Physiotherapy for continence and muscle function in prostatectomy: a randomised controlled trial.

OBJECTIVE: To assess the effectiveness of pre- and postoperative supervised pelvic floor muscle training (PFMT) on the recovery of continence and pelvic floor muscle (PFM) function after robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS: We carried out a single-blind randomised controlled trial involving 54 male patients scheduled to undergo RARP. The intervention group started supervised PFMT 2 months before RARP and continued for 12 months after surgery with a physiotherapist. The control group was given verbal instructions, a brochure about PFMT, and lifestyle advice. The primary outcome was 24-h pad weight (g) at 3 months after RARP. The secondary outcomes were continence status (assessed by pad use), PFM function, and the Expanded Prostate Cancer Index Composite (EPIC) score. RESULTS: Patients who participated in supervised PFMT showed significantly improved postoperative urinary incontinence (UI) compared with the control group (5.0 [0.0-908.0] g vs 21.0 [0.0-750.0] g; effect size: 0.34, P = 0.022) at 3 months after RARP based on 24-h pad weight. A significant improvement was seen in the intervention compared with the control group (65.2% continence [no pad use] vs 31.6% continence, respectively) at 12 months after surgery (effect size: 0.34, P = 0.030). Peak pressure during a maximum voluntary contraction was higher in the intervention group immediately after catheter removal and at 6 months, and a longer duration of sustained contraction was found in the intervention group compared with the control group. We were unable to demonstrate a difference between groups in EPIC scores. CONCLUSION: Supervised PFMT can improve postoperative UI and PFM function after RARP. Further studies are needed to confirm whether intra-anal pressure reflects PFM function and affects continence status in UI in men who have undergone RARP.

Effects of low-intensity extracorporeal shock wave therapy on lipopolysaccharide cystitis in a rat model of interstitial cystitis/bladder pain syndrome.

PURPOSE: To investigate the effect of low-intensity extracorporeal shock wave therapy (LiESWT) on lipopolysaccharide (LPS)-induced cystitis in an animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Sprague-Dawley rats were divided into three groups: control, cystitis (LPS group, intravesical injection of LPS (1 mg) twice), and cystitis with LiESWT (LiESWT group). On the third and fourth days, LiESWT was administered (0.12 mJ/mm2, 300 shots each time) on the lower abdomen toward the bladder. On the seventh day, the rats underwent pain assessment and a metabolic cage study. Subsequently, a continuous cystometrogram (CMG) was performed under urethane anaesthesia. Immunohistochemical studies were also performed, including S-100 staining, an immunohistochemical marker of Schwann cells in the bladder. RESULTS: In the LPS group, the pain threshold in the lower abdomen was significantly lower than that in the control group. In the metabolic cage study, the mean voided volume in the LPS group significantly increased. The CMG also revealed a significant decrease in bladder contraction amplitude, compatible with detrusor underactivity in the LPS group. Immunohistochemical studies showed inflammatory changes in the submucosa, increased fibrosis, and decreased S-100 stain-positive areas in the muscle layer of the LPS group. In the LiESWT group, tactile allodynia and bladder function were ameliorated, and S-100 stain-positive areas were increased. CONCLUSION: By restoring nerve damage, LiESWT improved lower abdominal pain sensitivity and bladder function in an LPS-induced cystitis rat model. This study suggests that LiESWT may be a new therapeutic modality for IC/BPS.

[A Case of Testicular Cancer with Solitary Iliac Bone Metastasis].

A 23-year-old male was aware of pain around his left hip joint and visited a nearby orthopedic clinic. Swelling of the right testis was pointed out, and a testicular tumor was suspected. He was referred to the urology department of a local hospital. Blood analysis showed an increase of α-fetoprotein (AFP) (3,620 ng/ml). Computed tomographic (CT) -scan revealed a left iliac bone metastasis and morbid fracture. Right radical inguinal orchiectomy was performed. The pathological examination revealed mixed germ cell tumor (embryonic carcinoma and immature teratoma: 70%, seminoma: 30%). The diagnosis was non-seminomatous germ cell tumor, stage IIIc, and poor risk on the International Germ Cell Consensus Classification. After one cycle of a bleomycin, etoposide and cisplatinum (BEP) regimen, he was referred to our hospital. After a total of 4 cycles of BEP, AFP was normalized. Denosumab was also administered monthly. The CT-scan showed a reduction of bone metastasis and recovery of ossification. Bone biopsy did not show viable tumor cells. Because extirpation of the remaining mass would require resection of the left part of the pelvic bone with significant functional loss of the left limb, we performed close follow-up after an additional 2 courses of the etoposide and cisplatin regimen. The patient is currently alive without recurrence at 45 months after the last systemic chemotherapy.

Effects of a new selective ß3 -adrenoceptor agonist, vibegron, on bladder and urethral function in a rat model of Parkinson's disease.

OBJECTIVES: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel ß3 -adrenoceptor agonist approved for the treatment of overactive bladder. However, how ß3 -adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease. METHODS: In a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity. RESULTS: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter-contraction interval (p < .05) and reduced voiding pressure (p < .01). However, no significant effects on urethral function were observed. CONCLUSIONS: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of ß3 -adrenoceptor agonists.

Associations of Death at Home with Medical Resources and Medical Activities in Cancer Patients: A Nationwide Study Using Japanese National Database.

BACKGROUND: Over half of the Japanese population hope to spend their last days at home; however, 73.0% die in hospitals. The proportion of deaths due to cancer in hospitals is even higher, at 82.4%, and is also high globally. Therefore, there is an urgent need to establish conditions that fulfill the hopes of patients, especially those with cancer, who hope to spend their last days at home. This study aimed to clarify medical resources and activities that are related to proportion of death at home among cancer patients. METHODS: We used data from the Japanese National Database and public data. Japan's Ministry of Health, Labour, and Welfare provides national data on medical services to applicants for research purposes. Using the data, we calculated the proportion of deaths at home in each prefecture. We also collected information on medical resources and activities from public data and conducted multiple regression analyses to investigate factors associated with the proportion of death at home. RESULTS: In total, 51,874 eligible patients were identified. The maximum and minimum proportions of death at home based on prefectures differed by approximately three-fold (14.8%-41.6%). We also identified scheduled home-visit medical care (coefficient=0.580) and acute and long-term care beds (coefficient=-0.317 and -0.245) as factors that increased and decreased the proportion of death at home, respectively. CONCLUSION: To fulfill the hopes of cancer patients to spend their last days at home, we recommend that the government develop policies to increase home visits by physicians and optimize hospital acute and long-term care beds.

Health care providers' perspectives on providing end-of-life psychiatric care in cardiology and oncology hospitals: a cross-sectional questionnaire survey.

BACKGROUND: Psychological distress is a major concern for patients with end-stage heart failure (HF). However, psychiatric care for patients with HF is not as organized as that for patients with cancer. Therefore, the aim of this study was to elucidate and compare the barriers faced by health care providers of cardiology and oncology hospitals in providing end-of-life psychiatric care to patients with HF and cancer, respectively. METHODS: We conducted a cross-sectional questionnaire survey among the health care providers of Japan. Questionnaires were mailed to physicians and nurses of 427 cardiology and 347 oncology hospitals in March 2018 to assess health care providers' perspectives. First, we compared the scores of the Palliative Care Difficulties Scale and the original scale of end-of-life psychiatric care difficulties between health care providers of cardiology and oncology hospitals. Second, we asked the health care providers to describe the barriers to providing end-of-life psychiatric care with an open-ended question and then compared the freely-provided descriptions using content analysis. RESULTS: A total of 213 cardiology and 224 oncology health care providers responded to the questionnaire. No significant differences were found between health care providers of cardiology and oncology hospitals in the frequency of experiencing barriers to providing end-of-life psychiatric care (59.8% and 62.2%, respectively). A content analysis identified the following eight barriers: "patients' personal problems," "family members' problems," "professionals' personal problems," "communication problems between professionals and patients," "problems specific to end-of-life care," "problems specific to psychiatric care," "problems of institution or system," and "problems specific to non-cancer patients." The "problems specific to noncancer patients" was described more frequently by health care providers in cardiology hospitals than that in oncology hospitals. However, there were no significant differences in other items between the two. CONCLUSION: Although health care providers of both cardiology and oncology hospitals faced barriers to providing end-of-life psychiatric care, those of cardiology hospitals particularly faced challenges pertaining to non-cancer patients, such as unpredictability of prognosis or insufficiency of guideline development. A system of psychiatric care, specifically for patients with HF, should be established.

Ureteral reimplantation during augmentation cystoplasty is not needed for vesicoureteral reflux in patients with neurogenic bladder: a long-term retrospective study.

BACKGROUND: To investigate the need for ureteral reimplantation for vesicoureteral reflux (VUR) during augmentation cystoplasty (AC) in the long term. METHODS: A total of 19 patients with a median age at surgery of 14 years (3-38 years) who underwent AC for neurogenic bladder with VUR between 1983 and 2016 were included in this study. The changes in VUR grade and urodynamic findings were retrospectively evaluated. We evaluated the renal function by periodic inspection of serum creatinine level and estimated glomerular filtration rate; eGFR. RESULTS: The median follow-up period from AC was 14.8 years (5.7-30 years). VUR was detected in 19 patients, involving 27 ureters. Reflux grade was V in 6, IV in 9, III in 5, II in 6, and I in 1. Ureteral reimplantation was not performed in 18 patients (26 ureters), whereas it was done for 1 patient (1 ureter) in the early era of our experience. Postoperative videourodynamics showed that the reflux was radiologically not verifiable in 23 ureters (85%), was downgraded in 3 ureters (11%), and was unchanged in 1 ureter (3%). There were no cases of deterioration of VUR. CONCLUSIONS: Ureteral reimplantation is not necessary for VUR during augmentation cystoplasty.

[A CASE OF URETEROARTERIAL FISTULA REQUIRING SURGICAL TREATMENT AFTER ENDOVASCULAR STENT PLACEMENT].

A 36-year-old woman was operated on at the age of 29 years for cervical cancer, and bilateral ureteral stents were inserted during radical hysterectomy. Subsequently, total pelvic irradiation and para-aortic lymph node irradiation were administered as postoperative radiation therapy. Four years following the surgery, the patient visited previous hospital for ureteral stent replacement; however, following this visit, there was no further contact with her. Seven years after the surgery, the patient presented with gross hematuria. Removal of right ureteral stent led to the observation of severe bleeding. The patient was, thus, transferred to our hospital because of suspected right ureteroarterial fistula. Angiography and intravascular ultrasonography showed a pseudoaneurysm at the distal end of the right common iliac artery. Thus, an endovascular stent graft was placed in the right common iliac artery, which led to resolution of the gross hematuria. One month after discharge, the patient developed right pyelonephritis and hydronephrosis; thus, she underwent right nephrostomy. Six months after undergoing right nephrostomy, the patient developed a fever of 39°C and started bleeding from the site of the right nephrostomy. A computerized tomography scan revealed a pseudoaneurysm in the right common iliac artery, and the endovascular stent graft was seen sliding into the artery. Thus, endovascular stent graft removal, pseudoaneurysm resection, and femoral-femoral artery bypass surgeries were performed. Thereafter, the patient showed no recurrence of infection or hematuria and no evidence of blood flow disorder to the lower extremities. In recent years, endovascular treatment for ureteroarterial fistulas is considered as the first-line treatment modality. However, in cases with infection, there is a possibility of vascular wall weakening, resulting in the formation of pseudoaneurysms, and sliding of the endovascular stent graft.

Examination of pelvic floor muscle elasticity in patients with interstitial cystitis/bladder pain syndrome using real-time tissue elastography.

INTRODUCTION AND HYPOTHESIS: The aim was to compare pelvic floor muscle (PFM) elasticity between interstitial cystitis/bladder pain syndrome (IC/BPS) patients and healthy women using real-time tissue elastography. METHODS: The subjects were 17 IC/BPS female patients (IC/BPS group; age 34-84 years), 10 healthy middle-aged women (middle-aged group; 50-80 years), and 17 healthy young adult women (young group; 23-37 years). The target sites of elastography were the striated urethral sphincter (SUS) and adipose tissue as the reference site; muscle elasticity was calculated as the strain ratio (SR) of the SUS to the reference site. Evaluations were performed at rest and during PFM contraction. The IC/BPS group completed lower urinary tract symptom and pain questionnaires. SUS SR was compared among the three groups. SUS SR at rest and during PFM contraction was compared among the three groups with the t-test and the Wilcoxon test. Associations between questionnaire results and SUS SR were evaluated by correlation analysis. RESULTS: There was no significant difference in age between the IC/BPS and middle-aged groups, but the young group was significantly younger than the other groups (p < 0.001). SUS SR at rest was significantly higher in the IC/BPS group than in the middle-aged (p = 0.014) and young groups (p = 0.002). Furthermore, in the IC/BPS group, there was no significant difference in SUS SR between at rest and during PFM contraction. SUS SR was not significantly correlated with questionnaire results for lower urinary tract symptoms. CONCLUSIONS: SUS SR at rest was significantly higher in the IC/BPS group than in the young and middle-aged groups.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Can ultrasound measurement of bladder wall thickness be a useful adjunct for regular urodynamics in children with spina bifida?

INTRODUCTION: Spina bifida is a major cause of neurologic bladder dysfunction among children. The goal of neurogenic bladder treatment is to preserve renal function. Close follow-up is essential, as lower urinary tract functions can change with patient growth. Presently, invasive urodynamics is the gold standard for precisely assessing lower urinary tract function. Ultrasound is a low-cost, non-invasive, uncomplicated examination that can be easily repeated. Bladder wall thickness (BWT) measurement by ultrasound has been proposed as a non-invasive alternative for identifying lower urinary tract dysfunctions. OBJECTIVE: Currently there are few reports on BWT in children with spina bifida, and BWT assessment methodology has yet to be defined. The present study aim was to investigate whether BWT could be a useful adjunct for regular urodynamics in children with spina bifida. We especially focused on the precise bladder volume during BWT measurements that were simultaneously performed with urodynamics. STUDY DESIGN: This prospective observational study investigated 33 patients with spina bifida who underwent video urodynamics. We assessed BWT measurements using ultrasound simultaneously performed with video urodynamics. BWT was calculated for the ventral and dorsal walls at 0%, 20%, 40%, 60%, 80%, and 100% of the expected bladder capacity. RESULTS: Median of bladder capacity was 240 mL, and bladder compliance was 19.2 mL/cmH2O. Detrusor overactivity was present in 66.7% and vesicoureteral reflux was present in 27.3% of the patients. BWT of the ventral wall was significantly lower than the dorsal wall. During increases in the bladder volume, both the ventral and dorsal walls exhibited proportional thinning (p < 0.05). There were no significant differences for BWT between males and females. Although there was a higher statistical tendency for detrusor overactivity versus without detrusor overactivity (p = 0.085), there were no significant differences found between patients with and without detrusor overactivity. DISCUSSION: This is the first report where multiple BWT measurements points with video urodynamics were simultaneously performed. Selection of bladder volumes for BWT measurements is critical. Our current study measured six points for each patient during urodynamics. However, available data was not sufficient for detecting bladder function. Until now, there has been no valid standard condition defined for measuring BWT and thus, lack of a standardized method has resulted in discrepancies among studies. CONCLUSION: Our measurement conditions showed BWT may not correlate with the degree of bladder detrusor dysfunction. As BWT ultrasound cannot identify bladder dysfunction of children with spina bifida, this cannot be used as a substitute for invasive urodynamics.

Girls and renal scarring as risk factors for febrile urinary tract infection after stopping antibiotic prophylaxis in children with vesicoureteral reflux.

PURPOSE: To clarify the incidence of and risk factors for febrile urinary tract infection in children with persistent vesicoureteral reflux (VUR) after the discontinuation of continuous antibiotic prophylaxis (CAP), retrospective chart review was performed. PATIENTS AND METHODS: Among children with primary VUR at 10 years of age or younger at presentation, those who had persistent VUR despite conservative management with CAP and who were subsequently followed after discontinuation of CAP were included. Kaplan-Meier curve and Cox's proportional hazard regression model were used for evaluation of the incidence of and risk factors for febrile urinary tract infection (fUTI) after stopping CAP. RESULTS: Among 144 children (99 boys and 45 girls), fUTI developed in 34. The 5-year fUTI-free rate after discontinuation of CAP was 69.4%. On multivariate analyses, girls (p = 0.008) and abnormalities on nuclear renal scans (p = 0.0019), especially focal defect (p = 0.0471), were significant factors for fUTI. Although the fUTI-free rate was not different between children who had no or 1 risk factor, it was significantly lower in children with 2 risk factors than in those with no or 1 risk factor. CONCLUSIONS: The present study revealed that girls and abnormal renal scan, especially focal defect, are risk factors for fUTI. Active surveillance without CAP for persistent VUR seems to be a safe option for children with no or 1 risk factor. Prophylactic surgery or careful conservative follow-up may be an option for girls with abnormal renal scan results if VUR persists under CAP.

Are sham-operated mice a valid comparator in studies using a bladder outlet obstruction model? A pitfall reveals a meaningful insight.

OBJECTIVE: To evaluate voiding behavior characteristics in intact and sham mice, and to examine whether intact mice show changes in "normal" micturition with aging. METHODS: A total of 72 8-week-old mice were divided into two groups - intact and sham - and the latter group was subjected to a sham of partial bladder outlet obstruction surgery. Urination frequency was evaluated (through metabolic cages) at 1, 2, 3, 6 and 12 months after the surgery (or at the equivalent time points for the intact mice). To address possible mechanisms for aging and surgical effects on urinary behavior, quantitative real-time polymerase chain reaction assays were carried out. Primary data were evaluated using scatter plots and descriptive statistics. RESULTS: In sham mice, urination frequency showed strong variation at the earlier post-surgical time points (especially at 1 month), with variation decreasing with time. Quantitative real-time polymerase chain reaction showed that the serotonin 2C receptor-encoding mRNA accumulated to >28-fold higher levels at 24 months compared with 3 months in intact mice. A major limitation of the quantitative real-time polymerase chain reaction experiments was that we did not separate whole bladder into muscle and mucosa. CONCLUSIONS: Although a sham operation is typically used in partial bladder outlet obstruction experiments to provide control animals, the sham group might itself show increased variation in micturition frequency at early times after surgery, compared with intact animals.

Endoscopic Submucosal Dissection Using EndoTrac, a Novel Traction Device.

BACKGROUND: Endoscopic submucosal dissection (ESD) is recognized as a minimally invasive and curative treatment for superficial gastrointestinal (GI) cancers. However, ESD is still challenging and time-consuming with a high risk of adverse events such as bleeding and perforation. Various traction methods have been explored for maintaining good visualization of the submucosal layer during ESD. We developed a novel traction device (the EndoTrac) which can easily tie the thread and has the ability to change the towing direction. The aim of this study is to evaluate safety and feasibility of ESD using the EndoTrac for GI neoplasms. PATIENTS AND METHODS: We retrospectively analyzed 44 patients (45 lesions) with esophageal, gastric, duodenal, and colorectal neoplasms who had undergone ESD using the EndoTrac device between June 2018 and May 2019. Primary outcome measures were preparation time, procedural success using the EndoTrac device, and ease of ability to change towing direction. RESULTS: Mean preparation time was 2 (2-5) min in esophagus, 3 (1-5) min in stomach, 6 (5-9) min in duodenum, and 4 (2-8) min in colorectum. The procedural success rate was 100% (8/8) in esophagus, 100% (21/21) in stomach, 100% (4/4) in duodenum, and 100% (12/12) in colorectum. The rate of successful towing to both proximal and distal sides was 100% (8/8) in esophagus, 100% (21/21) in stomach, 0% (0/4) in duodenum, and 100% (12/12) in colorectum. CONCLUSIONS: Use of the EndoTrac device appears to be a feasible approach to ESD for GI neoplasms.

Long-term administration of alpha-1 blocker can reverse the micturition pattern in a bladder outlet obstruction murine model.

OBJECTIVE: To investigate the effect of chronic administration of an alpha-1 blocker on micturition patterns in long-term partial bladder outlet obstruction. METHODS: Mice were divided into three groups: a normal group, in which animals were fed a standard diet; a partial bladder outlet obstruction group, in which the proximal urethra was tied and animals were fed a standard diet; and a partial bladder outlet obstruction + naftopidil group, in which the proximal urethra was tied and animals were fed a standard diet containing naftopidil. Micturition behavior was evaluated in all groups for 6 months after partial bladder outlet obstruction surgery. The parameters evaluated included voided volume, time per void, urination frequency and total urine volume. Quantitative assessment of gene expression was also carried out. RESULTS: Total urine volume, as well as total and average voided volume during night, was significantly decreased in partial bladder outlet obstruction + naftopidil mice compared with partial bladder outlet obstruction animals. The levels of transcripts encoding 5-hydroxytryptamine 2A and tissue inhibitor of metalloproteinase 2 were significantly decreased in the partial bladder outlet obstruction + naftopidil group compared with the partial bladder outlet obstruction group. CONCLUSIONS: Long-term administration of an alpha-1 blocker seems to reverse the disturbance of the micturition pattern caused by partial bladder outlet obstruction. Mechanistically, this effect might be mediated by changes in the expression of a serotonin receptor and/or in the activity of the fibrogenesis pathway.

Bladder outlet obstruction disrupts circadian bladder function in mice.

The circadian clock programs daily rhythms and coordinates multiple behavioural processes, including micturition. Partial bladder outlet obstruction (pBOO) in mice produces hyperactive voiding. However, long-term effects of pBOO on bladder function have not been clarified. In this study, we investigated micturition under conditions of impaired circadian bladder function by inducing long-term pBOO by tying the proximal urethra. Micturition behavior was evaluated at 1, 3, 6 and 12 months after surgery. We used automated voided stain on paper method for a precise micturition recording for mice. And quantitative assessment of gene expression was performed at 24 months after pBOO surgery using qRT-PCR procedure. The micturition frequencies in the pBOO group were significantly decreased at 3, 6, and 12 months compared to those at 1 month after operation in the same group (p < 0.05). Body weight of pBOO mice was significantly increased compared to sham operated mice at 12 months. The expression level of mRNA was exhibited a 3.4-fold nominal increased for a 5-HT2B receptor in the pBOO group compared to the sham group. The current study found that long-term pBOO led to disruption of the circadian bladder function (the day/night cycle) in mice, similar to those observed in human as nocturia. This disruption is possible involvement of the gain of body weight and/or serotonergic alteration after pBOO.

Serotonin in the rat prefrontal cortex controls the micturition reflex through 5-hydroxytryptamine 2A and 5-hydroxytryptamine 7 receptors.

OBJECTIVES: To identify the types of serotonin (5-hydroxytryptamine) receptors of the prefrontal cortex related to the micturition reflex. METHODS: Female Sprague-Dawley rats and a microinjection method were used for this study. Stainless steel guide cannulas were implanted bilaterally into the prefrontal cortex, and a polyethylene catheter was inserted into the bladder. Cystometric parameters (intercontraction interval and maximum voiding pressure) were measured before and after injection of any one of six specific antagonists of 5-hydroxytriptamine receptors (5-hydroxytryptamine 1A, 5-hydroxytryptamine 2A, 5-hydroxytryptamine 2C, 5-hydroxytryptamine 3, 5-hydroxytryptamine 4 and 5-hydroxytryptamine 7) into the prefrontal cortex. The prefrontal cortex was divided into two regions, namely the prelimbic cortex and the infralimbic cortex. The experiments were carried out in conscious and free-moving rats. RESULTS: The intercontraction interval value increased significantly after injection of the 5-hydroxytriptamine 2A receptor antagonist, MDL11939, into the prelimbic cortex of the rat prefrontal cortex (7.68 ± 1.28 vs 9.02 ± 1.41 min, P < 0.05), whereas the intercontraction interval value decreased significantly after injection of the 5-hydroxytriptamine 7 antagonist SB269970 into the prelimbic cortex (9.42 ± 0.39 vs 8.14 ± 0.71 min, P < 0.05). The intercontraction interval was unaffected by injection of either of these two antagonists into the infralimbic cortex. The other four antagonists (5-hydroxytryptamine 1A, 5-hydroxytryptamine 2C, 5-hydroxytryptamine 3 and 5-hydroxytryptamine 4) had no effect on the intercontraction interval after injection into the prelimbic cortex and the infralimbic cortex. The maximum voiding pressure was unaffected by injection of any one of the six 5-hydroxytriptamine antagonists into the prelimbic cortex and infralimbic cortex. CONCLUSIONS: In the rat prefrontal cortex5-hydroxytryptamine 2A receptors excite the micturition reflex, whereas 5-hydroxytryptamine 7 receptors inhibit this reflex.

Prognostic impact of local radiotherapy on metastatic urothelial carcinoma patients receiving systemic chemotherapy.

OBJECTIVE: To clarify the prognostic impact of local radiotherapy on metastatic urothelial carcinoma patients treated by systemic chemotherapy. METHODS: Of the 228 metastatic urothelial carcinoma patients treated with systemic chemotherapy, 97 received radiotherapy mainly to metastatic sites. In patients for whom the purpose of radiotherapy was not specified, more than 50 Gy irradiation was considered to be for disease consolidation for survival analysis, while less than 50 Gy was categorized as palliation. According to the Kaplan-Meier method, we analysed overall survival from the initiation of treatment for metastatic urothelial carcinoma until death or the last follow-up, using the log-rank test to assess the significance of differences. The Cox model was applied for prognostic factor analysis. RESULTS: Overall, there was no significant difference in survival between patients with and those without radiotherapy (P = 0.1532). When analysing the patients undergoing consolidative radiotherapy separately, these 25 patients showed significantly longer survival than the 72 patients with palliative radiotherapy (P = 0.0047), with a 3-year overall survival of 43.3%. Of the present cohort, 22 underwent metastasectomy for disease consolidation, and there was no overlapping case between the metastasectomy cohort and cohort receiving consolidative radiotherapy. After controlling for four independent prognostic factors (sex, performance status, haemoglobin level and number of organs with metastasis) in our previous study, radiotherapy for disease consolidation showed a marginal value (hazard ratio = 0.666, P = 0.0966), while metastasectomy remained significant (hazard ratio = 0.358, P = 0.0006). CONCLUSIONS: In the selected patients, long-term disease control could be achieved after consolidative radiotherapy for metastatic urothelial carcinoma disease. Our observations suggest that local ablative therapy (surgery or radiotherapy) could facilitate long-term disease control. However, the treatment decision should be individualized because of the lack of randomized control trials.

Pharmacologic effects of naldemedine, a peripherally acting µ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation.

BACKGROUND: Naldemedine (S-297995) is a peripherally acting µ-opioid receptor antagonist developed as a once-daily oral drug for opioid-induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo. METHODS: The binding affinity and antagonist activity of naldemedine against recombinant human µ-, δ-, and κ-opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine were investigated using animal models of morphine-induced inhibition of small and large intestinal transit, castor oil-induced diarrhea, antinociception, and morphine withdrawal. KEY RESULTS: Naldemedine showed potent binding affinity and antagonist activities for recombinant human µ-, δ-, and κ-opioid receptors. Naldemedine significantly reduced opioid-induced inhibition of small intestinal transit (0.03-10 mg kg-1 ; P < 0.05) and large intestinal transit (0.3-1 µmol L-1 ; P < 0.05). Naldemedine (0.03-1 mg kg-1 ) pretreatment significantly reversed the inhibition of castor oil-induced diarrhea by subcutaneous morphine (P < 0.01). Naldemedine (1-30 mg kg-1 ) pretreatment (1 or 2 hours) did not alter the analgesic effects of morphine in a model measuring the latency of a rat to flick its tail following thermal stimulation. However, a significant delayed reduction of the analgesic effect of morphine was seen with higher doses of naldemedine (10-30 mg kg-1 ). Some centrally mediated and peripherally mediated withdrawal signs in morphine-dependent rats were seen with naldemedine doses ≥3 and ≥0.3 mg kg-1 , respectively. CONCLUSIONS & INFERENCES: Naldemedine displayed potent binding affinity to, and antagonistic activity against, µ-, δ-, and κ-opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.