Treatment of established status epilepticus in the elderly - a study protocol for a prospective multicenter double-blind comparative effectiveness trial (ToSEE)

Background!#!Status epilepticus (SE) is a common neurological emergency condition that especially affects the elderly and old population. Older people with SE frequently have non-convulsive SE (NCSE) and are also at special risk of suffering a poor outcome. The application of benzodiazepines fails to control SE in about one third of the cases. For benzodiazepine refractory SE (BRSE) in elderly, there is little evidence that would justify the choice of one of the commonly used antiepileptic drugs. The present study aims to generate evidence for the treatment of BRSE in this age group.!##!Methods!#!We will conduct a prospective, randomized, double-blind comparative effectiveness study in more than twenty hospitals in Germany over a four-year period. Four hundred and seventy-seven elderly patients (≥ 65 years old) diagnosed with BRSE will be allocated by 1:1 randomization to receive either levetiracetam or valproate. All types of SE will be considered. For the diagnosis NCSE a verification by EEG is required. Levetiracetam or valproate will be administered in one single infusion. The primary endpoint is the stable cessation of ictal activity 15 min after the start of infusion persisting for the following 45 min of observation. EEG recording is maintained over the whole observation period, clinical examinations are conducted in predefined intervals. In case of treatment success patients and study staff remain blinded until 60 min after the start of the infusion. Adverse events will be recorded until the end of the study. EEG data will be reviewed by two external independent experts. To obtain data about the further treatment of SE, intrahospital complications and the functional outcome in the short term the study participants will be observed until the day of discharge or day 30 whichever is earliest.!##!Discussion!#!ToSEE is the first study which shall deliver evidence for the SE-therapy in the elderly and old population in a controlled prospective comparator study. By design it also shall collect information about therapy regimes and outcome aspects of this disease.!##!Trial registration!#!The trial has been registered at the German Clinical Trials Register on 3 July, 2020 ( DRKS00022308 ,  https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022308 )

PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase

Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on- chronic liver failure: A multicenter randomized trial (GRAFT study)

Background & Aims: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. Methods: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 mu g/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary effi- cacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. Results: Patients treated with G-CSF had a 90-day transplant free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the GCSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. Conclusions: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. ClinicalTrials.gov number: NCT02669680 Lay summary: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved