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Introduction: Limited evidence exists regarding differences in post-operative renal function and ileal conduit-related complications, including ureteroenteric anastomotic stricture (UAS) and parastomal hernia (PH), between radical cystectomy (RC) with extracorporeal urinary diversion (ECUD) and robot-assisted RC with intracorporeal UD (ICUD)., Methods: We retrospectively collected the baseline and post-RC follow-up data from 179 patients receiving RC with ileal conduit UD (152 ECUD and 27 ICUD). The estimated glomerular filtration rate (eGFR, mL/min/1.73 m 2 ) and occurrence of UAS and PH were post-operatively monitored. Chronic kidney disease (CKD) stages were determined based on eGFR level. UD-related complications were evaluated using the Clavien-Dindo system. Time-course changes in eGFR level and CKD-related survival rates were compared in both the original and propensity score-matched cohorts., Results: Although the original ECUD group had higher eGFR levels (median, 60.9 vs. 52.1), comparison of the adjusted cohorts revealed no significant difference at any time points, CKD upstaging-free survival, and CKD stage 3b-free survival. Out of 179 patients, three (1.7%), eight (4.5%), and 14 (7.8%) experienced grade I, II, and IIIa UAS, respectively. Thirteen (7.3%) developed PH during follow-up. No significant differences were observed in UAS rates (p = 0.38), PH rates (p = 0.69), CKD upstaging-free survival, and CKD stage 3b-free survival between two groups., Conclusion: No significant difference was observed in post-operative renal function and UD-related complication rates among the different types of surgery in patients undergoing RC in our institute. Further research is needed to determine the optimal surgical approach for each patient to minimize risks of CKD upstaging, UAS, and PH., (© 2025 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Real-world data on health-related quality of life (HRQoL) in advanced urothelial carcinoma (aUC) receiving immune checkpoint inhibitors (ICIs) are limited. This study included 42 patients with aUC who received second-line or later pembrolizumab (n = 19), maintenance avelumab followed by first-line chemotherapy (n = 13), or adjuvant nivolumab after radical surgery (n = 10). Time-course changes in the domains and scales related to HRQoL were evaluated using the EORTC QLQ-C30, FACT-G, and SF-8 questionnaires during ICI therapy. Anchor-based approaches for minimally important differences were determined as 'improved', 'stable', and 'deteriorated'. We found significant improvements after the start of pembrolizumab treatment on many scales. Almost none of the scales changed significantly in the avelumab and nivolumab groups. Approximately 80% of the pembrolizumab group had deteriorated social/family well-being in FACT-G. Approximately 60% of the patients in the avelumab group had deteriorated general health and vitality in SF-8. In the nivolumab group, none of the scales deteriorated in > 50% of the patients. Deterioration of physical function in the SF-8 was associated with occurrence of treatment-related adverse events ≥ grade 2 during ICI therapy (P = 0.013). Our findings demonstrated that majority of patients with aUC who received ICI therapy had a stable HRQoL, which was consistent with evidence from clinical trials., (© 2024. The Author(s).)

Purpose: There is significant lack on evidence regarding the effect of non-adherence to a recommended protocol in follow-up of high-risk non-muscle-invasive bladder cancer (NMIBC), or the impact of delaying detection of recurrent lesion. Here, we aimed to investigate the optimal frequency of follow-up cystoscopy of high-risk NMIBC with respect to oncological safety in the Japanese real-world clinical practice., Methods: This retrospective single-center study included 206 patients with primary high-risk NMIBC. The intensity (%) of follow-up cystoscopy was calculated based on actual visits for cystoscopy and guideline-recommended frequency in the first 24-month follow-up period. Inverse probability of treatment weighting analyses was used to reduce the risk of bias between groups. We performed a restricted cubic spline analysis with knots at intensity of follow-up cystoscopy ≤ 100% group to examine the possible association of progression risk with the intensity of follow-up as a continuous exposure., Results: The median intensity was 87.5% (interquartile range, 75-100). Adjusted multivariate analysis for MIBC-free and progression-free survival demonstrated no significant difference between adjusted ≤ 75% and > 75% intensity groups. A restricted cubic spline analysis suggested no significant effect of the intensity of follow-up on progression risk, and hazard ratios of patients of < 100% intensity were equivalent to those of patients of 100% intensity., Conclusion: Our finding suggested decreased intensity of follow-up cystoscopy did not affect oncological outcomes in patients with high-risk NMIBC. Further prospective trials directly aimed at investigating optimized follow-up schedules for NMIBC are mandatory before substantial changes to existing clinical guidelines., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Old plantations are iconic sites, and estimating stand parameters is crucial for valuation and management. This study aimed to estimate stand parameters of a 115-year-old Japanese larch ( Larix kaempferi (Lamb.) Carrière) plantation at the University of Tokyo Hokkaido Forest (UTHF) in central Hokkaido, northern Japan, using unmanned aerial vehicle (UAV) photogrammetry. High-resolution RGB imagery was collected using a DJI Matrice 300 real-time kinematic (RTK) at altitudes of 80 and 120 m. Structure from motion (SfM) technology was applied to generate 3D point clouds and orthomosaics. We used different filtering methods, search radii, and window sizes for individual tree detection (ITD), and tree height (TH) and crown area (CA) were estimated from a canopy height model (CHM). Additionally, a freely available shiny R package (SRP) and manually digitalized CA were used. A multiple linear regression (MLR) model was used to estimate the diameter at breast height (DBH), stem volume (V), and carbon stock (CST). Higher accuracy was obtained for ITD (F-score: 0.8-0.87) and TH (R 2 : 0.76-0.77; RMSE: 1.45-1.55 m) than for other stand parameters. Overall, the flying altitude of the UAV and selected filtering methods influenced the success of stand parameter estimation in old-aged plantations, with the UAV at 80 m generating more accurate results for ITD, CA, and DBH, while the UAV at 120 m produced higher accuracy for TH, V, and CST with Gaussian and mean filtering.

The clinical utility of urine nectins in bladder cancer (BCa) is unclear. We investigated the potential diagnostic and prognostic values of urine Nectin-2 and Nectin-4. Levels of urine Nectin-2, Nectin-4, and NMP-22 were quantified using an enzyme-linked immunosorbent assay in 122 patients with BCa, consisting of 78 with non-muscle-invasive BCa (NMIBC) and 44 with muscle-invasive BCa (MIBC), and ten healthy controls. Tumor nectin expression in MIBC was evaluated with immunohistochemical staining of transurethral resection specimens. The level of urine Nectin-4 (mean: 18.3 ng/mL) was much higher than that of urine Nectin-2 (mean: 0.40 ng/mL). The sensitivities of Nectin-2, Nectin-4, NMP-22, and cytology assays were 84%, 98%, 52%, and 47%, respectively; their specificities were 40%, 80%, 100%, and 100%, respectively. Both urine Nectin-2 and Nectin-4, though not NMP-22, were found to be significantly more sensitive than cytology. A four-titer grouping based on levels of urine Nectin-2/Nectin-4 (low/high, high/high, low/low, and high/low) showed a high capability for discriminating between NMIBC and MIBC. Neither urine Nectin-2 nor Nectin-4 levels had a significant prognostic value in NMIBC or MIBC. Urine levels correlated with tumor expression and serum levels in the Nectin-4 analysis, but not in the Nectin-2 analysis. Urine nectins are potential diagnostic biomarkers for BCa.

5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a metabolite of HO-1, was administered to sarcoma cells via carbon-monoxide-releasing molecule 2 (CORM2), it enhanced sphere-forming ability. We also compared the concentration of biliverdin (BVD) (a co-product of HO-1 activity alongside CO) with sphere-forming ability when HO-1 activity was inhibited using ZnPPIX in the dark. Both cell types showed a peak in sphere-forming ability at 60-80 μM BVD. Furthermore, a cell death inhibitor assay revealed that the HO-1-induced suppression of sphere formation was rescued by apoptosis or ferroptosis inhibitors. These findings suggest that in the absence of excitation, ALA promotes HO-1 expression and enhances the stemness of sarcoma cells, although excessive HO-1 upregulation induces apoptosis and ferroptosis. Our data indicate that systemic ALA administration induces both enhanced stemness and cell death in malignant cells located in dark environments deep in the body and highlight the need to pay attention to drug delivery and ALA concentrations during phototherapy.

Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p = 0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8 + T cells and dendritic cells were observed in the tumor microenvironment. Our findings reveal the positive effects of a probiotics mixture of Lactobacillus and Bifidobacterium in enhancing anti-tumor effects through the gut-tumor immune response axis. Future clinical trials are needed to evaluate the full benefits of this novel supplement with oral probiotics in patients with advanced urothelial carcinoma., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: To evaluate prognostic factors of biochemical recurrence (BCR) in each risk group of prostate cancer patients who underwent low-dose-rate brachytherapy (LDR-BT)., Methods: A total of 944 patients with clinically confirmed prostate cancer (cT1c-3aN0M0) who had underwent LDR-BT were enrolled. The low-, intermediate-, and high-risk groups included 278, 498, and 168 patients, respectively. The median age, PSA value at diagnosis, and the follow-up period were 70 years (range: 48-84), 7.2 ng/ml (range: 1.2-113), and 91 months (range: 2-192), respectively. We evaluated the BCR-free rate, BCR-free survival, clinical recurrence-free rate, overall survival (OS), and cancer-specific survival (CSS). We conducted multivariate analysis to elucidate prognostic factors of BCR for all patients and for each risk group., Results: The 5- and 10-year OS rates were 96.0% and 89.5% and the 5- and 10-year CSS rates were 99.8% and 99.1%, respectively, while the 5- and 10-year BCR-free rates were 96.6% and 92.5% in low-risk patients, 95.7% and 90.7% in intermediate-risk patients and 93.8% and 89.0% in high-risk patients, respectively. There were no significant differences between the risk groups. Age-adjusted multivariate analysis indicated biologically effective dose (BED) <180 Gy2 as an independent prognostic factor of BCR in all patients (p = 0.005). There were no independent factors in the low- and high-risk groups, but neoadjuvant androgen deprivation therapy (ADT) (p = 0.022) and BED <180Gy2 (p = 0.042) were independent prognostic factors in the intermediate-risk group., Conclusions: LDR-BT can achieve a higher recurrence-free survival with an adequate local radiation dose (BED ≥ 180 Gy2)., (© 2022 The Japanese Urological Association.)

Iron is an essential nutrient that facilitates cell proliferation and growth, and it can contribute to tumor growth. Although iron chelators have shown great potential in preclinical cancer models, they can cause adverse side‑effects. The aim of the present study was to determine whether treatment with 5‑aminolevurinic acid (5‑ALA) has antitumor effects in bladder cancer, by reduction of mitochondrial iron without using an iron chelator, through activation of heme synthesis. T24 and MGH‑U3 cells were treated with 5‑ALA. Ferrochelatase uses iron to convert protoporphyrin IX into heme, thus additional groups of T24 and MGH‑U3 cells were transfected with synthesized ferrochelatase small interfering RNA (siRNA) either to silence ferrochelatase or to provide a negative siRNA control group, and then cell viability, apoptosis, mitochondrial Fe 2+ , the cell cycle, and ferritin expression were analyzed in all groups and compared. As an in vivo assessment, mice with orthotopic bladder cancer induced using N‑butyl‑N‑(4‑hydro‑oxybutyl) were treated with 5‑ALA. Bladder weight and pathological findings were evaluated, and immunohistochemical analysis was performed for ferritin and proliferating cell nuclear antigen (PCNA). In the cells treated with 5‑ALA, proliferation was decreased compared with the controls, and apoptosis was not detected. In addition, the expression of Fe 2+ in mitochondria was decreased by 5‑ALA, expression of ferritin was also reduced by 5‑ALA, and the percentage of cells in the S phase of the cell cycle was significantly increased by 5‑ALA. In T24 and MGH‑U3 cells with silenced ferrochelatase, the inhibition of cell proliferation, decreased expression of Fe 2+ in mitochondria, reduced expression of ferritin, and increased percentage of cells in the S phase by treatment with 5‑ALA were weakened. In vivo , no mouse treated with 5‑ALA developed muscle‑invasive bladder cancer. The expression of ferritin was weaker in mice treated with 5‑ALA and that of PCNA was higher than that in mice treated without 5‑ALA. It was concluded that 5‑ALA inhibited proliferation of bladder cancer cells by activating heme synthesis.

Background: The naturally occurring amino acid 5-aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX) biosynthesised in the mitochondria. When accumulated PpIX is excited by light (wavelength of 625-635 nm), reactive oxygen species (ROS) are generated. Here, we investigated whether 5-ALA may increase the sensitisation of prostate cancer (PCA) cells to radiotherapy through the generation of ROS via its metabolite, PpIX., Methods: Effect of 5-ALA on PC-3 and DU-145 PCA cell lines treated with ionising radiation (IR) was examined in vitro and in vivo with assessment by clonogenic assay, mitochondrial function and ROS production under normoxia or hypoxia condition., Results: 5-ALA enhanced intra-mitochondrial ROS production immediately after exposure to IR and decreased mitochondrial membrane potential via increase of intra-cellular PpIX. IR with 5-ALA induced mitochondrial dysfunction and increased ATP production, switching energy metabolism to the quiescence. Under hypoxic condition, ROS burst and mitochondrial dysfunction were induced by IR with 5-ALA resulting reducing cancer stemness and radiation resistance., Conclusion: These results suggest that combined therapy with 5-ALA and radiation therapy is a novel strategy to improve the anti-cancer effects of radiation therapy for PCA., (© 2022. The Author(s).)

We compared clinical outcomes associated with seed brachytherapy (SEED-BT) alone and SEED-BT plus external-beam radiotherapy (EBRT) for intermediate-risk prostate cancer using propensity score-matched analysis. From 2006 to 2011, 993 patients diagnosed with intermediate-risk were treated with either SEED-BT alone (n = 775) or SEED-BT plus EBRT (n = 158) at 3 tertiary hospitals. In the propensity score-matched analysis (102 pairs), median follow-up was 95 months (range 18-153 months). The 8-year biochemical recurrence-free rate (bRFR) was significantly better with SEED-BT alone than with combined radiotherapy (93.3% vs. 88.4%; HR 0.396; 95% CI 0.158-0.991). Grade 2 or greater late genitourinary toxicities were significantly fewer with SEED-BT alone than with combined radiotherapy (21.0% vs. 33.2%; HR 0.521; 95% CI 0.308-0.881). Similarly, grade 2 or greater late gastrointestinal toxicities were significantly fewer with SEED-BT alone (0% vs. 12.2%; HR 0.125; 95% CI 0.040-0.390). For the unfavorable intermediate-risk subgroups, SEED-BT alone yielded a significantly better bRFR than the combined radiotherapy (HR 0.325; 95% CI 0.115-0.915). SEED-BT alone might be a better disease-management plan than SEED-BT plus EBRT for intermediate-risk prostate cancer regardless of favorable and unfavorable characteristics., (© 2022. The Author(s).)

The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2'-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin β1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.

Background: We compared the oncological outcomes of patients who received seed brachytherapy (SEED-BT) with those who received radical prostatectomy (RP) for intermediate-risk prostate cancer., Methods: Candidates were patients treated with either SEED-BT (n = 933) or RP (n = 334). One-to-one propensity score matching was performed to adjust the patients' backgrounds. We compared the biochemical recurrence (BCR)-free rate using the Phoenix definition (prostate-specific antigen [PSA] nadir plus 2 ng/mL) for SEED-BT and the surgical definition (PSA cut-off value of 0.2 ng/mL) for RP. We also directly compared the BCR-free rates using the same PSA cut-off value of 0.2 ng/mL for both SEED-BT and RP., Results: In the propensity score-matched analysis with 214 pairs, the median follow-up treatment was 96 months (range 1-158 months). Fifty-three patients (24.7%) were treated with combined SEED-BT and external-beam radiotherapy. Forty-three patients (20.0%) received salvage radiotherapy after RP. Comparing the BCR-free rate using the above definitions for SEED-BT and RP showed that SEED-BT yielded a significantly better 8-year BCR-free rate than did RP (87.4% vs. 74.3%, hazard ratio [HR] 0.420, 95% confidence interval [CI] 0.273-0.647). Comparing the 8-year BCR-free rate using the surgical definition for both treatments showed no significant difference between the two treatments (76.7% vs. 74.3%, HR 0.913, 95% CI 0.621-1.341). SEED-BT had a significantly better 8-year salvage hormonal therapy-free rate than did RP (92.0% vs. 85.6%, HR 0.528, 95% CI 0.296-0.942, P = 0.030). The 8-year metastasis-free survival rates (98.5% vs. 99.0%, HR 1.382, 95% CI 0.313-6.083, P = 0.668) and overall survival rates (91.9% vs. 94.6%, HR 1.353, 95% CI 0.690-2.650) did not significantly differ between the treatments., Conclusions: The BCR-free rates did not significantly differ between patients treated with SEED-BT and those treated with RP for intermediate-risk prostate cancer even when they were directly compared using the surgical definition for BCR. SEED-BT and RP can be adequately compared for oncological outcomes., (© 2022. The Author(s).)

The balance of programmed death-1 (PD-1)-expressing CD8 + T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression., Competing Interests: Declaration of interests H.Nishikawa received research funding from Ono Pharmaceutical for this work, research funding and honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb and MSD, honoraria from Ono Pharmaceutical, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. H.Nishikawa is the primary inventor on pending patents PCT/JP2020/0059919 belonging to the National Cancer Center Japan and BD Biosciences. S.Koyama received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. Y.Togashi received research grants from KOTAI Biotechnologies Inc., Daiichi-Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. T.Yoshida received grants from Ono Pharmaceutical, AstraZeneca, AMGEN, Daiichi Sankyo, Bristol-Myers Squibb, MSD, Abbvie, and Takeda, and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Chugai, Novartis, Lilly, Taiho, Archer DX, and Roche outside of this study. K.S. received paid consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono Pharmaceutical, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, Medi Science, and Eisai outside of this study. Y.S. received research funding from Ono Pharmaceutical and Janssen Pharma and personal fees from AstraZeneca, Chugai, and Pfizer. N.Y. received personal fees from Ono Pharmaceutical, grants from Bristol-Myers Squibb, grants and personal fees from Novartis Pharma K.K., outside the submitted work. All other authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Higher quality of postimplant dosimetric evaluation is associated with higher biochemical recurrence-free survival rates after low-dose-rate brachytherapy for localized prostate cancer. Postimplant prostate D90 is a key dosimetric parameter showing the quality of low-dose-rate brachytherapy. In this study, to improve the quality of low-dose-rate brachytherapy for localized prostate cancer, we investigated pre-implant factors affecting the reduction of postimplant prostate D90., Methods: A total of 441 patients underwent low-dose-rate brachytherapy monotherapy and 474 patients underwent low-dose-rate brachytherapy with external beam radiation therapy. Logistic regression analysis was carried out to identify predictive factors for postimplant D90 decline. The cut-off value of the D90 decline was set at 170 Gy and 130 Gy in the low-dose-rate brachytherapy monotherapy group and low-dose-rate brachytherapy with external beam radiation therapy group, respectively., Results: On multivariate analysis, neoadjuvant androgen deprivation therapy was identified as an independent predictive factor for the decline of postimplant D90 in both the low-dose-rate brachytherapy monotherapy group (P < 0.001) and low-dose-rate brachytherapy with external beam radiation therapy group (P = 0.003). Prostate volume changes and computed tomography/transrectal ultrasound prostate volume ratio were significantly and negatively correlated with the postimplant D90. The prostate volume changes and computed tomography/transrectal ultrasound prostate volume ratio were significantly higher in patients with neoadjuvant androgen deprivation therapy than those without neoadjuvant androgen deprivation therapy (P < 0.001)., Conclusions: Neoadjuvant androgen deprivation therapy decreased postimplant D90 with substantial prostate gland swelling after low-dose-rate brachytherapy. When neoadjuvant androgen deprivation therapy is required to reduce prostate volume for patients with large prostate glands and offer adequate local control for patients with high-risk prostate cancer before low-dose-rate brachytherapy, intraoperative D90 adjustment might be necessary., (© 2021 The Japanese Urological Association.)

Objectives: The bladder urothelium is not always impermeable. During sleep, the bladder might absorb urine in healthy individuals who sleep through the night. This study aimed to determine whether the bladder absorbs urine by using a method other than ultrasonic scanning and to simultaneously evaluate sleeping conditions., Methods: Eleven participants (five males, six females) aged 20 to 49 years without lower urinary tract symptoms or urination while sleeping were enrolled. Bladder volume was estimated by studying the relationship between dilution and absorbance of indigo carmine dissolved in urine. A 12F Foley catheter was inserted into the bladder before sleep. Urine samples (5 mL) were extracted at 2, 3, 4, 5, and 6 am sleep stages were monitored with a single-channel portable electroencephalograph device., Results: The estimated bladder volume at 6 am and voided volume immediately after rising were significantly correlated (Spearman's ρ = 0.62, P = .046). Eight participants (three males, five females) showed an absorption pattern of the estimated bladder volume change. In a male participant, the blue dye's strength gradually decreased until 4 am (estimated 859 mL) and increased from 5 am (estimated 455 mL). In another, the blue dye's strength increased at 4 am (estimated 449 mL) vs at 3 am (estimated 757 mL). In all participants, electroencephalograph data demonstrated that sleep was maintained despite having a full bladder., Conclusions: The bladder absorbs urine and maintains an approximate volume of functional bladder capacity during sleep to avoid incontinence and maintain sleep in adults due to an urge to void urine during the sleep cycle., (© 2021 John Wiley & Sons Australia, Ltd.)

Purpose: We investigated sleep parameters and patient-reported outcomes before, during, and after induction Bacillus Calmette-Guerin therapy using questionnaires and actigraphy in patients with non-muscle invasive bladder cancer., Methods: We investigated 10 patients who received Bacillus Calmette-Guerin therapy once weekly for 8 weeks. The International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, Functional Assessment of Cancer Therapy-Bladder, and multi-item Short Form-8 tools were used to assess patient-reported outcomes. Participants completed all questionnaires before (baseline), at the 4th and 8th doses, and 1 month after the last Bacillus Calmette-Guerin dose. The MotionWatch8 was fastened to patients' waist throughout the study. Composite sleep quality was determined based on sleep duration, efficiency, and fragmentation., Results: We observed a transient increase in frequency/nocturia subscores and the insomnia subscore. The number of patients with poor sleep quality increased from 0 (0%) at baseline to 7 (70%) at the 4th dose and to 6 (60%) patients at the 8th dose. Among 10 patients, 6 (60%) were assigned to the sleep deterioration group and 4 (40%) to the non-deterioration group. Sleep quality was restored to baseline levels in 5 of 6 patients (83%) within 1 month after the last dose in the sleep deterioration group, and the nocturia subscore of the International Prostate Symptom Score was significantly increased only in this group (P=0.03)., Conclusions: This is the first study that confirms intravesical Bacillus Calmette-Guerin-induced sleep quality deterioration based on a questionnaire survey and actigraphy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To compare the effects of naftopidil and silodosin administration on the quality of life of patients with prostate cancer who underwent low-dose-rate brachytherapy., Methods: In total, 141 men diagnosed with localized prostate cancer who were treated with low-dose-rate brachytherapy were enrolled. Patients were randomized (1:1) to the naftopidil (75 mg/day, n = 63) or silodosin group (8 mg/day, n = 64). Naftopidil and silodosin were administered 1 day after low-dose-rate brachytherapy, and were continued for at least 3 months. Using the University of California at Los Angeles Prostate Cancer Index and Sexual Health Inventory for Men scores, the mean changes and rates of deterioration from baseline were compared. The deterioration rates in the quality of life of patients at 1 and 3 months after low-dose-rate brachytherapy were evaluated based on the minimal important difference., Results: The rates of deterioration from baseline to 1 and 3 months after low-dose-rate brachytherapy were not significantly different between the two groups in terms of urinary function, urinary bother, bowel bother, sexual function or Sexual Health Inventory for Men scores. In contrast, there were significant differences in bowel function (naftopidil 1 month, 52%; 3 months, 52%; silodosin 1 month, 28%; 3 months, 34%; 1 month, P < 0.01; 3 months, P = 0.048) and sexual bother (naftopidil 3 months, 11%; silodosin 3 months, 29%; P = 0.01)., Conclusions: Naftopidil and silodosin provide different disease-specific quality of life outcomes in patients undergoing, especially in terms of bowel function and sexual bother. These findings can help in the selection of α-1 adrenoceptor antagonists after low-dose-rate brachytherapy., (© 2021 The Japanese Urological Association.)

Objectives: To evaluate the diagnostic performance of fluorescent voided urine cytology (FVUC) using a novel automated detection technology to screen for primary bladder cancer and for surveillance of recurrent bladder tumour., Patients and Methods: We created a rapid, objective, automated, and high-throughput detection device for hexylaminolevulinate-mediated FVUC, named the cellular fluorescence analysis unit-II (CFAU-II). Two different cohorts were used in this study: (i) screening test for primary bladder cancer (165 patients with bladder cancer and 52 controls), and (ii) surveillance test for detecting intravesical recurrent tumour (192 patients with treated non-muscle-invasive bladder cancer and 15 with post-nephroureterectomy upper urinary tract cancer). Voided urine samples were subjected to urine analysis, conventional VUC (cVUC), and FVUC. Diagnostic performance was compared between cVUC, FVUC, and a combination of the two., Results: A total of 614 urine samples were successfully collected, processed, and analysed. Comparative analysis of the screening test cohort demonstrated that the overall sensitivity of FVUC (63%, P < 0.001) and combination testing (72%, P < 0.001) was significantly higher than that of cVUC (29%). FVUC was found to be superior in most of the subgroups, especially in low-grade, Ta, and small tumours. Analysis of the surveillance test cohort showed that combination testing achieved a sensitivity of 82% and a negative predictive value of 98%, whereas those of cVUC were 39% and 96%, respectively. According to the pathological finding of recurrent tumours presenting false-negative result in the FVUC, the majority of the overlooked recurrent diseases were Ta low-grade tumours. Logistic regression analysis suggested an association between the risk of false-positive results and high density of urine white blood cells and alkaluria., Conclusion: The present findings clearly demonstrate that FVUC using the newly developed automation technology has superior sensitivity to cVUC for both screening for primary bladder cancer and recurrent tumour detection. It is essential to confirm the clinical usefulness of this method via further large-scale studies, in addition to ensuring its affordability and availability., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

Background: The administration of 5-aminolevulic acid hydrochloride (5-ALA·HCl) 3 h (range: 2-4 h) before photodynamic diagnosis (PDD) is recommended for detecting bladder tumors. However, there is insufficient evidence on the time duration for the fluorescence of PDD after oral administration of 5-ALA. We investigated the sustainability of the photodynamic effect and protoporphyrinⅨ (PpⅨ) after 5-ALA administration in a carcinogen-induced bladder tumor rat model and bladder cancer cell lines., Methods: The carcinogen-induced bladder tumor orthotopic rat model was established by the administration of N-butyl-N-(4-hydroxybutyl) nitrosamine., Results: Red fluorescence was visible 2-8 h after the oral administration of 5-ALA in the carcinogen-induced bladder tumor rat model. Plasma and intratissue PpⅨ (nM) progressed to a higher level at 2 h and remained almost constant 2-8 h after oral administration of 5-ALA. The peak fluorescence intensity of PpⅨ was observed 3-4 h after the administration of 5-ALA in bladder cancer cell lines. The accumulated PpⅨ remained for 4 h after the removal of 5-ALA in UMUC3 cells. It was not clearly visible 3 h after the removal of 5-ALA in MGHU3 and T24 cells. The expression level of ferrochelatase was significantly lower in UMUC3 cells than in other cells. Our findings suggest that 5-ALA-assisted PDD (ALA-PDD) can aid in detecting non-muscle-invasive bladder cancer 2-8 h after 5-ALA administration., Conclusion: Urologists might not be required to make excess effort to start ALA-PDD-assisted transurethral resection of bladder tumor after the administration of 5-ALA., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette-Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000-2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG.

Background: Transurethral resection of bladder tumor (TURBT) is an essential procedure both for the treatment and staging of bladder cancer, particularly non-muscle invasive bladder cancer (NMIBC). The dissemination of cancer cells during resection and the consequent seeding into the bladder mucosa is the main cause of post-TURBT intravesical recurrence. Although the tumor dissemination is inevitable during conventional TURBT (cTURBT), this drawback can be overcome by tumor resection in one piece with intact surrounding normal tissues, referred to as en bloc resection. We previously described the photodynamic diagnosis (PDD)-assisted en bloc TURBT (EBTUR) technique and its favorable outcomes. Based on our preliminary studies, this randomized controlled trial was designed to evaluate the superiority of PDD-EBTUR to PDD-cTURBT., Methods: The FLEBER study is a single-center randomized controlled trial in NMIBC patients who require TURBT. The longest diameter of the tumor must be between 6 and 30 mm. A total of 160 eligible patients will be enrolled after screening and randomly allocated to the PDD-EBTUR (experimental) and PDD-cTURBT (control) groups in a 1:1 ratio (80 cases to 80 cases). All patients will be treated using a single, immediate postoperative intravesical chemotherapy with epirubicin. The primary endpoint of this trial is the 2-year recurrence-free survival after surgery in pathologically proven low- or intermediate-risk NMIBC. All patients will be monitored by cystoscopy and urine cytology every 3 months for 2 years. Patient data including adverse events and complications, and data from frequency volume charts, pain scales, and health-related QOL questionnaires will be collected before and after the TURBT at indicated visits., Discussion: The goal of this trial is to determine the potential benefits of PDD-cTURBT and PDD-EBTUR followed by a single immediate postoperative intravesical chemotherapy in patients with low- or intermediate-risk NMIBC who undergo TURBT. Ultimately, our findings will lead to the development of better interventions and potentially change the standard of care., Trial Registration: This clinical trial was prospectively registered with the UMIN Clinical Trials Registry on 1 August 2020. The reference number is UMIN000041273 , and the Ethics Committee of Nara Medical University Approval ID is 2702.

Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome ( p = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16-0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact p = 0.011; incidence rate ratio 0.37, Clopper-Pearson confidence interval 0.15-0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT.

Background: A history of preoperative obstructive pyelonephritis has been reported as a risk factor for febrile urinary tract infection (fUTI) after ureteroscopic lithotripsy (URSL). But there is no clear evidence of risk factors for developing fUTI including the optimal timing of URSL after obstructive pyelonephritis treatment., Methods: Of the 1361 patients, who underwent URSL at our hospital from January 2011 to December 2017, 239 patients had a history of pre-URSL obstructive pyelonephritis. The risk factors were analyzed by comparing the patients' backgrounds with the presence or absence of fUTI after URSL. The factors examined were age, gender, body mass index, comorbidity, presence or absence of preoperative ureteral stent, stone position, stone laterality, stone size, Hounsfield unit (HU) value on computed tomography scan, history of sepsis during obstructive pyelonephritis, period from antipyresis to URSL, ureteral stenting period, operation time, and presence or absence of access sheath at URSL. In addition, the stone components and renal pelvic urinary culture bacterial species during pre-URSL pyelonephritis were also examined., Results: Post-URSL fUTI developed in 32 of 239 patients (13.4%), and 11 of these 32 cases led to sepsis (34.4%). Univariate analysis showed that stone position, stone maximum HU value, presence of sepsis during obstructive pyelonephritis, period from antipyresis to URSL, pre-URSL ureteral stent placement, operation time were risk factors of fUTI. Stone components and urinary cultures during pyelonephritis were not associated with risk of fUTI. Multivariate analysis showed that renal stone position, pre-URSL ureteral stent placement > 21 days, and operation time > 75 min were independent risk factors of fUTI following the URSL., Conclusions: F-UTI following the URSL could be avoided by ureteral stent placement period 21 days or less and operation time 75 min or less in patients with obstructive pyelonephritis.

Objective: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score., Methods: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves., Results: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models., Conclusions: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: 5-aminolevulinic acid (5-ALA) is a constituent of mitochondrial electron carriers, heme and cytochrome c, which are crucial for aerobic energy metabolism and cell apoptosis. We investigated the chemopreventive efficacy of 5-ALA against prostate cancer using the FVB-transgenic adenocarcinoma of mouse prostate (FVB-TRAMP) model., Methods: Samples were collected from 24 FVB-TRAMP mice at 12 and 20 weeks of age (named the first and second sets, respectively). Sixteen mice (from the first set) were randomly allocated into 3 treatment groups: 1) control (no treatment), 2) low dose of 5-ALA (30 mg/kg/day), and 3) high dose of 5-ALA (300 mg/kg/day). Similarly, 8 mice were divided into 2 treatment groups: 1) control and 2) high dose of 5-ALA (300 mg/kg/day). 5-ALA was orally administered to mice before cancer onset, from 6 weeks of age., Results: In the control group, prostate cancer was pathologically detected in 33 and 50 % of mice at 12 and 20 weeks, respectively, while 25% of 12-week old mice in the low-dose group were affected and none of the high-dose group mice developed prostate cancer. Immunohistochemical analysis showed higher expression of cytochrome c oxidase subunit 4 (COX4) in the prostate gland of the high-dose group compared to the control (P = 0.018). Similarly, enzyme-linked immunosorbent assay using lysed prostate tissue revealed higher amounts of cytochrome c in the prostate of the high-dose group compared to the control (P = 0.021). Furthermore, western blot analysis showed higher level of cleaved caspase-3 in mice in the high-dose group diagnosed with high-grade prostatic intraepithelial neoplasia., Conclusion: Our results suggest that oral 5-ALA may support the functional expression of mitochondrial cytochrome c and COX4, leading to caspase 3-dependent apoptosis in carcinogenesis in FVB-TRAMP mice. Future clinical studies are warranted to confirm the chemopreventive value of 5-ALA in prostate carcinogenesis. , .

Claudin-4 (CLDN4) is a tight junction protein to maintain the cancer microenvironment. We recently reported the role of the CLDN4 not forming tight junction in the induction of epithelial-mesenchymal transition (EMT). Herein, we investigated the role of CLDN4 in renal cell carcinoma (RCC), focusing on CLDN4. CLDN4 expression in 202 RCCs was examined by immunostaining. CLDN4 phosphorylation and subcellular localization were examined using high metastatic human RCC SN12L1 and low metastatic SN12C cell lines. In 202 RCC cases, the CLDN4 expression decreased in the cell membrane and had no correlation with clinicopathological factors. However, CLDN4 was localized in the nucleus in 5 cases (2%), all of which were pT3. Contrastingly, only 6 of 198 nuclear CLDN4-negative cases were pT3. CLDN4 was found in the nuclear fraction of a highly metastatic human RCC cell line, SN12L1, but not in the low metastatic SN12C cells. In SN12L1 cells, phosphorylation of tyrosine and serine residues was observed in cytoplasmic CLDN4, but not in membranous CLDN4. In contrast, phosphorylation of serine residues was observed in nuclear CLDN4. In SN12L1 cells, CLDN4 tyrosine phosphorylation by EphA2/Ephrin A1 resulted in the release of CLDN4 from tight junction and cytoplasmic translocation. Furthermore, protein kinase C (PKC)-ε phosphorylated the CLDN4 serine residue, resulting in nuclear import. Contrarily, in SN12C cells that showed decreased expression of EphA2/Ephrin A1 and PKCε, the activation of EphA2/EphrinA1 and PKCε induced cytoplasmic and nuclear translocation of CLDN4, respectively. Furthermore, the nuclear translocation of CLDN4 promoted the nuclear translocation of Yes-associated protein (YAP) bound to CLDN4, which induced the EMT phenotype. These findings suggest that the release of CLDN4 by impaired tight junction might be a mechanism underlying the malignant properties of RCC. These findings suggest that the release of CLDN4 by impaired tight junction might be one of the mechanisms of malignant properties of RCC.

Over the past decade, an "immunotherapy tsunami", more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.

Objectives: To evaluate the use of cyclooxygenase-2 inhibitors in patients receiving low-dose-rate brachytherapy for prostate cancer., Methods: A total of 310 patients with prostate cancer (cT1c-3aN0M0) who received low-dose-rate brachytherapy between May 2010 and July 2013 were enrolled and allocated to one of the two treatment groups (tamsulosin alone 0.2 mg/day for 6 months vs tamsulosin 0.2 mg/day for 6 months plus celecoxib 200 mg/day for 3 months). The primary end-point was the chronological change in international prostate symptom score, and the number of patients was assessed for the primary end-point. Biochemical recurrence-free, cancer-specific survival and overall survival rates 5 years after the last patient received low-dose-rate brachytherapy were retrospectively examined., Results: The median follow-up period after low-dose-rate brachytherapy was 72.0 months (range 3-99 months). A total of 12 (3.9%) patients experienced biochemical recurrence. The biochemical recurrence-free rate in the celecoxib group (5-year biochemical recurrence-free rate 98.5%) was significantly better (log-rank test P = 0.023, 95% confidence interval 0.07-0.63, hazard ratio 0.20) than that in the tamsulosin group (5-year biochemical recurrence-free rate 93.4%). None of the patients died from prostate cancer. However, 14 (4.5%) patients died of other causes. No significant difference was observed in terms of overall survival between the celecoxib and tamsulosin groups., Conclusions: The combination of cyclooxygenase-2 inhibitor and low-dose-rate brachytherapy can contribute to a better biochemical control of prostate cancer., (© 2020 The Japanese Urological Association.)

Chemotherapy-induced adverse effects can reduce the relative dose intensity and quality of life. In this study, we investigated the potential benefit of supplementary anamorelin and 5-aminolevulinic acid (5-ALA) as preventive interventions against a gemcitabine and cisplatin (GC) combination chemotherapy-induced adverse effects in a mouse model. Non-cancer-bearing C3H mice were randomly allocated as follows and treated for 2 weeks-(1) non-treated control, (2) oral anamorelin alone, (3) oral 5-ALA alone, (4) gemcitabine and cisplatin (GC) chemotherapy, (5) GC plus anamorelin, and (6) GC plus 5-ALA. GC chemotherapy significantly decreased body weight, food intake, skeletal muscle mass and induced severe gastric mucositis, which resulted in decreased ghrelin production and blood ghrelin level. The supplementation of oral anamorelin to GC chemotherapy successfully mitigated decrease of food intake during the treatment period and body weight loss at day 8. In addition, analysis of the resected muscles and stomach revealed that anamorelin suppressed chemotherapy-induced skeletal muscle atrophy by mediating the downregulation of forkhead box protein O-1 (FOXO1)/atrogin-1 signaling and gastric damage. Our findings suggest the preventive effect of anamorelin against GC combination chemotherapy, which was selected for patients with some types of advanced malignancies in clinical practice.

Background: Selecting the treatment procedure for cancer patients is a challenging task. We report our initial experience of complete laparoscopic radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC)., Methods: A total of four patients with UTUC underwent complete laparoscopic RNU combined with transvesical laparoscopic excision of the distal ureter using three 5-mm ports. Transvaginal specimen extraction was applied in female patients to reduce incisional pain and improve cosmesis. Peri-operative complications were evaluated using the Clavien-Dindo classification system. Postoperative pain was evaluated during hospitalization using a numeric pain rating scale (scales of 1 to 10). Patients who underwent retroperitoneal laparoscopic surgery combined with open excision of the distal ureter during the same period were included as a control group (conventional RNU, consisting of laparoscopic nephrectomy combined with open bladder cuff excision) for pain scale evaluation., Results: The novel surgery was successfully completed for all four patients (two males and two females). The mean pneumoperitoneum time for retroperitoneoscopic nephroureterectomy and specimen extraction was 174 min, while the mean pneumovesicum time for the ureteral orifice excision was 88 min. One male patient had bladder leakage at the suture site of the bladder wall, which lasted for 2 weeks. No patient experienced recurrent disease during the follow-up period (median, 10 months). Mild to moderate pain lasted for 5 or 6 days after RNU. A couple of days after surgery, the numeric pain rating scale of complete laparoscopic RNU and conventional RNU group reached its peak level at 3.0 ± 1.8 and 5.3 ± 2.8, respectively. There was no statistical difference in the degree of postoperative pain (P = 0.31)., Conclusions: We described our initial experience and outcome of complete laparoscopic RNU for UTUC. Further experience and research are required to determine whether this advanced laparoscopic technique yields better outcomes and has true clinical value.

Sarcopenia is a muscle loss syndrome known as a risk factor of various carcinomas. The impact of sarcopenia and sarcopenia-related inflammatory/nutritional markers in metastatic urothelial carcinoma (mUC) treated with pembrolizumab was unknown, so this retrospective study of 27 patients was performed. Psoas muscle mass index (PMI) was calculated by bilateral psoas major muscle area at the L3 with computed tomography. The cut-off PMI value for sarcopenia was defined as ≤6.36 cm 2 /m 2 for men and ≤3.92 cm 2 /m 2 for women. Neutrophil-to-lymphocyte ratio (NLR) ≥ 4.0 and sarcopenia correlated with significantly shorter progression-free survival (PFS) (hazard ratio (HR) 3.81, p = 0.020; and HR 2.99, p = 0.027, respectively). Multivariate analyses identified NLR ≥ 4.0 and sarcopenia as independent predictors for PFS (HR 2.89, p = 0.025; and HR 2.79, p = 0.030, respectively). Prognostic nutrition index < 45, NLR ≥ 4.0 and sarcopenia were correlated with significantly worse for overall survival (OS) (HR 3.44, p = 0.046; HR 4.26, p = 0.024; and HR 3.92, p = 0.012, respectively). Multivariate analyses identified sarcopenia as an independent predictor for OS (HR 4.00, p = 0.026). Furthermore, a decrease in PMI ≥ 5% in a month was an independent predictor of PFS and OS (HR 12.8, p = 0.008; and HR 6.21, p = 0.036, respectively). Evaluation of sarcopenia and inflammatory/nutritional markers may help in the management of mUC with pembrolizumab., Competing Interests: The authors declare no conflict of interest.

Background: Because patients with prostate-specific antigen (PSA) bounce do not experience biochemical recurrence (BCR) until PSA bounce occurs, the period until PSA bounce ends can be considered the so-called lead-time bias. Therefore, we evaluated differences in BCR-free rate in prostate cancer patients who were BCR-free 4 years after 125I-brachytherapy alone. Furthermore, we evaluated predictors for PSA bounce and the correlation between testosterone and PSA bounce., Methods: From 2004 to 2012, 256 patients with prostate adenocarcinoma underwent 125I-brachytherapy alone. PSA and testosterone levels were monitored prior to 125I-brachytherapy, at 1, 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months after 125I-brachytherapy and yearly after 5-year follow-up. PSA bounce was defined as ≥0.2 ng/ml increase above the interval PSA nadir, followed by a decrease to nadir or below., Results: BCR-free rate in patients with PSA bounce (100% 7-year BCR-free rate) was significantly better (P < 0.044) than that in patients without PSA bounce (95.7% 7-year BCR-free rate) in patients who were BCR-free 4 years after 125I-brachytherapy alone (n = 223). Age was the only predictor (odds ratio: 0.93, 95% confidence interval: 0.88-0.98, P = 0.004) for PSA bounce (n = 177). The testosterone level at PSA bounce was significantly higher (P = 0.036) than that at nadir before PSA bounce (87 cases)., Conclusions: Patients with PSA bounce had good BCR-free rate even in patients who were BCR-free 4 years after 125I-brachytherapy alone. Testosterone levels were higher at PSA bounce; increased testosterone levels may be a cause of PSA bounce., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle-invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony-stimulating factor (GM-CSF) to chemoimmunotherapy with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 10 5 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non-treated control (vehicle only); (ii) anti-mPD-L1 monotherapy; (iii) mGM-CSF monotherapy; (iv) anti-mPD-L1 plus mGM-CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti-mPD-L1; (vii) GC plus mGM-CSF; and (viii) GC plus anti-mPD-L1 plus mGM-CSF. After completing 2-week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti-mPD-L1 and mGM-CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti-mPD-L1, and mGM-CSF resulted in longer LR-free survival and cancer-specific survival compared to those in other groups. These effects involved an immunotherapy-related decrease in oncological properties such as tumor invasion capacity and epithelial-mesenchymal transition. mGM-CSF significantly decreased the accumulation of myeloid-derived suppressor cells in both the blood and tumor microenvironment and blood interleukin-6 levels. Supplementary GM-CSF to neoadjuvant GC plus PD-L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients undergoing pre-surgical DCE-MRI and PDD-assisted endoscopic surgery accompanied by biopsies of the eight segmentations were analyzed. Immunohistochemical analysis of the biopsies revealed hypervascularity of CIS lesions, a cause of strong submucosal contrast-enhancement. It was found that 56 (16.2%) of 344 biopsies had pathologically proven CIS. In the DCE-MRI, the overall sensitivity and specificity for detecting CIS were 48.2% and 81.9%, respectively. We set out two different combinations of PDD and DCE-MRI for detecting CIS. Combination 1 was positive when either the PDD or DCE-MRI were test-positive. Combination 2 was positive only when both PDD and DCE-MRI were test-positive. The overall sensitivity of combinations 1 and 2 were 75.0% and 37.5%, respectively (McNemar test, vs PDD alone; p = 0.041 and p < 0.001, respectively). However, the specificity was 74.0% and 91.7%, respectively (vs PDD alone; both p < 0.001). Our future goal is to establish 'MRI-PDD fusion transurethral resction of the bladder tumor (TURBT), which could be an effective therapeutic and diagnostic approach in the clinical management of high-risk disease.

Background: The aim of this study is to evaluate the clinical impact of intravesical Bacillus Calmette-Guérin (BCG)-induced changes in blood/urinary immune markers., Methods: Time-course changes in blood/urinary clinical parameters and mRNA expression of 13 genes in urine sediment taken eight times during the treatment course of intravesical BCG (before, every 2 weeks for 8 weeks, and after) in 24 patients with non-muscle invasive bladder cancer. The genes examined include cellular markers of four immune checkpoint proteins (PD-L1, PD-L2, PD-1, and CTLA-4), immunosuppressive cells (regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), pan-T lymphocytes, B lymphocytes, and neutrophils., Results: Significant transient increase in gene expression was observed for PD-L1, PD-1, FOXP3, and CD204 at 6-8 doses of BCG. The patients were stratified into two groups depending on the number of genes with increased mRNA expression. Fourteen (58%) had 0-1 genes upregulated, while 10 (42%) had 2-4 genes with increased expression. No patient in the 0-1 group experienced recurrence, while 70% of patients in the 2-4 group experienced recurrence ( p value = 0.037, hazard ratio = 5.93)., Conclusions: Our findings suggested that increases in more than one of PD-L1, PD-1, FOXP3, and CD204, expression in the urine sediments was associated with resistance to BCG treatment.

Purpose: The clinical management and follow-up of patients with recurrent prostate cancer after salvage radiotherapy (SRT) has not yet been established, and no standardized definition of biochemical recurrence (BCR) after SRT exists. We compared the impact of applying three different definitions of BCR following SRT on patient outcomes and prognostication., Subjects: Patients who received salvage androgen-deprivation therapy before the completion of SRT were excluded. The data of 118 men who had undergone salvage radiation as monotherapy for BCR after radical prostatectomy were reviewed. In all patients, SRT comprised irradiation to the prostatic bed (70 Gy) using three-dimensional conformal radiotherapy techniques. Treatment outcomes, including BCR-free survival and prognostic factors, were analyzed and compared among three definitions: The Nara, Radiation Therapy Oncology Group (RTOG) 9601, and GETUG-AFU 16 definitions., Results: The BCR rate differed significantly among the applied definitions. Multivariate analyses identified the same four independent prognostic factors, including primary Gleason pattern 4 or 5, negative resection margin, prostate-specific antigen (PSA) level before SRT 0.5 or more, and PSA doubling time before SRT <6 months, using the RTOG 9601 and GETUG-AFU 16 definitions, whereas only two of the four factors were identified using the Nara definition. Although the results obtained using the RTOG 9601 and GETUG-AFU 16 definitions were similar, the prognostic value of the four factors differed. According to the RTOG 9601 definition of BCR, a negative resection margin on prostatectomy specimens and short PSA doubling time before SRT were associated with no subsequent response in PSA level., Conclusions: The applied definition of BCR after SRT can influence the reported BCR-free rate and the potential prognostic factors. Establishment of the standardized definition is needed for the optimal management of patients with recurrent prostate cancer undergoing SRT.

Objectives: To evaluate the clinical benefit of bone-modifying agents and identify the risk factors of skeletal-related events in patients with genitourinary cancer with newly diagnosed bone metastasis., Methods: This was a multicenter retrospective study including a total of 650 patients with bone metastasis of the following cancer types: hormone-sensitive prostate cancer (n = 443), castration-resistant prostate cancer (n = 50), renal cell carcinoma (n = 80) and urothelial carcinoma (n = 77). Clinical factors at the time of diagnosis of bone metastasis were analyzed. Early treatment with bone-modifying agents was defined as follows: administration of bone-modifying agents before the development of skeletal-related events and within 6 months from the diagnosis of bone metastasis., Results: During the follow-up period (median 19.0 months, interquartile range 6.0-43.8 months), skeletal-related events were reported in 88 (20%) patients with hormone-sensitive prostate cancer, 17 (34%) patients with castration-resistant prostate cancer, 58 (73%) patients with renal cell carcinoma and 34 (44%) patients with urothelial carcinoma. Early treatment with bone-modifying agents significantly prolonged the time to the first skeletal-related event in castration-resistant prostate cancer, renal cell carcinoma and urothelial carcinoma, but not in hormone-sensitive prostate cancer. Bone pain and elevated alkaline phosphatase levels were independent predictive risk factors of the first skeletal-related event. The subgroup analysis showed that early treatment with bone-modifying agents was associated with prolonged time to the first skeletal-related events in patients with bone pain or elevated alkaline phosphatase levels., Conclusions: Early treatment with bone-modifying agents should be considered, especially for patients with bone pain and elevated alkaline phosphatase levels, to prevent skeletal-related events in patients with genitourinary cancer with bone metastasis., (© 2019 The Japanese Urological Association.)

Purpose: To assess the long-term changes in renal function, blood electrolyte levels, and nutritional indices after radical cystectomy and ileal conduit in patients with bladder cancer., Patients and Methods: In 129 patients who underwent radical cystectomy and ileal conduit, we evaluated clinicopathologic features, complications, and the change in the estimated glomerular filtration rate (eGFR) from baseline to 1, 2, 3, 4, 5, and 10 years postoperatively. Two nutritional indices, the geriatric nutritional risk index (GNRI) and prognostic nutrition index (PNI), were calculated with laboratory tests. The Student t-test, Mann-Whitney U test, paired t-test, or Wilcoxon's signed-rank test was used, as appropriate., Results: In the ileal conduit group, a parastromal hernia was observed in 10% of patients, whereas 13% had an ureteroenteric anastomotic stricture, which was associated with greater decline in the eGFR postoperatively. The first 5 year-decline in the eGFR was 1.74 mL/min/1.73 m2/year. The levels of only potassium showed a significant increase at 1 year postoperatively (mean: 4.34 mEq/L) and remained high compared with the baseline (4.14). Evaluation of the nutritional indices demonstrated that the GNRI, not PNI, showed a significant, transient increase from 1 to 4 years (range: 108?110) postoperatively compared with the baseline (105)., Conclusion: The first 5 year-decline was much higher than that among Japanese individuals who participated in an annual health examination program. Further research should be performed to identify an appropriate strategy for selecting the suitable type of urinary diversion and postoperative nutritional interventions to improve the clinical outcome of patients with bladder cancer.

Introduction: Small cell carcinoma of the prostate has a poor prognosis. Furthermore, treatments for small cell carcinoma of the prostate have not been established. We report a case where amrubicin was effective for second-line chemotherapy., Case Presentation: A 50-year-old man complaining of painful micturition was referred to our hospital. Due to high prostate-specific antigen level (16.57 ng/mL) and abnormal magnetic resonance imaging findings (cT2c), prostate biopsy was performed; mixed adenocarcinoma and small cell carcinoma of the prostate were observed. Radical prostatectomy was performed following a cT2cN0M0 diagnosis. One month after prostatectomy, fluorodeoxyglucose positron emission tomography/computed tomography showed metastatic lesions in the bone; the patient received androgen deprivation therapy and two cycles of cisplatin plus irinotecan. Due to new metastatic lesions and sustained abnormal pro-gastrin-releasing peptide levels, amrubicin was administered for second-line chemotherapy. Pro-gastrin-releasing peptide was normalized and positron emission tomography/computed tomography showed a complete metabolic response after 15 cycles of amrubicin., Conclusion: Amrubicin could serve as a second-line chemotherapeutic agent against small cell carcinoma of the prostate., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

The evidence of association between sexually transmitted infection and prostatic inflammation in human prostate cancer (PCa) is limited. Here, we sought to examine the potential association of prostatic infection with the inflammatory environment and prostate carcinogenesis. We screened surgical and biopsy specimens from 45 patients with PCa against a panel of sexually transmitted infection-related organisms using polymerase chain reaction and examined the severity of intraprostatic inflammation by pathologic examination. Among tested organisms, the rate of Mycoplasma genitalium (Mg) infection was significantly different between the prostate cancer cohort and benign prostate hyperplasia (BPH) cohort ( P = 0.03). Mg infection in the surgical specimens was associated with younger patients. The rate of extensive disease (pT2c⁻3b) was higher in Mg-positive patients than in Mg-negative patients ( P = 0.027). No significant correlation was observed between Mg infection status and the grade of intraprostatic inflammation. The detection sensitivity of biopsy specimens was 61% for Mg and 60% for human papillomavirus (HPV)18, indicating possible clinical application of this material. A comprehensive understanding of the correlation between the urogenital microbiome and inflammation would facilitate the development of strategies for PCa prevention. Further studies are required to explore its clinical utility in recommendations of early re-biopsy, close follow-up, and treatment by antibiotics.