Publications by authors named "Yasuhiko Igawa"

156 Publications

Evaluation of a Point-of-Care Ultrasound Educational Program for Nurse Educators.

J Contin Educ Nurs 2021 Aug 1;52(8):375-381. Epub 2021 Aug 1.

Background: The effectiveness of point-of-care ultrasound (POCUS) for nurses has been demonstrated; however, only a limited number of nurses have been trained to perform POCUS. This article reports on a POCUS train-the-trainer program for nurse educators that targets lower urinary track dysfunction.

Method: Nurse educators ( = 38) were invited to participate in a POCUS train-the-trainer program, which comprised an e-learning module and a hands-on seminar. Acquisition of knowledge and skills were assessed after the module and seminar, respectively.

Results: Questions from the "Basic Knowledge of Ultrasonography" test were answered correctly at a rate of 93.0% (, 8.5%). Measured values of bladder urinary volume using ultrasonography were in close agreement with actual values. All of the participants indicated that the program covered the content necessary to use in practice.

Conclusion: The POCUS train-the-trainer program equips nurse educators with the knowledge and skills needed for training nurses at their institutions. .
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http://dx.doi.org/10.3928/00220124-20210714-07DOI Listing
August 2021

Novel operative technique of advancement urethral meatoplasty utilizing buccal mucosa for Vulvar Paget's disease with urethral invasion: two case reports.

J Med Case Rep 2021 Mar 28;15(1):136. Epub 2021 Mar 28.

Department of Urology, The Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Vulvar Paget's disease (VPD) is a rare malignant disorder originating in the external genitalia. It occasionally invades into urethral or vaginal mucosa of female, making surgical treatment more complicating. In case of urethral invasion of Paget's cells, systematic mapping biopsy of urethral mucosa is the standard of care to determine the range of surgical resection. Resection of urethral mucosa and simple skin grafting often result in urethral stricture after surgery, which severely deteriorates patient's quality of life.

Case Presentation: We applied a new technique of advancement urethral meatoplasty using buccal mucosa, in two Japanese cases of VPD with urethral invasion. After broad resection of vulvar skin together with the urethral mucosa, buccal mucosa was implanted between advanced urethral mucosa and skin graft. In both cases, we could prevent urethral stricture one year and two years after surgery, respectively.

Conclusion: This technique prevented urethral stricture after surgery and could be a useful technique as part of urethroplasty for VPD.
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http://dx.doi.org/10.1186/s13256-021-02729-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005229PMC
March 2021

Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide-induced bladder inflammation and its associated hypersensitivity in mice.

Int J Urol 2021 Jan 7;28(1):107-114. Epub 2020 Oct 7.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1111/iju.14389DOI Listing
January 2021

Clinical characterization of interstitial cystitis/bladder pain syndrome in women based on the presence or absence of Hunner lesions and glomerulations.

Low Urin Tract Symptoms 2021 Jan 23;13(1):139-143. Epub 2020 Aug 23.

Japanese Red Cross Medical Center, Tokyo, Japan.

Objectives: To compare the clinical characteristics of three groups of female patients with interstitial cystitis/bladder pain syndrome (IC/BPS) classified according to the presence or absence of Hunner lesions (HL) and glomerulations.

Methods: The clinical records of 100 female patients with IC/BPS who underwent their first bladder hydrodistension at our institution were retrospectively reviewed. They were divided into patients having (HL-IC; n = 57) or lacking (BPS; n = 43) HL. BPS patients were further classified as those with (29) and without (14) glomerulations. Among these three subtypes, demographics, comorbidities, symptom parameters including a visual analog scale for pain scores, O'Leary and Sant Symptom and Problem (OSSI/OSPI) Indices, frequency volume chart variables, and bladder capacity at hydrodistension were compared.

Results: HL-IC patients were older and had higher OSSI/OSPI scores, greater daytime frequency and nocturia, reduced maximum and average voided volumes, and smaller bladder capacity at hydrodistension compared with BPS patients. Pain intensity and illness duration were comparable among the three groups. HL-IC patients had autoimmune disorders as comorbidities more often, but had psychiatric disorders and irritable bowel syndrome less often compared with BPS patients. No discernible differences in clinical characteristics of symptom severity and comorbid disorders were evident between BPS patients with and without glomerulations.

Conclusions: The presence of HL is associated with distinctive clinical characteristics, while glomerulations are not in female patients with IC/BPS. The presence of HL, but not glomerulations, is a robust phenotypic feature of IC/BPS in women.
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http://dx.doi.org/10.1111/luts.12344DOI Listing
January 2021

Pathophysiological changes of the lower urinary tract behind voiding dysfunction in streptozotocin-induced long-term diabetic rats.

Sci Rep 2020 03 6;10(1):4182. Epub 2020 Mar 6.

Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.

We evaluated pathophysiological characteristics of the lower urinary tract dysfunction in a streptozotocin (STZ)-induced diabetic rat model. STZ (60 mg/kg) was injected intraperitoneally into male Wistar rats. In vitro bladder muscle strip experiments, in vivo cystometry, and simultaneous recordings of bladder pressure + urethral perfusion pressure (BP + UPP) with or without intravenous administration of L-arginine (300 mg/kg) or tadalafil (0.03 mg/kg) were performed at several time points. In vitro muscle strip experiments demonstrated that diabetic rats had significantly higher contractile responses to carbachol at 4-16 weeks, and a tendency for higher contractile responses to electrical field stimulation at 4-12 weeks, but this was reversed at 16 weeks. Diabetic rats had significant increases in voided volume, residual volume, bladder capacity, maximal voiding pressure, and amplitude and frequency of non-voiding contractions at 16 weeks. Tadalafil decreased the residual volume in diabetic rats. Diabetic rats had significantly higher UPP nadir and mean UPP during high-frequency oscillation at 16 weeks, which were reversed by tadalafil or L-arginine administration. The present results suggest that urethral relaxation failure, probably related to impairment of the NO/cGMP signalling pathway, rather than bladder contractile dysfunction may be a prominent cause for voiding dysfunction in STZ-induced chronic diabetic rats.
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http://dx.doi.org/10.1038/s41598-020-61106-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060249PMC
March 2020

KPR-5714, a Novel Transient Receptor Potential Melastatin 8 Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats.

J Pharmacol Exp Ther 2020 05 26;373(2):239-247. Epub 2020 Feb 26.

Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan (O.N., Y.F., T.H., A.M., JI.K., H.H., Y.M., F.T.) and Department of Continence Medicine, the University of Tokyo Graduate School of Medicine, Tokyo, Japan (N.A., Y.I.).

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (A-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (-[()-3,3-difluoro-4-hydroxy-1-(2-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.
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http://dx.doi.org/10.1124/jpet.119.263616DOI Listing
May 2020

Clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury.

Int J Urol 2020 Apr 19;27(4):276-288. Epub 2020 Feb 19.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

The present article is an abridged English translation of the Japanese clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury updated as of July 2019. The patients are adult spinal cord injured patients with lower urinary tract dysfunction; special consideration of pediatric and elderly populations is presented separately. The target audience is healthcare providers who are engaged in the medical care of patients with spinal cord injury. The mandatory assessment includes medical history, physical examination, frequency-volume chart, urinalysis, blood chemistry, transabdominal ultrasonography, measurement of post-void residual urine, uroflowmetry and video-urodynamic study. Optional assessments include questionnaires on the quality of life, renal scintigraphy and cystourethroscopy. The presence or absence of risk factors for renal damage and symptomatic urinary tract infection affects urinary management, as well as pharmacological treatments. Further treatment is recommended if the maximum conservative treatment fails to improve or prevent renal damage and symptomatic urinary tract infection. In addition, management of urinary incontinence should be considered individually in patients with risk factors for urinary incontinence and decreased quality of life.
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http://dx.doi.org/10.1111/iju.14186DOI Listing
April 2020

Cardiovascular safety of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A post hoc analysis from the Japanese MILAI II study.

Low Urin Tract Symptoms 2020 Jan 30;12(1):68-80. Epub 2019 Sep 30.

Astellas Pharma Inc., Tokyo, Japan.

Objective: This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long-term safety and efficacy of antimuscarinic add-on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms.

Methods: MILAI II consisted of a 2-week screening period (patients received mirabegron 50 mg once daily) plus a 52-week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment-emergent adverse events (TEAEs), vital signs, and 12-lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post-baseline values reported.

Results: Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV-related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug-related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post-baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group.

Conclusion: A favorable CV safety profile was observed following long-term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.
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http://dx.doi.org/10.1111/luts.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004007PMC
January 2020

Immune-related adverse events predict the therapeutic efficacy of pembrolizumab in urothelial cancer patients.

Eur J Cancer 2019 07 10;116:114-115. Epub 2019 Jun 10.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.ejca.2019.05.017DOI Listing
July 2019

Longitudinal change of comprehensive lower urinary tract symptoms and various types of urinary incontinence during robot-assisted radical prostatectomy.

Neurourol Urodyn 2019 04 14;38(4):1067-1075. Epub 2019 Mar 14.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Japan.

Aims: To clarify longitudinal change of lower urinary tract symptoms (LUTS) and various types of urinary incontinence following robot-assisted radical prostatectomy (RARP) using validated questionnaires.

Materials And Methods: The core lower urinary tract symptom score (CLSS) and the International Consultation on Incontinence Questionnaire (ICIQ)-Short Form (SF) questionnaires were administered to 607 consecutive, treatment-naïve men receiving RARP before and after surgery. The time course of comprehensive LUTS and various types of urinary incontinence, including stress-, urgency-, and urinary incontinence with no obvious reason, were evaluated. Continence recovery rates were compared for the different types of incontinence using Cox hazard regression analysis.

Results: After surgery, stress urinary incontinence (SUI) was reported most frequently (32% of cases) as the chief complaint with the most impact on daily life, as assessed by the CLSS questionnaire, followed by urgency urinary incontinence (UUI; 27% of cases). The rates of continence recovery differed among the different types of urinary incontinence, such as after urinating, when dressed, when asleep, when physically active or exercising, when coughing or sneezing, before reaching the toilet, and for no obvious reason. Incontinence for no obvious reason at 1 month after RARP was a strongest prognostic factor of delayed continence recovery (hazard ratio, 0.61; P < 0.0001), whereas patients reporting SUI and UUI gradually regained continence.

Conclusions: Further time course on continent recovery after RARP would be more precisely predictable based on the incontinence status at one month postoperatively. Especially, incontinence with no obvious reason would be a significant factor for delayed recovery.
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http://dx.doi.org/10.1002/nau.23952DOI Listing
April 2019

β -Adrenoceptors in the normal and diseased urinary bladder-What are the open questions?

Br J Pharmacol 2019 07 3;176(14):2525-2538. Epub 2019 May 3.

Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.

β -Adrenoceptor agonists are used in the treatment of overactive bladder syndrome. Although the relaxant response to adrenergic stimulation in human detrusor smooth muscle cells is mediated mainly via β -adrenoceptors, the plasma concentrations of the therapeutic dose of mirabegron, the only clinically approved β -adrenoceptor agonist, are considerably lower than the EC for causing direct relaxation of human detrusor, suggesting a mechanism of action other than direct relaxation of detrusor smooth muscle. However, the site and mechanism of action of β -adrenoceptor agonists in the bladder have not been firmly established. Postulated mechanisms include prejunctional suppression of ACh release from the parasympathetic nerves during the storage phase and inhibition of micro-contractions through β -adrenoceptors on detrusor smooth muscle cells or suburothelial interstitial cells. Implications of possible desensitization of β -adrenoceptors in the bladder upon prolonged agonist exposure and possible causes of rarely observed cardiovascular effects of mirabegron are also discussed. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592861PMC
July 2019

Molecular Taxonomy of Interstitial Cystitis/Bladder Pain Syndrome Based on Whole Transcriptome Profiling by Next-Generation RNA Sequencing of Bladder Mucosal Biopsies.

J Urol 2019 08 8;202(2):290-300. Epub 2019 Jul 8.

Japanese Red Cross Medical Center , Tokyo.

Purpose: We systematically characterized gene expression, inflammation and neovascularization in patients with interstitial cystitis/bladder pain syndrome to obtain biological evidence supporting diagnosis and classification.

Materials And Methods: We sequenced RNA obtained from bladder mucosal biopsies of 33 patients with 3 subtypes of interstitial cystitis/bladder pain syndrome, including Hunner lesions in 12, no Hunner lesions in 11 but with glomerulations and neither Hunner lesions nor glomerulations in 10, and 9 controls. Differentially expressed genes of each subtype were searched to identify subtype specific biological pathways and candidate genes important for pathogenesis. Candidate genes were validated by quantitative polymerase chain reaction and immunohistochemistry. Digital immunohistochemical quantification was performed to assess subepithelial lymphoplasmacytic cell and microvessel density. Relationships between candidate gene over expression and symptom severity were explored.

Results: Patients with Hunner lesions showed a distinct gene expression profile associated with significant up-regulation of biological processes involving immune responses and infection, and an increase in subepithelial lymphoplasmacytic cell and microvessel density. Over expression of 2 candidate genes, VEGF and BAFF, correlated with symptom severity. Meanwhile, the gene expression profiles of patients with the 2 subtypes without Hunner lesions were similar to those of controls. No difference in biological pathways or subepithelial lymphoplasmacytic cell and microvessel density were detected between these 2 subtypes and controls.

Conclusions: Interstitial cystitis/bladder pain syndrome with Hunner lesions shows distinct genomic and histological features associated with immune responses and infection. In addition, VEGF and BAFF are potential disease biomarkers and therapeutic targets. This subtype should be considered separate from the syndrome.
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http://dx.doi.org/10.1097/JU.0000000000000234DOI Listing
August 2019

Feasibility of approximate measurement of bladder volume in male patients using the Lilium α-200 portable ultrasound bladder scanner.

Low Urin Tract Symptoms 2019 May 10;11(3):169-173. Epub 2019 Mar 10.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Objective: This study examined the accuracy of a new portable ultrasound bladder scanner, the Lilium α-200 (Lilium Otsuka, Kanagawa, Japan), by evaluating the correlation between bladder volumes periodically measured by the Lilium α-200 and instilled volume during video-urodynamic studies (V-UDS).

Methods: Using the Lilium α-200, fluid volume was measured prospectively in the bladders of patients with lower urinary tract dysfunction during V-UDS. This was done both immediately after micturition (for assessment of post-void residual [PVR] volume) and at 1-minute intervals during filling cystometry with patients in the supine position. These measurements were then compared with the PVR volume obtained directly by catheter drainage and instilled volume during cystometry using paired t tests and Spearman's rank correlation.

Results: Fifteen male patients (median age 70.5 years; range 18-84 years) were included in the study. The PVR volume measured by the Lilium α-200 was strongly correlated with that obtained by catheter drainage (r = 0.94; P < 0.0001). There was a strong correlation between instilled and bladder volumes measured by the Lilium α-200 at every minute during and at the end of instillation (281 measurements in 15 patients; r = 0.86; P < 0.0001). However, the relative error of bladder volumes measured by the Lilium α-200 during cystometry showed considerable variation (mean [± SD] 5.6 ± 62.9%).

Conclusions: Bladder volumes measured periodically by the Lilium α-200 during cystometry were strongly correlated with actual PVR or instilled volumes. However, they showed considerable variation and may not predict actual volume accurately. The Lilium α-200 is feasible for obtaining an approximate measure of bladder volume.
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http://dx.doi.org/10.1111/luts.12258DOI Listing
May 2019

Ultrasound-assisted prompted voiding care for managing urinary incontinence in nursing homes: A randomized clinical trial.

Neurourol Urodyn 2019 02 8;38(2):757-763. Epub 2019 Jan 8.

Japanese Red Cross Medical Center, Shibuya-ku, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/nau.23913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849834PMC
February 2019

RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats.

Life Sci 2019 Feb 20;218:89-95. Epub 2018 Dec 20.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.lfs.2018.12.031DOI Listing
February 2019

Long-term safety and efficacy of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A multicenter, randomized study in Japan (MILAI II study).

Int J Urol 2019 03 13;26(3):342-352. Epub 2018 Dec 13.

Astellas Pharma Inc., Tokyo, Japan.

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.
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http://dx.doi.org/10.1111/iju.13868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379522PMC
March 2019

Aggressive Cancer Behavior of Latent Gleason Pattern 5 in Prostatectomy Specimens.

Anticancer Res 2018 Nov;38(11):6529-6535

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background/aim: The aim of this study was to demonstrate the clinical significance of latent Gleason pattern (GP) 5 occasionally found in prostatectomy specimens.

Materials And Methods: Patients (n=605) undergoing radical prostatectomy were classified into three groups according to the presence of GP5 in the biopsy or in the prostatectomy specimens: 'GP5 negative', absence of GP in both specimens 'latent GP5', absence of GP5 in the biopsy specimen, but presense of GP5 in the prostatectomy specimen, and 'GP5 positive', presense of GP in both specimens. The characteristics of these three groups were analyzed.

Results: There were 381 men in the GP5-negative group, 155 in the latent GP5 group, and 69 in the GP5-positive group. Low- or intermediate-risk for prostate cancer, latent GP5 and surgical margin positivity were independent predictors of biochemical recurrence (Hazard ratio (HR): 3.1, 5.8, respectively, p=0.001, 0.0002, respectively).

Conclusion: Latent GP5 is an important prognostic factor that should be evaluated in patients with low- and intermediate-risk for prostate cancer before the initiation of treatment.
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http://dx.doi.org/10.21873/anticanres.13018DOI Listing
November 2018

May perioperative ultrasound-guided pelvic floor muscle training promote early recovery of urinary continence after robot-assisted radical prostatectomy?

Neurourol Urodyn 2019 01 30;38(1):158-164. Epub 2018 Oct 30.

Global Nursing Research Center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/nau.23811DOI Listing
January 2019

Attenuated lipopolysaccharide-induced inflammatory bladder hypersensitivity in mice deficient of transient receptor potential ankilin1.

Sci Rep 2018 10 23;8(1):15622. Epub 2018 Oct 23.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Transient receptor potential ankyrin 1 (TRPA1) channel expressed by urothelial cells and bladder sensory nerve fibers might act as a bladder mechanosensor and nociceptive transducer. To disclose the role of TRPA1 in bladder function and inflammation-associated hypersensitivity, we evaluated in vitro and in vivo bladder function and inflammatory mechanosensory and nociceptive responses to intravesical lipopolysaccharide (LPS)-instillation in wild type (WT) and TRPA1-knock out (KO) mice. At baseline before treatment, no significant differences were observed in frequency volume variables, in vitro detrusor contractility, and cystometric parameters between the two groups in either sex. LPS-instillation significantly increased voiding frequency and decreased mean voided volume at 24-48 hours after instillation in WT but not in TRPA1-KO mice. LPS-instillation also significantly increased the number of pain-like behavior at 24 hours after instillation in WT mice, but not in TRPA1-KO mice. Cystometry 24 hours after LPS-instillation revealed shorter inter-contraction intervals in the WT mice compared with TRPA1-KO mice. In contrast, inflammatory cell infiltration in the bladder suburothelial layer was not significantly different between the two groups. These results indicate that TRPA1 channels are involved in bladder mechanosensory and nociceptive hypersensitivity accompanied with inflammation but not in physiological bladder function or development of bladder inflammation.
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http://dx.doi.org/10.1038/s41598-018-33967-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199359PMC
October 2018

Gains in health utility associated with urinary catheter innovations.

Med Devices (Auckl) 2018 1;11:345-351. Epub 2018 Oct 1.

Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.

Purpose: To estimate gains in health utility for two different catheter features and a support service related to urinary catheters used for intermittent catheterization.

Patients And Methods: Two internet-based time trade-off (TTO) surveys were undertaken to value vignettes describing two innovative catheter features and a support service. The first TTO survey "Size and Service" included catheters with compact design and the availability of a support service for users; the second TTO survey "Phthalates" included avoidance of potentially harmful phthalates in the material of the catheters. All participants were from the UK; they traded health states against a time horizon that matched their total life expectancy. Sensitivity analyses were done to estimate the impact of extreme values on disutilities.

Results: The participants (n=890) estimated the incremental value of 0.031 (95% CI: 0.024-0.039), 0.009 (95% CI: 0.003-0.015), and 0.037 (95% CI: 0.027-0.046), respectively, for catheters with compact design, availability of support service, and catheters not containing phthalates.

Conclusions: Participants valued all three improvements in catheter design. To capture the impact of such design improvements on quality of life and utilities, vignette-based approaches can be a useful supplement to the conventional, generic tools.
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http://dx.doi.org/10.2147/MDER.S165778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171519PMC
October 2018

The impact of different scenarios for intermittent bladder catheterization on health state utilities: results from an internet-based time trade-off survey.

J Med Econ 2018 Oct 6;21(10):945-952. Epub 2018 Jul 6.

f Department of Continence Medicine , The University of Tokyo , Graduate school of Medicine , Tokyo , Japan.

Aims: Intermittent catheterization (IC) is the gold standard for bladder management in patients with chronic urinary retention. Despite its medical benefits, IC users experience a negative impact on their quality of life (QoL). For health economics based decision making, this impact is normally measured using generic QoL measures (such as EQ-5D) that estimate a single utility score which can be used to calculate quality-adjusted life years (QALYs). But these generic measures may not be sensitive to all relevant aspects of QoL affected by intermittent catheters. This study used alternative methods to estimate the health state utilities associated with different scenarios: using a multiple-use catheter, one-time-use catheter, pre-lubricated one-time-use catheter and pre-lubricated one-time-use catheter with one less urinary tract infection (UTI) per year.

Methods: Health state utilities were elicited through an internet-based time trade-off (TTO) survey in adult volunteers representing the general population in Canada and the UK. Health states were developed to represent the catheters based on the following four attributes: steps and time needed for IC process, pain and the frequency of UTIs.

Results: The survey was completed by 956 respondents. One-time-use catheters, pre-lubricated one-time-use catheters and ready-to-use catheters were preferred to multiple-use catheters. The utility gains were associated with the following features: one time use (Canada: +0.013, UK: +0.021), ready to use (all: +0.017) and one less UTI/year (all: +0.011).

Limitations: Internet-based survey responders may have valued health states differently from the rest of the population: this might be a source of bias.

Conclusion: Steps and time needed for the IC process, pain related to IC and the frequency of UTIs have a significant impact on IC related utilities. These values could be incorporated into a cost utility analysis.
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http://dx.doi.org/10.1080/13696998.2018.1486846DOI Listing
October 2018

Clinical significance of random bladder biopsy in primary T1 bladder cancer.

Mol Clin Oncol 2018 May 8;8(5):665-670. Epub 2018 Mar 8.

Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

The clinical significance of random bladder biopsies in primary non-muscle-invasive bladder cancer is unclear. The present study investigated the significance of positive random bladder biopsies in primary T1 NMIBC. The present study retrospectively reviewed the records of 71 patients with primary pT1N0M0 bladder cancer who underwent transurethral resection of the bladder tumor (TURBT) and concomitant random bladder biopsy. A total of 12 patients who received cystectomy immediately following the TURBT were excluded, and the remaining 59 patients were included in the analysis. Random bladder biopsy was defined as a cold-cup biopsy of pre-specified normal-looking areas in the bladder. The association of clinicopathological factors, including random biopsy results, with intravesical recurrence were assessed by univariate and multivariate Cox proportional hazards analyses. Of the 59 patients, 15 (25%) demonstrated carcinoma (CIS) lesions on random bladder biopsy: Five (33%) in biopsy specimens alone and the remaining 10 (67%) in biopsy and TUR specimens. Positive random biopsy was associated with preoperative positive urine cytology (P=0.011) and small size of the main tumor (P=0.008). Multivariate analysis demonstrated positive random biopsy as the sole independent poor prognostic factor for intravesical recurrence (hazard ratio: 4.69, P=0.014). The five patients who had CIS detected in biopsy specimens alone had worse, although non-significantly worse, recurrence-free survival compared with those with CIS detected in biopsy and TUR specimens (P=0.100). In conclusion, positive bladder random biopsy, equivalent to the presence of CIS, was an independent predictor of recurrence in primary T1 bladder cancer. Given that one-third of CIS lesions could not have been detected without biopsy, random bladder biopsy should be considered for patients with T1 tumors.
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http://dx.doi.org/10.3892/mco.2018.1587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920156PMC
May 2018

Inhibitory effects of silodosin on the bladder mechanosensitive afferent activities and their relation with bladder myogenic contractions in male rats with bladder outlet obstruction.

Neurourol Urodyn 2018 08 6;37(6):1897-1903. Epub 2018 Mar 6.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/nau.23547DOI Listing
August 2018

KPR-2579, a novel TRPM8 antagonist, inhibits acetic acid-induced bladder afferent hyperactivity in rats.

Neurourol Urodyn 2018 06 21;37(5):1633-1640. Epub 2018 Feb 21.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Aims: Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR-2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single-unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats.

Methods: Female Sprague-Dawley rats were used. Effects of cumulative intravenous (i.v.) administrations of KPR-2579 (0.03-1 mg/kg) on deep body temperature were investigated (N = 18). In separate animals, effects of bolus administration of KPR-2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by intravesical instillation of 0.1% AA were investigated using cystometry (N = 57) in a conscious free-moving condition or urethane-anesthetized condition, and SAA measurements (N = 41) were performed in a urethane-anesthetized condition.

Results: KPR-2579 at any doses tested did not affect body temperature. In cystometry measurements, a high dose (0.3 mg/kg) of KPR-2579 counteracted the shortened intercontraction interval provoked by AA instillation. In SAA measurements, 48 single afferent fibers (n = 24 in each fiber) were isolated. AA instillations significantly increased the SAAs of C fibers, but not of Aδ fibers, in the presence of KPR-2579's vehicle and a low dose (0.03 mg/kg) of KPR-2579. Pretreatment with a high dose (0.3 mg/kg) of KPR-2579 significantly inhibited the AA-induced activation of C-fiber SAAs.

Conclusion: The present results suggest that TRPM8 channels play a role in the AA-induced pathological activation of mechanosensitive bladder C fibers in rats. KRP-2579 may be a promising drug for hypersensitive bladder disorders.
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http://dx.doi.org/10.1002/nau.23532DOI Listing
June 2018

Age-related changes in function and gene expression of the male and female mouse bladder.

Sci Rep 2018 02 1;8(1):2089. Epub 2018 Feb 1.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1038/s41598-018-20406-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794976PMC
February 2018

Extent of Hunner lesions: The relationships with symptom severity and clinical parameters in Hunner type interstitial cystitis patients.

Neurourol Urodyn 2018 04 9;37(4):1441-1447. Epub 2018 Jan 9.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aims: To assess the clinical impact of Hunner lesions in patients with Hunner type interstitial cystitis (HIC).

Methods: The clinical records of 94 HIC patients who underwent their first hydrodistension (with lesion fulguration) were retrospectively reviewed. At surgery, the extent of each lesion was classified in terms of the relative involvement for the whole-bladder luminal surface; we defined four grades of involvement: <10%, 10-24%, 25-49%, and ≥50%; and two grades of severity: <25% (focal) and ≥25% (extensive). We examined the relationships between the extent of the lesions and all demographic characteristics, symptom scores, voiding symptoms, and bladder capacity. Factors predictive of the need for repeat hydrodistension were also explored.

Results: Symptom severity worsened as the lesional extent rose. Those with extensive lesions scored higher on the O'Leary and Sant Symptom (P = 0.004) and Problem Index scales (P < 0.001), the pain visual analog scale (P = 0.011), the International Prostate Symptom Score scale (P = 0.012), and a quality-of-life index (P = 0.020); and exhibited greater daytime urinary frequency (P = 0.040), more nocturia (P = 0.041), and a smaller bladder capacity (P = 0.007) than the focal group. No symptomatic or clinical parameters predicted the need for repeat hydrodistension.

Conclusions: The extent of Hunner lesions was associated with both symptom severity and bladder capacity but not with other clinical parameters, including the need for repeat hydrodistension, in patients with HIC.
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http://dx.doi.org/10.1002/nau.23467DOI Listing
April 2018

Pathophysiology of the underactive bladder.

Investig Clin Urol 2017 12 13;58(Suppl 2):S82-S89. Epub 2017 Nov 13.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Underactive bladder (UAB), which has been described as a symptom complex suggestive of detrusor underactivity, is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and slow stream often with storage symptoms. Several causes such as aging, bladder outlet obstruction, diabetes mellitus, neurologic disorders, and nervous injury to the spinal cord, cauda equine, and peripheral pelvic nerve have been assumed to be responsible for the development of UAB. Several contributing factors have been suggested in the pathophysiology of UAB, including myogenic failure, efferent and/or afferent dysfunctions, and central nervous system dysfunction. In this review article, we have described relationships between individual contributing factors and the pathophysiology of UAB based on previous reports. However, many pathophysiological uncertainties still remain, which require more investigations using appropriate animal models.
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http://dx.doi.org/10.4111/icu.2017.58.S2.S82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740034PMC
December 2017

Preoperative chronic kidney disease is predictive of oncological outcome of radical cystectomy for bladder cancer.

World J Urol 2018 Feb 28;36(2):249-256. Epub 2017 Nov 28.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: To evaluate the impact of preoperative chronic kidney disease (CKD) on oncological outcomes after radical cystectomy (RC) for bladder cancer.

Methods: We reviewed the medical records of patients with urothelial bladder carcinoma who underwent RC with curative intent at seven hospitals between 1990 and 2013. After excluding patients with a history of upper urinary tract urothelial cancer or neoadjuvant chemotherapy, we analyzed 594 cases for the study. Preoperative estimated glomerular filtration rate (eGFR) was calculated using the three-variable Japanese equation for GFR estimation from serum creatinine level and age. Patients were divided into four groups of different CKD stages based on eGFR values (mL/min/1.73 m), i.e., ≥ 60 (CKD stages G1-2), 45-60 (G3a), 30-45 (G3b), and < 30 (G4-5). Survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses addressed survivals after RC.

Results: Median age of patients was 67 years. Patients were classified into CKD stages: G1-2 (n = 388; 65.3%), G3a (n = 122; 20.5%), G3b (n = 51; 8.6%), and G4-5 (n = 33; 5.6%). During a median follow-up of 4.0 years, 200 and 164 patients showed cancer progression and died of bladder cancer, with the 5-year progression-free survival (PFS) and cancer-specific survival (CSS) of 64.9 and 70.2%, respectively. On multivariate analyses, CKD stages of G3b or greater, advanced pT stage, lymph node metastasis, and positive lymphovascular invasion were independent poor prognostic factors for PFS and CSS.

Conclusions: We demonstrated that the advanced preoperative CKD stage was significantly associated with poor oncological outcomes of the bladder cancer after RC.
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http://dx.doi.org/10.1007/s00345-017-2141-2DOI Listing
February 2018

Digital quantitative analysis of mast cell infiltration in interstitial cystitis.

Neurourol Urodyn 2018 02 24;37(2):650-657. Epub 2017 Oct 24.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/nau.23365DOI Listing
February 2018

Diagnostic value of urinary CXCL10 as a biomarker for predicting Hunner type interstitial cystitis.

Neurourol Urodyn 2018 03 19;37(3):1113-1119. Epub 2017 Oct 19.

Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Aim: To investigate the feasibility of chemokines and cytokines potentially elevated in the bladder tissue of Hunner type interstitial cystitis (HIC) as urinary markers for distinguishing HIC from non-Hunner type interstitial cystitis (NHIC) METHODS: Urine specimens were collected from 41 HIC patients, 25 NHIC patients, and 31 healthy volunteers (control). The supernatants of urine specimens were subjected to ELISA kits for measurements of 10 cytokines and chemokines, whose gene expression was known to be elevated in HIC bladder tissue. Urinary levels normalized by urinary creatinine (Cr) concentration were compared among three groups. Efficiency in differentiating IC and IC subtypes was explored by ROC analysis. The correlation of marker levels with symptom severity, assessed by O'Leary-Sant's symptom index (OSSI) and problem index (OSPI), was examined.

Results: The urinary levels of CXCL10 and NGF were significantly higher in HIC than NHIC. CXCL10 and NGF differentiated HIC against NHIC with AUC of 0.78 and 0.68, respectively. Combination of CXCL10 and NGF levels yielded an AUS of 0.81. The CXCL10 cut-off of 53.2 pg/mg Cr had sensitivity of 46.1%, specificity of 93.7%, positive predictive value of 97.7%, and negative predictive value of 60.0%. The urinary level of other cytokines showed no significant difference between HIC and NHIC. Significant correlation with symptoms was detected for CXCL10 alone.

Conclusion: The results suggested that increased urinary level of CXCL10 combined with or without high NGF level could be a promising supplementary biomarker for differentiating HIC from NHIC with modest sensitivity and high specificity.
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http://dx.doi.org/10.1002/nau.23431DOI Listing
March 2018
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