Publications by authors named "Hiromitsu Negoro"

91 Publications

Diurnal rhythms of urine volume and electrolyte excretion in healthy young men under differing intensities of daytime light exposure.

Sci Rep 2021 Jun 23;11(1):13097. Epub 2021 Jun 23.

Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 kawahara-cho, shogoin, sakyo-ku, Kyoto, 606-8507, Japan.

In humans, most renal functions, including urine volume and electrolyte excretions, have a circadian rhythm. Light is a strong circadian entrainment factor and daytime-light exposure is known to affect the circadian rhythm of rectal temperature (RT). The effects of daytime-light exposure on the diurnal rhythm of urinary excretion have yet to be clarified. The aim of this study was to clarify whether and how daytime exposure to bright-light affects urinary excretions. Twenty-one healthy men (21-27 years old) participated in a 4-day study involving daytime (08:00-18:00 h) exposure to two light conditions, Dim (< 50 lx) and Bright (~ 2500 lx), in a random order. During the experiment, RT was measured continuously. Urine samples were collected every 3 ~ 4 h. Compared to the Dim condition, under the Bright condition, the RT nadir time was 45 min earlier (p = 0.017) and sodium (Na), chloride (Cl), and uric acid (UA) excretion and urine volumes were greater (all p < 0.001), from 11:00 h to 13:00 h without a difference in total daily urine volume. The present results suggest that daytime bright light exposure can induce a phase shift advance in urine volume and urinary Na, Cl, and UA excretion rhythms.
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http://dx.doi.org/10.1038/s41598-021-92595-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222329PMC
June 2021

[Informed Consent of the Contraception for Male Cancer Patients under Treatment of Anti‒Cancer Medicine-Current and Future Status].

Gan To Kagaku Ryoho 2021 May;48(5):644-648

Dept. of Urology, University of Tsukuba.

Fertility preservation for male cancer patients is gradually being recognized and the network for clinical practice has progressed, accompanied with the increasing number of local governments which give a subsidy for their sperm cryopreservation. Sperm cryopreservation is recommended, not only for the risk of azoospermia but also for the possibility of increased risk of malformation due to sperm DNA damage. On the other hand, there is no sufficient evidence for the necessity of contraception, its proper duration, and effects depending on the action sites of the corresponding cancer medicine, making it difficult for clinicians to achieve consensus. Here, we discuss the current and future informational provision of contraception and fertility preservation for male cancer patients.
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May 2021

Protocol for development and validation of a prediction model for 5-year risk of incident overactive bladder in the general population: the Nagahama study.

BMC Urol 2021 May 13;21(1):78. Epub 2021 May 13.

Department of Urology, Faculty of Medicine, Kyoto University Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: An accurate prediction model could identify high-risk subjects of incident Overactive bladder (OAB) among the general population and enable early prevention which may save on the related medical costs. However, no efficient model has been developed for predicting incident OAB. In this study, we will develop a model for predicting the onset of OAB at 5-year in the general population setting.

Methods: Data will be obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. The baseline characteristics were measured between Nov 28, 2008 and Nov 28, 2010, and follow-up was performed every 5 years. From the total of 9,764 participants (male: 3,208, female: 6,556) at baseline, we will exclude participants who could not attend the follow-up assessment and those who were defined as having OAB at baseline. The outcome will be incident OAB defined using the Overactive Bladder Symptom Score (OABSS) at follow-up assessment. Baseline questionnaires (demographic, health behavior, comorbidities and OABSS) and blood test data will be included as predictors. We will develop a logistic regression model utilizing shrinkage methods (LASSO penalization method). Model performance will be evaluated by discrimination and calibration. Net benefit will be evaluated by decision curve analysis. We will perform an internal validation and a temporal validation of the model. We will develop a web-based application to visualize the prediction model and facilitate its use in clinical practice.

Discussion: This will be the first study to develop a model to predict the incidence of OAB.
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http://dx.doi.org/10.1186/s12894-021-00848-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120704PMC
May 2021

PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer.

Cancer Lett 2021 Jul 1;511:15-25. Epub 2021 May 1.

Department of Urology, Faculty of Medicine and Graduate School of Comprehensive Human Science, University of Tsukuba, Ibaraki, Japan.

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.
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http://dx.doi.org/10.1016/j.canlet.2021.04.014DOI Listing
July 2021

Retroperitoneal lymph node dissection for testicular cancer in a patient with a double inferior vena cava.

IJU Case Rep 2021 Mar 31;4(2):86-88. Epub 2021 Jan 31.

Department of Urology University of Tsukuba Hospital Tsukuba Ibaraki Japan.

Introduction: A double inferior vena cava is a rare anomaly with an incidence ranging from 0.3% to 3.0%. In patients with a double inferior vena cava, it is important to understand the precise anatomy and possible irregular lymph node flow when performing surgery for malignancies.

Case Presentation: A 60-year-old man with a non-seminoma was referred to our hospital after left high orchiectomy. Computed tomography revealed a double inferior vena cava and swollen masses in the para-aortic region. After four cycles of chemotherapy with etoposide and cisplatin, retroperitoneal lymph node dissection was safely performed with a modified template extended to the right side of the paracaval region by referring to three-dimensional images created by SYNAPSE VINCENT® software.

Conclusion: Preoperative three-dimensional images were useful to understand this patient's unusual and complicated anatomical positions.
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http://dx.doi.org/10.1002/iju5.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924090PMC
March 2021

The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8 T cells.

Cancer Immunol Immunother 2021 Feb 11. Epub 2021 Feb 11.

Osaka City University, Osaka, Japan.

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8 T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.
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http://dx.doi.org/10.1007/s00262-021-02870-2DOI Listing
February 2021

Urothelium-Specific Deletion of Connexin43 in the Mouse Urinary Bladder Alters Distension-Induced ATP Release and Voiding Behavior.

Int J Mol Sci 2021 Feb 5;22(4). Epub 2021 Feb 5.

Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Connexin43 (Cx43), the main gap junction and hemichannel forming protein in the urinary bladder, participates in the regulation of bladder motor and sensory functions and has been reported as an important modulator of day-night variations in functional bladder capacity. However, because Cx43 is expressed throughout the bladder, the actual role played by the detrusor and the urothelial Cx43 is still unknown. For this purpose, we generated urothelium-specific Cx43 knockout (uCx43KO) mice using Cre-LoxP system. We evaluated the day-night micturition pattern and the urothelial Cx43 hemichannel function of the uCx43KO mice by measuring luminal ATP release after bladder distention. In wild-type (WT) mice, distention-induced ATP release was elevated, and functional bladder capacity was decreased in the animals' active phase (nighttime) when Cx43 expression was also high compared to levels measured in the sleep phase (daytime). These day-night differences in urothelial ATP release and functional bladder capacity were attenuated in uCx43KO mice that, in the active phase, displayed lower ATP release and higher functional bladder capacity than WT mice. These findings indicate that urothelial Cx43 mediated ATP signaling and coordination of urothelial activity are essential for proper perception and regulation of responses to bladder distension in the animals' awake, active phase.
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http://dx.doi.org/10.3390/ijms22041594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914662PMC
February 2021

Cystoscopic Imaging for Bladder Cancer Detection Based on Stepwise Organic Transfer Learning with a Pretrained Convolutional Neural Network.

J Endourol 2021 Jul 4;35(7):1030-1035. Epub 2020 Dec 4.

Department of Urology, University of Tsukuba Hospital, Tsukuba, Japan.

Nonmuscle-invasive bladder cancer is diagnosed, treated, and monitored using cystoscopy. Artificial intelligence (AI) is increasingly used to augment tumor detection, but its performance is hindered by the limited availability of cystoscopic images required to form a large training data set. This study aimed to determine whether stepwise transfer learning with general images followed by gastroscopic images can improve the accuracy of bladder tumor detection on cystoscopic imaging. We trained a convolutional neural network with 1.2 million general images, followed by 8728 gastroscopic images. In the final step of the transfer learning process, the model was additionally trained with 2102 cystoscopic images of normal bladder tissue and bladder tumors collected at the University of Tsukuba Hospital. The diagnostic accuracy was evaluated using a receiver operating characteristic curve. The diagnostic performance of the models trained with cystoscopic images with or without stepwise organic transfer learning was compared with that of medical students and urologists with varying levels of experience. The model developed by stepwise organic transfer learning had 95.4% sensitivity and 97.6% specificity. This performance was better than that of the other models and comparable with that of expert urologists. Notably, it showed superior diagnostic accuracy when tumors occupied >10% of the image. Our findings demonstrate the value of stepwise organic transfer learning in applications with limited data sets for training and further confirm the value of AI in medical diagnostics. Here, we applied deep learning to develop a tool to detect bladder tumors with an accuracy comparable with that of a urologist. To address the limitation that few bladder tumor images are available to train the model, we demonstrate that pretraining with general and gastroscopic images yields superior results.
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http://dx.doi.org/10.1089/end.2020.0919DOI Listing
July 2021

Medical history of nocturnal enuresis during school age is an independent risk factor for nocturia in adults: The Nagahama study.

Neurourol Urodyn 2021 01 29;40(1):326-333. Epub 2020 Oct 29.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aim: To evaluate the relationship between nocturia and medical history of nocturnal enuresis: two conditions where diurnal urination rhythm is disturbed.

Methods: The Nagahama study is a longitudinal population-based health survey involving people aged 30-75 years in Nagahama city, Japan. Our analysis included 5,402 participants who completed enuresis and International Prostate Symptom Score questionnaires. Associations between nocturnal enuresis and nocturia were evaluated cross-sectionally and longitudinally with three models: (1) univariate analysis; (2) adjusted for basic characteristics (e.g., age, sex, body mass index, activity, alcohol, and smoking); and (3) adjusted for basic and clinical variables (e.g., hyperglycemia, hyperlipidemia, hypertension, renal insufficiency, insomnia, obstructive sleep apnea, and mental health).

Results: In total, 1,613 participants (29.9%) had a medical history of enuresis. The mean night-time frequency was 0.73 at baseline and 0.85 at the 5-year follow-up. The cross-sectional analysis showed participants with a medical history of enuresis had night-time frequency more often than those without this history (0.84 vs. 0.68, p < .0001). Significant differences were observed in Models 2 (p < .0001) and 3 (p < .0001). The longitudinal analysis showed nocturia progression was significantly related to a history of enuresis, with odds ratios of 1.32 (p < .0001) in Model 1, 1.21 (p < .01) in Model 2, and 1.22 (p < .01) in Model 3.

Conclusions: Medical history of enuresis during school age was significantly related to nocturia in adulthood in the cross-sectional analysis, and to progression to nocturia in the longitudinal analysis. These two conditions may possess a common causative association.
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http://dx.doi.org/10.1002/nau.24562DOI Listing
January 2021

Association between NT-proBNP and nocturia among community-dwelling elderly males and females: A cross-sectional analysis of the HEIJO-KYO study.

Neurourol Urodyn 2021 01 21;40(1):112-119. Epub 2020 Oct 21.

Department of Epidemiology, Nara Medical University School of Medicine, Nara, Japan.

Aims: To investigate the association between B-type natriuretic peptide (BNP) and nocturia among community-dwelling males and females.

Methods: A total of 1096 participants (mean age 71.9 ± 7.1 years, 518 [47.2%] males) were included in the study. The number of nocturnal voids was recorded in a self-reported urination diary, and nocturia was defined as two or more voids per night. Daytime serum concentration of the N-terminal fragment of BNP precursor (NT-proBNP) was measured. Multivariable logistic regression analysis was performed to determine the association between NT-proBNP and nocturia.

Results: Nocturia was observed in 23.5% of females and 37.1% of males. Higher NT-proBNP (log pg/ml) was associated with nocturia in both gender groups (females: odds ratio [OR]: 1.67, 95% confidence interval [95% CI], 1.21-2.34, p = .002; males: OR: 1.26, 95% CI, 1.01-1.59, p = .046), independent of confounding variables including night-time blood pressure, mean voided volume, and chronic kidney disease. Although the increase in prevalence of nocturia with higher NT-proBNP was equivalent in both genders, some effect of gender on the relationship between NT-proBNP and nocturia was observed (p = .037). Nocturnal urine volume was also significantly and independently associated with NT-proBNP level (females: β = 32.9 ml, 95% CI, 5.63-60.2, p = .018; males: β = 34.6 ml, 95% CI, 9.40-59.9, p = .007).

Conclusions: This study revealed higher serum NT-proBNP is significantly and independently associated with the prevalence of nocturia in both males and females. This is an exploratory cross-sectional study and the analyses are post hoc, so further research works are needed to clarify the causality and clinical value.
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http://dx.doi.org/10.1002/nau.24550DOI Listing
January 2021

[A Case of Retroperitoneal Bronchogenic Cyst Successfully Resected with Retroperitoneoscopic Surgery].

Hinyokika Kiyo 2020 Sep;66(9):307-311

The Department of Urology, University of Tsukuba Hospital.

A 32-year-old woman was referred to our hospital for consultation with a suspected left adrenal tumor detected by ultrasonography at a health check. Computed tomography and magnetic resonance imaging revealed a 3×1×4 cm multilocular cystic mass arising from the diaphragmatic crura, suggesting a retroperitoneal bronchogenic cyst. The patient underwent excision of the cyst and adjacent diaphragm using a retroperitoneoscopic approach. Retroperitoneal bronchogenic cysts are rare. We review the cases of 26 patients who underwent laparoscopic resection of a retroperitoneal bronchogenic cyst.
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http://dx.doi.org/10.14989/ActaUrolJap_66_9_307DOI Listing
September 2020

Reply by Authors.

J Urol 2020 11 4;204(5):1002. Epub 2020 Sep 4.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1097/JU.0000000000001138.02DOI Listing
November 2020

Cognitive behavioral therapy for overactive bladder in women: study protocol for a randomized controlled trial.

BMC Urol 2020 Aug 20;20(1):129. Epub 2020 Aug 20.

Department of Urology, Kyoto University Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Overactive bladder (OAB) symptoms affect daily life by decreasing health-related quality of life (HRQol). However, there remain no very effective treatment for OAB. Pharmacotherapy is one of the best treatments, but it is not always efficient and may incur adverse events. Although behavioral therapy is another effective treatment, there are very few structured treatment manuals on how to prescribe behavioral therapy to treat OAB for whom. Cognitive behavioral therapy (CBT) is a psychotherapy consisting of structured sessions to solve problems with the collaborative empiricism between therapists and patients. OAB symptoms are supposed to worsen with cognitive distortion, and CBT is expected to be effective in treating OAB by modifying such cognitive processes. In this trial, we will evaluate the efficacy of CBT for OAB.

Methods: A randomized, controlled, open-label, multicenter parallel-group superiority trial will be conducted. Participants with moderate to severe OAB symptoms with or without pharmacotherapy will be recruited and will be randomly allocated 1:1 to two different groups by minimization (age, baseline OAB severity, treatment status, types of intervention, and treating institutions). The intervention group will be prescribed an individual CBT program covering six techniques in 4 sessions (30 min each), with or without pharmacotherapy. The primary outcome is the change scores in an OAB-questionnaire (OAB-q) from baseline to the end of the trial (week 13). Secondary outcomes will include other patient reported outcome measures and the frequency volume chart. All analyses will be conducted on an intention-to-treat principle.

Discussion: This trial will determine the efficacy of CBT to treat OAB using a rigorous methodology. The effectiveness of CBT with a structured manual may not only lead to a new treatment option for patients suffering from OAB symptoms, but may also reduce the social burden by OAB.

Trial Registration: UMIN-CTR Clinical Trial, CTR-UMIN000038513 . Registered on November 7, 2019.
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http://dx.doi.org/10.1186/s12894-020-00697-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439638PMC
August 2020

Chronoradiation Therapy for Prostate Cancer: Morning Proton Beam Therapy Ameliorates Worsening Lower Urinary Tract Symptoms.

J Clin Med 2020 Jul 16;9(7). Epub 2020 Jul 16.

Department of Radiation Oncology, University of Tsukuba, Ibaraki 305-8575, Japan.

Background And Purpose: Worsening lower urinary tract symptoms (LUTS) are a frequent adverse event following proton beam therapy (PBT) for localized prostate cancer. We investigated the differences in worsening LUTS among patients who received PBT at different times of day.

Participants And Methods: Among 173 patients who underwent PBT for prostate cancer, 168 patients (median age 68.5 years) completed international prostate symptom score (IPSS) questionnaires and were included. Changes in the IPSS from baseline to the end of PBT were assessed by multiple linear regression analysis for age, National Comprehensive Cancer Network risk classification, androgen deprivation therapy, fractional PBT dose, clinical target volume, severity of IPSS, diabetes, LUTS medication use before PBT, anti-coagulant therapy and radiation time of day (morning (08:30-10:30), around noon (10:31-14:30), and late afternoon (14:31-16:30)).

Results: IPSS total score and IPSS-Quality of Life (QoL) score (12 patients were excluded due to missing IPSS-QoL score) increased from eight to 14.9 ( < 0.0001) and from two to four ( < 0.0001), respectively. Time of day (morning) was the only determinant for worsening LUTS (β = -0.24, < 0.01), voiding subscore (β = -0.22, < 0.05) and IPSS-QoL (β = -0.27, < 0.005), and was a determinant in item four (urgency) (β = -0.28, < 0.005) with age (β = 0.19, < 0.05).

Conclusions: Morning PBT for localized prostate cancer significantly ameliorated worsening LUTS and improved QoL compared with treatment around noon or late afternoon. Chronoradiation therapy for localized prostate cancer may be effective and further research to elucidate the underlying mechanism is warranted.
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http://dx.doi.org/10.3390/jcm9072263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408763PMC
July 2020

Clinical feasibility and acceptability of adding cognitive behavioral therapy to pharmacotherapy for drug-resistant overactive bladder in women: A single-arm pilot study.

Low Urin Tract Symptoms 2021 Jan 3;13(1):69-78. Epub 2020 Jul 3.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objectives: Drug-resistant overactive bladder (OAB) represents an unmet medical need in that treatment options are limited. We developed a treatment model based on cognitive behavioral therapy and evaluated its feasibility and acceptability for drug-resistant OAB in women.

Methods: This was an open-label, single-arm, multicenter pilot study. We defined drug-resistant OAB as OAB with moderate to severe symptoms despite pharmacotherapy for more than 12 weeks. A face-to-face intervention was prescribed as six sessions (30 minutes each) over 6 to 12 weeks according to a treatment manual. The effects were assessed by self-reported questionnaires and frequency voiding charts (FVC) at baseline, during intervention, immediately after intervention, and at follow-up.

Results: Ten patients participated in this study. Median age was 72 years, median OAB Symptom Score was nine points, and median duration of prior treatment for OAB was 5.5 years at baseline. Two participants dropped out of the study. Among the remaining patients, the scores of the OAB Questionnaire subscales improved (effect size: 0.75-1.73), and the mean urinary frequency in the FVC also improved from baseline (9.0 times, SD: 2.1) to follow-up (6.2 times, SD: 1.2). All participants were satisfied with the intervention. There were no adverse events during this study.

Conclusions: The new treatment based on cognitive behavioral therapy was well tolerated and feasible in women with drug-resistant OAB. Further randomized research is needed to rigorously evaluate the efficacy of the treatment.
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http://dx.doi.org/10.1111/luts.12333DOI Listing
January 2021

Impact of centralization in primary retroperitoneal sarcoma treatment: analysis using hospital-based cancer registry data in Japan.

Int J Clin Oncol 2020 Sep 25;25(9):1687-1694. Epub 2020 May 25.

Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1, Ten-nodai, Tsukuba, Ibaraki, 305-8575, Japan.

Background: To elucidate the clinicopathological features, hospital-based care volume and prognoses associated with primary retroperitoneal sarcoma (PRS).

Methods: Clinical data on PRS cases, diagnosed from 2008 to 2009 (cohort A) and from 2012 to 2015 (cohort B), were obtained from the national hospital-based cancer registry in Japan. Since data on survival, 5 years after PRS diagnosis, were available only for cohort A, patient prognoses were analyzed in this group alone.

Results: The numbers of participating hospitals were 154 in cohort A and 537 in cohort B. In total, 380 and 2011 patients with PRS were identified in cohorts A and B, respectively. The incidence of PRS among all the registered urogenital malignancies was 0.52% (2391/462,866). Liposarcoma was the most commonly observed PRS subtype (55.8%), followed by leiomyosarcoma (19.0%). In cohort A, the 5-year overall survival (OS) was 40.4%. The 5-year OS associated with stage I (n = 107), stages II and III (n = 61), and stage IV (n = 59) disease were 59%, 39%, and 6%, respectively. Only two institutions treated over ten patients per year in each cohort. When institutions were divided by hospital care volume (8 hospitals with ≥ = 3 cases and 149 with < 3 cases/year), there were any statistic differences in the OS.

Conclusions: We presented the distribution and prognoses associated with PRS using a real-world large cohort database. Centralization for PRS management was not established in Japan, while the prognosis did not significantly depend on the treatment volume of hospitals.
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http://dx.doi.org/10.1007/s10147-020-01709-7DOI Listing
September 2020

Impact of Nocturia on Mortality: The Nagahama Study.

J Urol 2020 11 12;204(5):996-1002. Epub 2020 May 12.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Purpose: Nocturia has been reported as a risk factor for mortality. However, evidence is limited and has a high risk of bias. We evaluated the association between nocturia and mortality using longitudinal data from the general Japanese population.

Materials And Methods: Data were obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. Nocturia was measured using the International Prostate Symptom Score. Mortality data were obtained from the Basic Resident Register in Nagahama City. We used Cox proportional hazard models and time-varying covariates at baseline and 5-year followup to analyze the association between nocturia and mortality.

Results: We analyzed 9,762 participants (median age 56.8 years, male 32.8%). The prevalence rates of nocturnal voiding at 0, 1, 2 and 3 or more times were 44.3%, 39.1%, 11.7% and 4.9%, respectively. A total of 263 participants died. Followup assessment was performed 3,224 (SD 537) days after baseline. According to multivariable Cox proportional hazard regressions, mortality increased dose dependently with the nocturnal voiding frequency as HR 1.46 for 1 time (95% CI 1.02-2.09), HR 1.85 for 2 times (95% CI 1.23-2.77) and HR 2.06 (95% CI 1.28-3.32) for 3 or more times in comparison with 0 times (p for trend=0.00084). In the time varying Cox proportional hazard regression the association was still significant (p for trend=0.0017).

Conclusions: According to this longitudinal study with a low incidence of missing data and high representation of the general population, nocturia is associated with mortality.
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http://dx.doi.org/10.1097/JU.0000000000001138DOI Listing
November 2020

Three-dimensional simulation analysis of microdissection testicular sperm extraction for patients with non-obstructive azoospermia.

Andrology 2020 09 18;8(5):1214-1221. Epub 2020 May 18.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Microdissection testicular sperm extraction (microTESE) is considered the gold standard method of sperm retrieval from patients with non-obstructive azoospermia (NOA). For careful and thorough examination of seminiferous tubules during microTESE, maximizing surface area of the testicles which we are able to search is essential.

Objectives: To develop a systematic procedure for microTESE to maximize surface area and to achieve high sperm retrieval rate (SRR) in microTESE.

Materials And Methods: We simulated microTESE using three-dimensional (3D) simulation model and analyzed mathematically the sum of the surface area in various methods. The best method obtained from this simulation model was applied to 102 patients with NOA from 2014 to 2018. These new clinical results were compared with those of 56 patients who underwent a previous method of microTESE from 2011 to 2014.

Results: The mathematical 3D simulation model of microTESE indicated that a longitudinal incision on the tunica albuginea and following transverse slicing incisions of testicular parenchyma maximized the surface area coverage. Forty-six (45%) out of 102 patients who underwent microTESE with the new method had successful retrieval of testicular spermatozoa compared with 16 (29%) of 56 patients with the previous method of microTESE (P = .04).

Discussion: Transverse resections of parenchyma in our method run parallel to the courses of intratesticular arteries and do not interfere with the blood supply. The small amount of extracted seminiferous tubules was equivalent to that of the previous method, and no patients exhibited post-operative symptoms of androgen deficiency in our study. As for post-operative pain, our new method was comparable with the previous method. Although our study needs a longer follow-up, there will be limited effects on testicular functions.

Conclusion: Longitudinal incision on the tunica albuginea and following transverse slicing incisions in the testicular parenchyma maximized the surface area and improved the SRR of microTESE.
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http://dx.doi.org/10.1111/andr.12812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522677PMC
September 2020

[Post-Operative Urethral Stricture after Holmium Laser Enucleation of the Prostate].

Hinyokika Kiyo 2019 Nov;65(11):445-449

The Department of Urology, Kyoto University Hospital.

Holmium laser enucleation of the prostate (HoLEP) is a safe and effective surgical procedure for patients suffering from comparatively larger benign prostatic hyperplasia. However, the rate of postoperative urethral stricture (POUS) is relatively high, which can render further invasive intervention. Here we assessed the POUS rate, riskfactors and outcomes in 206 patients with benign prostatic hyperplasia who underwent HoLEP at our hospital between January 2006 and December 2015. POUS was observed in 24 patients (11.7%). The rate of intraoperative urethral stricture was significantly higher in the patients with POUS (8 out of 24 patients, 33.3%) than in those without POUS (12 out of 186 patients, 6.6%). The odds ratio was 7.08, 95% and combination index (CI) was 2.53-19.9, p<0.001). The relative riskfor POUS based on intraoperative urethral stricture was 4.65 (95% CI : 2.28-9.48). The most common POUS site was external urethral orifice (12 out of 24 cases). The POUS onset was significantly earlier in patients with external urethral orifice than the other sites (p=0.0389). The site of postoperative stricture concurred with that of intraoperative stricture at a high rate (7 out of 8 patients). Significant differences were observed between patients with and without POUS within one month in international prostate symptom score, quality of life score and in Qmax after the operation, while they were improved by simple interventions such as bougie. In conclusion, we should consider the possibility of POUS when the patient had an intraoperative stricture in HoLEP.
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http://dx.doi.org/10.14989/ActaUrolJap_65_11_445DOI Listing
November 2019

Barriers for sperm cryopreservation in advanced germ cell tumor patients: a 20-year experience.

Int J Clin Oncol 2020 May 1;25(5):906-911. Epub 2020 Jan 1.

Department of Urology, Kyoto University Hospital, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 6068507, Japan.

Background: This study aimed to investigate barriers to sperm cryopreservation for patients with advanced germ cell tumors.

Methods: We reviewed data collected from patients who underwent chemotherapy for advanced germ cell tumors in our institutions from 1996 to 2016. We divided sperm cryopreservation procedures into three steps: offering information about sperm cryopreservation, patients' decision making and sperm collection, and investigating the barriers in each step.

Results: Of the 91 patients, 43 (47%) successfully completed sperm cryopreservation. Thirty (33%) patients were not offered information about sperm cryopreservation from the doctors. Nine patients (9.9%) were offered but declined preservation. Nine patients (9.9%) were not able to provide sperm because of azoospermia (5) and anejaculation (4). Among 43 patients who successfully provided sperm, 10 (23%) had their cryopreserved sperm used for 21 cycles of in vitro fertilization. Ten pregnancies and 7 fatherhoods were achieved. Thirteen patients (30%) had their cryopreserved sperm discarded without use, whereas 20 (47%) continued preserving their sperm for a median 12.5 years.

Conclusions: Not only offering proper information about sperm cryopreservation, but also shared decision making prior to chemotherapy, and considering fertility preservation before orchiectomy are imperative. The rate of use of preserved sperm was relatively high, but decision making for sperm disposal should also be supported.
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http://dx.doi.org/10.1007/s10147-019-01607-7DOI Listing
May 2020

Longitudinal Analysis of Bidirectional Relationships between Nocturia and Depressive Symptoms: The Nagahama Study.

J Urol 2020 May 21;203(5):984-990. Epub 2019 Nov 21.

Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Purpose: Although the association between nocturia and depressive symptoms has been demonstrated, the causal direction remains unclear. We investigated the directional association between nocturia and depressive symptoms using longitudinal data from the general population.

Materials And Methods: This longitudinal analysis was conducted as part of the Nagahama Cohort Project, a population based cohort study, with baseline and 5-year followup investigations. Nocturnal voiding frequency and mental health were measured with self-report questionnaires, the International Prostate Symptom Score and the 5-item Mental Health Inventory. Logistic regression analyses and a cross-lagged panel analysis were performed to analyze the bidirectional association between nocturia and depressive symptoms.

Results: With 9,764 participants at baseline, data from 8,285 were used in this analysis. Median age at baseline was 57.3 years and the proportion of men was 32.0%. New onset depressive symptoms and nocturia were observed among 369 and 793 participants, respectively. In adjusted logistic regression analyses we observed a clear dose-relationship between baseline nocturnal voiding frequency and new onset depressive symptoms (p for trend <0.001) and a weak association between baseline 5-item Mental Health Inventory and new onset nocturia (p for trend=0.0087). In a cross-lagged panel analysis the path coefficient from nocturnal voiding frequency to 5-item Mental Health Inventory (β=-0.06, p <0.001) was stronger than that from 5-item Mental Health Inventory to nocturnal voiding frequency (β=-0.02, p=0.047).

Conclusions: This longitudinal study demonstrated a bidirectional association between nocturia and depressive symptoms. The cross-lagged path coefficient suggested that nocturia could more likely be a cause than a result of depressive symptoms.
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http://dx.doi.org/10.1097/JU.0000000000000683DOI Listing
May 2020

Add-on effects of tadalafil in tamsulosin-treated patients with small benign prostatic enlargement: A randomized, placebo-controlled, double-blind, crossover study.

Neurourol Urodyn 2020 01 2;39(1):237-242. Epub 2019 Oct 2.

Department of Urology, Kyoto University Hospital, Kyoto, Japan.

Aim: To assess the add-on effects of tadalafil in patients with a relatively small benign prostatic enlargement (BPE) treated with tamsulosin.

Methods: From September 2014 to July 2018, we prospectively studied patients (aged 50 years or more) attending our hospital who had received tamsulosin for small BPE (20-40 mL) for 4 weeks at least and still had residual lower urinary tract symptoms (LUTS) with total International Prostate Symptom Scores (IPSS) of at least 8 and IPSS-quality of life scores at least 3. We randomized eligible patients into two groups: one of which received tadalafil 5 mg once daily for 6 weeks, followed by placebo for 6 weeks, and the other of which received placebo followed by tadalafil in the same manner. The patients were reviewed at our outpatient clinic after 2, 6, 8, and 12 weeks.

Results: There were 13 patients in the tadalafil-placebo and 13 in the placebo-tadalafil group. Their median ages (range) were 70 (65-85) and 73 (50-80) years, prostatic volumes (median) 30.0 (22.0-39.7) and 32.0 (20.1-39.5) mL, and total IPSS (median) 17 (10-27) and 16 (10-24), respectively. The primary endpoints, namely mean changes of total IPSS from baseline, were 1.85 on placebo and -3.42 on tadalafil; this difference is statistically significant (difference: -1.57; 95% confidence interval: -3.00, -0.69; P = .032). We encountered no adverse effects.

Conclusions: Add-on of tadalafil for symptomatic patients with small BPE treated with tamsulosin appears to be effective and safe.
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http://dx.doi.org/10.1002/nau.24175DOI Listing
January 2020

Low bladder capacity is an important predictor for comorbidity of interstitial cystitis with Hunner's lesion in patients with refractory chronic prostatitis/chronic pelvic pain syndrome.

Int J Urol 2019 06;26 Suppl 1:53-56

Ueda Urology Clinic, Kyoto, Japan.

Objective: To evaluate the predictive factors for comorbidity of Hunner-type interstitial cystitis in patients with chronic prostatitis/chronic pelvic pain syndrome using urethrocystoscopy.

Methods: Thirty-two male patients were included in this study. Between April 2012 and April 2016; they were diagnosed with chronic prostatitis/chronic pelvic pain syndrome according to the National Institutes of Health classification. Their symptoms were not improved by 3 months of behavioral and pharmacological therapies. They all underwent narrow band imaging-assisted urethrocystoscopy to assess whether the presence of Hunner's lesions correlated with other variables.

Results: Thirteen out of 32 patients (41%) had Hunner's lesions. Of the variables, maximal voided volume per micturition (106 ± 29 mL vs 171 ± 61 mL) and bladder capacity (267 ± 121 mL vs 407 ± 137 mL) were significantly smaller in patients with Hunner's lesions compared to those without. Other variables, apart from age, were not significantly different. Furthermore, patients with voided volume less than 150 mL were more likely to have Hunner's lesions than those with voided volume exceeding 150 mL.

Conclusions: Hunner-type interstitial cystitis is a common comorbidity among patients with refractory chronic prostatitis/chronic pelvic pain syndrome. In cases where voided volume is small, performing narrow band imaging-assisted urethrocystoscopy would be very helpful for detecting bladder mucosal changes such as Hunner's lesions.
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http://dx.doi.org/10.1111/iju.13975DOI Listing
June 2019

Reply by Authors.

J Urol 2019 08 8;202(2):360-361. Epub 2019 Jul 8.

Department of Urology, Kyoto University Hospital , Kyoto , Japan.

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http://dx.doi.org/10.1097/01.JU.0000559826.09631.1dDOI Listing
August 2019

Sleep Disturbance Worsens Lower Urinary Tract Symptoms: The Nagahama Study.

J Urol 2019 08 8;202(2):354. Epub 2019 Jul 8.

Department of Urology, Kyoto University Hospital , Kyoto , Japan.

Purpose: Multiple factors are associated with lower urinary tract symptoms and sleep disturbance is well known to be associated with nocturia. The association between sleep disturbance and lower urinary tract symptoms has not been sufficiently elucidated. We evaluated the impact of sleep disturbance on lower urinary tract symptoms, especially voiding symptoms, in the Nagahama Study.

Materials And Methods: The Nagahama Study is a prospective cohort study of healthy individuals. Among them study participants 50 years old or older who completed the I-PSS (International Prostate Symptom Score) questionnaire and a sleep problem questionnaire were included in this analysis and followed for 5 years. Sleep disturbance was stratified into poor sleep quality, sleep restriction and sleep medication use. We analyzed the association between sleep disturbance and worsening of lower urinary tract symptoms adjusted by various clinical factors on multivariate logistic regression analysis.

Results: Among the 5,297 participants the prevalence of lower urinary tract symptoms at baseline was 23% and the prevalence rates of poor sleep quality, sleep restriction and sleep medication were 20%, 6% and 7%, respectively. Participants with poor sleep quality, sleep restriction or sleep medication use had a significantly greater incidence of lower urinary tract symptoms and voiding symptoms than those without such characteristics (p <0.01). Poor sleep quality and sleep medication use were significantly associated with worsening lower urinary tract symptoms as defined by an I-PSS score increase of 4 or greater (OR 1.23, p = 0.03, and 1.67, p <0.01), and with worsening voiding symptoms, defined as an increase of 3 or greater (OR 1.35, p <0.005, and 1.85, p <0.001, respectively).

Conclusions: Sleep disturbance was significantly associated with the presence of lower urinary tract symptoms in a cross-sectional manner and with worsening lower urinary tract symptoms longitudinally.
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http://dx.doi.org/10.1097/JU.0000000000000212DOI Listing
August 2019

[A Case of Advanced Right Renal Pelvic Cancer with Left Supraclavicular Lymph Node Metastasis that Attained Long-Term Survival by Multidisciplinary Treatments].

Hinyokika Kiyo 2019 Jan;65(1):13-17

The Department of Urology, Kyoto University Hospital.

A man in his 70s was referred to our hospital for further examination of a positive occult blood finding. Imaging studies showed that the patient had right renal pelvic cancer with interaortocaval, multiple paracaval and left supraclavicular lymph node metastases (cT3N2Ml). Induction chemotherapy was performed with 5 cycles of MEC (methotrexate/epirubicin/cisplatin) followed by 2 cycles of GT (gemcitabine/paclitaxel). After the combined chemotherapies, the residual lesions were the primary tumor in the right renal pelvis and the left supraclavicular lymph node. Right total nephroureterectomy combined with lymph node dissection of paraaortic, paracaval, and interaortocaval area and left cervical area were performed. Histopathologically the postoperative T stage of the primary tumor was determined as ypT3. As for lymph nodes dissected, an interaortocaval lymph node alone, but not the other nodes, contained viable cancer cells. Adjuvant chemotherapy was performed with 7 courses of GT therapy. The patient had intravesical recurrence once and received transurethral resection of bladder tumor followed by intravesical instillations of Bacillus Calmette-Guerin (BCG). Finally, the patient has been free from recurrence for 10 years after the final treatment.
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http://dx.doi.org/10.14989/ActaUrolJap_65_1_13DOI Listing
January 2019

Duodenal obstruction induced by retroperitoneal progression of bladder cancer: a report of two cases.

Abdom Radiol (NY) 2019 04;44(4):1223-1229

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Bladder cancer usually forms a papillary structure. Progression along the cavity or membranous structures surrounding the bladder, rectum, or retroperitoneum without formation of a discrete mass is rare. We here present two patients with duodenal obstruction caused by retroperitoneal progression of bladder cancer, in both of whom computed tomography revealed bladder and rectal wall thickening with a malignant target sign, thickened mesorectal fascia with abnormal tissue stranding, and increased perirectal fat density. Both cancers progressed despite treatment, as indicated by faint abnormal tissue stranding and increased retroperitoneal fat density along the retromesenteric plane from the pelvis to the duodenum. Subsequently, both patients developed obstruction in the horizontal portion of the duodenum, still without formation of a mass lesion. These two patients highlight the challenges associated with retroperitoneal invasion by bladder cancer in the absence of a mass lesion and underscore the importance of considering cancer progression in patients with bowel obstruction, even when there is no obvious mass lesion and/or only minor retroperitoneal findings. Progression along the retromesenteric plane may be the key pathway via which progressive bladder cancer results in duodenal obstruction without or with a minor mass lesion.
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http://dx.doi.org/10.1007/s00261-018-1874-8DOI Listing
April 2019

[Initial Clinical Experience of Nivolumab for Metastatic Renal Cell Carcinoma].

Hinyokika Kiyo 2018 10;64(10):383-389

The Department of Urology, Kyoto University Hospital.

Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCC) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCC. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCC. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCC.
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http://dx.doi.org/10.14989/ActaUrolJap_64_10_383DOI Listing
October 2018

Sperm cryopreservation: Clinical and fertility outcomes in male oncological patients with germ cell tumors or hematological disorders.

Reprod Med Biol 2018 Oct 30;17(4):500-503. Epub 2018 Sep 30.

Ichioka Urological Clinic Symphonia-Oike 1F, Higashinotoin-Nijo sagaru Kyoto Japan.

Purpose: There is insufficient understanding of the effects of malignant diseases themselves and chemotherapy on semen quality and final fertility outcomes. Here, the authors focused on the patients with malignant diseases who cryopreserved sperm pre- or post-chemotherapy for future fertility, and revealed how clinical settings can affect semen quality and final outcomes.

Methods: The authors reviewed the records of 257 patients with malignant diseases who cryopreserved sperm. Among 257 cases, 113 men with germ cell tumors (GCTs) and 111 men with hematological disorders (HDs) were included in this study. Twenty-five patients who achieved successful outcomes using cryopreserved sperm were also analyzed.

Results: In the men with GCTs and HDs, respectively, differences were observed in age (28 vs 27 years), sperm concentration (32.6 vs 46.1 million/mL,  < 0.05), motility (42.2% vs 41.0%), and the rate of cryopreservation before chemotherapy (90% vs 59%,  < 0.0001). For successful pregnancies and deliveries, age at cryopreservation (30.0 vs 35.3 years,  < 0.05) and disease type (12/16 vs 3/9,  < 0.05) were significant factors.

Conclusions: Compared to patients with GCTs, those with HDs have a lower pregnancy and delivery rate, even though semen quality is higher. Disease type and age at cryopreservation are significant factors for successful outcomes.
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http://dx.doi.org/10.1002/rmb2.12246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194308PMC
October 2018

Laparoscopic excision of an acquired ureteral diverticulum: A case report.

Asian J Endosc Surg 2019 Oct 24;12(4):478-481. Epub 2018 Oct 24.

Department of Urology, Kyoto University Hospital, Kyoto, Japan.

Ureteral diverticula, especially acquired diverticula, are rare. Surgery is indicated when a diverticulum is accompanied by complications such as stones, pyelonephritis, stenosis, and signs of malignancy. A 59-year-old woman visited our urology department with asymptomatic macrohematuria. Enhanced CT scan revealed a right ureteral diverticulum with a 16-mm diameter that contained two tiny stones inside. After 8 months, the size of these stones increased; therefore, the patient underwent laparoscopic resection of the ureteral diverticulum and end-to-end anastomosis of the ureter. Subsequent histopathology of the excised specimen revealed an acquired diverticulum. Follow-up intravenous pyelography showed adequate urine passage with only minor dilatation of the pelvis at 3 months after the operation. The laparoscopic approach is believed to be feasible for ureteral diverticula cases that require ureteral end-to-end anastomosis.
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http://dx.doi.org/10.1111/ases.12663DOI Listing
October 2019