Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex.

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

Robot-assisted radical nephroureterectomy for right renal pelvic tumor post sacrocolpopexy with mesh: A case report.

INTRODUCTION: Robot-assisted nephroureterectomy for upper tract urothelial carcinoma has been increasingly performed as a minimally invasive procedure recently. However, there are concerns regarding its adoption in highly complex cases with dense adhesions. PRESENTATION OF CASE: An 86-year-old woman presented to our hospital with gross hematuria one year after having undergone robot-assisted sacrocolpopexy using a mesh for pelvic organ prolapse. Cystoscopy revealed hematuria from the right ureteral orifice. Computed tomography suggested right hydronephrosis; retrograde pyelography showed a defect in the right renal pelvis with class V urine cytology of the urine from the right kidney. Based on these findings, a right renal pelvic tumor was diagnosed, and robot-assisted nephroureterectomy was performed. The patient was discharged on postoperative day 7 without complications. DISCUSSION: To the best of our knowledge, this is the first case report in which robot-assisted radical nephroureterectomy was performed after robot-assisted sacrocolpopexy with a mesh. Dense tissue adhesions are encountered not only between the bladder and the anterior vaginal wall but also around the right ureter in the pelvis. In this case, dense adhesions were confirmed around the right ureter in the pelvis. CONCLUSION: Robot-assisted nephroureterectomy may be considered an option for minimally invasive surgery in cases with a history of pelvic organ prolapse surgery using mesh.

Hypopituitarism induced by pembrolizumab plus axitinib in the treatment of metastatic renal cell carcinoma: A case report.

Immune checkpoint inhibitor (ICI) therapies have broadened the armamentarium for metastatic renal cell carcinoma (mRCC). As the ICI therapy spreads in the clinical settings, immune-related adverse events are more of a concern for clinicians. The present study reports three cases of mRCC treated with pembrolizumab plus axitinib and diagnosed hypopituitarism based on clinical symptoms and hormonal profile. Acute methylprednisolone infusion therapy was necessary in one case because of severe adrenal hypofunction; however, the clinical symptoms of the other two cases were controlled with oral corticosteroid therapy. To the best of our knowledge, there is no report of pembrolizumab plus axitinib related hypopituitarism in the treatment of mRCC. The present cases suggests that hypopituitarism after pembrolizumab plus axitinib treatment for mRCC can be handled with steroid therapy even after the development of hypopituitarism.

Scrotal epidermoid cysts penetrating the penile corpora cavernosa: Two case reports.

Introduction: Epidermoid cysts are tumors and that rarely occur in intrascrotal extratesticular tissues. It is extremely rare for the tumors to penetrate the penile corpora cavernosa. Case presentation: We encountered a 4-year-old and a 6-year-old boy with intrascrotal tumors that penetrated the penile corpora cavernosa. Both the patients underwent tumor resection. In the former case, some of the tumor within the corpora cavernosa was left behind, while in the latter case, the tumor was completely resected. Pathological examination in both cases confirmed the diagnosis of epidermoid cysts. Conclusion: We should consider the possibility of epidermoid cysts in children presenting with intrascrotal tumors. Moreover, care should be taken when handling the corpora cavernosa during surgery.

Mirabegron for overactive bladder in frail patients 80 years or over (HOKUTO study).

BACKGROUND: We assessed the efficacy and safety of mirabegron, a ß3-adrenoceptor agonist, in older adults (≥ 80 years old) with overactive bladder (OAB). METHODS: OAB patients aged ≥ 80 years were enrolled in this prospective, single-arm observational study. OAB was diagnosed based on the OAB symptom score (OABSS); i.e., a total score of ≥ 3 points and an urgency score of ≥ 2 points. Patients who received 50 mg mirabegron once daily were evaluated at the baseline and at 4, 8, and 12 weeks. The changes from the baseline in the OABSS, International Prostate Symptom Score (IPSS), OAB questionnaire (OAB-q) score, and Vulnerable Elders Survey (VES-13) score were determined. Adverse events, laboratory tests, 12-lead electrocardiography, the QT interval according to Fridericia's formula (QTcF), uroflowmetry, the post-void residual urine volume (PVR), and the Mini-Mental State Examination (MMSE) score were used to assess safety. RESULTS: Forty-three patients (median age: 84 years, range: 80-96 years) were examined. They had high rates of comorbidities and polypharmacy. Mirabegron significantly improved in total score of the OABSS, including urgency and urge incontinence. The total IPSS, IPSS quality-of-life (QOL) index, and OAB-q scores also significantly improved. Mirabegron improved in the VES-13 score. There were no significant changes in laboratory test values, uroflowmetry findings, PVR, the QTcF, or MMSE score. Two patients (4.7%) withdrew from the study after experiencing adverse events. CONCLUSIONS: Mirabegron was well tolerated and significantly improved in OAB symptoms, and QOL in older patients. Trial registration The present clinical study was approved by University of Yamanashi Institutional Review Board prior to study initiation (ID1447) and was retrospectively registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (UMIN000045996) on Nov 6, 2021.

Effects of fatty acid metabolites on nocturia.

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice.

OBJECTIVES: Nocturia is a major problem in geriatric patients. Clock genes regulate circadian bladder function and Piezo type mechanosensitive ion channel component 1 (Piezo1) that senses bladder fullness. We utilized WT and Clock mutant (ClockΔ19/Δ19: nocturia phenotype) mice to determine if the effects of GsMTx4, a Piezo1 inhibitor, is dependent on circadian Piezo1 expression in the bladder. METHODS: We compared voiding behavior in mice after the administration of vehicle, low dose, or high dose of GsMTx4. Intraperitoneal injections (IP) were performed at Zeitgeber time (ZT) 0, lower Piezo1 expression phase (ZT0-IP) and ZT12, higher Piezo1 expression phase (ZT12-IP). Urine volume (Uvol), voiding frequency (VF), and urine volume per void (Uvol/v) were measured using metabolic cages. RESULTS: VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in ClockΔ19/Δ19 mice. VF decreased significantly at ZT0-IP in WT mice after both doses, but only decreased after high dose in ClockΔ19/Δ19 mice. Uvol/v increased in WT mice at ZT0-IP after both doses and at ZT12-IP after high dose. Uvol/v increased in ClockΔ19/Δ19 mice only at ZT0-IP after high dose. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP. CONCLUSIONS: The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level. The maximum effect occurred during sleep phase in WT. These results may lead to new therapeutic strategies against nocturia.

Cine magnetic resonance imaging provides novel predictors of early continence recovery after radical prostatectomy: Assessment of the dynamics of pelvic floor muscles.

AIMS: Postprostatectomy incontinence is a major complication of prostatectomy. Although pelvic floor muscle training can successfully treat postprostatectomy incontinence, evidence for how muscle movement affects continence recovery is lacking. We evaluated dynamic factors of prostatectomy patients using cine magnetic resonance imaging to identify risk factors for postprostatectomy incontinence and reveal the contribution of pelvic floor muscles to continence recovery. METHODS: A total of 128 prostate cancer patients who underwent robot-assisted laparoscopic surgery were enrolled. Cine magnetic resonance imaging was performed preoperatively and 6 months after surgery. Continence was defined as pad-free or use of safety pads. We defined the bladder neck elevation distance during pelvic floor muscle training as the bladder elevation distance. Patients with continence recovery within 1 month comprised the continence group (n = 48); other patients comprised the incontinence group (n = 80). RESULTS: The preoperative bladder elevation distance was significantly longer in the continence group than in the incontinence group (10.4 vs. 8.2 mm; p < .001). The postoperative bladder elevation distance of the continence group tended to be longer (9.9 vs. 8.9 mm; p = .057). Multivariate analysis showed that the preoperative bladder elevation distance significantly contributed to continence recovery (p = .016). Patients with a longer preoperative bladder elevation distance (>8.5 mm) experienced continence recovery significantly faster than patients with a shorter distance (<8.5mm) (p = .038). CONCLUSIONS: Bladder elevation distance, a novel dynamic parameter, was strongly associated with early continence recovery. Cine magnetic resonance imaging can assess a patient's risk of postprostatectomy incontinence and guide pelvic floor muscle training.

Metabolism of fatty acids and bile acids in plasma is associated with overactive bladder in males: potential biomarkers and targets for novel treatments in a metabolomics analysis.

OBJECTIVES: The present study was conducted to identify metabolites using a metabolomics approach and investigate the relationship between these metabolites and urgency as a major symptom of overactive bladder (OAB). PATIENTS AND METHODS: In 47 male participants without any apparent neurological disease, OAB was defined as an urgency score on the International Prostate Symptom Score of 2 and higher (OAB group, n = 26), while patients with a score of 1 or 0 were placed in a control group (n = 21). A comprehensive study on plasma metabolites was conducted, and metabolites were compared between the OAB and control groups. RESULTS: Age was significantly higher in the OAB group, while prostate volume did not differ between the groups. A 24-h bladder diary revealed that nocturnal urine volume, 24-h micturition frequency, nocturnal micturition frequency, and the nocturnal index were significantly higher in the OAB group, whereas maximum voided volume was significantly lower in this group. The metabolomics analysis identified 79 metabolites from the plasma of participants. The multivariate analysis showed that increases in the fatty acids (22:1), erucic acid and palmitoleic acid, and a decrease in cholic acid correlated with incidence of male OAB. A decrease in acylcarnitine (18:2)-3 and an increase in cis-11-eicosenoic acid also appeared to be associated with OAB in males. CONCLUSIONS: OAB in males may occur through the abnormal metabolism of fatty acids and bile acids. Further studies on these pathways will contribute to the detection of new biomarkers and development of potential targets for novel treatments.

[EVALUATING THE RELATIONSHIP BETWEEN LOWER URINARY TRACT SYMPTOMS AND ENDOTHELIAL FUNCTION USING FLOW-MEDIATED DILATION, AND THE EFFECTS OF TADALAFIL].

(Objective) Recently, lower urinary tract symptoms (LUTS) were reported to be associated with endothelial dysfunction. Endothelial function is non-invasively measured by flow-mediated dilation (FMD). As tadalafil has the potential to improve atherosclerosis, we evaluated the relationship between LUTS and endothelial function using FMD, and the effects of tadalafil. (Patients and methods) We conducted FMD examinations for a total of 122 males, and analyzed its association with IPSS, OABSS, and cardiovascular risks. Furthermore, 21 BPH patients received 5 mg of tadalafil per day for one year. We defined the Low FMD group as FMD < 3.9% and the Control group as other values, and compared the effects of tadalafil between groups. (Results) In the 122 male patients, FMD was negatively correlated with nocturia and OABSS. Patients with hypertension or coronary artery disease had a lower FMD than those without.In the tadalafil administration study, the Low FMD group achieved greater improvement of IPSS, OABSS and FMD than the Control group. (Conclusion) FMD examination revealed that endothelial dysfunction is closely associated with LUTS in males, and that tadalafil is effective for patients with endothelial dysfunction.

Metabolomic Analysis of Overactive Bladder in Male Patients: Identification of Potential Metabolite Biomarkers.

OBJECTIVES: To identify metabolites that are associated with an overactive bladder (OAB) using metabolomics. MATERIALS AND METHODS: A total of 58 male patients without apparent neurologic disease completed 24-hour bladder diaries of their micturition behavior and International Prostate Symptom Score (IPSS) for the assessment of micturition behavior and lower urinary tract symptoms. Urgency was defined as an IPSS urgency score of ≥2 (OAB group), and patients with IPSS urgency scores of ≤1 belonged to the control group. A comprehensive study of plasma metabolites was also conducted using capillary electrophoresis time-of-flight mass spectrometry. Metabolite levels were compared between the control and OAB groups using the Mann-Whitney U test. Potential metabolite biomarkers were selected using multivariate logistic regression analysis. RESULTS: Of the 58 subjects, the control and OAB groups consisted of 32 and 26 male patients, respectively. Nocturnal urinary volume, 24-hour micturition frequency, nocturnal micturition frequency, and the nocturia index were significantly higher in the OAB group. Metabolomic analysis revealed 60 metabolites in the subjects' plasma. The levels of 11 metabolites differed between the control and OAB groups. Multivariate analysis showed that an increased glutamate level and reduced arginine, glutamine, and inosine monophosphate levels are significantly associated with OAB in male patients. Reduced levels of asparagine and hydroxyproline could also be associated with OAB. CONCLUSIONS: Urgency is associated with abnormal metabolism. Analyses of amino acid profiles might aid the search for new treatment targets for OAB.

Metabolomics Approach to Male Lower Urinary Tract Symptoms: Identification of Possible Biomarkers and Potential Targets for New Treatments.

PURPOSE: We identified metabolites using a metabolomics approach and investigated the association between these metabolites and lower urinary tract symptoms. MATERIALS AND METHODS: We used a 24-hour bladder diary and I-PSS (International Prostate Symptom Score) to assess micturition behavior and lower urinary tract symptoms in 58 male patients without apparent neurological disease. Lower urinary tract symptoms were defined as a total I-PSS score of 8 or greater. Patients with a score of 7 or less were placed in the control group. A comprehensive study of plasma metabolites was also performed by capillary electrophoresis time-of-flight mass spectrometry. Metabolites were compared between the lower urinary tract symptoms and control groups using the Mann-Whitney U test. Biomarkers of male lower urinary tract symptoms from the metabolites were analyzed using multivariable logistic regression analysis to determine the OR. RESULTS: Of the 58 men 32 were in the lower urinary tract symptoms group and the remaining 26 were in the control group. The 24-hour bladder diary showed that nocturnal urine volume, 24-hour micturition frequency, nocturnal micturition frequency and the nocturia index were significantly higher in the lower urinary tract symptoms group. Metabolomics analysis identified 60 metabolites from patient plasma. Multivariate analysis revealed that increased glutamate and decreased arginine, asparagine and inosine monophosphate were significantly associated with lower urinary tract symptoms in males. Decreases in citrulline and glutamine could also be associated with male lower urinary tract symptoms. CONCLUSIONS: Male lower urinary tract symptoms may develop due to abnormal metabolic processes in some pathways. Potential new treatments for lower urinary tract symptoms can be developed by identifying changes in the amino acid profiles.

Development of novel and non-invasive diagnostic markers for lower urinary tract symptoms using urothelial cells in voided urine.

OBJECTIVES: We evaluated the association between lower urinary tract symptoms (LUTS) and the expression of connexin (Cx) and transient receptor potential (TRP) channel on urothelial cells non-invasively collected from voided urine in humans. METHODS: A total of 55 patients (36 males and 19 females, median age: 71 years old), who were followed up at University of Yamanashi Hospital, were enrolled in the present study. Urothelial cells were collected from voided urine of patients, and the mRNA expression of each subtype of Cxs and TRP channels was measured using quantitive real-time reverse transcription polymerase chain reaction. We then analyzed the correlation between the expression of Cxs and TRP channels and symptom scores in International Prostate Symptom Scoreand Overactive Bladder Symptom Score, in addition to Interstitial Cystitis Symptom Index (ICSI) from only interstitial cystitis (IC) patients. RESULTS: Non-adjusted statistical procedure using Spearman's rank-correlation showed that there were significant correlations between the following expressions and symptom scores; (positive correlations) Cx26 versus urgency score, Cx40 versus nocturia, TRPM2 versus intermittency, TRPV1 versus urge incontinence, (negative correlation) Cx40 versus intermittency, TRPM7 versus pollakisuria. However, a multiple comparison adjustment using Bonferroni correction showed that only Cx40 had a trend of correlation with nocturia in ICSI. CONCLUSIONS: The expressions of Cxs and TRP channels on urothelial cells in voided urine could be related to LUTS. Further analysis of urothelial cells in voided urine has the potential to reveal the mechanism of the LUTS and develop new markers with non-invasive methods.

Successful Radiotherapy for Advanced Small Cell Carcinoma of the Prostate with Syndrome of Inappropriate Secretion of Antidiuretic Hormone.

Small cell carcinoma of the prostate (SCCP) is rare in clinical practice. It is often accompanied with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present a case of SCCP with SIADH that was successfully treated with radiotherapy in the metastatic lymphnodes and prostate. The patient was an 81-year-old male with a castrate-resistant prostate cancer (CRPC) with invaded rectum and multiple metastases of pelvic lymphnodes. Hyponatremia was present. After radiotherapy, serum sodium increased and neuron-specific enolase (NSE) decreased. To our knowledge, this is the first case of SCCP with SIADH treated with radiotherapy to improve hyponatremia.

Tuberculous Granuloma in the Scrotal Skin After Intravesical Bacillus Calmette-Guerin Therapy for Bladder Cancer: A Case Report.

Rare cases of tuberculous urinary tract or genital infection caused by intravesical Intravesical Bacillus Calmette-Guerin (BCG) instillation therapy have been reported. We encountered a patient with tuberculous granuloma in the scrotal skin after intravesical BCG therapy for bladder cancer. There was evidence of infection in the scrotal skin, but not in the epididymis. To the best of our knowledge, this is the first report of tuberculous granuloma in the scrotal skin without epididymitis after intravesical BCG therapy. In our case, lower urinary tract symptoms such as the terminal dribbling of urine appear to support the theory of direct BCG inoculation.

Persistent Urinary Incontinence After Nephrectomy: A Case of Inverted-Y Ureteral Duplication with Ectopic Ureteral Insertion into the Vagina.

Inverted-Y ureteral duplication is one of the rarest anomalies of ureteral branching. We encountered a 20-year-old female patient with persistent incontinence even after nephrectomy for ectopic ureteral insertion into the vagina. She had inverted-Y ureteral duplication between the bladder and vagina, and urine was being transported from the bladder to the vagina. To the best of our knowledge, this is a rare case of inverted-Y ureteral duplication with ectopic ureteral insertion into the vagina as well as the ureter into the bladder, which became apparent due to persistent urinary incontinence even after nephrectomy.

Complete Laparoscopic Nephroureterectomy for the Upper Urinary Tract Urothelial Carcinoma in a Female Patient with Severe Senile Kyphosis: An Initial Case Report.

Kyphosis is usually described as the deformity of the spine that results in an abnormally round back. Patients with kyphosis form a challenging group to laparoscopic surgeons because of difficulties in positioning and abdominal approach. The narrow abdomen causes difficulty with trocar insertion and some operative procedures. Here we report the transperitoneal complete laparoscopic nephroureterectomy in a case of kyphosis. An 81-year-old woman underwent this operation for urothelial carcinoma of the upper urinary tract. We took best care of the positioning and the trocar insertion; we could have accomplished utilizing four ports at semilateral position without any troubles and complications. This procedure is safe and feasible, and not thought to be a contraindication for the patients with senile kyphosis.

Arterial and vena caval resections combined with pancreaticoduodenectomy in highly selected patients with periampullary malignancies.

BACKGROUND/AIMS: To obtain a margin-negative resection and increase the indication for resection of periampullary malignancies, pancreaticoduodenectomy with a SM-PVR (superior mesenterico-portal vein resection) has been performed. However, an arterial resection, other vascular resections except SM-PVR (e.g., an inferior vena caval resection), or a metastatic tumor resection combined with pancreaticoduodenectomy has yet to be fully elucidated because of the high risk of postoperative complications and extremely poor long-term survival in patients undergoing these exceptional procedures. The present report focused on highly selected patients undergoing an arterial resection or a vena caval resection associated with pancreaticoduodenectomy. METHODOLOGY: Besides 31 patients with periampullary tumors undergoing pancreaticoduodenectomy associated with SM-PVR in our department, a group of 4 patients underwent arterial resections and another patient underwent pancreaticoduodenectomy combined with a resection of liver metastasis together with an inferior vena caval resection. These five patients were reported in the present study. RESULTS: A 27 year-old-woman presented pancreatic ductal adenocarcinoma of the pancreatic head and a liver metastasis in which involvements of the superior mesenterico-portal vein and the inferior vena cava were shown. Pancreaticoduodenectomy was performed with SM-PVR associated with a left hemihepatectomy combined with a segment 1 resection and an inferior vena caval resection. The patient did not present severe postoperative complications and experienced a good quality of life during 16 months after surgery. Four other patients underwent arterial resections. These arterial resections were performed only when a margin-negative resection was feasible. The superior mesenteric artery was resected and reconstructed with a Goretex graft in one patient. The right hepatic artery was resected and reconstructed with a saphenous graft in two patients. The other patient underwent a resection of the common hepatic artery and reconstruction was performed with the splenic artery. Three of the four patients presented postoperative complications but were conservatively treated. Two patients are still alive 25 months and 8 months after surgery. One patient died of sepsis 5 months after surgery, and the other died of cancer progression 19 months after surgery. CONCLUSIONS: The indication for retropancreatic arterial resection associated with pancreaticoduodenectomy should be carefully evaluated only when a margin-negative resection can be achieved. An appropriate bypass method of arterial reconstruction should be selected because a direct end-to-end anastomosis is not always feasible. Hepatectomy for metastases of pancreatic ductal carcinoma should be also regarded as an exceptional procedure.