Publications by authors named "Joachim Gerß"

128 Publications

Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

Anesth Analg 2021 Mar 8. Epub 2021 Mar 8.

From the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Münster, Münster, Germany.

Background: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial.

Methods: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI.

Results: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes.

Conclusions: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.
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http://dx.doi.org/10.1213/ANE.0000000000005458DOI Listing
March 2021

Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data.

Eur J Drug Metab Pharmacokinet 2021 Mar 17;46(2):289-300. Epub 2021 Feb 17.

Department of Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.

Background And Objectives: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance.

Methods: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC) and time above different thresholds.

Results: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value.

Conclusion: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. ( www.clinicaltrials.gov , NCT01117441, first submitted date: May 3, 2010).
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http://dx.doi.org/10.1007/s13318-021-00670-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935823PMC
March 2021

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Am J Respir Crit Care Med 2021 May;203(9):1119-1126

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany.

The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI). To investigate whether renin concentrations are associated with hypotension and AKI. This is a single-center, prospective, observational study among patients undergoing cardiac surgery. The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 μU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 μU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 μU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%;  < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793;  = 0.007). Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.
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http://dx.doi.org/10.1164/rccm.202005-2050OCDOI Listing
May 2021

Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia.

Haematologica 2020 12 10;Online ahead of print. Epub 2020 Dec 10.

Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster.

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p.
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http://dx.doi.org/10.3324/haematol.2020.258525DOI Listing
December 2020

Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).

Eur J Cancer 2021 01 27;142:112-122. Epub 2020 Nov 27.

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework.

Methods: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics.

Results: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 ± 5.4% and 35.2 ± 5.1%, respectively. On univariate analyses, age at diagnosis (≥12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome.

Conclusions: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 ± 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR- and/or GLM+ belong to a high risk group (5-year, OS 32.5 ± 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials.
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http://dx.doi.org/10.1016/j.ejca.2020.10.004DOI Listing
January 2021

Influence of Meteorological Conditions on the Incidence of Chronic Subdural Haematoma, Subarachnoid and Intracerebral Haemorrhages - the "Bleeding Weather Hypothesis".

Turk Neurosurg 2020 ;30(6):892-898

University Hospital Münster, Department of Neurosurgery, Albert-Schweitzer-Campus 1, Münster, Germany.

Aim: To elucidate possible causal relationships on climate change and intracranial haematomas.

Material And Methods: In a retrospective study we examined all patients (N=1169) treated for subarachnoid haemorrhage (SAH; n=484), intracerebral haemorrhage (ICH; n=417) or chronic subdural haematoma (CSDH; n=268) in our department over a 7-yearperiod between 1st June 2005 until 31th May 2012. The date of admission was correlated with the corresponding meteorological parameters which included; mean daily temperature (°C), relative humidity (%), vapor pressure (hPa), barometric pressure (hPa), cloud amount (/8), and wind speed (m/s).

Results: Incidence of SAH tended to increase in April, ICH in January and CSDH in July, respectively, but ?² test did not reveal any statistical significance in seasonality for the three bleeding pathologies. Comparing the arithmetic average of meteorological key parameters of uneventful and eventful days by using student?s t-test within the three groups (SAH, ICH, CSDH) we could not demonstrate any statistical significance (p > 0.05). For SAH, logistic regression analyses revealed an increased risk associated with a decrease of barometric pressure (p=0.021).

Conclusion: Although our data suggest seasonal variabilities of SAH, ICH and CSDH, the single weather parameters do not demonstrate causal relationships with the incidence of cerebrovascular events. However, incidence of SAH tended to increase with changes of barometric pressure which confirms previously published results and might indicate a possible underlying relationship.
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http://dx.doi.org/10.5137/1019-5149.JTN.29821-20.2DOI Listing
April 2021

Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients.

Eur Heart J 2020 11;41(43):4168-4177

Department of Cardiology III-Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany.

Aims: To evaluate the use of novel oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) in adult congenital heart disease (ACHD) and assess outcome in a nationwide analysis.

Methods And Results: Using data from one of Germany's largest Health Insurers, all ACHD patients treated with VKAs or NOACs were identified and changes in prescription patterns were assessed. Furthermore, the association between anticoagulation regimen and complications including mortality was studied. Between 2005 and 2018, the use of oral anticoagulants in ACHD increased from 6.3% to 12.4%. Since NOACs became available their utilization increased constantly, accounting for 45% of prescribed anticoagulants in ACHD in 2018. Adult congenital heart disease patients on NOACs had higher thromboembolic (3.8% vs. 2.8%), MACE (7.8% vs. 6.0%), bleeding rates (11.7% vs. 9.0%), and all-cause mortality (4.0% vs. 2.8%; all P < 0.05) after 1 year of therapy compared with VKAs. After comprehensive adjustment for patient characteristics, NOACs were still associated with increased risk of MACE (hazard rate-HR 1.22; 95% CI 1.09-1.36) and increased all-cause mortality (HR 1.43; 95% CI 1.24-1.65; both P < 0.001), but also bleeding (HR 1.16; 95% CI 1.04-1.29; P = 0.007) during long-term follow-up.

Conclusion: Despite the lack of prospective studies in ACHD, NOACs are increasingly replacing VKAs and now account for almost half of all oral anticoagulant prescriptions. Particularly, NOACs were associated with excess long-term risk of MACE, and mortality in this nationwide analysis, emphasizing the need for prospective studies before solid recommendations for their use in ACHD can be provided.
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http://dx.doi.org/10.1093/eurheartj/ehaa844DOI Listing
November 2020

Mortality and morbidity in patients with congenital heart disease hospitalised for viral pneumonia.

Heart 2020 Oct 27. Epub 2020 Oct 27.

Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology, University Hospital Muenster, Muenster, Germany.

Objectives: Data on the clinical outcome of patients with congenital heart disease (CHD) affected by severe viral pneumonia are limited. We analysed morbidity and mortality of viral pneumonia and evaluated the association between medical conditions, medication, vaccination and outcome specifically in patients with CHD requiring hospitalisation for viral pneumonia.

Methods: Based on data from one of Germany's largest health insurers, all cases of viral pneumonia requiring hospital admission (2005-2018) were studied. Mortality, and composites of death, transplantation, mechanical circulatory support, ventilation or extracorporeal lung support served as endpoints.

Results: Overall, 26 262 viral pneumonia cases occurred in 24 980 patients. Of these, 1180 cases occurred in patients with CHD. Compared with patients without CHD, mortality rate was elevated in patients with CHD. As a group, patients with CHD aged 20-59 years even exceeded mortality rates in patients without CHD aged >60 years. No mortality was observed in patients with CHD with simple defects <60 years of age without associated cardiovascular risk factors. On multivariable logistic regression analysis, age, CHD complexity, chromosomal anomalies, cardiac medication, use of immunosuppressants and absence of vaccination for influenza emerged as risk factors of adverse outcome.

Conclusions: We present timely data on morbidity and mortality of severe viral pneumonia requiring hospital admission in patients with CHD. Need for mechanical ventilation and risk of death in CHD increase early in life, reaching a level equivalent to non-CHD individuals >60 years of age. Our data suggest that except for patients with isolated simple defects, patients with CHD should be considered higher-risk individuals when faced with severe viral pneumonia.
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http://dx.doi.org/10.1136/heartjnl-2020-317706DOI Listing
October 2020

Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial.

JAMA 2020 10;324(16):1629-1639

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany.

Importance: Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses.

Objective: To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality.

Design, Setting, And Participants: A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled.

Interventions: Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy.

Main Outcomes And Measures: Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections.

Results: Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002).

Conclusions And Relevance: Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality.

Trial Registration: ClinicalTrials.gov Identifier: NCT02669589.
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http://dx.doi.org/10.1001/jama.2020.18618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585036PMC
October 2020

[Status Quo - The requirements for medical habilitation in Germany].

Dtsch Med Wochenschr 2020 11 6;145(23):e130-e136. Epub 2020 Oct 6.

Klinik für Kardiologie, Fakultät für Gesundheit, Department Humanmedizin, Universität Witten/Herdecke, Witten, Deutschland.

Background: In Germany, the habilitation proves one's qualification for independent research and teaching. It is a prerequisite for obtaining the teaching qualification in the respective specialist area. The prerequisites are laid down in the habilitation regulations of universities and equivalent institutions. This review article aims to show the requirements for the habilitation of medical faculties.

Methods: The current regulations regarding habilitation and implementation of all 39 German medical faculties were analyzed according to the following criteria: total publications (n), first and last authorships (n), teaching achievements, considerations of third-party funding, patent rights, abstracts at congresses, participation in further didactic training, cumulative habilitation, prerequisite of doctorate or equivalent achievements, reviewer (n) and their affiliation, giving a university-wide and scientific lecture, as well as a teaching sample.

Results: A total of 37 habilitation requirements were included in the analysis. The requirements differ in several central points: above all in numbers of required first and last authorships, total numbers of publications and evaluation of the publication performance. A cumulative habilitation is possible at 97 % (n = 36) of the universities. There are also distinct differences regarding the requirements of the reviewers (only internal, internal and external, only external).

Conclusions: Each requirement and their weighting are often inconsistent between orders. In order to increase the transparency and appreciation of the scientific achievement, a standardization of the requirements seems expedient.
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http://dx.doi.org/10.1055/a-1210-5221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671823PMC
November 2020

Systematic evaluation of olfaction in patients with hereditary cystic kidney diseases/renal ciliopathies.

J Med Genet 2020 Sep 11. Epub 2020 Sep 11.

University Children's Hospital, Department of General Pediatrics, Universitätsklinikum Münster, Münster, Germany

Background: Hereditary cystic kidney diseases such as nephronophthisis, polycystic kidney disease and Bardet-Biedl syndrome (BBS) are caused by a dysfunction of primary cilia. Cilia are involved in a variety of cellular functions and perceptions, with one of them being the sense of smell. Hyposmia is a typical feature found in patients with BBS. However, reports of olfactory dysfunction in other cystic kidney diseases are sparse. Here we provide a systematic survey on olfaction in a large cohort of patients displaying genetically determined renal ciliopathies.

Methods: We performed a match-controlled systematic olfactory evaluation in a group of 75 patients with a defined genetic background using age adapted and validated odour identification tests.

Results: Test results revealed a significant olfactory deficit in patients carrying variants (n=4), while all other genetic disorders causing nephronophthisis (n=25) or polycystic kidney disease (n=18) were not associated with an impaired sense of smell. Also in patients with BBS, olfactory performance was depending on the underlying molecular defect. While defects in the gene (n=9) had no impact on the sense of smell, all other gene disorders (n=19) were associated with significant hyposmia. Noteworthy, there was no correlation of the olfactory deficit with the level of renal impairment.

Conclusion: Hyposmia is a part of the clinical spectrum of BBS and of other renal ciliopathies. Depending on the genetic background, clinicians should be aware of this subtle and so far underappreciated symptom when clinically assessing patients with or gene variants.
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http://dx.doi.org/10.1136/jmedgenet-2020-107192DOI Listing
September 2020

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction.

Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts.

Results: MTD was 3 mg/m tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t of 8 to 9 h without accumulation in daily administrations.

Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
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http://dx.doi.org/10.3390/cancers12061488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352358PMC
June 2020

Low-density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia.

Br J Haematol 2021 Feb 8;192(3):494-503. Epub 2020 Jun 8.

Department of Medicine A, University Hospital Münster, Münster, Germany.

The low-density lipoprotein receptor (LDLR) is a membrane receptor that mediates the endocytosis of low-density lipoprotein (LDL). Uptake of LDL has been proposed to contribute to chemotherapy resistance of acute myeloid leukaemia (AML) cell lines in vitro. In the present study, we analysed LDLR expression and survival using bone marrow biopsies from 187 intensively treated patients with AML. Here, increasing LDLR expression was associated with decreasing overall (58·4%, 44·2%, and 24·4%; P = 0·0018), as well as event-free survival (41·7%, 18·1%, and 14·3%; P = 0·0077), and an increasing cumulative incidence of relapse (33·9%, 55·1%, and 71·4%; P = 0·0011). Associations of LDLR expression with survival were confirmed in 557 intensively treated patients from two international validation cohorts. In the analytic and validation cohorts, LDLR expression remained associated with outcome in multivariable regression analyses including the European LeukemiaNet genetic risk classification. Thus, LDLR predicts outcome of patients with AML beyond existing risk factors. Furthermore, we found low expression levels of LDLR in most healthy tissues, suggesting it as a promising target for antibody-based pharmacodelivery approaches in AML.
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http://dx.doi.org/10.1111/bjh.16853DOI Listing
February 2021

Re: "Long Term Survival After Femoropopliteal Artery Revascularisation With Paclitaxel Coated Devices: A Propensity Score Matched Cohort Analysis".

Eur J Vasc Endovasc Surg 2020 07 23;60(1):152. Epub 2020 Apr 23.

University of Münster, Institute of Biostatistics and Clinical Research, Münster, Germany.

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http://dx.doi.org/10.1016/j.ejvs.2020.03.048DOI Listing
July 2020

Biomarker-guided implementation of the KDIGO guidelines to reduce the occurrence of acute kidney injury in patients after cardiac surgery (PrevAKI-multicentre): protocol for a multicentre, observational study followed by randomised controlled feasibility trial.

BMJ Open 2020 04 6;10(4):e034201. Epub 2020 Apr 6.

Anesthesiology, Intensive Care and Pain Medicine, Universitatsklinikum Munster, Munster, Nordrhein-Westfalen, Germany

Introduction: Acute kidney injury (AKI) is a frequent complication after cardiac surgery with adverse short-term and long-term outcomes. Although prevention of AKI (PrevAKI) is strongly recommended, the optimal strategy is uncertain. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommended a bundle of supportive measures in high-risk patients. In a single-centre trial, we recently demonstrated that the strict implementation of the KDIGO bundle significantly reduced the occurrence of AKI after cardiac surgery. In this feasibility study, we aim to evaluate whether the study protocol can be implemented in a multicentre setting in preparation for a large multicentre trial.

Methods And Analysis: We plan to conduct a prospective, observational survey followed by a randomised controlled, multicentre, multinational clinical trial including 280 patients undergoing cardiac surgery with cardiopulmonary bypass. The purpose of the observational survey is to explore the adherence to the KDIGO recommendations in routine clinical practice. The second phase is a randomised controlled trial. The objective is to investigate whether the trial protocol is implementable in a large multicentre, multinational setting. The primary endpoint of the interventional part is the compliance rate with the protocol. Secondary endpoints include the occurrence of any AKI and moderate/severe AKI as defined by the KDIGO criteria within 72 hours after surgery, renal recovery at day 90, use of renal replacement therapy (RRT) and mortality at days 30, 60 and 90, the combined endpoint major adverse kidney events consisting of persistent renal dysfunction, RRT and mortality at day 90 and safety outcomes.

Ethics And Dissemination: The PrevAKI multicentre study has been approved by the leading Research Ethics Committee of the University of Münster and the respective Research Ethics Committee at each participating site. The results will be used to design a large, definitive trial.

Trial Registration Number: NCT03244514.
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http://dx.doi.org/10.1136/bmjopen-2019-034201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245412PMC
April 2020

Therapeutic Drug Monitoring of Asparaginase: Intra-individual Variability and Predictivity in Children With Acute Lymphoblastic Leukemia Treated With PEG-Asparaginase in the AIEOP-BFM Acute Lymphoblastic Leukemia 2009 Study.

Ther Drug Monit 2020 06;42(3):435-444

Department of Pediatric Hematology and Oncology, University Children's Hospital of Münster, Münster, Germany.

Background: Therapeutic drug monitoring (TDM) can identify patients with subtherapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a precondition for targeted dosing and the diagnosis of SI.

Methods: In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, 2771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Münster. Two biweekly administrations of pegylated ASNase during induction and a third dose during reinduction or the high-risk block, which was administered several weeks later, were monitored. We calculated (1) the incidence of SI; and (2) the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intrapatient variability and to evaluate the predictivity of ASNase activity for the subsequent administration.

Results: The overall incidence of SI was low (4.9%). The positive predictive value of SI identified by one sample was ≤21%. Confirmation of SI by a second sample indicated a high positive predictive value of 100% for biweekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25% of the patients. These patients were likely to fail dose individualization based on TDM data.

Conclusions: To use TDM as a basis for clinical decisions, standardized clinical procedures are required and high intra-individual variability should be taken into account. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/DE.
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http://dx.doi.org/10.1097/FTD.0000000000000727DOI Listing
June 2020

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

Neuro Oncol 2020 07;22(7):1006-1017

Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany.

Background: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses.

Methods: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors.

Results: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%).

Conclusions: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
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http://dx.doi.org/10.1093/neuonc/noz244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339901PMC
July 2020

Macrophage-tumor cell interaction promotes ATRT progression and chemoresistance.

Acta Neuropathol 2020 05 17;139(5):913-936. Epub 2019 Dec 17.

Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and single-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68 cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients' survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68 macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and potentially to tumor recurrence.
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http://dx.doi.org/10.1007/s00401-019-02116-7DOI Listing
May 2020

Distinct Disease Phenotype of Ulcerative Colitis in Patients With Coincident Primary Sclerosing Cholangitis: Evidence From a Large Retrospective Study With Matched Cohorts.

Dis Colon Rectum 2019 12;62(12):1494-1504

Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.

Background: Primary sclerosing cholangitis is a classical extraintestinal manifestation in patients with ulcerative colitis. However, the impact of primary sclerosing cholangitis on the disease course is incompletely understood.

Objective: This study aimed to assess the impact of primary sclerosing cholangitis on disease phenotype and its course in patients with ulcerative colitis.

Design: This is a retrospective study with 3:1 matched cohorts.

Settings: Tertiary care center's electronic database was used for data analysis from 2000 and 2018.

Patients: Of 782 patients with ulcerative colitis, 77 patients who had coincident primary sclerosing cholangitis were included.

Main Outcome Measures: The primary outcomes evaluated were disease characteristics including colonic disease activity, temporal change of disease course, colorectal neoplasia, and colectomy rates.

Results: Disease activity during acute flares, assessed by the complete Mayo score, was significantly lower in patients with primary sclerosing cholangitis (6.2 vs 7.3; p < 0.001). In addition, disease activity in patients with primary sclerosing cholangitis was decreased, especially within the first 10 years after disease onset, and biological therapy with anti-tumor necrosis factor and anti-integrin agents was commenced less frequently (22% vs 35%; p = 0.043) and later (10-year risk: 17.4% vs 27.8%; p = 0.034). Patients with primary sclerosing cholangitis were younger at colitis diagnosis (23.3 vs 29.3 years; p < 0.001) and had more extensive disease (75% vs 46%; p < 0.001). Colorectal cancer was more frequently detected in patients with coincident primary sclerosing cholangitis (6/77 vs 16/705; p = 0.016). Colectomy rates did not differ between both groups (14.3% vs 14.5%; p = 0.56). In contrast, patients with ulcerative colitis had to undergo surgery more frequently because of therapy-refractant inflammation, whereas surgery due to neoplasia development was increased in patients with coincident primary sclerosing cholangitis (p = 0.013).

Limitations: The study was limited by its retrospective design.

Conclusion: Patients who have ulcerative colitis with coincident primary sclerosing cholangitis develop a distinct disease course characterized by an earlier disease onset and lower disease activity, but more frequent extensive disease manifestation and higher risk for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B45. FENOTIPO DE ENFERMEDAD DISTINTIVO DE LA COLITIS ULCERATIVA EN PACIENTES CON COLANGITIS ESCLEROSANTE PRIMARIA CONCOMITANTE: EVIDENCIA DE UN ESTUDIO RETROSPECTIVO GRANDE CON COHORTES EMPAREJADAS: La colangitis esclerosante primaria es una manifestación extraintestinal clásica en pacientes con colitis ulcerativa. Sin embargo, el impacto de la colangitis esclerosante primaria en el curso de la enfermedad no es comprendido completamente.Evaluar el impacto de la colangitis esclerosante primaria en el fenotipo y curso de la enfermedad en pacientes con colitis ulcerativa.Este es un estudio retrospectivo con cohortes emparejadas 3:1.La base de datos electrónica de un centro de atención terciaria se utilizó para el análisis de datos de 2000 a 2018.782 pacientes con colitis ulcerativa, 77 padecían colangitis esclerosante primaria concomitante y fueron incluidos.Se evaluaron las características de la enfermedad, incluida la actividad de enfermedad colónica, el cambio temporal del curso de la enfermedad, la neoplasia colorrectal y las tasas de colectomía.La actividad de la enfermedad durante los brotes agudos, evaluada por la puntuación completa de Mayo, fue significativamente menor en pacientes con colangitis esclerosante primaria (6.2 vs 7.3; p < 0.001). Además, la actividad de la enfermedad en pacientes con colangitis esclerosante primaria se redujo especialmente en los primeros 10 años después del inicio de la enfermedad, y la terapia biológica con agentes anti-TNF y anti-integrina se inició con menos frecuencia (22% vs 35%; p = 0.043) y más tarde (riesgo a 10 años: 17.4% vs 27.8%; p = 0.034). Los pacientes con colangitis esclerosante primaria eran más jóvenes en el momento del diagnóstico de colitis (23.3 vs 29.3 años; p < 0.001) y tenían enfermedad más extensa (75% vs 46%; p < 0.001). El cáncer colorrectal se detectó con mayor frecuencia en pacientes con colangitis esclerosante primaria concomitante (6/77 vs 16/705; p = 0.016). Las tasas de colectomía no fueron diferentes entre ambos grupos (14.3% vs 14.5%; p = 0.56). En contraste, los pacientes con colitis ulcerativa tuvieron que someterse a cirugía con mayor frecuencia debido a inflamación refractaria a la terapia, mientras que el desarrollo de neoplasia se incrementó en pacientes con colangitis esclerosante primaria concomitante (p = 0.013).El estudio estuvo limitado por su diseño retrospectivo.Los pacientes con colitis ulcerativa con colangitis esclerosante primaria concomitante desarrollan un curso de enfermedad distintivo caracterizado por un inicio temprano de la enfermedad y una menor actividad de la enfermedad, pero con manifestación de enfermedad extensa más frecuente y un mayor riesgo de cáncer colorrectal. Vea el resumen en video en http://links.lww.com/DCR/B45.
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http://dx.doi.org/10.1097/DCR.0000000000001496DOI Listing
December 2019

A Collagen Supplement Improves Skin Hydration, Elasticity, Roughness, and Density: Results of a Randomized, Placebo-Controlled, Blind Study.

Nutrients 2019 Oct 17;11(10). Epub 2019 Oct 17.

Dermatest GmbH, Engelstraße 37, D-48143 Münster, Germany.

The purpose of this randomized, placebo-controlled, blind study was to investigate the effects of the drinkable nutraceutical ELASTEN (QUIRIS Healthcare, Gütersloh, Germany) on skin aging and skin health. Drinking ampoules provides a blend of 2.5 g of collagen peptides, acerola fruit extract, vitamin C, zinc, biotin, and a native vitamin E complex. This controlled interventional trial was performed on 72 healthy women aged 35 years or older. They received either the food supplement ( = 36) or a placebo ( = 36) for twelve weeks. A skin assessment was carried out and based on objective validated methods, including corneometry (skin hydration), cutometry (elasticity), the use of silicon skin replicas with optical 3D phase-shift rapid in-vivo measurements (PRIMOS) (roughness), and skin sonography (density). The verum group was followed for an additional four weeks (without intake of the test product) to evaluate the sustainability of the changes induced by the intake of the test product. The test product significantly improved skin hydration, elasticity, roughness, and density. The differences between the verum group and the placebo group were statistically significant for all test parameters. These positive effects were substantially retained during the follow-up. The measured effects were fully consistent with the subjective assessments of the study participants. The nutraceutical was well tolerated.
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http://dx.doi.org/10.3390/nu11102494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835901PMC
October 2019

Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis.

Eur Heart J 2020 10;41(38):3732-3739

Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany.

Aims: Drug-eluting devices (DED) represent a well-established therapy being widely used for endovascular revascularization (EVR) of peripheral vessels. Recent data indicate a two-fold increased long-term mortality in patients treated with paclitaxel-based DED. The subsequent safety concerns affected international regulatory authorities to enunciate several alerts for further application of DED.

Methods And Results: In 9.2 million insurants of the German BARMER Health Insurance, data on the application of paclitaxel-based drug-eluting stents (DES) and drug-coated balloons (DCB) were retrieved from their introduction on the market in 2007 until present. All patients with first EVR between 2007 and 2015 were indexed and followed until 31 December 2017. Each subsequently applied DES, DCB, bare-metal stent, and uncoated balloon was included in further analyses. Multivariable Cox regression analysis considered potential non-linear time-dependent hazard ratios (HRs) of DES and DCB over 11 years. We identified 64 771 patients who underwent 107 112 EVR procedures using 23 137 DED. Multivariable Cox regression analysis showed paclitaxel-based DES not to be associated with increased long-term mortality for over 11 years past application (all P > 0.057). DCB was associated with decreased long-term mortality for the first year past application (HR 0.92; P < 0.001), and indifferent correlation in the years thereafter (all P > 0.202).

Conclusion: Our real-world analysis showed no evidence for increased mortality associated with paclitaxel-based DED for over 11 years.
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http://dx.doi.org/10.1093/eurheartj/ehz698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666867PMC
October 2020

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage.

Neurocrit Care 2020 06;32(3):742-754

Department of Neuroradiology, Asklepios Hospital Nord, Tangstedter Landstr. 400, 22417, Hamburg, Germany.

Background: Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD).

Methods: In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule.

Results: Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2.

Conclusions: Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.
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http://dx.doi.org/10.1007/s12028-019-00809-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272492PMC
June 2020

MRI identifies biochemical alterations of intervertebral discs in patients with low back pain and radiculopathy.

Eur Radiol 2019 Dec 5;29(12):6443-6446. Epub 2019 Jul 5.

Medical Faculty, Department of Diagnostic and Interventional Radiology, University Dusseldorf, 40225, Dusseldorf, Germany.

Key Points: • Molecular intervertebral disc damage was associated with LBP and radiculopathy.• Patients with radiculopathy and LBP demonstrated a depletion of gagCEST values compared with healthy controls.• GagCEST imaging may be a non-invasive tool for investigation of degeneration processes of lumbar intervertebral discs (IVDs). GagCEST imaging may be an imaging biomarker for biochemical IVD alterations.
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http://dx.doi.org/10.1007/s00330-019-06305-6DOI Listing
December 2019

[Current challenges in the assessment of ethical proposals-aspects of digitalization and personalization in the healthcare system].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):758-764

Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Paul-Ehrlich-Institut, Langen, Deutschland.

The global aim of medical ethics committees is to judge the scientific quality and the integrity of the content of medical research projects (studies), thereby assessing the benefit-risk profile. Apart from judging content-related aspects and the legal correctness, the study design and the analysis strategy must also be assessed from a biostatistical point of view. This very sophisticated task is further complicated by the fact that medical research constantly faces new challenges.Within this work, current developments in medical research that directly impact the assessability of ethical proposals will be identified and discussed. The aim is to sensitize researchers to the opportunities and challenges of new developments.The work focusses on the topics of digitalization in the healthcare system and individualized medicine. The authors illustrate some problems resulting from these developments that affect the ethical justification of medical research projects. Problems related to medical as well as biostatistical aspects are presented and their direct implications on the legal justification and ethical and moral conceptual integrity are highlighted.New developments in medical research such as digitalization and individualized medicine offer new perspectives for optimized therapies. These promising developments must be further advanced. A critical view on the so far only poorly investigated consequences of embedding new data sources and study designs must urgently accompany this process. Transparency and clarity in formulating ethical proposals is thereby of utmost importance.
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http://dx.doi.org/10.1007/s00103-019-02955-5DOI Listing
June 2019

Phase II clinical trial of pazopanib in patients with acute myeloid leukemia (AML), relapsed or refractory or at initial diagnosis without an intensive treatment option (PazoAML).

Ann Hematol 2019 Jun 21;98(6):1393-1401. Epub 2019 Mar 21.

Department of Medicine A, University Hospital Muenster, Muenster, Germany.

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52-86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1-3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogenetic/molecular risk (ELN 2010 criteria). The safety profile of pazopanib was as reported. The most common adverse events of any grade were gastrointestinal. Two patients achieved PR (blast reduction > 50%), 14 stable disease (SD), and 4 progressive disease. Median PFS was 65 days (95% CI 29-105). After the end of the study, 1 CRi and 1 CRp occurred on demethylating agents, and 1 CR upon alloSCT. In these patients, SD and improved general condition on pazopanib allowed therapy escalation. Median OS for the overall study population was 191 days (95% CI 87-435) and 1-year survival was 35%. There was no significant change in microvessel density. Clinical trial information: NCT01361334.
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http://dx.doi.org/10.1007/s00277-019-03651-9DOI Listing
June 2019

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

Haematologica 2019 09 31;104(9):1812-1821. Epub 2019 Jan 31.

Department of Pediatric Hematology and Oncology, University Childrens' Hospital of Münster, Münster, Germany.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at .
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http://dx.doi.org/10.3324/haematol.2018.206433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717578PMC
September 2019

Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill patients with acute kidney injury (RICH) trial: study protocol for a multicentre, randomised controlled trial.

BMJ Open 2019 01 21;9(1):e024411. Epub 2019 Jan 21.

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany.

Introduction: Acute kidney injury (AKI) is a well-recognised complication of critical illness which is of crucial importance for morbidity, mortality and health resource utilisation. Renal replacement therapy (RRT) inevitably entails an escalation of treatment complexity and increases costs for those patients with severe AKI. However, it is still not clear whether regional citrate anticoagulation or systemic heparin anticoagulation for continuous RRT (CRRT) is most appropriate. We hypothesise that, in contrast to systemic heparin anticoagulation, regional citrate anticoagulation for CRRT prolongs filter life span and improves overall survival in a 90-day follow-up period (coprimary endpoints).

Methods And Analysis: We will conduct a prospective, randomised, multicentre, clinical trial including up to 1450 critically ill patients with AKI requiring CRRT. We suggest to investigate the effect of regional citrate anticoagulation for CRRT as compared with systemic heparin anticoagulation. The two coprimary outcomes are filter life span and overall survival in a 90-day follow-up period. Secondary outcomes are length of stay in the intensive care unit; length of hospitalisation; duration of CRRT; recovery of renal function at days 28, 60, 90 and 1 year; requirement for RRT after days 28, 60, 90 and 1 year; 28 days, 60 days, 90 days and 1-year all-cause mortality; major adverse kidney events at days 28, 60, 90 and 1 year; bleeding complications; transfusion requirements; infection rate and costs of RRT. Additionally, in an add-on study involving several of the participating centres, blood samples from recruited patients will be collected at different time points to analyse whether the anticoagulation strategy has an impact on immune response as evidenced by leucocyte recruitment and function.

Ethics And Dissemination: The RICH trial has been approved by the Federal Institute for Drugs and Medical Devices, the leading Ethics Committee of the University of Münster and the corresponding Ethics Committee at each participating site.

Trial Registration Number: NCT02669589.
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http://dx.doi.org/10.1136/bmjopen-2018-024411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347902PMC
January 2019

Development and Prospective Randomized Evaluation of a Decision Aid for Prostate-specific Antigen-based Early Detection of Prostate Cancer in Men Aged Between 55 and 69Yr: The PSAInForm Trial.

Eur Urol 2019 07 18;76(1):1-3. Epub 2019 Jan 18.

Department of General Practice/Family Medicine University of Marburg, Philipps-University Marburg, Marburg, Germany.

For men interested in early detection of prostate cancer, the potential impact on decisional conflict of a decision aid with or without cost compensation for the prostate-specific antigen test will be investigated.
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http://dx.doi.org/10.1016/j.eururo.2019.01.008DOI Listing
July 2019

Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).

Acta Derm Venereol 2019 Apr;99(4):379-385

Department of Dermatology, University Hospital Muenster, Von-Esmarch-Str. 58, DE-48149 Münster, Germany.

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).
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http://dx.doi.org/10.2340/00015555-3120DOI Listing
April 2019

Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.

BMJ Open 2018 09 10;8(9):e022690. Epub 2018 Sep 10.

Department of Medicine, Division of Nephrology, Wuerzburg University Clinic, Wuerzburg, Germany.

Introduction: Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis.

Methods And Analysis: A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017.

Ethics And Dissemination: The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals.

Trial Registration Numbers: NCT02933697,Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144324PMC
September 2018