A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups

Mild Cognitive Impairment and Dementia in Patients with Parkinson's Disease

Cognitive deficits are frequent symptoms in patients with Parkinson's disease (PD) and typically include executive dysfunctions, memory dysfunctions (especially regarding strategic encoding and retrieval) as well as deficits in visuo-spatial functions and attention. The estimated point prevalence of mild cognitive impairment in PD patients (PD-MCI) for which research criteria were published in 2012 is 27 %, and further 30 % of the patients are estimated to suffer from Parkinson's Disease Dementia (PDD); longitudinally, most patients develop cognitive dysfunctions during the course of the disease. Given that these symptoms are highly frequent and of utmost relevance, neuropsychological diagnostics should be performed in all PD patients. The acetylcholinesterase inhibitor rivastigmine is approved for the treatment of PDD; other approved treatment options for cognitive dysfunctions in PD patients do not exist yet. Evidence of efficacy of non-pharmacological interventions is insufficient. However, first studies with cognitive training and exercise are promising

Effects of cognitive training with additional physical activity compared to pure cognitive training in healthy older adults

Cognitive training (CT) has been reported to improve cognition in older adults. Its combination with protective factors such as physical activity (CPT) has rarely been studied, but it has been suggested that CPT might show stronger effects than pure CT

Apolipoprotein E epsilon 4 does not affect cognitive performance in patients with Parkinson's disease

Introduction: Cognitive impairment is a common and disabling non-motor symptom in Parkinson's disease (PD). The apolipoprotein E (APOE) allele epsilon 4 is a known risk factor for Alzheimer's disease and has also been suggested to be a risk factor for dementia in PD and even a predictor of impairment in certain cognitive domains. Methods: A total of 447 PD patients (PD patients without cognitive impairment: n = 187; PD patients with mild cognitive impairment: n = 188; PD patients with dementia: n = 72) were included from an ongoing observational German multicenter cohort study (LANDSCAPE study). All patients underwent an extensive neuropsychological test battery, including assessments of memory, visuospatial functioning, attention, language, and executive function. APOE genotype was determined by an allelic discrimination assay. Linear regression analysis was used to explore the associations between APOE-epsilon 4 and cognitive performance. Results: The APOE-epsilon 4 allele was not associated with a diagnosis of cognitive impairment in PD (PD with mild cognitive impairment and PD with dementia) or with deficits in specific neuropsychological domains in our study cohort. Conclusion: Our data question the relevance of the APOE-epsilon 4 allele as a predictor of cognitive impairment in PD. (C) 2016 Elsevier Ltd. All rights reserved

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. : Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX). Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies. Keywords: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibito

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART