A Study of DNA Methylation of Bladder Cancer Biomarkers in the Urine of Patients with Neurogenic Lower Urinary Tract Dysfunction.

Background: Bladder cancer (BCa) in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) is a significant concern due to its advanced stage at diagnosis and high mortality rate. Currently, there is a scarcity of specific guidelines for BCa screening in these patients. The development of urine biomarkers for BCa seems to be an attractive non-invasive method of screening or risk stratification in this patient population. DNA methylation is an epigenetic modification, resulting in the transcriptional silencing of tumor suppression genes, that is frequently detected in the urine of BCa patients. Objectives: We aimed to investigate DNA hypermethylation in five gene promoters, previously associated with BCa, in the urine of NLUTD patients, and in comparison with healthy controls. Design, setting and participants: This was a prospective case-control study that recruited neurourology outpatients from a public teaching hospital who had suffered from NLUTD for at least 5 years. They all underwent cystoscopy combined with biopsy for BCa screening following written informed consent. DNA was extracted and DNA methylation was assessed for the RASSF1, RARß, DAPK, TERT and APC gene promoters via quantitative methylation-specific PCR in urine specimens from the patients and controls. Results: Forty-one patients of mixed NLUTD etiology and 35 controls were enrolled. DNA was detected in 36 patients' urine specimens and in those of 22 controls. In the urine specimens, DNA was hypermethylated in at least one of five gene promoters in 17/36 patients and in 3/22 controls (47.22% vs. 13.64%, respectively, p = 0.009). RASSF1 was hypermethylated in 10/17 (58.82%) specimens with detected methylation, APC in 7/17 (41.18%), DAPK in 4/17 (23.53%), RAR-ß2 in 3/17 (17.56%) and TERT in none. According to a multivariate logistic regression analysis, NLUTD and male gender were significantly associated with hypermethylation (OR = 7.43, p = 0.007 and OR = 4.21; p = 0.04, respectively). In the tissue specimens, histology revealed TaLG BCa in two patients and urothelial squamous metaplasia in five patients. Chronic bladder inflammation was present in 35/41 bladder biopsies. Conclusions: DNA hypermethylation in a panel of five BCa-associated genes in the urine was significantly more frequent in NLUTD patients than in the controls. Our results warrant further evaluation in longitudinal studies assessing the clinical implications and possible associations between DNA hypermethylation, chronic inflammation and BCa in the NLUTD population.

DNA Hypermethylation af a Panel Of Genes as an Urinary Biomarker For Bladder Cancer Diagnosis.

PURPOSE: Several studies have shown frequent changes in DNA methylation in bladder cancer (BCa), which vary among different geographical areas. The aim of this study is to examine the diagnostic accuracy of a panel of DNA methylation biomarkers in a Greek clinical setting contributing to the development of a universal panel of urine biomarkers. MATERIALS AND METHODS: Individuals with primary BCa and control individuals matching the gender, age and smoking status of the cancer patients were recruited. DNA methylation was assessed for the gene promoters of RASSF1, RARB, DAPK, TERT and APC in urine samples collected by spontaneous urination using quantitative Methylation Specific PCR (qMSP). All genes had been previously separately associated with BCa. RESULTS: Fifty patients and 35 healthy controls were recruited, with average age of 70.26 years and average smoking status of 44.78 pack-years. In the BCa group, DNA methylation was detected in 27 (61.4%) samples. RASSF1 was methylated in 52.2% of samples. Only 3 (13.6%) samples from the control group were methylated, all in the RASSF1 gene promoter. The specificity and sensitivity of this panel of genes to diagnose BCa was 86% and 61% respectively. The RASSF1 gene could diagnose BCa with specificity 86.4% and sensitivity 52.3%. CONCLUSION: Promoter DNA methylation of this panel of five genes could be further investigated as urine biomarker for the diagnosis of BCa. The RASSF1 could be a single candidate biomarker for predicting BCa patients versus controls. Studies are required in order to develop a geographically adjusted diagnostic biomarker for BCa.

Assessment of patients with lower urinary tract symptoms where an undiagnosed neurological disease is suspected: A report from an International Continence Society consensus working group.

AIM: Lower urinary tract symptoms (LUTS) are a common urological referral, which sometimes can have a neurological basis in a patient with no formally diagnosed neurological disease ("occult neurology"). Early identification and specialist input is needed to avoid bad LUTS outcomes, and to initiate suitable neurological management. METHODS: The International Continence Society established a neurological working group to consider: Which neurological conditions may include LUTS as an early feature? What diagnostic evaluations should be undertaken in the LUTS clinic? A shortlist of conditions was drawn up by expert consensus and discussed at the annual congress of the International Neurourology Society. A multidisciplinary working group then generated recommendations for identifying clinical features and management. RESULTS: The relevant conditions are multiple sclerosis, multiple system atrophy, normal pressure hydrocephalus, early dementia, Parkinsonian syndromes (including early Parkinson's Disease and Multiple System Atrophy) and spinal cord disorders (including spina bifida occulta with tethered cord, and spinal stenosis). In LUTS clinics, the need is to identify additional atypical features; new onset severe LUTS (excluding infection), unusual aspects (eg, enuresis without chronic retention) or "suspicious" symptoms (eg, numbness, weakness, speech disturbance, gait disturbance, memory loss/cognitive impairment, and autonomic symptoms). Where occult neurology is suspected, healthcare professionals need to undertake early appropriate referral; central nervous system imaging booked from LUTS clinic is not recommended. CONCLUSIONS: Occult neurology is an uncommon underlying cause of LUTS, but it is essential to intervene promptly if suspected, and to establish suitable management pathways.

Improvement in overactive bladder symptoms in patients using functional electrical stimulation of the common peroneal nerve for walking.

OBJECTIVE: Functional electrical stimulation is used to improve walking speed and reduces falls in people with upper motor neurone foot-drop. Following anecdotal observations of changes in bladder symptoms, an observational study was performed to explore this association further. DESIGN: A total of 47 consecutive patients attending for setup with functional electrical stimulation during a six-month period were asked to complete a questionnaire assessing bladder symptoms (ICIQ-OAB (International Consultation on Incontinence Questionnaire Overactive Bladder)) at baseline and three months during routine appointments. SUBJECTS: In all, 35 (75%) had multiple sclerosis and the other 12 subjects had a total of 9 diagnoses including 3 with stroke. Other conditions included cerebral palsy, motor neurone disease, hereditary spastic paraparesis, meningioma and spinocerebellar ataxias. RESULTS: Improvement in overactive bladder symptoms was not significant in the whole cohort, however, was significant in patients with multiple sclerosis ( n = 35; mean change in ICIQ-OAB score 1.0, P = 0.043). Specifically, significant improvements were seen in urgency and urge incontinence in multiple sclerosis patients. There was a significant negative correlation of moderate strength within the multiple sclerosis cohort between baseline walking speed and subsequent change in ICIQ-OAB score (correlation coefficient of r = -0.40, P = 0.046). Thus, greater changes in bladder symptoms were seen with lower baseline walking speeds. CONCLUSION: The results of this exploratory study suggest that functional electrical stimulation use does improve overactive bladder symptoms in people with multiple sclerosis. Further exploration is needed to study this association and explore whether the mechanism is similar to that of percutaneous tibial nerve stimulation, a recognized treatment for the overactive bladder.

Neurogenic voiding dysfunction.

PURPOSE OF REVIEW: This review aims to analyze and discuss all recently published articles associated with neurogenic voiding discussion providing readers with the most updated knowledge and trigger for further research. RECENT FINDINGS: They include the proposal of a novel classification system for the pathophysiology of neurogenic lower urinary tract dysfunction (NLUTD) which combines neurological defect in a distinct anatomic location, and data on bowel dysfunction, autonomic dysreflexia and urine biomarkers; review of patient-reported outcome measures in NLUTD; review of the criteria for the diagnosis of clinically significant urinary infections; novel research findings on the pathophysiology of NLUTD; and review of data on minimally and more invasive treatments. SUMMARY: Despite the extended evidence base on NLUTD, there is a paucity of high-quality new research concerning voiding dysfunction as opposed to storage problems. The update aims to inform clinicians about new developments in clinical practice, as well as ignite discussion for further clinical and basic research in the aforementioned areas of NLUTD.