Combination of urinary biomarkers and machine-learning models provided a higher predictive accuracy to predict long-term treatment outcomes of patients with interstitial cystitis/bladder pain syndrome.

PURPOSE: To identify predictive factors for satisfactory treatment outcome of the patients with IC/BPS using urine biomarkers and machine-learning models. METHODS: The IC/BPS patients were prospectively enrolled and provide urine samples. The targeted analytes included inflammatory cytokines, neurotrophins, and oxidative stress biomarkers. The patients with overall subjective symptom improvement of ≥ 50% were considered to have satisfactory results. Binary logistic regression, receiver-operating characteristic (ROC) curve, machine-learning decision tree, and random forest models were used to analyze urinary biomarkers to predict satisfactory results. RESULTS: Altogether, 57.4% of the 291 IC/BPS patients obtained satisfactory results. The patients with satisfactory results had lower levels of baseline urinary inflammatory cytokines and oxidative biomarkers than patients without satisfying results, including interleukin-6, monocyte chemoattractant protein-1 (MCP-1), C-X-C motif chemokine 10 (CXCL10), oxidative stress biomarkers 8-hydroxy-2'-deoxyguanosine (8-OHDG), 8-isoprostane, and total antioxidant capacity (TAC). Logistic regression and multivariable analysis revealed that lower levels of urinary CXCL10, MCP-1, 8-OHDG, and 8-isoprostane were independent factors. The ROC curve revealed that MCP-1 level had best area under curve (AUC: 0.797). In machine-learning decision tree model, combination of urinary C-C motif chemokine 5, 8-isoprostane, TAC, MCP-1, and 8-OHDG could predict satisfactory results (accuracy: 0.81). The random forest model revealed that urinary 8-isoprostance, MCP-1, and 8-OHDG levels had the most important influence on accuracy. CONCLUSION: Machine learning decision tree model provided a higher accuracy for predicting treatment outcome of patients with IC/BPS than logistic regression, and levels of 8-isoprostance, MCP-1, and 8-OHDG had the most important influence on accuracy.

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.

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.

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.

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.

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.

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.

Intravesical injections of platelet-rich plasma is effective and safe in treatment of interstitial cystitis refractory to conventional treatment-A prospective clinical trial.

AIMS: Current treatments for interstitial cystitis/bladder pain syndrome (IC/BPS) are usually unsuccessful in achieving long-term bladder pain relief and irritable symptom improvement. This study investigated the clinical efficacy of platelet-rich plasma (PRP) intravesical injections on IC/BPS patients refractory to conventional therapies. METHODS: Forty patients received four monthly intravesical injections of 10 mL PRP extracted from 50 mL of whole blood. The primary end-point was Global Response Assessment (GRA) at 3 months after the 4th PRP injection. Secondary endpoints included changes in O'Leary-Sant symptom score (OSS), visual analog scale (VAS) of pain, daily frequency, nocturia, functional bladder capacity (FBC), maximum flow rate, voided volume, post-void residual volume (PVR) from baseline to 3 months after the 4th PRP injection. RESULTS: All 40 patients (37 women and 3 men, aged 55.5 ± 11.1 years) completed the four injections and follow-up visits. GRA improved after the 1st PRP injection and the satisfaction persists till the primary end-point. The success rate was 45%, 52%, 70%, 70%, and 67.5% after the 1st, 2nd, 3rd, 4th, and 3 months after the 4th PRP injection, respectively. OSS and VAS also significantly decreased. The PVR did not change after repeated PRP injections, FBC increased, frequency, and nocturia were decreased after PRP injections. All patients were free of urinary tract infection or difficulty urinating. CONCLUSION: The study demonstrated that repeated intravesical injections of autologous PRP can increase bladder capacity and provide IC symptom improvement in patients with IC/BPS refractory to conventional therapy. Autologous PRP injection is safe and effective in selected patients.

Upregulation of neurotrophins and transforming growth factor-ß expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine-associated cystitis.

AIMS: To investigate the mechanism of bladder nerve hyperplasia and fibrosis in the patients with ketamine-associated cystitis (KC). METHODS: Sixteen patients with severe KC, six patients with mild KC, and five patients with localized invasive bladder cancer served as control patients. Bladder mucosa specimens were taken during the operations, and the specimens were stained for nerve growth factor (NGF) and S-100 to evaluated nerve hyperplasia. The quantitative Western blot analysis was performed for NGF, brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43), tropomyosin receptor kinase A and B (TrkA and TrkB), transforming growth factor-ß (TGF-ß), phosphorylated extracellular signal-regulated kinases (p-ERK), protein kinase B (p-Akt), and glycogen synthase kinase 3ß (p-GSK-3ß). RESULTS: The results demonstrated diffuse NGF expression in KC bladder epithelium, lamina propria, and muscle. The GAP-43, NGF, BDNF, TrkA, TGF-ß, p-ERK, P-AKT, and p-GSK-3ß expression in the bladder mucosa specimens of patients with severe KC was significantly higher than in patients with mild KC and control patients. Expression of neurotrophins was significantly correlated with bladder capacity and pain. NGF and BDNF expression were significantly higher in the KC bladder specimens with strongly positive S-100 staining. TGF-ß expression in the bladder specimens was significantly correlated with neurotrophins, p-ERK, P-AKT, and p-GSK-3ß levels. CONCLUSION: Our findings indicate upregulation of neurotrophins, TGF-ß, and activation of the cell proliferation kinases plays an important role in nerve hyperplasia and fibrosis mechanisms in severe KC bladders. The neurotrophins and TGF-ß interact as cause and effect, leading to bladder hypersensitivity and fibrosis in severe KC.

Long-term outcome and symptom improvement in patients with interstitial cystitis/bladder pain syndrome with or without regular follow-up and treatment.

AIMS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease, which is difficult to treat. Patients usually seek for new therapies and might not follow-up regularly. This study investigated long-term symptom changes in patients with IC/BPS, especially in those who were lost to follow-up. METHODS: We enrolled patients with IC/BPS with a history of >5 years and having comprehensive medical records, baseline IC symptom index and IC problem index, O'Leary-Sant symptom score, and visual analog scale (VAS). A telephone interview was conducted to assess current symptoms with the same questionnaires. A 5-point scale (from -1 to 3) was used to grade current treatment outcomes. RESULTS: A total of 198 patients with IC/BPS with a mean age of 57.4 ± 12.2 years were included. At a mean follow-up duration of 16.6 ± 9.75 years, 12% of the patients were free of symptoms and 47% exhibited symptom improvement of more than 50%. Totally, 47 (23.7%) patients were lost to follow-up for >5 years, and 151 (76.3%) had a regular follow-up. The patients with IC/BPS who were not regularly followed up had no Hunner's lesion, and had a higher bladder volume (P = .023), higher urine flow (P = .019), and fewer comorbidities (P = .014) than those who had a regular follow-up. The number of treatment modalities was significantly less in the patients who were lost to follow-up (P = .037). CONCLUSIONS: About half of the patients with IC/BPS exhibited symptom improvement with time, with or without regular follow-up and receiving a new treatment.

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.

Comparative study of efficacy and safety between bladder body and trigonal intravesical onabotulinumtoxina injection in the treatment of interstitial cystitis refractory to conventional treatment-A prospective, randomized, clinical trial.

PURPOSE: Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). However, the therapeutic efficacy of different injection sites is not well known. This study compared therapeutic efficacy and safety between bladder body and trigonal BoNT-A injection. MATERIALS AND METHODS: Patients were randomly treated with 100U of BoNT-A in 10 mL saline injected into 20 bladder body sites or 10 trigonal sites. The primary endpoint was changes of Visual Analog Scale (VAS) for Pain at 8th week after injection. Secondary endpoint included changes of Global Response Assessment (GRA), urinary frequency episodes, O'Leary-Sant score (OSS), and urodynamic study. RESULTS: Thirty-nine patients (bladder body, N = 20; trigone, N = 19) completed the study visits. Patients in both group had significant improvement in VAS, OSS, and functional bladder capacity after treatment. There was no significant difference in changes of urinary frequency, voided volume, post-void residual volume, and bladder capacity from baseline to 8 weeks between groups. Thirteen (65.0%) patients in bladder body group and 10 (52.6%) patients in trigone group had decrease of VAS more than 2 points after treatment (P = 0.43). Excellent symptom improvement (GRA ≥ 2) was noted in 9 (45%) patients with bladder body injection and 10 (52.6%) patients with trigonal injection (P = 0.63). Nine (45.0%) patients in bladder body group and 10 (52.6%) in trigonal group experienced dysuria after treatment (P = 0.52). CONCLUSION: No significant difference in the improvement of IC symptoms and urodynamic parameters after intravesical BoNT-A injection in the bladder body or trigone. The rate of adverse events was similar between groups.

Therapeutic effect of urethral sphincter onabotulinumtoxinA injection for urethral sphincter hyperactivity.

PURPOSE: Urethral sphincter hyperactivity resulting in voiding dysfunction is frequently encountered. Medical treatment might not achieve a satisfactory result. OnabotlinumtoxinA urethral sphincter injection relaxes sphincter tonicity and possibly resumes efficient voiding. This study analyzed the treatment outcomes and predictor for successful onabotulinumtoxinA treatment on these patients. METHODS: Patients with voiding dysfunction due to urethral sphincter hyperactivity and treated with injections of 100 U onabotulinumtoxinA into the urethral sphincter were retrospectively reviewed. Treatment outcomes were assessed 1 month after injection using the Global Response Assessment and were analyzed by demographic and baseline video-urodynamic characteristics. RESULTS: Of the 95 patients included, satisfactory outcomes were reported in 58 (61.1%) patients. Treatment outcome was not related to age, gender, or voiding dysfunction subtype. Patients with satisfactory outcomes had a significantly smaller volume at first sensation of filling (P = 0.046), greater detrusor pressure (P = 0.027), higher maximum flow rate (P = 0.017), and smaller post-void residual (P = 0.006). In multivariate analysis, an open bladder neck during voiding was the only predictor for successful outcome (88% in satisfactory outcome, 12% in failure outcome, P < 0.001). Patients with non-neurogenic voiding dysfunction had a significantly longer therapeutic duration than those with neurogenic voiding dysfunction (9.55 ± 4.18 vs 7.44 ± 2.91 months, P = 0.033). Increased urinary incontinence was reported in 18 patients, including 6 with stress urinary incontinence and 12 with urgency urinary incontinence. CONCLUSION: Subjective improvement was reported in 61.1% of patients with voiding dysfunction due to urethral sphincter hyperactivity after onabotulinumtoxinA urethral sphincter injection. An open bladder neck during voiding at baseline predicts a successful outcome.

Histopathological characteristics of ketamine-associated uropathy and their clinical association.

AIM: To investigate the histopathological findings in ketamine-associated uropathy (KU) and their clinical association. METHODS: Thirty-eight KU patients had received history investigation and video urodynamic study. Twelve of them were clinically mild KU who were admitted for cystoscopic hydrodistention. The other 26 patients were severe KU who were admitted for enterocystoplasty with or without ureter reimplantation. Bladder and ureter specimens were harvested during operation, and a single pathologist reviewed all specimens under hematoxylin and eosin stain. The severity of histopathological findings was graded with a 4-point scale (0: none, 1: mild, 2: moderate, and 3: severe) RESULTS: Inflammatory cells infiltrations and nerve hyperplasia were found in the mucosa, muscle, and subserosal layers of KU bladders and ureter. In the mild KU bladder mucosa, the predominant component of the infiltrating inflammatory cells was lymphocytes. In contrast, neutrophils, eosinophils, lymphocytes, and plasma cells infiltration were noted in the mucosa of almost all severe KU bladders. Clinical severe KU was significantly correlated with severe to moderate lymphocytes, plasma cells, neutrophils, eosinophils infiltration, and nerve hyperplasia in bladder mucosa. KU patients with moderate or severe neutrophils or lymphocytes infiltration in bladder mucosa had significantly more severe bladder pain and smaller bladder capacity. CONCLUSION: The histological findings of KU showed whole-layer inflammation and nerve hyperplasia in bladder mucosa. The severity of inflammatory cell infiltration in the bladder mucosa is associated with clinical symptoms. A histopathological examination might be a useful tool to discriminate the KU severity in patients.

Patient characteristics for different therapeutic strategies in the management ketamine cystitis.

AIMS: Long-term ketamine abuse results in severely inflamed bladder and intractable bladder pain. Currently there is no guideline for clinician to follow how to manage patients with ketamine cystitis (KC). This study analyzed the KC patient characteristics between who received conservative management and augmentation enterocystoplasty (AE). METHODS: A total of 53 patients with chronic ketamine abuse and lower urinary tract symptoms were included in this study. All of the patients have been initially treated conservatively but fail. They were admitted for detailed urological examinations. Patients were classified according to their maximal bladder capacity (MBC). The patients with extremely small MBC (<100 ml) with or without upper urinary tract damage and very small MBC with upper urinary tract damage were recommended to receive AE. The patient characteristics and treatment outcome are compared between patients with AE and conservative treatment. RESULTS: Among them, 28 patients underwent AE and 25 were managed with conservative treatment. The only significant difference between groups was more patients with urgency urinary incontinence underwent AE. Patients underwent AE had significantly smaller MBC, thicker bladder wall, and higher incidence of vesicoureteral reflux. Patients underwent AE reported a good outcome. Most of patients received conservative treatment had a fair result. CONCLUSIONS: KC patients who already developed a contracted bladder with extremely small bladder capacity (<300 ml) with irreversible urinary tract change, partial cystectomy, and AE seems necessary for early restoration of a normal lower urinary tract function. The treatment outcome of AE is better than patients with conservative treatment. Neurourol. Urodynam. 36:687-691, 2017. © 2016 Wiley Periodicals, Inc.

Long-term follow up and predictive factors for successful outcome of transurethral incision of the bladder neck in women with detrusor underactivity.

BACKGROUND/PURPOSE: Detrusor underactivity (DU) is a common urologic problem. Our previous study revealed the transurethral incision of the bladder neck (TUI-BN) improves short-term voiding efficiency (VE) in female patients with DU. This study focused on the long-term outcomes of TUI-BN and identified the predictive factors of satisfactory outcomes. METHODS: A total 50 women with DU for whom medical treatment failed underwent TUI-BN. The urodynamic parameters at baseline and follow-up visits were analyzed. Patients with VEs >50% were considered to have satisfactory outcomes. Baseline urodynamic parameters were analyzed as factors predictive of outcomes. RESULTS: After a mean follow up of 61.8 months, 26 of 50 patients had satisfactory outcomes. The mean VE, maximum flow rate, voided volume, detrusor pressure, and postvoid residual volume significantly improved after TUI-BN. A higher intravesical pressure [Pves, odds ratio (OR) = 1.023, p = 0.013] and smaller first sensation of bladder filling (OR = 0.990, p = 0.020) at baseline were predictive factors for satisfactory outcomes. The multivariate analysis revealed that only baseline Pves was a significant predictor of satisfactory outcomes (OR = 1.024, p = 0.038). The receiver operating characteristic curve analysis of baseline Pves showed that the area under the curve was 0.767 (95% confidence interval = 0.624-0.876). The optimal cutoff value of Pves for a satisfactory outcome was 45 cmH2O, which had a specificity of 78.26% and acceptable sensitivity of 73.08%. CONCLUSION: TUI-BN improved VE in women with DU over the long term. A higher Pves compared to a lower Pves was predictive of satisfactory surgical outcomes.

Possible pathophysiology of ketamine-related cystitis and associated treatment strategies.

Ketamine-related cystitis is characterized by ketamine-induced urinary frequency and bladder pain. It has become a serious problem in recent years. The most typical grossly pathological bladder change with ketamine related cystitis is a contracted bladder and bladder wall thickening. Ulcerative cystitis with an easily bleeding mucosa is a common cystoscopic finding. Microscopically, the urothelium is denuded and is infiltrated by inflammatory cells, such as mast cells and eosinophils. The pathogenesis of ketamine-related cystitis is complicated and involves many different pathways. Past evidence suggests a direct toxic effect, bladder barrier dysfunction, neurogenic inflammation, immunoglobulin-E-mediated inflammation, overexpression of carcinogenic genes, abnormal apoptosis and nitric oxide synthase-mediated inflammation contribute to the pathogenesis of ketamine-related cystitis. The first step to managing ketamine-related cystitis is always asking patients to cease ketamine. Medical treatment might be helpful in patients with early ketamine-related cystitis and abstinence from ketamine. Several case studies showed that the intravesical installation of hyaluronic acid and intravesical injection of botulinum toxin type A were effective for symptom relief in selected patients. For patients with irreversible pathological change, such as contracted bladder, augmentation enterocystoplasty might be the only solution to increase bladder capacity and relieve intractable bladder pain.

Elevated serum IgE may be associated with development of ketamine cystitis.

PURPOSE: Previous studies revealed bladder mast cell and eosinophil cell infiltration in patients with ketamine cystitis. Due to possible hypersensitivity in those with this condition we investigated the association of serum Ig, histology findings and symptoms in patients with ketamine cystitis. MATERIALS AND METHODS: We evaluated patients with ketamine cystitis for maximal bladder capacity, serum IgE, IgG and IgM, and pain visual analog scale score. Bladder biopsies were assessed for mast cells and eosinophils. Patients with interstitial cystitis/bladder pain syndrome, acute bacterial cystitis and controls were also studied. We used the Mann-Whitney U test for nonparametric data to compare serum IgE among groups with p <0.017 considered significant. RESULTS: Median serum IgE was significantly higher in the 20 patients with ketamine cystitis (205.5 IU/ml, IQR 36.9, 514.0) than in the 10 controls (33.4 IU/ml, IQR 13.5, 71.7, p = 0.015) and the 15 with acute bacterial cystitis (34.6 IU/ml, IQR 24.2, 101.9, p = 0.015). It was marginally higher than in the 13 patients with interstitial cystitis/bladder pain syndrome (65.8 IU/ml, IQR 11.9, 133.0, p = 0.029). Of patients with ketamine cystitis the median visual analog scale pain score was significantly higher in those with serum IgE greater than compared to less than 200 IU/ml. Maximal bladder capacity was significantly less in patients with ketamine cystitis who had higher IgE. Patients with severe or moderate bladder eosinophil infiltration had a greater visual analog scale score, higher serum IgE and smaller maximal bladder capacity than patients with no or mild eosinophil infiltration. Serum IgE and the visual analog scale score correlated significantly (r(2) = 0.318, p = 0.01). CONCLUSIONS: Patients with ketamine cystitis had higher serum IgE than patients with interstitial cystitis/bladder pain syndrome or acute bacterial cystitis, or controls. Serum IgE and the severity of eosinophil infiltration were associated with bladder pain severity and small maximal bladder capacity.