Publications by authors named "Philipp Steininger"

25 Publications

  • Page 1 of 1

Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2.

Lancet Infect Dis 2021 09 29;21(9):1212-1213. Epub 2021 Jul 29.

Institute of Virology, School of Medicine, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany; DZIF, partner sites Munich and Cologne/Bonn, Germany. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(21)00420-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321428PMC
September 2021

Correction to: Diagnostic performance of four SARS-CoV-2 antibody assays in patients with COVID-19 or with bacterial and non-SARS-CoV-2 viral respiratory infections.

Eur J Clin Microbiol Infect Dis 2021 Sep;40(9):1999-2004

Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054, Erlangen, Germany.

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http://dx.doi.org/10.1007/s10096-021-04301-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284185PMC
September 2021

Estimates and Determinants of SARS-Cov-2 Seroprevalence and Infection Fatality Ratio Using Latent Class Analysis: The Population-Based Tirschenreuth Study in the Hardest-Hit German County in Spring 2020.

Viruses 2021 06 10;13(6). Epub 2021 Jun 10.

Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.

SARS-CoV-2 infection fatality ratios (IFR) remain controversially discussed with implications for political measures. The German county of Tirschenreuth suffered a severe SARS-CoV-2 outbreak in spring 2020, with particularly high case fatality ratio (CFR). To estimate seroprevalence, underreported infections, and IFR for the Tirschenreuth population aged ≥14 years in June/July 2020, we conducted a population-based study including home visits for the elderly, and analyzed 4203 participants for SARS-CoV-2 antibodies via three antibody tests. Latent class analysis yielded 8.6% standardized county-wide seroprevalence, a factor of underreported infections of 5.0, and 2.5% overall IFR. Seroprevalence was two-fold higher among medical workers and one third among current smokers with similar proportions of registered infections. While seroprevalence did not show an age-trend, the factor of underreported infections was 12.2 in the young versus 1.7 for ≥85-year-old. Age-specific IFRs were <0.5% below 60 years of age, 1.0% for age 60-69, and 13.2% for age 70+. Senior care homes accounted for 45% of COVID-19-related deaths, reflected by an IFR of 7.5% among individuals aged 70+ and an overall IFR of 1.4% when excluding senior care home residents from our computation. Our data underscore senior care home infections as key determinant of IFR additionally to age, insufficient targeted testing in the young, and the need for further investigations on behavioral or molecular causes of the fewer infections among current smokers.
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http://dx.doi.org/10.3390/v13061118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230374PMC
June 2021

Diagnostic performance of four SARS-CoV-2 antibody assays in patients with COVID-19 or with bacterial and non-SARS-CoV-2 viral respiratory infections.

Eur J Clin Microbiol Infect Dis 2021 Sep 9;40(9):1983-1997. Epub 2021 Jun 9.

Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054, Erlangen, Germany.

SARS-CoV-2 antibody assays are used for epidemiological studies and for the assessment of vaccine responses in highly vulnerable patients. So far, data on cross-reactivity of SARS-CoV-2 antibody assays is limited. Here, we compared four enzyme-linked immunosorbent assays (ELISAs; Vircell SARS-CoV-2 IgM/IgA and IgG, Euroimmun SARS-CoV-2 IgA and IgG) for detection of anti-SARS-CoV-2 antibodies in 207 patients with COVID-19, 178 patients with serological evidence of different bacterial infections, 107 patients with confirmed viral respiratory disease, and 80 controls from the pre-COVID-19 era. In COVID-19 patients, the assays showed highest sensitivity in week 3 (Vircell-IgM/A and Euroimmun-IgA: 78.9% each) and after week 7 (Vircell-IgG: 97.9%; Euroimmun-IgG: 92.1%). The antibody indices were higher in patients with fatal disease. In general, IgM/IgA assays had only limited or no benefit over IgG assays. In patients with non-SARS-CoV-2 respiratory infections, IgG assays were more specific than IgM/IgA assays, and bacterial infections were associated with more false-positive results than viral infections. The specificities in bacterial and viral infections were 68.0 and 81.3% (Vircell-IgM/IgA), 84.8 and 96.3% (Euroimmun-IgA), 97.8 and 86.0% (Vircell-IgG), and 97.8 and 99.1% (Euroimmun-IgG), respectively. Sera from patients positive for antibodies against Mycoplasma pneumoniae, Chlamydia psittaci, and Legionella pneumophila yielded particularly high rates of unspecific false-positive results in the IgM/IgA assays, which was revealed by applying a highly specific flow-cytometric assay using HEK 293 T cells expressing the SARS-CoV-2 spike protein. Positive results obtained with anti-SARS-CoV-2 IgM/IgA ELISAs require careful interpretation, especially if there is evidence for prior bacterial respiratory infections.
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http://dx.doi.org/10.1007/s10096-021-04285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189710PMC
September 2021

Pearls & Oy-sters: SARS-CoV-2 Infection of the CNS in a Patient With Meningeosis Carcinomatosa.

Neurology 2021 03 8;96(10):496-499. Epub 2020 Dec 8.

From the Institute of Clinical and Molecular Virology (P.A.S., C.M., M.T., K.K., A.E.) and Departments of Neurology (F.S., S.B., J.K.), Medicine 1 (A.E.K.), Neuropathology (R.C.), and Neuroradiology (T.E.), University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000011357DOI Listing
March 2021

Validation of a SARS-CoV-2 RNA RT-PCR assay for high-throughput testing in blood of COVID-19 convalescent plasma donors and patients.

Transfusion 2021 02 9;61(2):368-374. Epub 2020 Nov 9.

Department of Transfusion Medicine and Hemostaseology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: The frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia in blood donors is uncertain. Thus, assays for SARS-CoV-2 RNA detection in blood, validated on commercially available polymerase chain reaction (PCR) systems, are required to allow a good comparability of data.

Study Design And Methods: The cobas SARS-CoV-2 dual-target reverse transcriptase PCR (RT-PCR) assay, licensed for respiratory swab SARS-CoV-2 RNA testing, was validated for detection of viral RNA in blood. For the validation panel, SARS-CoV-2-positive plasma samples were prepared by spiking SARS-CoV-2-positive respiratory specimens in negative human plasma. The 95% limit of detection (LOD95) was determined by probit analysis. For clinical validation, coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) donors and patients with COVID-19 with a severe disease course treated in an intensive care unit (ICU) were included.

Results: The validation of the SARS-CoV-2 RT-PCR assay for blood demonstrated high sensitivity and specificity and intra- and inter-assay precision and efficiency. The LOD95 for SARS-CoV-2 RNA was 5.0 genome copies/mL (95% confidence interval [CI], 3.3-12 copies/mL) for target 1 and 4.3 genome copies/mL (95% CI, 2.9-10 copies/mL) for target 2. In a cohort of 39 CCP donors with 66 CCP donations no SARS-CoV-2 RNA in plasma was detected. Screening of 25 blood samples of 19 ICU patients with COVID-19 showed six positive results for SARS-CoV-2 RNA in at least one target of the assay.

Conclusion: The SARS-CoV-2 RNA assay, only licensed for respiratory swabs, performed on a PCR system for high-throughput testing, showed a good assay performance for blood testing.
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http://dx.doi.org/10.1111/trf.16178DOI Listing
February 2021

Rapid response flow cytometric assay for the detection of antibody responses to SARS-CoV-2.

Eur J Clin Microbiol Infect Dis 2021 Apr 20;40(4):751-759. Epub 2020 Oct 20.

Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

SARS-CoV-2 has emerged as a previously unknown zoonotic coronavirus that spread worldwide causing a serious pandemic. While reliable nucleic acid-based diagnostic assays were rapidly available, only a limited number of validated serological assays were available in the early phase of the pandemic. Here, we evaluated a novel flow cytometric approach to assess spike-specific antibody responses.HEK 293T cells expressing SARS-CoV-2 spike protein in its natural confirmation on the surface were used to detect specific IgG and IgM antibody responses in patient sera by flow cytometry. A soluble angiotensin-converting-enzyme 2 (ACE-2) variant was developed as external standard to quantify spike-specific antibody responses on different assay platforms. Analyses of 201 pre-COVID-19 sera proved a high assay specificity in comparison to commercially available CLIA and ELISA systems, while also revealing the highest sensitivity in specimens from PCR-confirmed SARS-CoV-2-infected patients. The external standard allowed robust quantification of antibody responses among different assay platforms. In conclusion, our newly established flow cytometric assay allows sensitive and quantitative detection of SARS-CoV-2-specific antibodies, which can be easily adopted in different laboratories and does not rely on external supply of assay kits. The flow cytometric assay also provides a blueprint for rapid development of serological tests to other emerging viral infections.
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http://dx.doi.org/10.1007/s10096-020-04072-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572153PMC
April 2021

SARS-CoV-2 samples may escape detection because of a single point mutation in the N gene.

Euro Surveill 2020 10;25(39)

Institute of Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) Erlangen, Germany.

We found that a single nucleotide polymorphism (SNP) in the nucleoprotein gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a patient interfered with detection in a widely used commercial assay. Some 0.2% of the isolates in the EpiCoV database contain this SNP. Although SARS-CoV-2 was still detected by the other probe in the assay, this underlines the necessity of targeting two independent essential regions of a pathogen for reliable detection.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.39.2001650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531073PMC
October 2020

A Monte Carlo based scatter removal method for non-isocentric cone-beam CT acquisitions using a deep convolutional autoencoder.

Phys Med Biol 2020 07 13;65(14):145002. Epub 2020 Jul 13.

Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.

The primary cone-beam computed tomography (CBCT) imaging beam scatters inside the patient and produces a contaminating photon fluence that is registered by the detector. Scattered photons cause artifacts in the image reconstruction, and are partially responsible for the inferior image quality compared to diagnostic fan-beam CT. In this work, a deep convolutional autoencoder (DCAE) and projection-based scatter removal algorithm were constructed for the ImagingRing system on rails (IRr), which allows for non-isocentric acquisitions around virtual rotation centers with its independently rotatable source and detector arms. A Monte Carlo model was developed to simulate (i) a non-isocentric training dataset of ≈1200 projection pairs (primary + scatter) from 27 digital head-and-neck cancer patients around five different virtual rotation centers (DCAE), and (ii) an isocentric dataset existing of ≈1200 projection pairs around the physical rotation center (DCAE). The scatter removal performance of both DCAE networks was investigated in two digital anthropomorphic phantom simulations and due to superior performance only the DCAE was applied on eight real patient acquisitions. Measures for the quantitative error, the signal-to-noise ratio, and the similarity were evaluated for two simulated digital head-and-neck patients, and the contrast-to-noise ratio (CNR) was investigated between muscle and adipose tissue in the real patient image reconstructions. Image quality metrics were compared between the uncorrected data, the currently implemented heuristic scatter correction data, and the DCAE corrected image reconstruction. The DCAE corrected image reconstructions of two digital patient simulations showed superior image quality metrics compared to the uncorrected and corrected image reconstructions using a heuristic scatter removal. The proposed DCAE scatter correction in this study was successfully demonstrated in real non-isocentric patient CBCT acquisitions and achieved statistically significant higher CNRs compared to the uncorrected or the heuristic corrected image data. This paper presents for the first time a projection-based scatter removal algorithm for isocentric and non-isocentric CBCT imaging using a deep convolutional autoencoder trained on Monte Carlo composed datasets. The algorithm was successfully applied to real patient data.
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http://dx.doi.org/10.1088/1361-6560/ab8954DOI Listing
July 2020

Evaluation of circulating cell-free DNA as a molecular monitoring tool in patients with metastatic cancer.

Oncol Lett 2020 Feb 9;19(2):1551-1558. Epub 2019 Dec 9.

IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, A-5020 Salzburg, Austria.

The clinical decisions made when treating patients with metastatic cancer require knowledge of the current tumor extent and response to therapy. For the majority of solid tumors, a response assessment, which is based on imaging, is used to guide these decisions. However, measuring serum protein biomarkers (i.e. tumor markers) may be of additional use. Furthermore, tumor markers exhibit variable specificity and sensitivity and cannot therefore be solely relied upon when making decisions regarding cancer treatment. Therefore, there is a clinical requirement for the identification of specific, sensitive and quantitative biomarkers. In recent years, circulating cell-free DNA (cfDNA) and mutation-specific circulating cell-free tumor DNA (cftDNA) have been identified as novel potential biomarkers. In the current study, cfDNA and cftDNA were compared using imaging-based staging and current tumor markers in 15 patients with metastatic colorectal, pancreatic or breast cancer. These patients were treated at the Third Medical Department of Paracelsus Medical University Salzburg (Austria). The results of the current study demonstrated a statistically significant correlation between the concentration changes of cfDNA and cftDNA and response to treatment, which was assessed by imaging. A correlation was not indicated with current clinically used tumor markers, including carcinoembryonic antigen, carcinoma antigen 15-3 and carcinoma antigen 19-9. The present study also indicated a correlation between cfDNA and cftDNA and the tumor volume of metastatic lesions, which was not observed with the current clinically used tumor markers. In conclusion, cfDNA and cftDNA exhibit the potential to become novel biomarkers for the response assessment following cancer treatment, and may serve as a tool for the estimation of tumor volume. The current study further supports the increasingly important role of cfDNA and cftDNA as new monitoring tools for use during cancer therapy.
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http://dx.doi.org/10.3892/ol.2019.11192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956108PMC
February 2020

Characterization of a universal screening approach for congenital CMV infection based on a highly-sensitive, quantitative, multiplex real-time PCR assay.

PLoS One 2020 9;15(1):e0227143. Epub 2020 Jan 9.

Institute of Clinical and Molecular Virology, University Hospital Erlangen, Erlangen, Germany.

The majority of congenital cytomegalovirus (cCMV) infections are asymptomatic at birth and therefore not diagnosed. Approximately 10-15% of these infants develop late-onset hearing loss and other developmental disorders. Implementation of a universal screening approach at birth may allow early initiation of symptomatic interventions due to a closer follow-up of infants at risk and offers the opportunity to consider treatment of late-onset disease. Real-time PCR assays for the detection of CMV DNA in buccal swab samples demonstrated feasibility and good clinical sensitivity in comparison to a rapid culture screening assay. Because most cCMV infections remain asymptomatic, a universal screening assay that stratifies CMV infected infants according to low and high risk of late-onset cCMV disease could limit the parental anxiety and reduce follow-up costs. We therefore developed and characterized a screening algorithm based on a highly-sensitive quantitative real-time PCR assay that is compatible with centralized testing of samples from universal screening and allows to determine CMV DNA load of saliva samples either as International Units (IU)/ml saliva or IU/105 cell equivalents. 18 of 34 saliva samples of newborns that tested positively by the screening algorithm were confirmed by detection of CMV DNA in blood and/or urine samples obtained during the first weeks of life. All screening samples that could not be confirmed had viral loads of <2.3x105 IU/ml saliva (median: 6.8x103) or 1.3x105 IU/105 cell equivalents (median: 4.0x102). The viral load of screening samples with confirmed cCMV infection ranged from 7.5x102 to 8.2x109 IU/ml saliva (median: 9.3x107) or 1.5x102 to 5.6x1010 IU/105 cell equivalents (median: 3.5x106). Clinical follow-up of these newborns with confirmed cCMV infection should reveal whether the risk of late-onset cCMV disease correlates with CMV DNA load in early life saliva samples and whether a cut-off can be defined identifying cCMV infected infants with or without risk for late-onset cCMV disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952102PMC
May 2020

Two Cases of Severe Tick-Borne Encephalitis in Rituximab-Treated Patients in Germany: Implications for Diagnosis and Prevention.

Open Forum Infect Dis 2017 26;4(4):ofx204. Epub 2017 Sep 26.

Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital of Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Rituximab (RTX) has become a standard therapy for certain B cell malignancies and autoimmune diseases. We report 2 RTX-treated patients who developed severe tick-borne encephalitis virus (TBEV) infection. The inability to generate new antibody responses renders RTX-treated patients susceptible to TBEV, impedes laboratory diagnosis, and necessitates preventive vaccination in endemic areas.
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http://dx.doi.org/10.1093/ofid/ofx204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903409PMC
September 2017

Nine-degrees-of-freedom flexmap for a cone-beam computed tomography imaging device with independently movable source and detector.

Med Phys 2017 Jan;44(1):132-142

Institute for Research and Development on Advanced Radiation Technologies (radART), Paracelsus Medical University, Salzburg, Austria.

Purpose: Couch-mounted cone-beam computed tomography (CBCT) imaging devices with independently rotatable x-ray source and flat-panel detector arms for acquisitions of arbitrary regions of interest (ROI) have recently been introduced in image-guided radiotherapy (IGRT). This work analyzes mechanical limitations and gravity-induced effects influencing the geometric accuracy of images acquired with arbitrary angular constellations of source and detector in nonisocentric trajectories, which is considered essential for IGRT. In order to compensate for geometric inaccuracies of this modality, a 9-degrees-of-freedom (9-DOF) flexmap correction approach is presented, focusing especially on the separability of the flexmap parameters of the independently movable components of the device.

Methods: The 9-DOF comprise a 3D translation of the x-ray source focal spot, a 3D translation of the flat-panel's active area center and three Euler-rotations of the detector's row and column vectors. The flexmap parameters are expressed with respect to the angular position of each of the devices arms. Estimation of the parameters is performed, using a CT-based structure set of a table-mounted, cylindrical ball-bearing phantom. Digitally reconstructed radiograph (DRR) patches are derived from the structure set followed by local 2D in-plane registration and subsequent 3D transform estimation by nonlinear regression with outlier detection.

Results: Flexmap parameter evaluations for the factory-calibrated system in clockwise and counter-clockwise rotation direction have shown only minor differences for the overall set of flexmap parameters. High short-term reproducibility of the flexmap parameters has been confirmed by experiments over 10 acquisitions for both directions, resulting in standard deviation values of ≤0.183 mm for translational components and ≤0.0219 deg for rotational components, respectively. A comparison of isocentric and nonisocentric flexmap evaluations showed that the mean differences of the parameter curves reside within their standard deviations, confirming the ability of the proposed calibration method to handle both types of trajectories equally well. Reconstructions of 0.1 mm and 0.25 mm steel wires showed similar results for the isocentric and nonisocentric cases. The full-width at half maximum (FWHM) measure indicates an average improvement of the calibrated reconstruction of 85% over the uncalibrated reconstruction. The contrast of the point spread function (PSF) improved by 310% on average over all experiments. Moreover, a reduced amount of artifacts visible in nonisocentric reconstructions of a head phantom and a line-pair phantom has been achieved by separate application of the 9-DOF flexmap on the geometry described by the independently moving source arm and detector arm.

Conclusions: Using a 9-DOF flexmap approach for correcting the geometry of projections acquired with a device capable of independent movements of the source and panel arms has been shown to be essential for IGRT use cases such as CBCT reconstruction and 2D/3D registration tasks. The proposed pipeline is able to create flexmap curves which are easy to interpret, useful for mechanical description of the device and repetitive quality assurance as well as system-level preventive maintenance. Application of the flexmap has shown improvements of image quality for planar imaging and volumetric imaging which is crucial for patient alignment accuracy.
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http://dx.doi.org/10.1002/mp.12033DOI Listing
January 2017

Non-occlusive mesenteric ischaemia in out of hospital cardiac arrest survivors.

Eur Heart J Acute Cardiovasc Care 2018 Aug 3;7(5):450-458. Epub 2017 Jan 3.

1 Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria.

Background And Aim Of The Study: Non-occlusive mesenteric ischaemia (NOMI) is characterised by hypoperfusion of the intestines without evidence of mechanical obstruction, potentially leading to extensive ischaemia and necrosis. Low cardiac output appears to be a major risk factor. Cardiopulmonary resuscitation aims at restoring blood flow after cardiac arrest. However, post restoration of spontaneous circulation, myocardial stunning limits immediate recovery of sufficient cardiac function. Since after successful cardiopulmonary resuscitation patients are often ventilated and sedated, NOMI might be underdiagnosed and potentially life-saving treatment delayed.

Material And Methods: A prospectively maintained multi-purpose cohort of out of hospital cardiac arrest survivors, who had successful restoration of spontaneous circulation, was used for this retrospective database analysis. Patients' charts were screened for clinical, radiological or pathological evidence of NOMI and clinical data were collected.

Results: Between 2000 and 2014, 1780 patients who were successfully resuscitated after out of hospital cardiac arrest were screened for NOMI. Twelve patients (0.68 %) suffered from NOMI and six of those died (50 %). Patients suffering from NOMI tended to have a longer duration until restoration of spontaneous circulation (27 vs. 20 min, p=0.128) and had significantly higher lactate (14 mmol/l vs. 8 mmol/l, p=0.002) and base deficit levels at admission (-17 vs. -10, p=0.012). Median leukocyte counts in NOMI patients peaked at the day of diagnosis.

Conclusion: NOMI is a rare but life-threatening and potentially curable complication following successful cardiopulmonary resuscitation. Lactate and base deficit at admission could help to identify patients at risk for developing NOMI who might benefit from increased clinical attention.
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http://dx.doi.org/10.1177/2048872616687096DOI Listing
August 2018

Technical Note: Procedure for the calibration and validation of kilo-voltage cone-beam CT models.

Med Phys 2016 Sep;43(9):5199

Université de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Lyon 1, Centre Léon Bérard, Lyon 69373 Cedex 08, France.

Purpose: The aim of this work is to propose a general and simple procedure for the calibration and validation of kilo-voltage cone-beam CT (kV CBCT) models against experimental data.

Methods: The calibration and validation of the CT model is a two-step procedure: the source model then the detector model. The source is described by the direction dependent photon energy spectrum at each voltage while the detector is described by the pixel intensity value as a function of the direction and the energy of incident photons. The measurements for the source consist of a series of dose measurements in air performed at each voltage with varying filter thicknesses and materials in front of the x-ray tube. The measurements for the detector are acquisitions of projection images using the same filters and several tube voltages. The proposed procedure has been applied to calibrate and assess the accuracy of simple models of the source and the detector of three commercial kV CBCT units. If the CBCT system models had been calibrated differently, the current procedure would have been exclusively used to validate the models. Several high-purity attenuation filters of aluminum, copper, and silver combined with a dosimeter which is sensitive to the range of voltages of interest were used. A sensitivity analysis of the model has also been conducted for each parameter of the source and the detector models.

Results: Average deviations between experimental and theoretical dose values are below 1.5% after calibration for the three x-ray sources. The predicted energy deposited in the detector agrees with experimental data within 4% for all imaging systems.

Conclusions: The authors developed and applied an experimental procedure to calibrate and validate any model of the source and the detector of a CBCT unit. The present protocol has been successfully applied to three x-ray imaging systems. The minimum requirements in terms of material and equipment would make its implementation suitable in most clinical environments.
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http://dx.doi.org/10.1118/1.4961400DOI Listing
September 2016

Influenza A virus drift variants reduced the detection sensitivity of a commercial multiplex nucleic acid amplification assay in the season 2014/15.

Arch Virol 2016 Sep 17;161(9):2417-23. Epub 2016 Jun 17.

Institute of Virology, Medical Center - University of Freiburg, Hermann-Herder-Str. 11, 79104, Freiburg, Germany.

The influenza season 2014/15 was dominated by drift variants of influenza A(H3N2), which resulted in a reduced vaccine effectiveness. It was not clear if the performance of commercial nucleic-acid-based amplification (NAT) assays for the detection of influenza was affected. The purpose of this study was to perform a real-life evaluation of two commercial NAT assays. During January-April 2015, we tested a total of 665 samples from patients with influenza-like illness using the Fast Track Diagnostics Respiratory pathogens 21, a commercial multiplex kit, (cohorts 1 and 2, n = 563 patients) and the Xpert Flu/RSV XC assay (cohort 3, n = 102 patients), a single-use cartridge system. An in-house influenza real-time RT-PCR (cohort 1) and the RealStar Influenza RT-PCR 1.0 Kit (cohort 2 and 3) served as reference tests. Compared to the reference assay, an overall agreement of 95.9 % (cohort 1), 95 % (cohort 2), and 98 % (cohort 3) was achieved. A total of 24 false-negative results were observed using the Fast Track Diagnostics Respiratory pathogens 21 kit. No false-negative results occurred using the Xpert Flu/RSV XC assay. The Fast Track Diagnostics Respiratory pathogens 21 kit and the Xpert Flu/RSV XC assay had sensitivities of 90.7 % and 100 % and specificities of 100 % and 94.1 %, respectively, compared to the RealStar 1.0 kit. Upon modification of the Fast Track Diagnostics Respiratory pathogens 21 kit, the sensitivity increased to 97.3 %. Influenza virus strains circulating during the 2014/15 season reduced the detection sensitivity of a commercial NAT assay, and continuous monitoring of test performance is therefore necessary.
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http://dx.doi.org/10.1007/s00705-016-2930-8DOI Listing
September 2016

Filtered-backprojection reconstruction for a cone-beam computed tomography scanner with independent source and detector rotations.

Med Phys 2016 May;43(5):2344

Institute for Research and Development on Advanced Radiation Technologies (radART), Paracelsus Medical University, Strubergasse 16, Salzburg 5020, Austria and medPhoton GmbH, Strubergasse 16, Salzburg 5020, Austria.

Purpose: A new cone-beam CT scanner for image-guided radiotherapy (IGRT) can independently rotate the source and the detector along circular trajectories. Existing reconstruction algorithms are not suitable for this scanning geometry. The authors propose and evaluate a three-dimensional (3D) filtered-backprojection reconstruction for this situation.

Methods: The source and the detector trajectories are tuned to image a field-of-view (FOV) that is offset with respect to the center-of-rotation. The new reconstruction formula is derived from the Feldkamp algorithm and results in a similar three-step algorithm: projection weighting, ramp filtering, and weighted backprojection. Simulations of a Shepp Logan digital phantom were used to evaluate the new algorithm with a 10 cm-offset FOV. A real cone-beam CT image with an 8.5 cm-offset FOV was also obtained from projections of an anthropomorphic head phantom.

Results: The quality of the cone-beam CT images reconstructed using the new algorithm was similar to those using the Feldkamp algorithm which is used in conventional cone-beam CT. The real image of the head phantom exhibited comparable image quality to that of existing systems.

Conclusions: The authors have proposed a 3D filtered-backprojection reconstruction for scanners with independent source and detector rotations that is practical and effective. This algorithm forms the basis for exploiting the scanner's unique capabilities in IGRT protocols.
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http://dx.doi.org/10.1118/1.4945418DOI Listing
May 2016

Hsa-miR-375 is a predictor of local control in early stage breast cancer.

Clin Epigenetics 2016 8;8:28. Epub 2016 Mar 8.

Department of Radiation Oncology, Paracelsus Medical University, SALK, Müllner Hauptstraße 48, A-5020 Salzburg, Austria ; radART - Institute for Research and Development on Advanced Radiation Technologies, Paracelsus Medical University, Salzburg, Austria.

Background: A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer.

Results: Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value = 0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p = 0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value = 0.000195 HR = 0.76, 95 % CI 0.66-0.88; corrected p value = 0.005).

Conclusions: Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor α (ER-α)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted.
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http://dx.doi.org/10.1186/s13148-016-0198-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784328PMC
April 2016

Comparison of two different rectal spacers in prostate cancer external beam radiotherapy in terms of rectal sparing and volume consistency.

Radiother Oncol 2015 Aug 28;116(2):221-5. Epub 2015 Jul 28.

Dpt. of Radiation Oncology, St. Johanns-Spital, Paracelsus Medical University of Salzburg, Austria; Institute for Research and Development on Advanced Radiation Technologies (radART), St. Johanns-Spital, Paracelsus Medical University of Salzburg, Austria.

Background And Purpose: In external beam radiation (EBRT) of the prostate, the rectum is the dose-limiting organ at risk, and sparing of the anterior rectal wall is a prerequisite for safe delivery of doses beyond 70 Gy. Spatial sparing of the rectum can be achieved by introducing a spacer material into the retroprostatic space, thus separating the anterior rectal wall from the PTV.

Materials And Methods: Two spacer technologies, Spacer OAR, a polyethylene glycol gel and ProSpace, a saline inflated balloon, were compared in terms of spacer volume, stability, and dose reduction to the anterior rectum wall in 78 patients.

Results: Both spacer systems significantly reduced the rectum surface encompassed by the 95% isodose (gel: -35%, p<0.01; balloon -63.4%, p<0.001) compared to a control group. The balloon spacer was superior in reducing rectum dose (-27.7%, p=0.034), but exhibited an average volume loss of >50% during the full course of treatment of 37-40 fractions, while the volume of gel spacers remained fairly constant.

Conclusions: In choosing between the two spacer technologies, the advantageous dose reduction of the balloon needs to be weighed up against the better volume consistency of the gel spacer with respect to the duration of hypofractionated vs normofractionated regimens.
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http://dx.doi.org/10.1016/j.radonc.2015.07.027DOI Listing
August 2015

Normal tissue complication models for clinically relevant acute esophagitis (≥ grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid).

Radiat Oncol 2015 May 28;10:121. Epub 2015 May 28.

Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, 5020, Salzburg, Austria.

Background: One of the primary dose-limiting toxicities during thoracic irradiation is acute esophagitis (AE). The aim of this study is to investigate dosimetric and clinical predictors for AE grade ≥ 2 in patients treated with accelerated radiotherapy for locally advanced non-small cell lung cancer (NSCLC).

Patients And Methods: 66 NSCLC patients were included in the present analysis: 4 stage II, 44 stage IIIA and 18 stage IIIB. All patients received induction chemotherapy followed by dose differentiated accelerated radiotherapy (DART-bid). Depending on size (mean of three perpendicular diameters) tumors were binned in four dose groups: <2.5 cm 73.8 Gy, 2.5-4.5 cm 79.2 Gy, 4.5-6 cm 84.6 Gy, >6 cm 90 Gy. Patients were treated in 3D target splitting technique. In order to estimate the normal tissue complication probability (NTCP), two Lyman models and the cutoff-logistic regression model were fitted to the data with AE ≥ grade 2 as statistical endpoint. Inter-model comparison was performed with the corrected Akaike information criterion (AICc), which calculates the model's quality of fit (likelihood value) in relation to its complexity (i.e. number of variables in the model) corrected by the number of patients in the dataset. Toxicity was documented prospectively according to RTOG.

Results: The median follow up was 686 days (range 84-2921 days), 23/66 patients (35 %) experienced AE ≥ grade 2. The actuarial local control rates were 72.6 % and 59.4 % at 2 and 3 years, regional control was 91 % at both time points. The Lyman-MED model (D50 = 32.8 Gy, m = 0.48) and the cutoff dose model (Dc = 38 Gy) provide the most efficient fit to the current dataset. On multivariate analysis V38 (volume of the esophagus that receives 38 Gy or above, 95 %-CI 28.2-57.3) was the most significant predictor of AE ≥ grade 2 (HR = 1.05, CI 1.01-1.09, p = 0.007).

Conclusion: Following high-dose accelerated radiotherapy the rate of AE ≥ grade 2 is slightly lower than reported for concomitant radio-chemotherapy with the additional benefit of markedly increased loco-regional tumor control. In the current patient cohort the most significant predictor of AE was found to be V38. A second clinically useful parameter in treatment planning may be MED (mean esophageal dose).
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http://dx.doi.org/10.1186/s13014-015-0429-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450607PMC
May 2015

Possible reasons for variable leukapheresis collection outcomes with automated apheresis systems.

Transfusion 2014 Oct;54(10):2584-5

Transfusion Medicine and Haemostaseology Department, University Hospital Erlangen, Erlangen, Germany.

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http://dx.doi.org/10.1111/trf.12799DOI Listing
October 2014

Influence of imaging source and panel position uncertainties on the accuracy of 2D∕3D image registration of cranial images.

Med Phys 2012 Sep;39(9):5547-56

School of Medical Physics and Engineering, Eindhoven University of Technology, MB Eindhoven, The Netherlands.

Purpose: To determine the effects of imager source and panel positioning uncertainties on the accuracy of dual intensity-based 2D∕3D image registration of cranial images.

Methods: An open source 2D∕3D image registration algorithm has been developed for registration of two orthogonal x-rays to a 3D volumetric image. The initialization files of the algorithm allow for nine degrees of freedom system calibration including x, y, z positions of the source and panel, and three rotational degrees of freedom of the panel about each of the three translational axes. A baseline system calibration was established and a baseline 2D∕3D registration between two orthogonal x-rays and the volumetric image was determined. The calibration file was manipulated to insert errors into each of the nine calibration variables of both imager geometries. Rigid six degrees of freedom registrations were iterated for each panel or source positional error over a range of predetermined calibration errors to determine the resulting error in the registration versus the baseline registration due to the manipulated error of the panel or source calibration.

Results: Panel and source translational errors orthogonal to the imager∕panel axis introduced the greatest errors in the registration accuracy (4.0 mm geometric error results in up to 2.7 mm registration error). Panel rotation about the imaging direction also resulted in errors of the registration (2.0° geometric error results in up to 1.7° registration error). Differences in magnification and panel tilt and roll, i.e., source and∕or panel translation along the imaging direction and panel rotations about the orthogonal axes had minimal effects on the registration accuracy (below 0.3 mm and 0.2° registration error).

Conclusions: While five of the nine imaging system variables were found to have a considerable effect on 2D∕3D registration accuracy of cranial images, the other four variables showed minimal effects. Vendors typically provide simplified calibration procedures which aim to remove encountered geometric uncertainties by accounting for two panel translations. This study shows that at least the five relevant positional variables should be separately calibrated, if accurate alignment is required for 2D∕3D registration.
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http://dx.doi.org/10.1118/1.4742866DOI Listing
September 2012

Leukapheresis in non-cytokine-stimulated donors with a new apheresis system: first-time collection results and evaluation of subsequent cryopreservation.

Transfusion 2013 Apr 15;53(4):747-56. Epub 2012 Jul 15.

Transfusion Medicine and Hemostaseology Department, University Hospital Erlangen, Erlangen, Germany.

Background: Adoptive cell therapy based on mononuclear cells (MNCs) became an important modality of cancer immunotherapy. Data about collection results and donor response of leukapheresis with the Spectra Optia v.5.0 (Terumo BCT) in nonmobilized donors are required.

Study Design And Methods: Twelve MNC collections were performed using the Spectra Optia v.5.0 in non-cytokine-stimulated donors. Leukapheresis products and peripheral blood samples from donors were assayed for CD45+, CD34+, CD3+, and CD14+ cells by flow cytometry. Prefreeze and postthaw cell counts, cell viability, and numbers of colony-forming units were assessed in cryobags and compared to data from cryovials.

Results: Leukapheresis yielded a mean of 5.26×10(9) ±2.2×10(9) CD45+ cells, 1.5×10(9) ±0.77×10(9) CD14+ monocytes, and 2.28×10(9) ±1.2×10(9) CD3+ Tcells by processing 6690±930mL of whole blood. A significant positive correlation between yield of CD3+ Tcells and residual platelets (PLTs) and red blood cells (RBCs) was observed. This did not apply for CD34+ and CD14+ white blood cell subsets. Mean collection efficiencies for CD14+ monocytes and CD3+ Tcells were 61.8±17 and 37.2±18%, respectively. Recovery of CD14+ cells after cryopreservation was 75.2±8.2%, which was significantly lower than recovery of CD45+ cells (81.4±5.5%; p=0.01).

Conclusion: This study of a small cohort demonstrates that the Spectra Optia v.5.0 is capable of collecting low product volumes with satisfactory MNC yields and low residual RBCs and PLTs in non-cytokine-mobilized apheresis. Our data suggest that cryovials can serve as a representative surrogate for the primary product cryobag.
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http://dx.doi.org/10.1111/j.1537-2995.2012.03787.xDOI Listing
April 2013

First clinical release of an online, adaptive, aperture-based image-guided radiotherapy strategy in intensity-modulated radiotherapy to correct for inter- and intrafractional rotations of the prostate.

Int J Radiat Oncol Biol Phys 2012 Aug 30;83(5):1624-32. Epub 2011 Dec 30.

University Clinic for Radiotherapy and Radio-Oncology, Salzburg, Austria.

Purpose: We developed and evaluated a correction strategy for prostate rotations using direct adaptation of segments in intensity-modulated radiotherapy (IMRT).

Method And Materials: Implanted fiducials (four gold markers) were used to determine interfractional translations, rotations, and dilations of the prostate. We used hybrid imaging: The markers were automatically detected in two pretreatment planar X-ray projections; their actual position in three-dimensional space was reconstructed from these images at first. The structure set comprising prostate, seminal vesicles, and adjacent rectum wall was transformed accordingly in 6 degrees of freedom. Shapes of IMRT segments were geometrically adapted in a class solution forward-planning approach, derived within seconds on-site and treated immediately. Intrafractional movements were followed in MV electronic portal images captured on the fly.

Results: In 31 of 39 patients, for 833 of 1013 fractions (supine, flat couch, knee support, comfortably full bladder, empty rectum, no intraprostatic marker migrations >2 mm of more than one marker), the online aperture adaptation allowed safe reduction of margins clinical target volume-planning target volume (prostate) down to 5 mm when only interfractional corrections were applied: Dominant L-R rotations were found to be 5.3° (mean of means), standard deviation of means ±4.9°, maximum at 30.7°. Three-dimensional vector translations relative to skin markings were 9.3 ± 4.4 mm (maximum, 23.6 mm). Intrafractional movements in 7.7 ± 1.5 min (maximum, 15.1 min) between kV imaging and last beam's electronic portal images showed further L-R rotations of 2.5° ± 2.3° (maximum, 26.9°), and three-dimensional vector translations of 3.0 ±3.7 mm (maximum, 10.2 mm). Addressing intrafractional errors could further reduce margins to 3 mm.

Conclusion: We demonstrated the clinical feasibility of an online adaptive image-guided, intensity-modulated prostate protocol on a standard linear accelerator to correct 6 degrees of freedom of internal organ motion, allowing safe and straightforward implementation of margin reduction and dose escalation.
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http://dx.doi.org/10.1016/j.ijrobp.2011.10.009DOI Listing
August 2012

"Augmented reality" in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

Strahlenther Onkol 2008 Feb;184(2):93-9

University Clinic for Radiotherapy and Radio-Oncology, Salzburg, Austria.

Background And Purpose: In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.

Patients And Methods: Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.

Results: Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).

Conclusion: The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.
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http://dx.doi.org/10.1007/s00066-008-1742-5DOI Listing
February 2008
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