Helios Hospital Schwerin

INTRODUCTION: Next to existing terminology of the lower urinary tract, due to its increasing complexity, the terminology for pelvic floor dysfunction in women may be better updated by a female-specific approach and clinically based consensus report. METHODS: This report combines the input of members of the Standardization and Terminology Committees of two international organizations, the International Urogynecological Association (IUGA), and the International Continence Society (ICS), assisted at intervals by many external referees. Appropriate core clinical categories and a subclassification were developed to give an alphanumeric coding to each definition. An extensive process of 15 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A terminology report for female pelvic floor dysfunction, encompassing over 250 separate definitions, has been developed. It is clinically based with the six most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Female-specific imaging (ultrasound, radiology, and MRI) has been a major addition while appropriate figures have been included to supplement and help clarify the text. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

OBJECTIVE: Physical activity (PA) can improve cardiovascular risk in the general population and in patients with type 2 diabetes. Studies also indicate an HbA(1c)-lowering effect in patients with type 2 diabetes. Since reports in patients with type 1 diabetes are scarce, this analysis aimed to investigate whether there is an association between PA and glycemic control or cardiovascular risk in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 18,028 adults (≥18 to <80 years of age) from Germany and Austria with type 1 diabetes from the Diabetes-Patienten-Verlaufsdokumentation (DPV) database were included. Patients were stratified according to their self-reported frequency of PA (PA0, inactive; PA1, one to two times per week; PA2, more than two times per week). Multivariable regression models were applied for glycemic control, diabetes-related comorbidities, and cardiovascular risk factors. Data were adjusted for sex, age, and diabetes duration. P values for trend were given. SAS 9.4 was used for statistical analysis. RESULTS: An inverse association between PA and HbA(1c), diabetic ketoacidosis, BMI, dyslipidemia (all P < 0.0001), and hypertension (P = 0.0150), as well as between PA and retinopathy or microalbuminuria (both P < 0.0001), was present. Severe hypoglycemia (assistance required) did not differ in PA groups (P = 0.8989), whereas severe hypoglycemia with coma was inversely associated with PA (P < 0.0001). CONCLUSIONS: PA seemed to be beneficial with respect to glycemic control, diabetes-related comorbidities, and cardiovascular risk factors without an increase of adverse events. Hence, our data underscore the recommendation for subjects with type 1 diabetes to perform regular PA.

OBJECTIVE: To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. DESIGN: Multicentre retrospective case-control study. SETTING: 23 hospitals in northern Germany. PARTICIPANTS: 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. MAIN OUTCOME MEASURES: Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. RESULTS: 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P = 0.03), fewer deaths (0% v 5%, p = 0.029), required no abdominal surgery, and excreted E coli for a shorter duration. CONCLUSIONS: Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

PURPOSE: Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. MATERIALS AND METHODS: An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. RESULTS: Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. CONCLUSIONS: Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.

BACKGROUND: May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases. METHODS: To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). RESULTS: Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. CONCLUSIONS: Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

BACKGROUND AND PURPOSE: Incomplete occlusion and recanalization of large and wide-neck brain aneurysms treated by endovascular therapy remains a challenge. We present preliminary clinical and angiographic results of an experimentally optimized Surpass flow diverter for treatment of intracranial aneurysms in a prospective, multicenter, nonrandomized, single-arm study. MATERIALS AND METHODS: At 24 centers, 165 patients with 190 intracranial aneurysms of the anterior and posterior circulations were enrolled. The primary efficacy end point was the percentage of intracranial aneurysms with 100% occlusion on 6-month DSA. The primary safety end point was neurologic death and any stroke through a minimum follow-up of 6 months. RESULTS: Successful flow-diverter delivery was achieved in 161 patients with 186 aneurysms (98%); the mean number of devices used per aneurysm was 1.05. Clinical follow-up (median, 6 months) of 150 patients (93.2%), showed that the primary safety end point occurred in 18 subjects. Permanent neurologic morbidity and mortality were 6% and 2.7%, respectively. Morbidity occurred in 4% and 7.4% of patients treated for aneurysms of the anterior and posterior circulation, respectively. Neurologic death during follow-up was observed in 1.6% and 7.4% of patients with treated intracranial aneurysms of the anterior and posterior circulation, respectively. Ischemic stroke at ≤30 days, SAH at ≤7 days, and intraparenchymal hemorrhage at ≤7 days were encountered in 3.7%, 2.5%, and 2.5% of subjects, respectively. No disabling ischemic strokes at >30 days or SAH at >7 days occurred. New or worsening cranial nerve deficit was observed in 2.7%. Follow-up angiography available in 158 (86.8%) intracranial aneurysms showed 100% occlusion in 75%. CONCLUSIONS: Clinical outcomes of the Surpass flow diverter in the treatment of intracranial aneurysms show a safety profile that is comparable with that of stent-assisted coil embolization. Angiographic results showed a high rate of intracranial aneurysm occlusion.

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thyroid dysfunctions. Advances in mathematical and simulative modeling of pituitary-thyroid feedback control have improved our understanding of physiological mechanisms governing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel's TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

OBJECTIVE: Evidence based on controlled studies is still limited for treatment strategies that prevent recurrence of suicide attempts. Findings from observational as well as meta-analytic studies strongly suggest that lithium may have suicide-protective properties. METHOD: Patients with a recent suicide attempt in the context of an affective spectrum disorder (n = 167) were treated with either lithium or placebo during a 12-month period. RESULTS: Survival analysis showed no significant difference of suicidal acts between lithium and placebo-treated individuals (adjusted hazard ratio 0.517; 95% CI 0.18-1.43). However, post hoc analysis revealed that all completed suicides had occurred in the placebo group accounting for a significant difference in incidence rates (P = 0.049). CONCLUSION: Results indicate that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with affective disorders. Our findings contribute to the growing body of evidence suggesting a specific antisuicidal effect of lithium.

Neonatal alloimmune thrombocytopenia (NAIT) is a fetomaternal incompatibility most commonly induced by maternal anti-HPA-1a, IgG alloantibodies against a polymorphic epitope of the glycoprotein IIb/IIIa complex in approximately 97.5% of white patients. Current guidelines recommend transfusion of immunologically compatible platelets to prevent cerebral hemorrhage, the most severe complication in affected newborns. Such platelet concentrates, however, are often not readily available. In a retrospective analysis in German and Canadian centers, 27 newborns with NAIT were identified who received platelets from random donors. Unexpectedly, 24 of 27 newborns showed an increase above a threshold of 40 x 10(9) platelets per liter, with moderate (n = 8) or significant (n = 16) platelet count increments (more than 80 x 10(9)/L). We conclude that transfusion of platelet concentrates from random donors is an appropriate strategy in the management of unexpected, severe NAIT predominantly in first pregnancies, pending the availability of compatible platelets.

Abstract Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions 1–3 . Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus 4,5 . This suggests that mutations in disordered proteins may alter condensate properties and function 6–8 . Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

PURPOSE: Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A standard definition of nonmuscle invasive bladder cancer progression as determined by reproducible and reliable procedures is needed. We examine current definitions of nonmuscle invasive bladder cancer progression, and propose a new definition that will be more clinically useful in determining patient prognosis and comparing treatment options. MATERIALS AND METHODS: The IBCG (International Bladder Cancer Group) analyzed published clinical trials and meta-analyses that examined nonmuscle invasive bladder cancer progression as of December 2012. The limitations of the definitions of progression used in these trials were considered, as were additional parameters associated with the advancement of nonmuscle invasive bladder cancer. RESULTS: The most commonly used definition of nonmuscle invasive bladder cancer progression is an increase in stage from nonmuscle invasive to muscle invasive disease. Although this definition is clinically important, it fails to include other important parameters of advancing disease such as progression to lamina propria invasion and increase in grade. CONCLUSIONS: The IBCG proposes the definition of nonmuscle invasive bladder cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high. Investigators should consider the use of this new definition to help standardize protocols and improve the reporting of progression.

AIMS: Considerable differences in the long-term trends of heart failure (HF) exist between different countries. To extend the existing knowledge on HF epidemiology in Germany, we analysed trends of HF-related hospitalizations, hospital days and in-hospital deaths during a 14-year period (2000-2013). METHODS AND RESULTS: Data were derived from the official German Federal Health Monitoring System, which includes an annual and complete enumeration of inpatients at the time of discharge from the hospital. HF cases were identified by the primary diagnosis code for HF (I50). From 2000 to 2013, the absolute number of HF-related hospitalizations increased by 65.4% (239 694-396 380 cases) and by 28.4% after age-standardization (261-335 per 100 000 population). Accordingly, the absolute number of HF-related hospital days increased by 22.1% (3.4-4.2 million hospital days), despite a marked decrease by 25.9% in average length of stay (14.3-10.6 days). With approximately 35 000 in-hospital deaths (∼45 per 100 000 population), the annual number of HF-related in-hospital deaths remained consistently high, and in-hospital mortality rate in HF patients constituted 9.3% in 2013. Patients aged >65 years were disproportionately affected. In 2013, HF was the leading cause of disease-related hospitalizations and in-hospital deaths, representing 2.1% and 8.8% of all cases, respectively. CONCLUSION: In Germany, the burden of HF is growing further, and the risk of death in HF remains high. These trends can only be partly attributed to demographic developments suggesting an exigent need for increased awareness and enhanced efforts in the prevention and management of HF.

OBJECTIVE: To investigate the efficacy and safety of levodopa plus benserazide in the treatment of restless legs syndrome (RLS), in terms of the frequency of periodic limb movements (PLMs), objective and subjective criteria of sleep, onset of action, and withdrawal effects. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, crossover trial, with two 4-week treatment periods. SETTING: Outpatient units of three specialist centers in Germany. PATIENTS: Eligible patients had to fulfill the diagnostic criteria of the International RLS Study Group and have sleep disturbances and PLMs during sleep shown on polysomnography at screening. Thirty-five patients were recruited, of whom 32 (13 men, 19 women) completed the study. INTERVENTIONS: Patients received a single dose of standard-release levodopa/benserazide 100/25 mg or placebo at bedtime each night for 4 weeks, before crossing over to receive the alternative treatment for a further 4 weeks; the dose could be doubled if required. The average dosages were 159 +/- 31 mg of levodopa and 1.56 +/- 0.29 capsules of placebo. RESULTS: Levodopa/benserazide significantly reduced the number of PLMs per hour (p<0.0001), increased the time in bed without limb movements (p<0.0001), and improved subjective quality of sleep (p=0.0004). The onset of action was rapid after the first dose, and full efficacy was achieved within the first few days of therapy; these improvements disappeared immediately when treatment was discontinued. Levodopa/benserazide treatment was well tolerated and safe. CONCLUSIONS: Levodopa/benserazide is effective and safe in the treatment of RLS. Objective and subjective measures of sleep improved rapidly after the first dose. RLS symptoms recurred immediately after treatment was discontinued.

Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p&lt;0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10 −10 and 0.002 (OR allelic =1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Several lines of evidence point to an involvement of the olivo-cerebellar system in the pathogenesis of essential tremor (ET), with clinical signs of cerebellar dysfunction being present in some subjects in the advanced stage. Besides motor coordination, the cerebellum is critically involved in motor learning. Evidence of motor learning deficits would strengthen the hypothesis of olivo-cerebellar involvement in ET. Conditioning of the eyeblink reflex is a well-established paradigm to assess motor learning. Twenty-three ET subjects (13 males, 10 females; mean age 44.3 +/- 22.3 years, mean disease duration 17.4 +/- 17.3 years) and 23 age-matched healthy controls were studied on two consecutive days using a standard delay eyeblink conditioning protocol. Six ET subjects exhibited accompanying clinical signs of cerebellar dysfunction. Care was taken to examine subjects without medication affecting central nervous functioning. Seven ET subjects and three controls on low-dose beta-blocker treatments, which had no effect on eyeblink conditioning in animal studies, were allowed into the study. The ability to acquire conditioned eyeblink responses was significantly reduced in ET subjects compared with controls. Impairment of eyeblink conditioning was not due to low-dose beta-blocker medication. Additionally, acquisition of conditioned eyeblink response was reduced in ET subjects regardless of the presence of cerebellar signs in clinical examination. There were no differences in timing or extinction of conditioned responses between groups and conditioning deficits did not correlate with the degree of tremor or ataxia as rated by clinical scores. The findings of disordered eyeblink conditioning support the hypothesis that ET is caused by a functional disturbance of olivo-cerebellar circuits which may cause cerebellar dysfunction. In particular, results point to an involvement of the olivo-cerebellar system in early stages of ET.

OBJECTIVE: Pheochromocytomas are rare chromaffin cell-derived tumors causing paroxysmal episodes of headache, palpitation, sweating and hypertension. Life-threatening complications have been described in case reports and small series. Systematic analyses are not available. We took an opportunity of a large series to make a survey. DESIGN AND METHODS: We analyzed records of patients diagnosed with pheochromocytomas in three geographically spread German referral centers between 2003 and 2012 (n=135). RESULTS: Eleven percent of the patients (ten women, five men) required in-hospital treatment on intensive care units (ICUs) due to complications caused by unsuspected pheochromocytomas. The main reasons for ICU admission were acute catecholamine induced Tako-Tsubo cardiomyopathy (n=4), myocardial infarction (n=2), acute pulmonary edema (n=2), cerebrovascular stroke (n=2), ischemic ileus (n=1), acute renal failure (n=2), and multi organ failure (n=1). One patient required extracorporeal membrane oxygenation due to a hypertensive crisis with lung edema occurring during delivery (n=1). Two patients died of refractory shock and pheochromocytomas were found postmortem. Two patients were treated by emergency surgery. Compared to pheochromocytoma patients without life-threatening events (n=120), patients with complications had a significant larger maximal tumor diameter (7.0 vs 4.5 cm, P<0.01), higher levels of catecholamines (20- vs ninefold upper limit of normal, P<0.01), and tended to be younger (42 vs 51 years, P=0.05). CONCLUSION: Although pheochromocytomas are rare, they are likely to be associated with a life-threatening situation. Clinicians have to be aware of these situations and perform a timely diagnosis.

OBJECTIVE: To assess the efficacy and safety of the dopamine agonist cabergoline (CAB) in patients with restless legs syndrome (RLS). METHODS: Patients with moderate to severe RLS were randomized into four groups receiving placebo, 0.5 mg, 1 mg, or 2 mg CAB once daily in a double-blind, placebo-controlled, multicenter dose-finding trial followed by an open long-term extension trial of 47 weeks. Efficacy was assessed with the RLS-6 scales and International RLS Study Group severity scale (IRLS). RESULTS: A total of 85 patients (age 56 +/- 10 years, 71% females) were treated. Severity of RLS-6 scale symptoms during the night (the primary endpoint) was markedly improved by all CAB doses compared to placebo (placebo: -1.4 +/- 3.1, 0.5 mg CAB: -4.2 +/- 3.0 [p = 0.0082], 1.0 mg CAB: -4.0 +/- 2.9 [p = 0.0040], 2.0 mg CAB: -4.8 +/- 3.7 [p = 0.0026]). Similar results were found for the RLS severity at bedtime and during the day, IRLS, and satisfaction with sleep. A stable, clinically relevant improvement was achieved in all efficacy measures (severity during the night: change between last assessment and baseline: -5.6 +/- 2.5, rate of remission: 71.2%) throughout 1 year with a mean CAB dose of 2.2 mg per day. During long-term treatment, 6 of 66 treated patients were affected (n = 2) or possibly affected (n = 4) by mild augmentation. Under CAB therapy up to 1 year, 11 of 85 patients discontinued treatment due to a drug-related adverse event. CONCLUSIONS: Cabergoline is an efficacious and well-tolerated option for the treatment of restless legs symptoms during the night and the day.

PURPOSE: Low, intermediate and high risk categories have been defined to help guide the treatment of patients with nonmuscle invasive bladder cancer (Ta, T1, CIS). However, while low and high risk disease has been well classified, the intermediate risk category has traditionally comprised a heterogeneous group that does not fit into either of these categories. As a result, many urologists remain uncertain about the categorization of patients as intermediate risk as well as the selection of the most appropriate therapeutic option for this patient population. We review the current literature and clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer and, based on our findings, provide urologists with a better understanding of this heterogeneous risk group as well as practical recommendations for the treatment of intermediate risk patients. MATERIALS AND METHODS: The IBCG analyzed published clinical trials, meta-analyses and current clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer available as of September 2013. The definitions of intermediate risk, patient outcomes and guideline recommendations were considered, as were the limitations of the available literature and additional parameters that may be useful in guiding treatment decisions in intermediate risk patients. RESULTS: Current definitions and management recommendations for intermediate risk nonmuscle invasive bladder cancer vary. The most simple and practical definition is that proposed by the IBCG and the AUA of multiple and/or recurrent low grade Ta tumors. The IBCG suggests that several factors should be considered in clinical decisions in intermediate risk disease, including number (greater than 1) and size (greater than 3 cm) of tumors, timing (recurrence within 1 year) and frequency (more than 1 per year) of recurrence, and previous treatment. In patients without these risk factors a single, immediate instillation of chemotherapy is advised. In those with 1 to 2 risk factors adjuvant intravesical therapy (intravesical chemotherapy or maintenance bacillus Calmette-Guérin) is recommended, and previous intravesical therapy should be considered when choosing between these adjuvant therapies. For those patients with 3 to 4 risk factors, maintenance bacillus Calmette-Guérin is recommended. It is also important that all intermediate risk patients are accurately risk stratified at initial diagnosis and during subsequent followup. This requires appropriate transurethral resection of the bladder tumor, vigilance to rule out carcinoma in situ or other potential high risk tumors, and review of histological material directly with the pathologist. CONCLUSIONS: Intermediate risk disease is a heterogeneous category, and there is a paucity of independent studies comparing therapies and outcomes in subgroups of intermediate risk patients. The IBCG has proposed a management algorithm that considers tumor characteristics, timing and frequency of recurrence, and previous treatment. Subgroup analyses of intermediate risk subjects in pivotal EORTC trials and meta-analyses will be important to validate the proposed algorithm and support clear evidence-based recommendations for subgroups of intermediate risk patients.

We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline.

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (> or =300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time.