Abstract: Introduction: Esophageal adenocarcinoma (EAC) often recurs systemically despite therapy with a curative aim. New diagnostic and therapeutic approaches are urgently needed. A promising field is liquid biopsy, meaning the investigation of tumor-associated cells in the peripheral blood, for example cancer-associated macrophage-like cells (CAML). The aim of this multicentric study was to investigate the presence and cytomorphological appearance of CAML in patients with non-metastatic and operable esophageal cancer. Methods: Blood samples from 252 patients with locally advanced EAC were obtained before starting curative treatment including surgery, and then processed using ScreenCell® filtration devices. Cytological analysis was performed via May-Grünwald-Giemsa staining. CAML were defined by their morphological characteristics. We also performed immunofluorescence staining with the mesenchymal marker vimentin on a subset of our study cohort. Results: We detected cytomorphologically heterogeneous CAML in 31.8% (n=80) patients. Their presence and cell count did not correlate significantly with pretherapeutic cTNM. Even in patients with small tumors and no lymph-node infiltration, cell counts were high. CAML showed heterogenous staining patterns for vimentin. Conclusion: This is one of the first studies demonstrating the presence and phenotype of CAML in a uniquely broad cohort of EAC patients. As they are believed to be representatives of the inflammatory tumor microenvironment shed into the bloodstream, their presence in non-metastatic EAC is a promising finding

Abstract: Introduction Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is a last resort treatment option in patients with severe COVID-19 related acute respiratory distress syndrome (ARDS). Mortality in these critically ill patients is high. Elevated interleukin-6 (IL-6) levels in these severe courses are associated with poor outcome. Extracorporeal cytokine adsorption is an approach to lower elevated IL-6 levels. However, there is no randomised controlled data on the efficacy of cytokine adsorption and its effect on patient outcome in severe COVID-19 related ARDS requiring V-V ECMO support. Methods and analysis We here report the protocol of a 1:1 randomised, controlled, parallel group, open-label intervention, superiority multicentre trial to evaluate the effect of extracorporeal cytokine adsorption using the CytoSorb device in severe COVID-19 related ARDS treated with V-V ECMO. We hypothesise that extracorporeal cytokine adsorption in these patients is effectively reducing IL-6 levels by 75% or more after 72 hours as compared with the baseline measurement and also reducing time to successful V-V ECMO explantation. We plan to include a total of 80 patients at nine centres in Germany. Ethics and dissemination The protocol of this study was approved by the ethical committee of the University of Freiburg as the leading institution (EK 285/20). Additional votes will be obtained at all participating centres. Trial registration numbers NCT04385771 and DRKS 00021248

Abstract: The assessment of safety is an important aspect of the evaluation of new therapies in clinical trials, with analyses of adverse events being an essential part of this. Standard methods for the analysis of adverse events such as the incidence proportion, that is the number of patients with a specific adverse event out of all patients in the treatment groups, do not account for both varying follow-up times and competing risks. Alternative approaches such as the Aalen-Johansen estimator of the cumulative incidence function have been suggested. Theoretical arguments and numerical evaluations support the application of these more advanced methodology, but as yet there is to our knowledge only insufficient empirical evidence whether these methods would lead to different conclusions in safety evaluations. The Survival analysis for AdVerse events with VarYing follow-up times (SAVVY) project strives to close this gap in evidence by conducting a meta-analytical study to assess the impact of the methodology on the conclusion of the safety assessment empirically. Here we present the rationale and statistical concept of the empirical study conducted as part of the SAVVY project. The statistical methods are presented in unified notation, and examples of their implementation in R and SAS are provided

Abstract: The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions