Effect of perioperative tamsulosin on successful ureteral access sheath placement and stent-related symptom relief: A double-blinded, randomized, placebo-controlled study.

PURPOSE: This study investigated the effect of administering tamsulosin before surgery on the successful insertion of a 12/14 French (F) ureteral access sheath (UAS) during the procedure, as well as the impact of preoperative and postoperative tamsulosin use on symptoms related to the ureteral stent. MATERIALS AND METHODS: This study was a randomized, single-center, double-blinded, placebo-controlled trial involving 200 patients who underwent unilateral retrograde intrarenal surgery. Patients received either tamsulosin (0.4 mg) or placebo 1 week before surgery until stent removal. Patients were randomly assigned to one of four groups. Group 1 received tamsulosin throughout the study period. Group 2 received tamsulosin before surgery and placebo after surgery. Group 3 received placebo before surgery and tamsulosin after surgery. Group 4 received placebo before and after surgery. The USSQ (Ureteral Stent Symptom Questionnaire) was completed between postoperative days 7 and 14 immediately before stent removal. RESULTS: A total of 160 patients were included in this analysis. Their mean age was 55.0±11.0 years, and 48 patients (30.0%) were female. In the group that received preoperative tamsulosin, the success rate of 12/14F UAS deployment was significantly higher than that of the preoperative placebo group (88.0 vs. 75.3%, p=0.038). Preoperative and postoperative tamsulosin did not significantly alleviate symptoms related to the ureteral stent. CONCLUSIONS: Our results revealed that preoperative administration of tamsulosin improved the success of larger-sized UAS, whereas preoperative and postoperative tamsulosin use did not significantly alleviate symptoms related to ureteral stents.

Stem cell therapy for interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with limited treatment options. Current multidisciplinary approach targeting bladder inflammation and urothelial dysfunction has limited durable effect that major surgery is ultimately required for both Hunner and non-Hunner type IC. Various investigational attempts are underway to avoid such operations and preserve the urinary bladder. Stem cell therapy is a fascinating option for treating chronic illnesses. Stem cells can self-renew, restore damaged tissue, and have paracrine effects. The therapeutic efficacy and safety of stem cell therapy have been demonstrated in numerous preclinical models, primarily chemically induced cystitis rat models. Only one clinical trial (phase 1 study) has investigated the safety of human embryonic stem cell-derived mesenchymal stem cells in three Hunner-type IC patients. Under general anesthesia, participants underwent cystoscopic submucosal stem cell injection (2.0 × 107 stem cells/5 mL). No safety issues were reported up to 12 months of follow-up and long-term follow-up (up to 3 years). Although there were variations in therapeutic response, all patients reported significant improvement in pain at 1 month postoperatively. One patient underwent fulguration of the Hunner lesion after the trial, but others reported an overall improvement in pain. The analysis on phase 1/2a trial which had several modifications in protocol is currently ongoing. Despite several limitations that need to be overcome, stem cell therapy could be a potential therapeutic option for treating IC/BPS. Clinical outcome on phase 1/2a trial is important and might provide more insight into the clinical application of stem cell therapy for IC/BPS.

Assessment of the Therapeutic Effectiveness of Glutathione-Enhanced Mesenchymal Stem Cells in Rat Models of Chronic Bladder Ischemia-Induced Overactive Bladder and Detrusor Underactivity.

Overactive bladder (OAB) and detrusor underactivity (DUA) are representative voiding dysfunctions with a chronic nature and limited treatment modalities, and are ideal targets for stem cell therapy. In the present study, we investigated the therapeutic efficacy of human mesenchymal stem cells (MSCs) with a high antioxidant capacity generated by the Primed Fresh OCT4 (PFO) procedure in chronic bladder ischemia (CBI)-induced OAB and DUA rat models. Sixteen-week-old male Sprague-Dawley rats were divided into three groups (sham, OAB or DUA, and stem cell groups; n=10, respectively). CBI was induced by bilateral iliac arterial injury (OAB, 10 times; DUA, 30 times) followed by a 1.25% cholesterol diet for 8 weeks. Seven weeks after injury, rats in the stem cell and other groups were injected with 1×106 PFO-MSCs and phosphate buffer, respectively. One week later, bladder function was analyzed by awake cystometry and bladders were harvested for histological analysis. CBI with a high-fat diet resulted in atrophy of smooth muscle and increased collagen deposits correlating with reduced detrusor contractility in both rat models. Arterial injury 10 and 30 times induced OAB (increased number of non-voiding contractions and shortened micturition interval) and DUA (prolonged micturition interval and increased residual volume), respectively. Injection of PFO-MSCs with the enhanced glutathione dynamics reversed both functional and histological changes; it restored the contractility, micturition interval, residual volume, and muscle layer, with reduced fibrosis. CBI followed by a high-fat diet with varying degrees of arterial injury induced OAB and DUA in rats. In addition, PFO-MSCs alleviated functional and histological changes in both rat models.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis.

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.

The usefulness and ergonomics of a new robotic system for flexible ureteroscopy and laser lithotripsy for treating renal stones.

PURPOSE: To investigate the usefulness and ergonomics of a newly developed robotic system for flexible ureteroscopy (easyUretero). MATERIALS AND METHODS: During in vitro testing, six participants performed renal stone removal four times in an artificial kidney-ureter-bladder model. Each participant manipulated a single-use digital flexible ureteroscope (LithoVue) with their hands and the robotic system, sequentially. We compared the task completion times of each participant. The ergonomics of and operational satisfaction with each procedure were assessed by questionnaires. In vivo tests evaluated the operability and safety of the robotic system in two live female pigs. We checked that all the steps of flexible lithotomy for renal stones could be completed individually. RESULTS: The task completion time with the robotic system during in vitro testing was significantly longer than with manual ureteroscopy regardless of the operator's competence level (expert professors: 282.6±92.4 seconds vs. 73.6±43.3 seconds, p<0.001; fellows: 247.5±57.7 seconds vs. 95.8±43.7 seconds, p<0.001; residents: 281.3±111.0 seconds vs. 188.6±138.6 seconds, p<0.001). The residents took more time to remove the upper and mid caliceal stones with the robotic system. The ergonomic evaluation was better for the robotic system, but operational satisfaction was lower, and there was no statistical difference among the groups. In vivo tests showed that all the steps of robotic flexible ureteroscopy could be completed without difficulty. No safety issues were encountered during the procedure. CONCLUSIONS: The robotic system (easyUretero) was ergonomic and safe for flexible ureteroscopy and laser lithotripsy for renal stones.

Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study.

There are still no definite treatment modalities for interstitial cystitis (IC). Meanwhile, stem cell therapy is rising as potential alternative for various chronic diseases. This study aimed to investigate the safety of the clinical-grade mesenchymal stem cells (MSCs) derived from human embryonic stem cells (hESCs), code name MR-MC-01 (SNU42-MMSCs), in IC patients. Three female IC patients with (1) symptom duration >6 months, (2) visual pain analog scale (VAS) ≥4, and (3) one or two Hunner lesions <2 cm in-office cystoscopy within 1 month were included. Under general anesthesia, participants received cystoscopic submucosal injection of SNU42-MMSCs (2.0 × 107/5 mL) at the center or margin of Hunner lesions and other parts of the bladder wall except trigone with each injection volume of 1 mL. Follow-up was 1, 3, 6, 9, and 12 months postoperatively. Patients underwent scheduled follow-ups, and symptoms were evaluated with validated questionnaires at each visit. No SNU42-MMSCs-related adverse events including immune reaction and abnormalities on laboratory tests and image examinations were reported up to 12-month follow-up. VAS pain was temporarily improved in all subjects. No de novo Hunner lesions were observed and one lesion of the first subject was not identifiable on 12-month cystoscopy. This study reports the first clinical application of transurethral hESC-derived MSC injection in three patients with IC. hESC-based therapeutics was safe and proved to have potential therapeutic efficacy in IC patients. Stem cell therapy could be a potential therapeutic option for treating IC.

Effects of different types of hysterectomies on postoperative urodynamics and lower urinary tract symptoms.

PURPOSE: To evaluate the effects of different hysterectomies-simple hysterectomy (SH) and radical hysterectomy (RH) with or without radiation therapy (RT) on urodynamics and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: Among patients who underwent urodynamic study between 2009 and 2019, those with RH history due to cervical cancer and SH for uterine myoma were included. Clinical parameters were compared after adjusting clinically significant baseline variables with multivariate regression. RESULTS: A total of 289 patients (RH-only, n=57; RH+RT, n=72; SH, n=160) were included. Age at hysterectomy, gap between urodynamic study and hysterectomy, body mass index, hypertension and vaginal delivery history were adjusted. Stress urinary incontinence was more likely to occur in SH group (p<0.001), while urgency urinary incontinence was more prevalent in patients with history of RH (odds ratio [OR] 6.4, 95% confidence interval 2.171-18.855; p=0.001). There was no difference in OR of mixed urinary incontinence. Higher proportion of RH patients complained of recurrent urinary tract infection and voiding symptoms requiring intermittent catheterization. On urodynamic study, RH groups had lower maximal flow rate, larger post-void residual, decreased bladder sensation and impaired detrusor contractility (all p<0.001) than SH group. Adjuvant RT resulted in decreased compliance and decrease in volume of the first sense to void. CONCLUSIONS: Predominant LUTS differed among patients after different types of hysterectomy. RH resulted in inefficient bladder emptying, leading to recurrent urinary tract infection and voiding symptoms requiring intermittent catheterization. Adjuvant RT exacerbated bladder compliance and increased bladder sensation.

Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome.

Mesenchymal stem cell (MSC) therapy is a promising treatment for various intractable disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). However, an analysis of fundamental characteristics driving in vivo behaviors of transplanted cells has not been performed, causing debates about rational use and efficacy of MSC therapy. Here, we implemented two-photon intravital imaging and single cell transcriptome analysis to evaluate the in vivo behaviors of engrafted multipotent MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) in an acute IC/BPS animal model. Two-photon imaging analysis was performed to visualize the dynamic association between engrafted M-MSCs and bladder vasculature within live animals until 28 days after transplantation, demonstrating the progressive integration of transplanted M-MSCs into a perivascular-like structure. Single cell transcriptome analysis was performed in highly purified engrafted cells after a dual MACS-FACS sorting procedure and revealed expression changes in various pathways relating to pericyte cell adhesion and cellular stress. Particularly, FOS and cyclin dependent kinase-1 (CDK1) played a key role in modulating the migration, engraftment, and anti-inflammatory functions of M-MSCs, which determined their in vivo therapeutic potency. Collectively, this approach provides an overview of engrafted M-MSC behavior in vivo, which will advance our understanding of MSC therapeutic applications, efficacy, and safety.

A Preclinical Study of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells for Treating Detrusor Underactivity by Chronic Bladder Ischemia.

BACKGROUND: The therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms. METHODS: Sixteen-week-old male Sprague-Dawley rats were divided into five groups (n = 10). The DUA groups underwent 30 bilateral repetitions of endothelial injury to the iliac arteries to induce CBI, while the sham control group underwent a sham operation. All rats used in this study received a 1.25% cholesterol diet for 8 weeks. M-MSCs at a density of 2.5, 5.0, or 10.0 × 105 cells (250 K, 500 K, or 1000 K; K = a thousand) were injected directly into the bladder 7 weeks post-injury, while the sham and DUA group were treated only with vehicle (phosphate buffer solution). One week after M-MSC injection, awake cystometry was performed on the rats. Then, the bladders were harvested, studied in an organ bath, and prepared for histological and gene expression analyses. RESULTS: CBI by iliac artery injury reproduced voiding defects characteristic of DUA with decreased micturition pressure, increased micturition interval, and a larger residual volume. The pathological DUA properties were improved by M-MSC treatment in a dose-dependent manner, with the 1000 K group producing the best efficacy. Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transplanted M-MSCs mainly engrafted as vimentin and NG2 positive pericytes rather than myocytes, leading to increased angiogenesis in the CBI bladder. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transport-related pathways, which were restored by M-MSC therapy. CONCLUSIONS: Single injection of M-MSCs directly into the bladder of a CBI-induced DUA rat model improved voiding profiles and repaired the bladder muscle atrophy in a dose-dependent manner.

Features of Various Bladder Lesions and Their Impact on Clinical Symptoms and Recurrence in Interstitial Cystitis.

PURPOSE: We aimed to investigate the impact of various bladder lesions on the clinical symptoms and recurrence of interstitial cystitis (IC). MATERIALS AND METHODS: Patients with IC who underwent transurethral resection and cauterization for Hunner lesions (HLs) were enrolled. Features of HLs-noninflamed, inflamed, and gradually inflamed-and associated cystoscopic findings, including waterfall bleeding (none, focal or extensive), submucosal hemorrhage, and mucosal streak, were analyzed to investigate their association with preoperative symptoms and recurrence. RESULTS: We included 272 procedures from 141 patients (male:female ratio 37:104) with a mean±SD age of 61.4±10.5 years. Recurrence was observed in 160 procedures after a mean of 15.6 months (range 0.7-91.7); repeat transurethral resection and cauterization was performed in 131 cases. The number of HLs observed at each procedure was variable, and sufficient bladder filling revealed hidden lesions in 10.7% of cases. Waterfall bleeding was frequently accompanied with inflamed/gradually inflamed HLs. Inflammatory HLs were associated with smaller functional bladder capacity and preoperative urgency (p=0.007). Extensive waterfall bleeding was associated with smaller functional bladder capacity (p=0.006). On multivariate analysis, initially inflamed HLs (HR: 1.675, 95% CI: 1.022-2.746, p=0.041) and gradual inflammatory changes in HLs (HR: 1.893, 95% CI: 1.050-3.410, p=0.034) were found to be risk factors for recurrence. CONCLUSIONS: Sufficient bladder filling revealed hidden HLs. The features of HLs were not associated with subjective symptoms; inflamed changes were a predictive factor for IC recurrence, and associated with frequent urgency episodes and smaller bladder capacity.

Therapeutic Efficacy of Human Embryonic Stem Cell-Derived Multipotent Stem/Stromal Cells in Diabetic Detrusor Underactivity: A Preclinical Study.

Mesenchymal stem/stromal cell (MSC) therapy is a promising approach for treatment of as yet incurable detrusor underactivity (DUA), which is characterized by decreased detrusor contraction strength and/or duration, leading to prolonged bladder emptying. In the present study, we demonstrated the therapeutic potential of human embryonic stem cell (ESC)-derived multipotent MSCs (M-MSCs) in a diabetic rat model of DUA. Diabetes mellitus (DM) was induced by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) into 8-week-old female Sprague-Dawley rats. Three weeks later, various doses of M-MSCs (0.25, 0.5, and 1 × 106 cells) or an equivalent volume of PBS were injected into the outer layer of the bladder. Awake cystometry, organ bath, histological, and gene expression analyses were evaluated 1 week (short-term) or 2 and 4 weeks (long-term) after M-MSC transplantation. STZ-induced diabetic rats developed DUA, including phenotypes with significantly longer micturition intervals, increased residual urine amounts and bladder capacity, decreased micturition pressure on awake cystometry, and contractile responses to various stimuli in organ bath studies. Muscle degeneration, mast cell infiltration, fibrosis, and apoptosis were present in the bladders of DM animals. A single local transplantation of M-MSCs ameliorated DUA bladder pathology, including functional changes and histological evaluation, and caused few adverse outcomes. Immunostaining and gene expression analysis revealed that the transplanted M-MSCs supported myogenic restoration primarily by engrafting into bladder tissue via pericytes, and subsequently exerting paracrine effects to prevent apoptotic cell death in bladder tissue. The therapeutic efficacy of M-MSCs was superior to that of human umbilical cord-derived MSCs at the early time point (1 week). However, the difference in efficacy between M-MSCs and human umbilical cord-derived MSCs was statistically insignificant at the later time points (2 and 4 weeks). Collectively, the present study provides the first evidence for improved therapeutic efficacy of a human ESC derivative in a preclinical model of DM-associated DUA.

Analyzing the factors that influence occult metastasis in oral tongue cancer.

OBJECTIVES: We accessed the various clinico-histopathological factors, and their association with occult metastasis (OM) in oral tongue squamous cell carcinoma (OTSCC). MATERIALS AND METHODS: One hundred-nine patients with OTSCC were divided into the elective neck dissection (END) group and the watchful waiting (WW) group. Age, sex, T-stage, depth of invasion and differentiation were evaluated to determine the correlation between clinico-histopathological factors and OM. For immunohistochemical analysis, paraffin-embedded blocks of 41 OTSCC specimens were examined with antibodies (VEGF-c, c-Met, and ROR1). RESULTS: The group with tumor thickness of oral tongue cancer ≥3 mm had higher incidence of OM than those with a thickness of <3 mm. The depth of invasion was statistically correlated with OM (P=0.022). Immunohistochemical analysis showed that high expression of VEGF-c (P=0.043), c-Met (P=0.009), and ROR-1 (P=0.003) were statistically correlated with OM. CONCLUSION: The analysis of these clinico-histopathological and immunohistochemical factors can help to determine neck dissection in clinically negative (cN0) patients.

Current and Future Directions of Stem Cell Therapy for Bladder Dysfunction.

Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue regeneration. Mesenchymal stem cells are multipotent progenitor cells with enhanced proliferation and differentiation capabilities and less tumorigenicity than conventional adult stem cells; these cells are also easier to acquire. Bladder dysfunction is often chronic in nature with limited treatment modalities due to its undetermined pathophysiology. Most treatments focus on symptom alleviation rather than pathognomonic changes repair. The potential of stem cell therapy for bladder dysfunction has been reported in preclinical models for stress urinary incontinence, overactive bladder, detrusor underactivity, and interstitial cystitis/bladder pain syndrome. Despite these findings, however, stem cell therapy is not yet available for clinical use. Only one pilot study on detrusor underactivity and a handful of clinical trials on stress urinary incontinence have reported the effects of stem cell treatment. This limitation may be due to stem cell function loss following ex vivo expansion, poor in vivo engraftment or survival after transplantation, or a lack of understanding of the precise mechanisms of action underlying therapeutic outcomes and in vivo behavior of stem cells administered to target organs. Efficacy comparisons with existing treatment modalities are also needed for the successful clinical application of stem cell therapies. This review describes the current status of stem cell research on treating bladder dysfunction and suggests future directions to facilitate clinical applications of this promising treatment modality, particularly for bladder dysfunction.

Induction of detrusor underactivity by extensive vascular endothelial damages of iliac arteries in a rat model and its pathophysiology in the genetic levels.

We tried to establish a reliable detrusor underactivity (DUA) rat model and to investigate pathophysiology of chronic bladder ischemia (CBI) on voiding behavior and bladder function. Adult male rats were divided into five groups. The arterial injury (AI) groups (AI-10, AI-20, AI-30) underwent vascular endothelial damage (VED) of bilateral iliac arteries (with 10, 20, and 30 bilateral repetitions of injury, respectively) and received a 1.25% cholesterol diet. The sham group underwent sham operation and received the same diet. Controls received a regular diet. After 8 weeks, all rats underwent unanesthetized cystometrogram. Bladder tissues were processed for organ bath investigation, immunohistochemistry staining, and genome-wide gene expression analysis. Awake cystometry analysis showed that frequency of voiding contractions and micturition pressure were lower in the AI-30 group than in sham group (p < 0.01). Contractile responses to various stimuli were lower in AI-20 and AI-30 groups (both p < 0.001). In the AI-20 and AI-30 groups, atherosclerotic occlusion in the iliac arteries, tissue inflammation, fibrosis, denervation, and apoptosis of bladder muscle were prominent compared to the sham. Mechanistically, the expression of purinergic receptor P2X-1 was reduced in the AI-30 group, and the genome-wide gene expression analysis revealed that genes related to IL-17 and HIF-1 signaling pathways including INF-γ receptor-1 and C-X-C motif chemokine ligand-2 were upregulated in the CBI-induced DUA rat model. A rat model of progressive VED successfully induced DUA. Abnormal tissue inflammation, fibrosis, denervation, and bladder muscle tissue apoptosis may be involved in CBI-induced DUA pathophysiology.

De novo or resolved urgency and urgency urinary incontinence after midurethral sling operations: How can we properly counsel our patients?

Purpose: To evaluate de novo and resolved urgency and urgency urinary incontinence (UUI) after midurethral sling operations in patients with stress urinary incontinence (SUI) and mixed urinary incontinence (MUI). Materials and Methods: Patients who underwent midurethral sling operations because of SUI and MUI between January 2012 and December 2016 were reviewed. Patients were divided into three groups (pure SUI, SUI with urgency, and MUI). Patients with MUI were subcategorized as SUI predominant, equivalent, and UUI predominant. Postoperative de novo, persistent or disappearance of urgency or UUI were compared. Results: A total of 334 patients were included: 76 with pure SUI, 78 with SUI with urgency, and 180 with MUI. In the MUI group, 138 patients were SUI predominant, 12 patients were equivalent, and 30 patients were UUI predominant. De novo urgency developed in 5 patients (6.6%) in the pure SUI group. In the SUI with urgency group, 51 patients (65.4%) became urgency-free, and 3 (3.8%) developed de novo UUI. UUI resolved in 135 patients (75.0%): 110 (79.7%) in the SUI-predominant group, 9 (75.0%) in the equivalent group, and 16 (53.3%) in the UUI-predominant group. The patients' preoperative perception of predominant UUI was the predictive factor for persistent UUI in the multivariate analysis (hazard ratio, 5.722; p=0.001). Conclusions: De novo urgency and UUI developed in a relatively small number of patients after a midurethral sling operation. The resolution rate of UUI was significantly low in patients who had previous pelvic surgery or who preoperatively perceived UUI as a more bothersome symptom.

Urodynamic study for distinguishing multiple system atrophy from Parkinson disease.

OBJECTIVE: To evaluate the differences in urodynamic findings between multiple system atrophy (MSA) and Parkinson disease (PD) and to identify the differential diagnostic ability of urodynamic study. METHODS: We reviewed patients with MSA or PD who underwent urodynamic studies between January 2011 and August 2018. Patients with probable MSA and PD determined by movement disorder specialists at our center were included. Patients with alleged MSA or PD from outside hospitals, atypical or secondary parkinsonism, and any history of pelvic operation or radiation therapy were excluded. RESULTS: A total of 219 patients, 107 with MSA (male:female 50:57) and 112 with PD (male:female 57:55), were included. Patients with MSA had shorter disease duration and were referred for urologic evaluation earlier (p < 0.001). Detrusor overactivity and associated urine leakage were prominent in PD (p < 0.001). Patients with MSA showed lower maximal flow rate (4.0 ± 5.8 vs 9.1 ± 8.3 mL/s, p < 0.001) and larger postvoid residual (290.8 ± 196.7 vs 134.0 ± 188.1 mL, p < 0.001) with decreased compliance (44.9% vs 10.7%, p < 0.001) and impaired contractility (24.9 ± 33.8 vs 65.7 ± 51.1, p < 0.001). Postvoid residual from a pressure-flow study had the highest sensitivity and specificity (74.8% and 75.9%), followed by detrusor pressure at maximal uroflow (72.6% and 70.5%), bladder contractility index, and postvoid residual from uroflowmetry (71.0% and 70.5%, respectively). CONCLUSIONS: Patients with MSA showed lower maximal flow rate, larger postvoid residual with decreased compliance, and impaired contractility, whereas patients with PD had higher incidence of detrusor overactivity and associated leakage. For differential diagnosis, postvoid residual from a pressure-flow study provided the best sensitivity and specificity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urodynamic measures can distinguish patients with MSA from those with PD.

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model.

Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 µg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.

Patterns and predictors of Hunner lesion recurrence in patients with interstitial cystitis.

AIMS: To evaluate the patterns and predictive factors associated with Hunner lesions (HLs) recurrence in patients with interstitial cystitis (IC). METHODS: This study was a retrospective analysis of data from patients with IC who underwent transurethral resection and cauterization (TUR-C) of HLs between October 2011 and December 2017. Symptoms were evaluated using the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF), O'Leary-Sant Interstitial Cystitis Symptom Index, and Visual Analogue Scale (VAS). Patients attended follow-up visits every 3 months; cystoscopy was performed immediately in patients with aggravated symptoms. Recurrence was defined as a VAS score greater than or equal to 4 and HLs recurrence on cystoscopy. RESULTS: A total of 91 patients were enrolled (25 male, 66 female): median follow-up was 30.6 months. HLs recurrence occurred in 101 sites (53 patients), 21.8% in the previous TUR-C site, 18.8% de novo, and 59.4% at both previous and de novo sites. The recurrence rate was approximately 12.7%, 40%, and 55.2% at 6, 12, and 18 months, respectively. A higher PUF bother score was the only predictive factor of recurrence (odds ratio: 1.142, 95% confidence interval: 1.016-1.284, P = 0.026), with a cut-off value of 7.5 (sensitivity: 67.9%, specificity: 62.5%). In case of late recurrence (>18 months), there was no predictive factor. CONCLUSIONS: The HLs recurrence pattern was unpredictable, involving both previous TUR-C and de novo areas. More accurately defining the HLs resection margin may lead to better surgical outcomes but this remains to be proven.

Synergistic Effects of N-Acetylcysteine and Mesenchymal Stem Cell in a Lipopolysaccharide-Induced Interstitial Cystitis Rat Model.

The purpose of this study was to reduce the amount of stem cells used in treating preclinical interstitial cystitis (IC model) by investigating the synergistic effects of multipotent mesenchymal stem cells (M-MSCs; human embryonic stem cell-derived) and N-acetylcysteine (NAC). Eight-week-old female Sprague-Dawley rats were divided into seven groups, i.e., sham (n = 10), lipopolysaccharide/protamine sulfate (LPS/PS; n = 10), LPS/PS + NAC (n = 10), LPS/PS with 25K MSC (n = 10), LPS/PS with 50K MSC (n = 10) LPS/PS + 25K MSC + NAC (n = 10), and LPS/PS + 50K MSC + NAC (n = 10). To induce the IC rat model, protamine sulfate (10 mg, 45 min) and LPS (750 µg, 30 min) were instilled once a week for five consecutive weeks via a transurethral PE-50 catheter. Phosphate-buffered saline (PBS) was used in the sham group. One week after the final instillation, M-MSCs with two suboptimal dosages (i.e., 2.5 or 5.0 × 104 cells) were directly transplanted into the outer-layer of the bladder. Simultaneously, 200 mg/kg of NAC or PBS was intraperitoneally injected daily for five days. The therapeutic outcome was evaluated one week after M-MSC or PBS injection by awake cystometry and histological analysis. Functionally, LPS/PS insult led to irregular micturition, decreased intercontraction intervals, and decreased micturition volume. Both monotherapy and combination therapy significantly increased contraction intervals, increased urination volume, and reduced the residual volume, thereby improving the urination parameters compared to those of the LPS group. In particular, a combination of NAC dramatically reduced the amount of M-MSCs used for significant restoration in histological damage, including inflammation and apoptosis. Both M-MSCs and NAC-based therapy had a beneficial effect on improving voiding dysfunction, regenerating denudated urothelium, and relieving tissue inflammation in the LPS-induced IC/BPS rat model. The combination of M-MSC and NAC was superior to MSC or NAC monotherapy, with therapeutic efficacy that was comparable to that of previously optimized cell dosage (1000K) without compromised therapeutic efficacy.

Longitudinal intravital imaging of transplanted mesenchymal stem cells elucidates their functional integration and therapeutic potency in an animal model of interstitial cystitis/bladder pain syndrome.

Rationale: Mesenchymal stem cell (MSC) therapy may be a novel approach to improve interstitial cystitis/bladder pain syndrome (IC/BPS), an intractable disease characterized by severe pelvic pain and urinary frequency. Unfortunately, the properties of transplanted stem cells have not been directly analyzed in vivo, which hampers elucidation of the therapeutic mechanisms of these cells and optimization of transplantation protocols. Here, we monitored the behaviors of multipotent stem cells (M-MSCs) derived from human embryonic stem cells (hESCs) in real time using a novel combination of in vivo confocal endoscopic and microscopic imaging and demonstrated their improved therapeutic potency in a chronic IC/BPS animal model. Methods: Ten-week-old female Sprague-Dawley rats were instilled with 10 mg of protamine sulfate followed by 750 µg of lipopolysaccharide weekly for 5 weeks. The sham group was instilled with phosphate-buffered saline (PBS). Thereafter, the indicated dose (0.1, 0.25, 0.5, and 1×106 cells) of M-MSCs or PBS was injected once into the outer layer of the bladder. The distribution, perivascular integration, and therapeutic effects of M-MSCs were monitored by in vivo endoscopic and confocal microscopic imaging, awake cystometry, and histological and gene expression analyses. Results: A novel combination of longitudinal intravital confocal fluorescence imaging and microcystoscopy in living animals, together with immunofluorescence analysis of bladder tissues, demonstrated that transplanted M-MSCs engrafted following differentiation into multiple cell types and gradually integrated into a perivascular-like structure until 30 days after transplantation. The beneficial effects of transplanted M-MSCs on bladder voiding function and the pathological characteristics of the bladder were efficient and long-lasting due to the stable engraftment of these cells. Conclusion: This longitudinal bioimaging study of transplanted hESC-derived M-MSCs in living animals reveals their long-term functional integration, which underlies the improved therapeutic effects of these cells on IC/BPS.