Cannabidiol Alleviates Chronic Prostatitis and Chronic Pelvic Pain Syndrome via CB2 Receptor Activation and TRPV1 Desensitization.

PURPOSE: This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1 cells and prostatitis-induced by 17ß-estradiol and dihydrotestosterone in a rat model, focusing on its therapeutic potential for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). MATERIALS AND METHODS: RWPE-1 cells were stratified in vitro into three groups: (1) controls, (2) cells with LPS-induced inflammation, and (3) cells with LPS-induced inflammation and treated with CBD. Enzyme-linked immunosorbent assays and western blots were performed on cellular components and supernatants after administration of CBD. Five groups of six Sprague-Dawley male rats were assigned: (1) control, (2) CP/CPPS, (3) CP/CPPS and treated with 50 mg/kg CBD, (4) CP/CPPS and treated with 100 mg/kg CBD, and (5) CP/CPPS and treated with 150 mg/kg CBD. Prostatitis was induced through administration of 17ß-estradiol and dihydrotestosterone. After four weeks of CBD treatment, a pain index was evaluated, and prostate tissue was collected for subsequent histologic examination and western blot analysis. RESULTS: CBD demonstrated efficacy in vivo for CP/CPPS and in vitro for inflammation. It inhibited the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway by activating the CB2 receptor, reducing expression of interleukin-6, tumor necrosis factor-alpha, and cyclooxygenase-2 (COX2) (p<0.01). CBD exhibited analgesic effects by activating and desensitizing the TRPV1 receptor. CONCLUSIONS: CBD inhibits the TLR4/NF-κB pathway by activating the CB2 receptor, desensitizes the TRPV1 receptor, and decreases the release of COX2. This results in relief of inflammation and pain in patients with CP/CPPS, indicating CBD as a potential treatment for CP/CPPS.

Implication of cystic fluid cytology of renal cell carcinoma on surgical practice.

OBJECTIVES: To evaluate the incidence of positive cystic fluid cytology and its risk factors in cystic renal cell carcinoma (RCC) addressing its implication on the current surgical practice. METHODS: All clinically diagnosed Bosniak III, IV cystic renal masses from March 2019 to August 2022 were studied prospectively. Database of patients' demographics and cystic tumor characteristics were recorded. Partial or radical nephrectomies were performed by either laparoscopic or robotic approach. Cystic fluid was collected right after specimen retrieval in the surgical field and examined by pathologist. Cytology results were compared to the demographic, perioperative variables using univariate and multivariate analysis. RESULTS: A total of 70 patients of histologically confirmed cystic RCC were included. Sixty seven patients underwent radical nephrectomy with laparoscopic or robotic approaches, while 3 patients underwent radical nephrectomy. There was no intraoperative cystic rupture or fluid spillage. Positive cystic fluid cytology findings were identified in 34 (48.6%) patients, while negative cystic fluid cytology were identified in 36 (51.4%) cases. Definite malignant cells were observed in 28 patients while the other six patients showed highly suspicious atypical cells. Histologically, 24 (70.8%) patients were proven clear cell RCC and 25 (73%) showed Fuhrman grade 1 or 2 in final histologic review in positive group. Univariate and multivariate regression analysis between positive and negative cytology groups showed that the presence of the malignant cells in cystic fluid was significantly associated with patients' age (> 55 years) and Bosniak grade of cystic tumor (p < 0.05). CONCLUSIONS: Definite malignant cells in cystic fluid cytology were observed through our study. Additionally, patients' age (> 55 years) and Bosniak grade were the significant risk factors of positive cytology in cystic RCC. Therefore, necessity of meticulous manipulation of cystic renal tumors, despite their clinical features, should not be underemphasized to avoid the least possible tumor cell seeding in case of cystic rupture when operating such high risk of positive cytology.

Duration of diabetes mellitus and risk of kidney and bladder cancer: a longitudinal nationwide cohort study.

Previous studies have suggested that diabetes mellitus (DM) may increase the risk of kidney and bladder cancer; however, little is known about the duration of DM. We aimed to analyze the risk of kidney and bladder cancer according to the duration of DM in a longitudinal nationwide cohort. This study was conducted in a cohort of 9,773,462 participants ≥ 20 years old who underwent a National Health Examination in 2009 and were followed up until December 2017. Cox-proportional hazard models were used to evaluate the risk of kidney and bladder cancer in relation to the duration of DM. During follow-up (mean 7.3 years), kidney and bladder cancer occurred in 11,219 and 13,769 participants, respectively. DM was associated with an increased risk of kidney and bladder cancer (hazard ratio (HR), 95% confidence interval (95% CI); 1.14, 1.09-1.20 and 1.23, 1.17-1.28, respectively). Compared to fasting glucose < 100 mg/dL, impaired fasting glucose (IFG) and longer DM duration were associated with increased risks (HR, 95% CI): IFG (1.05, 1.01-1.10), new-onset DM (1.13, 1.03-1.24), DM < 5 years (1.11, 1.02-1.20), and DM ≥ 5 years (1.25, 1.15-1.36) in kidney cancer; IFG (1.05, 1.01-1.09), new-onset DM (1.10, 1.01-1.19), DM < 5 years (1.26, 1.18-1.35), and DM ≥ 5 years (1.34, 1.26-1.43) in bladder cancer, respectively. Our findings suggest that the subjects with IFG and longer duration of DM had a higher risk for kidney and bladder cancer than those without DM.

Continuous administration of mirabegron has advantages in inhibition of central sensitization compared with short-term treatment cessation in a mouse model of overactive bladder.

AIMS: There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. METHODS: Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, ß-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. RESULTS: OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, the CON group exhibited reduced ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, the CON group showed better improvements in nonvoiding contractions (0.16 ± 0.09 vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder ß3 receptors and CCL2 of L6-S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to the CES group. CONCLUSIONS: Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Retroperitoneoscopic lumbar sympathectomy for the treatment of primary plantar hyperhidrosis.

BACKGROUND: Primary plantar hyperhidrosis (PPH) is an idiopathic disease, characterized by excessive sweating of the feet. It leads to significant disturbance in private and professional daily lifestyle, due to excessive sweating. The aim of this study is to present the safety, efficacy and procedures of retroperitoneoscopic lumbar sympathectomy (RLS) for treatment of PPH. METHODS: RLS was performed 60 times in 30 patients (18 men, 12 women) with PPH in our institution from May 2019 to October 2020. All procedures were carried out by laparoscopy with retroperitoneal approach. Clinical data including patient demographics and perioperative, postoperative outcomes were evaluated. Recurrence of symptoms, and any adverse effects of surgery were evaluated after 7 to 30 days in outpatient clinic, and thereafter every 6 months. RESULTS: Mean age of patients was 33.6 (± standard deviation 10.8) years. Fourteen and fifteen patients were previously treated with medical therapy or endoscopic thoracic sympathectomy (ETS) respectively. Mean preoperative quality of life (QoL) score of patients was 91.8 (VERY BAD), but postoperative 12 months (QoL) score decreased to 29.1 (MUCH BETTER). There was no serious postoperative complication. During the mean 22 months of follow-up period, no compensatory sweating was observed. CONCLUSIONS: RLS can be a safe and effective surgical treatment for severe PPH, especially for the patients with persistent plantar sweating even after conservative management and ETS. RLS also could be offered to surgeons who are familiar with retroperitoneal space anatomy as feasible surgical treatment for PPH.

ROBO1 protein expression is independently associated with biochemical recurrence in prostate cancer patients who underwent radical prostatectomy in Asian patients.

BACKGROUND: The purpose of this study is to investigate the correlation between ROBO1 expression and prostate cancer aggressiveness. METHODS: ROBO1 expression was evaluated in normal prostate epithelial cells (PrEC) and different prostate cancer cell lines by Western blot analysis. The migration and invasion of native and ROBO1 knockdown cells were evaluated using migration chambers and a Matrigel-coated membrane, respectively. Samples from 145 patients who underwent radical prostatectomy between June 2000 and June 2008, were retrieved from the paraffin files for tissue microarray (TMA) with immunohistochemical analysis. Biochemical recurrence (BCR)-free survival curves were estimated using the Kaplan-Meier and Cox regression methods in two groups of patients classified according to the degree of ROBO1 expression (low or high expression). RESULTS: ROBO1 is highly expressed in the prostate cancer cell lines. All ROBO1 knockdown cells (PC3, 22Rv1 and DU 145) showed markedly decreased migration and invasiveness compared to native cells. In 145 patients with radical prostatectomy, the Kaplan-Meier curves and log-rank test for BCR-free survival stratified by ROBO1 expression in organ-confined (pT2) or not (pT3), showed significant differences in 10-year survival between the ROBO1 high and low expression groups (87.2% versus 52.6% in pT2; P=0.047, 51.0% versus 36.9% in pT3; P=0.033). The multivariable-adjusted model showed a markedly increased hazard ratio (HR) in patients with high ROBO1 expression compared to the patients with low ROBO1expression in every model. CONCLUSIONS: ROBO1 may play an important role in the migration and invasion of prostate cancer cells, and was independently associated with BCR.

Incidence of posterolateral and retrorenal colon in supine and prone position in percutaneous nephrolithotomy.

Colon injury is a distressing complication during percutaneous nephrolithotomy (PCNL). Posterolateral colon (PLC) and retrorenal colon (RRC) are known to be the risk factors of colonic injury during PCNL. We evaluated the incidence of PLC and RRC in both supine and prone position of patients who underwent PCNL in our institution, and determined the risk factors of PLC and RRC through a review of computed tomography (CT) scan. To define PLC and RRC, we divided kidney into anterior, anterolateral, posterolateral and retrorenal zone by drawing three parallel lines in the CT scan. Among a total of 102 patients, PLC and RRC were identified in 16 (15.7%) cases in supine, and 25 (24.5%) cases in the prone position. PLC and RRC were most frequently present in the upper and lower pole of the left kidney in prone position compared to supine (p value less than 0.001). Risk factors of PLC and RRC in the prone position were old age (over 68), lower body mass index (BMI), and thinner perirenal fat layer. Therefore, an initial percutaneous puncture in PCNL needs to be carefully accessed to those patients with such high risks of colon injury.

Impact of preoperative factors on recovery of continence after artificial urinary sphincter implantation in postprostatectomy incontinence.

BACKGROUND: The purpose of this study was to determine the influence of preoperative factors on the recovery of continence after artificial urinary sphincter (AUS) implantation in postprostatectomy incontinence. MATERIALS AND METHODS: Seventy-two patients who underwent AUS implantation between April 2006 and March 2020 were analyzed. The clinical features and preoperative urodynamic parameters were correlated with the postoperative continence rate using linear and logistic regression analysis. The recovery of continence was defined by the patient requiring no use of a protective urine pad during the 24 hours. RESULTS: Of the 72 patients, 57 (79.2%) recovered continence (dry group), while 15 (20.8%) were wearing more than 1 pad per day (wet group) on the last follow-up visit. In the clinical characteristics, only the interval between radical prostatectomy and AUS (in months) showed a statistically significant difference (35.4 ± 26.2 in the dry group, 22.7 ± 12.2 in the wet group, p = 0.009). Other preoperative clinical features such as the underlying disease, surgical methods, size of prostate, tumor stage, and radio nor hormonal therapy did not present statistically significant differences.Of the preoperative urodynamic parameters, only the abdominal leak point pressure (ALPP) showed statistical significance when related to surgical outcomes by 88.6 ± 33.6 in the dry group and 66.1 ± 29.6 in wet the group (P = 0.024). The number of patients for whom ALPP was higher than 80 cm H2O was 61.4% in the dry group and 20% in the wet group (95% confidence interval: 1.612-25.11). Other preoperative UDS features including detrusor underactivity, maximum urethral closure pressure, and others were not statistically significant. CONCLUSIONS: The interval between RP and AUS, as well as the preoperative ALPP, can be possible predictive factors for the surgical outcomes of AUS implantation. In addition, an ALPP of >80 cm H2O has a high degree of predictability for success of AUS surgical outcomes in post-RP incontinence.

Distinct mutation profiles between primary bladder cancer and circulating tumor cells warrant the use of circulating tumors cells as cellular resource for mutation follow-up.

BACKGROUND: While circulating tumor cells may serve as minimally invasive cancer markers for bladder cancers, the relationship between primary bladder cancers and circulating tumor cells in terms of somatic mutations is largely unknown. Genome sequencing of bladder tumor and circulating tumor cells is highlighted to identify the somatic mutations of primary bladder cancer. METHODS: Bladder cancer tissue was collected by transurethral resection of the bladder and preserved by snap-freezing. Circulating tumor cells were Isolated from the blood obtained before treatment. We performed whole exome sequencing of 20 matched pairs of primary bladder cancers and circulating tumor cells to identify and compare somatic mutations of these two different genomic resources. RESULTS: We observed that mutation abundances of primary bladder cancers and circulating tumor cells were highly variable. The mutation abundance was not significantly correlated between matched pairs. Of note, the mutation concordance between two resources was only 3-24% across 20 pairs examined, suggesting that the circulating tumor cell genomes of bladder cancer patients might be genetically distinct from primary bladder cancers. A relative enrichment of mutations belonging to APOBEC-related signature and a depletion of C-to-G transversions were observed for primary- and circulating tumor cells specific mutations, respectively, suggesting that distinct mutation forces might have been operative in respective lesions during carcinogenesis. CONCLUSIONS: The observed discrepancy of mutation abundance and low concordance level of mutations between genomes of primary bladder cancers and circulating tumor cells should be taken into account when evaluating clinical utility of circulating tumor cells for treatments and follow-up of bladder cancers. TRIAL REGISTRATION: Patients were selected and registered retrospectively, and medical records were evaluated.

Initial Use of High-Dose Anticholinergics Combined with Alpha-Blockers for Male Lower Urinary Tract Symptoms with Overactive Bladder: A Prospective, Randomized Preliminary Study.

OBJECTIVES: To evaluate the clinical efficacy of initial combined treatment of alpha-blocker plus dose-dependent anticholinergic agent compared to the alpha-blocker monotherapy in benign prostatic hyperplasia patients with overactive bladder. METHODS: Male lower urinary tract symptoms (LUTS) patients with International Prostate Symptom Score (IPSS) of 8 or higher, total overactive bladder Symptom Score (OABSS) of 3 or higher, and 2 points or higher in the OABSS questionnaire number 2 were enrolled. Eligible subjects (total n = 146) were randomly assigned to receive tamsulosin 0.2 mg (Group I, n = 44), tamsulosin 0.2 mg plus solifenacin 5 mg (Group II, n = 55), or tamsulosin 0.2 mg plus solifenacin 10 mg (Group III, n = 47) for 12 weeks. Efficacy and safety assessments for each group were done using detailed questionnaires, and evaluating urinary parameters such as maximal urinary flow rate (Qmax) and postvoid residual volume (PVR) at 4 and 12 weeks. RESULTS: Groups II and III (combined use of tamsulosin and solifenacin) showed significant improvement in storage symptoms compared to group I (tamsulosin monotherapy), as reflected by IPSS storage subscore and OABSS (P < 0.05). Dry mouth developed in four (7%) and eight (17%) cases in group II and III, respectively, so that one (2%) and three (6%) cases dropped out in group II and III, respectively. Two cases (4%) of AUR developed in group III, and one of them was withdrawn (2%) from the study. CONCLUSIONS: Initial combined treatment of tamsulosin plus solifenacin for men with LUTS improves storage symptoms significantly, but dose modification is necessary to prevent adverse events.

Changes in Nocturia and Lower Urinary Tract Symptoms after Radical Prostatectomy.

PURPOSE: The goal of this study was to evaluate changes in nocturia and other lower urinary tract symptoms (LUTS) after laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP). MATERIALS AND METHODS: We reviewed the medical records of 96 patients who underwent LRP or RALP for clinically localized prostate cancer and completed the International Prostate Symptom Score (IPSS) questionnaire, which provided a basis for assessing their symptoms. We also evaluated maximal flow rate and post-void residual urine volume over a follow-up period of at least 24 months. We divided the patients into three groups according to postoperative changes in the frequency of nocturia. RESULTS: Voiding symptoms significantly improved over the course of 24 months in patients who underwent LRP or RALP. However, most patients showed persistent or increased nocturia after LRP or RALP. Moreover, more than one third of the patients (33/96) presented with exacerbated nocturia (1.0±0.9 episodes of preoperative nocturia vs. 3.0±1.3 episodes of postoperative nocturia). Multiple regression analysis showed that preoperative IPSS storage sub-score had negative association with the nocturia after radical prostatectomy (p=0.005). However, patients' age, body mass index, preoperative prostate specific antigen, Gleason score, T-stage, and prostate volume had no association. CONCLUSIONS: The present study showed that nocturia was influenced by a range of factors, including other storage LUTS and the relief of bladder outlet obstruction after radical prostatectomy. Moreover, the preoperative storage symptoms are regarded as an important factor which influences the changes of nocturia after radical prostatectomy.

Synergistic effect of mesenchymal stem cells infected with recombinant adenovirus expressing human BDNF on erectile function in a rat model of cavernous nerve injury.

PURPOSE: To evaluate the combined role of mescenchymal stem cells (MSCs) infected with recombinant adenoviruses expressing human BDNF (rAd/hBDNF) on the erectile dysfunction in rat with cavernous nerve injury. MATERIALS AND METHODS: Rats divided into 4 groups: control group, bilateral cavernous nerve crushing group (BCNC group), BCNC with MSCs group and BCNC with MSCs infected with rAd/hBDNF group. After 4-week, functional assessment was done. PKH26 and BDNF staining of major pelvic ganglion and masson's trichrome staining of corpus cavernosum were performed. Western blot analysis of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) was done in corpus cavernosum. RESULTS: After 4 weeks, BCNC with MSCs and MSCs infected with rAd/hBDNF groups showed significantly well-preserved erectile function compared with BCNC group. Moreover, the erectile function of MSCs infected with rAd/hBDNF group was significantly well-preserved than BCNC with MSCs group. The smooth muscle of corpus cavernosum was significantly preserved in BCNC with MSCs and MSCs infected with rAd/hBDNF groups compared with BCNC group. More preservation of smooth muscle was observed in rats with MSCs infected with rAd/hBDNF than with MSCs alone. Significant increase expression of eNOS and nNOS was noted in rats with MSCs infected with rAd/hBDNF than with MSCs alone. CONCLUSIONS: The erectile function was more preserved after injection with MSCs infected with rAd/hBDNF in rat with ED caused by cavernous nerve injury. Therefore, the use of MSC infected with rAd/hBDNF may have a better treatment effect on ED cause by cavernous nerve injury.