Sophie Vanbelle

Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults

BackgroundSulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults.Methods10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria.ResultsNo clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation.ConclusionAlthough the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas.Trial RegistrationCurrent Controlled Trials ISRCTN45828668

A bootstrap method for comparing correlated kappa coefficients

Cohens kappa coefficient is traditionally used to quantify the degree of agreement between two raters on a nominal scale. Correlated kappas occur in many settings (e.g., repeated agreement by raters on the same individuals, concordance between diagnostic tests and a gold standard) and often need to be compared. While different techniques are now available to model correlated κ coefficients, they are generally not easy to implement in practice. The present paper describes a simple alternative method based on the bootstrap for comparing correlated kappa coefficients. The method is illustrated by examples and its type I error studied using simulations. The method is also compared with the generalized estimating equations of the second order and the weighted least-squares methods.

Objective Physical Activity Assessment in Patients With Chronic Organ Failure: A Validation Study of a New Single-Unit Activity Monitor

OBJECTIVE To validate a new activity monitor (CAM) in patients with chronic organ failure during 1 hour of unconstrained activity assessment. DESIGN A validation study in which participants wore a CAM (placed on the thigh) for 1 hour while they were videotaped. Participants were instructed to continue their normal daily routine at the rehabilitation center. SETTING CIRO+, A Centre of Expertise for Chronic Organ Failure. PARTICIPANTS Chronic organ failure patients (N=10) with a large range of functional exercise capacity. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Agreement in time spent on activities and postures according to video and CAM. RESULTS Cohen kappa coefficients for transient events resulted in an almost perfect agreement (0.85 ± 0.08) between the CAM and video. CONCLUSIONS The CAM is a promising single-sensor unobtrusive tool for providing accurate data on the type and duration of daily activities in the home environment of patients with chronic organ failure.

Reasoning versus knowledge retention and ascertainment throughout a problem-based learning curriculum.

Context  Since 2000, problem‐based learning (PBL) seminars have been introduced into the curriculum of medical studies at the University of Liège. We aimed to carry out a cross‐sectional investigation of the maturational increase in biomedical reasoning capacity in comparison with factual knowledge retention throughout the curriculum.

Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: an exploratory study

AIM The aim of this study was to assess the levels and diagnostic accuracy of a set of potential biomarkers of periodontal tissue metabolism in gingival crevicular fluid (GCF) from patients with chronic periodontitis (CP) and asymptomatic apical periodontitis ( AAP). MATERIALS AND METHODS Thirty one GCF samples from 11 CP patients, 44 GCF samples from 38 AAP patients and 31 GCF samples from 13 healthy volunteers were obtained (N = 106). Matrix metalloproteinases (MMPs) -2 and -9 were determined by zymography; levels of MMP-8 by ELISA and IFMA and MPO by ELISA. IL-1, IL-6, TNFα, DKK-1, Osteonectin, Periostin, TRAP-5 and OPG were determined by a multiplex quantitative panel. Statistical analysis was performed using linear mixed-effects models. RESULTS The MMP-9 and MMP-8 were higher in CP, followed by AAP, versus healthy individuals (p < 0.05). ProMMP-2, MPO, IL-1, IL-6, PTN, TRAP-5 and OPG were significantly higher in CP when compared with AAP and healthy patients (p < 0.05). The highest diagnostic accuracies were observed for ProMMP-2, ProMMP-9, MMP-8 and TRAP-5 (AUC > 0.97) in CP, and for the active form of MMP-9 and MMP-8 (AUC > 0.90) in AAP. CONCLUSION Gingival crevicular fluid composition is modified by CP and AAP. MMP-9 and MMP-8 show diagnostic potential for CP and AAP, whereas MMP-2 and TRAP-5 are useful only for CP.

A New Interpretation of the Weighted Kappa Coefficients

Reliability and agreement studies are of paramount importance. They do contribute to the quality of studies by providing information about the amount of error inherent to any diagnosis, score or measurement. Guidelines for reporting reliability and agreement studies were recently provided. While the use of the kappa-like family is advised for categorical and ordinal scales, no further guideline in the choice of a weighting scheme is given. In the present paper, a new simple and practical interpretation of the linear- and quadratic-weighted kappa coefficients is given. This will help researchers in motivating their choice of a weighting scheme.

Characteristics and expectations of patients with erectile dysfunction: results of the SCORED study

In an observational study in men with erectile dysfunction (ED) consulting a general practitioner (GP) or urologist in Belgium, demographics, ED characteristics (including erection hardness score), co-morbidities and treatment expectations were evaluated using a structured questionnaire. In total, 341 GPs and 41 urologists recruited 1492 patients. Most (74%) were untreated and 25% had ED for >3 years. Considering PDE5 inhibitors, erection hardness (89%) and maintenance (92%) were considered ‘very important’ by most patients. Only 18% of physicians initiated discussion about ED, despite 41% of patients having ⩾3 known risk factors. The questionnaire was considered helpful by 81% of GPs and 83% of their patients. Overall, patients are under-diagnosed, and physicians are reluctant to ask about ED. A questionnaire including erection hardness score is useful to facilitate discussion about ED in general practice. Erection hardness and maintenance are more important to patients as compared to fast onset or long duration of action.

Penetration of enrofloxacin into the nasal secretions and relationship between nasal secretions and plasma enrofloxacin concentrations after intramuscular administration in healthy pigs

The pharmacokinetic behaviour of enrofloxacin (ENRO) in plasma and nasal secretions of healthy pigs was investigated, after a single-dose intramuscular administration of 2.5 mg/kg body weight of the drug. Blood samples and nasal secretions were collected at predetermined times after drug administration. Concentrations of ENRO and its active metabolite ciprofloxacin (CIPRO) were determined in plasma and nasal secretions by high-performance liquid chromatography (HPLC). CIPRO was not detected probably because we investigated young weaned pigs. The data collected in 12 pigs for ENRO were subjected to noncompartmental analysis. In plasma, the maximum concentration of drug (C(max)), the time at which this maximum concentration of drug (T(max)) was reached, the elimination half-life (t(1/2)(beta)) and the area under the concentration vs. time curve (AUC) were, respectively, 694.7 ng/mL, 1.0 h, 9.3 h and 8903.2 ngxh/mL. In nasal secretions, C(max), T(max), t(1/2)(beta) and AUC were, respectively, 871.4 ng/mL, 2.0 h, 12.5 h and 11 198.5 ngxh/mL. In a second experiment conducted in 10 piglets, the relationship between concentrations of ENRO measured in the plasma and the nasal secretions has been determined following single-dose intramuscular administration of 2.5, 10 or 20 mg/kg body weight of the drug. It has been demonstrated that, among several variables, i.e., (1) the dose administered, (2) the time between intramuscular injection and blood sampling, (3) the age, (4) the sex, (5) the animal body weight and (6) the plasma concentration of the drug, only the latter influenced significantly the ENRO concentration in nasal secretions. Practically, using a generalized linear mixed model, ENRO concentrations in the nasal secretions (microg/mL) can be predicted taking into account the ENRO concentrations in plasma (microg/mL), according to the following equation:

Lifestyle Behaviours and Plasma Vitamin C and β-Carotene Levels from the ELAN Population (Liège, Belgium)

Several factors, including fruit and vegetables intakes, have been shown to significantly influence the plasma concentrations of the two antioxidants vitamin C and β-carotene. Deficiency levels of 6 mg/L (34.2 μM) for vitamin C and of 0.22 mg/L (0.4 μM) for β-carotene have been suggested below which cardiovascular risk might be increased. The present study performed on 897 presumably healthy subjects aged 40–60 years aimed to examine how modifiable lifestyle factors may be related to vitamin C and/or β-carotene deficiency. Gender, smoking, lack of regular physical activity and of daily fruit consumption (≥2/day), and social status (in particular, unemployment) were found to be significant risk factors for vitamin C deficiency. For β-carotene deficiency, the same factors were identified except social status; moreover, overweight and OC use in women were also found to have a deleterious effect. For non exposed subjects, the probability of developing vitamin C deficiency was 4% in men and 2.4% in women. This probability increased to 66.3% for men and to 44.3% for women (and even to 50.4% under OC use), when all risk factors were present. For β-carotene deficiency, the corresponding probabilities were equal to 29.7% in men and 13.7% in women (no risk factor present), and to 86.1% for men and 69.9% (91.6% for OC use) for women (all factors present), respectively.

Hierarchical modeling of agreement

Kappa-like agreement indexes are often used to assess the agreement among examiners on a categorical scale. They have the particularity of correcting the level of agreement for the effect of chance. In the present paper, we first define two agreement indexes belonging to this family in a hierarchical context. In particular, we consider the cases of a random and fixed set of examiners. Then, we develop a method to evaluate the influence of factors on these indexes. Agreement indexes are directly related to a set of covariates through a hierarchical model. We obtain the posterior distribution of the model parameters in a Bayesian framework. We apply the proposed approach on dental data and compare it with the generalized estimating equations approach.