Liver-HERO: hepatorenal syndrome-acute kidney injury (HRS-AKI) treatment with transjugular intrahepatic portosystemic shunt in patients with cirrhosis-a randomized controlled trial.

BACKGROUND: Patients with cirrhosis and ascites (and portal hypertension) are at risk of developing acute kidney injury (AKI). Although many etiologies exist, hepatorenal AKI (HRS-AKI) remains a frequent and difficult-to-treat cause, with a very high mortality when left untreated. The standard of care is the use of terlipressin and albumin. This can lead to reversal of AKI, which is associated to survival. Nevertheless, only approximately half of the patients achieve this reversal and even after reversal patients remains at risk for new episodes of HRS-AKI. TIPS is accepted for use in patients with variceal bleeding and refractory ascites, which leads to a reduction in portal pressure. Although preliminary data suggest it may be useful in HRS-AKI, its use in this setting is controversial and caution is recommended given the fact that HRS-AKI is associated to cardiac alterations and acute-on-chronic liver failure (ACLF) which represent relative contraindications for transjugular intrahepatic portosystemic shunt (TIPS). In the last decades, with the new definition of renal failure in patients with cirrhosis, patients are identified at an earlier stage. These patients are less sick and therefore more likely to not have contraindications for TIPS. We hypothesize that TIPS could be superior to the standard of care in patients with HRS-AKI. METHODS: This study is a prospective, multicenter, open, 1:1-randomized, controlled parallel-group trial. The main end-point is to compare the 12-month liver transplant-free survival in patients assigned to TIPS compared to the standard of care (terlipressin and albumin). Secondary end-point include reversal of HRS-AKI, health-related Quality of Life (HrQoL), and incidence of further decompensation among others. Once patients are diagnosed with HRS-AKI, they will be randomized to TIPS or Standard of Care (SOC). TIPS should be placed within 72 h. Until TIPS placement, TIPS patients will be treated with terlipressin and albumin. Once TIPS is placed, terlipressin and albumin should be weaned off according to the attending physician. DISCUSSION: If the trial were to show a survival advantage for patients who undergo TIPS placement, this could be incorporated in routine clinical practice in the management of patients with HRS-AKI. TRIAL REGISTRATION: Clinicaltrials.gov NCT05346393 . Released to the public on 01 April 2022.

Sirolimus-Coated Balloon Angioplasty of Infra-popliteal Lesions for the Treatment of Chronic Limb-Threatening Ischemia: Study Protocol for the Randomized Controlled LIMES Study.

PURPOSE: Evidence on efficacy and long-term safety of paclitaxel-coated devices is still conflicting. Therefore, this study aims to assess whether sirolimus-coated balloon angioplasty is safe and effective for the treatment of infra-popliteal occlusions in patients with chronic limb-threatening ischemia (CLTI). STUDY DESIGN: The randomized controlled, single-blinded, multicentre, investigator-initiated study aims to enrol 230 participants with CLTI and infra-popliteal occlusions at up to 25 centres. Patients will be randomized in a 1:1 ratio to either sirolimus-coated balloon angioplasty or to plain old balloon angioplasty (POBA). Bailout stenting in case of flow-limiting dissection or ≥ 50% residual diameter stenosis is permitted. OUTCOME MEASURES: Primary outcome is the Kaplan-Meier estimate of primary patency at 6 months, defined as the absence of target lesion occlusion with restoration of in-line flow to the ankle. Key secondary outcome is non-inferiority in the proportionate occurrence of major adverse limb events and perioperative all-cause death at 30 days. Overall, participants will be followed for 36 months to assess further secondary efficacy and safety outcomes. ASSUMED GAIN OF KNOWLEDGE: If sirolimus-coated balloon angioplasty turns out to be superior to uncoated-balloon angioplasty regarding patency of infra-popliteal lesions without safety signals, it could become a welcome treatment option for patients with CLTI. Trial Registration ClinicalTrial.gov Identifier: NCT04772300, German Clinical Trials Register: DRKS00024629. Level of Evidence Level 2a, randomized controlled trial.

Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis (REMOVE): Results From a Multicenter Randomized Controlled Trial.

BACKGROUND: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with postoperative organ dysfunction. We investigated the effect of hemoadsorption during IE surgery on postoperative organ dysfunction. METHODS: This multicenter, randomized, nonblinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption (integration of CytoSorb to cardiopulmonary bypass) or control. The primary outcome (change in sequential organ failure assessment score [ΔSOFA]) was defined as the difference between the mean total postoperative SOFA score, calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention to treat. A predefined intergroup comparison was performed using a linear mixed model for ΔSOFA including surgeon and baseline SOFA score as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in 6 organ systems, each scored from 0 to 4. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, duration of mechanical ventilation, and vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients. RESULTS: Between January 17, 2018, and January 31, 2020, a total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and 2 in the control group were excluded because they did not undergo surgery. The primary outcome, ΔSOFA, did not differ between the hemoadsorption and the control group (1.79±3.75 and 1.93±3.53, respectively; 95% CI, -1.30 to 0.83; P=0.6766). Mortality at 30 days (21% hemoadsorption versus 22% control; P=0.782), duration of mechanical ventilation, and vasopressor and renal replacement therapy did not differ between groups. Levels of interleukin-1ß and interleukin-18 at the end of integration of hemoadsorption to cardiopulmonary bypass were significantly lower in the hemoadsorption than in the control group. CONCLUSIONS: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcome measures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03266302.

Head-to-head comparison of sirolimus- versus paclitaxel-coated balloon angioplasty in the femoropopliteal artery: study protocol for the randomized controlled SIRONA trial.

BACKGROUND: Endovascular revascularization has established as the first-line therapy of femoropopliteal artery disease. Paclitaxel-coated balloon angioplasty proved to be superior to plain old balloon angioplasty (POBA) regarding prevention of restenosis and need for recurrent revascularization. Over the past years, paclitaxel was the only active drug to inhibit neointimal proliferation which could be processed to an appropriate balloon coating. The purpose of this study is to assess whether efficacy and safety of sirolimus-coated balloon angioplasty is noninferior to paclitaxel-coated balloon angioplasty. METHODS: This randomized controlled, single-blinded, multicentre, investigator-initiated noninferiority trial aims to enrol a total of 478 participants with symptomatic femoropopliteal artery disease of Rutherford category 2 to 4 due to de novo stenosis or restenosis. After pre-dilation, participants will be allocated in a 1:1 ratio to either sirolimus- or paclitaxel-coated balloon angioplasty. Post-dilation with the drug-coated balloon (DCB) used or standard balloon is mandatory in case ≥ 50%, and optional in case of ≥ 30% residual diameter stenosis. Bailout stenting with bare-metal nitinol stents should be conducted in case of flow-limiting dissection. Primary noninferiority endpoints are primary patency and the composite of all-cause mortality, major target limb amputation, and clinically driven target lesion revascularization at 12 months. Secondary outcomes are clinical and hemodynamic improvement, change in health-related quality of life, and safety throughout 60 months. DISCUSSION: Although concerns about long-term safety of paclitaxel-coated devices were not confirmed by recent patient-level data analyses, conflicting evidence contributed to a loss of confidence among patients and physicians. Therefore, sirolimus, known for a broader therapeutic range than paclitaxel, may serve as a welcome alternative. This will be justified if noninferiority of sirolimus-coated balloon angioplasty against the current standard of paclitaxel-coated balloon angioplasty can be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04475783 . Registered on 17 July 2020 EUDAMED No. CIV-20-11-035172, DRKS00022452.

Mid-German Sepsis Cohort (MSC): a prospective observational study of sepsis survivorship.

PURPOSE: The Mid-German Sepsis Cohort (MSC) aims to investigate mid-term and long-term functional disabilities in sepsis survivors from intensive care unit (ICU) discharge until 1 year after. Secondary, post-acute mortality and morbidity, health-related quality of life and healthcare utilisation will be investigated. PARTICIPANTS: The MSC comprises adult (aged ≥18 years) patients who were treated for (severe) sepsis or septic shock on ICU. The participants were recruited between 15 April 2016 and 30 November 2018 from five German centres. Three thousand two hundred and ten patients with sepsis were identified, of which 1968 survived their ICU stay and were eligible for enrolment in the follow-up cohort. Informed consent for follow-up assessment was provided by 907 patients (46.1% of eligible patients). FINDINGS TO DATE: The recruitment of the participants for follow-up assessments and the baseline data collection is completed. Incidence of sepsis was 116.7 patients per 1000 ICU patients. In this cohort profile, we provide an overview of the demographics and the clinical characteristics of both the overall sepsis cohort and the ICU survivors who provided informed consent for follow-up assessment (907 out of 1968 ICU survivors (46.1%)). FUTURE PLANS: The follow-ups are conducted 3, 6 and 12 months after ICU discharge. Another yearly follow-up up to 5 years after ICU discharge is pursued. Several cooperation and satellite projects were initiated. This prospective cohort offers a unique resource for research on long-term sequelae of sepsis survivors. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00010050).

Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis.

BACKGROUND: Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response. METHODS: Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously. DISCUSSION: The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.

Assessing efficacy of CytoSorb haemoadsorber for prevention of organ dysfunction in cardiac surgery patients with infective endocarditis: REMOVE-protocol for randomised controlled trial.

INTRODUCTION: Infective endocarditis (IE) is associated with high mortality and morbidity. Multiple organ failure is the main cause of death after surgery for IE. Cardiopulmonary bypass (CPB) can cause a systemic inflammatory response. In a pilot study (REMOVE-pilot (Revealing mechanisms and investigating efficacy of hemoad-sorption for prevention of vasodilatory shock in cardiac surgery patients with infective endocarditis - a multicentric randomized controlled group sequential trial)), we found that plasma profiles of cytokines during and after CPB were higher in patients with IE compared with patients with non-infectious valvular heart disease. Sequential Organ Failure Assessment (SOFA) scores on the first and second postoperative days and in-hospital mortality were also higher in IE patients. This protocol describes the design of the REMOVE trial on cytokine-adsorbing columns, for example, CytoSorb, for non-selective removal of cytokines. The aim of the REMOVE study is to demonstrate efficacy of CytoSorb on the prevention of multiorgan dysfunction in patients with IE undergoing cardiac surgery. METHODS AND ANALYSIS: The REMOVE study is an interventional randomised controlled multicenter trial with a group sequential (Pocock) design for assessing efficacy of CytoSorb in patients undergoing cardiac surgery for IE. The change in mean total SOFA (∆ SOFA) score between preoperative and postoperative care will be used as primary endpoint. Data on 30-day mortality, changes in cytokines levels, duration of mechanical ventilation, length of intensive care unit and hospital stay, and postoperative stroke will be collected as secondary endpoints. An interim analysis will be conducted after including 25 participating patients per study arm (with a focus on feasibility of the recruitment as well as differences in cytokines and cell-free DNA levels). ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board and ethics committee of the University of Jena as well as by the corresponding ethics committee of each participating study centre. The results will be published in a renowned international medical journal, irrespective of the outcomes of the study. TRIAL REGISTRATION NUMBER: The ClinicalTrials.gov registry (NCT03266302).

A novel method to analyze nucleocytoplasmic transport in vivo by using short peptide tags.

Regulated nucleocytoplasmic transport is of vital importance for maintaining the physiology of the cell, and disturbed nucleocytoplasmic shuttling of certain proteins has been found in a variety of diseases including cancer. The most frequently used procedure to analyze those processes is to fuse the protein of interest to a fluorescent protein such as GFP (green fluorescent protein)--a technique that is prone to impair normal protein function and subcellular localization. We report a novel approach to monitor nucleocytoplasmic transport processes in vivo by combining short TetR inducing peptide tags (TIP) with a TetR-controlled reporter gene in a human cell line. The technology is exemplified by demonstrating nucleocytoplasmic shuttling of the glucocorticoid receptor and activity of two further TIP fusions to cancer-related proteins. The technology presented provides the basis for efficient screening systems to isolate compounds altering the nucleocytoplasmic distribution of a protein of interest.

Model systems for rapid and slow induction of apoptosis obtained by inducible expression of pro-apoptotic proteins.

Killing tumor cells is a central goal of non-surgical cancer therapy and induction of apoptosis in the malignant cells is the major strategy used to achieve it. However, this may have serious drawbacks, since apoptotic cells reportedly induce immunological tumor tolerance and activate a tumor repopulation program. The debate on which type of cell death has the most beneficial therapeutic effects in cancer treatment is intense and controversial. Stringently regulated, doxycycline-inducible transgene expression systems trigger cell death in a defined manner, which might help us find answers to these problems. A conditional suicide switch established transiently in Jurkat T-cells was used to test a set of pro-apoptotic proteins for their potency to induce cell death. The activated forms of caspase-3 (revCasp-3) and Bid (tBid) were very effective and, therefore, analyzed after stable integration into human leukemia and murine melanoma cell lines. Expression of either protein resulted in more than 95% cell death, but with strongly different kinetics. 85% cell death was observed if tBid and revCasp-3 were expressed for 4-6 hours and 18-24 hours, respectively. The human cell lines expressing these suicide switches can serve as cancer models in xeno-transplanted mice, the corresponding murine cell lines allow syngeneic and allogeneic murine cancer models to be established.