Do symptoms of sleepiness and insomnia in US veterans with obstructive sleep apnea vary by age?

INTRODUCTION: The influence of aging on the clinical presentation of obstructive sleep apnea (OSA) is not well characterized in US veterans. Our aims were to (1) examine age and established predictors of sleepiness and insomnia symptoms in veterans with OSA and (2) determine if the relationship between predictors of the Epworth sleepiness scale (ESS) and insomnia severity index (ISI) depended on age. METHODS: We performed a retrospective analysis of veterans diagnosed with OSA at the Miami VA in 2014. On polysomnography (PSG) night, questionnaires were completed querying socio-demographics, insomnia (ISI), sleepiness (ESS), and self-reported sleep duration. Regression modeling was performed to explore association of variables with (1) ESS and (2) ISI. Analyses were performed in two steps: (1) variables were tested for main effects and (2) product of age and each variable found to have an association at a significance level of p < 0.10 with primary outcome were entered separately to test for interaction. RESULTS: The sample consisted of 483 veterans (93% male, age 52 ± 13 years, 41% black, 34% Hispanic). Having a regular bed partner, higher weighted medical comorbidities, chronic pain diagnosis, and shorter sleep duration were associated with ESS. Age did not moderate the relationship between these variables and ESS. Younger age, Hispanic ethnicity, higher educational level, shorter sleep duration, mood, and pain diagnoses were each associated with the ISI. Furthermore, an age-sleep duration interaction term was associated with the ISI (b = - 0.03; p = 0.005). For all participants, there was an inverse relationship between sleep duration and ISI. However, for any sleep duration, older veterans reported lower levels of insomnia than younger veterans. DISCUSSION: Older veterans with OSA may report lower ISI scores. Alternative assessment methods for comorbid insomnia among older individuals with OSA may be needed.

Education Coupled With In-Situ High Fidelity Simulation Improves Medical-Surgical RN Code Blue Comfort Levels.

Pediatric, cardiopulmonary arrest is a rare event outside intensive care units in children's hospitals. Medical-surgical RNs rarely are involved in code situations and are often uncomfortable in performing necessary tasks. We implemented a multi-disciplinary educational plan, coupled with in-situ high-fidelity simulation, aimed at improving medical-surgical, RN comfort levels during codes. 260 medical surgical RNs on 10 separate hospital units parficipated. Pre and post intervention surveys were collected and compared. Results revealed a significant increase in the proportion of RNs responding "very comfortable" in all categories. Education, coupled with in-situ high-fidelity simulation, is an effective tool to increase RN comfortable levels during codes.

Urologist led one-stop testicular clinic: the UK 'gold standard'.

Prompt diagnosis and early treatment for testicular cancer is vital. To help with this a one-stop, urologist run, testicular clinic with testicular ultrasound scanning as an integral part of the clinic format was introduced to investigate patients in an efficient and timely manner. The aim of this study was to assess the feasibility and efficiency of running a one-stop testicular clinic. A prospectively collected electronic database of all patients attending a one-stop testicular clinic at a busy university hospital was interrogated over a 6-year period. Only new referral males, above the age of 15 years old were included. Case notes were reviewed retrospectively. A total of 1757 patients were found with a median age of 36. 6.3 % had a suspicious ultrasound scan and overall 5.6 % were found to have malignancy histologically. In addition a significant proportion of men with a history of testicular maldescent went on to develop testicular cancer (p < 0.01). Median time from referral to clinic and clinic to orchidectomy for suspected testicular cancers was 9 and 5 days respectively (95 % CI). Some of the benefits of a urologist run one-stop testicular clinic include: timely diagnosis and treatment, early reassurance with normal investigations, the discovery of clinically unsuspecting malignancy and the increase in teaching opportunities. These collective benefits must improve patient experience and benefit the department as a whole. A urologist led one-stop testicular clinic should be regarded as the gold standard.

Calcium channel blockade reduces mechanical strain-induced extracellular matrix gene response in lamina cribrosa cells.

PURPOSE: This study examines the effect of the L-type calcium channel blocker verapamil on mechanical strain-induced extracellular matrix genes in optic nerve head lamina cribrosa (LC) cells. METHODS: Changes in LC cell intracellular calcium [Ca(2+)]i following hypotonic cell membrane stretch were measured with the fluorescent probe fura-2/AM. Fluorescence intensity was measured, after labelling, by calcium (Ca2+) imaging confocal microscopy. Confluent human LC cell cultures were serum starved for 24 h prior to exposure to cyclical mechanical strain (1 Hz, 15%) for 24 h in the presence or absence of verapamil (10 mm). Transforming growth factor-ß 1 (TGF-ß1), collagen 6A3 (COL6A3) and chondroitin sulfate proteoglycan 2 (CSPG2) mRNA expression levels were assessed by quantitative RT-PCR. RESULTS: Hypotonic cell membrane stretch of LC cells from normal donors significantly increased [Ca2+]i (p<0.05). Exposure to cyclical mechanical strain (15% strain) produced a statistically significant increase in the three matrix genes that were examined (TGF-ß1, COL6A3 and CSPG2). This response in both cyclical and mechanical stretch was significantly reduced by pretreating LC cells with the L-type calcium channel blocker verapamil (p<0.05). CONCLUSIONS: This study provides evidence of a novel mechanotransduction pathway linking mechanical strain, cation channel function and the induction of LC cell matrix gene transcription. This highlights the potential involvement of calcium influx in the activation of matrix remodelling responses in the optic nerve head and supports the rationale that calcium channel blockers may attenuate disease progression in glaucoma.

Insomnia symptoms in South Florida military veterans with epilepsy.

BACKGROUND: Despite the high prevalence of insomnia in veterans with epilepsy, it remains understudied. Our aim was to identify the associations of insomnia with epilepsy, comorbidities, and treatment-related variables in South Florida veterans. METHODS: We performed a cross-sectional analysis of veterans attending an epilepsy clinic over 18 months. Participants completed standardized assessments of seizure and sleep. Insomnia was defined as 1) difficulty with sleep onset, maintenance, or premature awakenings with daytime consequences or 2) sedative-hypnotic use on most nights of the previous month. RESULTS: One hundred sixty-five veterans (87% male, age 56 ± 15 years) were included: 66 reporting insomnia (40%). In logistic regression analysis, insomnia was significantly associated with post-traumatic seizure etiology, lamotrigine prescription, and mood and psychotic disorders. Female gender and levetiracetam treatment were associated with lower odds for insomnia. CONCLUSION: Insomnia was associated with post-traumatic epilepsy, mood/psychotic comorbidities, and antiepileptic regimen. Insomnia represents an under-recognized opportunity to improve comprehensive epilepsy care.

Determinants of continuous positive airway pressure adherence in a sleep clinic cohort of South Florida Hispanic veterans.

PURPOSE: There are little existing data on continuous positive airway pressure (CPAP) adherence in US Hispanic veterans with obstructive sleep apnea (OSA). Our aim was to describe determinants of 1-month adherence in a sleep clinic cohort of South Florida Hispanic veterans. METHODS: Hispanic veterans referred to the Miami VA sleep clinic were recruited and completed questionnaires about sleep apnea risk, sleep quality, insomnia symptoms, sleepiness, depression/anxiety, acculturation, personality traits, and cognitions about OSA and CPAP. Individuals at risk for OSA were scheduled for baseline polysomnography (PSG), followed by in-lab CPAP titration or a trial of auto-CPAP. Participants with OSA accepting CPAP therapy were asked to return after 7 and 30 days of treatment for adherence verification and to repeat questionnaires. RESULTS: One hundred twenty-four participants (94 % men) were enrolled with 114 completing overnight PSG. Eighty-six out of 95 participants (91 %) with sleep apnea syndrome or moderate to severe OSA accepted CPAP treatment. Fifty-nine participants completed both follow-up visits with a mean CPAP use at 30 days of 3.6 ± 2.0 h. The only independent predictor of 7-day mean daily CPAP use was the baseline Insomnia Severity Index while the best predictor of 30-day mean daily CPAP use was the 7-day mean daily use. CONCLUSIONS: Our study suggests that South Florida Hispanic veterans with OSA evaluated in a sleep clinic show poor CPAP adherence. Insomnia and poor early use predicted poor adherence overall. Larger prospective studies with other race-ethnic groups are needed to determine the role of ethnicity and race in CPAP adherence among US veterans with OSA.

Sleep-related falling out of bed in Parkinson's disease.

BACKGROUND AND PURPOSE: Sleep-related falling out of bed (SFOB), with its potential for significant injury, has not been a strong focus of investigation in Parkinson's disease (PD) to date. We describe the demographic and clinical characteristics of PD patients with and without SFOB. METHODS: We performed a retrospective analysis of 50 consecutive PD patients, who completed an REM sleep behavior disorder screening questionnaire (RBDSQ), questionnaires to assess for RBD clinical mimickers and questions about SFOB and resulting injuries. Determination of high risk for RBD was based on an RBDSQ score of 5 or greater. RESULTS: Thirteen patients reported history of SFOB (26%). Visual hallucinations, sleep-related injury, quetiapine and amantadine use were more common in those patients reporting SFOB. Twenty-two patients (44%) fulfilled criteria for high risk for RBD, 12 of which (55%) reported SFOB. Five patients reported injuries related to SFOB. SFOB patients had higher RBDSQ scores than non-SFOB patients (8.2±3.0 vs. 3.3±2.0, p<0.01). For every one unit increase in RBDSQ score, the likelihood of SFOB increased two-fold (OR 2.4, 95% CI 1.3-4.2, p<0.003). CONCLUSIONS: SFOB may be a clinical marker of RBD in PD and should prompt confirmatory polysomnography and pharmacologic treatment to avoid imminent injury. Larger prospective studies are needed to identify risk factors for initial and recurrent SFOB in PD.

Insomnia characteristics and clinical correlates in Operation Enduring Freedom/Operation Iraqi Freedom veterans with post-traumatic stress disorder and mild traumatic brain injury: an exploratory study.

BACKGROUND: There is limited data on chronic insomnia in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans, in whom post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) often co-exist. Our aim was to compare sleep characteristics of three groups of OEF/OIF veterans: (1) healthy sleepers (HS), (2) those with insomnia associated with PTSD and mTBI (PTSD-mTBI), and (3) those with insomnia associated with PTSD alone. METHODS: Consecutive veterans with insomnia complaints (> 6 months) were recruited over 6 months from the Miami VA Post Deployment clinic. Participants completed a sleep disorders clinical interview, medical history, and questionnaires about insomnia, sleepiness, pain, fatigue, depression, PTSD, and health-related quality of life. They underwent polysomnography (PSG) with 2 weeks of actigraphy (ACT) and sleep diaries. RESULTS: There were no differences in demographics or most questionnaire responses between PTSD and PTSD-mTBI groups. Subjective daytime sleepiness was significantly greater in PTSD-mTBI subjects compared with HS and PTSD participants. Significant co-morbid sleep disorders were noted in insomnia patients. PSG and ACT wake after sleep onset was significantly shorter in PTSD-mTBI subjects as compared with PTSD participants. CONCLUSION: Insomnia patients with PTSD-mTBI were subjectively sleepier despite spending less time awake during the night than PTSD subjects, possibly as a consequence of head trauma.

Oxidative stress, mitochondrial dysfunction and calcium overload in human lamina cribrosa cells from glaucoma donors.

PURPOSE: Oxidative stress is implicit in the pathological changes associated with glaucoma. The purpose of this study was to compare levels of oxidative stress in glial fibrillary acid-negative protein (GFAP) lamina cribrosa (LC) cells obtained from the optic nerve head (ONH) region of 5 normal (NLC) and 4 glaucomatous (GLC) human donor eyes and to also examine mitochondrial function and calcium homeostasis in this region of the ONH. METHODS: Intracellular reactive oxygen species (ROS) production was examined by a thiobarbituric acid reactive substances (TBARS) assay which measures malondialdehyde (MDA), a naturally occurring product of lipid peroxidation and is used as an indicator of oxidative stress. Mitochondrial membrane potential (MMP) and intracellular calcium ([Ca(2+)](i)) levels were evaluated by flow cytometry using the JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetrabenzimidazolecarbocyanine iodide) and fluo-4/AM probes respectively. Anti-oxidant and Ca(2+) transport system gene and protein expression were determined by real time polymerase chain reaction (RT-PCR) using gene-specific primer/probe sets and western immunoblotting, respectively. RESULTS: Intracellular ROS production was increased in GLC compared to NLC (27.19 ± 7.05 µM MDA versus 14.59 ± 0.82 µM MDA, p < 0.05). Expression of the anti-oxidants Aldo-keto reductase family 1 member C1 (AKR1C1) and Glutamate cysteine ligase catalytic subunit (GCLC) were significantly lower in GLC (p = 0.02) compared to NLC control. MMP was lower in GLC (57.5 ± 6.8%) compared to NLC (41.8 ± 5.3%). [Ca(2+)](i) levels were found to be higher (p < 0.001) in GLC cells compared to NLC. Expression of the plasma membrane Ca(2+)/ATPase (PMCA) and the sodium-calcium (NCX) exchangers were lower, while intracellular sarco-endoplasmic reticulum Ca(2+)/ATPase 3 (SERCA) expression was significantly higher in GLC compared to NLC. Subjection of NLC cells to oxidative stress (200 µM H(2)0(2)) reduced expression of Na(+)/Ca2(+) exchanger 1 (NCX 1), plasma membrane Ca2+ ATPase 1 (PMCA 1), and PMCA 4 as determined by RT-PCR. CONCLUSIONS: Our data finds evidence of oxidative stress, mitochondrial dysfunction and impaired calcium extrusion in GLC cells compared to NLC cells and suggests their importance in the pathological changes occurring at the ONH in glaucoma. Future therapies may target reducing oxidative stress and / or [Ca(2+)](i).

Cadherin switching dictates the biology of transitional cell carcinoma of the bladder: ex vivo and in vitro studies.

Bladder cancer is the fifth most common malignancy in the UK. Clinically, the most important process in determining prognosis is the development of invasion, initially of the lamina propria and then beyond as these transitional cell carcinomas (TCCs) progress from stage pT1 to stages T2+. Cadherins and catenins are the main mediators of cell-cell interactions in epithelial tissues, and loss of membranous E-cadherin immunoreactivity is strongly correlated with high grade, advanced stage and poor prognosis in bladder cancer and other malignancies. However, the role of P-cadherin is yet to be fully elucidated in bladder TCC. The objectives of this study were to establish how the expression of cadherins and catenins determines clinical and in vitro behaviour in bladder TCC. Utilizing immunohistochemistry, immunofluorescence and western blotting, we demonstrated a significant reduction in the expression of E-cadherin and beta-catenin as grade and stage of bladder TCC progress, accompanied by a significant increase in P-cadherin expression (all p < 0.05, Pearson's chi2 test). Increased P-cadherin expression was also associated with a significantly worse bladder cancer-specific survival (log rank p = 0.008), with Cox regression showing P-cadherin to be an independent prognostic factor. Utilizing a variety of tissue culture models in a range of functional studies, we demonstrated that P-cadherin mediates defective cell-cell adhesion and enhances anchorage-independent growth. The results provide evidence that increased P-cadherin expression promotes a more malignant and invasive phenotype of bladder cancer, and appears to have a novel role late in the disease.

A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder.

PURPOSE: We conducted a multicenter randomized trial in the United Kingdom to determine the efficacy of radical radiotherapy in reducing the incidence of progression of pT1G3 transitional cell carcinoma of the bladder to muscle invasive disease and subsequent disease fatality. MATERIALS AND METHODS: Patients with a new diagnosis of pT1G3 NXM0 transitional cell carcinoma with unifocal disease and no carcinoma in situ (group 1), or with multifocal disease and/or carcinoma in situ (group 2) were eligible for the trial. Patients in group 1 were randomized between observation and radiotherapy to the bladder, and in group 2 between intravesical therapy and radiotherapy. RESULTS: From September 1991 to February 2003 a total of 210 patients from 37 centers in the United Kingdom were entered into the study. There were 77 patients in group 1 and 133 patients in group 2, and 6 patients were excluded from analysis because they were found to have pT2 disease by the reference pathologist. No evidence of an advantage with radiotherapy was found in terms of progression-free interval (hazard ratio 1.07; 95% CI 0.65, 1.74; p = 0.785), progression-free survival (hazard ratio 1.35; 95% CI 0.92, 1.98; p = 0.133) or overall survival (hazard ratio 1.32; 95% CI 0.86, 2.04; p = 0.193). CONCLUSIONS: To our knowledge this is the largest randomized trial performed in patients with pT1G3 disease for which 210 patients were recruited during 11 years. There is no evidence that radiotherapy is better than more conservative treatment. The prognosis of this group of patients appears to be poor irrespective of treatment and new treatment strategies need to be investigated.

Bicalutamide (Casodex) 150 mg plus standard care in early non-metastatic prostate cancer: results from Early Prostate Cancer Trial 24 at a median 7 years' follow-up.

Trial 24, one of three ongoing trials in the Early Prostate Cancer programme, is evaluating the efficacy and tolerability of bicalutamide (Casodex) 150 mg following standard care (radiotherapy, radical prostatectomy or watchful waiting) in patients with early, non-metastatic prostate cancer. At 7 years' median follow-up, addition of bicalutamide significantly improved objective progression-free survival (PFS) for patients with locally advanced disease, reducing the risk of progression by 34% versus standard care alone (hazard ratio 0.66; 95% confidence interval 0.55, 0.79; P<0.001). In localized disease, a significant difference in objective PFS was not found. There was no significant difference in overall survival.

Bicalutamide ('Casodex') 150 mg in addition to standard care in patients with nonmetastatic prostate cancer: updated results from a randomised double-blind phase III study (median follow-up 5.1 y) in the early prostate cancer programme.

Trial 24 is one of three placebo-controlled trials within the ongoing bicalutamide ('Casodex') Early Prostate Cancer (EPC) programme evaluating bicalutamide 150 mg/day in addition to radical prostatectomy, radiotherapy or watchful waiting for T1b-4, any N, M0 prostate cancer. In Trial 24, at 5.1 y median follow-up, the addition of bicalutamide significantly (P < 0.0001) improved objective progression-free survival (PFS) and prostate-specific antigen PFS compared with standard care alone. There was no significant difference in overall survival (P = 0.746). In the context of the whole EPC programme, long-term bicalutamide is not appropriate for localised disease, yet provides advantages in delaying disease progression in patients with locally advanced prostate cancer.

CD40 expression in prostate cancer: a potential diagnostic and therapeutic molecule.

CD40, a member of the TNF receptor superfamily, is widely expressed on human immune cells. It is also frequently expressed on epithelial malignancies, suggesting that CD40 may contribute to the pathogenesis of some cancers. Activation of CD40 in cancer cells induces growth inhibition and sensitization to apoptotic stimuli. This study investigates CD40 expression in archival tissue from patients with prostate cancer. In all cases, normal prostatic acini expressed CD40, however, in 56 of 57 cases of prostate cancer no CD40 expression was detected. In the one other case, patchy CD40 expression was associated with prostatic in situ neoplasia. In conclusion, invasive prostate cancer is a CD40-negative tumour. These data may be relevant as a diagnostic tool; in providing insight into progression of cancer from normal epithelium; and in identifying novel therapeutic strategies for prostate cancer.

An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium.

Screening of synthetic retinoids for activity against prostate carcinoma cell lines has identified antagonists of retinoic acid receptors (RARs) as potent growth inhibitors (Hammond et al, 2001, Br J Cancer 85, 453-462). Here we report that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of prostate carcinoma cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM. It had similar effects (at approximately 250 nM) on the prostate carcinoma lines LNCaP, DU-145 and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 microM. The growth of tumour cells was also inhibited more than that of normal cells when RARbeta together with RARgamma, but not RARalpha alone, were antagonised. Treatment of LNCaP cells with AGN194310 arrested them in G1 of cell cycle within 12 h, with an accompanying rise in the level of p21(waf1). The cells underwent apoptosis within 3 days, as indicated by mitochondrial depolarisation, Annexin V binding and DNA fragmentation. Apoptosis was caspase-independent: caspases were neither cleaved nor activated, and DNA fragmentation was unaffected by the pan-caspase inhibitor Z-VAD-FMK. The ability of AGN 194310 to induce apoptosis of prostate cancer cells and its differential effect on malignant and normal prostate epithelial cells suggests that this compound may be useful in the treatment of prostate cancer.

Is the efficacy of hormonal therapy affected by lymph node status? data from the bicalutamide (Casodex) Early Prostate Cancer program.

OBJECTIVES: To report an exploratory subgroup analysis assessing the extent to which the overall benefit found in the Early Prostate Cancer program is dependent on lymph node status at randomization. The program is ongoing, and the overall survival data are immature. The first combined analysis of the bicalutamide (Casodex) Early Prostate Cancer program at 3 years' median follow-up showed that bicalutamide, 150 mg once daily, plus standard care (radical prostatectomy, radiotherapy, or watchful waiting), significantly reduced the risk of objective progression and prostate-specific antigen (PSA) doubling in patients with localized/locally advanced prostate cancer. METHODS: Men (n = 8113) with localized/locally advanced disease received bicalutamide 150 mg or placebo once daily, plus standard care. The time to event data (objective progression, PSA doubling) was analyzed by lymph node status at randomization. RESULTS: Compared with standard care alone, bicalutamide significantly reduced the risk of objective progression, irrespective of lymph node status, with the most pronounced reduction in patients with N+ (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.15 to 0.56) compared with those with N0 (HR 0.59; 95% CI 0.48 to 0.73) and Nx (HR 0.60; 95% CI 0.50 to 0.72) disease. The largest decrease in risk of PSA doubling with bicalutamide was observed in N+ disease (HR 0.16; 95% CI 0.09 to 0.29), with significantly reduced risks seen in N0 (HR 0.45; 95% CI 0.40 to 0.51) and Nx (HR 0.38; 95% CI 0.33 to 0.44) disease. CONCLUSIONS: The greatest reduction in the risk of objective progression and PSA doubling with bicalutamide was seen in patients with N+ disease. However, bicalutamide also provided a statistically significant benefit in those with N0 and Nx disease.

Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.

We conducted a phase I/II study investigating synchronous chemoradiotherapy with mitomycin C and infusional 5-fluorouracil (5-FU) in muscle invasive bladder cancer. Early dose escalation results were previously published. We report the long-term toxicity and efficacy results with the optimised regimen. Patients with muscle invasive bladder cancer with glomerular filtration rate >25 ml min(-1) were eligible. Mitomycin (12 mg m(-2) on day 1 only) and infusional 5-FU (500 mg m(-2) day(-1)) for 5 days were administered during weeks 1 and 4 of radiotherapy of 55 Gy in 20 fractions. A total of 41 patients were enrolled, median age was 68 years, 33 were male and eight female patients. Out of the 41 patients, 20 (49%) had hydronephrosis at presentation and 25 (62%) had T3b or T4 disease. Four patients experienced Grade III thrombocytopenia and three patients had Grade III neutropenia. There were no episodes of febrile neutropenia. Four patients experienced Grade III diarrhoea and 1 Grade III urgency and dysuria. Six patients did not undergo cystoscopic evaluation due to early metastatic spread although there was no clinical suggestion of bladder failure. In all, out of 35 evaluable patients, 25 (71%) had macroscopic complete response at 3-month cystoscopy, and biopsy confirmed in 24 out of 25. A total of 16 (39%) patients remain alive with a median follow-up of 50.7 (range 23.5-68.8) months, 14 with a functioning bladder with no reported long-term treatment-related bladder or bowel toxicity. Five out of 41 patients have undergone salvage cystectomy: two for persistent CIS, two T1 and one muscle invasive recurrence. Four patients have received intravesical chemotherapy, of whom two remain alive with a functioning bladder. Overall 12-, 24- and 60-month (m) survival rates were 68, 49 and 36%. Local and distant progression free rates were 82 and 86% at 12-m and 79 and 75% at 24-m. Organ preservation using multimodality therapy is feasible and safe, even in patients with poor renal reserve, and does not compromise salvage therapies. A national phase III trial BC2001 (www.bc2001.org.uk) exploring the effects of synchronous chemoradiotherapy with this regimen is currently recruiting.

The role of beta-catenin signaling in the malignant potential of cystitis glandularis.

PURPOSE: Chronic inflammation is a risk factor for malignant transformation in the bladder. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) is a mediator of such inflammation that induces nuclear localization of the adherens junction component beta-catenin. This mechanism has a key role in the initiation and progression of the premalignant lesion Barrett's metaplasia of the esophagus. Cystitis glandularis is a metaplastic lesion of the bladder urothelium occurring in the presence of chronic inflammation and in up to 13% of asymptomatic bladders. Two subtypes are described (typical and intestinal/colonic) with uncertain malignant potential. Etiologically and histologically cystitis glandularis mimics Barrett's metaplasia. We investigated the roles of beta-catenin and TNFalpha in cystitis glandularis. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence were used to demonstrate the expression and localization of E-cadherin, beta-catenin and TNFalpha in 9 sections of typical cystitis glandularis and 4 of intestinal/colonic cystitis glandularis. Appropriate controls were used for all experiments. RESULTS: Immunohistochemistry demonstrated normal membranous expression of E-cadherin and beta-catenin in all cystitis glandularis sections with increased TNFalpha expression. Immunofluorescence showed nuclear localization of beta-catenin in the intestinal/colonic subtype only, which was not observed in typical cystitis glandularis. CONCLUSIONS: The presence of nuclear beta-catenin suggests that intestinal/colonic cystitis glandularis shares the same signaling pathway with the premalignant lesion Barrett's metaplasia of the esophagus and the intestinal/colonic subtype of cystitis glandularis may have the potential to progress to malignancy. This finding has important implications for the management of this lesion.