Adjuvant Chemotherapy in Patients with Locally Advanced Upper Tract Urothelial Carcinoma with or without Kidney Transplantation.

Background: The incidence of upper tract urothelial carcinoma (UTUC) is uniquely high in kidney transplant (KT) recipients in Taiwan. The evidence of adjuvant chemotherapy (AC) in UTUC is contradictory. We have sought to determine whether AC is associated with potential benefits related to locally advanced UTUC after KT. Methods: We retrospectively analyzed 134 patients with locally advanced UTUC (at least stage T2) and patients who were administrated AC after unilateral or bilateral nephroureterectomy with bladder cuff excision. Of these 134 patients, 57 patients fulfilled our inclusion criteria. We used 23 KT and 34 non-KT locally advanced UTUC patients for comparison. Results: The mean follow-up time was 52.35 ± 34.56 and 64.71 ± 42.29 months for the KT and non-KT groups, respectively. The five-year disease-free survival (DFS) and overall survival (OS) rates were 45.7% vs. 70.2% and 62.8% vs. 77.6%, for the KT and non-KT groups. The Kaplan-Meier curve and the log rank test revealed significant differences in the DFS and OS rates between the two groups, p = 0.015 and 0.036. The influence of chemotherapy on graft kidney function was mild. Only three in the KT group and two in the non-KT group developed > grade 2 nephrotoxicity. Conclusions: Our study suggested that KT patients with locally advanced UTUC who had been administered AC after surgery presented worse OS and DFS than non-KT patients. KT patients tolerated the AC course well, and their nephrotoxicity levels were mild and acceptable.

Adverse Events of Everolimus in Patients with Tuberous Sclerosis Complex Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

Background: Although regarded as a potentially efficient approach to address tuberous sclerosis complex (TSC)-associated complications, the adverse event profile of everolimus has not yet been fully elucidated. The present study aimed to clarify the adverse event spectrum in patients with TSC who are using everolimus for common indications, in comparison to those who do not use everolimus. Materials and Methods: We recruited patients with TSC who were followed up annually at TSC integrated clinics or referred for medical assistance. Medical reviews and laboratory investigations were performed at baseline and annually by clinical physicians. The adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Common adverse events in everolimus users included hypercholesterolemia (55%), gingivostomatitis (50%), proteinuria (50%), and hyperglycemia (40%). Compared with everolimus nonusers, the occurrence of gingivostomatitis and proteinuria was significantly higher in everolimus users (gingivostomatitis, p=0.02; proteinuria, p=0.02). Among the everolimus users, 12 patients had level I CTCAE, and five had level II CTCAE. None of the everolimus users presented with CTCAE level III or higher. Conclusion: Patients with TSC who are everolimus users had a higher tendency to develop gingivostomatitis and proteinuria compared to nonusers. However, no differences were observed in the occurrence of other adverse events between everolimus users and nonusers.

SUMO1 and Defective Spermatozoa Correlate with Endogenous Hydrogen Peroxide and Live Birth Outcome in Intrauterine Insemination Cycles for Unexplained Infertility.

This study aimed to investigate the correlation between hydrogen peroxide (H2O2), small ubiquitin-like modifier molecules (SUMO), and pregnancy outcomes in couples with unexplained infertility (UI) undergoing intrauterine insemination (IUI) treatment. We prospectively collected semen samples from 56 couples with UI and divided the spermatozoa into motile and immotile fractions by density gradient centrifugation (DSC). Immunofluorescence staining was used to examine the immunostaining and localization of nuclear pore complex (NPC), SUMO1, and SUMO2/3 in spermatozoa. We detected H2O2 levels by chemiluminescence methods. We found that H2O2 levels correlated with NPC (neck) (r = 0.400) and NPC (tail) (r = 0.473) in motile sperm fractions. In immotile fractions, H2O2 positively correlated with NPC (tail) (r = 0.431) and SUMO1 (neck) (r = 0.282). Furthermore, the positive NPC (tail) group had a significantly lower live birth rate than the negative NPC group (17.9% = 5/28 vs. 42.9% = 12/28). In conclusion, H2O2 positively correlated with SUMO1 (neck) and NPC (tail) in human spermatozoa. The DSC may partially eliminate defective spermatozoa (positive NPC staining); however, if defective spermatozoa remain in the motile fraction, this scenario is associated with a low live birth rate following IUI treatment.

New Hydronephrosis in the Native Kidney Is Associated with the Development of De Novo Urinary Bladder Urothelial Carcinoma in Patients with Post-Kidney Transplantation.

Increased malignancy after kidney transplantation (KT) is by far the most troublesome issue. Among these malignancies, urothelial carcinoma (UC) incidence is uniquely high in Taiwan. We want to know whether routine sonography to detect native hydronephrosis is associated with the development of de novo urinary bladder urothelial carcinoma (UBUC) in post-KT recipients. From 2003 to 2018, we retrospectively analyzed 1005 KT patients, 58 of whom were subsequently diagnosed with UBUC. The association between new native hydronephrosis and post-KT UBUC was analyzed with univariate and multivariate logistic regression analyses and a Kaplan-Meier plot. We excluded cases of people who had upper urinary tract urothelial carcinoma (UTUC) and were diagnosed prior to UBUC. There were 612 males (60.9%) and 393 females (39.1%), with a mean age of 48.2 ± 12.0 years old at KT. The mean follow-up period was 118.6 ± 70.2 months, and the diagnosis of UBUC from KT to UBUC was 7.0 ± 5.1 years. New native kidney hydronephrosis occurred more frequently in the UBUC group (56.4% versus 6.4%, p < 0.001) than the non-UBUC group. Multivariate analysis disclosed that native hydronephrosis is the only statistically significant factor for UBUC, with an odds ratio of 16.03 (95% CI, 8.66-29.68; p < 0.001). UBUC in post-KT patients with native hydronephrosis also showed a tendency toward multifocal lesions upon presentation (47.8%). Post-KT UBUC is characterized by pathologically aggressive and multiple foci lesions. Native kidney hydronephrosis may be a deciding factor of post-KT UBUC.

Melatonin induces cell cycle arrest and suppresses tumor invasion in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.

Long-Term Surveillance and Management of Urological Complications in Chronic Spinal Cord-Injured Patients.

Bladder dysfunction is a common complication after chronic spinal cord injury (SCI). Patients may experience renal function loss, urinary tract infection (UTI), urolithiasis, bladder cancer, and even life-threatening events such as severe sepsis or renal failure. Suitable patient care may prevent UTI and urinary incontinence, decrease medication use, and preserve renal function. As the primary goal is to preserve renal function, management should be focused on facilitating bladder drainage, the avoidance of UTI, and the maintenance of a low intravesical pressure for continence and complete bladder emptying. Currently, several bladder management options are available to SCI patients: (1) reflex voiding; (2) clean intermittent catheterization; (3) indwelling catheterization. The target organ may be the bladder or the bladder outlet. The purposes of intervention include the following: (1) increasing bladder capacity and/or decreasing intravesical pressure; (2) increasing bladder outlet resistance; (3) decreasing bladder outlet resistance; (4) producing detrusor contractility; (5) urinary diversion. Different bladder management methods and interventions may have different results depending on the patient's lower urinary tract dysfunction. This review aims to report the current management options for long-term bladder dysfunction in chronic SCI patients. Furthermore, we summarize the most suitable care plans for improving the clinical outcome of SCI patients.

The Impact of Transoral Robotic Surgery on Erectile Dysfunction and Lower Urinary Tract Symptoms in Male Patients with Moderate-to-Severe Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA), lower urinary tract symptoms (LUTS), and erectile dysfunction (ED) are chronic conditions that seriously affect middle-aged men. This study aimed to evaluate the changes in the presence of these conditions after transoral robotic surgery (TORS) for OSA. This prospective observational study recruited 48 men with moderate-to-severe OSA (mean age 40.6 ± 8.1 years) who underwent TORS from October 2019 to November 2021 at a tertiary center. Baseline polysomnographic parameters, Epworth Sleepiness Scale (ESS), and demographic characteristics were measured. The evaluations of LUTS and ED were based on self-administered International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF-5) questionnaires, respectively, before TORS. The treatment outcomes were assessed three months postoperatively in the patients undergoing TORS due to moderate-to-severe OSA. There was significant Apnea-Hypopnea Index (AHI) reduction from 53.10 ± 25.77 to 31.66 ± 20.34 three months after undergoing TORS (p < 0.001). There was also a significant decrease in the total IPSS score (5.06 ± 5.42 at baseline to 2.98 ± 2.71 at three months postoperatively, p = 0.001), the storage domain, and the voiding domain (p < 0.05). The ED also improved significantly, as seen in the IIEF score (20.98 ± 3.32 to 22.17± 3.60, p = 0.007). The reduction of AHI was associated with changes in body weight and the lowest oxygen saturation (SpO2) levels during sleep (rho = 0.395, p = 0.005; rho = 0.526, p < 0.001, respectively). However, the reduction in AHI was not significantly associated with improvement in IPSS or IIEF scores (p > 0.05). For men with moderate-to-severe OSA, TORS can significantly improve the polysomnography parameters, sleep-related questionnaire scores, and quality of life, and alleviate ED and LUTS. AHI reduction is not a crucial factor for ED and LUTS improvement after TORS for OSA, especially in ED.

Effective dose for kidney-ureter-bladder plain radiography, intravenous urography, and abdominal computed tomography scan: A phantom study.

Abdominal colic pain or hematuria is suspected to be caused by urinary tract stones. Commonly used X-ray examinations include kidney-ureter-bladder plain radiography (KUB), intravenous urography (IVU), and abdominal computed tomography (CT). In this study, a high-sensitivity thermoluminescent dosimeter (TLD) was embedded in a Rando phantom to directly measure organ dose and evaluate effective dose. During each experiment, 139 TLD measurement points that cover almost all organs (as recommended by the ICRP 103 report) were examined. Red bone-marrow and remainder tissues have a high tissue weighting factor (0.12), and they are widely distributed. In the phantom, 34 TLDs and 31 TLDs were embedded in the red bone-marrow and remainder tissues to improve the accuracy and representativeness of organ doses. The detailed organ dose distributions for KUB, IVU, and abdominal CT are presented. The effective doses for KUB and IVU were 0.22 and 1.51 mSv, respectively, and those for two abdominal CTs were 8.21 and 9.27 mSv. This experiment presents a conversion factor of 0.0177 mSv·mGy-1 cm-1 for the abdominal CT examination, which differs from most of the conversion factors obtained through the Monte Carlo simulation method.

PNU-74654 Suppresses TNFR1/IKB Alpha/p65 Signaling and Induces Cell Death in Testicular Cancer.

Testicular cancer (TC) is a rare malignancy worldwide and is the most common malignancy in males aged 15-44 years. The Wnt/ß-catenin signaling pathway mediates numerous essential cellular functions and has potentially important effects on tumorigenesis and cancer progression. The search for drugs to inhibit this pathway has identified a small molecule, PNU-74654, as an inhibitor of the ß-catenin/TCF4 interaction. We evaluated the therapeutic role of PNU-74654 in two TC cell lines, NCCIT and NTERA2, by measuring cell viability, cell cycle transition and cell death. Potential pathways were evaluated by protein arrays and Western blots. PNU-74654 decreased cell viability and induced apoptosis of TC cells, with significant increases in the sub G1, Hoechst-stained, Annexin V-PI-positive rates. PNU-74654 treatment of both TC cell lines inhibited the TNFR1/IKB alpha/p65 pathway and the execution phase of apoptosis. Our findings demonstrate that PNU-74654 can induce apoptosis in TC cells through mechanisms involving the execution phase of apoptosis and inhibition of TNFR1/IKB alpha/p65 signaling. Therefore, small molecules such as PNU-74654 may identify potential new treatment strategies for TC.

Concomitant Detrusor and External Urethral Sphincter Botulinum Toxin-A Injections in Male Spinal Cord Injury Patients with Detrusor Overactivity and Detrusor Sphincter Dyssynergia.

OBJECTIVE: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia. DESIGN: An open treatment trial with pre- and posttreatment evaluations. SUBJECTS: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization. METHODS: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared. RESULTS: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks. CONCLUSION: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative.

Chidamide and mitomycin C exert synergistic cytotoxic effects against bladder cancer cells in vitro and suppress tumor growth in a rat bladder cancer model.

Intravesical instillation (IVI) of Bacillus Calmette-Guerin (BCG) can prevent bladder cancer recurrence, but this agent has been out of stock in recent years. IVI of other agents, like chidamide, a histone deacetylase (HDAC) inhibitor, may have the potential to exert a therapeutic effect against bladder cancer by modifying the gene expression profiles associated with histone modifications that occur during cancer tumorigenesis. Here, we investigated the in vitro therapeutic effect of chidamide and/or mitomycin C in bladder cancer cell lines and screened related molecular pathways using an antibody array. We also quantitatively analyzed the synergistic effect of IVI of chidamide and mitomycin C in vivo in an N-methyl-N-nitrosourea (MNU)-induced rat bladder cancer model. The synergistic cytotoxic effect of chidamide plus mitomycin C was confirmed in both T24 and UMUC3 cells, with significantly greater induction of apoptosis elicited with chidamide plus mitomycin C than with either drug alone. The antibody array identified the Axl signaling pathway as the key target of the synergistic effect. Expression of Axl and its related downstream molecules, including claspin and survivin, was significantly suppressed. In the rat bladder cancer model, IVI of chidamide plus mitomycin C reduced tumor burden (Ki67 index) to a greater extent than either drug alone. Our results suggest that chidamide and mitomycin act synergistically to reduce MNU-induced bladder cancer. These findings provide new insights into a new and potentially effective approach to treating bladder cancer.

Association of Interstitial Cystitis/Bladder Pain Syndrome with Stress-Related Diseases: A Nationwide Population-Based Study.

BACKGROUND: Stress-related diseases (SRDs) are adjustment disorders triggered by stressful life changes. There is a growing body of evidence showing that stress plays an important role in the pathophysiology of IC/BPS. In the present study, we investigated the association between SRDs and a subsequent association of interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: We performed a nested case-control study from the Longitudinal Health Insurance Database (LHID) of Taiwan. The two-year time-varying association between SRDs and IC/BPS was explored to distinguish the short- or long-term effects of these factors. We then conducted multiple conditional logistic regressions to evaluate the adjusted odds ratio (OR) of IC/BPS in patients with a history of SRDs. RESULTS: A total of 1103 IC/BPS patients and 4412 non-IC/BPS patients were analyzed. For all SRDs, the significantly increased risks were obtained in 2 years before IC/BPS diagnosis, and the higher OR was observed within 3 months before the diagnosis of IC/BPS. Multiple conditional logistic regressions showed that patients who had prior medical care for urinary tract infection (OR = 10.95, 95% CI = 9.07 to 13.22), chronic obstructive pulmonary disease (OR = 1.48, 95% CI = 1.13 to 1.93), peptic ulcer (OR = 1.69, 95% CI = 1.37 to 2.09), inflammatory bowel syndrome (OR = 1.66, 95% CI = 1.21 to 2.29), autoimmune diseases (OR = 1.48, 95% CI = 1.11 to 1.97), depression (OR = 1.54, 95% CI = 1.24 to 1.91), sleep disorders (OR = 1.45, 95% CI = 1.19 to 1.78), and allergic rhinitis (OR = 1.29, 95% CI = 1.03 to 1.62) within 2 years had a significant risk of IC/BPS. CONCLUSIONS: Our study demonstrates that the health care for SRDs within the previous 2 years is associated with an increased risk of subsequent IC/BPS. The time-varying association provides an important insight that helps us to identify cases with IC/BPS, especially among patients with repeated UTI visits.

Native Kidney Hydronephrosis Is Associated with Upper Urinary Tract Urothelial Carcinoma in Post-Kidney Transplantation Patients.

BACKGROUND: Upper urinary tract urothelial carcinoma (UTUC) is the most common malignancy occurring after kidney transplantation (KT) in Taiwan. The aim of this study was to investigate the association between native kidney hydronephrosis and UTUC in post-KT patients. METHODS: From 2003 to 2018, we conducted a retrospective cohort study that enrolled 1005 post-KT patients, 67 of whom were subsequently diagnosed with UTUC. We divided patients into two groups based on whether or not they had UTUC. Multivariate analysis and Kaplan-Meier plot were used to evaluate if native kidney hydronephrosis was associated with post-KT UTUC. RESULTS: The total cohort consisted of 612 men (60.9%) and 393 women (39.1%) with a mean age of 48.2 ± 12.0 at KT. The mean follow-up time was 118.6 ± 70.2 months, and mean time from KT to UTUC was 7.53 years. There was a significant gender difference with a female predominance among the UTUC patients (73.1% versus 26.9%, p < 0.001). Native kidney hydronephrosis occurred more frequently in the UTUC group (68.7% versus 4.8%, p < 0.001). Multivariate analysis showed that native kidney hydronephrosis and female gender were significantly associated with UTUC with odds ratios of 35.32 (95% CI, 17.99-69.36; p < 0.001) and 3.37 (95% CI, 1.55-7.29; p = 0.002), respectively. UTUC in the post-KT patients also showed aggressive pathological characteristics and a tendency toward bilateral lesions (41.8%). CONCLUSIONS: Native kidney hydronephrosis is significantly associated with post-KT UTUC patients in Taiwan. Native kidney hydronephrosis may be a deciding factor for standard nephroureterectomy and bladder cuff excision in selected patients. Nevertheless, almost half of the patients with kidney hydronephrosis do not present with UTUC at the end of our study.

Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer.

Azacitidine, an inhibitor of DNA methylation, shows therapeutic effects against several malignancies by inducing apoptosis and inhibiting tumor cell proliferation. However, the anti-tumor effects of azacitidine on urinary bladder urothelial carcinoma (UBUC), especially following intravesical instillation (IVI), are not established. Here, UBUC cell lines were used to analyze the in vitro therapeutic effects of azacitidine. Potential signaling pathways were investigated by antibody arrays and Western blotting. The N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat UBUC model was used for in vivo quantitative analysis of tumor burden. Azacitidine significantly inhibited DNMT expression in UBUC cell lines and reduced cell viability and clonogenic activity, as determined by MTT and colony formation assays, while also inducing significant cytotoxic effects in the form of increased sub-G1 and Annexin V-PI populations (all p < 0.05). Antibody arrays confirmed the in vitro suppression of TNF-R1 and the induction of TRAIL-R2 and their downstream signaling molecules. TNF-R1 suppression reduced claspin and survivin expression, while TRAIL-R2 activation induced cytochrome C and caspase 3 expression. Rats with BBN-induced bladder cancer had a significantly reduced tumor burden and Ki67 index following IVI of azacitidine (p < 0.01). Our study provides evidence for a reduction in BBN-induced bladder cancer by IVI of azacitidine through alterations in the TRAIL-R2 and TNF-R1 signaling pathways. These findings might provide new insights for further clinical trials.

A 3-year longitudinal survey of overactive bladder in community-dwelling male residents aged 40 years and above.

OBJECTIVES: To evaluate the short-term evolution and risk factors of overactive bladder (OAB) in community-dwelling male residents aged 40 years and above in central Taiwan. METHODS: This was a 3-year longitudinal cohort study. From January 2012 to December 2012, community residents aged 40 years and above, living in central Taiwan, were invited to participate in this study. A yearly Overactive Bladder Symptom Score (OABSS) questionnaire was used to assess the prevalence, incidence, remission, persistence, and relapse of OAB for three consecutive years. OAB was defined as total OABSS ≧4 and urgency score ≧2. RESULTS: Nine hundred forty-one male residents aged ≧40 years were recruited. The prevalence of OAB was 15%. The male residents with OAB were older, had a history of urological surgery, were unemployed, had lower educational levels, and lower yearly incomes compared with male residents without OAB. The prevalence increased with age when stratified into different age cohorts (40-49, 7%; 50-59, 12.7%; 60-69, 18.2%; ≧70, 32%; P < .001). Age ≧60 (odds ratio [OR] 2.58; 95% CI, 1.62-4.11) and history of urological surgery (OR 2.85; 95% CI, 1.29-6.30) were the major risk factors after multivariable logistic regression analysis. Eight hundred participants completed all the 3 years' questionnaires. The second- and third-year incidence rates of OAB were 10% (69/691) and 6.2% (42/674), respectively. The remission rates were 47.7% (52/109) and 46% (58/126), respectively. The two-year OAB persistence rate was 30.3% (33/109). CONCLUSIONS: The prevalence and yearly incidence of OAB are high in community-dwelling male residents aged ≧40 years in central Taiwan. Age is an important risk factor.