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Makito Miyake,1 Nobutaka Nishimura,1,2 Takuto Shimizu,1,3 Mikiko Ohnishi,4 Masaomi Kuwada,4 Yoshitaka Itami,5 Takeshi Inoue,5 Kenta Ohnishi,6 Yoshihiro Matsumoto,6 Takanori Yoshida,7 Yoshihiro Tatsumi,8 Masatake Shinohara,9 Shunta Hori,1 Yosuke Morizawa,1 Daisuke Gotoh,1 Yasushi Nakai,1 Satoshi Anai,1 Kazumasa Torimoto,1 Katsuya Aoki,1 Tomomi Fujii,10 Nobumichi Tanaka,1,11 Kiyohide Fujimoto1 1Department of Urology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 2Department of Urology, Okanami General Hospital, Iga, Mie, Japan; 3Department of Urology, Saiseikai Chuwa Hospital, Nara, Japan; 4Department of Urology, Matsusaka Chuo General Hospital, Matsusaka, Mie, Japan; 5Department of Urology, Nara Prefecture General Medical Center, Nara, Japan; 6Department of Urology, Hoshigaoka Medical Center, Hirakata, Osaka, Japan; 7Department of Urology, Tane General Hospital, Osaka, Japan; 8Department of Urology, JCHO Yamato Koriyama Hospital, Koriyama, Nara, Japan; 9Department of Urology, Osaka Gyoumeikan Hospital, Osaka, Japan; 10Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 11Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, 634-8522, JapanCorrespondence: Makito Miyake, Department of Urology, Nara Medical University, 840 Shijo-cho, Nara, 634-8522, Japan, Tel +81-744-22-3051 (ext 2338), Fax +81-744-22-9282, Email makitomiyake@yahoo.co.jpPurpose: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment.Patients and Methods: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model.Results: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age < 70 years), those who received radical surgery, and those without visceral metastasis.Conclusion: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.Keywords: urinary bladder neoplasms, immunotherapy, chemotherapy, survival, propensity score

Shunta Hori, Nobumichi Tanaka, Kota Iida, Yasushi Nakai, Makito Miyake, Satoshi Anai, Kazumasa Torimoto, Kiyohide Fujimoto Department of Urology, Nara Medical University, Kashihara, Nara, 634-8522, JapanCorrespondence: Nobumichi TanakaDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, JapanTel +81-744-22-3051Fax +81-744-22-9282Email sendo@naramed-u.ac.jpPurpose: Reports suggest that partial nephrectomy provides no significant benefit in terms of cancer-specific and overall survival (OS) compared to radical nephrectomy. Here, we focused on survival in terms of life expectancy and investigated the significance of partial nephrectomy for localized renal cell carcinoma (RCC) patients.Patients and Methods: Our retrospective study included 937 patients (median age 63 years) with localized RCC who underwent partial nephrectomy or radical nephrectomy. Various predictive factors were explored, and the association between actual OS and life expectancy was analyzed.Results: Performance status (PS) ≥ 1 and tumor size ≥ 40 mm were identified as independent poor prognostic factors for cancer-specific survival. Age ≥ 60, male sex, PS ≥ 1, C-reactive protein elevation, pT1b stage, and radical nephrectomy were identified as independent poor prognostic factors for OS. OS and life expectancy did not differ in the partial nephrectomy group (P=0.11). OS was significantly shorter than life expectancy in the radical nephrectomy group (P< 0.0001). In PS0 or pT1a patients, there was a significant difference between actual OS and life expectancy in the radical nephrectomy group (P< 0.0001), but not in the partial nephrectomy group (P=0.15). In patients with a life expectancy ≥ 10 years, PS0, and pTa, OS and life expectancy differed in the radical nephrectomy group, but not in the partial nephrectomy group.Conclusion: Partial nephrectomy can improve actual OS, and notably, PS and tumor size are crucial factors that determine the choice of surgical procedure. Further research is needed to establish appropriate treatment strategies and criteria for clinical practice.Keywords: life expectancy, nephrectomy, performance status, renal cell carcinoma, tumor size

Shunta Hori, Katsuya Aoki, Nobutaka Nishimura, Yosuke Morizawa, Daisuke Gotoh, Shinji Fukui, Yasushi Nakai, Makito Miyake, Kazumasa Torimoto, Kiyohide Fujimoto Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, JapanCorrespondence: Kiyohide FujimotoDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanTel +81-744-22-3051Fax +81-744-22-9282Email kiyokun@naramed-u.ac.jpPurpose: Cryptorchidism is one of the most common congenital abnormalities in pediatric urology, and orchiopexy is performed for the prevention of testicular damage and malignant transformation. We examined the distribution and outcomes of cryptorchidism under a single investigator at our institute.Patients and Methods: This retrospective study included 283 boys diagnosed with cryptorchidism at our institute. Cryptorchidism was diagnosed based on the medical history and physical examination findings. Boys without spontaneous resolution after 6 months of age were indicated for orchiopexy. We investigated the 12-year trend in the distribution and outcomes of cryptorchidism at the institute.Results: The mean age at diagnosis, gestational age, and birth weight were 2 years, 37 weeks, and 2740 g, respectively. A total of 170 boys underwent orchiopexy under 2 years of age, and 136 boys underwent orchiopexy under the age of 1 year, while 62 boys underwent orchiopexy over the age of 3 years. Abnormalities of the epididymis and disclosure of the processus vaginalis were observed in 44 (25%) and 72 boys (41%), respectively. Comparison of boys with or without hypospadias showed that the age at orchiopexy was higher in boys with hypospadias than in those without hypospadias (P=0.028). In addition, boys without hypospadias had a higher rate of abnormality of the epidermis than those with hypospadias (P=0.024).Conclusion: Our findings suggest that most boys with cryptorchidism are treated under the age of 2 years and the incidence of epididymal abnormality is relatively high, especially in boys with hypospadias. An understanding of the natural features of cryptorchidism could lead to better management and outcomes. Further research is warranted to develop an appropriate treatment timeline in boys with cryptorchidism.Keywords: cryptorchidism, hypospadias, orchiopexy, pediatrics, spontaneous resolution

Yosuke Morizawa, Katsuya Aoki, Shunta Hori, Daisuke Gotoh, Makito Miyake, Yasushi Nakai, Kazumasa Torimoto, Nobumichi Tanaka, Kiyohide Fujimoto Department of Urology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Kiyohide FujimotoDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanTel +81-744-22-3051Fax +81-744-22-9282Email kiyokun@naramed-u.ac.jpPurpose: To determine the clinical efficacy of endoscopic transurethral incision (TUI) for boys with refractory daytime incontinence due to a posterior urethral valve with or without nocturnal enuresis.Patients and Methods: A total of 20 boys with daytime incontinence were assessed. Twelve boys underwent TUI (TUI+ group) and eight boys continued receiving oral drugs (TUI- group). The primary endpoint was the cure rate associated with TUI or NE in both groups.Results: Only two boys achieved daytime continence 6 months after TUI, but no boys were cured of nocturnal enuresis 6 months after TUI. The median time to daytime continence was significantly longer in the TUI+ than in the TUI- group (52 vs 27 months, respectively; log rank P = 0.041) and the median time to dry nights was significantly longer in the TUI+ than in the TUI- group (56 vs 36 months, respectively; log rank P = 0.021).Conclusion: TUI might be not effective in boys with refractory daytime incontinence.Keywords: pediatric, daytime incontinence, enuresis, TUI

Yasushi Nakai,1 Nobumichi Tanaka,1 Satoshi Anai,1 Makito Miyake,1 Isao Asakawa,2 Yosuke Morizawa,1 Shunta Hori,1 Kazumasa Torimoto,1 Tomomi Fujii,3 Masatoshi Hasegawa,2 Kiyohide Fujimoto1 1Department of Urology, Nara Medical University, Nara, Japan; 2Department of Radiation Oncology, Nara Medical University, Nara, Japan; 3Department of Pathology, Nara Medical University, Nara, Japan Purpose: The aim of this study was to evaluate the chronological changes in lower urinary tract symptoms (LUTSs), disease-related quality of life (QOL), and health-related QOL (HR-QOL) of patients who received intensity-modulated radiotherapy (IMRT).Patients and methods: In 121 patients who had received IMRT and were followed up for >2 years, the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), Expanded Prostate Cancer Index Composite (EPIC), and 8-Item Short-Form Health Survey (SF-8) were used before IMRT, at the halfway point in IMRT, immediately after IMRT, and 1–24 months after the completion of IMRT.Results: The IPSS and OABSS and the urinary and bowel domains of the EPIC indicated that QOL worsened at the halfway point in IMRT, further worsened more severely immediately after IMRT, and then improved. The sexual domain of the EPIC significantly decreased at the halfway point in IMRT, which significantly lowered until 24 months. The scores of physical functioning, role physical, bodily pain, vitality, social functioning, and role emotional domains in the SF-8 significantly decreased and reached their lowest points immediately after IMRT.Conclusion: QOL worsened the most severely in patients immediately after IMRT for prostate cancer. This knowledge can influence treatment recommendations and enable patients to make better informed decisions. Keywords: chronological changes, intensity-modulated radiotherapy, prostate cancer, quality of life, radiotherapy

Abstract Background Fluctuations in blood glucose level cause endothelial dysfunction and play a critical role in onset and/or progression of atherosclerosis. We hypothesized that fluctuation in blood glucose levels correlate with vascular endothelial dysfunction and that this relationship can be assessed using common bedside medical devices. Methods Fluctuations in blood glucose levels were measured over 24 hours by continuous glucose monitoring (CGM) on admission day 2 in 57 patients with type 2 diabetes mellitus. The reactive hyperemia index (RHI), an index of vascular endothelial function, was measured using peripheral arterial tonometry (EndoPAT) on admission day 3. Results The natural logarithmic-scaled RHI (L_RHI) correlated with SD (r=−0.504; PPP=0.001) and percentage of time ≥200 mg/dl (r=−0.292; P=0.028). In 12 patients with hypoglycemia, L_RHI also correlated with the percentage of time at hypoglycemia (r=−0.589; P=0.044). L_RHI did not correlate with HbA1c or fasting plasma glucose levels. Furthermore, L_RHI did not correlate with LDL cholesterol, HDL cholesterol, and triglyceride levels or with systolic and diastolic blood pressures. Finally, multivariate analysis identified MAGE as the only significant determinant of L_RHI. Conclusions Fluctuations in blood glucose levels play a significant role in vascular endothelial dysfunction in type 2 diabetes. Trial registration UMIN000007581

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).)

Background: Controversial issues in registering candidates for deceased-donor kidney transplantation (DDKT) comprise various factors, including age, life expectancy, and dialysis duration. We investigated patient characteristics on the waiting list and discussed suitable criteria in Japan, which has a long waiting period., Methods: This study included 592 patients on the waiting list for DDKT at our institute between 1982 and 2023. We retrospectively reviewed patients' medical charts and obtained their clinical information. Patient characteristics according to outcomes and eligibility criteria for applying for or renewing registration were investigated. No prisoners were used in the study, and the participants were neither coerced nor paid., Results: Approximately 70%, 45%, and 14.5% of the registered patients were aged >60, >70, and 80 years, respectively. The number of patients aged ≥70 years gradually decreased over time. The median waiting periods of patients who underwent and interrupted DDKT were 13 and 7 years, respectively. Patients in their 70s with a >15-year dialysis period tended to have opportunities for DDKT. Living-donor kidney transplantation was performed in patients aged <60 years. Waiting patients were significantly younger and had a shorter dialysis duration. Advanced age at registration was associated with a significantly high risk of interruption., Conclusions: Advanced age and longer dialysis periods were considered at registration because patients with these factors tended to experience interruptions despite the long waiting period and high cost. Although older patients can undergo DDKT, factors including surgical cost and risks are considered. Eligibility/ineligibility criteria should be established for DDKT waiting lists in Japan., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab., Methods: A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rate on ICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup., Results: ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from - 29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT., Conclusions: Our study provides real-world evidence regarding difference of oncological efficacy between maintenance avelumab and subsequent pembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Aims: To investigate changes in subjective and objective sleep quality after desmopressin administration in patients with nocturia due to nocturnal polyuria (NP) using electroencephalography (EEG) and the Pittsburgh sleep quality index (PSQI)., Methods: Twenty male patients (≥65 years old) with NP participated in this study. The inclusion criteria were nocturnal frequency ≥ 2, NP index (NPi) ≥ 0.33, first uninterrupted sleep period (FUSP) ≤ 2.5 h, serum sodium concentration ≥ 135 mEq/L, and estimated glomerular filtration rate ≥ 50 mL/min/1.73 m 2 . Participants were given 50 μg of desmopressin to be taken orally once daily before bed. The primary endpoint was the change in the duration of slow-wave sleep (nonrapid eye movement sleep stages 3 and 4), as evaluated by EEG 28 days from the baseline. The visual analog scale (VAS) was used as an additional indicator of sleep quality., Results: Analysis of data from 15 participants (median age: 74.0 [70.5, 76.0] years) revealed that from before to after desmopressin administration, significant decreases occurred in the median nocturnal frequency (3.0 [2.0, 4.0] to 1.5 [1.0, 2.0]) and NPi (0.445 [0.380, 0.475] to 0.360 [0.250, 0.430]). Furthermore, FUSP was significantly prolonged from 120.0 (94.0, 150.0) min to 210.0 (203.8, 311.3) min. Although the VAS scores improved, slow-wave sleep duration and the PSQI global score showed no significant differences (68.50 [47.50, 75.50] and 48.00 [38.00, 66.50]; 5.0 [5.0, 10.0] and 7.0 [5.0, 9.0] min, respectively)., Conclusion: Oral administration of 50 μg desmopressin improved nocturnal frequency and FUSP in older individuals with NP but did not significantly enhance sleep quality. In older adults, decreased nighttime urinary frequency may enhance quality of life; however, its influence on objective sleep quality may be limited., (© 2024 Wiley Periodicals LLC.)

Background: It is unclear whether a hydrogel spacer can improve quality of life (QOL) in patients undergoing low-dose-rate brachytherapy (LDR-BT) alone or in combination with intensity-modulated radiotherapy (IMRT)., Methods: We enrolled patients with prostate cancer who underwent LDR-BT alone with (n = 186) or without (n = 348) a hydrogel spacer, or underwent LDR-BT in combination with IMRT with (n = 70) or without (n = 217) a hydrogel spacer. QOL was evaluated using Expanded Prostate Cancer Index Composite (EPIC) questionnaires at baseline and 1, 3, 6, 12, and 24 months after implantation. The groups were compared using propensity score matching analysis., Results: Among patients who underwent LDR-BT alone, there were no differences regarding changes in urinary, bowel, sexual, or hormonal domain scores between the spacer and no-spacer groups; however, the dose at the bowel was significantly lower in the spacer group than in the no-spacer group. Among patients who underwent LDR-BT in combination with IMRT, there were no differences regarding changes in urinary, sexual, or hormonal domain scores between the spacer and no-spacer groups. However, the changes in the bowel domain score were significantly lower in the spacer group than in the no-spacer group (p < 0.001)., Conclusions: A hydrogel spacer may not improve impaired urinary, bowel, or sexual QOL in patients undergoing LDR-BT alone. However, in patients undergoing LDR-BT in combination with IMRT, a hydrogel spacer can improve impaired bowel QOL but not sexual or urinary QOL., (© 2024 Wiley Periodicals LLC.)

Unresectable, metastatic, advanced urothelial carcinoma (aUC) is an aggressive disease and is treated with platinum-containing first-line chemotherapy, followed by immune checkpoint inhibitors and antibody-drug conjugates. Response to first-line chemotherapy is a vital priority in sequential treatment strategies because a better response to first-line chemotherapy is associated with a better response to subsequent therapies. Gemcitabine plus carboplatin chemotherapy is conventionally recommended for cisplatin-ineligible patients. This multicenter, single-arm prospective trial will investigate whether dose-dense methotrexate, vinblastine, doxorubicin, and carboplatin (DD-MVACarbo) chemotherapy is superior to gemcitabine plus carboplatin chemotherapy in terms of efficacy in platinum-naïve, cisplatin-ineligible patients with aUC. After screening and registration, a total of 46 patients will be treated with this novel chemotherapy regimen. The primary endpoint is the objective response rate. The secondary endpoints include disease control rate, patient-reported outcomes, and adverse events. No evidence of this novel intervention is available as of July 2024. The results are expected to change the standard of care and improve the management of patients with aUC.

Background: Photodynamic diagnosis-assisted transurethral resection of bladder tumors (PDD-TURBT) enhances detection of elusive lesions compared to standard white light-transurethral resection of bladder tumors (WL-TURBT). If minimal light exposure during PDD-TURBT induces the accumulation of reactive oxygen species (ROS), potentially resulting in phototoxicity in small lesions, apoptosis may be triggered in residual small tumors, allowing them to escape resection. We investigated the hypothesis of a potential photodynamic therapeutic effect during PDD-TURBT., Methods and Materials: Our study, conducted between January 2016 and December 2020 at Nara Medical University Hospital, focused on a specific emphasis on ROS production. Immunohistochemical analysis for thymidine glycol and N ε -hexanoyl-lysine was performed on 69 patients who underwent 5-aminolevulinic acid-mediated PDD-TURBT and 28 patients who underwent WL-TURBT. Additionally, we incrementally applied the minimal irradiation energy to T24 and UM-UC-3 cells treated with 5-aminolevulinic acid using instruments similar to those used in PDD-TURBT and evaluated intracellular ROS production and phototoxicity., Results: Immunohistochemical analysis revealed a significant increase in production of thymidine glycol and N ε -hexanoyl-lysine within the PDD-TURBT group. In T24 and UM-UC-3 cells treated with 5-aminolevulinic acid and light exposure, immunofluorescent staining demonstrated a dose-dependent increase in intracellular ROS production. In addition, higher irradiation energy levels were associated with a greater increase in ROS production and phototoxicity, as well as more significant decrease in mitochondrial membrane potential., Conclusion: Although the irradiation energy used in PDD-TURBT did not reach the levels commonly used in photodynamic therapy, our findings support the presence of a potential cytotoxic effect on bladder lesions during PDD-TURBT., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Nobutaka Nishimura et al.)

Background: The clinical importance of nutrition and inflammation in patients with end-stage renal disease is well established. In this study, we investigated the role of nutritional and inflammatory indicators in the patient outcomes of living donor kidney transplant recipients., Methods: We included 204 consecutive patients who underwent kidney transplantation at our institute between 2003 and 2022. We retrospectively reviewed medical charts to obtain clinical information. Six nutritional indicators and two inflammatory indicators were assessed. Patient outcomes were investigated, and predictive factors were explored., Results: The median patient age and follow-up period were 48 years and 99 months, respectively. The cohort included patients with preoperative malnutrition and microinflammation. No significant differences in graft survival were identified according to nutritional and inflammatory indicators, whereas the survival index, controlled nutritional status, and C-reactive protein levels were associated with patient survival. The survival index was an independent indicator of survival and death in patients with functioning grafts (P = 0.047 and P = 0.013, respectively). Furthermore, the C-reactive protein level could distinguish between low and high mortality risks in patients with good nutrition (P = 0.019)., Conclusions: Our findings suggest that nutrition and inflammation indicators play important roles in predicting outcomes in living donor kidney transplantation recipients. Further research is warranted to establish optimal management strategies., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background/aim: This study investigated the follow-up rate of living kidney donors and explored the factors related to continuous follow-up and remnant renal function, enabling the optimal management of living kidney donors., Patients and Methods: We retrospectively evaluated 180 living kidney donors who underwent donor nephrectomies at our institute. Clinical information was obtained from medical charts, and remnant renal function was defined as the estimated glomerular filtration rate 12 months after donor nephrectomy., Results: Overall, 6/180 donors (3.3%) were lost to follow-up within a year, and the follow-up rate gradually declined yearly. Independent risk factors for loss to follow-up included a follow-up period <60 months and graft survival of the recipient (p=0.002 and p=0.043, respectively). Recipient survival was correlated with loss to follow-up; however, this was not significant (p=0.051). Regarding remnant renal function, age ≥60 years, preoperative estimated glomerular filtration rate <74 ml/min/1.73 m 2 , and a Δsingle-kidney estimated glomerular filtration rate <9.3 ml/min/1.73m 2 were independent risk factors for poorly preserved remnant renal function (p=0.036, p<0.0001, and p<0.0001, respectively). Using propensity score matching to adjust for preoperative factors, a Δsingle-kidney estimated glomerular filtration rate <9.3 ml/min/1.73 m 2 was the only significant postoperative factor for poorly preserved remnant renal function (p=0.023)., Conclusion: An increased 5-year follow-up rate could lead to an increase in long-term follow-up, and recipient prognosis may be correlated with the living kidney donor follow-up status. Furthermore, Δsingle-kidney estimated glomerular filtration rate was identified as a factor for establishing the optimal precision follow-up management of living kidney donors., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Although routine surveillance imaging to examine upper urinary tract urothelial cancer recurrence during follow-up of nonmuscle invasive bladder cancer is recommended, its necessity remains invalidated. A single-institute long-term follow-up cohort study to evaluate the clinical impact of routine surveillance imaging and identify risk factors for upper urinary tract urothelial cancer recurrence after nonmuscle invasive bladder cancer treatment was conducted., Methods and Materials: A retrospective chart review of 864 patients with primary nonmuscle invasive bladder cancer who underwent initial transurethral resection of bladder tumor between 1980 and 2020 was conducted. The opportunities to diagnose its recurrence were examined. Moreover, oncological outcomes included upper urinary tract urothelial cancer recurrence-free survival and overall survival., Results: Of 864 patients, 19 (2.2%) experienced upper urinary tract urothelial cancer recurrence. Among 19 patients, recurrence was detected through routine imaging in 12 (63.2%), cystoscopy in 2 (10.5%), urine cytology in 2 (10.5%), and presence of gross hematuria in 1 (5.3%). All patients had high- or highest-risk NMIBC at diagnosis of primary nonmuscle invasive bladder cancer. On multivariate Fine-Gray proportional regression analyses, a tumor size of ≥30 mm and carcinoma in situ were independently associated with short upper urinary tract urothelial cancer recurrence-free survival ( P =0.040 and 0.0089, respectively)., Conclusion: Most patients experiencing upper urinary tract urothelial cancer recurrence were diagnosed by routine surveillance imaging, suggesting its clinical importance, especially for patients with nonmuscle invasive bladder cancer accompanied by a tumor size of ≥30 mm and carcinoma in situ., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Nobutaka Nishimura et al.)

Hypertension is a major cause of cardiovascular diseases such as myocardial infarction and stroke. Cardiovascular fibrosis occurs with hypertension and contributes to vascular resistance, aortic stiffness, and cardiac hypertrophy. However, the molecular mechanisms leading to fibroblast activation in hypertension remain largely unknown. There are two types of fibrosis: replacement fibrosis and reactive fibrosis. Replacement fibrosis occurs in response to the loss of viable tissue to form a scar. Reactive fibrosis occurs in response to an increase in mechanical and neurohormonal stress. Although both types of fibrosis are considered adaptive processes, they become maladaptive when the tissue loss is too large, or the stress persists. Myofibroblasts represent a subpopulation of activated fibroblasts that have gained contractile function to promote wound healing. Therefore, myofibroblasts are a critical cell type that promotes replacement fibrosis. Although myofibroblasts were recognized as the fibroblasts participating in reactive fibrosis, recent experimental evidence indicated there are distinct fibroblast populations in cardiovascular reactive fibrosis. Accordingly, we will discuss the updated definition of fibroblast subpopulations, the regulatory mechanisms, and their potential roles in cardiovascular pathophysiology utilizing new knowledge from various lineage tracing and single-cell RNA sequencing studies. Among the fibroblast subpopulations, we will highlight the novel roles of matrifibrocytes and immune fibrocytes in cardiovascular fibrosis including experimental models of hypertension, pressure overload, myocardial infarction, atherosclerosis, aortic aneurysm, and nephrosclerosis. Exploration into the molecular mechanisms involved in the differentiation and activation of those fibroblast subpopulations may lead to novel treatments for end-organ damage associated with hypertension and other cardiovascular diseases., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

To celebrate 100 years of American Heart Association-supported cardiovascular disease research, this review article highlights milestone papers that have significantly contributed to the current understanding of the signaling mechanisms driving hypertension and associated cardiovascular disorders. This article also includes a few of the future research directions arising from these critical findings. To accomplish this important mission, 4 principal investigators gathered their efforts to cover distinct yet intricately related areas of signaling mechanisms pertaining to the pathogenesis of hypertension. The renin-angiotensin system, canonical and novel contractile and vasodilatory pathways in the resistance vasculature, vascular smooth muscle regulation by membrane channels, and noncanonical regulation of blood pressure and vascular function will be described and discussed as major subjects., Competing Interests: Disclosures None.

Objectives: Many congenital hydronephroses spontaneously resolve. This study evaluated a long-term follow-up of more than 4 years of patients with congenital hydronephrosis at a single center., Methods: In total, 215 patients (286 kidneys) with congenital hydronephrosis were included. Hydronephrosis outcomes (resolution, improvement, and persistence) and time-to-outcome were evaluated., Results: Fourteen patients underwent early surgical intervention until the age of 2 years. A total of 189 congenital hydronephrosis cases (66%) showed resolution at a median of 16 months (interquartile range: 7-21 months) and 169 (80%) of 210 kidneys with grade I to II hydronephrosis showed resolution at a median of 14 months (interquartile range: 6-23 months). Of 76 kidneys with grade III to IV hydronephrosis, 24 (32%) showed resolution at a median of 29 months (interquartile range: 24-41 months), and 56 (74%) showed improvement to grade II or less at a median of 12 months (interquartile range: 5-23 months). Of the 76 kidneys with grade III to IV hydronephrosis, five required delayed pyeloplasty at a median of 66 months (interquartile range: 42-89 months). One patient was asymptomatic, with a marked worsening of hydronephrosis and decreased renal function 6 years after the resolution of hydronephrosis., Conclusions: None of the patients with grade I to II hydronephrosis required surgical treatment, and a shorter follow-up may be sufficient. Grade III to IV severe hydronephrosis should be considered for a longer and more careful follow-up, given the possibility of asymptomatic exacerbation of hydronephrosis., (© 2024 The Japanese Urological Association.)

Background/aim: Botulinum toxin intravesical injection therapy (hereafter, botulinum therapy) is approved in Japan for treating urinary urgency, frequency, and urinary incontinence due to refractory overactive bladder or neurogenic bladder. Although botulinum therapy is classified as urinary incontinence surgery, it is minimally invasive, effective, and safe. However, there are few reports on the actual use of botulinum therapy and examination of its effects and side-effects. Herein, we report real-world data on botulinum therapy., Patients and Methods: Patients who received botulinum therapy for refractory overactive bladder at the Nara Medical University and affiliated facilities from May 2020 to May 2022 were enrolled. The patient background, treatment efficacy, and safety were retrospectively reviewed., Results: Twenty-three cases of refractory overactive bladder (age: 68.4±14.1 years; 7 males, 16 females; 17 outpatient, 6 hospitalized) were enrolled. Pretreatment, the overactive bladder symptom score (OABSS) was 10.1±2.7, and post-void residual urine volume was 27.1±31.6 ml. Botulinum was administered once, twice, thrice, and four times in 11, eight, three, and one cases, respectively. OABSS decreased to 6.1±3.2 2 weeks after botulinum therapy (p<0.0001), and the effect persisted at 6.6±3.2 after 12 weeks (p<0.0001). Post-void residual urine volume increased to 74.6±79.2 ml after 2 weeks (p=0.0010), but subsequently improved to 33.9±42.0 ml after 12 weeks (p=0.0002). Adverse events included post-void residual urine volume of 200 ml or more in three patients (7.5%) and urinary retention grade 2 in two (5.0%)., Conclusion: Botulinum therapy is effective and relatively safe for refractory overactive bladders., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mitochondrial dysfunction has been implicated in various types of cardiovascular disease including hypertension. Mitochondrial fission fusion balance is critical to mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular disease. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested the hypothesis that inhibition of mitochondrial fission attenuates the development of hypertension and associated vascular remodeling. In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor, mdivi1, significantly inhibited angiotensin II-induced development of hypertension assessed by radiotelemetry. Histological assessment of hearts and aortas showed that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both the endothelial and medial layers of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight-to-body weight ratio as well as by echocardiography. In ex vivo experiments, mdivi1 inhibited vasoconstriction and abolished the enhanced vascular reactivity by angiotensin II in small mesenteric arteries. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

A time-course questionnaire survey using the chemotherapy-induced taste alteration scale (CiTAS) was conducted in patients with advanced urothelial carcinoma (UC) treated with systemic chemotherapy and/or immunotherapy. A total of 37 patients receiving systemic therapy with enfortumab vedotin (EV), platinum-based chemotherapy and immune checkpoint inhibitors were included in this study. No significant changes were observed in any of the CiTAS subscales during platinum-based chemotherapy and immune checkpoint inhibitor treatment, while EV therapy induced significant dysgeusia. Among 10 patients treated with EV, dysgeusia was associated with a substantial negative effect on the health-related quality-of-life domains, particularly global health status/QOL (mean ± standard deviation: 52 ± 19 in dysgeusia group vs 89 ± 13 in non-dysgeusia group) and mental component summary (47 ± 5.1 vs 53 ± 2.0). The fatigue symptom score was higher in the dysgeusia group at the post-third cycle of EV (47 ± 16 vs 15 ± 17). Severe dysgeusia can be induced by EV therapy, which is usually not observed in other systemic therapies for advanced UC.

Background: The clinical significance of nutrition and inflammation in dialysis patients is well established. This study aimed to evaluate the association between prognosis and indicators of nutrition and inflammation., Methods: A total of 253 consecutive patients who underwent peritoneal dialysis (PD) as primary renal replacement therapy at our institute between 2006 and 2021 were included. We retrospectively reviewed the patient's medical charts and obtained their clinical information. Nine nutritional and two inflammatory indicators were assessed. Patient outcomes were investigated, and predictive factors were explored., Results: The median age and follow-up period were 65 years and 54 months, respectively. Most nutritional indicators and C-reactive protein (CRP) levels showed a significant correlation with residual renal function. Multivariate analysis revealed that the survival index, nutritional risk index for Japanese hemodialysis patients, and CRP levels were independent indicators of patient survival (P < 0.001, P = 0.034, and P = 0.005, respectively) and cardiovascular disease-free survival (P = 0.009, P = 0.04, and P = 0.017, respectively). Patients with a survival index < 19 and CRP ≥ 0.5 had a high risk of mortality and cardiovascular death (P < 0.0001 and P = 0.0002, respectively)., Conclusions: Our findings suggest that indicators of nutrition and inflammation play important roles in predicting patient outcomes. Further research is warranted to establish optimal management strategies for patients on PD., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objective: Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events in patients receiving enfortumab vedotin., Methods: A multicentre database was used to register 556 patients diagnosed with metastatic urothelial carcinoma from 2008 to 2023; 34 patients (6.1%) treated with enfortumab vedotin were included. Best radiographic objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (v1.1) during treatments. Overall survival and progression-free survival were estimated (Kaplan-Meier method). Toxicities were reported according to the Common Terminology Criteria for Adverse Events, version 5.0. The relative dose intensity, which could impact oncological outcomes, was calculated., Results: The median number of enfortumab vedotin therapy cycles was 5. The best objective response to enfortumab vedotin was partial response, stable disease and progressive disease in 19 (56%), 5 (15%) and 10 (29%) patients, respectively. The median overall survival and progression-free survival after the first enfortumab vedotin dose were 16 and 9 months, respectively. No significant relationship was observed between survival outcomes after enfortumab vedotin initiation and the enfortumab vedotin relative dose intensity. The median overall survival from first-line platinum-based chemotherapy initiation was 42 months. Twenty-six (76%) patients experienced any grade of enfortumab vedotin-related toxicities; eight (24%) experienced Grades 3-4 toxicities, the most common being skin toxicity (any grade, 47%; Grades 3-4, 12%)., Conclusions: Here, we report real-world evidence for enfortumab vedotin therapy in Japan. Tumour responses and safety profiles were comparable with those of clinical trials on this novel treatment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

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.)

Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts ( p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35-0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered.

Objective: To evaluate quality of life (QOL) after non-nerve-sparing, robot-assisted radical prostatectomy (RARP) and factors associated with worsened QOL., Methods: Patients who underwent non-nerve-sparing RARP (n = 115) were enrolled. The Expanded Prostate Cancer Index Composite and 8-item Short Form Health Survey were used to evaluate QOL at baseline and postoperative 1, 3, 6, 12, and 24 months. Preoperative factors were evaluated by multivariate analysis for worsened QOL., Results: Postoperative 24-month urinary QOL worsened in 68 of 115 (59%) patients. In multivariate analysis, membranous urethral length ≥10.8 mm [odds ratio (OR): .26, 95% confidence interval (CI): .07-.96] and intravesical prostatic protrusion ≥12 mm (OR: .14, 95% CI .06-.35) were significantly associated with maintaining postoperative 24-month urinary QOL. Significantly more patients with intravesical prostatic protrusion ≥12 mm than < 12 mm had improved urinary QOL. At postoperative 24 months, 43 of 115 (38%) patients had worsened sexual QOL. In multivariate analysis, higher Sexual Health Inventory for Men score (OR: 8.39, 95% CI 2.28-30.9), sexual activity (OR: 6.94, 95% CI: 2.27-21.2), and intercourse activity (OR: 6.81, 95% CI: 1.64-28.3) preoperatively were significantly associated with worsened postoperative 24-month sexual QOL. More patients with high preoperative intercourse activity (12/23,53%) had significantly worsened (p = .009) QOL regarding sexual bother than those who had no preoperative intercourse activity (21/92, 23%)., Conclusion: After non-nerve-sparing RARP, patients with long membranous urethral length and/or intravesical prostatic protrusion maintain urinary QOL. Patients with high intercourse activity presented with impairment of sexual QOL after non-nerve-sparing RARP., (© 2023 John Wiley & Sons Australia, Ltd.)