Possible role of intravenous administration of mesenchymal stem cells to alleviate interstitial cystitis/bladder pain syndrome in a Toll-like receptor-7 agonist-induced experimental animal model in rat.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) categorized with and without Hunner lesions is a condition that displays chronic pelvic pain related to the bladder with no efficacious treatment options. There are strong associations suggested between Hunner-type IC and autoimmune diseases. Recently, we established an animal model of Hunner-type IC using a Toll-like receptor-7 (TLR7) agonist. Intravenous infusion of mesenchymal stem cells (MSCs) can be used to treat injury via multimodal and orchestrated therapeutic mechanisms including anti-inflammatory effects. Here, we investigated whether infused MSCs elicit therapeutic efficacy associated with the TLR7-related anti-inflammatory pathway in our Hunner-type IC model. METHODS: Voiding behaviors were monitored 24 h prior to the Loxoribine (LX), which is a TLR7 agonist instillation in order to establish a Hunner-type IC model (from - 24 to 0 h) in female Sprague-Dawley rats. LX was instilled transurethrally into the bladder. At 0 h, the initial freezing behavior test confirmed that no freezing behavior was observed in any of the animals. The LX-instilled animals were randomized. Randomized LX-instilled rats were intravenously infused with MSCs or with vehicle through the right external jugular vein. Sampling tissue for green fluorescent protein (GFP)-positive MSCs were carried out at 48 h. Second voiding behavior tests were monitored from 72 to 96 h. After the final evaluation of the freezing behavior test at 96 h after LX instillation (72 h after MSC or vehicle infusion), histological evaluation with H&E staining and quantitative real-time polymerase chain reaction (RT-PCR) to analyze the mRNA expression levels of inflammatory cytokines were performed. RESULTS: Freezing behavior was reduced in the MSC group, and voiding behavior in the MSC group did not deteriorate. Hematoxylin-eosin staining showed that mucosal edema, leukocyte infiltration, and hemorrhage were suppressed in the MSC group. The relative expression of interferon-ß mRNA in the bladder of the MSC group was inhibited. Numerous GFP-positive MSCs were distributed mainly in the submucosal and mucosal layers of the inflammatory bladder wall. CONCLUSION: Intravenous infusion of MSCs may have therapeutic efficacy in a LX-instilled Hunner-type IC rat model via a TLR7-related anti-inflammatory pathway.

Outcomes of open partial nephrectomy for renal cell carcinoma in the minimally invasive approach era.

BACKGROUND: We investigated the characteristics and outcomes of patients who underwent open partial nephrectomy (OPN) in the minimally invasive approach era. MATERIALS AND METHODS: We retrospectively reviewed 52 patients (55 cases) who underwent OPN from May 2009 to March 2016. We assessed perioperative change in estimated glomerular filtration rate (eGFR), complications, and oncological outcomes. Tumor complexity was evaluated using the R.E.N.A.L nephrometry score (NS) and the modified NS. RESULTS: Fifteen cases (27%) had imperative indications and 40 (73%) had elective indications. The elective cases were more likely to have adverse tumor complexity based on NS. The perioperative complication rate defined as a Clavien-Dindo grade ≥IIIa was 11%. The rate of postoperative decline in eGFR at 1 month, 1 year, and 2 years was 22%, 20%, and 21%, respectively. Multivariate analysis revealed that male gender (odds ratio [OR] 11.8, p = 0.03), NS ≥9 (OR 13.9, p = 0.02), modified NS ≥11 (OR 13.5, p = 0.01), and cold ischemic time ≥40 minutes (OR 7.9, p = 0.04) were significantly associated with worsening eGFR at 1 year after surgery. During a median follow-up period of 52 months, the 5-year overall survival and recurrence-free survival rates were 93% and 84%, respectively. CONCLUSIONS: OPN is acceptable with regard to oncological outcomes and complications in the minimally invasive surgery era. We propose that OPN should be the preferred approach in cases in which it is technically difficult to preserve maximum renal function via a minimally invasive approach.

Long-term tadalafil administration can prevent functional and structural changes of the urinary bladder in male rats with partial bladder outlet obstruction.

AIMS: There have been few reports on whether long-term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes. METHODS: Eight-week-old male Sprague-Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks. RESULTS: In BOO rats, a significant increase in the number of non-voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats. CONCLUSIONS: Long-term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non-obstructed rats.

[RENAL CELL CARCINOMA METASTASIS TO BLADDER DURING MOLECULAR TARGETED THERAPY WITH PAZOPANIB: REPORT OF TWO CASES].

Renal cell carcinoma (RCC) metastasis to the bladder is rare. We report two cases that occurred metachronously during pazopanib treatment for other metastases. To our knowledge, this is the first report to demonstrate bladder metastasis from RCC during molecular targeted therapy with pazopanib. (Case 1) A woman in her 60s was referred to our department for evaluation of an incidental right renal tumor. Dynamic CT showed a 6 cm renal cell carcinoma. In February 201X she underwent laparoscopic right radical nephrectomy, revealing clear cell carcinoma (grade 1>2), stage pT3aN0M0. In February 201X+1 she complained of left pelvic pain. She was found to have metastasis to two iliac bones and an occipital bone. She received pazopanib, in addition to a bone modifying agent and radiotherapy for the iliac bones. After 8 months, she complained of asymptomatic gross hematuria in spite of having stable disease for bone metastasis. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor on the posterior wall. She underwent transurethral resection of bladder tumor (TUR-BT). Histological examination showed metastatic RCC. Thereafter she received sequential therapies (axitinib, sunitinib, nivolumab). She remains alive without recurrence in the bladder 51 months after TUR-BT. (Case 2) A woman in her 60s presented to our department with a complaint of painless gross hematuria. A dynamic CT showed an 8.5 cm renal cell carcinoma and multiple lung metastases. In March 201Y she underwent right radical nephrectomy, revealing clear cell carcinoma (grade 2>3), stage pT2aN0M1. In June 201Y she started pazopanib. After 9 months CT showed a bladder tumor in addition to progression of lung metastases. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor at dome. She underwent TUR-BT. Histological examination showed metastatic RCC. She had no recurrence in the bladder during follow-up although she died of RCC.

Serum testosterone level is a useful biomarker for determining the optimal treatment for castration-resistant prostate cancer.

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

[Predictive Factor of Urinary Continence after Robot-Assisted Laparoscopic Radical Prostatectomy].

We examined the postoperative urinary continence rate, and preoperative and postoperative factors predicting postoperative urinary continence for patients who underwent robot-assisted laparoscopic radical prostatectomy (RARP) at our hospital. In all, 122 patients who received RARP were retrospectively analyzed. All patients answered a questionnaire to evaluate the urinary condition and also had a follow-up period of 6 months or longer after surgery. We defined urinary continence to be the use of 1 pad per day or less, including a safety pad. Membranous urethral length (MUL) was measured using sagittal sections of T1-weighted MRI. Postoperative urinary incontinence rates were 48.7, 72.4, 82.6 and 86.8% at 3, 6, 12 and 24 months after surgery, respectively. MUL was a significant predictive factor of urinary continence at 6 months after surgery (p<0.01). We examined the factors predicting the urinary continence recovery at 6 months after surgery, including only patients who did not obtain urinary continence at 1 month after surgery. Two factors, MUL of 11 mm or longer and two pads per day at 1 month after surgery, were significant predictive factors of urinary continence recovery at 6 months after surgery (P=0.02, P=0.04). Patients who had a long MUL could easily obtain urinary continence after RARP compared to those with a short MUL. Most patients with a long MUL and with use of 2 pads per day at 1 month after surgery could obtain urinary continence at 6 months after surgery, even if they had urinary incontinence at 1 month after surgery.

[LONGITUDINAL CHANGES OF FREE TESTOSTERONE LEVELS AND SEXUAL FUNCTION IN JAPANESE MEN EVALUATING TWO CROSS-SECTIONAL COMMUNITY-BASED STUDIES].

(Purpose) We conducted cross-sectional studies two times, in 1992 and 2007 and investigated the longitudinal changes of fT levels and sexual function by comparing the results. (Methods) In 1992 and 2007, we conducted cross-sectional surveys about lower urinary tract symptoms and sexual function in male inhabitants aged 40 to 79 years in Shimakaki village, Hokkaido. Comparing the results of these surveys, we analyzed longitudinal changes in fT levels and sexual function. FT levels were measured by radioimmunoassay and sexual function was evaluated using a validated questionnaire. (Results) A total of 123 inhabitants participated in the both surveys. The average age at the initial survey was 57.2 years.Complications causing sexual dysfunction were observed in 43 participants (35%) and 75 participants (61%) in the first and second surveys, respectively. Average fT levels were 12.9 pg/ml and 4.4 pg/ml in the first and second surveys, respectively. Linear approximations of fT (Y) using age (X) were Y = -0.12 X+19.6 and Y = -0.10 X+11.6, for the first and second surveys, respectively. Although decreased fT levels with aging were comparable in both surveys, fT levels were lower in the second survey than in the first survey. There was no significant association between fT levels and sexual function. (Conclusions) The fT levels at the time of the second surey were lower than those in the first survey. The fT level has no significant association with sexual function.

Evaluation and simplification of the occupational slip, trip and fall risk-assessment test.

OBJECTIVE: The purpose of this investigation is to evaluate the efficacy of the occupational slip, trip and fall (STF) risk assessment test developed by the Japan Industrial Safety and Health Association (JISHA). We further intended to simplify the test to improve efficiency. METHODS: A previous cohort study was performed using 540 employees aged ≥50 years who took the JISHA's STF risk assessment test. We conducted multivariate analysis using these previous results as baseline values and answers to questionnaire items or score on physical fitness tests as variables. The screening efficiency of each model was evaluated based on the obtained receiver operating characteristic (ROC) curve. RESULTS: The area under the ROC obtained in multivariate analysis was 0.79 when using all items. Six of the 25 questionnaire items were selected for stepwise analysis, giving an area under the ROC curve of 0.77. CONCLUSION: Based on the results of follow-up performed one year after the initial examination, we successfully determined the usefulness of the STF risk assessment test. Administering a questionnaire alone is sufficient for screening subjects at risk of STF during the subsequent one-year period.

[Treatment of hemodialyzed patient by targeted therapy in metastatic renal cell carcinoma: a case report].

Experience with treatment of hemodialyzed patients by targeted therapy is limited to the few cases reported. Little information has been provided on the safety and toxicity profile of temsirolimus and sorafenib when administered in hemodialyed patients with renal cell carcinoma (RCC). Herein, we report an RCC patient undergoing hemodialysis treated with temsirolimus and sorafenib for 16 months. The patient was a 69-year-old man who was diagnosed with right RCC. He underwent nephrectomy for a pT1b tumor in December 2002. Hemodialysis was introduced in July 2003 (7 months after nephrectomy). Seven years later, CT showed retroperitoneal nodal metastases. He was started on temsirolimus. Although 8 cycles of this therapy were done, we discontinued it because of progressive disease. The CTCAE (Common Terminology Criteria for Adverse Events) grade 3 adverse events were thrombopenia, but no adverse events of grade 4 or greater developed. Secondly, he was started on sorafenib. CT showed a partial response with a 45% decrease in tumor bulk using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. He has partial response for 13 months. He presented high blood pressure requiring pharmacological treatment, but no adverse events of grade 4 or greater developed. Patients with terminal renal failure can be offered temsirolimus and sorafenib treatment with close clinical and laboratory monitoring. Treatment of RCC patient undergoing hemodialysis by targeted therapy appears to be feasible and effective.

An industry-based cohort study of the association between weight gain and hypertension risk among rotating shift workers.

OBJECTIVES: We investigated whether the association between shift work and hypertension is independent of weight gain. METHODS: Subjects were 10,173 male employees (9209 daytime workers, 964 three-shift workers; mean follow-up period: 12.7 years). Hypertension was defined as systolic blood pressure 140 mm Hg or more or diastolic blood pressure 90 mm Hg or more. The risk of developing hypertension among shift workers was estimated using a Cox proportional hazards model with adjustment for several factors. RESULTS: Analysis revealed that "shift work" (hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.68, 2.03), "baseline body mass index" (HR: 1.13; 95% CI: 1.12, 1.15), and "increase in body mass index during follow-up" (HR: 1.15; 95% CI: 1.13, 1.17) were significant independent risk factors for hypertension. CONCLUSIONS: Shift work is a significant risk factor for hypertension that is independent of both starting weight and weight gained over years of work.

A cross-sectional study of workplace social capital and blood pressure: a multilevel analysis at Japanese manufacturing companies.

OBJECTIVES: We examined the contextual effect of workplace social capital on systolic blood pressure (SBP). DESIGN: Cross-sectional. SETTING: A conglomerate from 58 workplaces in Japan. PARTICIPANTS: Of the 5844 workers at a Japanese conglomerate from 58 workplaces, 5368 were recruited. Individuals who received drugs for hypertension (n=531) and who lacked information on any variable (n=167) were excluded from the analyses, leaving 4735 individuals (3281 men and 1454 women) for inclusion. PRIMARY AND SECONDARY OUTCOME MEASURES: Systolic blood pressure. RESULTS: The contextual effect of workplace social capital on SBP was examined using a multilevel regression analysis with a random intercept. Coworker support had a contextual effect at the workplace level (coefficient=-1.97, p=0.043), while a lack of trust for coworkers (coefficient=0.27, p=0.039) and lack of helpfulness from coworkers were associated with SBP (coefficient=0.28, p=0.002). CONCLUSIONS: The present study suggested that social capital at the workplace level has beneficial effects on SBP.

[A case of Crohn's disease developing bladder rupture 4 months after laparoscopic sigmoidectomy with partial cystectomy for vesicosigmoidal fistula].

A 32-year-old well-nourished man having a vesicosigmoidal fistula due to Crohn's disease received laparoscopic sigmoidectomy with partial cystectomy. The bladder wall was closed with an all-layer running suture and additional interrupted sutures using 2-0 Vicryl. Four months after surgery, the suture site on the bladder showed perforation to the abdominal cavity. Since the same event occurred again 6 months after surgery, open partial cystectomy was performed to repair the perforated site 8 months after the initial surgery. The perforated site showed a thinning bladder wall composed of normal urothelium, scar tissue and thin detrusor muscle. Non-caseating granuloma was not found in the specimen, even though it was slightly observed in the margin of the detrusor muscle resected in the initial surgery. Although it was possible that the persisting activity of Crohn's disease, subclinical impaired nutrition due to Crohn's disease or insufficient suturing of the bladder wall were involved in the bladder rupture, the definitive cause remains unknown.

Retrospective cohort study of the risk of impaired glucose tolerance among shift workers.

OBJECTIVES: The aim of this study was to investigate the effect of shift working on the risk of developing impaired glucose tolerance (IGT). METHODS: This study comprised 6413 male employees (5608 daytime workers, 512 3-shift workers and 293 2-shift workers) whose work schedules remained constant during the follow-up period (mean follow-up period 9.9 years). IGT was defined as Hemoglobin A1c ≥ 5.9%. The Cox proportional hazards model was used to estimate the risk of developing IGT, after making adjustments for age, smoking, alcohol consumption, leisure-time physical activity, body mass index (BMI) and Hemoglobin A1c (HbA1c) at baseline. Analysis was additionally performed for a sub-cohort of 1625 workers with BMI of 20.0-25.0 kg/m² that did not change by >2.0 kg/m² during the follow up period. RESULTS: The risk of developing IGT was significantly elevated among both 3-shift workers [hazard ratio (HR) 1.78, 95% confidence interval (95% CI) 1.49- 2.14] and 2-shift workers (HR 2.62, 95% CI 2.17-3.17). Significant elevations of the risk were still observed at the additional analysis on the sub-cohort (3-shift work: HR 3.55, 95% CI 2.02-6.25; 2-shift work: HR 4.86, 95% CI 2.62-9.01). CONCLUSIONS: Both 2- and 3-shift workers were associated with a high risk factor of developing IGT compared to day workers. Moreover, 2-shift workers had a higher risk than 3-shift workers. The risk was observed even among workers whose body mass remained within the normal range.