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Summary. A mixed model is a flexible tool for joint modeling purposes, especially when the gathered data are unbalanced. However, computational problems due to the dimension of the joint covariance matrix of the random effects arise as soon as the number of outcomes and/or the number of used random effects per outcome increases. We propose a pairwise approach in which all possible bivariate models are fitted, and where inference follows from pseudo-likelihood arguments. The approach is applicable for linear, generalized linear, and nonlinear mixed models, or for combinations of these. The methodology will be illustrated for linear mixed models in the analysis of 22-dimensional, highly unbalanced, longitudinal profiles of hearing thresholds.

Abstract:We investigated the spatiotemporal variables of gait leading up to freezing. Gait analysis was carried out on 14 patients with Parkinson's disease in the off phase of the medication cycle. A computerised, three-dimensional gait analysis system was used to measure the walking pattern. After several trials of normal walking with voluntary stopping, distracting manoeuvres and obstacles on the walkway were used to provoke freezing or festination. The gait variables of normal (off phase), festinating, prestop, and prefreezing strides were analysed using analysis of variance for repeated-measures. Cadence was excessively increased (68%) and stride length decreased (69%) during festination compared with normal off walking; a pattern which remained pronounced when comparing prefreezing strides with normal stopping. Analysing in more detail the three steps before a freeze, we found a progressive decrease of stride length and stable cadence rates and proportions of double support phases. The relationship between cadence and stride length exhibited an exponential increase of cadence with a decreasing stride length during festination and freezing. Results suggest that freezing is caused by a combination of an increasing inability to generate stride length superimposed on a dyscontrol of the cadence of walking.

Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

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The diagnostic accuracy for the localization of impacted canines and the detection of canine-induced root resorption of maxillary incisors were compared between conventional radiographic procedures using one two-dimensional (2D) panoramic radiograph with that of two three-dimensional (3D) cone beam computed tomography (CBCT) scans. The clinical records of 60 consecutive patients who had impacted or ectopically erupting maxillary canines were identified from those seeking orthodontic treatment. For each case, two sets of radiographic information were obtained. The study sample was divided into two groups: group A (n = 30) included those for whom a dental pantomograph (DPT) and CBCT obtained with a 3D Accuitomo-XYZ Slice View Tomograph were available and group B (n = 30) who had a DPT and CBCT obtained with a Scanora. The DPT and CBCT images were subsequently analysed by 11 examiners. Statistical analysis included an evaluation of the agreement between observers based on the standard error of the measurement, kappa statistics and coefficient of concordance, as well as an assessment of the differences between 2D and 3D imaging employing Wilcoxon signed rank and McNemar tests. There was a highly significant difference between the 2D and 3D images in the width of the canine crown (P < 0.001) and in canine angulation to the occlusal plane. Moreover, there was a highly significant difference between the DPT and Scanora CBCT images in canine angulation to the midline (P < 0.001). There was also a significant difference between 2D and 3D images with respect to canine location (P = 0.0074 for group A and P = 0.0008 for group B). The presence or absence of root resorption of the lateral incisor was also significantly different in both groups (P = 0.0201 and P < 0.001 for groups A and B, respectively). Detection of central incisor root resorption was significantly different between the Accuitomo and DPT images (P = 0.045). There was also a significant difference in the severity of lateral incisor root resorption between the DPT and CBCT in both groups (P = 0.02). The results of this study suggest that CBCT is more sensitive than conventional radiography for both canine localization and identification of root resorption of adjacent teeth.

Purpose:To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Experimental Design: Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Results: Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Conclusion: Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.In spite of multimodal therapy, including maximal safe neurosurgical resection followed by radiochemotherapy and maintenance chemotherapy, malignant or high-grade gliomas (HGG) continue to have a dismal prognosis (1). Prognosis after relapse is even worse (2, 3), with a median progression-free survival (PFS) of 2 months, and virtually all patients being dead 18 months after the relapse. Even in pediatric patients with relapsed HGG, the prognosis is poor (4).The rationale, the preclinical, and the early clinical evidence to develop dendritic cell (DC)-based immunotherapy for HGG has been reviewed by our research group (5, 6) and by others (7 -14). Vaccination is done with autologous mature monocyte-derived ex vivo generated DC loaded with autologous tumor lysate. The characteristics and in vitro function of the vaccine have been analyzed (15, 16). We described some early clinical experience on feasibility and toxicity that we obtained in a small group of patients (17,18).For the implementation of immunotherapy in clinical practice for patients with relapsed HGG, an observational prospective cohort comparison trial, HGG-IMMUNO, was designed, in which adjuvant autologous DC vaccination is done in patients with relapsed HGG after maximal new resection of the relapsed tumor. Except for the time window in cohort A, which was the