[Syncope in children and adolescents: are the current guidelines being followed?] / Synkopenabklärung bei Kindern und Jugendlichen ­ Handeln wir gemäß der aktuellen Leitlinie?

BACKGROUND: Syncope in childhood and adolescence is frequent and in most cases benign. A thorough history taking, complete physical examination, electrocardiography and further diagnostic work-up as indicated should rule out possible cardiac syncope. OBJECTIVE: To evaluate whether the diagnosis of syncope was performed according to the currently valid S2k guideline. MATERIAL AND METHODS: Retrospective study (January 2015-December 2017), University Children's Hospital of Saarland, Homburg, Germany. All patients aged 1-18 years presenting with the primary complaint of syncope were included. RESULTS: In this study 262 patients presented with a history of syncope (161 female (61.5%), 101 male (38.5%), median age 12.5 ± 3.9 years). Of these, 183 (69.8%) were reflex syncopes, 36 (13.7%) presyncopes, 35 (13.4%) undefined and 8 (3.1%) cardiac syncope. Out of 262 patients, 43 (16.4%) were diagnosed in accordance with the published guidelines and 13/43 (30.2%) correctly received further diagnostic work-up. In 219/262 patients (83.6%) basic diagnostic testing was not sufficient and 135/219 (61.6%) were submitted to further unnecessary diagnostic tests. CONCLUSION: Better adherence to the syncope guidelines bears the potential to avoid unnecessary and costly auxiliary medical tests while correctly diagnosing patients with syncope.

Genome-Wide DNA Methylation Profiling in Early Stage I Lung Adenocarcinoma Reveals Predictive Aberrant Methylation in the Promoter Region of the Long Noncoding RNA PLUT: An Exploratory Study.

INTRODUCTION: Surgical procedure is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable number of patients experience recurrence within the first 2 years after complete resection. Suitable prognostic biomarkers that identify patients at high risk of recurrence (who may probably benefit from adjuvant treatment) are still not available. This study aimed at identifying methylation markers for early recurrence that may become important tools for the development of new treatment modalities. METHODS: Genome-wide DNA methylation profiling was performed on 30 stage I lung adenocarcinomas, comparing 14 patients with early metastatic recurrence with 16 patients with a long-term relapse-free survival period using methylated-CpG-immunoprecipitation followed by high-throughput next-generation sequencing. The differentially methylated regions between the two subgroups were validated for their prognostic value in two independent cohorts using the MassCLEAVE assay, a high-resolution quantitative methylation analysis. RESULTS: Unsupervised clustering of patients in the discovery cohort on the basis of differentially methylated regions identified patients with shorter relapse-free survival (hazard ratio: 2.23; 95% confidence interval: 0.66-7.53; p = 0.03). In two validation cohorts, promoter hypermethylation of the long noncoding RNA PLUT was significantly associated with shorter relapse-free survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93; p < 0.026) and could be reported as an independent prognostic factor in the multivariate Cox regression analysis. CONCLUSIONS: Promoter hypermethylation of the long noncoding RNA PLUT is predictive in patients with early stage I adenocarcinoma at high risk for early recurrence. Further studies are needed to validate its role in carcinogenesis and its use as a biomarker to facilitate patient selection and risk stratification.

Generation of alloreactivity-reduced donor lymphocyte products retaining memory function by fully automatic depletion of CD45RA-positive cells.

BACKGROUND AIMS: For patients needing allogeneic stem cell transplantation but lacking a major histocompatibility complex (MHC)-matched donor, haplo-identical (family) donors may be an alternative. Stringent T-cell depletion required in these cases to avoid lethal graft-versus-host disease (GVHD) can delay immune reconstitution, thus impairing defense against virus reactivation and attenuating graft-versus-leukemia (GVL) activity. Several groups reported that GVHD is caused by cells residing within the naive (CD45RA+) T-cell compartment and proposed use of CD45RA-depleted donor lymphocyte infusion (DLI) to accelerate immune reconstitution. We developed and tested the performance of a CD45RA depletion module for the automatic cell-processing device CliniMACS Prodigy and investigated quality attributes of the generated products. METHODS: Unstimulated apheresis products from random volunteer donors were depleted of CD45RA+ cells on CliniMACS Prodigy, using Good Manufacturing Practice (GMP)-compliant reagents and methods throughout. Using phenotypic and functional in vitro assays, we assessed the cellular constitution of CD45RA-depleted products, including T-cell subset analyses, immunological memory function and allo-reactivity. RESULTS: Selections were technically uneventful and proceeded automatically with minimal hands-on time beyond tubing set installation. Products were near-qualitatively CD45RA+ depleted, that is, largely devoid of CD45RA+ T cells but also of almost all B and natural killer cells. Naive and effector as well as γ/δ T cells were greatly reduced. The CD4:CD8 ratio was fivefold increased. Mixed lymphocyte reaction assays of the product against third-party leukocytes revealed reduced allo-reactivity compared to starting material. Anti-pathogen responses were retained. DISCUSSION: The novel, closed, fully GMP-compatible process on Prodigy generates highly CD45RA-depleted cellular products predicted to be clinically meaningfully depleted of GvH reactivity.