Katrin Jensen

Meta-analysis Shows That Detection of Circulating Tumor Cells Indicates Poor Prognosis in Patients With Colorectal Cancer

BACKGROUND & AIMS The prognostic significance of circulating (CTCs) and disseminated tumor cells in patients with colorectal cancer (CRC) is controversial. We performed a meta-analysis of available studies to assess whether the detection of tumor cells in the blood and bone marrow (BM) of patients diagnosed with primary CRC can be used as a prognostic factor. METHODS We searched the Medline, Biosis, Science Citation Index, and Embase databases and reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB), mesenteric/portal blood (MPB), or BM of patients with CRC. Meta-analyses were performed using a random effects model, with hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. RESULTS A total of 36 studies, including 3094 patients, were eligible for final analyses. Pooled analyses that combined all sampling sites (PB, MPB, and BM) associated the detection of tumor cells with poor recurrence-free survival (RFS) (HR = 3.24 [95% CI: 2.06-5.10], n = 26, I(2) = 77%) and overall survival (OS) (2.28 [1.55-3.38], n = 21, I(2) = 66%). Stratification by sampling site showed that detection of tumor cells in the PB compartment was a statistically significant prognostic factor (RFS: 3.06 [1.74-5.38], n = 19, I(2) = 78%; OS: 2.70 [1.74-4.20], n = 16, I(2) = 59%) but not in the MPB (RFS: 4.12 [1.01-16.83], n = 8, I(2) = 75%; OS: 4.80 [0.81-28.32], n = 5, I(2) = 82%) or in the BM (RFS: 2.17 [0.94-5.03], n = 4, I(2) = 78%; OS: 1.50 [0.52-4.32], n = 3, I(2) = 84%). CONCLUSION Detection of CTCs in the PB indicates poor prognosis in patients with primary CRC.

Elective midline laparotomy closure: the INLINE systematic review and meta-analysis.

Objective: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. Methods: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. Results: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 (I2 = 0%). Seven studies incorporating elective and emergency procedures revealed inconclusive and heterogeneous results (I2 = 45%–85%). No studies have evaluated closure methods solely in the emergency setting so far. Conclusion: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.

Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

BackgroundThe 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.DesignGACHE 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.Conclusion372 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 RegistrationCurrent Controlled TrialsISRCTN45122933

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

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.

Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract – A systematic review and meta-analysis

BACKGROUND Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer. METHODS We performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva). FINDINGS Data were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43-0.70), losses at 3p (0.36, 95%CI 0.27-0.48) and losses at 11q (0.33, 95%CI 0.26-0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78-0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20-0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00-0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce. INTERPRETATION 3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare.

The prognostic effect of cardiac rehabilitation in the era of acute revascularisation and statin therapy: A systematic review and meta-analysis of randomized and non-randomized studies – The Cardiac Rehabilitation Outcome Study (CROS)

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.

Biomarker Changes after Strenuous Exercise Can Mimic Pulmonary Embolism and Cardiac Injury—A Metaanalysis of 45 Studies

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.

Meta-analysis of reconstruction techniques after low anterior resection for rectal cancer

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.

Role of ultrasound compared to age‐related formulas for uncuffed endotracheal intubation in a pediatric population

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.

Regional confidence bands for ROC curves.

The performance of a diagnostic test is characterised by its specificity and sensitivity. For a quantitative diagnostic test these criteria depend on the selected cut-off point. The receiver operating characteristic (ROC) curve of a quantitative diagnostic test is generated by plotting sensitivity against specificity as the cut-off point runs through the whole range of possible test values. In practice, the ROC curve is estimated from clinical data. One important goal is to select an optimal cut-off point. For this purpose the sample variability has to be taken into account. Recently, Campbell has introduced nonparametric asymptotic simultaneous confidence bands that are valid for the whole ROC curve. In this paper a nonparametric asymptotic approach for the construction of regional confidence bands for ROC curves is proposed. It can be applied for any specificity interval of interest. Our approach is based on the asymptotic theory of empirical and quantile processes. To investigate the small sample properties of the different approaches, a Monte Carlo study was conducted using normal and log-normal data. A method for sample size calculation is presented. Finally, the approaches are applied to a tumour marker in the diagnosis of bone marrow metastases.