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Objective: To characterize first and second recurrence patterns using 26years of cohort-level follow-up and microsimulation modeling., Methods: Patients diagnosed with nonmuscle-invasive bladder cancer in Stockholm County between 1995 and 1996 were included. Clinical, pathological, and longitudinal follow-up data were gathered. Logistic regressions, Kaplan Meier curves, and Cox proportional hazards models were run to generate assumptions for a microsimulation model, simulating first and second recurrence and progression for 10,000 patients., Results: Three hundred eighty-six patients were included: 67.4% were male; >50% were TaLG; and 37.5% were American Urological Association high-risk. Median time to recurrence was 300days. Three patients had missing data. Cohort follow-up has been carried out for 26years. For simulated first-recurrences, low-risk patients recurred at 56.6% over 15years of follow-up, with 2.2% muscle-invasive (MI) progression; intermediate-risk patients recurred at 62.8%, with 4.3% MI progression; high-risk patients recurred at 48.7% over 15years, with MI progression at 14.3%. For second recurrences, 70.7%, 75.7%, and 84.7% of low, medium, and high-risk patients recurred. No patients were seen to have first recurrences after 9years, with low, but notable, rates beyond 5years., Conclusion: These data suggest that low-, intermediate-, and high-risk patients without recurrence at 5years may be potentially transitioned to less invasive monitoring., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Objective: To examine whether objective bladder function after robot-assisted radical hysterectomy (RRH) for early-stage cervical cancer is correlated with subjective patient-reported outcomes and quality of life during the first year after RRH., Design: Prospective observational study., Setting: Karolinska University Hospital, Sweden., Patients: Women with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA2-IB1) between July 2017 and May 2019 were assessed for eligibility., Interventions: RRH., Measurements and Main Results: Subjective bladder function was evaluated with the Female Lower Urinary Tract Symptoms and Urinary Incontinence Quality of Life modules of the International Consultation on Incontinence Questionnaire. Objective urinary function was characterized with urodynamic tests, and the nerves ablated at RRH were quantified by using immunohistochemical staining of biopsies from the resected paracervix, vesicouterine, and sacrouterine ligaments. Twenty-seven women were included for analysis at baseline, 2 weeks, 3 months, and 12 months after surgery. RRH caused hypotonia of the urinary bladder (p <.05). Patient-reported outcomes of voiding and filling dysfunction were most significant 2 weeks after surgery (p <.05) but for most of the women, bladder function recovered within 3 months. No correlations were found with either subjective or objective urinary function and the number of ablated nerves., Conclusion: For most women, objective and subjective urinary bladder dysfunction recovered within 3 months after RRH. The absence of correlation between functional outcomes and ablated autonomous nerves suggests that other underlying causes play a significant role. Early detection of bladder overextension after RRH is paramount, and the role of postoperative bladder catheterization needs further investigation., (Copyright © 2022 AAGL. Published by Elsevier Inc. All rights reserved.)

Lower urinary tract symptoms (LUTS), e.g., urinary frequency, pressure, urgency, and overactive bladder syndrome, are commonly reported in children with attention-deficit/hyperactivity disorder (ADHD). Understanding the co-occurrence of these conditions has implications regarding clinical approaches, treatments, and improved quality of life. We conducted a systematic review and meta-analysis to examine the relationships between LUTS and ADHD in children. We searched for articles published between January 1990 and July 2019, in PubMed, CENTRAL, and PsycNet. Two authors independently screened all articles and extracted data. We performed random-effect meta-analyses for ADHD with pooled outcomes for LUTS. We identified 119 relevant articles in the literature and 18 articles fulfilled the inclusion criteria for the systematic review, of which, 5 articles had sufficient data for meta-analysis. Examining ADHD among individuals with LUTS, the odds ratio was 2.99 (95% CI 1.13, 7.88, p < 0.001), compared to controls. In multiple studies, the mean overall score for LUTS, using a standardized measure, was significantly higher in patients with ADHD in comparison to controls, and the severity of ADHD was positively associated with the severity of LUTS. Younger age in children was correlated with a higher LUTS score. Different subtypes of urinary incontinence demonstrated differences in behavioral problems and psychiatric comorbidity. Sex differences in LUTS were not consistent across articles. Our results indicate clinically significant associations between ADHD and LUTS in children. Because LUTS and ADHD are common disorders in children, clinicians should be aware of these associations as they inform optimal assessment and treatment strategies., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Lower urinary tract symptoms (LUTS), such as voiding symptoms, overactive bladder, and interstitial cystitis, and anxiety disorders are often comorbid conditions in patients. However, the existing evidence regarding the rates and nature of the co-occurrence of these conditions has not been systematically evaluated. The aim of this study was to examine these relationships., Methods: We conducted a systematic review and meta-analysis to examine the relationship between LUTS and anxiety. We searched for articles published from January 1990 to July 2019 in PubMed, CENTRAL, PsycINFO, and Google Scholar. Outcomes were anxiety-related disorders and symptoms (clinically significant anxiety) and LUTS. We performed random-effects meta-analyses, inspected funnel plots, and applied the Egger's test to evaluate publication bias. We followed PRISMA guidelines and recorded our protocol on PROSPERO (ID = CRD42019118607)., Results: We identified 814 articles, of which 94 fulfilled inclusion criteria, and 23 had sufficient data for meta-analysis. The odds ratio (OR) for clinically significant anxiety among individuals with LUTS was 2.87 (95% CI: 2.38,3.46, p < .001). The OR for LUTS among individuals with clinically significant anxiety was 2.87 (95% CI: 1.07,7.74, p < .001), although very few studies examined this relationship. A large value of I 2 index suggests high heterogeneity between studies., Conclusion: The results demonstrate a significant association between clinically significant anxiety and LUTS in both females and males. There were limited studies on younger individuals and on individuals ascertained for clinically significant anxiety, which should motivate further study in these areas. Understanding the co-occurrence of these conditions will lead to better prevention and interventions to ameliorate the progression of the symptoms and improve the quality of life. A thorough assessment of anxiety may provide more optimal care for LUTS patients., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: Bacillus Calmette-Guérin (BCG)-treatment is an established treatment for bladder cancer, but its mechanisms of action are not fully understood. High-risk non-muscle invasive bladder-cancer (NMIBC)-patients failing to respond to BCG-treatment have worse prognosis than those undergoing immediate radical cystectomy and identification of patients at risk for BCG-failure is of high priority. Several studies indicate a role for nitric oxide (NO) in the cytotoxic effect that BCG exerts on bladder cancer cells. In this study we investigated whether NO-synthase (NOS)-gene polymorphisms, NOS2-promoter microsatellite (CCTTT)n, and the NOS3-polymorphisms-786T>C (rs2070744) and Glu298Asp (rs1799983), can serve as possible molecular markers for outcome after BCG-treatment for NMIBC., Materials and Methods: All NMIBC-patients from a well-characterized population based cohort were analyzed (n=88). Polymorphism data were combined with information from 15-years of clinical follow-up. The effect of BCG-treatment on cancer-specific death (CSD), recurrence and progression in patients with varying NOS-genotypes were studied using Cox proportional hazard-models and log rank tests., Results: BCG-treatment resulted in significantly better survival in patients without (Log rank: p=0.006; HR: 0.12, p=0.048), but not in patients with a long version ((CCTTT)n ≧13 repeats) of the NOS2-promoter microsatellite. The NOS3-rs2070744(TT) and rs1799983(GG)-genotypes showed decreased risk for CSD (Log rank(TT): p=0.001; Log rank(GG): p=0.010, HR(GG): 0.16, p=0.030) and progression (Log rank(TT): p<0.001, HR(TT): 0.05, p=0.005; Log rank(GG): p<0.001, HR(GG): 0.10, p=0.003) after BCG-therapy compared to the other genotypes. There was also a reduction in recurrence in BCG-treated patients that was mostly genotype independent. Analysis of combined genotypes identified a subgroup of 30% of the BCG-treated patients that did not benefit from BCG-treatment., Conclusions: Our results suggest that the investigated polymorphisms influence patient response to BCG-treatment and thus may serve as possible markers for identification of BCG-failures., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Treatment with Bacillus Calmette Guerin (BCG) bladder instillations is an established treatment modality for superficial urinary bladder cancer and carcinoma in situ (CIS), but the anti-tumor mechanisms following BCG instillations remain largely unknown. Previous data show increased nitric oxide (NO) concentrations in the urinary bladder from patients treated with BCG suggesting that NO-formation may be involved in the BCG mediated effect. In the present study we evaluated 11 patients with urinary bladder cancer who had received BCG treatment and 11 tumor free control subjects. We performed immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) on bladder biopsies to establish inducible nitric oxide synthase (iNOS) protein levels and localization as well as iNOS mRNA expression. Endogenous NO formation in the bladder was also measured. In patients with bladder cancer who had received BCG treatment iNOS-like immunoreactivity was found in the urothelial cells but also in macrophages in the submucosa. Furthermore, endogenously formed NO was significantly increased (p<0.001) in the BCG treated patients and they had a ten-fold increase in mRNA expression for iNOS compared to healthy controls (p=0.003). In conclusion iNOS was found to be localized to the urothelium and macrophages underlying it. Our study also confirms elevated levels of endogenously formed NO and increased mRNA expression and protein levels for iNOS in patients with BCG treated bladder cancer. These data further support the notion that NO may be involved in the anti-tumor mechanism that BCG exerts on bladder cancer cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Interstitial cystitis is a chronic inflammatory disease of the bladder and luminal nitric oxide has been shown to be increased in the bladder in patients with interstitial cystitis. We analyzed endogenous nitric oxide formation and inducible nitric oxide synthase gene expression in the bladder of patients with interstitial cystitis to obtain further knowledge of the localization of inducible nitric oxide synthase in the bladder mucosa., Materials and Methods: Six patients with interstitial cystitis and 8 controls were studied. In these 2 groups endogenous nitric oxide formation was measured and inducible nitric oxide synthase expression in bladder biopsies was analyzed at the transcriptional and protein levels by real-time polymerase chain reaction and Western blot, respectively. Immunohistochemistry for inducible nitric oxide synthase was also performed., Results: Patients with interstitial cystitis had higher inducible nitric oxide synthase mRNA expression and nitric oxide formation than controls (p <0.01 and <0.001, respectively). Inducible nitric oxide synthase protein expression was up-regulated in the interstitial cystitis group. Immunohistochemistry showed that inducible nitric oxide synthase was predominantly localized to the urothelium in patients with interstitial cystitis but inducible nitric oxide synthase-like immunoreactivity was also found in macrophages in the bladder mucosa., Conclusions: The increased levels of endogenously formed nitric oxide in patients with interstitial cystitis correspond to increased inducible nitric oxide synthase mRNA expression and protein levels in these patients. Furthermore, inducible nitric oxide synthase was found to be localized to the urothelium but it was also found in macrophages in the bladder mucosa. Whether high levels of endogenously formed nitric oxide are a part of the pathogenesis in interstitial cystitis and whether it has a protective or damaging role remain to be elucidated.

The purpose of the study was to analyze endogenous nitric oxide (NO) formation and NO-synthase (NOS) gene expression in the urinary bladder from patients with urinary bladder cancer and to investigate the relationship between local NO formation, treatment with Bacillus Calmette Guerin (BCG) and clinical stage in bladder cancer patients. One hundred and three patients with bladder cancer were studied. Endogenous formation of NO was measured in 72 patients, including 6 patients with BCG treated bladder cancer and 6 tumor free control subjects. iNOS expression was analyzed at transcriptional and protein level in biopsies from 31 patients with bladder cancer by real time polymerase chain reaction (PCR) and Western blot (WB), respectively. Three patients in this group had received BCG treatment. Eight biopsies from normal bladder served as control for PCR and WB analysis. Patients with carcinoma in situ (CIS) had higher iNOS expression (p<0.01) and NO formation (p<0.01) than control subjects and patients with papillary tumors without concomitant CIS. Markedly increased iNOS expression (p<0.05) and NO formation (p<0.001) were also found in patients treated with BCG as compared to the other groups. In conclusion, the presence of elevated NO concentration and iNOS expression in the urinary bladder from BCG treated patients and patients with CIS further supports the notion that NO may be an important factor in bladder cancer biology and that the BCG effect on superficial bladder cancer may partly be due to stimulation of local NO formation.

Improved oxygenation has previously been shown in patients with acute lung injury when ventilated in prone position. We hypothesized that this was due to higher regional production of nitric oxide in dorsocaudal lung regions. We measured nitric oxide synthase mRNA expression and nitric oxide production by citrulline assay in ventral and dorsal lung tissue from patients. In volunteers, regional lung perfusion in prone and supine postures was assessed by single photon emission computed tomography using (99m)Tc macroaggregated albumin before and after inhibition of nitric oxide synthase by N(G)-monomethyl-L-arginine infusion. Nitric oxide synthase mRNA expression and nitric oxide production were significantly higher in dorsal compared with ventral lung regions. In supine posture, lung perfusion was shifted to ventral parts during nitric oxide synthase inhibition, whereas in the prone posture lung perfusion remained unchanged. Our results suggest a role for endogenous nitric oxide in regulation of regional pulmonary perfusion.