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Background There is still no reference standard for the implantation of totally implantable venous access ports (TIVAPs). A recently published multicentre randomised controlled trial (RCT) revealed a significantly greater risk of pneumothorax after closed cannulation than after an open strategy. The aim of this meta-analysis was to provide an update of the available evidence for the safety and effectiveness of primary open versus closed cannulation strategy. Methods RCTs comparing outcomes of open cut-down of the cephalic vein and closed cannulation of the subclavian vein were sought systematically in MEDLINE, Web of Science and CENTRAL. The primary outcome was the occurrence of pneumothorax. A beta-binominal model was applied to combine the respective outcomes, and results are presented as odds ratios (OR) with 95% confidence interval (CI). Results Six RCTs with a total of 1831 patients were included in final analysis. Meta-analysis showed statistically significant superiority of the open cut-down technique regarding pneumothorax (OR 0.308, 95% CI 0.122 to 0.776), but a statistically significant higher failure of the primary technique for the open cut-down technique than for closed cannulation (OR 2.364, 95% CI 1.051 to 5.315). There were no significant differences between the two procedures regarding other morbidity endpoints. Conclusion This meta-analysis shows a general superiority of open cut-down of the cephalic vein over closed cannulation of the subclavian vein regarding the occurrence of pneumothorax. Open cut-down should be the first-line approach for TIVAP implantation. Closed cannulation should be performed with ultrasound as second-line procedure if the open technique fails. Systematic review registration PROSPERO CRD42013005180

OBJECTIVE Generation of pilot data for planning of prospective BET-studies for treatment of dilatory Eustachian tube (ET) dysfunction in children. STUDY DESIGN Retrospective multicenter analysis. SETTING Nine ENT departments at tertiary care teaching hospitals. PATIENTS 4-12-year-old children with chronic otitis media with effusion (COME) for more than 3 months or more than 3 episodes of acute otitis media during the last year, having failed standard surgical therapy at least once. INTERVENTION BET with or without paracentesis, ventilation tube insertion, or tympanoplasty. MAIN OUTCOME MEASURES Tympanic membrane appearance, tympanometry, and hearing threshold. RESULTS Two hundred ninety-nine ETs of 167 children were treated. Mean age was 9.1 years (95% confidence interval [95% CI]: 8.7-9.4 yr). In 249 ears (83.3%), COME and/or retraction of the tympanic membrane were the indication for BET. Median hearing threshold was 20 dB HL (95% CI: 0-46 dB). One hundred fifty-five ears (51.8%, 95% CI: 46.1-57.4%) showed a tympanogram type B. Treatment consisted of BET without other interventions ("BET-only") in 70 children, 128 ears. Median length of follow-up for 158 (94.6%) children was 2.6 months (95% CI: 0.3-16.1 mo). After treatment, the tympanic membrane appeared normal in 196 ears (65.6%, 95% CI: 60.0-70.8%, p

Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.

Abstract. Abstracts: Objective: In current international research, early intervention in children with autism-spectrum disorder (ASD) focuses on naturalistic developmental behavioral interventions (NDBI). The manualized Frankfurt Early Intervention Program for preschool-aged children with ASD (A-FFIP) implements NDBI principles within a low-intensity approach of 2 h intervention/week. The present case-control study established effect sizes of change in autistic symptoms, comorbid behavioral problems as well as IQ after one year. Methodology: An intervention group ( N = 20; age: 3.4–7.9 years) and a treatment-as-usual control group ( N = 20; age: 3.2–7.3 years) of children with ASD were matched for developmental and chronological age. The outcome measures used were the ADOS severity score, the Child Behavior Checklist, and cognitive development. Results: After one year, the A-FFIP group showed a trend towards greater improvement in autistic symptoms (η 2 = .087 [95 %-CI: .000–.159]) and significantly greater improvements in cognitive development (η 2 = .206 [CI: .012–.252]) and global psychopathology (η 2 = .144 [CI: .001–.205]) compared to the control group. Conclusion: The efficacy of A-FFIP should be established in a larger, sufficiently powered, randomized controlled study.

Background Despite numerous studies and meta-analyses the prognostic effect of cardiac rehabilitation is still under debate. This update of the Cardiac Rehabilitation Outcome Study (CROS II) provides a contemporary and practice focused approach including only cardiac rehabilitation interventions based on published standards and core components to evaluate cardiac rehabilitation delivery and effectiveness in improving patient prognosis. Design A systematic review and meta-analysis. Methods Randomised controlled trials and retrospective and prospective controlled cohort studies evaluating patients after acute coronary syndrome, coronary artery bypass grafting or mixed populations with coronary artery disease published until September 2018 were included. Results Based on CROS inclusion criteria out of 7096 abstracts six additional studies including 8671 patients were identified (two randomised controlled trials, two retrospective controlled cohort studies, two prospective controlled cohort studies). In total, 31 studies including 228,337 patients were available for this meta-analysis (three randomised controlled trials, nine prospective controlled cohort studies, 19 retrospective controlled cohort studies; 50,653 patients after acute coronary syndrome 14,583, after coronary artery bypass grafting 163,101, mixed coronary artery disease populations; follow-up periods ranging from 9 months to 14 years). Heterogeneity in design, cardiac rehabilitation delivery, biometrical assessment and potential confounders was considerable. Controlled cohort studies showed a significantly reduced total mortality (primary endpoint) after cardiac rehabilitation participation in patients after acute coronary syndrome (prospective controlled cohort studies: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20–0.69; retrospective controlled cohort studies HR 0.64, 95% CI 0.53–0.76; prospective controlled cohort studies odds ratio 0.20, 95% CI 0.08–0.48), but the single randomised controlled trial fulfilling the CROS inclusion criteria showed neutral results. Cardiac rehabilitation participation was also associated with reduced total mortality in patients after coronary artery bypass grafting (retrospective controlled cohort studies HR 0.62, 95% CI 0.54–0.70, one single randomised controlled trial without fatal events), and in mixed coronary artery disease populations (retrospective controlled cohort studies HR 0.52, 95% CI 0.36–0.77; two out of 10 controlled cohort studies with neutral results). Conclusion CROS II confirms the effectiveness of cardiac rehabilitation participation after acute coronary syndrome and after coronary artery bypass grafting in actual clinical practice by reducing total mortality under the conditions of current evidence-based coronary artery disease treatment. The data of CROS II, however, underscore the urgent need to define internationally accepted minimal standards for cardiac rehabilitation delivery as well as for scientific evaluation.

Individualized therapies for patients with biomarkers are moving more and more into the focus of research interest when developing new treatments. Hereby, the term individualized (or targeted) therapy denotes a treatment specifically developed for biomarker-positive patients. A network meta-analysis model for a binary endpoint combining the evidence for a targeted therapy from individual patient data with the evidence for a non-targeted therapy from aggregate data is presented and investigated. The biomarker status of the patients is either available at patient-level in individual patient data or at study-level in aggregate data. Both types of biomarker information have to be included. The evidence synthesis model follows a Bayesian approach and applies a meta-regression to the studies with aggregate data. In a simulation study, we address three treatment arms, one of them investigating a targeted therapy. The bias and the root-mean-square error of the treatment effect estimate for the subgroup of biomarker-positive patients based on studies with aggregate data are investigated. Thereby, the meta-regression approach is compared to approaches applying alternative solutions. The regression approach has a surprisingly small bias even in the presence of few studies. By contrast, the root-mean-square error is relatively greater. An illustrative example is provided demonstrating implementation of the presented network meta-analysis model in a clinical setting.

Background Current guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial. Methods PubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided. Results Ten randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P = .23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P = .07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P = .12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P = .002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P = .004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities. Conclusions Intensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To compare and rank preoperative chemoradiotherapy and chemotherapy treatment modalities for patients with resectable adenocarcinoma of the esophagus and esophagogastric junction, in terms of overall survival and other patient‐relevant outcomes, by conducting a network meta‐analysis.

Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases. Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the “Association of the Scientific Medical Societies in Germany” (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation. Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction

Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients’ groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.

Objective To systematically evaluate evidence on prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance. Methods Systematic literature search conducted of Medline, Web of Science, Cochrane Library, and the conference proceedings of the ASCO, AUA, and EAU meetings (last search: October 2016), according to our prospectively registered protocol (PROSPERO registration number CRD42014009434). Identified records were reviewed according to the Cochrane Method Group of Prognosis Reviews recommendations and the PRISMA reporting guideline. Study quality was appraised with the Quality in Prognosis Studies (QUIPS) tool. Results Nineteen studies reporting on 26 potential prognostic factors were included in our analysis. Among the most frequently reported factors, tumor size (continuous or dichotomized) was significantly associated with relapse in 10/14 studies with a hazard ratio (HR) ranging from 1.33 (95% confidence interval [CI]: 1.14–1.56) to 3.17 (95% CI: 1.08–9.26). Rete testis invasion was significantly associated with relapse in only 4/13 studies with a HR ranging from 1.18 (95% CI: 0.92–1.51) to 1.36 (95% CI: 0.81–2.28). Lymphovascular invasion, young age, and preoperative HCG level had no association with relapse. Our findings are limited by heterogeneity of study designs, potential reporting bias, and moderate-to-poor study quality. Conclusion In stage I seminoma, tumor size is the most valuable prognostic factor on which to base relapse risk and to counsel patients about adjuvant treatment. Large tumor size was defined quite inhomogenously among the included studies, so no distinct cutoff value for tumor size can be recommended. Other potential prognostic factors including rete testis invasion play a minor role in stage I seminoma.

SummaryBackground Ultrasound measurements of the airway are useful for determining correctly sized, uncuffed endotracheal tubes in children. Aims The primary objective of this study was to evaluate the influence of ventilation pressure on the sonographically measured tracheal diameter at different levels. Methods A total of 100 patients (under 7 years) were enrolled in this study. Six sonographic measurements of minimal transverse diameters at 3 locations (vocal chords, cricoid cartilage, and proximal trachea) and at 2 different ventilation pressures (0 and 15 mbar) were performed before the intubation procedure. The intubating anesthesiologists were blinded to the results of the ultrasound measurements. The rate of agreement of the outer diameter of the correctly sized endotracheal tube (reference) with the 6 sonographic diameters was determined. In addition, the correct tube sizes were compared with the results of traditional prediction methods (Penlington's and Cole's formula in children ≥1 year and a decision table in children

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. We retrieved PubMed/Medline literatures on genotype–phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta-analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p

Background Recurrence of colorectal liver metastases after a first hepatectomy is common (4–48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. Methods A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. Results In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. Discussion Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life.

Background Patients with non-ischemic dilated cardiomyopathy (NIDCM) are at increased risk of ventricular arrhythmias and sudden cardiac death (SCD). However, identifying patients at high risk for life-threatening ventricular arrhythmia (LTVA) who may benefit from an implantable cardioverter defibrillator (ICD) remains challenging. Methods We searched MEDLINE and EMBASE for prognostic studies describing predictors of LTVA (defined as sustained ventricular tachycardia (VT), haemodynamically unstable VT, ventricular fibrillation, (aborted) SCD or appropriate ICD intervention) in patients with NIDCM. We excluded articles with composite heart failure and arrhythmic endpoints but lacking (subgroup) analysis for LTVA. Study quality and risk of bias was assessed using the QUIPS-tool, and articles with high risk of bias in ≥2 areas were excluded from analysis. Univariable hazard ratios of reported predictors were pooled from the remaining studies in a meta-analysis using a random-effects model and presented with 95% confidence interval (CI). Results Out of 1996 unique citations, 51 studies were included comprising 9798 patients with 1493 arrhythmic events. 28 studies were pooled for meta-analysis (mean age 55±4.1 years, 72% male) with a mean follow-up of 3.7±1.9 years. Crude event rate was 4.3% (95% CI 4.02–4.57) per year. From our meta-analysis, hypertension (HR 1.95; CI [1.26–3.00]), history of out of hospital cardiac arrest or sustained VT (HR 4.15; CI [1.32–13.02]), T-wave alternans (HR 6.50; CI [2.46–17.14]), LVEDV per 10ml/m2 increase (HR 1.10; CI [1.10–1.10]), LVESV per 10ml/m2 increase (HR 1.10; CI [1.00–1.22]) and delayed gadolinium enhancement (HR 5.55; CI [4.02–7.67]) were significantly associated with LTVA (figure). The quality of evidence was moderate and there was significant heterogeneity (median i2 57%; IQR 76%) among studies. Additionally from data that could not be pooled, decreased LVEF, history of nsVT and decreased heart rate variability were significantly associated with LTVA. Summary of meta-analysis results Conclusion The risk of LTVA in NIDCM is 4.3% per year and is considerably higher in patients with hypertension, history of LTVA, decreased LVEF, high LVEDV, high LVESV, T-wave alternans, history of nsVT, decreased heart rate variability and delayed gadolinium enhancement. These results may help determine appropriate candidates for ICD implantation. The high heterogeneity in reported results indicate the need for future multicentre studies to further improve risk stratification in NIDCM. Acknowledgement/Funding ERA-CVD JTC2016: DETECTIN-HF, 680969 & Dutch Heart Foundation (2016T096)

BACKGROUND Standard androgen suppression therapy (AST) using surgical or medical castration is considered a mainstay of advanced hormone-sensitive prostate cancer treatment. AST can be initiated early when disease is asymptomatic or deferred when patients suffer symptoms of disseminated prostate cancer. OBJECTIVES To assess the effects of early versus deferred standard AST for advanced hormone-sensitive prostate cancer. SEARCH METHODS For this Cochrane Review update, we performed a comprehensive search of multiple databases (CENTRAL, MEDLINE, Embase, Web of Science; last searched November 2018) and two clinical trial registers, with no restrictions on the language of publication or publication status. We also searched bibliographies of included studies and conference proceedings (last searched January 2019). SELECTION CRITERIA We included all randomised controlled trials (RCTs) with a direct comparison of early versus deferred standard AST. We excluded all other study designs. Participants included had advanced hormone-sensitive prostate cancer receiving surgical or medical castration. DATA COLLECTION AND ANALYSIS Two review authors independently classified studies and abstracted data. The primary outcomes were time to death of any cause and serious adverse events. Secondary outcomes were time to disease progression, time to death from prostate cancer, adverse events and quality of life. We performed statistical analyses using a random-effects model and assessed the certainty of evidence according to GRADE. We performed subgroup analyses for advanced but non-metastatic disease (T2-4/N+ M0), metastatic disease (M1), and prostate-specific antigen (PSA) relapse. MAIN RESULTS We identified seven new RCTs since publication of the original review in 2002. In total, we included 10 RCTs.Primary outcomesEarly AST probably reduces the risk of death from any cause over time (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75 to 0.90; moderate-certainty evidence; 4767 participants). This corresponds to 57 fewer deaths (95% CI 80 fewer to 31 fewer) per 1000 participants at 5 years for the moderate risk group and 23 fewer deaths (95% CI 32 fewer to 13 fewer) per 1000 participants at 5 years in the low risk group. We downgraded for study limitations. Early versus deferred AST may have little or no effect on serious adverse events (risk ratio (RR) 1.05, 95% CI 0.95 to 1.16; low-certainty evidence; 10,575 participants) which corresponds to 6 more serious adverse events (6 fewer to 18 more) per 1000 participants. We downgraded the certainty of evidence for study limitations and selective reporting.Secondary outcomesEarly AST probably reduces the risk of death from prostate cancer over time (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence). This corresponds to 62 fewer prostate cancer deaths per 1000 (95% CI 87 fewer to 31 fewer) at 5 years for the moderate risk group and 24 fewer death from prostate cancer (95% CI 34 fewer to 12 fewer) per 1000 men at 5 years in the low risk group. We downgraded the certainty of evidence for study limitations.Early AST may decrease the rate of skeletal events (RR 0.37, 95% CI 0.17 to 0.80; low-certainty evidence) corresponding to 23 fewer skeletal events per 1000 (95% CI 31 fewer to 7 fewer). We downgraded for study limitations and imprecision. It may also increase fatigue (RR 1.41, 95% CI 1.23 to 1.62; low-certainty evidence), corresponding to 31 more men with this complaint per 1000 (95% CI 18 more to 48 more). We downgraded for study limitations and imprecision. It may increase the risk of heart failure (RR 1.90, 95% CI 1.09 to 3.33; low-certainty evidence) corresponding to 27 more events per 1000 (95% CI 3 more to 69 more). We downgraded the certainty of evidence for study limitations and imprecision.Global quality of life is probably similar after two years as assessed with the EORTC QLQ-C30 (version 3.0) questionnaire (mean difference -1.56, 95% CI -4.50 to 1.38; moderate-certainty evidence) with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. AUTHORS' CONCLUSIONS Early AST probably extends time to death of any cause and time to death from prostate cancer. It may slightly decrease the rate of skeletal events. Rates of serious adverse events and quality of life may be similar. It may increase fatigue and may increase the risk of heart failure. Better quality trials would be particularly important to better understand the outcomes related to possible treatment-related harm, for which we only found low-certainty evidence.

Background Exercise-based cardiac rehabilitation (ebCR) often includes various psychological interventions for lifestyle change or distress management. However, the additional benefit of specific psychological interventions on depression, anxiety, quality of life, cardiac morbidity and cardiovascular or total mortality is not well investigated. Design Systematic review and meta-analysis. Methods Randomized controlled trials and controlled cohort trials published between January 1995 and October 2017 comparing ebCR with or without pre-specified psychosocial interventions were selected and evaluated on the basis of predefined inclusion and outcome criteria. Results Out of 15,373 records, 20 studies were identified, including 4450 patients with coronary artery disease (88.5%) or congestive heart failure (11.5%), respectively. Studies were of low to moderate quality and methodological heterogeneity was high. As compared with ebCR alone, additional psychological interventions for lifestyle change or distress management showed a trend to reduce depressive symptoms (standardized mean difference –0.13, 95% confidence interval (CI) –0.30; 0.05). Furthermore, during a follow-up of five years, distress management was associated with a trend to reduce cardiac morbidity (risk ratio 0.74, 95% CI 0.51; 1.07). There was no evidence for an additional impact of either psychological lifestyle change interventions or distress management on anxiety, quality of life, cardiovascular or total mortality. Conclusions Specific psychological interventions offered during ebCR may contribute to a reduction of depressive symptoms and cardiac morbidity, but there remains considerable uncertainty under which conditions these interventions exert their optimal effects. (CRD42015025920).

IntroductionCardiac arrest is a leading cause of death in industrialised countries. Cardiopulmonary resuscitation (CPR) guidelines follow the principles of closed chest compression as described for the first time in 1960. Mechanical CPR devices are designed to improve chest compression quality, thus considering the improvement of resuscitation outcomes. This protocol outlines a systematic review and meta-analysis methodology to assess trials investigating the therapeutic effect of automated mechanical CPR devices at the rate of return of spontaneous circulation, neurological state and secondary endpoints (including short-term and long-term survival, injuries and surrogate parameters for CPR quality) in comparison with manual chest compressions in adults with cardiac arrest.Methods and analysisA sensitive search strategy will be employed in established bibliographic databases from inception until the date of search, followed by forward and backward reference searching. We will include randomised and quasi-randomised trials in qualitative analysis thus comparing mechanical to manual CPR. Studies reporting survival outcomes will be included in quantitative analysis. Two reviewers will assess independently publications using a predefined data collection form. Standardised tools will be used for data extraction, risks of bias and quality of evidence. If enough studies are identified for meta-analysis, the measures of association will be calculated by dint of bivariate random-effects models. Statistical heterogeneity will be evaluated by I2-statistics and explored through sensitivity analysis. By comprehensive subgroup analysis we intend to identify subpopulations who may benefit from mechanical or manual CPR techniques. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Ethics and disseminationNo ethical approval will be needed because data from previous studies will be retrieved and analysed. Most resuscitation studies are conducted under an emergency exception for informed consent. This publication contains data deriving from a dissertation project. We will disseminate the results through publication in a peer-reviewed journal and at scientific conferences.PROSPERO registration numberCRD42017051633.

BACKGROUND: The prognostic effect of multi-component cardiac rehabilitation (CR) in the modern era of statins and acute revascularisation remains controversial. Focusing on actual clinical practice, the aim was to evaluate the effect of CR on total mortality and other clinical endpoints after an acute coronary event. DESIGN: Structured review and meta-analysis. METHODS: Randomised controlled trials (RCTs), retrospective controlled cohort studies (rCCSs) and prospective controlled cohort studies (pCCSs) evaluating patients after acute coronary syndrome (ACS), coronary artery bypass grafting (CABG) or mixed populations with coronary artery disease (CAD) were included, provided the index event was in 1995 or later. RESULTS: Out of n = 18,534 abstracts, 25 studies were identified for final evaluation (RCT: n = 1; pCCS: n = 7; rCCS: n = 17), including n = 219,702 patients (after ACS: n = 46,338; after CABG: n = 14,583; mixed populations: n = 158,781; mean follow-up: 40 months). Heterogeneity in design, biometrical assessment of results and potential confounders was evident. CCSs evaluating ACS patients showed a significantly reduced mortality for CR participants (pCCS: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20-0.69; rCCS: HR 0.64, 95% CI 0.49-0.84; odds ratio 0.20, 95% CI 0.08-0.48), but the single RCT fulfilling Cardiac Rehabilitation Outcome Study (CROS) inclusion criteria showed neutral results. CR participation was also associated with reduced mortality after CABG (rCCS: HR 0.62, 95% CI 0.54-0.70) and in mixed CAD populations. CONCLUSIONS: CR participation after ACS and CABG is associated with reduced mortality even in the modern era of CAD treatment. However, the heterogeneity of study designs and CR programmes highlights the need for defining internationally accepted standards in CR delivery and scientific evaluation.

Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. We retrieved PubMed/Medline literature on genotype–phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27 %), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100 % by age of 70. A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.

Network meta-analysis is becoming a common approach to combine direct and indirect comparisons of several treatment arms. In recent research, there have been various developments and extensions of the standard methodology. Simultaneously, cluster randomized trials are experiencing an increased popularity, especially in the field of health services research, where, for example, medical practices are the units of randomization but the outcome is measured at the patient level. Combination of the results of cluster randomized trials is challenging. In this tutorial, we examine and compare different approaches for the incorporation of cluster randomized trials in a (network) meta-analysis. Furthermore, we provide practical insight on the implementation of the models. In simulation studies, it is shown that some of the examined approaches lead to unsatisfying results. However, there are alternatives which are suitable to combine cluster randomized trials in a network meta-analysis as they are unbiased and reach accurate coverage rates. In conclusion, the methodology can be extended in such a way that an adequate inclusion of the results obtained in cluster randomized trials becomes feasible. Copyright © 2016 John Wiley & Sons, Ltd.

Incisional hernias are one of the most common long-term complications associated with open abdominal surgery. The aim of this review and meta-analysis was to systematically assess laparoscopic versus open abdominal surgery as a general surgical strategy in all available indications in terms of incisional hernia occurrence. A systematic literature search was performed to identify randomized controlled trials comparing incisional hernia rates after laparoscopic versus open abdominal surgery in all indications. Random effects meta-analyses were calculated and presented as risk differences (RD) with their corresponding 95 % confidence intervals (CI). 24 trials (3490 patients) were included. Incisional hernias were significantly reduced in the laparoscopic group (RD −0.06, 95 % CI [−0.09, −0.03], p = 0.0002, I 2 = 75). The advantage of the laparoscopic procedure persisted in the subgroup of total-laparoscopic interventions (RD −0.14, 95 % CI [−0.22, −0.06], p = 0.001, I 2 = 87 %), whereas laparoscopically assisted procedures did not show a significant reduction of incisional hernias compared to open surgery (RD −0.01, 95 % CI [−0.03, 0.01], p = 0.31, I 2 = 35 %). Wound infections were significantly reduced in the laparoscopic group (RD −0.06, 95 % CI [−0.09, −0.03], p

Background Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer. Methods MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed. Discussion The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization. Systematic review registration PROSPERO CRD42017073064 Electronic supplementary material The online version of this article (10.1186/s13643-018-0678-9) contains supplementary material, which is available to authorized users.

BACKGROUND Biomarkers are well established for diagnosis of myocardial infarction [cardiac troponins, high-sensitivity cardiac troponins (hs-cTn)], exclusion of acute and chronic heart failure [B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)] and venous thromboembolism (d-dimers). Several studies have demonstrated acute increases in cardiac biomarkers and altered cardiac function after strenuous sports that can pretend a cardiovascular emergency and interfere with state-of-the-art clinical assessment. METHODS We performed a systematic review and metaanalysis of biomarker and cardiovascular imaging changes after endurance exercise. We searched for observational studies published in the English language from 1997 to 2014 that assessed these biomarkers or cardiac function and morphology directly after endurance exercise. Of 1787 identified abstracts, 45 studies were included. RESULTS Across all studies cardiac troponin T (cTnT) exceeded the cutoff value (0.01 ng/mL) in 51% (95% CI, 37%–64%) of participants. The measured pooled changes from baseline for high-sensitivity cTnT (hs-cTnT) were +26 ng/L (95% CI, 5.2–46.0), for cTnI +40 ng/L (95% CI, 21.4; 58.0), for BNP +10 ng/L (95% CI, 4.3; 16.6), for NT-proBNP +67 ng/L (95% CI, 49.9; 84.7), and for d-dimer +262 ng/mL (95% CI, 165.9; 358.7). Right ventricular end diastolic diameter increased and right ventricular ejection fraction as well as the ratio of the early to late transmitral flow velocities decreased after exercise, while no significant changes were observed in left ventricular ejection fraction. CONCLUSIONS Current cardiovascular biomarkers (cTnT, hs-cTnT, BNP, NT-proBNP, and d-dimer) that are used in clinical diagnosis of pulmonary embolism, acute coronary syndrome, and heart failure are prone to alterations due to strenuous exercise. Hence, it is necessary to take previous physical exercise into account when a cardiac emergency is suspected.

Background Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. Methods This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. Results Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. Conclusion After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Summary Objective To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs). Methods The MEDLINE, Embase, and Cochrane Library databases were searched. Randomized controlled clinical trials (RCTs) involving adults or children with symptoms suggestive of uncomplicated UTI and that compared different PIV regimes or PIV versus other antibiotics were included. Meta-analyses were conducted to obtain direct and indirect efficacy estimates. PIV regimes were categorized into high total dosage, moderate total dosage, and low total dosage. The risk of bias was evaluated using the Cochrane tool. Results Twenty-four RCTs were identified. No difference in clinical cure was found for the high vs. moderate (short-term: risk ratio (RR) 1.01, p =0.813; long term: RR 1.09, p =0.174) or high vs. low dosage comparisons (mean difference 0, 95% confidence interval −0.44 to 0.45, p =1). For bacteriological cure, comparisons of high vs. moderate dosage (short term: RR 1.05, p =0.056; long term: RR 1.05, p =0.131) and high vs. low dosage (short term: RR 1.02, p =0.759; long term: RR 1.13, p =0.247) showed a trend in favor of the high dosage treatment. Results for relapse, re-infection, and failure were inconclusive and not statistically significant. Patients treated with high dosages were 40% ( p =0.062) and 44% ( p =0.293) more likely to report mild to moderate adverse events. Conclusions There is insufficient evidence to support the use of an optimal combination of dosage, frequency, and duration of PIV therapy for the treatment of uncomplicated lower UTI. Evidence is limited due to the high risk of bias, poor reporting, and heterogeneous study data.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine if the omission of postoperative whole breast radiation therapy (WBRT) in selected postmenopausal women with early, favourable breast cancer, results in clinically acceptable, low local recurrence rates compared to women who receive postoperative WBRT.

Hintergrund: Taglich werden im Bereich Medizin und Gesundheitsinterventionen ca. 75 klinische Studien und 11 systematische Ubersichtsarbeiten veroffentlicht. Diese stetig wachsende Zahl an Publikationen erschwert deren zeitnahe Wahrnehmung. Dadurch kann sich die Umsetzung von neuen wirksamen Diagnostik- und Therapieverfahren in die klinische Routine verzogern. Umgekehrt kommen moglicherweise unwirksame oder gar schadliche Verfahren weiterhin zum Einsatz. Die evidenzbasierte Medizin (EBM) verlangt bei der Entscheidungsfindung fur den individuellen Patienten die Berucksichtigung aktueller hochwertiger Evidenz. Randomisiert-kontrollierte Studien (RCTs) zum Nachweis der Wirksamkeit und Sicherheit von chirurgischen Interventionen stellen in der patientenorientierten Forschung den „Goldstandard“ dar. Systematische Ubersichtsarbeiten (Systematic Reviews) bundeln die Ergebnisse einzelner Studien zu einer bestimmten Fragestellung. Zum Auffinden relevanter Publikationen sind Grundkenntnisse der systematischen Literatursuche notwendig und hilfreich. Material und Methoden: Der vorliegende Artikel illustriert anhand von bebilderten Anleitungen verschiedene Moglichkeiten der Literatursuche in der Datenbank Medline zum Auffinden von klinischen Studien und Systematic Reviews. Ergebnisse und Schlussfolgerung: Abhangig vom Thema und dem Ziel der Literatursuche konnen Zeit und Aufwand variieren. Im Praxisalltag ist eine systematische Literatursuche meist unrealistisch. Kliniker, die sich einen schnellen Einblick uber die aktuelle Evidenz zu einem klinischen Problem verschaffen mochten, konnen dazu auf aktuelle systematische Ubersichtsarbeiten zuruckgreifen. Wahrend einer systematischen Literatursuche konnen mehrere Herangehensweisen und verschiedene Strategien notig sein.

Summary Background: It is often difficult to determine the correct size of endotracheal tubes (ETT) needed for intubating pediatric patients. Therefore, we evaluated the role of ultrasound in pediatric patients to compare the correct size of an uncuffed (ETT) with the minimal transverse diameter of the subglottic airway (MTDSA) measured by ultrasound and with tube size predicted by different age-related formulas. Methods: A total of 50 pediatric patients ≤5 years were enrolled. As a standard, we defined the adequate ETT size with no audible leakage below a ventilation pressure of 15 mbar and with an audible leakage above 25 mbar. The maximum allowed difference between the prediction method result and the ETT that fit was defined as 0.3 mm. Ultrasound was performed before the intubation procedure; the intubating anesthesiologists were blinded to the results of the ultrasound measurement. Agreement between the two age-based formulas most commonly used at our department and MTDSA with the correct ETT size (standard) was analyzed using a Bland–Altman plot. Correlation and regression analyses were performed and the numbers of correct intubation trials recorded. Results: The frequency of bias ≤0.3 mm between each method and the correct ETT in the first attempt was

Background Breast cancer is the most common form of cancer and the second leading cause of death amongst women in Europe. Amongst five invasive cancers per 1000 women detected in screening, 2.7 were < 15 mm in diameter; and others reported that over one third of excised breast lesions were clinically occult. The challenge is to accurately locate small non-palpable lesions intraoperatively for optimal therapeutic outcome. A secondary important goal is to remove the smallest amount possible of healthy glandular tissue for optimal cosmesis. Currently the most widely adopted approach (80% in one survey) in guided breast-conserving surgery for excising non-palpable breast lesions is wire-guided localization (WGL). With the clinical setting shifting towards earlier non-palpable breast lesions being detected through screening, we investigated whether the current standard in assisting surgical excision of these lesions, WGL, yields the best therapeutic outcome for women with breast cancer. Objectives To assess the therapeutic outcomes of any new form of guided surgical intervention for non-palpable breast lesions against wire-guided localization, the current gold standard. Search methods We searched the Cochrane Breast Cancer Group's (CBCG) Specialized Register, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal from the earliest available date up to 30 March 2015. We also handsearched recent conference proceedings and sought information from experts in the field. Selection criteria Two review authors, BC and RJ, independently screened by title and abstract the studies we had identified through the search strategy; when this was inconclusive, they examined the full-text article for inclusion. We resolved any discrepancies regarding eligibility by discussion with a third review author, RA. Data collection and analysis Three review authors, BC, JW, and RJ, independently extracted data using a standardized data sheet. We performed all analyses using Review Manager (RevMan) or the R meta package, and in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We reported results via a graphical assessment using forest plots showing the study estimates. We considered and discussed additional subgroup and sensitivity analyses. Main results We identified 11 randomized controlled trials (RCTs) that met the inclusion criteria of this Cochrane review and included eight trials in the meta-analyses. Six RCTs compared radioguided occult lesion localization (ROLL) versus WGL, and two RCTs compared radioactive iodine (125I) seed localization (RSL) versus WGL. Of the three remaining trials, one RCT compared cryo-assisted techniques (CAL) versus WGL, one compared intraoperative ultrasound-guided lumpectomy (IOUS) versus WGL, and one compared modified ROLL technique in combination with methylene dye (RCML) versus WGL. Of the trials we included in the meta-analysis, there were a total of 1273 participants with non-palpable breast lesions (627 participants (WGL); 443 participants (ROLL); and 203 participants (RSL)). The participant population varied considerably between included trials, which included participants with both non-palpable benign and malignant lesions, and varied in defining clear margins. The included trials did not report any long-term outcomes. In general, the outcomes of WGL, ROLL and RSL were comparable. ROLL demonstrated favourable results in successful localization (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.16 to 2.28; 869 participants; six trials), positive excision margins (RR 0.74, 95% CI 0.42 to 1.29; 517 participants; five trials), and re-operation rates (RR 0.51, 95% CI 0.21 to 1.23; 583 participants; four trials) versus WGL, but none were statistically significant. WGL was significantly superior to RSL in successfully localizing non-palpable lesions (RR 3.85, 95% CI 1.21 to 12.19; 402 participants; two trials). However, for successful excision, ROLL and RSL have comparable outcomes versus WGL (ROLL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 871 participants; six trials; RSL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 402 participants; two trials). These findings were similar in that RSL demonstrated favourable results over WGL in positive tumour margins (RR 0.67, 95% CI 0.43 to 1.06; 366 participants; two trials), and re-operation rates (RR 0.80, 95% CI 0.48 to 1.32; 305 participants; one trial) but neither reached statistical significance. In contrast, WGL had fewer postoperative complications to both ROLL (RR 1.18, 95% CI 0.71 to 1.98; 642 participants; four trials) and RSL (RR 1.51, 95% CI 0.75 to 3.03; 305 participants; one trial), although this was also not statistically significant. The overall quality of evidence was good. The main risk of bias amongst included studies consisted of incomplete data sets, selective reporting, and allocation concealment. Interpretation and applicability of this meta-analysis was hindered by the mixed indication of diagnostic versus therapeutic purposes when undertaking WGL, ROLL, or RSL, leading to a high level of mixed pathology in numerous trials. Other limitations include underpowered studies, lack of data in standardized format for meta-analysis, lack of complete data amongst the trials, and absence of long-term data. Authors' conclusions Owing to a lack of trials in certain localization techniques, we could only draw conclusions about ROLL and RSL versus WGL. There is no clear evidence to support one guided technique for surgically excising a non-palpable breast lesion over another. Results from this Cochrane review support the continued use of WGL as a safe and tested technique that allows for flexibility in selected cases when faced with extensive microcalcification. ROLL and RSL could be offered to patients as a comparable replacement for WGL as they are equally reliable. Other techniques such as IOUS, RCML, and CAL are of academic interest, but recommendation for routine use in the clinical environment and oncological outcomes require further validation. The results of this Cochrane review also stress the need for more fully powered RCTs to evaluate the best technique according to the comprehensive criteria described, with a more consistent and standardized approach in outcome reporting.

The evaluation of diagnostic tests (DT) or procedures is not subject to uniform regulations. However, a thorough evaluation of DT which are intended for use in routine medical practice is advisable or even indispensible for economic, medical, and ethical reasons. This article addresses some important aspects of this evaluation: the facets of "evaluating a DT", common validity measures for qualitative and quantitative DT, the applicability and generalizability of estimates of diagnostic accuracy, objectives and design of studies for evaluating DT, as well as specific methodological problems of theses studies.

To investigate the role of irradiated volumes at intraoperative radiation therapy in the development of ureteral injury in dogs.Sixteen beagle dogs were randomized to receive 30 Gy of intraoperative radiation therapy in the right ureter. Lead shielding ensured that different volumes were irradiated. Six dogs received a 4 x 12-cm field, five dogs a 4 x 8-cm field, and five dogs a 4 x 4-cm field. Follow-up included magnetic resonance (MR) imaging, clinical examination, and resting sequential renography. Twelve months after irradiation, the animals were killed, and autopsy was performed. Functional outcome was defined as MR imaging and renography findings and was evaluated statistically by using the Cochran-Armitage test at a.05 significance level.Twelve months after therapy, ureteral obstruction with consecutive hydronephrosis of the right kidney was observed in four of six animals that received the largest volume of irradiation. Two dogs that received the medium volume developed ureteral obstruction. None of the five dogs that received the smallest volume showed abnormal findings (P.05). The irradiated parts of the ureters in all dogs showed abnormal histopathologic findings, such as fibrosis.The probability of ureteral obstruction following intraoperative radiation therapy increases with the irradiated partial volume of the ureter.

Background Options for reconstruction after low anterior resection (LAR) for rectal cancer include straight or side-to-end coloanal anastomosis (CAA), colonic J pouch and transverse coloplasty. This systematic review compared these techniques in terms of function, surgical outcomes and quality of life. Methods A systematic literature search (MEDLINE, Embase and the Cochrane Library, from inception of the databases until November 2014) was conducted to identify randomized clinical trials comparing reconstructive techniques after LAR. Random-effects meta-analyses were carried out, and results presented as weighted odds ratios or mean differences with corresponding 95 per cent c.i. A network meta-analysis was conducted for the outcome anastomotic leakage. Results The search yielded 965 results; 21 trials comprising data from 1636 patients were included. Colonic J pouch was associated with lower stool frequency and antidiarrhoeal medication use for up to 1 year after surgery compared with straight CAA. Transverse coloplasty and side-to-end CAA had similar functional outcomes to the colonic J pouch. No superiority was found for any of the techniques in terms of anastomotic leak rate. Conclusion Colonic J pouch and side-to-end CAA or transverse coloplasty lead to a better functional outcome than straight CAA for the first year after surgery.

Purpose: To investigate the influence of intraoperatively irradiated volume on soft-tissue fibrosis. Methods and Materials: Fifty-three patients with soft-tissue sarcoma of the extremities were treated with intraoperative radiotherapy (IORT) (median dose 15 Gy) and postoperative fractionated therapy (median dose 46 Gy). The median follow-up was 41.5 months (range 18–94). Late toxicity was classified according to the LENT-SOMA criteria. A Cox regression model was calculated to identify the parameters that could influence soft-tissue fibrosis Grade 3 or 4. Five parameters were observed: extent of surgical procedure, IORT in case of recurrence, extent of IORT volume, extent of IORT dose, and extent of postoperative volume. In addition, a logistic regression model was calculated to demonstrate the relationship between the IORT volume and fibrosis development. Results: The overall survival rate after 5 years was 84%. The actuarial tumor control rate was 90% after 5 years. Eleven patients developed soft-tissue fibrosis. Five patients developed Grade 3 fibrosis and 1 patient developed Grade 4 fibrosis. Only the IORT volume had a significant influence on Grade 3 or 4 fibrosis development. An IORT volume of 210 cm 3 conveyed a 5% risk (confidence interval 1–20%) of the development of severe fibrosis. The risk of severe Grade 3 or 4 fibrosis increased to 50% (confidence interval 15–80%) if a volume of 420 cm 3 was irradiated. Conclusion: The effect of volume in patients treated with IORT was remarkable. The ratio of side effects was relatively low. The risk of soft-tissue Grade 3 or 4 fibrosis increased with the extent of the IORT volume. Compared with the literature, IORT provides excellent local control in these patients.

Studies. Purpose: Measurement of the oscillating CSF flow in the spinal canal (SC) of healthy volunteers and in patients with post-traumatic syringomyelia (PTS) using an optimized MRI protocol as well as to determine whether stenosis induced velocity changes are detectable using MRI. Methods: In 68 healthy volunteers quantitative studies of CSF flow in the cervical, thoracic, and lumbar regions were performed. First, an optimized sequence was developed and tested in 19 volunteers using four different flow-encoding velocities (4, 8, 12, 16 cm/s). Secondly, the optimized sequence was employed in 49 volunteers to measure the different CSF patterns in the cervical, thoracic, and lumbar spinal canals (CSC, TSC, LSC). Part three of the study, in which patients with PTS are being examined is still underway. We measured the maximum velocity (cm/s). the pixel area (mm 2 ), and the stroke volume (ml/s). Using a flow model the velocities prior to and after compression with 5 different power levels were measured at the stenosis and at a distance of 70 cm. Results: A total of 226 dynamic measurements have been performed - so far 76 in the first part (62=81.5% evaluable) and 150 in the second part - using the optimized sequence and optimal flow velocities. A flow-encoding sequence of 12 cm/s was found best in the CSC and one of 6 cm/s in the TSC and LSC. The maximum velocity in the CSC was 0.95 cm/s with the flow being directed caudal and 0.38 cm/s with the flow being directed cranial. In the TSC the values were 4.7 cm/s and 1.65 cm/s and in the LSC 0.96 cm/s and 0.59 cm/s. The highest velocities were found at the TSC, which has the smallest diameter compared to the CSC and LSC. In the 4 patients with PTS, the maximum velocities were between 0.09 cm/s anal 0.97 cm/s with the flow being directed cranial and between 0.04 cm/s and 1.03 cm/s with the flow being directed caudal. The stroke volumina in the CSC were between 0.1 and 1.23 ml/s (mean: 0.48 ml/s) and 0.2 and 2.45 ml/s (mean: 0.66ml/s) in the TSC and in the LSC 0.08 ml/s and 0.67 ml/s (mean: 0.29 ml/s). The results of the flow model studies showed an increase of velocity between 2.06 and 4.94 cm/s (mean: 3.31 cm/s) at the stenosis and 1.1 and 1.33 cm/s (mean: 1.23 cm/s) at a distance of 70 cm. Conclusion: Quantitative measurement of the oscillating CSF flow in the entire spinal canal (SC) is possible using an optimized MRI protocol as well as to detect stenosis induced velocity changes. Due to the high interindividual variability in the data of spinal CSF dynamics, further studies are necessary to collect normal data. The detection of movement of CSF in a post-traumatic spinal cord lesion may alter the therapeutic management.

Treatment for Lateral Epicondylitis of the Elbow. Introduction : Previously published studies concerning, extracorporeal shock-wave therapy (ESWT) in the treatment of lateral epicondylitis do not fulfil the biometric standards of modern clinical research. The objectiv of the trial is to show that ESWT is effective in the treatment of chronic LE. Method: A prospective, randomised, placebo-controlled, single-blinded, multicenter trial with an independent blinded observer was designed. The effectiveness of ESWT is evaluated by comparison with a control group in which sham-ESWT is performed, both under local anaesthesia. Outcome is determined on the basis of the Roles/ Maudsley-Score. Inclusion criteria are a history of at least 6 months of LE and failure of conventional treatment. The therapy includes 3 sessions of low energy ESWT with 2000 impulses (energy flux density 0.07-0.09 mJ/mm 2 ). Sample size is 272 patients. Status: Randomisation started in October 1998 and is planned over a period of two and a half years. Conclusion: Only a randomised clinical trial with adequate contol of placebo effects and observer bias can provide the required evidence for the efficiency of ESWT in the treatment of lateral epicondylitis of the elbow.

The evaluation of diagnostic tests play an important role in clinical research. Though detailed standards have been developed for treatment evaluation, widely accepted methodological standards in diagnostic test research are still lacking. Following recent methodological research German biostatisticians usually distinguish between 4 types of diagnostic validation studies (Phase I to IV). The diagnostic value of a test can be described by indexes like sensitivity, specificity and predictive values. Sensitivity and specificity are so-called nosological probabilities whereas predictive values describe the probabilities of the disease given a positive or negative test result, respectively. These posterior probabilities depend on the prevalence of the disease in question. The methodological problems that arise in the planning of diagnostic studies differ from those encountered in treatment evaluation. This contribution presents an annotated checklist of the most important faults and shortcomings in the planning and the analysis of diagnostic validation studies. Avoiding these deficiencies may help that the study results are accepted by biostatisticians, clinicians and cost units.

Background The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. Methods We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. Results We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p < 0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. Conclusion Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation.

Energized vessel-sealing systems have been proposed to save operation time and reduce post-operative complications. The aim of the present systematic review was to compare operation time and postoperative morbidity for ultrasonic and electrothermal bipolar-activated devices with conventional hemostasis techniques and with each other in open thyroidectomy. A systematic literature search (MEDLINE, Cochrane Library, EMBASE and ISI Web of Science) was performed to identify randomised controlled trials (RCTs) comparing conventional hemostasis techniques, ultrasonic devices (Harmonic® scalpel) and/or electrothermal bipolar-activated vessel sealing systems (Ligasure®) during open thyroidectomy. For the primary endpoint (operation time), a network meta-analysis with Bayesian random effects model was performed. Pairwise meta-analyses with random effects were calculated for primary and secondary endpoints. One hundred sixteen publications were evaluated for eligibility; 35 RCTs (4,061 patients) were included. There was considerable methodological and clinical heterogeneity of included trials. The Harmonic scalpel significantly reduced operation time compared with conventional techniques (22.26 min, 22.7 min in the inconsistency model). The use of Ligasure significantly reduced operation time in total thyroidectomy (13.84 min in the consistency model, 12.18 min in the inconsistency model). In direct comparison, operations with the Harmonic scalpel were faster than with Ligasure (8.42 min in the consistency model, 2.45 min in the inconsistency model). The rates of recurrent nerve palsy and postoperative hypocalcaemia did not significantly differ in the intervention groups. This meta-analysis shows superiority of ultrasonic devices in terms of operation time compared with conventional hemostasis techniques in thyroid surgery, with no detriment to safety outcomes.

Background: The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal (GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and other outcomes. Objectives: To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups. Search methods: We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases, conference proceedings, and reference lists of retrieved papers. Selection criteria: We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive either chemotherapy with or without radiotherapy followed by surgery, or surgery alone. Data collection and analysis: Two independent review authors identified eligible trials. We solicited individual patient data (IPD) from all selected trials. We performed meta-analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect of several covariables on overall survival. Main results: We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality. Authors' conclusions: Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients.

e16057Background: Many efforts have been made to introduce prognostic factors into decision-making on adjuvant treatment in stage I seminoma. A number of clinical, histopathological and molecular f...

Basaloid carcinoma represents a rare variant of nonsmall cell lung cancer (NSCLC), which has shown a poor prognosis in a number of studies. Although it is considered to derive from a pluri- or multipotent pulmonary stem cells, little is known about the expression and clinical significance of stem cell antigens in this variant. Stage-specific embryonic antigen-4 (SSEA-4) was analysed by immunohistochemistry in 38 patients with resected early-stage basaloid NSCLC who had a median follow-up of 72.9 months. The expression of SSEA-4 was related to clinico-pathological characteristics, to the expression of the adult stem cell antigens CD117, CD133 and breast cancer resistance protein 1 (BCRP1), and to prognosis. SSEA-4 was positive in 37% of the specimens and showed no association with clinico-pathological characteristics or the expression of adult stem cell antigens. Cox proportional hazards regression analysis revealed a 6.0-fold increased risk of relapse (p = 0.001) and a 4.2-fold increased risk of disease-related mortality (p = 0.017) in SSEA-4-positive patients, while SSEA-4-negative patients showed a prognosis comparable with that of other early-stage NSCLC. SSEA-4 is expressed in a fraction of basaloid NSCLC and is associated with poor prognosis.

A combination of bilateral superficial cervical plexus block (BSCPB) and general anesthesia is recommended for thyroid surgery. Proof of the efficacy of this combination remains weak. Furthermore, data on the safety of this regimen are lacking. Therefore, a meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of BSCPB as an adjunct to general anesthesia in patients receiving thyroid surgery was performed.A meta-analysis of RCT was performed that included interventional groups evaluating the efficacy of BSCPB 6 and 24 hours after thyroid surgery.Eight RCT, including a total of 799 patients (463 who underwent BSCPB and 336 controls), were analyzed. A meta-analysis demonstrated a reduction in pain scores 6 hours (Hedges' g: -0.46 [95% CI: -0.74 to -0.19]; p=0.001) and 24 hours postoperatively (Hedges' g: -0.49 [95% CI: -0.71 to -0.27]; p0.001) in patients who had undergone BSCPB. The relative risk for postoperative nausea and vomiting (PONV) was 0.80 (95% CI: 0.58 to 1.09, p=0.159) in patients receiving BSCPB. Procedure-related adverse events were reported in three of the 476 patients who had undergone BSCPB (0.6%; 95% CI: 0.1% to 2.0%). These three patients had transient paresis of the brachial plexus, combined with a diaphragmatic paresis in one case, and all spontaneously resolved.The combination of BSCPB and general anesthesia has a significant benefit in reducing pain 6 and 24 hours after thyroid surgery. However, the effect on pain reduction is too small to be of clinical relevance. Although it is a safe procedure, the existing evidence allows for no recommendation concerning the application of BSCPB in thyroid surgery. Further trials should evaluate a dose-response relationship and the incidence of PONV with this regimen.

To evaluate the optimal technique and material for abdominal fascia closure after midline laparotomy, first by means of a precisely defined study population and follow-up period and second by the surgically driven aspects.Overview of existing systematic reviews and meta-analysis of randomized controlled trials. A systematic literature search (Medline, Embase, and The Cochrane Central Register of Controlled Trials) was performed to identify randomized controlled trials in elective and emergency populations comparing suture techniques (continuous vs. interrupted) and materials (rapidly vs. slowly vs. nonabsorbable). Random effects conventional and cumulative meta-analyses were calculated and presented as odds ratios and the corresponding 95% confidence intervals.Five systematic reviews and 14 trials including 7711 patients (6752 midline incisions) were analyzed. None of the systematic reviews differentiated elective versus emergency laparotomy. The analysis of available primary studies revealed significant lower hernia rates using a continuous (vs. interrupted) technique (OR: 0.59; P=0.001) with slowly absorbable (vs. rapid-absorbable) suture material (OR: 0.65; P=0.009) in the elective setting, which was in contrast to the conflicting results of existing systematic reviews. No statistical heterogeneity was detected in the elective setting (I=0%). Seven studies incorporating elective and emergency procedures revealed inconclusive and heterogeneous results (I=45%-85%). No studies have evaluated closure methods solely in the emergency setting so far.No further trials should be conducted for evaluation of technique and available materials for elective midline abdominal fascial closure, according to the results of our cumulative meta-analysis. Future trials will have to define the optimal closure strategy in the emergency setting and relevance of new suture materials and other strategies such as the use of prophylactic mesh in targeted subpopulations.

Background The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question. Design GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage. Conclusion 372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients. Trial Registration Current Controlled Trials ISRCTN45122933

Aims and background The incidence of colorectal cancer varies from one country to another although the variation is not much different in neighboring countries. Even in one country there is no relevant variation in incidence from one province to another. A study of different provinces in a vast developing country, Iran, was performed to determine the incidence of colorectal cancer. Methods Information from cancer registries of four provinces in the north, north-west and central-south of Iran regarding colorectal cancer was gathered for analysis. A total of 1628 cases with colorectal cancer in a total population of 6,435,549 was identified. Results and conclusions In all provinces, there were more male than female patients with colorectal cancer. The study also showed that the incidence of the disease in young patients was higher than expected. Except for Israel because of genetic factors, these provinces showed one of the highest ASR among Asian countries. This finding probably indicates more westernization in the Iranian diet with a genetic influence. Some social habits including dietary and tobacco smoking may also influence the incidence of colorectal cancer in the Iranian population. Community-related risk factors need further investigation, especially in the high-risk Northern part of the country.