Statin administration ameliorates ischemia-induced overactive bladder with improvement of blood flow and anti-inflammatory effects in rats.

AIMS: Statins are widely used to treat dyslipidemia and have been shown to reduce the risk of ischemic heart disease and cerebrovascular disease. The effects of statins on ischemia-induced overactive bladder (OAB) and the associated mechanisms were investigated in a rat model of chronic pelvic ischemia. METHODS: A pelvic ischemia model was created by iliac arterial injury (AI) and a high-fat diet using male Sprague-Dawley rats. Rats were assigned to 3 groups: control group, AI group, and AI + statin group. The control group underwent sham operation and was fed a normal diet. The AI group underwent AI surgery and was fed a high-cholesterol diet. The AI + statin group was administered a statin for 4 weeks. Cystometry was performed for 8 weeks after surgery. Blood flow was evaluated by laser meter. Thickness of the iliac arteries was measured, and microvascular density in the lamina propria was evaluated by immunostaining for CD31. Expressions of inflammatory cytokines in the bladder were measured by real-time PCR. RESULTS: Cystometry showed a significantly shorter voiding interval and lower bladder capacity in the AI group than in the control group. The AI + statin group showed improvement of these findings. The AI group showed decreased bladder blood flow, increased iliac arterial wall thickening, and decreased microvascular density compared to the control group. Statin administration improved blood flow. Iliac arterial wall thickening was suppressed, and microvascular density was increased by statin administration, though not significantly. Real-time PCR showed significantly higher expressions of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the AI group than in the control group, and IL-6 and IL-8 expressions were lower in the AI + statin group than in the AI group. CONCLUSIONS: The present results suggest that statins are effective in OAB caused by arteriosclerosis and ischemia. The mechanism of their effects involves improved bladder blood flow and decreased bladder inflammation.

Contemplation of the Effect of Nivolumab Plus Cabosantinib Therapy on Cerebral Hemorrhage in Patients with Brain Metastasis of Renal Cell Carcinoma: A Case Report.

Although the response to combination therapy has been reported in patients with brain metastases from advanced renal cancer, treatment-related cerebral hemorrhage has not been adequately studied. The CheckMate 9ER clinical trial of nivolumab and cabozantinib excluded patients with brain metastases. Therefore, the associated treatment outcomes in these patients with brain metastases are unclear. Herein, we report a case of bleeding from brain metastases in a patient with advanced renal cancer after gamma knife combination therapy with nivolumab and cabozantinib. Fortunately, the cerebral hemorrhage of the patient was alleviated by conservative treatment. Despite treatment interruption, the metastatic lesions reduced in size, and treatment was gradually resumed. In this case study, we report the risk of cerebral hemorrhage in combination therapy for brain metastasis cases, how to manage hemorrhage cases, and their prognosis.

Ectopic endometriosis in the pelvic cavity evokes bladder hypersensitivity via transient receptor potential ankyrin 1 hyperexpression in rats.

INTRODUCTION AND HYPOTHESIS: In women with chronic pelvic pain (CPP), interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis frequently coexist. The mechanism of these diseases coexisting is explained by cross-sensitization between endometriosis and IC/BPS. The overlapped symptoms may be related to cross-sensitization with transient receptor potential vanilloid 1 (TRPV1) and/or transient receptor potential ankyrin 1 (TRPA1) hyperexpression. This study was aimed at exploring whether bladder hypersensitivity is evoked in the surgically induced ectopic endometriosis rat and whether TRPV1 and/or TRPA1 play a vital role. METHODS: A total of 63 Sprague-Dawley female rats were divided into two groups, 39 for physiological examination and 24 for molecular analysis. Surgical induction of ectopic endometriosis (ENDO, n=27), surgical sham treatment (n=18), and treatment for endometriosis by GnRH analog (ENDO-G) (n=18) were performed. Bladder function was investigated by cystometry (for TRPV1 in the sham [n=6] and ENDO [n=9] groups and for TRPA1 in the sham [n=6], ENDO [n=9], and ENDO+G [n=9] groups), and TRPV1 and TRPA1 mRNA expressions were measured using real-time qPCR in the bladder and dorsal root ganglia (DRGs). RESULTS: On cystometry, the relative intercontraction interval (ICI) after/before resiniferatoxin (RTx; TRPV1 activator) infusion to the bladder showed no significant difference between the two groups, whereas relative ICI after/before allyl isothiocyanate (AITC; TRPA1 activator) infusion was significantly lower in the ENDO group than in the sham group. TRPA1 mRNA expression in the bladder and L5 DRG was considerably higher in the ENDO group than in the sham group on real-time qPCR. TRPA1 mRNA hyperexpression and bladder hypersensitivity after AITC infusion were reduced in the ENDO-G group. CONCLUSIONS: Bladder cross-sensitization in ENDO rats occurs in association with hyperexpression of TRPA1 at both the DRG and the bladder mucosa. This can be understood by the "cross-sensitization of endometriosis to bladder" theory explaining overlapping symptoms among BPS/IC and ectopic endometriosis.

Low-energy shock wave therapy ameliorates ischemic-induced overactive bladder in a rat model.

This study was to evaluate whether Low-energy shock wave therapy (LESW) improves ischemic-induced overactive bladder in rats and investigate its therapeutic mechanisms. Sixteen-week-old male Sprague-Dawley rats were divided into three groups: arterial injury (AI), AI with LESW (AI-SW), and control groups. LESW was irradiated in AI-SW during 20-23 weeks of age. At 24 weeks of age, conscious cystometry was performed (each n = 8). The voiding interval was shortened in AI (mean ± SEM: 5.1 ± 0.8 min) than in control (17.3 ± 3.0 min), whereas significant improvements were observed in AI-SW (14.9 ± 3.3 min). The bladder blood flow was significantly increased in AI-SW than in AI. Microarray analysis revealed higher gene expression of soluble guanylate cyclase (sGC) α1 and ß1 in the bladder of AI-SW compared to AI. Protein expression of sGCα1 and sGCß1 was higher in AI-SW and control groups than in AI. Cyclic guanosine monophosphate (cGMP) was elevated in AI-SW. As an early genetic response, vascular endothelial growth factor and CD31 were highly expressed 24 h after the first LESW. Suburothelial thinning observed in AI was restored in AI-SW. Activation of sGC-cGMP may play a therapeutic role of LESW in the functional recovery of the bladder.

Minimal residual membranous urethral length and membranous urethral length predict poor recovery from incontinence after robot-assisted radical prostatectomy and after open radical prostatectomy.

OBJECTIVES: To investigate how much minimal residual membranous urethral length (mRUL) and maximal urethral length (MUL) measured on MRI preoperatively affect postoperative urinary incontinence (PUI) and recovery in robot-assisted radical prostatectomy (RARP) and open radical prostatectomy (ORP). METHODS: The subjects were 190 and 110 patients undergoing RARP and ORP, respectively, in our institution. Patients underwent preoperative MRI for prostate cancer evaluation and completed the quality of life questionnaire of the Expanded Prostate Cancer Index Composite instrument before and 1, 3, 6, and 12 months after surgery. The parameters of mRUL and MUL were measured on MRI and analyzed along with other parameters including age, body mass index, and nerve sparing. RESULTS: The median mRUL and MUL were 7.81 and 14.27 mm in the RARP group and 7.15 and 13.57 mm in the ORP group, respectively. Recovery rates from PUI were similar in the two groups. Multivariate analyses showed that mRUL was a predictor of baseline continence, whereas shorter MUL was a predictor of poor recovery from PUI. Patients with both shorter mRUL and MUL had significantly worse recoveries from PUI after RARP and ORP than patients with longer mRUL and MUL. CONCLUSIONS: Minimal residual membranous urethral length contributes to urethral function as basal urinary continence, whereas MUL represents the potential of recovery from PUI in RARP and ORP. The MUL measured by preoperative MRI can predict poor recovery from PUI after radical prostatectomy and combined evaluation of MUL and mRUL support to anticipate poor recovery of PUI.

Severe Inflammatory Idiopathic Multicentric Castleman's Disease Coexisting with Advanced Renal Cancer: A Case Report.

The present case study was conducted on a 74-year-old man who visited our department due to a left renal and retroperitoneal tumor on computed tomography (CT). The patient was diagnosed with left renal cancer lymph node metastasis and was hospitalized a few weeks prior to surgery due to fever, malaise, and severe appetite loss. Biochemical laboratory findings at admission showed markedly high levels of inflammation. The cause of high inflammatory response was paraneoplastic syndrome. Tumor resection was considered necessary, and left nephrectomy and lymphadenectomy were performed; however, it did not improve the inflammatory response. After operation, positron emission tomography-CT revealed hyperaccumulation of 18F-fluorodeoxyglucose in the bone marrow throughout the body. Pathological examination of the resected specimen and bone marrow aspiration revealed the coexistence of idiopathic multicentric Castleman disease (CD) and renal cancer. Prednisolone and tocilizumab were administered for idiopathic multicentric CD and a tyrosine kinase inhibitor for renal cancer; however, they had poor therapeutic effect, and the patient died. CD is characterized by systemic symptoms due to the overproduction of interleukin-6. Treatment for idiopathic multicentric CD involves steroid and anti-interleukin-6 therapy. The diagnostic criteria for CD require the exclusion of malignant tumors although there are some cases in which CD and malignant tumors coexist. The prognosis for CD is relatively good; however, as in this case, the prognosis of CD coexisting with uncontrollable renal cancer is insufficient due to poor improvement in the inflammatory response.

Deliberation on Deferred Cytoreductive Nephrectomy and Postoperative Treatment for Advanced Renal Cell Carcinoma: A Case Report.

In a rare case, free from systemic therapy, deferred cytoreductive nephrectomy was implemented in treating an advanced renal cell carcinoma with liver, lung, and splenic colon metastases. A 59-year-old man diagnosed with advanced renal cell carcinoma underwent deferred cytoreductive nephrectomy due to a partial response to systemic treatment after a period of 1 year. After the surgery, no additional treatment was implemented. Furthermore, after 10 months, the patient had no recurrence of renal cell carcinoma. Through a review of this case and deferred cases in the current literature, we could emphasize the importance of image evaluation and pathological findings as an indication for surgery and subsequent treatment options. However, there is room for debate with regards to the indications for deferred cytoreductive nephrectomy as well as a therapeutic strategy after the surgery. This report discusses the significance of deferred cytoreductive nephrectomy in terms of prognosis and quality-of-life improvement in advanced renal cancer.

Combination Therapy of Pembrolizumab plus Axitinib for a Patient on Hemodialysis with Metastatic Renal Cell Carcinoma: A Case Report.

Here, we discuss the safety and management of adverse events associated with pembrolizumab plus axitinib combination therapy for metastatic renal cell carcinoma in patients on hemodialysis. A 76-year-old man was diagnosed with cT3aN0M0 renal cell carcinoma due to gross hematuria. Stereoscopic radiotherapy for metastatic lesions of the ipsilateral kidney was performed 9 years after right laparoscopic radical nephrectomy. Soon after, the patient started to receive hemodialysis due to end-stage renal disease. Further stereoscopic radiotherapy was needed for metastasis of the ipsilateral kidney and lung. Fifteen years after diagnosis, systemic therapy was necessary to control new metastases, such as in the right scapular bone. We selected pembrolizumab plus axitinib combination therapy as the first-line systemic therapy for any risk as defined by the International Metastatic RCC Database Consortium. Although we needed to pay attention to the adverse events unique to hemodialysis, he underwent this combination therapy without any difficulty for 6 months. Here, we report the practice of combination therapy in patients on hemodialysis in light of the literature.

Impact of cancer therapy on post-treatment ejaculation disorder and sexual life in testicular cancer survivors.

OBJECTIVE: To evaluate the impact of cancer therapy on post-treatment ejaculation in patients with testicular cancer. METHODS: A total of 74 testicular cancer survivors provided completed International Index of Erectile Function-15 questionnaires before and after treatment between 2010 and 2017. Sexual function, particularly ejaculatory function, was evaluated before and after treatment. In this study, patients who answered "1 = almost never/never" or "2 = a few times" for questionnaire number 9 (ejaculation frequency) were defined as having "ejaculation disorder." RESULTS: Of 74 testicular cancer survivors, 50 (68%) had no ejaculation disorders before treatment. Four (44%) of nine survivors, who received chemotherapy and retroperitoneal lymph node dissection, developed ejaculation disorders after treatment. On multivariate analysis, retroperitoneal lymph node dissection was a significant predictor of post-treatment ejaculation disorder (P = 0.042). Of 60 survivors with evaluable ejaculation function after treatment, 24 (40%) did not attempt sexual intercourse, and multivariate analysis showed ejaculation disorder had a significant negative impact on having sexual intercourse (P = 0.035). Furthermore, the mean International Index of Erectile Function-15 scores in the groups with and without ejaculation disorders after treatment were 24.0 and 51.9, respectively (P < 0.001). CONCLUSION: Ejaculation disorders occur at high rate after retroperitoneal lymph node dissection. Many testicular cancer survivors reporting no sexual intercourse have ejaculation disorders, suggesting an adverse impact on sexual life. Urologists should provide proper counselling regarding the risk of ejaculation disorder and its possible impact on sexual life.

High luteinizing hormone weakens urinary continence mechanisms in association with prostaglandin E2 elevation in a postmenopausal rat model.

AIMS: To explore the role of luteinizing hormone (LH) in the urinary continence mechanism, urethral function was investigated using a postmenopausal rat model with high serum LH concentrations and the postmenopausal rat model given a gonadotropin releasing hormone (GnRH) antagonist to lower LH concentrations. METHODS: Adult female rats were divided into: 1) sham group; 2) ovariectomy group (OVX) with removal of bilateral ovaries; 3) OVX and GnRH-antagonist administered group (OVX + G); and 4) sham and GnRH-antagonist administered group (Sham + G). Urethral function was evaluated by the sneeze-induced urethral continence reflex experiment, and serum LH and prostaglandin E2 (PGE2) concentrations were measured. RESULTS: In the sneeze-induced urethral continence reflex experiment, urethral baseline pressure (UBP) and the amplitude of the urethral response during sneezing (A-URS) were measured. The UBP was significantly decreased in the OVX group than in the other groups. A-URS was significantly lower in the OVX group than in the Sham group, but with no significant difference compared with the OVX + G group. Lowering the serum LH by a GnRH-antagonist improved UBP to the same level as in the Sham group. The serum PGE2 concentration was significantly higher in the OVX group than in the other groups. CONCLUSIONS: The results suggested that the increased serum LH concentration in the OVX rat model worsened the continence mechanism. This mechanism is probably associated with an increased PGE2 concentration, because PGE2 caused urethral smooth muscle relaxation. A GnRH-antagonist might improve urinary incontinence by decreasing the serum LH and PGE2 concentrations.

Estimated Minimal Residual Membranous Urethral Length on Preoperative Magnetic Resonance Imaging Can Be a New Predictor for Continence After Radical Prostatectomy.

OBJECTIVE: To identify a parameter predicting postoperative recovery of urinary continence after radical prostatectomy, associations between parameters on preoperative magnetic resonance imaging (MRI) and postoperative continence status were investigated. METHODS: This prospective study enrolled 113 patients with localized prostate cancer who underwent MRI before radical prostatectomy. Continence was evaluated using the Expanded Prostate Index Composite instrument before surgery and at 1, 3, 6, 12, 18, 24, and 36 months postoperatively. We developed a novel parameter, minimal residual membranous urethral length (mRUL), defined as the distance between the lower margins of the puboperinealis and bulbospongiosus muscles in a direction parallel with the urethra on preoperative MRI, which is supposed to represent the minimal intact residual part of the membranous urethra during RP. Thicknesses of the levator ani and periurethral sphincter complex were also estimated on MRI. RESULTS: Continence recovery was significantly faster in patients with longer mRUL (≥6.4 mm) than in patients with shorter mRUL (<6.4 mm; log-rank test, P = .003). Interestingly, incontinence rate before radical prostatectomy was significantly lower in patients with longer mRUL (2.0%) than in those with shorter mRUL (17.5%; P = .008). Multivariate analysis showed that longer mRUL was significantly related to superior continence recovery (hazard ratio, 0.78; P = .005). Thicknesses of the levator ani and periurethral sphincter complex were not associated with continence recovery. CONCLUSION: Preoperative mRUL offers an independent predictor of continence recovery after radical prostatectomy and is also associated with preoperative (baseline) continence status.

Crucial roles of nitric oxide synthases in ß-adrenoceptor-mediated bladder relaxation in mice.

The specific roles of nitric oxide (NO) synthases (NOSs) in bladder smooth muscle remain to be elucidated. We examined the roles of NOSs in ß-adrenoceptor (AR)-mediated bladder relaxation. Male mice (C57BL6) deficient of neuronal NOS [nNOS-knockout (KO)], endothelial NOS (eNOS-KO), neuronal/endothelial NOS (n/eNOS-KO), neuronal/endothelial/inducible NOS (n/e/iNOS-KO), and their controls [wild-type (WT)] were used. Immunohistochemical analysis was performed in the bladder. Then the responses to relaxing agents and the effects of several inhibitors on the relaxing responses were examined in bladder strips precontracted with carbachol. Immunofluorescence staining showed expressions of nNOS and eNOS in the urothelium and smooth muscle of the bladder. Isoproterenol-induced relaxations were significantly reduced in nNOS-KO mice and were further reduced in n/eNOS-KO and n/e/iNOS-KO mice compared with WT mice. The relaxation in n/e/iNOS-KO mice was almost the same as in n/eNOS-KO mice. Inhibition of Ca2+-activated K+ (KCa) channel with charybdotoxin and apamin abolished isoproterenol-induced bladder relaxation in WT mice. Moreover, direct activation of KCa channel with NS1619 caused comparable extent of relaxations among WT, nNOS-KO, and n/eNOS-KO mice. In contrast, NONOate (a NO donor) or hydrogen peroxide (H2O2) (another possible relaxing factor from eNOS) caused minimal relaxations, and catalase (H2O2 scavenger) had no inhibitory effects on isoproterenol-induced relaxations. These results indicate that both nNOS and eNOS are substantially involved in ß-AR-mediated bladder relaxations in a NO- or H2O2-independent manner through activation of KCa channels.

[Upper tract urothelial carcinoma associated with giant hydronephrosis due to ligation of a ureter: a case report].

A 73-year-old woman was referred to our hospital with a complaint of left lumbar backache. Computed tomography (CT) revealed left giant hydronephrosis containing high-density fluid suspected of hemorrhage in the renal pelvis and swelling of cervical and mediastinal lymph nodes. Positron emission tomography (PET)-CT showed a small high uptake lesion in the left kidney parenchyma, and cervical and mediastinal lymph nodes. Percutaneous pelvic puncture yielded discharge of hemorrhagic fluid with negative cytology. Preoperative diagnosis was left giant hydronephrosis due to ligation of a left ureter at uterine myomectomy 43 years ago with renal hemorrhage caused by recent back injury, and cervical and mediastinal lymph node involvement of unknown origin. Because severe lumbar backache persisted, we performed palliative left nephrectomy and biopsy of cervical lymph nodes. The pathological diagnosis was invasive urothelial carcinoma with squamous differentiation and lymph node involvement.

[Successful chemotherapy with a docetaxel regimen for primary signet-ring cell carcinoma of the urinary bladder-a case report].

Primary signet-ring cell carcinoma of the bladder is rare and has a poor prognosis. In addition, there are few successful chemotherapies for it. We report a case of chemotherapy with a docetaxel regimen which was efficacious in a 64-year-old Japanese man suffering from the disease. The onset of bilateral hydronephrosis led to the detection of his bladder tumor, and its pathological diagnosis was signet-ring cell carcinoma(immunohistochemistry showed cytokeratin 7+/20±). He was treated with chemotherapy rather than with surgery because the tumor invaded the abdominal wall and groin. To treat his disease, we performed 2 courses of a chemotherapy regimen comprised of S-1 and cisplatin, but it was not efficacious. We chose docetaxel as a second-line chemotherapy regimen,(60mg/m2, tri-weekly), and a clinical examination including contrast-enhanced CT showed that his disease had successfully responded to the chemotherapy.