Effects of a comprehensive educational group intervention in older women with cognitive complaints: a randomized controlled trial

Hoogenhout, E. M., De Groot, R. H. M., Van der Elst, W., Jolles J. (2012). Effects of a comprehensive educational group intervention in older women with cognitive complaints: a randomized controlled trial. Aging & Mental Health, 16, 135-144. doi:10.1080/13607863.2011.598846OBJECTIVE: The current study presents a new comprehensive educational group intervention that offers psycho-education about cognitive aging and contextual factors (i.e., negative age stereotypes, beliefs, health, and lifestyle), focuses on skills and compensatory behavior, and incorporates group discussion. Its effects were investigated in community-dwelling older women who report normal age-related cognitive complaints. METHODS: A randomized controlled trial with an experimental and waiting list control condition was carried out in a sample of 50 women aged 60-75 years. As the main problem of these individuals were perceived cognitive deficits without actual cognitive decrements, metacognition served as the primary outcome measure. Objective cognitive functioning and psychological wellbeing were secondary outcome measures. A double baseline and a follow- up assessment were carried out. RESULTS: Participants in the experimental condition reported significantly fewer negative emotional reactions towards cognitive functioning (U = 164.500, p = .004). The reported effect size (δ = -.473) could be interpreted as large. CONCLUSIONS: This new comprehensive educational group intervention reduces negative emotional reactions towards cognitive functioning, which seems a prerequisite for improved subjective cognitive functioning and wellbeing. It can potentially contribute the wellbeing of an important and large group of older adults

The Neurovegetative Complaints Questionnaire in the Maastricht Aging Study: psychometric properties and normative data

Hoogenhout, E. M., Van der Elst, W., De Groot, R. H. M., Van Boxtel, M. P. J., & Jolles, J. (2010). The neurovegetative complaints questionnaire in the Maastricht aging study: Psychometric properties and normative data. Aging and Mental Health, 14(5), 613-23.Neurovegetative and somatic symptoms (such as headaches, heart palpitations, and dizziness) have a high prevalence. These symptoms are often indicative for ‘masked depression’ or ‘depression without sadness’, especially in older adults. At present, no instrument exists that enables the assessment of these symptoms. The current study presents a questionnaire that assesses neurovegetative and somatic complaints, as well as reactive emotional complaints: the ‘Neurovegetative Complaints Questionnaire’ (NCQ). The factor structure, internal consistency, and validity of the NCQ were evaluated in a large sample of 1,105 healthy subjects aged 24-81 years from the Maastricht Aging Study. The effects of age, gender and educational level on the NCQ measures were established to provide demographically corrected normative data. Two constructs underlay the responses to the NCQ items, i.e., the Neurovegetative/Somatic and Reactive/Emotional complaints factors (eigenvalues were 4.63 and 1.65 respectively, 33.0 % of the variance was explained, Pearson’s r between both factors equalled .448). Internal consistency of both scales was acceptable (i.e. Cronbach’s α = .74 and .71, respectively) and convergent validity was sufficient (Pearson’s r = |.387 - .499|). Females and older participants were characterized by more Neurovegetative/ Somatic and Reactive/Emotional complaints compared to males and younger people. Demographically corrected regression-based norms were provided for use in research and clinical settings. The NCQ is a psychometrically sound questionnaire that is specifically aimed at assessing neurovegetative/somatic and reactive/emotional complaints, symptoms that often are indicative for a ‘masked depression’

No Higher Risk of CRPS After External Fixation of Distal Radial Fractures – Subgroup Analysis Under Randomised Vitamin C Prophylaxis§

Operative and conservative treatment of wrist fractures might lead to complex regional pain syndrome (CRPS) type I

Clusters with random size: maximum likelihood versus weighted estimation

Abstract: There are many contemporary designs that do not use a random sample of a fixed, a priori determined size. In case of informative cluster sizes, the cluster size is influenced by the the cluster's data, but here we cope with some issues that even occur when the cluster size and the data are unrelated. First, fitting models to clusters of varying sizes is often more complicated than when all cluster have the same size. Secondly, in such cases, there usually is no so-called complete sufficient statistic

Combined osimertinib, dabrafenib and trametinib treatment for advanced non-small-cell lung cancer patients with an osimertinib-induced BRAF V600E mutation

INTRODUCTION: Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations. METHODS: Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered. RESULTS: Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy. CONCLUSION: BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation

Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors

Immunotherapy for metastasized non-small-cell lung cancer (NSCLC) can show long-lasting clinical responses. Selection of patients based on programmed death-ligand 1 (PD-L1) expression shows limited predictive value for durable clinical benefit (DCB). We investigated whether early treatment effects as measured by a change in circulating tumor DNA (ctDNA) level is a proxy of early tumor response to immunotherapy according to response evaluation criteria in solid tumors v1.1 criteria, progression-free survival (PFS), DCB, and overall survival (OS). To this aim, blood tubes were collected from advanced-stage lung adenocarcinoma patients (n = 100) receiving immune checkpoint inhibitors (ICI) at baseline (t(0)) and prior to first treatment evaluation (4-6 weeks; t(1)). Nontargetable (driver) mutations detected in the pretreatment tumor biopsy were used to quantify tumor-specific ctDNA levels using droplet digital PCR. We found that changes in ctDNA levels were strongly associated with tumor response. A > 30% decrease in ctDNA at t(1) correlated with a longer PFS and OS. In total, 80% of patients with a DCB of >= 26 weeks displayed a > 30% decrease in ctDNA levels. For patients with a PD-L1 tumor proportion score of >= 1%, decreasing ctDNA levels were associated with a higher frequency a DCB (80%) and a prolonged median PFS (85 weeks) and OS (101 weeks) compared with patients with no decrease in ctDNA (34%; 11 and 39 weeks, respectively). This study shows that monitoring of ctDNA dynamics is an easy-to-use and promising tool for assessing PFS, DCB, and OS for ICI-treated NSCLC patients

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non-Small-Cell Lung Cancer With Rare or Complex Mutational Profiles

PURPOSEMolecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non-small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG).METHODSThe UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed.RESULTSThe MTB recommended targeted therapy for 59 of 110 NSCLC cases with complex molecular profiles: 24 within a clinical trial, 15 in accordance with guidelines (on label) and 20 off label. All but 16 recommendations involved patients with an EGFR or ALK mutation. Treatment outcome was analyzed for patients with available follow-up (10 on label and 16 off label). Adherence to the MTB recommendation (21 of 26; 81%) resulted in an objective response rate of 67% (14 of 21), with a median progression-free survival of 6.3 months (interquartile range, 3.2-10.6 months) and an overall survival of 10.4 months (interquartile range, 6.3-14.6 months).CONCLUSIONTargeted therapy recommendations resulting from the UMCG-MTB workflow for complex molecular profiles were highly adhered to and resulted in a positive clinical response in the majority of patients with metastatic NSCLC

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer:Local Experience and Review of the Literature

Introduction Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors. Patients and methods Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors. Results Of the pooled population of 387 patients in this analysis, 239 (62%) received at least one additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of six published models and observed clinical benefit ranged from 64 to 87%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented. Conclusion Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients

Chronic Obstructive Pulmonary Disease Is Not Associated with KRAS Mutations in Non-Small Cell Lung Cancer

Mutations in epithelial growth factor receptor (EGFR), as well as in the EGFR downstream target KRAS are frequently observed in non-small cell lung cancer (NSCLC). Chronic obstructive pulmonary disease (COPD), an independent risk factor for developing NSCLC, is associated with an increased activation of EGFR. In this study we determined presence of EGFR and KRAS hotspot mutations in 325 consecutive NSCLC patients subjected to EGFR and KRAS mutation analysis in the diagnostic setting and for whom the pulmonary function has been determined at time of NSCLC diagnosis. Information about age at diagnosis, sex, smoking status, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) was collected. Chronic obstructive pulmonary disease(COPD) was defined according to 2013 GOLD criteria. Chi-Square, student t-test and multivariate logistic regression were used to analyze the data. A total of 325 NSCLC patients were included, 193 with COPD and 132 without COPD. COPD was not associated with presence of KRAS hotspot mutations, while EGFR mutations were significantly higher in non-COPD NSCLC patients. Both female gender (HR 2.61; 95% CI: 1.56-4.39; pT and G>C transversions were significantly more frequent in females (86.2%) than in males (61.5%) (p = 0.008). The exon 19del mutation was more frequent in non-smokers (90%) compared to current or past smokers (36.8%). In conclusion, KRAS mutations are more common in females and smokers, but are not associated with COPD-status in NSCLC patients. EGFR mutations are more common in non-smoking NSCLC patients