Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

EBV infection mediated BDNF expression is associated with bladder inflammation in interstitial cystitis/bladder pain syndrome with Hunner's lesion.

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both Epstein-Barr virus (EBV) latency infection genes EBNA-1 and LMP-1 and EBV lytic infection BZLF-1 and BRLF-1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV-associated inflammatory genes in HIC bladders, such as TNF-α and IL-6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain-derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV-infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B-cell-specific transcription. Knockdown of BDNF in EBV-infected B cells resulted in the inhibition of cell proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV-infected B cells into rat bladder walls resulted in a higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV-infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV-infected B cells in HIC pathogenesis. © 2022 The Pathological Society of Great Britain and Ireland.

Safety and efficacy of an α1 -blocker plus mirabegron compared with an α1 -blocker plus antimuscarinic in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and overactive bladder: A systematic review and network meta-analysis.

AIM: Antimuscarinics and the ß3-adrenoreceptor agonist, mirabegron, are commonly used for treating patients with overactive bladder (OAB) and α1 -adrenoreceptor antagonists (α1 -blockers) are the main pharmacological agents used for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). As these conditions commonly occur together, the aim of this systematic review was to identify publications that compared the use of an α1 -blocker plus mirabegron with an α1 -blocker plus antimuscarinic in men with LUTS secondary to BPH and OAB. A meta-analysis was subsequently conducted to explore the safety and efficacy of these combinations. METHODS: Included records had to be from a parallel-group, randomized clinical trial that was ≥8 weeks in duration. Participants were male with LUTS secondary to BPH and OAB. The indirect analyses that were identified compared an α1 -blocker plus OAB agent with an α1 -blocker plus placebo. The PubMed/Medical Literature Analysis and Retrieval System Online, the Excerpta Medica Database, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry were searched for relevant records up until March 5, 2020. Safety outcomes included incidences of overall treatment-emergent adverse events (TEAEs) and urinary retention, postvoid residual volume, and maximum urinary flow (Qmax ). Primary efficacy outcomes were micturitions/day, incontinence episodes/day, and urgency episodes/day, and secondary outcomes were Overactive Bladder Symptom Score and International Prostate Symptom Score. A Bayesian network meta-analysis approach was used for the meta-analysis. RESULTS: Out of a total of 1039 records identified, 24 were eligible for inclusion in the meta-analysis. There were no statistically significant differences between the α1 -blocker plus mirabegron and α1 -blocker plus antimuscarinic groups in terms of the comparisons identified for all the safety and efficacy analyses conducted. Numerically superior results were frequently observed for the α1 -blocker plus mirabegron group compared with the α1 -blocker plus antimuscarinic group for the safety parameters, including TEAEs, urinary retention, and Qmax . For some of the efficacy parameters, most notably micturitions/day, numerically superior results were noted for the α1 -blocker plus antimuscarinic group. Inconsistency in reporting and study variability were noted in the included records, which hindered data interpretation. CONCLUSION: This systematic review and meta-analysis showed that an α1 -blocker plus mirabegron and an α1 -blocker plus antimuscarinic have similar safety and efficacy profiles in male patients with LUTS secondary to BPH and OAB. Patients may, therefore, benefit from the use of either combination within the clinical setting.

Outcomes of laparoscopic, robotic and open nephroureterectomy with bladder cuff excision in patients with T3T4 upper urinary tract urothelial carcinoma: a multi-center retrospective study.

BACKGROUND: Nephroureterectomy with bladder cuff excision is the standard treatment for high-risk upper urinary tract urothelial carcinoma (UTUC). The role of minimally invasive surgery in treating locally advanced UTUC remains controversial. This study aimed to compare the outcomes of open, laparoscopic, and robotic surgeries for managing locally advanced UTUC. METHODS: We retrospectively reviewed 705 patients with locally advanced UTUC from multiple institutions throughout Taiwan. Perioperative outcomes and oncological outcomes, such as cancer-specific survival, overall survival, disease-free survival and bladder-free survival, were compared between the open, laparoscopic and robotic groups. RESULTS: The minimally invasive group had better overall and cancer-specific survival (CSS) rates. The 2-year CSS rates of the open, laparoscopic and robotic groups were 71%, 83%, and 77% respectively (p < 0.001). The robotic group had similar outcomes to the laparoscopic group. (p = 0.061, 0.825, 0.341 for OS, CSS, DFS respectively.) More lymph node dissections were performed and more lymph nodes were harvested in the robotic group (p = 0.009). CONCLUSIONS: Our results demonstrated that minimally invasive surgery, including laparoscopic and robotic surgery, for locally advanced UTUC resulted in oncological outcomes that are non-inferior to those of open surgery.

Using Urine Biomarkers to Differentiate Bladder Dysfunctions in Women with Sensory Bladder Disorders.

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner's interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. A retrospective analysis of 191 women who underwent a videourodynamic study (VUDS) was conducted, with some also receiving cystoscopic hydrodistention to confirm the presence of NHIC. Participants were categorized into four groups: DO (n = 51), HSB (n = 29), NHIC (n = 81), and normal controls (n = 30). The urine levels of inflammatory and oxidative stress biomarkers were measured. The DO patients exhibited elevated IP-10 levels, while the HSB patients had decreased TAC and 8-OHdG levels. The NHIC patients showed lower IL-2 and higher TNF-α levels. A TNF-α ≥ 1.05 effectively identified NHIC, with an AUROC of 0.889, a sensitivity of 98.8%, and a specificity of 81.3%. An IP-10 ≥ 6.31 differentiated DO with an AUROC of 0.695, a sensitivity of 56.8%, and a specificity of 72.3%. An 8-OHdG ≤ 14.705 and a TAC ≤ 528.7 identified HSB with AUROCs of 0.754 and 0.844, respectively. The combination of 8-OHdG and TAC provided an AUROC of 0.853 for HSB. These findings suggest that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 are promising non-invasive biomarkers for distinguishing between these conditions, which may improve diagnosis and management.

Efficacy of single and repeated transurethral bladder neck incisions for female voiding dysfunction.

OBJECTIVE: This study aimed to assess the efficacy of single and repeat transurethral bladder neck incision (TUI-BN) for female voiding dysfunction caused by bladder outlet obstruction (BNO). Further, the predictive factors associated with better treatment outcomes were identified. METHODS: Women with voiding difficulty due to BNO who underwent TUI-BN were included in this research. All patients underwent videourodynamics study at baseline and after TUI-BN. Successful outcome was defined as a voiding efficiency of ≥ 66.7% and a global response assessment score of ≥ 2 after treatment. Repeat TUI-BN was considered for patients with insufficient improvement. The outcomes of repeat surgery, surgical complications, and predictive factors of successful outcomes were evaluated. RESULTS: In total 158 cases, the success rates were 61.4% and 45.2% after the first and second TUI-BN, respectively, with an overall cumulative rate of 70.3%. The success rates were comparable between patients with detrusor underactivity (DU) and those without (54.9% vs. 68.4%). The absence of a previous history of suburethral sling and a high baseline corrected maximum flow rate were a significant predictor of favorable outcomes. The cumulative rate of regaining self-voiding function was 95.1%. The incidence rates of vesico-vaginal fistula and de novo stress urinary incontinence requiring surgery were 1.2% and 2.5%, respectively. CONCLUSIONS: Regardless of the presence of DU, TUI-BN is effective against female voiding dysfunction caused by BNO. Repeat procedures are beneficial and can improve self-voiding function. A high corrected maximum flow rate and the absence of a previous history of suburethral sling can contribute to greater success rates.

Impact of pathological response on oncological outcomes in patients with upper tract urothelial cancer receiving neo-adjuvant chemotherapy.

PURPOSE: The purpose of this study is to evaluate the rates of pathological complete response (ypT0N0/X) and pathological response (ypT1N0/X or less) in patients with upper tract urothelial cancer who were treated with neo-adjuvant chemotherapy and to examine their impact on oncological outcomes. METHODS: This study is a multi-institutional retrospective analysis of patients with high-risk upper tract urothelial cancer who underwent neoadjuvant chemotherapy and radical nephroureterectomy between 2002 and 2021. Logistic regression analyses were used to investigate all clinical parameters for response after neoadjuvant chemotherapy. Cox proportional hazard models were performed to assess the effect of the response on the oncological outcomes. RESULTS: A total of 84 patients with UTUC who received neo-adjuvant chemotherapy were identified. Among them, 44 (52.4%) patients received cisplatin-based chemotherapy, and 22 (26.2%) patients had a carboplatin-based regimen. The pathological complete response rate was 11.6% (n = 10), and the pathological response rate was 42.9% (n = 36). Multifocal tumors or tumors larger than 3 cm significantly reduced the odds of pathological response. In the multivariable Cox proportional hazard model, pathological response was independently associated with better overall survival (HR 0.38, p = 0.024), cancer-specific survival (HR 0.24, p = 0.033), and recurrence-free survival (HR 0.17, p = 0.001), but it was not associated with bladder recurrence-free survival (HR 0.84, p = 0.69). CONCLUSION: Pathological response after neo-adjuvant chemotherapy and radical nephroureterectomy is strongly associated with patient survival and recurrence, and it might be a good surrogate for evaluating the efficacy of neo-adjuvant chemotherapy in the future.

Use of Urinary Biomarkers in Discriminating Interstitial Cystitis/Bladder Pain Syndrome from Male Lower Urinary Tract Dysfunctions.

To analyze the urinary biomarkers in men with lower urinary-tract symptoms (LUTS) and identify interstitial cystitis/bladder pain syndrome (IC/BPS) from the other lower urinary-tract dysfunctions (LUTDs) by the levels of characteristic urinary biomarkers. In total, 198 men with LUTS were prospectively enrolled and urine samples were collected before intervention or medical treatment. Videourodynamic studies were routinely performed and the LUTDs were diagnosed as having bladder-outlet obstruction (BOO) such as bladder-neck dysfunction, benign prostatic obstruction, or poor relaxation of external sphincter (PRES); and bladder dysfunction such as detrusor overactivity (DO), hypersensitive bladder (HSB), and IC/BPS. Patients suspicious of IC/BPS were further confirmed by cystoscopic hydrodistention under anesthesia. The urine samples were investigated for 11 urinary inflammatory biomarkers including eotaxin, IL-6, IL-8, CXCL10, MCP-1, MIP-1ß, RANTES, TNF-α, NGF, BDNF, and PGE2; and 3 oxidative stress biomarkers 8-OHdG, 8-isoprostane, and TAC. The urinary biomarker levels were analyzed between LUTD subgroups and IC/BPS patients. The results of this study revealed that among the patients, IC/BPS was diagnosed in 48, BOO in 66, DO in 25, HSB in 27, PRES in 15, and normal in 17. Patients with BOO had a higher detrusor pressure and BOO index than IC/BPS, whereas patients with IC/BPS, BOO, and DO had a smaller cystometric bladder capacity than the PRES and normal subgroups. Among the urinary biomarkers, patients with IC/BPS had significantly higher levels of eotaxin, MCP-1, TNF-α, 8-OHdG, and TAC than all other LUTD subgroups. By a combination of different characteristic urinary biomarkers, TNF-α, and eotaxin, either alone or in combination, had the highest sensitivity, specificity, positive predictive value, and negative predictive value to discriminate IC/BPS from patients of all other LUTD subgroups, BOO, DO, or HSB subgroups. Inflammatory biomarker MCP-1 and oxidative stress biomarkers 8-OHdG and TAC, although significantly higher in IC/BPS than normal and PRES subgroups, did not have a diagnostic value between male patients with IC/BPS and the BOO, DO, or HSB subgroups. The study concluded that using urinary TNF-α and eotaxin levels, either alone or in combination, can be used as biomarkers to discriminate patients with IC/BPS from the other LUTD subgroups in men with LUTS.

Sensory Receptor, Inflammatory, and Apoptotic Protein Expression in the Bladder Urothelium of Patients with Different Subtypes of Interstitial Cystitis/Bladder Pain Syndrome.

The aim of this study was to investigate the expression levels of sensory receptors, inflammatory proteins, and pro-apoptotic proteins in the urothelium of non-Hunner's interstitial cystitis (NHIC) bladders of patients with different clinical and cystoscopic phenotypes. The urothelia from the bladders of 52 NHIC patients were harvested. The expression of sensory receptors, including TRPV1, TRPV4, TRPA1, H1-receptors, and sigma-1 receptors; the inflammatory proteins p38 and tryptase; and the pro-apoptotic proteins, such as caspase-3, BAD, and BAX in the urothelium, were investigated using immunohistochemistry and Western blotting. We compared the expression levels of these proteins in NHIC subtypes according to IC symptom scores, visual analog scores of bladder pain, maximal bladder capacity, glomerulation grades, and combined maximal bladder capacity and glomerulations after cystoscopic hydrodistention. The expression levels of TRPV1, TRPV4, sigma-1, P38, tryptase, caspase-3, and BAD were significantly increased in the urothelium of IC/BPS patients compared with the expression levels in the controls. TRPV1 was significantly associated with IC symptom severity. However, no significant differences in sensory receptor expression in the IC/BPS bladders with different bladder conditions were detected. Inflammatory and pro-apoptotic protein expression levels in the urothelium were similar among the IC/BPS subgroups. This study concluded that IC/BPS patients with frequency and bladder pain complaints have higher levels of urothelial sensory receptors, and inflammatory and pro-apoptotic proteins. The expression levels of these sensory receptors, inflammatory proteins, and pro-apoptotic proteins are not significantly different among IC/BPS bladders with different conditions.

The Tumor Necrosis Factor-α Level in Platelet-Rich Plasma Might Be Associated with Treatment Outcome in Patients with Interstitial Cystitis/Bladder Pain Syndrome or Recurrent Urinary Tract Infection.

Using platelet-rich plasma (PRP) injections to treat urological diseases has attracted great attention. This study investigated the impact of cytokine concentrations in PRP on the treatment outcome of patients with recurrent urinary tract infection (rUTI) and interstitial cystitis/bladder pain syndrome (IC/BPS). Forty patients with IC/BPS and twenty-one patients with rUTI were enrolled for four-monthly repeated PRP injections. PRP was collected at the first injection and analyzed with multiplex immunoassays for 12 target cytokines. In patients with IC/BPS, a Global Response Assessment (GRA) score ≥ 2 was defined as a successful outcome. In rUTI patients, ≤2 episodes of UTI recurrence during one year of follow-up was considered a successful outcome. Nineteen (47.5%) patients with IC/BPS and eleven (52.4%) patients with rUTI had successful outcomes. The IC/BPS patients with successful outcomes had significantly lower levels of tumor necrosis factor-α (TNF-α) in their PRP than those with unsuccessful outcomes (p = 0.041). The rUTI patients with successful outcomes also had a lower level of TNF-α (p = 0.025) and a higher level of epidermal growth factor (p = 0.035) and transforming growth factor-ß2 (p = 0.024) in PRP than those with unsuccessful outcomes. A lower level of TNF-α in PRP might be a potentially predictive factor of treatment outcome.

Comparison of oncological outcomes for hand-assisted and pure laparoscopic radical nephroureterectomy: results from the Taiwan Upper Tract Urothelial Cancer Collaboration Group.

PURPOSE: Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. METHODS: We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. RESULTS: The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). CONCLUSIONS: The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.

Effect of videourodynamic subtypes on treatment outcomes of female dysfunctional voiding.

INTRODUCTION AND HYPOTHESIS: Dysfunctional voiding (DV) is not uncommon in women and is typically challenging to treat. This study retrospectively investigated the long-term treatment outcomes of DV women with different videourodynamics (VUDS) characteristics. METHODS: Data of women with VUDS-proven DV (n = 302) were retrospectively analyzed. All patients at first received biofeedback pelvic floor muscle training and medications; urethral sphincter botulinum toxin A injection was administered after treatment failure. Long-term follow-up outcomes were graded by global response assessment (GRA) and objective responses of decrease of detrusor pressure (Pdet), increase in maximum flow rate (Qmax) and voiding efficiency (VE). The treatment outcomes were investigated among different VUDS subgroups. RESULTS: Of 302 women, 165 (54.6%) had mid-urethral DV, 117 (38.7%) had distal urethral DV, and 20 (6.6%) had both bladder neck dysfunction (BND) and mid-urethral DV. A total of 170 (56.3%) patients were available for follow-up VUDS after treatment. Pdet was decreased in all three subgroups, but increase in Qmax and VE was only noted in the BND plus DV subgroup. Overall, 120 (70.6%) patients showed improvement (GRA ≥ 1), including 14 with BND plus DV (93.3%), 50 with mid-urethral DV (60.8%) and 56 with distal urethral DV (77.8%) (p = 0.044). All three subgroups showed significant reduction in bladder outlet obstruction index after treatment, with BND plus DV subgroup showing the greatest reduction. CONCLUSIONS: Women with DV have different VUDS characteristics resulting from different pathophysiological mechanisms and treatment results. The VUDS characteristics may help predict treatment outcomes of female DV.

Usefulness of Urinary Biomarkers for Assessing Bladder Condition and Histopathology in Patients with Interstitial Cystitis/Bladder Pain Syndrome.

This study investigated the usefulness of urinary biomarkers for assessing bladder condition and histopathology in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We retrospectively enrolled 315 patients (267 women and 48 men) diagnosed with IC/BPS and 30 controls. Data on clinical and urodynamic characteristics (visual analog scale (VAS) score and bladder capacity) and cystoscopic hydrodistention findings (Hunner's lesion, glomerulation grade, and maximal bladder capacity (MBC)) were recorded. Urine samples were utilized to assay inflammatory, neurogenic, and oxidative stress biomarkers, including interleukin (IL)-8, C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin, IL-6, macrophage inflammatory protein 1 beta (MIP-1ß), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 8-isoproatane, and total antioxidant capacity. Further, specific histopathological findings were identified via bladder biopsy. The associations between urinary biomarker levels and bladder conditions and histopathological findings were evaluated. The results reveal that patients with IC/BPS had significantly higher urinary MCP-1, eotaxin, TNF-α, PGE2, 8-OHdG, and 8-isoprostane levels than controls. Patients with Hunner's IC (HIC) had significantly higher IL-8, CXCL10, BDNF, eotaxin, IL-6, MIP-1ß, and RANTES levels than those with non-Hunner's IC (NHIC). Patients with NHIC who had an MBC of ≤760 mL had significantly high urinary CXCL10, MCP-1, eotaxin, IL-6, MIP-1ß, RANTES, PGE2, and 8-isoprostane levels and total antioxidant capacity. Patients with NHIC who had a higher glomerulation grade had significantly high urinary MCP-1, IL-6, RANTES, 8-OHdG, and 8-isoprostane levels. A significant association was observed between urinary biomarkers and glomerulation grade, MBC, VAS score, and bladder sensation. However, bladder-specific histopathological findings were not well correlated with urinary biomarker levels. The urinary biomarker levels can be useful for identifying HIC and different NHIC subtypes. Higher urinary inflammatory and oxidative stress biomarker levels are associated with IC/BPS. Most urinary biomarkers are not correlated with specific bladder histopathological findings; nevertheless, they are more important in the assessment of bladder condition than bladder histopathology.

Clinical Relevance of Bladder Histopathological Findings and Their Impact on Treatment Outcomes among Patients with Interstitial Cystitis/Bladder Pain Syndrome: An Investigation of the European Society for the Study of Interstitial Cystitis Histopathological Classification.

PURPOSE: We investigate the clinical significance of European Society for the Study of Interstitial Cystitis (ESSIC) bladder histopathological classification and its impact on treatment outcomes among patients with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Bladder biopsy specimens obtained from severe, treatment refractory interstitial cystitis/bladder pain syndrome cases were analyzed by a single pathologist blinded to clinical data. Inflammatory cell infiltration and urothelium denudation, eosinophil infiltration, plasma cell infiltration, lamina propria hemorrhage and granulation in specimens were evaluated separately. Patients with at least 1 histopathological finding were classified as ESSIC type C, with the rest being classified as ESSIC type A. Current overall treatment outcomes were determined via telephone interview. RESULTS: Bladder specimens were obtained from 352 patients with interstitial cystitis/bladder pain syndrome. Bladder inflammation, urothelium denudation, eosinophil and plasma cell infiltration, lamina propria hemorrhage and granulation were present in 69.6%, 44.6%, 9.1%, 15.3%, 4.8% and 5.1% of the bladder specimens, respectively. Approximately 78.7% of the patients included were ESSIC type C and had a smaller cystometric bladder capacity and higher bladder pain compared to ESSIC type A. Although individual histopathological findings were not associated with treatment outcome, a higher proportion of ESSIC type A patients had worse, unchanged or less than 25% improvement outcomes compared to ESSIC type C (43.1% vs 25.8%, p=0.025). CONCLUSIONS: Bladder histopathological findings were associated with clinical parameters and differences in patient reported treatment outcomes. Accordingly, patients with interstitial cystitis/bladder pain syndrome who had no remarkable bladder histopathological findings had less favorable treatment outcomes compared to those who did.

High percentage of neurologic deficits in the electrophysiology study of the lower urinary tract in patients with detrusor underactivity and chronic urinary retention.

OBJECTIVES: Both detrusor underactivity (DU) and bladder outlet obstruction are the common causes of chronic urinary retention. Some novel treatment approaches focus on modulating micturition reflex and external urethral sphincter (EUS) function. This study used electrophysiologic (EP) studies to investigate the micturition reflex and EUS conditions of chronic urinary retention patients. METHODS: Sixty patients with urodynamic DU and chronic urinary retention were studied using (1) bulbocavernous reflex (BCR) by electric stimulation, (2) electromyography (EMG) of the EUS, and (3) nerve conduction velocity (NCV) studies of the pudendal nerve. The EP findings were analyzed in DU patients with different etiologies. RESULTS: The BCR was positive in 41.7% of patients. In EMG studies, denervation, reinnervation, and reduced recruitment of the EUS were observed in 21.7%, 71.7%, and 88.3% patients, respectively. Decreased amplitude of pudendal nerve conduction in NCV studies was noted in 73.3% of patients. Patients with sacral neuropathy had a lower BCR positive rate (p = 0.001), a nonsignificant but higher denervation rate (p = 0.059) in EMG studies, and a higher rate of decreased amplitude in NCV (p = 0.011) than those without sacral neuropathy. Excluding patients with sacral neuropathy or diabetes mellitus, a high percentage of neurologic deficits was still detected in EP studies. CONCLUSIONS: Chronic urinary retention patients with urodynamic DU not only have bladder dysfunction, but also potential neuropathy in the sacral reflexes, pudendal nerve, or urethral sphincter innervation. The neurologic deficits explored in EP studies may affect the decision-making around the therapy to restore the voiding function in DU.

Decreased urothelial cytoskeleton and cell proliferation protein expression suggest interstitial cystitis/bladder pain syndrome patients with Hunner's lesion and grade 3 glomerulation might be different from other types of patients.

OBJECTIVES: To explore the expression of cytoskeletal and cell proliferation proteins in urothelial cells of patients diagnosed with various clinical subtypes of interstitial cystitis/bladder pain syndrome. METHODS: Biopsy specimens from 85 interstitial cystitis/bladder pain syndrome patients were classified according to findings on cystoscopy. Cytokeratins and cell proliferation proteins detected in the specimens were evaluated with immunofluorescence staining and quantified with western blotting. A total of 22 patients diagnosed with pure stress urinary incontinence were enrolled as controls. RESULTS: Interstitial cystitis/bladder pain syndrome patients with Hunner's lesion and with grade 3 glomerulation hemorrhage had smaller bladder capacities than the other interstitial cystitis/bladder pain syndrome patients without Hunner's lesion. Diminished expression of CK14, CK20, cell proliferation protein tumor protein 63, sonic hedgehog, and fibroblast growth factor receptors 3 and 4, and increased expression of CK5 and BCL2-associated X protein were observed in biopsy specimens from patients with Hunner's lesion compared with those from patients without Hunner's lesion and controls. In the patients with grade 3 glomerulation hemorrhage, lower expression levels of urothelial CK20, tumor protein 63 and fibroblast growth factor receptor 4, and lower expression of CK5 and BCL2-associated X protein were detected compared with other types of NHIC. CONCLUSION: A diminished expression of proliferation proteins tumor protein 63 and the mature urothelium marker CK20, and increased expression of the immature marker CK5 in specimens from both Hunner's lesion and grade 3 glomerulation hemorrhage patients can be observed. The urothelium of patients with interstitial cystitis/bladder pain syndrome might be in a state of persistent or chronic injury that could relate to the limited expression of cell proliferation proteins.

Urine cytokines as biomarkers for diagnosing interstitial cystitis/bladder pain syndrome and mapping its clinical characteristics.

The objective of the present study was to investigate the diagnostic values of urine cytokines in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) and to identify their correlations with clinical characteristics. Urine samples were collected from 127 patients with IC/BPS [European Society for the Study of Interstitial Cystitis (ESSIC) types 1 and 2] and 28 controls. Commercially available multiplex immunoassays (MILLIPLEX map kits) were used to analyze 31 targeted cytokines. Cytokine levels between patients with IC/BPS and controls were analyzed using ANOVA. Receiver-operating characteristic curves of each cytokine to distinguish IC/BPS from controls were generated for calculation of the area under the curve. Patients with IC/BPS had urine cytokine profiles that differed from those of controls. Between patients with ESSIC type 1 and 2 IC/BPS, urine cytokine profiles were also different. Among cytokines with high diagnostic values (i.e., area under the curve > 0.7) with respect to distinguish patients with ESSIC type 2 IC/BPS from controls, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), macrophage inflammatory protein (MIP)-1ß, and IL-8 were of higher sensitivity, whereas macrophage chemoattractant protein (MCP)-1, chemokine (C-X-C motif) ligand 10 (CXCL10), and eotaxin-1 were of higher specificity. In multivariate logistic regression models controlling for age, sex, body mass index, and diabetes mellitus, the urine cytokines with high diagnostic values (MCP-1, RANTES, CXCL10, IL-7, and eotaxin-1) remained statistically significant in differentiating IC/BPS and controls. MCP-1, CXCL10, eotaxin-1, and RANTES were positively correlated with glomerulation grade and negatively correlated with maximal bladder capacity. In conclusion, patients with IC/BPS had urine cytokine profiles that clearly differed from those of controls. Urine cytokines might be useful as biomarkers for diagnosing IC/BPS and mapping its clinical characteristics.

Single onabotulinumtoxinA 200U dose improved clinical symptoms but not urothelial dysfunction in neurogenic detrusor overactivity due to spinal cord injury.

OBJECTIVE: To evaluate the changes in urothelial dysfunction protein expressions in bladder after onabotulinumtoxin injection and correlate that with clinical outcomes in spinal cord injury (SCI) patients. METHODS: Twenty-six patients with neurogenic detrusor overactivity (NDO) and urinary incontinence due to suprasacral SCI were treated with onabotulinumtoxinA 200U detrusor injection. Urodynamic studies and bladder biopsies were obtained at baseline, 3, and 6 months after treatment. Biopsy tissues were investigated for E-cadherin, zonula occludens-1 (ZO-1), mast cell activity, and urothelial cell apoptosis, sensory protein expression including purinergic receptor P2X3, endothelial NOS, inducible NOS, ß3-adrenoceptors, and muscarinic receptors M2 and M3. Differences in functional protein expression between controls and SCI patients and between successful and failed treatment groups were analyzed. RESULTS: SCI patients had significantly lower E-cadherin, higher mast cell activity, increased apoptosis, decreased M3 and eNOS expressions than the controls at baseline. Of the 26 patients, 17 (65%) showed improvement in bladder capacity by >50% at 3 months; however, improvement declined by 6 months after treatment. The urothelial expression of E-cadherin and ZO-1 increased at 3 months but had declined at 6 months. The urothelial sensory protein expression did not change significantly after treatment. M3 receptor density was significantly decreased in SCI patients at baseline and patients with treatment success 3 months after injection (p = 0.01). CONCLUSION: A single injection of onabotulinumtoxinA 200U improved clinical symptoms but did not significantly alter urothelial sensory protein expression. The results imply that a single 200U onabotulinumtoxinA dose might not be adequate for urothelial dysfunction in NDO. IRB: TCGH 098-53.

Possible predictor of early recovery on urinary continence after laparoscopic radical prostatectomy - Bladder neck level and urodynamic parameters.

BACKGROUND/PURPOSE: To investigate the relationship between post-operative bladder neck levels and urodynamic parameters and their effect on urinary incontinence after laparoscopic radical prostatectomy (LRP). METHODS: Forty-eight consecutive patients undergoing LRP were retrospectively reviewed. All patients were assessed using retrograde cystography after LRP and were grouped according to their bladder neck position: Level 0: at or above the superior margin of the symphysis pubis (SMSP); Level -1: at <2 cm below SMSP; and Level -2: at >2 cm below SMSP. Urodynamic studies were conducted at baseline as well as at 1 and 3 months post-operatively. Early recovery of urinary continence was defined as no urine leakage or only one pad/day used within 3 months after surgery. Demographic characteristics, changes in urodynamic parameters, and continence outcomes were analyzed. RESULTS: Overall rate of early recovery of urinary continence was 33.3%. Patients with higher bladder neck levels experienced a significantly earlier recovery of urinary continence in univariate analysis (77.8%, 29.2%, and 13.3% for bladder neck levels 0, -1, and -2, respectively, p = 0.004). Patients with early recovery of urinary continence had significantly longer functional profile lengths (FPLs) 1 month post-surgery (21.0 mm vs 14.8 mm, p = 0.019). Higher bladder neck levels were significantly associated with longer FPLs at 1 month (p = 0.032). CONCLUSION: Bladder neck level is associated with FPLs at 1 month post-surgery, which is the possible predictor of early recovery of urinary continence after LRP. Patients with longer FPL at 1 month after LRP have a higher rate of early recovery of urine continence.

Epstein-Barr Virus as a Potential Etiology of Persistent Bladder Inflammation in Human Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: Interstitial cystitis/bladder pain syndrome is characterized by bladder inflammation without bacterial infection. Although viral infection is a potential etiological cause, few studies have been reported. MATERIALS AND METHODS: Bladder specimens were obtained from patients with interstitial cystitis/bladder pain syndrome and from patients with stress urinary incontinence as controls. Bladder specimens were tested for Epstein-Barr encoded RNAs by in situ hybridization and for Epstein-Barr DNA by quantitative real-time polymerase chain reaction, serology and immunohistochemical staining. RESULTS: Enrolled in study were 16 patients with interstitial cystitis/bladder pain syndrome and Hunner lesions, 23 without interstitial cystitis/bladder pain syndrome or Hunner lesions and 10 controls. The positive rate of Epstein-Barr encoded RNA on in situ hybridization in bladder specimens from patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions was 50% vs 8.6%. No Epstein-Barr encoded RNA was found in control specimens. On quantitative real-time polymerase chain reaction Epstein-Barr DNA was detected in 68.8% vs 16.7% of bladder specimens in patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions. The median viral load was 1,836 copies per ml (range 216 to 75,144). Only 1 control specimen was Epstein-Barr positive on quantitative real-time polymerase chain reaction. All serum samples from patients with interstitial cystitis/bladder pain syndrome showed past Epstein-Barr viral infection. Epstein-Barr infection was present in 87.5% vs 17.4% of bladder specimens from patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions for a total of 46.2% with interstitial cystitis/bladder pain syndrome. Immunohistochemical staining of CD3 and CD20 revealed that Epstein-Barr infection was mainly restricted to T lymphocytes in bladders showing interstitial cystitis/bladder pain syndrome. CONCLUSIONS: Bladder Epstein-Barr infection in T cells may be linked to the pathogenesis of persistent inflammation in patients with interstitial cystitis/bladder pain syndrome.