Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Pre-first-line chemotherapy risk stratification for overall survival in advanced urothelial carcinoma in sequential therapy era.

PURPOSE: To explore pre-treatment risk factors for overall survival (OS) in advanced urothelial carcinoma (UC) patients treated with first-line (1L) chemotherapy in sequential therapy (ST) era. Additionally, to evaluate the proportion of patients who were not able to undergo subsequent immune checkpoint inhibitor (ICI) therapy according to the subgroups stratified by the risk factors. METHODS: A multicenter retrospective study was conducted. Metastatic or locally advanced UC patients treated between 2017 and 2022 were included. The Kaplan-Meier method with the log-rank test and multivariate Cox regression models were used to address OS. RESULTS: Three hundred and fourteen patients treated with 1L chemotherapy were included in the study and 57 (18.2%) patients were not able to proceed to subsequent ICI therapy. Pre-chemotherapy risk factors for OS in 314 patients were ECOG-PS 1 or more, having no primary site resection, C-reactive protein (CRP) level of 3 mg/dL or more, and non-cisplatin-based regimen. Patients having 3 or 4 risk factors had higher risk for not being able to receive ST (Mann-Whitney U test, P < 0.001). As risk factors for OS in 230 patients who were able to receive ST, having no primary site resection, a neutrophil to lymphocyte ratio of 3 or more, and the presence of liver metastasis were identified. CONCLUSION: We reported the risk factors for OS in advanced UC patients treated with 1L chemotherapy in ST era. Patients with high risk for OS may not be able to proceed to subsequent ICI therapy even in the ST era.

Third nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2020 and 2021: Antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus.

The Japanese surveillance committee conducted a third nationwide surveillance of antimicrobial susceptibility of acute uncomplicated cystitis at 55 facilities throughout Japan between April 2020 and September 2021. In this surveillance, we investigated the susceptibility of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Staphylococcus saprophyticus (S. saprophyticus) for various antimicrobial agents by isolating and culturing bacteria from urine samples. In total, 823 strains were isolated from 848 patients and 569 strains of target bacteria, including E. coli (n = 529, 92.9 %), K. pneumoniae (n = 28, 4.9 %), and S. saprophyticus (n = 12, 2.2 %) were isolated. The minimum inhibitory concentrations of 18 antibacterial agents were determined according to the Clinical and Laboratory Standards Institute manual. In premenopausal patients, there were 31 (10.5 %) and 20 (6.8 %) fluoroquinolone (FQ)-resistant E. coli and extended-spectrum ß-lactamase (ESBL)-producing E. coli, respectively. On the other hand, in postmenopausal patients, there were 75 (32.1 %) and 36 (15.4 %) FQ-resistant E. coli and ESBL-producing E. coli, respectively. The rate of FQ-resistant E. coli and ESBL-producing E. coli in post-menopausal women was higher than that for our previous nationwide surveillance (20.7 % and 32.1 %: p = 0.0004, 10.0 % and 15.4 %; p = 0.0259). For pre-menopausal women, there was no significant difference in the rate of FQ-resistant E. coli and ESBL-producing E. coli between this and previous reports, but the frequency of FQ-resistant E. coli and ESBL-producing E. coli exhibited a gradual increase. For appropriate antimicrobial agent selection and usage, it is essential for clinicians to be aware of the high rate of these antimicrobial-resistant bacteria in acute uncomplicated cystitis in Japan.

Fourth national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from patients with complicated urinary tract infections.

INTRODUCTION: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. MATERIALS AND METHODS: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. RESULTS: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 µg/mL) decreased from 14.7% to 7.7%. DISCUSSION: Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years.

Development and preliminary evaluation of a novel procedure for creation of an ileal conduit stoma aimed at preventing parastomal hernia.

OBJECTIVES: Our previous study suggested that the operative procedure is critical for the development of parastomal hernia. We developed a novel procedure for the creation of an ileal conduit stoma to prevent parastomal hernia. Herein we evaluate the efficacy and safety of the procedure. METHODS: A total of 113 Japanese patients underwent radical cystectomy and ileal conduit diversion for bladder cancer from January 2017 through December 2021 at our institution. After excluding those with incomplete data, 103 patients consisting of 46 (44.7%) with the conventional procedure and 57 (55.3%) with the novel procedure were consecutively enrolled. The main points of the novel procedure are as follows: (1) the passage of the ileal conduit is ≤2.4 cm in diameter in principle; (2) the posterior rectus sheath and peritoneum are vertically incised 2 cm laterally from the middle of the stoma site to make an oblique passage for the ileal conduit; and (3) the anterior rectus sheath and posterior rectus sheath with peritoneum are fixed to the ileal conduit separately. RESULTS: Radiography-based parastomal hernia was observed in 11 patients (10.7%) with a median follow-up of 22.0 months. The incidences of parastomal hernia were 3.5% and 19.6% in the novel and the conventional procedure groups, respectively (p = 0.011). The former had a significantly lower cumulative incidence of parastomal hernia (p = 0.008, log-rank test). No specific complications associated with the procedure were observed. CONCLUSIONS: The results of the preliminary cohort study suggest that the novel procedure is safe and effective for the prevention of parastomal hernia.

Intrinsic and extrinsic factors causing hyperplasia of the prostate.

Prostatic hyperplasia is very common in elderly men and is a typical disease that reduces quality of life. Histologically, hyperplasia of the prostate gland causes obstruction at the bladder outlet, resulting in symptoms such as a weak urine stream. Various factors have been considered to cause histological enlargement of the prostate, but the underlying cause is still unknown. The factors that cause prostate hyperplasia can be broadly classified into intrinsic and extrinsic ones. Extrinsic factors include things that we directly come into contact with such as bacteria and food. On the other hand, intrinsic factors are those that cause changes in functions originally provided in the body due to some cause, including extrinsic factors, such as chronic inflammation and an imbalance of sex hormones. A large number of reports have been made to date regarding the etiology of prostatic hyperplasia, although they have not yet clarified the fundamental cause(s). The various factors currently known should be outlined for future research. Should it be possible to prevent this highly prevalent prostatic hyperplasia which is mainly cause of dcreasing quality of life, there is no doubt that it would be a huge contribution to humanity.

Prevalence and impact on daily life of lower urinary tract symptoms in Japan: Results of the 2023 Japan Community Health Survey (JaCS 2023).

OBJECTIVES: A large-scale nationwide epidemiological survey of lower urinary tract symptoms (LUTS) was conducted via the Internet in 2023 to clarify the current prevalence of LUTS and evaluate its impact on daily life in Japan. METHODS: The survey was conducted among individuals aged 20-99 years old who had anonymously registered with a Japanese online research company. The survey consisted of 48 questions related to LUTS and daily life. RESULTS: A total of 6210 participants (3088 females and 3122 males), who were selected by probability sampling based on the composition of the Japanese population (age range: 20-99), were recruited. The overall prevalence of LUTS was 77.9% among the subjects aged ≥20 and 82.5% among those aged ≥40. The prevalence of LUTS differed between the sexes and trends toward significant increases in prevalence with age were seen for almost all LUTS. Furthermore, the prevalence of overactive bladder (OAB) was 11.9% among the subjects aged ≥20 and 13.8% among those aged ≥40. This study also showed that LUTS negatively affected daily life. However, the percentage of subjects who visited a physician to receive treatment for LUTS was low, including for participants with a history of treatment for LUTS, although this increased with age. CONCLUSION: The prevalence of LUTS, including OAB, increased with age and negatively affected daily life. However, since the percentage of patients who visit a physician to receive treatment for LUTS remains low, further educational activities regarding LUTS are necessary.

Gap analysis between trainees' subjective competencies and the competencies expected by instructors in urology: A need assessment survey in Japan.

OBJECTIVE: According to the rapid progress in surgical techniques, a growing number of procedures should be learned during postgraduate training periods. This study aimed to clarify the current situation regarding urological surgical training and identify the perception gap between trainees' competency and the competency expected by instructors in Japan. METHODS: Regarding the 40 urological surgical procedures selected via the Delphi method, we collected data on previous caseloads, current subjective autonomy, and confidence for future skill acquisition from trainees (<15 post-graduate years [PGY]), and the competencies when trainees became attending doctors expected by instructors (>15 PGY), according to a 5-point Likert scale. In total, 174 urologists in Hokkaido Prefecture, Japan were enrolled in this study. RESULTS: The response rate was 96% (165/174). In a large proportion of the procedures, caseloads grew with accumulation of years of clinical practice. However, trainees had limited caseloads of robotic and reconstructive surgeries even after 15 PGY. Trainees showed low subjective competencies at present and low confidence for future skill acquisition in several procedures, such as open cystectomy, ureteroureterostomy, and ureterocystostomy, while instructors expected trainees to be able to perform these procedures independently when they became attending doctors. CONCLUSION: Trainees showed low subjective competencies and low confidence for future skill acquisition in several open and reconstructive procedures, while instructors considered that these procedures should be independently performable by attending doctors. We believe that knowledge of these perception gaps is helpful to develop a practical training program.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

[A Case of Neuropathic Lower Urinary Tract Dysfunction Due to Spina Bifida Occulta Discovered at the Age of 19 Years and Successfully Treated with Multidisciplinary Therapy].

A 19-year-old man had been aware of dysuria and urinary incontinence since childhood but did not seek medical attention. He was diagnosed with acute pyelonephritis due to lower urinary tract dysfunction associated with spina bifida occulta and tethered cord syndrome (TCS) due to spinal cord lipoma. After placement of a urethral catheter and antibacterial chemotherapy, the patient was cured of acute pyelonephritis. He was treated with solifenacin and started clean self-intermittent catheterization (CIC). Shortly after the start of CIC, the acute pyelonephritis flared up again, and he was managed with a reinserted urethral catheter until an untethering operation. Preoperative video urodynamics showed that the bladder morphology was Ogawa classification grade III with vesicoureteral reflux (VUR) at 92 ml infusion. With the combination of an untethering operation and additional mirabegron, the functional bladder capacity was increased to 353 ml and VUR improved, allowing for safe urinary management of the CIC. TCS can be diagnosed at any age and requires appropriate urinary management and therapeutic intervention as early as possible after diagnosis.

[Two Cases of Retroperitoneal Synovial Sarcoma].

We experienced two cases of renal primary synovial sarcoma. Case 1: A 29-year-old man underwent laparoscopic radical nephrectomy and was originally diagnosed with renal cell carcinoma. Case 2: A 25-year-old man was treated by open radical nephrectomy since radiographical findings indicated tumor invasion to the ureter causing hydronephrosis. Both cases were pathologically diagnosed as renal synovial sarcomas, and were followed using computed tomography. Recurrence was observed within a year in both cases.

Comparison of incidence of acute kidney injury after robot-assisted radical prostatectomy with that after open retropubic and extraperitoneal laparoscopic radical prostatectomies in patients with prostate cancer.

Background: We retrospectively evaluated the postoperative renal function in patients who had undergone radical prostatectomy to compare the incidences of postoperative acute kidney injury (AKI) among the patients who had undergone robot-assisted radical prostatectomy (RARP), retropubic radical prostatectomy (RRP), and extraperitoneal laparoscopic radical prostatectomy (exLRP). Materials and methods: Patients with prostate cancer who had undergone radical prostatectomy at our institution between 2008 and 2014 were included. Robot-assisted radical prostatectomy was performed using an intraperitoneal approach in a 25-degree Trendelenburg position, whereas other procedures were performed with the patient in the supine position. We evaluated the serum creatinine levels and estimated glomerular filtration rates immediately after surgery and on postoperative day 1. We evaluated the incidence of AKI after prostatectomy using the Acute Kidney Injury Network criteria of the Kidney Disease: Improving Global Outcomes guidelines. Results: A total of 150 consecutive patients were included, with each of the 3 groups (RARP, RRP, and exLRP) comprising 50 patients. Postoperative AKI was observed in 15 (30.0%), 1 (2.0%), and 3 (6.0%) patients in the RARP, RRP, and exLRP groups, respectively. Stage 1 AKI was observed in all the patients except one. The incidence of AKI in RARP group was significantly higher than that in the other groups (p < 0.001). In the RARP group, the serum creatinine level was significantly elevated immediately after the surgery; however, it returned to baseline on postoperative day 1. Surgical procedures were the only independent factor associated with AKI incidence. Conclusions: This study suggest that compared with RRP and exLRP, RARP is associated with a higher incidence of postoperative AKI, although most patients recover rapidly. Intra-abdominal pneumoperitoneum may contribute to AKI onset.

Affinity of ß-Lactam Antibiotics for Neisseria gonorrhoeae Penicillin-Binding Protein 2 Having Wild, Cefixime-Reduced-Susceptible, and Cephalosporin (Ceftriaxone)-Resistant penA Alleles.

Multidrug-resistant Neisseria gonorrhoeae is a serious concern worldwide. Resistance to ß-lactam antibiotics occurs through mutations in penicillin-binding proteins (PBPs), acquisition of ß-lactamases, and alteration of antibiotic penetration. Mosaic structures of penA, which encodes PBP2, play a major role in resistance to ß-lactams, especially cephalosporins. Ceftriaxone (CRO) is recognized as the only satisfiable antibiotic for the treatment of gonococcal infections; however, CRO-resistant isolates have emerged in the community. Here, we examined the affinity of ß-lactam antibiotics for recombinant PBP2 in a competition assay using fluorescence-labeled penicillin. We found no or little difference in the affinities of penicillins and meropenem (MEM) for PBP2 from cefixime (CFM)-reduced-susceptible strain and cephalosporin-resistant strain. However, the affinity of cephalosporins, including CRO, for PBP2 from the cephalosporin-resistant strain was markedly lower than that for PBP2 from the CFM-reduced-susceptible-resistant strain. Notably, piperacillin (PIP) showed almost the same affinity for PBP2 from penicillin-susceptible, CFM-reduced-susceptible, and cephalosporin (including CRO)-resistant strains. Thus, PIP/tazobactam and MEM are candidate antibiotics for the treatment of CRO-resistant/multidrug-resistant N. gonorrhoeae.

Comparison of Oncological Outcomes of Pembrolizumab as Second-line Therapy and Maintenance Avelumab Therapy in Advanced Urothelial Carcinoma After Platinum-based Chemotherapy.

BACKGROUND/AIM: Sequential therapy using chemotherapy and subsequent immune checkpoint inhibitor (ICI) treatment prolongs the survival of patients with advanced urothelial carcinoma (UC). However, no comparison data for oncological outcome between pembrolizumab and avelumab has been reported. Thus, we compared oncological outcomes between pembrolizumab as second-line therapy and maintenance avelumab therapy in patients with advanced UC. PATIENTS AND METHODS: We retrospectively evaluated patients with advanced UC treated with pembrolizumab or avelumab between January 2018 and February 2023. We compared oncological outcomes after adjusting for patient characteristics. Immune-related adverse events (AEs) in each group were evaluated using the Common Terminology Criteria for Adverse Events. RESULTS: There were 186 and 44 patients in the pembrolizumab- and avelumab-treated cohorts, respectively. After propensity score matching, 43 patients from each group were selected and analyzed. Median progression-free survival from the initiation of pembrolizumab and avelumab treatments was 126 and 139 days, respectively (log-rank test, p=0.625). Median overall survival in the pembrolizumab and avelumab cohorts were 658 days and not reached, respectively (log-rank test, p=0.249). Thirty-eight (20.4%) and 14 (31.8%) all-grade immune-related AEs were observed in 186 pembrolizumab- and 44 avelumab-treated patients, respectively (chi-squared test, p=0.112). Regarding endocrine-related AEs, 12 (6.5%) and none (0%) were observed in pembrolizumab- and avelumab-treated patients, respectively (Fisher's exact probability test, p=0.129). CONCLUSION: Pembrolizumab and maintenance avelumab therapy provide equivalent oncological outcomes in patients with advanced UC. Although no significant difference was observed, there might be a potential risk of higher endocrine-related AEs due to pembrolizumab compared to avelumab maintenance therapy.

Which characteristics are associated with changes in medication status for lower urinary tract symptoms among patients with prostate cancer receiving external beam radiotherapy?

Background: We clarified the predictive factors for changes in the status of medications for lower urinary tract symptoms (LUTS) 2 years after local radiotherapy for nonmetastatic prostate cancer. Materials and methods: We retrospectively included patients who underwent local external radiotherapy for nonmetastatic prostate cancer in 8 institutions between April 2001 and March 2016. Patients were divided into the medication and no-medication group based on the use of drugs for LUTS before radiotherapy. We defined improvement of LUTS as when the patient did not require medication for LUTS at 24 months after radiotherapy in the medication group and as deterioration when medication was required in the no-medication group. Logistic regression analysis was used to evaluate predictive factors for changes in medication status. Results: Altogether, 505 patients were divided into a no-medication group (n = 352) and a medication group (n = 153). The number of patients with deterioration and improvement in LUTS was 49 (14%) and 36 (23%), respectively. In the multivariate analysis, the predictive variables for deterioration were the International Prostate Symptom Score (≥8; odds ratio [OR], 2.21; p = 0.014) and the biopsy Gleason score (≤3 + 4 = 7; OR, 2.430; p = 0.008) in the no-medication group, whereas those for improvement were age (<75 years old; OR, 5.81; p = 0.002), the quality of life score (<3; OR, 3.15; p = 0.028), and a positive biopsy core rate (≥50%; OR, 2.530; p = 0.027) in the medication group. Conclusions: These predictive factors for changes in the status of medications for LUTS at 2 years after external radiotherapy may help determine the definitive therapy for nonmetastatic prostate cancer.

Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.