Publications by authors named "Uwe Malzahn"

49 Publications

Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson's disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial.

Neurol Res Pract 2020 19;2:41. Epub 2020 Oct 19.

Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.

Introduction: Dementia in Parkinson's disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM.

Methods: We aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 - V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates.

Perspective: The feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD.

Trial Registration: ClinicalTrials.gov identifier (NCT number): NCT02589925.
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http://dx.doi.org/10.1186/s42466-020-00086-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650115PMC
October 2020

Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients.

Cardiovasc Ultrasound 2020 Sep 16;18(1):39. Epub 2020 Sep 16.

Department of Internal Medicine B, Division of Cardiology, University Medicine, Greifswald, Germany.

Background: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients.

Methods: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR.

Results: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean ∆LVMI (ASE-CMR): 19.5 ± 19.48 g/m, p < 0.001; mean ∆LVMI (Th-CMR): 15.9 ± 15.89 g/m, p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in ∆LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively).

Conclusions: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients.

Trial Registration: The data was derived from the following clinical trial: NCT01691053 , registered on 19 September 2012 before enrollment of the first participant.
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http://dx.doi.org/10.1186/s12947-020-00217-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495823PMC
September 2020

Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey.

Front Endocrinol (Lausanne) 2020 10;11:381. Epub 2020 Jul 10.

The International Fund "Help for Patients With Radiation-Induced Thyroid Cancer 'ARNICA"', Minsk, Belarus.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case-control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial "misdiagnosis."
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http://dx.doi.org/10.3389/fendo.2020.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381297PMC
July 2020

[Development of a German telephone version of the IQCODE (The Informant Questionnaire on Cognitive Decline in the Elderly) within a cohort of relatives of ischemic stroke patients].

Fortschr Neurol Psychiatr 2020 Nov 10;88(11):698-703. Epub 2020 Jun 10.

Institut für Klinische Epidemiologie und Biometrie, Universität Würzburg.

Objectives: To date, no validated long or short telephone version of the German "Informant Questionnaire on Cognitive Decline in the Elderly" (IQCODE) exists for determining cognitive changes over a period of 10 years by interviewing relatives.

Method: Sixty relatives of 60 ischemic stroke patients were interviewed both face-to-face and by phone with the 26-item German IQCODE version in randomized order. Inter-method reliability was calculated as between-method agreement and quantified by a weighted kappa with Fleiss-Cohen weights. A short telephone version of the IQCODE was developed with the Variance Inflation Factor (VIF). Its reliability in regard to the 26-item telephone ICQODE version was calculated by Spearman's correlation coefficient.

Results: The weighted kappa between the telephone and face-to-face interview was 0.84 (95 % confidence interval: 0.72-0.97). The short version of the IQCODE consists of 10 items. Spearman's Correlation Coefficient in regard to the long and short telephone version of the IQCODE was 0.97 (95 % confidence interval 0.96-0.99).

Conclusions: A long and short telephone version of the IQ-CODE for detecting cognitive changes in the elderly within a period of 10 years was developed by interviewing relatives.
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http://dx.doi.org/10.1055/a-1113-7652DOI Listing
November 2020

Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography.

Acta Anaesthesiol Scand 2020 04 26;64(4):517-525. Epub 2019 Dec 26.

Department of Anaesthesia and Critical Care, University Hospital of Würzburg, Würzburg, Germany.

Background: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post-operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity.

Methods: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left-sided open or video-thoracoscopic procedures have been investigated. Pre-operative measurements with EIT and spirometry were compared with data obtained 3 days post-operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx' (ipsilateral/contralateral). Thus, COVx' shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two-way ANOVA for repeated measurements (side, time).

Results: The perioperative shift of COVx' was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right-sided surgery (COVx'-1.97 pixel matrix points, P < .001), but not after the left-sided surgery (COVx'-0.61, P = .425). The forced vital capacity (%predicted) decreased from 94 (83-109)% (median [quartiles]; [left-sided]) and 89 (80-97)% (right-sided surgery) to 61 (59-66)% and 62 (40-72)% (P < .05), respectively. The perioperative changes in forced vital capacity (%predicted) were weakly associated with the shift of COVx'.

Conclusion: Only after right-sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups.
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http://dx.doi.org/10.1111/aas.13525DOI Listing
April 2020

Pallidal neurostimulation versus botulinum toxin injections in the treatment of cervical dystonia: protocol of a randomized, sham-controlled trial (StimTox-CD).

Neurol Res Pract 2019 28;1. Epub 2019 Feb 28.

Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.

Background: Selective peripheral denervation via botulinum neurotoxin injections into dystonic muscles is the first-line treatment for cervical dystonia. Pallidal neurostimulation is a potent alternative, but currently restricted to patients failing on neurotoxin therapy. As botulinum neurotoxin is partially effective but often unsatisfactory in a relevant proportion of patients, earlier neurostimulation might be advantageous in providing stable symptom control and preventing disability. This trial intends to demonstrate, that pallidal neurostimulation is superior to neurotoxin injections in best clinical practice for controlling the symptoms of cervical dystonia and that it is safe in patients with a partial therapy response to peripheral denervation. We hypothesize a better outcome in everyday functioning and health-related quality of life of neurostimulated patients.

Methods: We aim to recruit 66 cervical dystonia patients into a double-blind comparison of pallidal neurostimulation versus botulinum neurotoxin type A. Eligible patients need ≥25% motor symptom reduction 4 weeks after a neurotoxin test injection, but are willing to undergo DBS surgery due to unsatisfactory symptom control. All participants will be implanted with a DBS system, and randomized into 2 groups: First group will receive effective neurostimulation and saline injections into dystonic muscles. Second group is treated with regular neurotoxin injections and undergoes a sham-stimulation. Primary outcome is the change in TWSTRS total score between baseline and 6 months of therapy. Secondary outcome parameters are corresponding changes in TWSTRS motor score, Tsui score, CDQ-24 and SF-36. Safety will be assessed by frequency and severity of reported adverse events. Statistical analysis includes intention-to-treat and per protocol populations, analysis based on imputation of missing values and analysis adjusting for differences in baseline TWSTRS. After 6 months of blinded treatment all patients will receive open-label neurostimulation and neurotoxin treatment as needed, and are followed up 48 weeks after randomization.

Perspective: We will assess if pallidal neurostimulation is a safe and effective alternative to selective peripheral denervation by botulinum toxin injections in cervical dystonia, which may be offered earlier in the course of disease based on patient preference. A positive study outcome would influence future treatment guidelines of cervical dystonia.

Trial Registration: EudraCT registration number: 2016-001378-13.
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http://dx.doi.org/10.1186/s42466-019-0007-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650073PMC
February 2019

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients.

Kidney Int 2019 04 31;95(4):983-991. Epub 2019 Jan 31.

Comprehensive Heart Failure Center, University and University Hospital Würzburg, Würzburg, Germany; Department of Medicine I, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.
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http://dx.doi.org/10.1016/j.kint.2018.11.025DOI Listing
April 2019

A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

N Engl J Med 2018 Aug;379(5):428-439

From the University of Leipzig, Department of Endocrinology and Nephrology (W.F., A.T.), and Leipzig University Medical Center, Integrated Research and Treatment Center Adiposity Diseases (W.F.), Leipzig, the Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg (I.C., M.K., M.F.), and the Clinical Trial Center (U.M.) and Central Laboratory (M.F.), University Hospital Würzburg, Würzburg, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich (J.S.), the Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg (J.F.), and Experimental and Clinical Endocrinology, University Hospital Lübeck, Lübeck (G.B.) - all in Germany; the Clinic of Endocrinology, Diabetology and Metabolism (J.R., I.S., B.W., E.C., M.C.-C.) and the Clinical Trial Unit (D.R.V.), Department of Clinical Research, University of Basel and University Hospital Basel, Basel, the Department of Endocrinology, Kantonsspital St. Gallen, St. Gallen (T.D., S.B.), the Department of Endocrinology, Inselspital Bern, Bern (E.C.), the Department of Endocrinology, Luzerner Kantonsspital, Lucerne (C.H., S.F.), and the Division of Endocrinology, Diabetology and Metabolism, Medical University Clinic, Kantonsspital Aarau, Aarau (B.M.) - all in Switzerland; and Faculdade de Medicina da UFMG, Universidade Federal de Minas Gerais (J.D., A.R.-O.), and Hermes Pardini Institute (J.D.), Belo Horizonte, Brazil.

Background: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin.

Methods: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked.

Results: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test.

Conclusions: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).
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http://dx.doi.org/10.1056/NEJMoa1803760DOI Listing
August 2018

Retinal changes in Parkinson's disease and glaucoma.

Parkinsonism Relat Disord 2018 11 21;56:41-46. Epub 2018 Jun 21.

Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany; Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany. Electronic address:

Background: The topic of retinal neurodegeneration in PD is controversial, therefore the objective was to compare macular ganglion cell complex (mGCC) and peripapillary retinal nerve fiber layer (pRNFL) thickness in PD using 2 Spectral-Domain (SD) Optical Coherence Tomography (OCT) devices.

Methods: In total, 146 eyes of 130 age-similar patients were included, of these 46 eyes of 30 PD patients, 60 eyes of 60 glaucoma patients and 40 eyes of 40 healthy controls. Peripapillary RNFL and mGCC were measured. Correlation analyses were performed for evaluation of association between pRNFL or mGCC and PD severity using the Movement Disorder Society (MDS)-Unified Parkinson Disease Rating Scale (UPDRS). Scatterplots were used to evaluate relationships between disease duration, dopamine dose, olfactory assessment and retinal thickness.

Results: No significant difference was found for both eyes of PD patients compared to healthy subjects neither for overall mGCC nor each sector. However, the ipsilateral eye to the most-affected body side with bradykinesia in PD patients had a statistically significant thinner superior pRNFL compared to healthy controls (P = 0.03). There was no significant correlation between pRNFL or mGCC and disease severity; also, the scatterplots did not indicate a correlation between disease duration, dopamine dose, olfactory testing and OCT results.

Conclusions: Imaging of the retina revealed thinning of some retinal layers of the ipsilateral eye to the most-affected body side in PD patients compared to healthy controls. Peripapillary RNFL and mGCC did not correlate to disease severity; however, this was a fairly small and heterogeneous group of PD patients.
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http://dx.doi.org/10.1016/j.parkreldis.2018.06.016DOI Listing
November 2018

The Effect of Antiseptics in the Prophylaxis of Infection in Orthopaedic Surgery.

Z Orthop Unfall 2018 Oct 14;156(5):567-573. Epub 2018 Jun 14.

Orthopaedic Department, König-Ludwig-Haus, University of Würzburg.

Introduction: Over the past decade, the incidence of revision arthroplasty has increased substantially. One of the main reasons for revision arthroplasty is periprosthetic joint infection, often resulting in multiple surgical interventions with variable success and poor clinical outcome. Intraoperative wound irrigation has been proposed to reduce bacterial contamination and thus the risk of periprosthetic infection. However, there is currently no widely accepted recommendation for the use of topical antiseptics within the operative setting for primary implantation. We performed a systematic review of studies pertaining to the use of intraoperative topical antiseptics and their effectiveness in preventing infection of orthopaedic implants.

Materials And Methods: A comprehensive literature search including MEDLINE (PubMed), Cochrane Library, and Current Contents Medicine (CCMED-Medpilot) was performed according to a standardised protocol.

Results: Overall, 1905 articles were initially assessed. Four studies met the inclusion criteria and remained for further analysis, comprising two prospective cohort studies using retrospective control groups (evidence level II - III) and two randomised controlled trials (evidence level I). 0.35% Povidone-iodine (PVP-I) was used in three of these studies and a solution of 6.25% PVP-I and 6.25%-hydrogen peroxide (HO) in one study for intraoperative wound irrigation. There was a clear trend in all studies suggesting that intraoperative topical antiseptics are effective in preventing periprosthetic infection.

Conclusion: Although no clear regimen can be recommended, the available literature indicates that the use of intraoperative topical antiseptics is of clinical relevance in preventing infection of orthopaedic implants. Further randomised controlled trials are recommended.
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http://dx.doi.org/10.1055/a-0608-5292DOI Listing
October 2018

Stimulation of the mesencephalic locomotor region for gait recovery after stroke.

Ann Neurol 2017 Nov 11;82(5):828-840. Epub 2017 Nov 11.

Department of Neurology, University Hospital Würzburg, Würzburg, Germany.

Objective: One-third of all stroke survivors are unable to walk, even after intensive physiotherapy. Thus, other concepts to restore walking are needed. Because electrical stimulation of the mesencephalic locomotor region (MLR) is known to elicit gait movements, this area might be a promising target for restorative neurostimulation in stroke patients with gait disability. The present study aims to delineate the effect of high-frequency stimulation of the MLR (MLR-HFS) on gait impairment in a rodent stroke model.

Methods: Male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and chronic implantation of a stimulating electrode into the right MLR. Gait was assessed using clinical scoring of the beam-walking test and video-kinematic analysis (CatWalk) at baseline and on days 3 and 4 after experimental stroke with and without MLR-HFS.

Results: Kinematic analysis revealed significant changes in several dynamic and static gait parameters resulting in overall reduced gait velocity. All rats exhibited major coordination deficits during the beam-walking challenge and were unable to cross the beam. Simultaneous to the onset of MLR-HFS, a significantly higher walking speed and improvements in several dynamic gait parameters were detected by the CatWalk system. Rats regained the ability to cross the beam unassisted, showing a reduced number of paw slips and misses.

Interpretation: MLR-HFS can improve disordered locomotor function in a rodent stroke model. It may act by shielding brainstem and spinal locomotor centers from abnormal cortical input after stroke, thus allowing for compensatory and independent action of these circuits. Ann Neurol 2017;82:828-840.
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http://dx.doi.org/10.1002/ana.25086DOI Listing
November 2017

Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study.

BMC Neurol 2017 Aug 11;17(1):159. Epub 2017 Aug 11.

Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.

Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting.

Methods: IS patients were recruited on the SU of the University Hospital Würzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95% confidence intervals (95% CI) were calculated.

Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71-0.89) to 0.93 (95% CI 0.87-0.96), and κ from 0.39 (-95% CI 0.14-0.92) to 0.79 (95% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95% CI 0.40-0.85).

Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.
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http://dx.doi.org/10.1186/s12883-017-0937-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553778PMC
August 2017

Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation.

Neurology 2017 Aug 19;89(7):687-696. Epub 2017 Jul 19.

From the Division of Brain Sciences (E.K., A.D.G., R.V.), Department of Stroke Medicine, and Department of Primary Care and Public Health (F.T.F.), Imperial College, London, UK; Aalborg Thrombosis Research Unit (P.B.N., G.Y.H.L.), Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Denmark; Institute of Cardiovascular Sciences (G.Y.H.L.), University of Birmingham, UK; Department of Neurology (J.B.K., H.B.H.), University of Erlangen-Nuremberg, Erlangen, Germany; Institute for Clinical Evaluative Sciences (J.F.), Toronto; Thrombosis and Atherosclerosis Research Institute (S.S.), Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Stroke Unit (J.M.-F.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; Department of Neurology and Neurosurgery (C.S.G.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (A.V., A.B.), Massachusetts General Hospital, Harvard Medical School, Boston; Thrombosis Center (D.P.), Careggi Hospital, Florence, Italy; Department of Neurology (C.W.), University Hospital of Duisburg-Essen, Essen; Clinical Trial Center Würzburg (U.M., P.H.), University Hospital Würzburg; and Institute of Clinical Epidemiology and Biometry (P.H.), Comprehensive Heart Failure Center, University Würzburg, Germany.

Objective: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up.

Methods: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method.

Results: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, = 0.84).

Conclusions: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.
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http://dx.doi.org/10.1212/WNL.0000000000004235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562962PMC
August 2017

Voxelwise distribution of acute ischemic stroke lesions in patients with newly diagnosed atrial fibrillation: Trigger of arrhythmia or only target of embolism?

PLoS One 2017 24;12(5):e0177474. Epub 2017 May 24.

Department of Neurology, University of Heidelberg, Heidelberg, Germany.

Objective: Atrial fibrillation (AF) is frequently detected after ischemic stroke for the first time, and brain regions involved in autonomic control have been suspected to trigger AF. We examined whether specific brain regions are associated with newly detected AF after ischemic stroke.

Methods: Patients with acute cerebral infarctions on diffusion-weighted magnetic resonance imaging were included in this lesion mapping study. Lesions were mapped and modeled voxelwise using Bayesian Spatial Generalised Linear Mixed Modeling to determine differences in infarct locations between stroke patients with new AF, without AF and with AF already known before the stroke.

Results: 582 patients were included (median age 68 years; 63.2% male). AF was present in 109/582 patients [(18.7%); new AF: 39/109 (35.8%), known AF: 70/109 (64.2%)]. AF patients had larger infarct volumes than patients without AF (mean: 29.7 ± 45.8 ml vs. 15.2 ± 35.1 ml; p<0.001). Lesions in AF patients accumulated in the right central middle cerebral artery territory. Increasing stroke size predicted progressive cortical but not pontine and thalamic involvement. Patients with new AF had more frequently lesions in the right insula compared to patients without AF when stroke size was not accounted for, but no specific brain region was more frequently involved after adjustment for infarct volume. Controlled for stroke size, left parietal involvement was less likely for patients with new AF than for those without AF or with known AF.

Conclusions: In the search for brain areas potentially triggering cardiac arrhythmias infarct size should be accounted for. After controlling for infarct size, there is currently no evidence that ischemic stroke lesions of specific brain areas are associated with new AF compared to patients without AF. This challenges the neurogenic hypothesis of AF according to which a relevant proportion of new AF is triggered by ischemic brain lesions of particular locations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177474PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443524PMC
September 2017

Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer.

BMC Cancer 2017 01 3;17(1). Epub 2017 Jan 3.

Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany.

Background: In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery.

Methods: Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2).

Results: A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003).

Conclusions: Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact.
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http://dx.doi.org/10.1186/s12885-016-3024-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209814PMC
January 2017

Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia - The PREDICT study.

J Cereb Blood Flow Metab 2017 Dec 14;37(12):3671-3682. Epub 2016 Oct 14.

1 NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.

Stroke-associated pneumonia is a frequent complication after stroke associated with poor outcome. Dysphagia is a known risk factor for stroke-associated pneumonia but accumulating evidence suggests that stroke induces an immunodepressive state increasing susceptibility for stroke-associated pneumonia. We aimed to confirm that stroke-induced immunodepression syndrome is associated with stroke-associated pneumonia independently from dysphagia by investigating the predictive properties of monocytic HLA-DR expression as a marker of immunodepression as well as biomarkers for inflammation (interleukin-6) and infection (lipopolysaccharide-binding protein). This was a prospective, multicenter study with 11 study sites in Germany and Spain, including 486 patients with acute ischemic stroke. Daily screening for stroke-associated pneumonia, dysphagia and biomarkers was performed. Frequency of stroke-associated pneumonia was 5.2%. Dysphagia and decreased monocytic HLA-DR were independent predictors for stroke-associated pneumonia in multivariable regression analysis. Proportion of pneumonia ranged between 0.9% in the higher monocytic HLA-DR quartile (≥21,876 mAb/cell) and 8.5% in the lower quartile (≤12,369 mAb/cell). In the presence of dysphagia, proportion of pneumonia increased to 5.9% and 18.8%, respectively. Patients without dysphagia and normal monocytic HLA-DR expression had no stroke-associated pneumonia risk. We demonstrate that dysphagia and stroke-induced immunodepression syndrome are independent risk factors for stroke-associated pneumonia. Screening for immunodepression and dysphagia might be useful for identifying patients at high risk for stroke-associated pneumonia.
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http://dx.doi.org/10.1177/0271678X16671964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718319PMC
December 2017

Self-gated Non-Contrast-enhanced Functional Lung MR Imaging for Quantitative Ventilation Assessment in Patients with Cystic Fibrosis.

Radiology 2017 04 6;283(1):242-251. Epub 2016 Oct 6.

From the Department of Diagnostic and Interventional Radiology (S.V., A.M.W., J.K., A.S.K., D.S., C.W., H.K., T.A.B.), Department of Pediatrics (F.S., H.H.), and Clinical Trial Center Würzburg (U.M.), University Hospital Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany; and Centre of Advanced Imaging, University of Queensland, Brisbane, Australia (D.S.).

Purpose To assess the clinical feasibility of self-gated non-contrast-enhanced functional lung (SENCEFUL) magnetic resonance (MR) imaging for quantitative ventilation (QV) imaging in patients with cystic fibrosis (CF). Materials and Methods Twenty patients with CF and 20 matched healthy volunteers underwent functional 1.5-T lung MR imaging with the SENCEFUL imaging approach, in which a two-dimensional fast low-angle shot sequence is used with quasi-random sampling. The lungs were manually segmented on the ventilation-weighted images to obtain QV measurements, which were compared between groups. QV values of the patients were correlated with results of pulmonary function testing. Three radiologists rated the images for presence of ventilation deficits by means of visual inspection. Mann-Whitney U tests, receiver operating characteristic analyses, Spearman correlations, and Gwet agreement coefficient analyses were used for statistical analysis. Results QV of the entire lungs was lower for patients with CF than for control subjects (mean ± standard deviation, 0.09 mL/mL ± 0.03 vs 0.11 mL/mL ± 0.03, respectively; P = .007). QV ratios of upper to lower lung halves were lower in patients with CF than in control subjects (right, 0.84 ± 0.2 vs 1.16 ± 0.2, respectively [P < .001]; left, 0.88 ± 0.3 vs 1.11 ± 0.1, respectively [P = .017]). Accordingly, ventilation differences between the groups were larger in the upper halves (Δ = 0.04 mL/mL, P ≤ .001-.002). QV values of patients with CF correlated with forced vital capacity (r = 0.7; 95% confidence interval [CI]: 0.21, 0.91), residual volume (static hyperinflation, r = -0.8; 95% CI: -0.94, 0.42), and forced expiratory volume in 1 second (airway obstruction, r = 0.7; 95% CI: 0.21, 0.91). Disseminated small ventilation deficits were the most frequent involvement pattern, present in 40% of the functional maps in CF versus 8% in the control subjects (P < .001). Conclusion SENCEFUL MR imaging is feasible for QV assessment. Less QV, especially in upper lung parts, and correlation to vital capacity and to markers for hyperinflation and airway obstruction were found in patients with CF. RSNA, 2016.
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http://dx.doi.org/10.1148/radiol.2016160355DOI Listing
April 2017

Cardiac monitoring for detection of atrial fibrillation after TIA: A systematic review and meta-analysis.

Int J Stroke 2017 01 29;12(1):33-45. Epub 2016 Sep 29.

1 Division of Brain Sciences, Department of Stroke Medicine, Imperial College, London, UK.

Background and purpose The detection rate of atrial fibrillation has not been studied specifically in transient ischemic attack (TIA) patients although extrapolation from ischemic stroke may be inadequate. We conducted a systematic review and meta-analysis to determine the rate of newly diagnosed atrial fibrillation using different methods of ECG monitoring in TIA. Methods A comprehensive literature search was performed following a pre-specified protocol the PRISMA statement. Prospective observational studies and randomized controlled trials were considered that included TIA patients who underwent cardiac monitoring for >12 h. Primary outcome was frequency of detection of atrial fibrillation ≥30 s. Analyses of subgroups and of duration and type of monitoring were performed. Results Seventeen studies enrolling 1163 patients were included. The pooled atrial fibrillation detection rate for all methods was 4% (95% CI: 2-7%). Yield of monitoring was higher in selected (higher age, more extensive testing for arrhythmias before enrolment, or presumed cardioembolic/cryptogenic cause) than in unselected cohorts (7% vs 3%). Pooled mean atrial fibrillation detection rates rose with duration of monitoring: 4% (24 h), 5% (24 h to 7 days) and 6% (>7 days), respectively. Yield of non-invasive was significantly lower than that of invasive monitoring (4% vs. 11%). Significant heterogeneity was observed among studies (I=60.61%). Conclusion This first meta-analysis of atrial fibrillation detection in TIA patients finds a lower atrial fibrillation detection rate in TIA than reported for IS and TIA cohorts in previous meta-analyses. Prospective studies are needed to determine actual prevalence of atrial fibrillation and optimal diagnostic procedure for atrial fibrillation detection in TIA.
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http://dx.doi.org/10.1177/1747493016669885DOI Listing
January 2017

Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts.

PLoS One 2016 9;11(9):e0162188. Epub 2016 Sep 9.

Department of Epidemiology and Health Monitoring, Robert Koch Institute Berlin, Berlin, Germany.

Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008-11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40-65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162188PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017762PMC
August 2017

Outcome of Surgical or Endovascular Treatment of Giant Intracranial Aneurysms, with Emphasis on Age, Aneurysm Location, and Unruptured Aneuryms--A Systematic Review and Meta-Analysis.

Cerebrovasc Dis 2016 15;41(3-4):187-98. Epub 2016 Jan 15.

Department of Neurosurgery, Charitx00E9; - Universitaetsmedizin Berlin, Berlin, Germany.

Background: Designing treatment strategies for unruptured giant intracranial aneurysms (GIA) is difficult as evidence of large clinical trials is lacking. We examined the outcome following surgical or endovascular GIA treatment focusing on patient age, GIA location and unruptured GIA.

Methods: Medline and Embase were searched for studies reporting on GIA treatment outcome published after January 2000. We calculated the proportion of good outcome (PGO) for all included GIA and for unruptured GIA by meta-analysis using a random effects model.

Results: We included 54 studies containing 64 study populations with 1,269 GIA at a median follow-up time (FU-T) of 26.4 months (95% CI 10.8-42.0). PGO was 80.9% (77.4-84.4) in the analysis of all GIA compared to 81.2% (75.3-86.1) in the separate analysis of unruptured GIA. For each year added to patient age, PGO decreased by 0.8%, both for all GIA and unruptured GIA. For all GIA, surgical treatment resulted in a PGO of 80.3% (95% CI 76.0-84.6) compared to 84.2% (78.5-89.8, p = 0.27) after endovascular treatment. In unruptured GIA, PGO was 79.7% (95% CI 71.5-87.8) after surgical treatment and 84.9% (79.1-90.7, p = 0.54) after endovascular treatment. PGO was lower in high quality studies and in studies presenting aggregate instead of individual patient data. In unruptured GIA, the OR for good treatment outcome was 5.2 (95% CI 2.0-13.0) at the internal carotid artery compared to 0.1 (0.1-0.3, p < 0.1) in the posterior circulation. Patient sex, FU-T and prevalence of ruptured GIA were not associated with PGO.

Conclusions: We found that the chances of good outcome after surgical or endovascular GIA treatment mainly depend on patient age and aneurysm location rather than on the type of treatment conducted. Our analysis may inform future research on GIA.
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http://dx.doi.org/10.1159/000443485DOI Listing
December 2016

Pulmonary wedge resection plus parietal pleurectomy (WRPP) versus parietal pleurectomy (PP) for the treatment of recurrent primary pneumothorax (WOPP trial): study protocol for a randomized controlled trial.

Trials 2015 Nov 30;16:540. Epub 2015 Nov 30.

Department of Cardiothoracic Surgery, University Hospital Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.

Background: For the surgical treatment of recurrent primary spontaneous pneumothoraces (rPSP) different operative therapies are applied to achieve permanent freedom from recurrence.

Methods/design: This multicenter clinical trial evaluates the long-term results of two commonly applied surgical techniques for the treatment of rPSP. Based on the inclusion and exclusion criteria, and after obtaining the patients' informed consent, participants are randomized into the two surgical treatment arms: pulmonary wedge resection plus parietal pleurectomy (WRPP) or parietal pleurectomy alone (PP). Consecutively, all study participants will be followed up for two years to evaluate the surgical long-term effect. The primary efficacy endpoint is the recurrence rate of pneumothorax within 24 months after surgery. The calculated sample size is 360 patients (n = 180 per treatment arm) to prove superiority of one of the two treatments. So far, 22 surgical sites have submitted their declaration of commitment, giving the estimated number of participating patients.

Discussion: A prospective randomized clinical trial has been started to compare two established surgical therapies to evaluate the long-term results regarding recurrence rates. Furthermore, cost of treatment, and influence on the perioperative morbidity and mortality as well as on quality of life are analyzed. If the study reveals equivalence for both surgical techniques, unnecessary pulmonary resections could be avoided.

Trial Registration: ClinicalTrials gov: NCT01855464 , 06.05 2013.
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http://dx.doi.org/10.1186/s13063-015-1060-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663732PMC
November 2015

iROLL: does 3-D radioguided occult lesion localization improve surgical management in early-stage breast cancer?

Eur J Nucl Med Mol Imaging 2015 Oct 9;42(11):1692-1699. Epub 2015 Jul 9.

Department of Nuclear Medicine, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

Purpose: To prospectively evaluate the feasibility of 3-D radioguided occult lesion localization (iROLL) and to compare iROLL with wire-guided localization (WGL) in patients with early-stage breast cancer undergoing breast-conserving surgery and sentinel lymph node biopsy (SLNB).

Methods: WGL (standard procedure) and iROLL in combination with SLNB were performed in 31 women (mean age 65.1 ± 11.2 years) with early-stage breast cancer and clinically negative axillae. Patient comfort in respect of both methods was assessed using a ten point scale. SLNB and iROLL were guided by freehand SPECT (fhSPECT). The results of the novel 3-D image-based method were compared with those of WGL, ultrasound-based lesion localization, and histopathology.

Results: iROLL successfully detected the malignant primary and at least one sentinel lymph node in 97% of patients. In a single patient (3%), only iROLL, and not WGL, enabled lesion localization. The variability between fhSPECT and ultrasound-based depth localization of breast lesions was low (1.2 ± 1.4 mm). Clear margins were achieved in 81% of the patients; however, precise prediction of clear histopathological surgical margins was not feasible using iROLL. Patients rated iROLL as less painful than WGL with a pain score 0.8 ± 1.2 points (p < 0.01) lower than the score for iROLL.

Conclusion: iROLL is a well-tolerated and feasible technique for localizing early-stage breast cancer in the course of breast-conserving surgery, and is a suitable replacement for WGL. As a single image-based procedure for localization of breast lesions and sentinel nodes, iROLL may improve the entire surgical procedure. However, no advantages of the image-guided procedure were found with regard to prediction of complete tumour resection.
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http://dx.doi.org/10.1007/s00259-015-3121-7DOI Listing
October 2015

Control of relapsed or refractory acute myeloid leukemia by clofarabine in preparation for allogeneic stem cell transplant.

Leuk Lymphoma 2015 24;56(12):3365-9. Epub 2015 Sep 24.

a Medical Hospital II, University of Wuerzburg , Wuerzburg , Germany.

Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations.
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http://dx.doi.org/10.3109/10428194.2015.1020059DOI Listing
September 2016

The value of ADC, T2 signal intensity, and a combination of both parameters to assess Gleason score and primary Gleason grades in patients with known prostate cancer.

Acta Radiol 2016 Jan 12;57(1):107-14. Epub 2014 Dec 12.

Department of Radiology, Charité - Universitätsmedizin Berlin, Germany

Background: The ability to non-invasively analyze tumor aggressiveness is an important predictor for individual treatment stratification and patient outcome in prostate cancer (PCA).

Purpose: To evaluate: (i) whether apparent diffusion coefficient (ADC), the T2 signal intensity (SI), and a combination of both parameters allow for an improved discrimination of Gleason Score (GS) ≥7 (intermediate and high risk) and GS <7 (low risk) in PCA; and (ii) whether ADC may distinguish between 3 + 4 and 4 + 3 PCA (primary Gleason grades [pGG]).

Material And Methods: Prostatectomy specimens of 66 patients (mean age, 63 ± 5.6 years; 104 PCA foci) with a preceding multiparametric 1.5 T endorectal coil magnetic resonance imaging (MRI) were included. ADC (b values = 0, 100, 400, 800 s/mm(2)), standardized T2 (T2s), and the ADC/T2s ratio were tested for correlation with GS applying multivariate analysis. ADC cutoff values were calculated for prediction of GS and pGG, and logarithm of the odds (LOGIT) was used to express the probability for GS and pGG. Diagnostic accuracy was assessed by ROC analysis.

Results: We found an almost linear negative relationship of ADC for GS ≥7 (P = 0.002). The effect of ADC for GS ≥7 (adjusted odds ratio = 0.995) was almost identical for peripheral and transition zone PCA (P = 0.013 and P < 0.001, respectively). ADC showed an AUC of 78.9% for discrimination between GS <7 and GS ≥7. An ADC cutoff of <1.005 × 10(-3 )mm(2)/s indicated a GS ≥7 (90.5% sensitivity, 62.5% specificity). Within the group of GS = 7 PCA, an ADC > 0.762 × 10(-3 )mm(2)/s indicated a pGG of 3 (AUC = 69.6%).

Conclusion: T2s and the ADC/T2s ratio do not provide additional information regarding prediction of GS. ADC values have a good discriminatory power to distinguish tumors with GS ≥7 from GS <7 and to predict pGG in GS = 7 PCA.
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http://dx.doi.org/10.1177/0284185114561915DOI Listing
January 2016

18 FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation.

Oncotarget 2014 Sep;5(17):7381-91

Department of Hematology and Oncology,Medical Center, University of Würzburg, Würzburg.

The aim of this study was to investigate the prognostic value of 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients. Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202130PMC
http://dx.doi.org/10.18632/oncotarget.2290DOI Listing
September 2014

Repeatability of peripapillary retinal nerve fiber layer and inner retinal thickness among two spectral domain optical coherence tomography devices.

Invest Ophthalmol Vis Sci 2014 Sep 16;55(10):6536-46. Epub 2014 Sep 16.

Department of Ophthalmology, University of Würzburg, Germany.

Purpose: To compare measurement of macular inner retina and peripapillary retinal nerve fiber layer (pRNFL) thickness using two spectral-domain optical coherence tomography (SD-OCT) devices in glaucoma patients, patients with ocular hypertension, idiopathic and atypical Parkinson disease, and healthy controls.

Methods: A total of 171 eyes of 146 participants underwent successful pRNFL and macular scanning and automated measurement of ganglion cell layer+inner plexiform layer (GCL-IPL) using Cirrus HD-OCT or retinal nerve fiber layer+GCL-IPL (RNFL-GCL-IPL) using RTVue-100. Macular RNFL was added to the GCL-IPL thickness measured by Cirrus and was compared to the RNFL-GCL-IPL thickness of the RTVue in the corresponding Cirrus sectors. Intraclass correlation coefficient (ICC) was calculated to determine repeatability of three consecutive measurements; ICC and Bland-Altman analysis to assess agreement between OCTs; Pearson's correlation coefficient to assess strength of linear correlation.

Results: Repeatability of average macular RNFL-GCL-IPL thickness measurement was excellent with an ICC of 0.998 for Cirrus and 0.995 for RTVue. Repeatability was also good for average pRNFL thickness measurements. Both instruments demonstrated a good consistency in measurements with ICC values ranging from 0.844 to 0.862 for macular RNFL-GCL-IPL and 0.718 to 0.958 for pRNFL thickness.

Conclusions: Measurement of pRNFL and macular RNFL-GCL-IPL thickness has a high degree of repeatability for both OCT devices. Despite a high correlation between measurements of the two OCT devices and fair to excellent ICC values representing a high consistency in the measurements of the two devices, RTVue measured a thicker macular RNFL-GCL-IPL and pRNFL thickness.
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http://dx.doi.org/10.1167/iovs.14-15072DOI Listing
September 2014

Validity of negative high-resolution diffusion-weighted imaging in transient acute cerebrovascular events.

Stroke 2013 Sep 11;44(9):2598-600. Epub 2013 Jul 11.

Department of Neurology, Charité University Hospital Berlin, Berlin, Germany.

Background And Purpose: A significant amount of strokes are reported to be diffusion-weighted imaging (DWI) negative in acute imaging. We attempted to quantify the rate of false-negative high-resolution (hr) DWI and to identify a valid screening tool to guide follow-up MRI to diagnose infarction initially not visible on hrDWI.

Methods: An a priori-defined post hoc analysis of a prospective 3T MRI cohort of acute cerebrovascular events imaged within 24 hours of ictus. Basic demographics, risk factors, National Institute of Health Stroke Scale, and imaging parameters were recorded.

Results: Of 151 patients with negative acute hrDWI, 63 received follow-up scans depicting infarction in 7 cases (11.1%). Persistence of clinical symptoms as established by National Institute of Health Stroke Scale on the following day was strongly associated with infarction on follow-up MRI (odds ratios, 17.5; 95% confidence interval, 2.83-108.12). Negative predictive value of follow-up National Institute of Health Stroke Scale was 0.96.

Conclusions: Infarcts are frequently invisible on initial hrDWI, but we may well trust in negative hrDWI in completely transient cerebrovascular events.
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http://dx.doi.org/10.1161/STROKEAHA.113.001594DOI Listing
September 2013

Laminar infarcts in clinical routine: a prospective analysis in standard stroke unit patients.

J Neurol 2013 Aug 17;260(8):2118-23. Epub 2013 May 17.

Department of Neurology, Charite-University Medicine Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.

The present study aimed to investigate prospectively the frequency of laminar infarcts (LI) within a standard stroke unit population. Laminar infarcts follow neuroanatomical borders rather than the vascular architecture. The LI are rarely noticed in clinical routine because they are typically not detected by computed tomography. As there is a lack of systemic studies about this specific infarct pattern, little is known about their frequency, clinical characteristics or pathophysiological mechanisms. Consecutive acute ischemic stroke unit patients were prospectively enrolled during a 12 month period. The LI were defined as ischemic lesions following the gyral anatomy of the cerebral cortex. The clinical assessment included a standardized questionnaire, clinical syndromes and standard diagnostic results. There were 491 consecutive ischemic stroke patients enrolled (243 female, mean age 75 ± 12 years). The MRI revealed no laminar lesion crossing vascular territories and 28 patients with LI non-crossing vascular territories (7 %). According to the TOAST classification, 61 % of LI were classified as stroke of undetermined etiology (TOAST V) including 46 % with completed evaluation (TOAST Vb). In contrast to these findings, only 20 % of the whole study cohort with non-laminar infarcts were classified as TOAST V. The results indicate that LI are rare. In clinical routine, patients with LI require particular attention. Within the TOAST classification, this specific infarct pattern seems to be underrepresented.
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http://dx.doi.org/10.1007/s00415-013-6948-5DOI Listing
August 2013

Should transesophageal echocardiography be performed in acute stroke patients with atrial fibrillation?

J Clin Neurosci 2013 Apr 4;20(4):554-9. Epub 2013 Feb 4.

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.

The diagnostic need for echocardiography in acute stroke patients with documented atrial fibrillation (AF) is controversial because the index stroke per se is an indication for therapeutic anticoagulation according to guidelines. We retrospectively analyzed medical records of 2390 stroke patients consecutively admitted over a 2-year period to three different stroke units at university hospitals in Berlin, Germany. AF was diagnosed in 21.2% (n=506) of 2185 patients with acute ischemic stroke or transient ischemic attack. Overall, 36.6% (n=185) of all AF patients underwent transesophageal echocardiography (TEE) or transthoracic echocardiography within days of hospital admission. According to multivariate analysis, age and in-hospital conventions determined the diagnostic use of TEE in stroke patients with known AF, while the existing cardiovascular risk profile had no impact. Major cardiac sources of embolism were identified by echocardiography in 9.7% (n=18) of all AF patients with acute stroke, including non-AF-related sources of embolism in 3.8% (n=7). However, echocardiographic findings did not result in any therapeutic intervention other than immediate anticoagulation. Furthermore, echocardiographic findings had no impact on the prescription of anticoagulants at hospital discharge or long-term survival. Taken together, our data indicate that diagnostic echocardiography offers only a little additional information and does not impact clinical management and outcome in acute stroke patients with known AF.
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http://dx.doi.org/10.1016/j.jocn.2012.03.049DOI Listing
April 2013

Decision-making in the diagnosis and treatment of stroke-associated pneumonia.

J Neurol Neurosurg Psychiatry 2012 Dec 28;83(12):1225-30. Epub 2012 Sep 28.

NeuroCure Clinical Reseach Center (NCRC), Center for Stroke Research Berlin (CSB), Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Background: Stroke-associated pneumonia (SAP) is associated with impaired outcome in acute stroke patients. Current European and American guidelines for acute stroke care are lacking standardised recommendations for the management of SAP. We investigated current diagnostic and treatment practice for SAP in German stroke units (SU).

Methods: We developed a standardised questionnaire including characteristics of SU, questions related to antibiotic treatment approaches of SAP and five case vignettes describing relevant clinical scenarios based on Centers for Disease Control and Prevention (CDC) criteria for 'clinically defined pneumonia'. All certified German SU were invited to take part in the survey.

Results: The survey took place from April to August 2010. Of all 162 German SU contacted, 83 (51%) responded. Classification and regression trees analysis suggested that SAP was diagnosed on the basis of clinical criteria such as fever and stroke severity. Chest x-ray showed only limited influence on the diagnosis of SAP. C-reactive protein was frequently requested as additional diagnostic information (38-76%). Group 3 cephalosporines and (acyl-) aminopenicillins/β-lactamase inhibitors are the most frequently used antibiotics (46-60%) in empiric mono (58%) and combination (42%) therapy. A minority of SU (5%) use prophylactic antibiotic treatment. Standardised procedures are available in 61% of SU.

Conclusion: Clinical criteria were the main determinants for SAP diagnosis. In contrast, chest x-ray--the central diagnostic item in CDC criteria--was of minor importance. Our survey demonstrates heterogeneous diagnostic and therapeutic strategies in German SU. Future studies need to establish and to evaluate standardised criteria for SAP care.
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http://dx.doi.org/10.1136/jnnp-2012-302194DOI Listing
December 2012