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We present a direct Lagrangian simulation that computes key warm-rain processes in a vertically developing cloud, including cloud condensation nuclei (CCN) activation, condensational growth, collisional growth, and droplet gravitational settling. This simulation, which tracks the motion and growth of individual particles, is applied to a kinematic simulation of an extremely vertically elongated quasi-one-dimensional domain, after which the results are compared with those obtained from a spectral-bin model, which adopts the conventional Eulerian framework. The comparison results, which confirm good bulk statistical agreement between the Lagrangian and conventional spectral-bin simulations, also show that the Lagrangian simulation is free from the numerical diffusion found in the spectral-bin simulation. After analyzing the Lagrangian statistics of the surface raindrops that reach the ground surface, back-trajectory scrutiny reveals that the Lagrangian statistics of surface raindrops contains the information about the sky where the raindrops grow like the shape does for snow crystals.

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Enterovirus D68 (EV-D68), a pathogen that causes respiratory symptoms, mainly in children, has been implicated in acute flaccid myelitis, which is a poliomyelitis-like paralysis. Currently, there are no licensed vaccines or treatments for EV-D68 infections. Here, we investigated the optimal viral inactivation reagents, vaccine adjuvants, and route of vaccination in mice to optimize an inactivated whole-virion (WV) vaccine against EV-D68. We used formalin, β-propiolactone (BPL), and hydrogen peroxide as viral inactivation reagents and compared their effects on antibody responses. Use of any of these three viral inactivation reagents effectively induced neutralizing antibodies. Moreover, the antibody response induced by the BPL-inactivated WV vaccine was enhanced when adjuvanted with cytosine phosphoguanine oligodeoxynucleotide (CpG ODN) or AddaVax (MF59-like adjuvant), but not with aluminum hydroxide (alum). Consistent with the antibody response results, the protective effect of the inactivated WV vaccine against the EV-D68 challenge was enhanced when adjuvanted with CpG ODN or AddaVax, but not with alum. Further, while the intranasal inactivated WV vaccine induced EV-D68-specific IgA antibodies in the respiratory tract, it was less protective against EV-D68 challenge than the injectable vaccine. Thus, an injectable inactivated EV-D68 WV vaccine prepared with appropriate viral inactivation reagents and an optimal adjuvant is a promising EV-D68 vaccine., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasuo Yoshioka reports financial support was provided by The Research Foundation for Microbial Diseases of Osaka University. Chikako Kataoka-Nakamura reports financial support was provided by The Research Foundation for Microbial Diseases of Osaka University. Yuta Kunishima reports financial support was provided by The Research Foundation for Microbial Diseases of Osaka University. Yasuo Yoshioka reports a relationship with The Research Foundation for Microbial Diseases of Osaka University that includes: employment. Chikako Kataoka-Nakamura reports a relationship with The Research Foundation for Microbial Diseases of Osaka University that includes: employment. Yuta Kunishima reports a relationship with The Research Foundation for Microbial Diseases of Osaka University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To evaluate the significance of local radiation therapy (LRT) for prevention of local symptoms (LSs) caused by muscle-invasive bladder cancer (MIBC)., Methods: We retrospectively reviewed the clinical records of 133 patients from 13 hospitals. MIBC patients with or without metastases who were treated with LRT alone from January 2015 through December 2020 were enrolled. Exclusion criteria were urinary diversion (UD) prior to LRT, non-MIBC, or lack of clinical information. LSs were defined as hematuria requiring invasive treatment or transfusion, UD after LRT, bladder tamponade, and opioid use for bladder pain., Results: One hundred fourteen patients were finally enrolled in the study. During the median follow-up period of 13.5 months, 30 patients (26.3%) had LSs. Risk factors of LSs in multivariate analysis were a prior history of non-MIBC (NMIBC) (hazard ratio [HR] 2.99; 95% confidence interval [CI], 1.36 to 6.56; P < 0.01), radiation dose of less than 50 Gray (Gy) (HR 3.99; 95% CI, 1.80 to 8.82; P < 0.01), and tumor stage 3 or more (HR 2.43; 95% CI, 1.14 to 5.21; P = 0.02). Risk factors of overall survival (OS) in multivariate analysis were being female (HR 3.32; 95% CI, 1.68 to 6.58; P < 0.01), an age-adjusted Charlson Comorbidity index of 6 or more (HR 2.19; 95% CI, 1.18 to 4.10; P = 0.01), distant metastases (HR 3.20; 95% CI, 1.39 to 6.58; P < 0.01), and tumor size of 40 mm or more (HR 2.38; 95% CI, 1.34 to 4.52; P < 0.01). Toxicity (all grades) occurred in 40.4% of the patients, 4.8% with grade 3 or more and 95.2% with lower grades., Conclusions: We determined the risk factors for LSs in MIBC patients treated with LRT alone. An escalated-dose of 50 Gy or more may contribute to prevention of LSs caused by MIBC. Thus, dose-escalated LRT for MIBC patients who can expect favorable survival may be a good option to avoid future annoying LSs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We aimed to prospectively compare lower urinary tract symptoms in premenopausal and postmenopausal women with acute uncomplicated cystitis before and after antibiotic therapy., Materials and Methods: This study included adult women with acute uncomplicated cystitis who visited 4 institutions between 2019 and 2020. After registration, we administered oral antibiotics and prospectively documented the changes in lower urinary tract symptoms from the first visit to a follow-up visit at 1 week using the Core Lower Urinary Tract Symptoms Score (CLSS) questionnaire., Results: After treatment, pyuria disappeared in 60 of the 66 patients (14 premenopausal and 46 postmenopausal). The CLSS total score (range) changed from 13 (3-29) to 4 (0-18) with a significant improvement in all CLSS items. At baseline, nocturia, urgency, and urgency incontinence were more prominent in postmenopausal women than in premenopausal women. In contrast, baseline urethral pain and quality of life index were more severe in premenopausal women than in postmenopausal women. After treatment, the CLSS total score was still higher in postmenopausal women, as reflected by the relatively higher scores for nocturia and urgency, irrespective of the comparable scores for urethral pain and the quality of life index in the 2 groups., Conclusions: Our results suggest that if storage symptoms persist, they should be carefully interpreted according to menopausal status., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

Background: The nutritional status during early life can have enduring effects on an animal's metabolism, although the mechanisms underlying these long-term effects are still unclear. Epigenetic modifications are considered a prime candidate mechanism for encoding early-life nutritional memories during this critical developmental period. However, the extent to which these epigenetic changes occur and persist over time remains uncertain, in part due to challenges associated with directly stimulating the fetus with specific nutrients in viviparous mammalian systems., Results: In this study, we used medaka as an oviparous vertebrate model to establish an early-life high-fat diet (HFD) model. Larvae were fed with HFD from the hatching stages (one week after fertilization) for six weeks, followed by normal chow (NC) for eight weeks until the adult stage. We examined the changes in the transcriptomic and epigenetic state of the liver over this period. We found that HFD induces simple liver steatosis, accompanied by drastic changes in the hepatic transcriptome, chromatin accessibility, and histone modifications, especially in metabolic genes. These changes were largely reversed after the long-term NC, demonstrating the high plasticity of the epigenetic state in hepatocytes. However, we found a certain number of genomic loci showing non-reversible epigenetic changes, especially around genes related to cell signaling, liver fibrosis, and hepatocellular carcinoma, implying persistent changes in the cellular state of the liver triggered by early-life HFD feeding., Conclusion: In summary, our data show that early-life HFD feeding triggers both reversible and persistent epigenetic changes in medaka hepatocytes. Our data provide novel insights into the epigenetic mechanism of nutritional programming and a comprehensive atlas of the long-term epigenetic state in an early-life HFD model of non-mammalian vertebrates., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To evaluate factors to predict overall survival of metastatic urothelial carcinoma patients treated with gemcitabine plus cisplatin chemotherapy or pembrolizumab therapy., Methods: We retrospectively evaluated two metastatic urothelial carcinoma cohorts treated with (i) gemcitabine plus cisplatin or (ii) pembrolizumab. The gemcitabine plus cisplatin cohort was treated from December 2005 through December 2014 while the pembrolizumab cohort was treated from January 2018 through December 2020. Using multivariate analyses, we evaluated the risk factors for overall survival in each cohort and compared them. None of the gemcitabine plus cisplatin cohort patients were treated with pembrolizumab. All patients in the pembrolizumab cohort were treated with prior platinum-based chemotherapy., Results: There were 184 patients in the gemcitabine plus cisplatin cohort and 91 in the pembrolizumab cohort. The mean follow-up periods were 714 and 284 days, respectively. In multivariate analysis, the risk factors for overall survival in the gemcitabine plus cisplatin cohort were liver metastasis, worse Eastern Cooperative Oncology Group performance status (1 or more), no primary site resection, and a high prognostic index (1 or more). In the pembrolizumab cohort, liver metastasis, bone metastasis, and worse Eastern Cooperative Oncology Group-performance status (1 or more), and high prognostic index (1 or more) were the risk factors for overall survival. In the pembrolizumab cohort, patients with a complete response or partial response during prior platinum-based chemotherapy had better overall survival with the following pembrolizumab treatment than those with stable or progressive disease (P = 0.004)., Conclusions: Considering the similarity of these risk factors in two sequential treatments, it may be possible to predict the response to pembrolizumab according to the response to prior chemotherapy., (© 2022 The Japanese Urological Association.)

Objectives: To evaluate the risk factors for intravesical recurrence in patients with newly diagnosed Ta high-grade non-muscle-invasive bladder cancer and the optimal management to reduce the risk of recurrence., Methods: We retrospectively evaluated Ta high-grade bladder cancer in patients who were newly diagnosed by transurethral resection from January 2007 through October 2018. Using multivariate analyses, we evaluated the risk factors and therapeutic options affecting intravesical recurrence and stratified the patients according to the risk numbers., Results: We included 390 patients and the median follow-up period was 31 months after the initial transurethral resection. According to multivariate analysis, having a previous history of upper urinary tract carcinoma, and multiple and sessile tumors were risk factors for intravesical recurrence (P = 0.001, P = 0.02 and P = 0.01, respectively). Risk groups were stratified according to these risk factors into favorable, intermediate and poor. In the entire cohort, induction and immediate intravesical instillation therapy were treatment options to reduce intravesical recurrence (P < 0.01 and P = 0.02, respectively). Analyses in each risk group showed that a second transurethral resection was the only therapeutic option to reduce intravesical recurrence in the favorable group (P = 0.048), whereas induction intravesical instillation therapy was effective in the intermediate and poor risk groups (P = 0.01 and P < 0.01, respectively), as was immediate intravesical instillation for the poor risk group (P < 0.001)., Conclusions: Sessile, multiple tumors and a history of upper urinary tract carcinoma are risk factors for intravesical recurrence in Ta high-grade bladder cancer patients., (© 2021 The Japanese Urological Association.)

Introduction: The aim of this study was to monitor the development of drug-resistant bacteria isolated from acute uncomplicated cystitis (AUC) and to evaluate methodology of the survey conducted by collecting only clinical data., Methods: We enrolled female patients at least 16 years of age diagnosed with AUC in 2018. Patient information including age, menopausal status, and results of bacteriological examination were collected and analyzed regardless of bacterial identification, antimicrobial susceptibility testing or extended-spectrum β-lactamase (ESBL) detection method., Results: A total of 847 eligible cases were collected. Escherichia coli (E. coli) was the most frequently isolated bacterial species at about 70%, with proportions of fluoroquinolone-resistant E. coli (QREC) and ESBL-producing E. coli isolates at 15.6% and 9.5% of all E. coli isolates, respectively. The proportion of Staphylococcus saprophyticus (S. saprophyticus) was significantly higher in premenopausal women. Regarding the drug susceptibility of E. coli, isolates from Eastern Japan had significantly higher susceptibility to cefazolin, cefotiam and cefpodoxime and lower susceptibility to levofloxacin in postmenopausal women. ESBL-producing E. coli isolates had a high susceptibility to tazobactam-piperacillin, cefmetazole, carbapenems, aminoglycosides, and fosfomycin. In S. saprophyticus, the susceptibility to β-lactams including carbapenems was 40-60%., Conclusions: The proportions of QREC and ESBL-producing E. coli were increasing trends and lower susceptibility to LVFX in postmenopausal women was observed. Such surveillance, consisting of the collecting only clinical data, could be conducted easily and inexpensively. It is expected to be continuously performed as an alternative survey to conventional one collecting bacterial strains., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients., Materials and Methods: We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists., Results: Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m 2 were significant predictors for ARONJ., Conclusion: ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.

Gemcitabine (GEM) is currently a standard chemotherapeutic agent for metastatic urothelial carcinoma (mUC). Fever isknown to be an adverse effect of GEM ; however, itsincidence, etiology and clinical significance have not been evaluated. The objective of this study was to elucidate the characteristics and clinical significance of fever associated with GEM in patients with mUC receiving GEM plus cisplatin (GC) chemotherapy. Between 2005 and 2014, 184 patientswith mUC who received first-line GC therapy at 10 institutions were enrolled. GEM-associated fever (GEMAF) was defined as a body temperature ≥37.5ºC within 96 hours after administration of GEM with no evidence of specific conditions causing fever including infection. Clinical parametersbefore GC therapy were evaluated to determine predictorsof GEMAF. Furthermore, the impact of GEMAF on clinical outcomeswasals o evaluated. The median age was70 years and median follow-up was14.2 months. GEMAF wasobs erved in 44 patients (23.9%). In multivariate analysis, elevated C-reactive protein (CRP) before chemotherapy was an independent predictive factor for GEMAF (oddsratio 2.450, p＝0.041). There was a significant difference in progression-free survival (median 6.7 vs 8.0 months, p＝0.031) and cancer-specific survival (median 12.0 vs 15.8 months, p＝0.045) between patients with and without GEMAF. Results of this study suggest that GEMAF is a common adverse event of GC therapy for mUC and can be a poor prognostic factor. GEMAF may be associated with systemic inflammatory response induced by the tumor in patients with mUC.

Background: To best employ radium-223 dichloride (Ra-223) for patients with castration-resistant prostate cancer (CRPC) and bone metastasis, we investigated the bone-predominant status in patients treated with Ra-223., Methods: We retrospectively evaluated 127 CRPC patients who underwent treatment with Ra-223. The patients were divided into three groups based on the types of dynamic changes of bone metastasis between diagnosis and just before Ra-223: (a) only known lesions; (b) de novo lesions; (c) new progressive lesions. We developed the risk assessment using predictive factors based on progression-free survival (PFS)., Results: During the median follow-up period of 10.4 months, the median PFS in the only known lesions group was 11.3 months compared to 8.1 months in the de novo lesions group and 5.1 months in the new progressive lesions group (P < .001). In multivariate analysis, the type of the new progressive lesions in bone metastasis (HR 1.45, 95% CI 1.13-1.66, P = .003), performance status of >1 (HR 1.74, 95% CI 1.04-2.89, P = .034), PSA value of >100 ng/mL (HR 1.59, 95% CI 1.02-2.50, P = .043), and PSA doubling time (PSADT) of <3 months (HR 1.53, 95% CI 1.11-2.03, P = .007) were independent unfavorable predictive factors for PFS. The risk assessment for PFS was highlighted when the type of dynamic changes of bone metastasis was combined with PSADT just before Ra-223 treatment. This was associated with non-bone metastasis progression, especially visceral metastasis, and overall survival., Conclusions: Risk assessment in combination with dynamic changes of bone metastasis and PSADT determines the bone-predominant metastasis type to benefit from Ra-223., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Our aim was to evaluate the usefulness of serum testosterone to guide treatment decision for castration-resistant prostate cancer (CRPC)., Methods: We conducted a retrospective analysis of 115 patients with CRPC treated with either abiraterone (n = 43) or enzalutamide (n = 72). A serum testosterone level was measured at time of starting of abiraterone or enzalutamide. We determined whether serum testosterone influenced the outcomes of androgen receptor (AR)-targeted therapy., Results: In the very-low testosterone group (<5 ng/dl), the rate of prostate-specific antigen (PSA) response was significantly higher among patients treated with abiraterone compared to enzalutamide (62 vs. 32%, respectively; P = 0.033), with no difference in the low testosterone group (5-<50 ng/dl) (93 vs. 81%, respectively; P = 0.429). During the median follow-up of 26 months, PSA progression-free survival was significantly longer in the low testosterone group than in the very-low testosterone group (12.2 vs. 4.5 months, P<0.001). In the very-low testosterone group, enzalutamide use (HR 3.07, 95% CI 1.36-6.94; P = 0.007), primary androgen deprivation therapy <12 months (HR 2.50, 95% CI 1.23-5.08; P = 0.011) and bone metastases (HR 2.60, 95% CI 1.20-5.64; P = 0.015) were significantly associated with PSA progression., Conclusion: Patients with a serum testosterone level ≥5 ng/dl were more likely to receive therapeutic benefits from AR-targeted therapy compared to those with serum testosterone levels <5 ng/dl. However, even for those with a very low serum testosterone level, the efficacy of abiraterone was slightly higher than that of enzalutamide. Therefore, serum testosterone level is a useful biomarker for informing treatment selection for CRPC., (Copyright © 2019. Published by Elsevier Inc.)

There are several reports that vouch for the usefulness of diffusion-weighted image (DWI) in making a diagnosis before treatment. However, no study has evaluated the effect of radiotherapy (RT) for unresectable gastric cancer. In the present case report, we evaluated the effectiveness of RT using DWI. An 81-year-old man was hospitalized with a broken bone and then diagnosed with advanced gastric cancer with breeding. He had chorionic renal failure and surgery was impossible. Further, contrast-enhanced computed tomography and magnetic resonance imaging (MRI) were not performed due to renal failure, whereas palliative RT was performed. We followed up the patient using blood test and MRI (DWI) to estimate whether bleeding had stopped or not after radiotherapy. Hemostasis effect was found after 2 weeks of RT. In DWI examination, there was a decrease in the tumor signal intensity 30 days after RT. Similarly, at day 60, the tumor signal intensity further decreased on DWI and the blood test results indicated no progression of anemia. At 4 months after the RT, the patient died because of respiratory failure without any bleeding. DWI is useful not only for the initial diagnosis but also for evaluating the effectiveness of RT.Trial registration: National clinical study registered number: UMIN000026362.

Objectives: To evaluate a regimen of targeted prophylaxis using rectal swab culture in patients undergoing transrectal ultrasound-guided prostate biopsy, and to investigate the characteristics of isolated fluoroquinolone-resistant Escherichia coli., Methods: A prospective study was carried out from June 2013 through December 2014. Rectal swabs were cultured on agar plates containing either 2 μg/mL levofloxacin or 1 μg/mL sitafloxacin before transrectal ultrasound-guided prostate biopsy. Patients with susceptible organisms received levofloxacin or sitafloxacin, whereas those with resistant organisms received directed antimicrobial prophylaxis according to the results of the antimicrobial susceptibility test. Patients with infectious complications after prostate biopsy were identified, and characteristics of patients carrying fluoroquinolone-resistant Escherichia coli were analyzed., Results: A total of 397 men underwent transrectal ultrasound-guided prostate biopsy. Of these patients, 74 (18.6%) had fluoroquinolone-resistant Escherichia coli. All fluoroquinolone-resistant Escherichia coli were susceptible to amikacin and meropenem. The risk factor for possible fluoroquinolone-resistant Escherichia coli was age of ≥73 years. Three (0.7%) patients who received appropriate antimicrobial prophylaxis had high-grade fever after the prostate biopsy. However, the pathogens were not fluoroquinolone-resistant Escherichia coli., Conclusions: Targeted antimicrobial prophylaxis in patients undergoing transrectal ultrasound-guided prostate biopsy can be associated with reducing severe infectious complications caused by fluoroquinolone-resistant Escherichia coli., (© 2019 The Japanese Urological Association.)

Purpose: We prospectively evaluated the 90-day postoperative mortality and morbidity of open radical cystectomy by using a standardized reporting methodology. Additionally, we assessed the preoperative characteristics to determine risk factors for major complications., Methods: This multicenter prospective study included 185 consecutive patients undergoing open radical cystectomy from October 2010 through March 2014. Postoperative complications within 90 days were recorded and graded according to the modified Clavien-Dindo classification., Results: Totally, 328 postoperative complications were observed in 149 patients (80.5%). Of these events, 73 (22.2%) were high grade (≥ Grade III), and developed in 46 patients (24.9%). Three patients (1.6%) died postoperatively. Urinary tract infection, wound complications, and paralytic ileus were common complications that occurred in 55 (29.7%), 42 (22.7%) and 41 (22.2%) patients, respectively. Ureteroenteric stricture was diagnosed in 13 of the 151 patients (8.6%) undergoing intestinal urinary diversion. Emergency room visits were required for 13 patients (7.0%) and readmission after discharge was needed for 36 (19.5%). A body mass index ≥ 25 kg/m 2 , smoking history and Charlson Comorbidity Index ≥ 2 were independent risk factors for high-grade complications, and their odds ratios (95% confidence intervals) were 2.357 (1.123-4.948), 2.843 (1.225-6.596) and 3.025 (1.390-6.596), respectively., Conclusions: Open radical cystectomy is associated with a high incidence of postoperative complications. Most, however, are of low grade. Our results suggest that obesity, a smoking history, and increasing comorbidity are risk factors for major complications.

Objectives: The aim of this study was to clarify the prognostic indicators for upper tract urothelial carcinoma (UTUC) following intravesical bacillus Calmette-Guérin (BCG) therapy for nonmuscle-invasive bladder cancer (NMIBC)., Methods: Data from 402 patients who received intravesical BCG therapy between January 1990 and November 2011 were collected from 10 institutes. The median follow-up interval from transurethral resection of the bladder tumor (TURBT) followed by BCG treatment was 50.0 months (IQR: 31.8-77.0). Of these patients, 186 (46.3%) had intravesical recurrence during the follow-up period after BCG therapy., Results: Thirty patients (7.5%) were diagnosed with UTUC after BCG therapy. The 10-year recurrence-free survival rates for UTUC (RFS-UTUC) was 87.5%. In univariate and multivariate analyses, the independent predicting factors for UTUC were intravesical recurrence (P = 0.016) and tumor morphology at TURBT before BCG (P = 0.045). The 10-year RFS-UTUC of patients with intravesical recurrence and others, were 80.6% and 95.0%, respectively. The 10-year RFS-UTUC of patients with papillary pedunculated tumors and nonpapillary or nonpedunculated were 96.1% and 84.6%, respectively., Conclusions: The frequency of UTUC in patients with NMIBC after BCG therapy is not negligible. Two independent predicting factors (intravesical recurrence and nonpapillary nonpedunculated at TURBT before BCG) were identified for UTUC. These results might be useful to predict UTUC after BCG therapy for NMIBC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Bitter taste avoidance behavior (BAB) plays a fundamental role in the avoidance of toxic substances with a bitter taste. However, the molecular basis underlying the development of BAB is unknown. To study critical developmental events by which taste buds turn into functional organs with BAB, we investigated the early phase development of BAB in postnatal mice in response to bitter-tasting compounds, such as quinine and thiamine. Postnatal mice started to exhibit BAB for thiamine and quinine at postnatal day 5 (PD5) and PD7, respectively. Histological analyses of taste buds revealed the formation of microvilli in the taste pores starting at PD5 and the localization of type 2 taste receptor 119 (TAS2R119) at the microvilli at PD6. Treatment of the tongue epithelium with cytochalasin D (CytD), which disturbs ACTIN polymerization in the microvilli, resulted in the loss of TAS2R119 localization at the microvilli and the loss of BAB for quinine and thiamine. The release of ATP from the circumvallate papillae tissue due to taste stimuli was also declined following CytD treatment. These results suggest that the localization of TAS2R119 at the microvilli of taste pores is critical for the initiation of BAB., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To determine prognostic factors for overall survival (OS) in renal cell carcinoma (RCC) patients with bone metastasis in the targeted-therapy era., Patients and Methods: We conducted a retrospective multi-institutional review of the medical records of 149 RCC patients with bone metastasis. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify independent factors associated with OS., Results: The median OS was 13.4 months. In multivariate analysis, molecular-targeted therapy, nephrectomy and surgery for bone metastasis were independent prognostic factors. Bone-modifying agents (BMAs) were not associated with OS. The median OS of patients receiving molecular-targeted therapy after diagnosis of bone metastasis was significantly better than that of those who did not receive targeted therapy., Conclusion: Molecular-targeted therapy, nephrectomy and surgery for bone metastasis should be considered for RCC patients with metastasis in the bones., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Our aim was to prospectively analyze the 3-year outcomes of naftopidil treatment for patients with benign prostatic hyperplasia (BPH), including those who dropped out during follow-up and had retreatment for BPH after termination of the drug within 3 years., Patients and Methods: Naftopidil, 50 mg/d or 75 mg/d, was given to 117 patients having BPH aged 50 years and older who had international prostate symptom scores (IPSS) ≥8. They were prospectively followed for 3 years with periodic evaluation. If naftopidil was terminated, the reason was determined. For patients with termination, an outcome survey was done to evaluate the status of retreatment for BPH at 3 years., Results: Twenty-five patients (21.4%) continued the same medication for 3 years. The total IPSS, quality of life index, BPH problem index, and maximum flow rate were significantly improved during 3 years. Treatment failure defined as symptomatic progression (an increase in the IPSS of ≥4 points compared to the baseline value), development of acute urinary retention, conversion to other α1-blockers, add-on of a 5α-reductase inhibitor, or conversion to surgery was observed in 41 patients (35.0%). In the univariate analysis, age, prostate volume, and serum prostate-specific antigen were predictors of treatment failure. Of the 50 patients who discontinued naftopidil during the follow-up, only 13 (26%) patients reported that they needed retreatment with α1-blockers and/or surgery within 3 years., Conclusion: Long-term efficacy of naftopidil was observed, although older age, increased prostate volume, and elevated prostate-specific antigen at baseline were highly likely to result in treatment failure. Even after termination for various reasons, only a small portion of the patients needed retreatment for BPH within 3 years.

(Objective) We investigated the clinical features of patients under surveillance for localized renal masses. (Methods) This study was a retrospective analysis of 15 patients who were diagnosed as having clinically localized renal cell carcinoma and were placed under surveillance and 68 patients who underwent immediate radical operation for renal masses. (Results) The age at diagnosis in the surveillance group was significantly higher than in the immediate operation group (median, 81 vs. 65 years, respectively, P<0.01). The Charlson Comorbidity Index in the surveillance group was significantly higher than in the immediate operation group (median, 5 vs. 2, respectively, P<0.01) and 10 patients (67%) had complications, which was one of the reasons for surveillance. The median initial tumor size in the surveillance group was 2.5 cm (1.5-10.1). There was no significant difference in the tumor size between the two groups. During a median follow-up of 19 months (6-55) the median tumor growth rate was 0.29 cm per year (-0.19-0.65) in the surveillance group. Of the 15 patients with computed tomography follow-up, four underwent surgical resection of the renal masses after surveillance. The histological diagnosis was clear cell renal cell carcinoma in all four. During follow-up, two patients died of other causes and one patient had bone metastasis but there was no death related to the renal masses in the surveillance group. (Conclusions) The appropriateness of the surveillance should be considered when we initiate surveillance for patients with renal masses because metastasis was detected in one patient in this study. On the other hand, surveillance may be an acceptable management method for elderly or severely comorbid patients because there were two deaths from other causes in the surveillance group.

Objectives: To evaluate the appearance of chemotherapy-induced nausea and vomiting, and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-hydroxytryptamine 3-receptor antagonists and dexamethasone during gemcitabine and cisplatin chemotherapy in patients with advanced urothelial cancer., Methods: We carried out a multi-institutional study including 122 patients who received gemcitabine and cisplatin for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled chemotherapy-induced nausea and vomiting events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake., Results: First-generation 5-hydroxytryptamine 3-receptor antagonists (ondansetron or granisetron) plus dexamethasone were used for 75 patients (cohort 1), and palonosetron with dexamethasone plus aprepitant for 47 patients (cohort 2). Patients in cohort 2 had significantly higher complete response (defined as no emetic episodes and no rescue medication use) rates than those in cohort 1 during the overall phase in the first cycle (85.7% vs 65.3%, P = 0.012), and all cycles (78.7% vs 50.7%, P = 0.0019) of gemcitabine and cisplatin. Patients in cohort 2 were more likely to achieve more favorable chemotherapy-induced nausea and vomiting control; that is, a lower grade of nausea, vomiting or anorexia, lower incidence of rescue therapy required, and shorter time to become chemotherapy-induced nausea- and vomiting-free than patients in cohort 1., Conclusions: The present results show that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in urothelial cancer patients treated with gemcitabine and cisplatin than first-generation 5-hydroxytryptamine 3-receptor antagonists plus dexamethasone., (© 2015 The Japanese Urological Association.)

To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the Japanese Society of Chemotherapy, the Japanese Association of Infectious Disease, and the Japanese Society of Clinical Microbiology conducted the second nationwide surveillance from January to September 2011. With the cooperation of 42 medical institutions throughout Japan, 1036 strains belonging to 8 clinically relevant bacterial species were collected. Among methicillin-resistant Staphylococcus aureus (MRSA) strain, the vancomycin (VCM) MIC for 5.5% (3/55) of the strains was 2 μg/mL. Ampicillin, VCM, and linezolid were relatively active against 209 Enterococcus faecalis strains. The proportion of fluoroquinolone (FQ)-resistant strains was >20%. The MIC90 of FQs against the 382 Escherichia coli strains was 2-64 mg/L and the proportion resistant to FQs was approximately 30%. However, susceptibility of E. coli to sitafloxacin was still high (MIC90 = 2 mg/L). Fifty-eight (15.2%) of 382 E. coli, 6 (4.5%) of 132 Klebsiella pneumoniae, 1 (2.4%) of 41 Klebsiella oxytoca and 4 (6.8%) of 59 Proteus mirabilis strains were suspected of producing extended-spectrum beta-lactamase. Of 93 Pseudomonas aeruginosa strains, the proportions resistant to imipenem, amikacin, and ciprofloxacin were 21.5%, 4.3%, and 20.4%, respectively. Four strains (4.3%) were found to be multidrug-resistant. In complicated UTI cases, all of MRSA and E. faecalis were susceptible to all anti-MRSA agents. Sitafloxacin was active against other FQ-resistant E. coli strains. The isolation of extended-spectrum beta-lactamase-producing and multidrug-resistant strains increased., (Copyright © 2015. Published by Elsevier Ltd.)

Escherichia coli is the most commonly isolated bacterium in urinary tract infections, especially in acute uncomplicated cystitis. It is reported that fluoroquinolone-resistant E. coli is increasing. However, according to the guidelines for antimicrobial use published by the Japanese Associations for Infectious Diseases (JAID) and the Japanese Society of Chemotherapy (JSC) in 2014, the first line antimicrobial regimen for the treatment of acute uncomplicated cystitis is a 3-day regimen with fluoroquinolone. We analyzed the causative bacteria and clinical efficacy of antimicrobial treatment in acute uncomplicated cystitis cases at our institute. Patients diagnosed as having acute uncomplicated cystitis who had ≥ 10(4) colony-forming units/mL of bacteria in their midstream urine in our outpatient clinic between 2012 and 2013 were enrolled in this study. We analyzed their clinical data retrospectively. From 173 patients, 212 strains were isolated. Of these, 135 (63.7%) were E. coli, including 15 strains (11.1%) that were levofloxacin resistant. One hundred twenty-three patients (63.7%) were treated with cephalosporin, and 46 patients (26.6%) were treated with fluoroquinolone. In all, 140 patients (80.9%) visited the outpatient clinic for an average of 8.4 days after their treatment. For 130 patients (92.6%), the clinical outcomes of antimicrobial treatment were judged as effective. The clinical outcomes were effective in 92.1% of the patients with cephalosporin treatment and in 97.1% of those with fluoroquinolone treatment. Only one patient who had levofloxacin-resistant E. coli in her urine was treated with fluoroquinolone. The clinical outcome was effective. Of the E. coli isolated from acute uncomplicated cystitis patients, 11.1% were levofloxacin-resistant strains. However, the clinical efficacy of antimicrobial treatment was relatively high (92.9%) in this study. The antimicrobial treatment for acute uncomplicated cystitis recommended by the guidelines published by the JAID and JSC was effective in the current situation.

Objective: Although some new drugs for castration-resistant prostate cancer are available, docetaxel still plays an important role in castration-resistant prostate cancer treatment. In this study, we evaluated the efficacy and safety of docetaxel and prednisolone in patients with castration-resistant prostate cancer., Methods: We conducted a retrospective chart review of castration-resistant prostate cancer patients who received docetaxel and prednisolone at 14 hospitals in the Sapporo Medical University Urologic Oncology Consortium from August 2004 to December 2011., Results: A total of 140 patients with castration-resistant prostate cancer received docetaxel and prednisolone (median age, 73.8 years; median prostate specific antigen, 54.7 ng/ml). A median of six cycles (range: 1-43) of docetaxel and prednisolone was administered per patient. Median follow-up was 13.7 months. Median overall survival was 22.0 months. The log-rank test revealed that prostate specific antigen before docetaxel and prednisolone (<50 ng/ml) and the prostate specific antigen reduction rate (≥30%) were associated with overall survival (P < 0.001 and P < 0.001, respectively). Eighty patients (57.1%) achieved a prostate specific antigen reduction rate of over 30%. All except two (97.5%) reached 30% prostate specific antigen reduction within five cycles of docetaxel and prednisolone. There were two (1.4%) treatment-related deaths due to adverse events, which were interstitial lung disease, and febrile neutropenia and bacterial pneumonia. Interstitial lung disease occurred in 14 (10.0%) patients within a median of 2.5 cycles of docetaxel and prednisolone. Grade 5 interstitial lung disease was seen after three cycles of docetaxel and prednisolone., Conclusions: If a prostate specific antigen reduction rate of over 30% is not obtained within five cycles of docetaxel and prednisolone, other treatment options should be considered. Although most patients safely received docetaxel and prednisolone, we must always keep interstitial lung disease in mind as a possible lethal adverse event., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We retrospectively reviewed the medical records of patients with metastatic clear cell renal cell carcinoma who received molecular targeted therapy between 2005 and 2011. Cancer-specific survival was analyzed using the Kaplan-Meier method. Predictors of cancer-specific survival were analyzed using the Cox regression hazards model. A total of 89 patients, consisting of 50 first line patients and 39 patients receiving prior cytokine were included in the analysis. The two-year cancer-specific survival rate of the firstlinegroup was 60.2% and that of theprior cytokinethe rapy group was 62.1%. In univariateanalysis, Karnofsky performance status (KPS)＜80%, time from diagnosis to treatment less than one year, bone metastasis and C-reactive protein (CRP)＞1.3 mg/dl in were statistically significant prognostic factors (p＜0.05). In multivariate analysis, time from diagnosis to treatment less than one year (HR 2.46, 95%CI 1.11-5.82, p＝0.025) and CRP (HR 4.92, 95%CI 2.23-11.3, p＜0.001) were independent prognostic factors. Time from diagnosis to treatment less than one year and CRP were independent prognostic factors in patients who received molecular targeted therapy.

Objective: The aims of this study were to clarify the prognostic factors and to validate the bacillus Calmette-Guérin failure classification advocated by Nieder et al. in patients with non-muscle-invasive bladder cancer who had intravesical recurrence after bacillus Calmette-Guérin therapy., Methods: Data from 402 patients who received intravesical bacillus Calmette-Guérin therapy between January 1990 and November 2011 were collected from 10 institutes. Among these patients, 187 with bacillus Calmette-Guérin failure were analyzed for this study., Results: Twenty-nine patients (15.5%) were diagnosed with progression at the first recurrence after bacillus Calmette-Guérin therapy. Eighteen (62.1%) of them died of bladder cancer. A total of 158 patients were diagnosed with non-muscle-invasive bladder cancer at the first recurrence after bacillus Calmette-Guérin therapy. Of them, 23 (14.6%) underwent radical cystectomy. No patients who underwent radical cystectomy died of bladder cancer during the follow-up. On multivariate analysis of the 135 patients with bladder preservation, the independent prognostic factors for cancer-specific survival were age (≥70 [P = 0.002]), tumor size (≥3 cm [P = 0.015]) and the Nieder classification (bacillus Calmette-Guérin refractory [P < 0.001]). In a subgroup analysis, the estimated 5-year cancer-specific survival rates in the groups with no positive, one positive and two to three positive factors were 100, 93.4 and 56.8%, respectively (P < 0.001)., Conclusions: Patients with stage progression at the first recurrence after bacillus Calmette-Guérin therapy had poor prognoses. Three prognostic factors for predicting survival were identified and used to categorize patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin into three risk groups based on the number of prognostic factors in each one., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate the clinical impact on progression and recurrence according to presence and absence of a muscle layer, we conducted a retrospective, multicenter study., Methods: We retrospectively reviewed 247 patients who received transurethral resection (TUR) of bladder tumors and were pathologically diagnosed as having T1G3 bladder cancer from 1990 to 2009. We ruled out 8 patients who received immediate cystectomy and analyzed the remaining 239 T1G3 patients. Patients who had invasion to the prostatic urethra and patients who underwent a second TUR were not included., Results: TUR specimens from 194 patients were confirmed to have a definite muscle layer and those from 45 did not. The median follow-up period was 53 months, ranging from 3 to 181 months. The progression-free survival rates at 5 years after TUR were 91.1 % for patients who had a muscle layer in their specimen and 77.3 % for those who did not (p = 0.005, log-rank test). Multivariate analysis indicated that the absence of a muscle layer was a risk factor for progression (p = 0.006, Cox proportional hazards analysis)., Conclusions: Patients without a muscle layer in the specimen had high risk for progression. The initial TUR must have a muscle layer in the specimen. Variations of progression rates in previous studies might be due to different proportions of patients who had a muscle layer in TUR specimens.

The objective of this study was to provide precise data on the incidence of sexually transmitted diseases (STDs) in Hokkaido. The goal of this prospective surveillance, study was to clarify the STD incidence between 1998 and 2001 in Hokkaido, Japan. The incidence of gonococcal infection in men was found to be 127-199 per 100000 people per year, which was three or four times higher than that for women. Female genital chlamydial infection had an incidence of 300-400 with a female to male ratio of two or three to one. Younger adults had higher incidences of gonococcal and chlamydial infections than older people. In conclusion, the current study of STDs revealed high incidences of gonococcal and chlamydial infections in the Hokkaido area, and there was no decreasing trend in STD incidence during these 4 years.

The purpose of this retrospective study was to identify the surgical outcome and complications of laparoscopic adrenalectomy at Sapporo Medical University Hospital. One hundred fifty-six patients underwent laparoscopic adrenalectomy due to primary aldosteronism in 64 (41.0%), Cushing's syndrome in 34 (21.8%), endocrinological non-functioning tumors in 27 (17.3%), pheochromocytoma in 23 (14.7%) and others. The median time of the surgery was 140 minutes (range 70 to 345) and the median volume of blood loss was 10 ml (0-1,200). From 1999, the operation time was around the median time of this study and from 2006, it was commonly below the median time of this study. There were 4 cases (2.6%) with complications; however, no severe cases occurred. In conclusion, laparoscopic adrenalectomy in our hospital has been performed safely as a standard treatment.

Three patients who had metastatic urothelial carcinoma have been administered gemcitabine monotherapy (GEM). A 78-year-old male who underwent nephroureterectomy for right ureteral cancer presented with liver and retroperitoneal lymph node metastases postoperatively. GEM was administered because of severe renal insufficiency. Although 8 cycles of this therapy were done, we discontinued it because of progressive disease. A 68-year-old male who underwent nephroureterectomy for left ureteral cancer presented with retroperitoneal lymph node metastasis postoperatively. GEM for the purpose of maintenance therapy was administered after first-line chemotherapy. He maintained a stable disease after 9 cycles. A 70-year-old female who underwent transurethral resection of a bladder tumor presented with neck lymph node metastasis postoperatively. She was administered GEM for second-line chemotherapy as an outpatient because she did not want hospital treatment. However, it failed due to progressive disease after 3 cycles. There were few adverse events that forced the patient to be admitted into the hospital, although bone marrow suppression of grade 3 or 4 occurred in 2 patients. GEM for metastatic urothelial carcinoma may be adapted for patients who have severe renal insufficiency and need maintenance therapy.