（特許第6900610号、特許第6918333号）を取得し得た。今回の研究目的はペプチドワクチンと各IO-drugとの併用による抗腫瘍免疫増強効果について、実際の臨床検体を用いて検討することである。COVID-19禍の影響を受け十分なサンプル収集ができなかったが、腎癌担癌患者でIO-drug非投与患者、投与患者からのサンプルを用いてIO治療によるワクチン効果増強についてパイロット研究を行い検討してきた。なお、一連のCTL誘導に関する研究結果などについては特許の関係上公表していない。

腎細胞癌に対する新規マルチペプチドワクチン（CA9、VEGFR1、EPOR、PDL1、HIF1：5種類のターゲット分子）の開発に着手し、HLA-A2拘束性の新規ペプチドのうち一部（EPOR、PDL1、HIF1）を同定し、臨床的な有用性について検討中である。また、以前に開発したCA9およびVEGFR1ペプチドワクチンをあわせて、マルチペプチドワクチンを確立する予定である。

前立腺癌患者より末梢血を採取し、末梢血単核球細胞を遠心分離とHLA-Aをanti-HLA-A11 monoclonal antibody, anti-HLA-A31 mAbとanti-HLA-A33 mAbを使用しフローサイトメトリーにて同定しHLA-A3 supertype allelesのうちHLA-A11,-A31,-A33陽性のものを対象とした。7種類の前立腺癌関連抗原のクラスI拘束性ペプチドを1抗原10種類合成し、次にLNCaPにHLA-A11,-A31,-A33分子を発現させる為にHLA-A1101,-A3101,-A3303プラスミドcDNAを挿入しHLA-A1101,-A3101,-A3303強発現LNCaPトランスフェクタントを樹立した。 また、約20例ほどのHLAタイピング及びPBMCの採取をすることができた。

腎細胞癌に対する新規ペプチドワクチン（5種類のターゲット分子）の開発に着手し、HLA-A24拘束性の新規ペプチド（EPOR、PDL1、HIF1）を同定した。EPOR、PDL1ワクチンの特許を申請し、HIF1については準備中である。また、以前に開発したCA9およびVEGFR1ペプチドワクチンをあわせて、マルチペプチドワクチンを確立した。

現在、癌ワクチン療法の多くはHLA-A3 supertype alleles陽性症例に対する適応はない。今回、癌ワクチン療法適応拡大のためにHLA-A3 supertype alleles陽性前立腺癌患者に対し癌ワクチン療法に応用し得るEZH2由来ペプチドの同定を試みた。HLA-A3 supertype alleles親和性より5種類のEZH2由来ペプチドを準備し免疫学的アッセイを施行した。結果、EZH2733-741ペプチドが最もペプチド特異的細胞障害性Tリンパ球を誘導し、癌ワクチン療法に応用しうるペプチドであることが示された。

腎細胞癌に対する新規ペプチドワクチン(5 種類のターゲット分子)の開発に着手し、一部の新規ペプチド(EPORxx)を同定した。現在特許申請準備中である。また、以前に開発したVEGFR1 ペプチドワクチンを用いた第1/2 相臨床試験を18 人の患者に対し施行し、安全性と有効性について示した。

新規ペプチドワクチン候補として、CA9、VEGFRl、EPORについてスクリーニングを行った。CA9については新規ペプチドに加え、改変ペプチドも合成し、MHCクラスI-binding affinityを調べ、5種類に絞り、CTLアッセイを行い、他の2分子に関しては、ルミネックスをもちいてIgG反応性を参考にしてCTLアッセイを行い、4-6種類に絞り込んだ。CA9とインターフェロン併用の第I -II相臨床研究およびVEGFR1ペプチドワクチンの第1相臨床研究を開始した。