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Purpose To elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. Materials and methods Paired bladder mucosal biopsies, one sample each from the Hunner lesion and non-lesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin, and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-β, IFN-γ, TNF, TGF-β1, HIF1α, IL-2, IL-4, IL-6, IL-10, and IL-12A. The results were compared between the lesion and non-lesion areas. Results RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (N=24) included "HIF1α signaling pathway", "PI3K-Akt signaling pathway", "RAS signaling pathway", and "MAPK signaling pathway." By contrast, down-regulated pathways (N=6) included "basal cell carcinoma" and "protein digestion and absorption". The mRNA levels of HIF1α, IFN-γ, and IL-2 and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and non-lesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation, and CD4/CD8 T-lymphocyte ratio. Conclusions Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.

Objective To study the role of transient receptor potential melastatin 2 in bladder function and inflammation-associated hypersensitivity. Methods We evaluated physiological function of the bladder and intravesical lipopolysaccharide-induced inflammatory nociceptive responses in female wild-type and transient receptor potential melastatin 2-knockout mice. In vivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as in vitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0 mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain-like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation. Results Few phenotypic differences in in vivo and in vitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24-48 h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin 2-knockout mice, whereas an increased voiding frequency was observed in wild-type mice. At 24 h after intravesical lipopolysaccharide instillation, the numbers of bladder pain-like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild-type mice compared with those in both transient receptor potential melastatin 2-knockout mice and in wild-type mice treated with saline instillation. Conclusions Although the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin 2-knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin 2 channels in these processes.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, debilitating condition of unknown etiology characterized by persistent pain perceived to be related to the urinary bladder and lower urinary tract symptoms. Evidence shows that immunological inflammatory responses underlie the pathophysiology of IC/BPS with Hunner lesions but not that of IC/BPS without Hunner lesions. Here, we review the current understanding of the immunological inflammatory nature of IC/BPS with Hunner lesions and the clinical outcomes of immunomodulatory therapies. Open trials show that steroids improve validated symptom scores and pain scale score markedly in patients with IC/BPS with Hunner lesions. Open trials and a randomized study show that cyclosporine A improves urinary frequency, pain intensity, and bladder capacity significantly in IC/BPS patients, showing therapeutic superiority in the Hunner lesion subtype. A randomized double-blind study showed that certolizumab pegol significantly improves patient-reported global response assessments of pain, urgency, and overall symptoms, and reduces the Interstitial Cystitis Symptom/Problem Index scores and pain scale score at 18 weeks. These results suggest that immunomodulatory therapy is more effective for IC/BPS patients with Hunner lesions than for IC/BPS without Hunner lesions. IC/BPS with Hunner lesions is associated specifically with immunological overreactions in the bladder; thus, immunomodulatory therapy could be a promising treatment option. Further studies focusing on the therapeutic responsiveness of IC/BPS subtypes are warranted to promote a tailored approach to clinical management of IC/BPS. To achieve this therapeutic strategy, clear and proper subtyping of IC/BPS is mandatory.

Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

Introduction: The paucity and maldistribution of physicians among various specialties are key issues facing the Japanese health care system. Studies have shown that young physicians place more emphasis on work-life balance while selecting their specialty and that they prefer controllable lifestyle (CL) specialties over noncontrollable lifestyle (NCL) specialties. As this may be a cause of maldistribution, we investigated the relationship between views on work-life balance and specialty selection among young physicians in Japan. Methods: An online questionnaire was sent to 1451 residents (postgraduate years 1-5) at 60 Japanese Red Cross hospitals across Japan. Results: In all, 226 physicians responded (response rate: 15%), with 21% in CL and 74% in NCL specialties. When compared with NCL specialties, CL specialties had less overtime (43% vs. 16%, p = 0.001), considered life to be more important than work (26% vs. 15%, p = 0.018), and were more likely to give precedence to work-life balance over medical interest while choosing their specialty (49% vs. 30%, p < 0.001). Furthermore, physicians were more likely to change their choice of specialty, contrary to their professional interest, because of social reasons (49% vs. 26%, p = 0.007). Conclusions: Our study suggests that young physicians in CL specialties have better working hours and place more emphasis on work-life balance while choosing their specialty compared with those in NCL specialties. The increase in the number of physicians in CL specialties is likely attributable to the growing preference for an optimal work-life balance among young physicians; this seems to have increased the maldistribution of physicians among various specialties. Institutional mechanisms to support the lifestyle of physicians (especially in NCL specialties) are required to provide a balanced medical service in Japan.

OBJECTIVES To evaluate the outcomes of partial and total cystectomy in patients with refractory Hunner-type interstitial cystitis (HIC). METHODS Patients with end-stage HIC who underwent supratrigonal partial cystectomy with augmentation ileocystoplasty (PC-CP) or total cystectomy with ileal conduit (TC-IC) were identified retrospectively. Changes in the 11-point numerical rating scale of bladder pain and in 7-grade quality of life (QOL) scores were evaluated. Changes in the O'Leary and Sant's Symptom Index (OSSI) and O'Leary and Sant's Problem Index (OSPI) were analyzed in patients with PC-CP. Peri- and postoperative complications and patient satisfaction with overall outcomes were examined. RESULTS Four patients (one female) underwent PC-CP and 13 (nine females) underwent TC-IC. Bladder pain persisted in three PC-CP patients, but resolved completely in all TC-IC patients. Pain scale and QOL scores improved significantly in patients with TC-IC (P

Overactive bladder (OAB) is a syndrome with symptoms such as urinary frequency, urinary urgency and urge incontinence. The aim of this study is to assess the validity and reliability of the Turkish overactive bladder symptom score (OABSS) and to evaluate the results of mirabegron treatment with OABSS. The study was carried out with 117 patients who applied to the urology outpatient clinic between June 2018–January 2019. OABSS Turkish validation was developed from the English version. Demographic data of the patients were recorded. The OABSS, overactive bladder questionnaire (OAB-v8) and International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) were filled out by the patients. The patients were asked to fill in these questionnaires after 2 weeks. Patients receiving mirabegon treatment were evaluated with the same questionnaires and bladder diaries after 8 weeks. A total of 117 OAB patients, including 82 OAB-wet and 35-OAB dry, were included in the study. The mean age of the patients was 46.79 ± 14.26 (18–78) years, and the mean duration of OAB complaint was 32.28 ± 32.21 months. The mean score of the OABSS is 9.9 ± 3.14. The results of the reliability assessment showed that the intraclass correlation coefficient of the total OABSS score was 0.71 (weighted coefficients of individual item points, 0.635–0.831), and the Cronbach α was 0.736. In the validity analysis, the OABSS total score was highly correlated with that belonging to other questionnaire forms (OAB-v8, ICIQ-SF and bladder diary). After the treatment with mirabegron, mean OABSS scores of the patients improved significantly from baseline to the 8th week (p

The aim of this study was to establish permutation for cancer risk estimation in the urothelium. Twenty-six samples of normal control urothelium obtained from patients without urothelial carcinomas (C), 47 samples of non-cancerous urothelium without noticeable morphological changes obtained from patients with urothelial carcinomas (N), and 46 samples of the corresponding cancerous tissue (T) in the learning cohort and 64 N samples in the validation cohort, i.e. 183 tissue samples in total, were analyzed. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation 450K BeadChip, and DNA methylation levels were verified using pyrosequencing and MassARRAY. Amplicon sequencing was performed using the GeneRead DNAseq Targeted Panels V2. Although N samples rarely showed genetic mutations or copy number alterations, they showed DNA methylation alterations at 2502 CpG sites compared to C samples, and such alterations were inherited by or strengthened in T samples, indicating that DNA methylation alterations may participate in field cancerization in the urothelium. Receiver operating characteristic curve analysis confirmed the feasibility of cancer risk estimation to identify urothelium at the precancerous stage by DNA methylation quantification. Cancer risk estimation permutation was established using a combination of two marker CpG loci on the HOXC4, TENM3 and TLR1 genes (sensitivity and specificity 96–100%). Among them, the diagnostic impact of 10 patterns of permutation was successfully validated in the validation cohort (sensitivity and specificity 94–98%). These data suggest that cancer risk estimation using procedures such as urine tests during health checkups might become applicable for clinical use.

Objectives Perinephric fat invasion (PFI) of renal cell carcinoma (RCC) is known to be associated with adverse pathological features and poor prognosis. We analyzed these associations using a sub-group of the RCC registry of The Cancer Registration Committee of the Japanese Urological Association. Methods The study cohort of 2998 non-metastatic cases was retrieved from RCC registry (3648 in total). We compared clinicopathological characteristics of cases with PFI (n = 256) and without PFI (n = 2742), and investigated the impact of PFI on cancer-specific survival using univariate and multivariate analyses. Results Compared with non-PFI cases, PFI cases were older (P = 0.003), and more likely to be hypertensive (P = 0.034) and symptomatic at presentation (P < 0.001). PFI tumors were larger (P < 0.001), and more often have sarcomatoid component (P < 0.001) and tumor thrombus (P < 0.001). Cancer-specific survival was significantly shorter in cases with PFI than without (P < 0.001). The difference in survival tended to be greater in cases with large tumors but was significant in small tumor sub-groups. Cancer-specific survival was significantly shorter in cases with both PFI and renal vein involvement (RVI) in comparison to those with PFI or RVI alone (P = 0.011, P = 0.007, respectively). On multivariate analysis PFI with and without sinus fat invasion remained as an independent risk factor along with symptom at presentation, low body mass index, hypertension, multiple tumors, large tumor size (>7.0 cm), sarcomatoid component and RVI. Conclusions PFI was associated with advanced age and aggressive pathological features. PFI is an independent prognostic factor in non-metastatic RCC.

Aims To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l -menthol or prostaglandin E2 (PGE2) instillation in rats. Main methods The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l -menthol (6 mM) or PGE2 (60 μM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. Key findings RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l -menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l -menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l -menthol- and PGE2-induced activation of C-fiber SAAs. Significance The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT.

Introduction In the development of terminology of the lower urinary tract, due to its increasing complexity, the terminology for male lower urinary tract and pelvic floor symptoms and dysfunction needs to be updated using a male-specific approach and via a clinically-based consensus report. Methods This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 22 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Results A Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction, encompassing around 390 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in male lower urinary tract and pelvic floor dysfunction. Male-specific imaging (ultrasound, radiology, CT, and MRI) has been a major addition whilst appropriate figures have been included to supplement and help clarify the text. Conclusions A consensus-based Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Aims To determine whether ultrasound-assisted prompted voiding (USAPV) care is more efficacious than conventional prompted voiding (CPV) care for managing urinary incontinence in nursing homes. Methods Thirteen participating nursing homes in Japan were randomized to CPV (n = 7) or USAPV care group (n = 6). Residents of the allocated nursing homes received CPV (n = 35) or USAPV (n = 45) care for 8 weeks. In the CPV group, caregivers asked the elderly every 2-3 h whether they had a desire to void and prompted them to void when the response was yes. In the USAPV group, caregivers regularly monitored bladder urine volume by an ultrasound device and prompted them to void when the volume reached close to the individually optimized bladder capacity. Frequency-volume chart was recorded at the baseline and after the 8-week intervention to measure the daytime urine loss. Results The change in daytime urine loss was statistically greater in the USAPV (median, -80.0 g) than in the CPV (median, -9.0 g; P = .018) group. The proportion of elderly individuals whose daytime urine loss decreased by >25% was 51% and 26% in the USAPV and CPV group, respectively (P = .020). Quality-of-life measures of elderly participants showed no significant changes in both groups. The care burden scale score of caregivers was unchanged in the USAPV group (P = .59) but significantly worsened in the CPV group (P = .010) after the intervention. Conclusions USAPV is efficacious and feasible for managing urinary incontinence in nursing homes.

Objectives To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron. Methods During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions. Results Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores. Conclusions Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms.

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at days 7– 28 with a peak at day 21 tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Electrocautery is a promising treatment option for patients with Hunner type interstitial cystitis (HIC), but frequently requires multiple sessions due to recurrence of the lesions. In the present study, we assessed the relationship between the frequency of electrocautery of Hunner lesions and changes in maximum bladder capacity (MBC) at hydrodistension in a large cohort of 118 HIC patients. Three mixed-effect linear regression analyses were conducted for MBC against (1) the number of sessions; (2) the number of sessions and the time between each session and the first session; and (3) other relevant clinical parameters in addition to the Model (2). The mean number of sessions was 2.8 times. MBC decreased approximately 50 mL for each additional electrocautery session, but this loss was offset by 10 mL for each year the subsequent session was postponed. MBC of

Objective To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. Methods Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. Results For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. Conclusions This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

Background An advisory board concluded that a new, comprehensive overactive bladder (OAB) patient-reported outcome (PRO) measure should be developed in accordance with regulatory guidelines. The OAB-Bladder Assessment Tool (OAB-BAT) was developed with qualitative input from OAB patients and experts to measure symptoms, bother, impacts, and satisfaction with treatment. Objective Psychometric evaluation of the OAB-BAT assessing PRO OAB symptoms, bother, and impacts during a 7-d recall period. Design, setting, and participants Psychometric testing was conducted for a 28-d observational study of 170 OAB patients. Eligibility criteria included clinician-confirmed OAB diagnosis with at least eight micturitions per day. Outcome measurements and statistical analysis Assessments included the OAB-BAT, a 7-d bladder diary, and co-validating OAB PROs. Analysis included classical and modern test theories. A scoring algorithm was developed and psychometric properties were assessed. Results and limitations The majority of participants were women (72.4%) with moderate OAB symptom severity (53.5%). More than one-third of participants (34.1%) were incontinent. Responses were well balanced across bother and impact items, while symptom frequency items showed sparse responses. Analysis supported an eight-item unidimensional model based on bother and impacts. No items performed differently by gender or continence status. The OAB-BAT showed internal consistency (ω = 0.918), retest reliability (two-way random intraclass correlation coefficient = 0.81), and convergent validity with the OAB-q (r > 0.4). Known groups showed the expected trend. Comparisons between OAB-BAT scores and components of the bladder diary showed a moderate effect size (r > 0.4). Conclusions The eight-item OAB-BAT with 7-d recall is valid and reliable as an OAB PRO measure. Structural modeling, balanced with content validity considerations, produced robust scores. The OAB-BAT is a useful addition to the clinical assessment of patients, designed to complement the use of bladder diaries for monitoring OAB outcomes, in clinical trial and clinical practice environments. Future studies will need to assess the treatment satisfaction items in a larger sample of patients receiving OAB treatment. Patient summary We tested a questionnaire designed to assess overactive bladder (OAB) symptoms, bother, satisfaction, and impacts by asking patients to complete it on a weekly basis. We found that the questionnaire accurately captures the symptoms and impacts that are most important to patients with OAB. We conclude that the questionnaire could be a useful instrument and, after further assessment in clinical practice and research, a possible alternative to a bladder diary in measuring OAB outcomes.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC., 上部尿路上皮がんの分子分類と新規分子診断 --尿中遺伝子変異の検出で高精度の診断が可能--. 京都大学プレスリリース. 2021-06-15.

INTRODUCTION AND OBJECTIVE:Bacillus Calmette-Guerin related cystitis (BCG cystitis) shares similar clinicopathological features with Hunner lesion interstitial cystitis (HIC) such as hypersensitive...

INTRODUCTION AND OBJECTIVE:Glomerulations have been considered a good diagnostic marker for interstitial cystitis/bladder pain syndrome (IC/BPS). We systematically characterized gene expression, in...

The clinical guidelines for interstitial cystitis and related symptomatic conditions were revised by updating our previous guidelines. The current guidelines define interstitial cystitis/bladder pain syndrome as a condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases. The characteristic symptom complex is collectively referred as hypersensitive bladder symptoms. Interstitial cystitis/bladder pain syndrome is divided into Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis and bladder pain syndrome represent interstitial cystitis/bladder pain syndrome with Hunner lesions and interstitial cystitis/bladder pain syndrome without Hunner lesions, respectively. So-called non-Hunner-type interstitial cystitis featured by glomerulations or bladder bleeding after distension is included in bladder pain syndrome. The symptoms are virtually indistinguishable between Hunner-type interstitial cystitis and bladder pain syndrome; however, Hunner-type interstitial cystitis and bladder pain syndrome should be considered as a separate entity of disorder. Histopathology totally differs between Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis is associated with severe inflammation of the urinary bladder accompanied by lymphoplasmacytic infiltration and urothelial denudation, whereas bladder pain syndrome shows little pathological changes in the bladder. Pathophysiology would also differ between Hunner-type interstitial cystitis and bladder pain syndrome, involving interaction of multiple factors, such as inflammation, autoimmunity, infection, exogenous substances, urothelial dysfunction, neural hyperactivity and extrabladder disorders. The patients should be treated differently based on the diagnosis of Hunner-type interstitial cystitis or bladder pain syndrome, which requires cystoscopy to determine the presence or absence Hunner lesions. Clinical studies are to be designed to analyze outcomes separately for Hunner-type interstitial cystitis and bladder pain syndrome.

Aims The efficacy of perioperative pelvic floor muscle training (PFMT) for continence recovery after robot-assisted radical prostatectomy (RARP) remains unclear. Visualization of the bladder neck and urethra using transperineal ultrasound (US) may promote self-recognition of urethral closure during PFM contraction. This study aimed to examine whether transperineal US-guided PFMT promotes early recovery of post-RARP incontinence. Methods This prospective cohort study included 116 men undergoing RARP. All men were offered to undergo transperineal US-guided PFMT, and 36 men agreed. The protocol consisted of biofeedback PFMT using transperineal US before RARP and 1-month after RARP with verbal instruction of PFMT immediately after urethral catheter removal. The remaining 80 patients received verbal instruction for PFMT alone. Continence recovery was defined as the number of days requiring a small pad (20 g) per day by self-report. Results No differences were observed in demographic or peri-operative parameters between the two groups except the longer operative time in the US-guided PFMT group. The mean time until continence recovery was significantly shorter in the US-guided PFMT group (75.6 ± 100.0 days) than in the verbal-PFMT group (121.8 ± 132.0 days, P = 0.037). Continence recovery rates within 30 days were 52.8% (19/36) and 35.4% (28/80) in the US-guided PFMT and verbal-PFMT groups, respectively (P = 0.081). US-guided PFMT was associated with better postoperative continence status (adjusted hazard ratio [95% confidence interval]: 0.550 [0.336-0.900], P = 0.017). Conclusions The results showed that transperineal US-guided PFMT perioperatively was associated with early recovery of urinary continence after RARP.

Background The role of radical prostatectomy in treating non-metastatic prostate cancer patients with high prostate-specific antigen levels remains unclear. We evaluated the feasibility and oncological outcomes of radical prostatectomy in non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher. Methods This retrospective study included 31 patients who were diagnosed as very high-risk prostate cancer (clinical stage of any T, N0-1 M0 and PSA levels ≥50 ng/ml) and underwent radical prostatectomy either as a monotherapy or as a component of multimodal therapy (RP group). Surgery-related complications were investigated. Time to castration-resistant prostate cancer, cancer-specific survival, and overall survival were estimated using the Kaplan-Meier method. A total of 47 patients with very high-risk prostate cancer who were treated with androgen deprivation therapy without local therapy served as a control group (ADT group). Survivals were compared between RP group and ADT group in exploratory analyses. Results The median pretreatment prostate-specific antigen was 87 ng/ml and 100 ng/ml in the RP and ADT groups, respectively (P = 0.67). Surgical complications of Clavien-Dindo Grade 3 were documented in nine patients (29%). Ten-year castration-resistant prostate cancer-free, cancer-specific and overall survivals were 78%, 81% and 77% in RP group, respectively, and they were significantly better than those of ADT group (54%, P = 0.006; 54%, P = 0.006 and 38%, P < 0.001). Exploratory multivariate analysis identified radical prostatectomy as the only significant factor associated with a better cancer-specific survival (hazard ratio: 0.25, P = 0.006). Conclusions Radical prostatectomy is feasible for non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher. Radical prostatectomy is a viable option for select patients with non-metastatic, very high-risk prostate cancer.

Aims We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. Methods BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." Results The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. Conclusion The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats.

We investigated age-related changes in in vivo and in vitro functions and gene expression of the bladder of male and female mice. Mature and aged (12 and 27–30 month old) C57BL/6 mice of both sexes were used. Frequency volume, conscious free-moving cystometry and detrusor contractile and relaxant properties in in vitro organ bath were evaluated. mRNA expression level of muscarinic, purinergic, and β-adrenergic receptors and gene expression changes by cDNA microarray analysis of the bladder were determined. Cystometry demonstrated storage and voiding dysfunctions with ageing in both sexes. Detrusor strips from aged mice showed weaker contractile responses particularly in the cholinergic component and weaker relaxant responses to isoproterenol. These age-related impairments were generally severer in males. mRNA expression of bladder tissue was decreased for M3 muscarinic receptors in aged males and β2-adrenoceptors in aged females. cDNA microarray analysis results, albeit substantial sex difference, indicated “cell-to-cell signaling and interaction” as the most common feature of age-related gene expression. In summary, aged mice demonstrated voiding and storage dysfunctions resembling to detrusor hyperactivity with impaired contractility (DHIC), which were more pronounced in males. Genomic changes associated with aging may contribute to the age-related bladder functional deterioration in mice.

Aims To develop a comprehensive patient-reported bladder assessment tool (BAT) for assessing overactive bladder (OAB) symptoms, bother, impacts, and satisfaction with treatment. Methods Subjects were consented and eligibility was confirmed by a recruiting physician; subjects were then scheduled for in-person interviews. For concept elicitation and cognitive interviews, 30 and 20 subjects, respectively, were targeted for recruitment from US sites. All interviews were conducted face-to-face, audio-recorded, transcribed verbatim, anonymized, and analyzed using a qualitative data analysis software program. A draft BAT was created based on the results of the concept elicitation interviews and further revised based on cognitive interviews as well as feedback from an advisory board of clinical and patient-reported outcome (PRO) experts. Results Nocturia, daytime frequency, and urgency were reported by all subjects (n = 30, 100.0%), and incontinence was reported by most subjects (n = 25, 83.3%). The most frequently reported impacts were waking up to urinate (n = 30, 100.0%), embarrassment/shame (n = 24, 80.0%), stress/anxiety (n = 23, 76.7%), and lack of control (n = 23, 76.7%). Following analysis, item generation, cognitive interviews, and advisory board feedback, the resulting BAT contains four hypothesized domains (symptom frequency, symptom bother, impacts, and satisfaction with treatment) and 17 items with a 7-day recall period. Conclusions The BAT has been developed in multiple stages with input from both OAB patients and clinical experts following the recommended processes included in the FDA PRO Guidance for Industry. Once fully validated, we believe it will offer a superior alternative to use of the bladder diary and other PROs for monitoring OAB patients in clinical trials and clinical practice.

Aims To evaluate the significance of mast cell infiltration in interstitial cystitis (IC) by comparison with equally inflamed controls using a digital quantification technique. Methods Bladder biopsy specimens from 31 patients with Hunner type IC and 38 patients with non-Hunner type IC were analyzed. Bladder biopsy specimens from 37 patients without IC, including 19 non-specific chronic cystitis ("non-IC cystitis") specimens and 18 non-inflamed bladder ("normal bladder") specimens, were used as controls. Mast cell tryptase-, CD3-, CD20-, and CD138-immunoreactive cells were quantified using digital image analysis software to evaluate both mast cell and lymphoplasmacytic cell densities. Mast cell and lymphoplasmacytic cell densities were counted independently in the entire lamina propria and detrusor areas and compared among the four groups. Results In the lamina propria, there were no significant differences in mast cell and lymphoplasmacytic cell densities between Hunner type IC and non-IC cystitis or between non-Hunner type IC and normal bladder specimens. In the detrusor, the mast cell densities were not significantly different among the four groups. Mast cell density was correlated with lymphoplasmacytic cell density, but not with clinical parameters. Conclusions Mast cell density is not significantly different between IC specimens and non-IC control specimens with a similar degree of background inflammation. The intensity of mast cell infiltration generally correlated with that of lymphoplasmacytic cells. We conclude that mast cell count is of no value in the differential diagnosis between IC and other etiologies.

Inactivating mutation and consequent expression loss of stromal antigen 2 (STAG2, also known as SA2), a component of the cohesion complex, is one of the most common genetic aberrations in urothelial carcinoma. However, the clinicopathologic or prognostic significance of STAG2 alterations in upper tract urothelial carcinoma (UTUC) is largely unknown. This study immunohistochemically examined the expression of STAG2 in 171 patients with UTUC. The correlations of STAG2 loss with clinicopathologic features and patients’ prognoses were examined. Loss of STAG2 expression was observed in 28 cases (16%). Loss of STAG2 was significantly correlated with histological low grade, papillary architecture, noninvasive tumors, absence of concomitant carcinoma in situ, and lower Ki-67 expression. Loss of STAG2 alone was not significantly associated with patients’ prognoses in either the uni- or multivariate analysis. However, STAG2 loss was significantly associated with worse clinical outcome in UTUC with high Ki-67 proliferation indexes, but not in UTUC with low Ki-67 expression. Loss of STAG2 was generally associated with less aggressive features in UTUC. However, the STAG2 loss was an ominous sign in the subpopulation with higher Ki-67 proliferation indexes. Examining both STAG2 and Ki-67 status may be useful for identifying aggressive clinical behavior of UTUC.

Background Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. Objective To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. Design, setting, and participants DNA sequencing data were pooled from three collaborative genomic cohorts ( n =754) and our institutional database ( n =295). All patients had clinical data and identification of somatic mutations from their primary tumors. Outcome measurements and statistical analysis Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing ( q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. Results and limitations Association with tumor size was found for mutations in BAP1 ( q =0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 ( q =0.004) and TP53 ( q =0.001) were associated with decreased CSS in a multivariable model; only TP53 ( q =0.005) remained significant when SSIGN score was included. SETD2 mutations ( q =0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. Conclusions In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53 . After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. Patient summary Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Aims To examine the outcomes of lower urinary tract symptoms (LUTS) and urodynamic test results after cerebrospinal fluid (CSF) shunt surgery in idiopathic normal pressure hydrocephalus (iNPH). Methods Records of 48 patients (33 men; 15 women), who met the definite iNPH criteria and underwent CSF shunt surgery, were retrospectively analyzed. LUTS and their impact on quality of life (QOL) were evaluated using an all-or-none questionnaire targeting four symptoms, the Overactive Bladder Symptoms Score (OABSS), and the QOL index. Urodynamic investigations included filling cystometry and pressure-flow studies performed before and after surgery. Results Forty-seven (98%) patients complained of LUTS, 41 (87%) patients of whom experienced LUTS improvement after surgery. The OABSS and QOL index, which before surgery were 6.8 ± 0.7 and 4.1 ± 0.4, respectively, significantly decreased to 4.6 ± 0.6 and 3.2 ± 0.3, respectively, after surgery. The maximum cystometric capacity (174.9 ± 13.3 mL to 222.4 ± 14.7 mL) and bladder compliance (35.8 ± 4.4 ml/cmH2O to 52.1 ± 5.4 ml/cmH2O) significantly increased after surgery. Detrusor overactivity, which was observed in 37 (77%) patients preoperatively, became undetectable in 7 patients postoperatively. Voiding dysfunction (defined as maximum flow rate 100 mL) was observed in 29 (60%) patients, 22 (75%) of whom had detrusor underactivity before surgery. None of the voiding urodynamic parameters significantly improved postoperatively. Conclusions iNPH is often associated with LUTS and both storage and voiding dysfunctions. CSF shunt surgery improved LUTS and storage dysfunction, with limited effects on voiding dysfunction.

Introduction: We hypothesized that presence of plasma cell neoplasms might be a risk for thrombosis of arteriovenous fistulas (AVFs) as well as other well-known factors including age, sex, race, and presence of diabetes mellitus or certain vascular disorders. Methods: In this single-center, retrospective study based on medical record data, we investigated the influence of plasma cell neoplasms and the above-mentioned factors on the occurrence of complete occlusive thrombosis of the AVF within 30 days after surgery for creation of the AVF. Thrombosis was defined as the absence of bruit or thrill on auscultation and palpation, throughout systole and diastole. Findings: We retrospectively assessed the medical records of 91 patients with end-stage renal failure, including 8 patients with plasma cell neoplasm (5 with multiple myeloma and 3 with amyloid light-chain amyloidosis), who underwent surgical creation of an AVF at the wrist or anatomical snuff box for the first time between April 2014 and December 2016. Early thrombosis (i.e., within 30 days of surgery) occurred in 50.0% (4/8) and 10.8% (9/83) of patients with and without plasma cell neoplasm, respectively (P = 0.013). Multivariate analysis revealed that, after adjusting for baseline characteristics, plasma cell neoplasm was the only significant risk factor for early AVF thrombosis (odds ratio, 38.8; 95% confidence interval, 4.0–378.9; P = 0.0017). Discussion: Considering the poor prognosis of plasma cell neoplasm and its association with higher risk for AVF thrombosis, another type of vascular access is likely to be more suitable than AVF in such patients.

Temsirolimus is an inhibitor of mammalian target of rapamycin and interstitial lung disease (ILD) is known to be one of the adverse events associated with temsirolimus, which usually improves rapidly after discontinuation of the drug and rarely worsens thereafter. Herein, we report a case of delayed exacerbation of ILD after discontinuation of temsirolimus for metastatic renal cell carcinoma in an 86-year-old male with chronic ILD. The patient developed gradually worsening dyspnea five weeks after an initiation of temsirolimus and was admitted to our facility. On his admission, although a pulmonary function test revealed a decreased diffusion capacity, there was no obvious progression of ILD on HRCT scan. His dyspnea once improved after discontinuation of temsirolimus, but it recurred and acute exacerbation of ILD was diagnosed 40 days after his last administration of temsirolimus. He received high-dose steroid therapy, however, he deteriorated and died. Histopathological examination of the lungs at autopsy revealed overlapping diffuse alveolar damage with chronic interstitial changes. In the present case, since there were no specific factors that could have caused acute exacerbation of ILD except for temsirolimus, it was considered to contribute to the exacerbation of underlying ILD. In conclusion, physicians should be aware of the possibility of temsirolimus-induced ILD not only while the medication is administered, but also even after it is discontinued. It is important to carefully interview the patient and to recognize the value of physiological tests, such as respiratory function tests and blood gas analysis, as well as imaging findings on HRCT.

The present article is the abbreviated English translation of the Japanese guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia updated as of the end of 2016. The target patients are men aged >50 years complaining of lower urinary tract symptoms, with or without benign prostatic hyperplasia, and the target readers are non-urological general physicians and urologists. Mandatory assessment for general physicians is medical history, physical examination, urinalysis and measurement of serum prostate-specific antigen. Additional mandatory assessment for urologists is symptoms and quality of life assessment by questionnaires, uroflowmetry, residual urine measurement, and prostate ultrasonography. Nocturia requires special attention, as it can result from nocturnal polyuria and/or sleep disturbance rather than lower urinary tract disorders. Functional lower urinary tract disorders with or without benign prostatic hyperplasia are primarily managed by conservative therapy and medications, such as α1 -blockers and phosphodiesterase-type 5 inhibitors. Use of other medications or combination pharmacotherapy is to be reserved for urologists. 5α-Reductase inhibitors and anticholinergics or β3 agonists are indicated for men with enlarged prostates and overactive bladder symptoms, respectively. Surgical intervention for bladder outlet obstruction is considered for persistent symptoms or benign prostatic hyperplasia-related comorbidities. Surgical modalities should be optimized by the patient's characteristics, performance of equipment and the surgeon's experience.

Objective Our objective was to investigate predictors of early continence outcome after robot-assisted radical prostatectomy (RARP). Methods Clinical records were prospectively collected in 272 patients who underwent RARP. Clinical parameters, continence rates, and time to achieve continence were investigated and analyzed. Recovery of continence was defined as achieving complete continence (pad-free). Results In the univariate analysis, young age (≤67 years) and low pT stage (≤pT2) were significantly associated with continence achieved within 2 weeks after RARP (P = 0.0343 and P = 0.0406, respectively). Low prostate weight was the only factor associated with recovery of continence within 1 month (P = 0.0461). Multivariate analysis revealed that young age (≤67 years) and low pT stage (≤pT2) were statistically significant predictors of continence within 2 weeks after RARP (P = 0.040 and P = 0.015, respectively). Conclusion Young age and low pT stage were independent predictors of early continence.

Objectives To investigate predictors of continence outcomes after robot-assisted radical prostatectomy. Methods Clinical records of 272 patients who underwent robot-assisted radical prostatectomy were investigated. Preoperative Overactive Bladder Symptom Score, International Prostate Symptom Score and clinicopathological factors were investigated, and relationships between factors and recovery of continence after robot-assisted radical prostatectomy were assessed. The presence of overactive bladder was defined as having urgency for more than once a week and having ≥3 points according to the Overactive Bladder Symptom Score. Results Age (≤66 years) was significantly associated with continence within 6 months after robot-assisted radical prostatectomy (P = 0.033). The absence of overactive bladder and lower Overactive Bladder Symptom Score (

Background: While semiannual 60 mg denosumab is a common treatment for osteoporosis, the impact of monthly 120 mg denosumab, the common treatment protocol for bone metastases from solid tumors, on bone metabolism is unclear. Materials and Methods: We reviewed 15 patients with bone-metastatic prostate cancer who initiated monthly 120 mg denosumab in conjunction with androgen deprivation therapy between 2013 and 2014. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry (DXA), before treatment and annually thereafter. Bone metabolism markers, including urine N-terminal telopeptide (uNTx) and bone type alkaline phosphatase (BAP), were monitored monthly. Results: Twelve of 15 (80%) patients had evaluable DXA before treatment, and of them, eight underwent DXA after a year of initiation without discontinuation of denosumab. Percent changes in BMD from baseline were +6.2% at the lumbar spine and +7.6% at the femoral neck, both of which were significant ncreases (both P

[abstFig src='/00290002/15.jpg' width='300' text='Proposed method for tracking and following respiratory organ motion' ] High intensity focused ultrasound (HIFU) is potentially useful for treating stones and/or tumors. With respect to HIFU therapy, it is difficult to focus HIFU on the focal lesion due to respiratory organ motion, and this increases the risk of damaging the surrounding healthy tissues around the target focal lesion. Thus, this study proposes a method to cope with the fore-mentioned problem involving tracking and following the respiratory organ motion via a visual feedback and a prediction model for respiratory organ motion to realize highly accurate servoing performance for focal lesions. The prediction model is continuously updated based on the latest organ motion data. The results indicate that respiratory kidney motion of two healthy subjects is successfully tracked and followed with an accuracy of 0.88 mm by the proposed method and the constructed system.