Coburg, Germany
Coburg, Germany

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Kuhnt T.,University of Rostock | Sandner A.,Martin Luther University of Halle Wittenberg | Wendt T.,Friedrich - Schiller University of Jena | Engenhart-Cabillic R.,University of Marburg | And 7 more authors.
Annals of Oncology | Year: 2010

Background: Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN. Patients and methods: Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/m2 initial dose on day -7 of HART, followed by 250 mg/m2 weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m2 using a classical 3 + 3 dose escalation algorithm. Results: Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%). Conclusions: The combination of cisplatin with cetuximab and HART is active, well tolerated and merits additional investigation. The recommended weekly dose of cisplatin for phase II studies is 40 mg/m2. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Hoffmann B.A.,University of Hamburg | Brachmann J.,Hospital Coburg | Andresen D.,Vivantes Hospital | Eckardt L.,University of Munster | And 10 more authors.
Heart Rhythm | Year: 2011

Background: Catheter ablation (CA) is considered the treatment of choice for patients with atrioventricular nodal reentrant tachycardia (AVNRT). However, there is a tendency to avoid CA in the elderly because of a presumed increased risk of periprocedural atrioventricular (AV) nodal block. Objective: The purpose of this prospective registry was to assess age-related differences in the efficacy and safety of CA within a large population with AVNRT. Methods: A total of 3,234 consecutive patients from 48 German trial centers who underwent CA of AVNRT between March 2007 and May 2010 were enrolled in this study. The cohort was divided into three age groups: <50 years (group 1, n = 1,268 [39.2%]; median age = 40 [30.0-45.0] years, 74.1% women), 50-75 years old (group 2, n = 1,707 [52.8%]; 63.0 [58.0-69.0] years, 63.0% women), and > 75 years old (group 3, n = 259 [8.0%]; 79.0 [77.0-82.0] years, 50.6% women). Results: CA was performed with radiofrequency current (RFC) in 97.7% and cryoablation technology in 2.3% of all cases. No differences were observed among the three groups with regard to primary CA success rate (98.7% vs. 98.8 % vs. 98.5%; P = .92) and overall procedure duration (75.0 minutes [50.0-105.0]; P = .93). Hemodynamically stable pericardial effusion occurred in five group 2 (0.3%) and two group 3 (0.8%) patients but in none of the group 1 (P <.05) patients. Complete AV block requiring permanent pacemaker implantation occurred in two patients in group 1 (0.2%) and six patients in group 2 (0.4%) but none in group 3 (P = 0.41). During a median follow-up period of 511.5 days (396.0-771.0), AVNRT recurrence occurred in 5.7% of all patients. Patients >75 years (group 3) had a significantly longer hospital stay (3.0 days [2.0-5.0]) compared with group 1 (2.0 days [1.0-2.0]) or group 2 (2.0 days [1.0-3.0]) patients (P <.0001). Conclusion: CA of AVNRT is highly effective and safe and does not pose an increased risk for complete AV block in patients over 75 years of age, despite a higher prevalence of structural heart disease. Antiarrhythmic drug therapy is often ineffective in this age group; thus, CA for AVNRT should be considered the preferred treatment even in elderly patients. © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.


PubMed | Praxisklinik Herz und Gefasse, University of Hamburg, Heart Center Munich Bogenhausen, Herz und Gefass Klinik and 8 more.
Type: Journal Article | Journal: Heart rhythm : the official journal of the Heart Rhythm Society | Year: 2016

Stratification of patients with atrial fibrillation (AF) according to mechanistic and prognostic criteria may optimize the effectiveness and safety of catheter ablation. In women, AF is associated with more severe symptoms and worse prognosis.We sought to assess sex-related differences in catheter ablation procedures and outcome in a large cohort of patients with AF.A total of 3652 patients (1198 women [33%]; 2454 men [67%]) included in the German Ablation Registry were analyzed. Periprocedural parameters and outcome at 12-month follow-up were compared between male and female patients.Women were older at the time of ablation (women: 63.6 years; men: 59.1 years; P < .0001) and exhibited a higher prevalence of paroxysmal AF (women: 72%; men: 61%; P < .0001). They were less often affected by cardiovascular disease and reduced left ventricular function. Energy application duration and overall procedure duration were shorter in women. Conversely, the rate of major inhospital complications was increased in female patients (1.9% vs 0.8%; P = .023) and mainly driven by major bleeding events. At follow-up, women experienced higher AF recurrence rates (women: 50%; men: 45%; P = .017) and more often received oral medication for rhythm and rate control. In addition, the rate of pacemaker implantation was higher in the female cohort. Women more frequently reported femoral access site complications (women: 6%; men: 3%; P < .001). Overall, male patients were more often free from AF-related symptoms and satisfied with the treatment.Catheter ablation of AF was associated with a distinct sex-related outcome and complication profile that requires consideration in clinical practice.


Hecht M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Zimmer L.,University of Duisburg - Essen | Loquai C.,University Hospital Mainz | Weishaupt C.,University of Munster | And 20 more authors.
Annals of Oncology | Year: 2015

Background: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. Methods: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. Results: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P=0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. Conclusion: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib. © The Author 2015.


Hoffmann B.A.,University of Hamburg | Kuck K.-H.,Asklepios Hospital St Georg | Andresen D.,Vivantes Hospital | Spitzer S.G.,Praxisklinik Herz und Gefasse | And 11 more authors.
Journal of Cardiovascular Electrophysiology | Year: 2014

Acute Complication Rate in AF Ablation Introduction Catheter ablation (CA) has emerged as a widespread therapeutic option in the treatment of atrial fibrillation (AF). Currently, no safety data with regard to the impact of the underlying structural heart diseases (SHD) are available. We sought to assess the risk for acute and long-term complications during CA of AF in relation to underlying SHD. Methods and Results We included 6,211 patients in a prospective registry undergoing CA of AF in 41 nationwide centers. All patients were divided into 4 groups according to the underlying heart disease: No SHD (69.4%), hypertensive heart disease (HHD) (12.0%), coronary artery disease (CAD) (15.1%), and cardiomyopathy (CM) (3.6%). In univariate analysis, patients with HHD had an overall complication rate of 7.28%, whereas patients without an SHD had a significantly lower rate of 6.01% (P < 0.01). Multivariate analysis revealed that HHD (adjusted odds ratio [OR]: 1.97 [95% confidence interval (CI): 1.02-3.83], P = 0.0442) and age (years; OR: 1.04 [95% CI: 1.01-1.07], P = 0.0155) were independent predictors of severe, nonfatal complications and death. Other SHD including CAD (OR: 1.48 (0.73-3.00), P = 0.2797) and CM (OR: 2.37 [0.70-7.99], P = 0.1630) failed to reach statistical significance. Male sex was protective (OR: 0.47 [95% CI: 0.27-0.81], P = 0.0062). Conclusion In general, CA of AF has a low number of severe complications. In our prospective registry HHD emerged as an independent predictor of severe, nonfatal complications during AF ablation but other SHD including CAD and CM did not. The influence of HHD on the complication rate should be considered in patient selection. © 2013 Wiley Periodicals, Inc.


Kruger T.,RWTH Aachen | Oelenberg S.,RWTH Aachen | Kaesler N.,RWTH Aachen | Schurgers L.J.,Maastricht University | And 12 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

OBJECTIVE-: Vascular calcification is an independent risk factor for cardiovascular disease. Once thought to be a passive process, vascular calcification is now known to be actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Gla protein). Warfarin is a vitamin K antagonist, widely prescribed to reduce coagulation by inhibiting vitamin K-dependent coagulation factors. Recently, it became clear that vitamin K antagonists also affect vascular calcification by inactivation of matrix Gla protein. Here, we investigated functional cardiovascular characteristics in a mouse model with warfarin-induced media calcification. APPROACH AND RESULTS-: DBA/2 mice received diets with variable concentrations of warfarin (0.03, 0.3, and 3 mg/g) with vitamin K1 at variable time intervals (1, 4, and 7 weeks). Von Kossa staining revealed that warfarin treatment induced calcified areas in both medial layer of aorta and heart in a dose-and time-dependent fashion, which could be inhibited by simultaneous vitamin K2 treatment. With ongoing calcification, matrix Gla protein mRNA expression decreased, and inactive matrix Gla protein expression increased. TdT-mediated dUTP-biotin nick end labeling-positive apoptosis increased, and vascular smooth muscle cell number was concomitantly reduced by warfarin treatment. On a functional level, warfarin treatment augmented aortic peak velocity, aortic valve-peak gradient, and carotid pulse-wave velocity. CONCLUSION-: Warfarin induced significant calcification with resulting functional cardiovascular damage in DBA/2 wild-type mice. The model would enable future researchers to decipher mechanisms of vascular calcification and may guide them in the development of new therapeutic strategies. © 2013 American Heart Association, Inc.


Westenfeld R.,University Hospital Dsseldorf | Krueger T.,RWTH Aachen | Schlieper G.,RWTH Aachen | Cranenburg E.C.M.,Maastricht University | And 8 more authors.
American Journal of Kidney Diseases | Year: 2012

Background: Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin Kdependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin Kdependent proteins in hemodialysis patients, assessed by circulating dephosphorylated- uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). Study Design: Interventional randomized nonplacebo-controlled trial with 3 parallel groups. Setting & Participants: 53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. Interventions: Menaquinone-7 (vitamin K 2) treatment at 45, 135, or 360 μg/d for 6 weeks. Outcomes: Plasma levels of dephosphorylated- uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. Measurements: Plasma levels were assessed using enzyme-linked immunosorbent assays. Results: At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated- uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K 2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, respectively. Limitations: Small sample size. Conclusions: This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K 2 supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation. © 2012 National Kidney Foundation, Inc.


Maier S.,Innsbruck Medical University | Kreczy A.,Hospital Coburg | Weirich-Schwaiger H.,Innsbruck Medical University | Utermann G.,Innsbruck Medical University | Janecke A.R.,Innsbruck Medical University
European Journal of Pediatrics | Year: 2010

Hereditary gingival fibromatosis (HGF) is a rare, clinically variable disorder characterized by slowly progressive fibrous overgrowth of the gingiva. Four gene loci have been mapped for autosomal dominant non-syndromic HGF (adHGF). The molecular basis of adHGF remains largely unknown, with only a single SOS1 gene mutation identified so far at the gingival fibromatosis 1 (GINGF1) locus in one family. We identified an adHGF family with ten affected individuals in whom onset of gingival fibromatosis concurred with the eruption of the primary teeth. In order to identify the molecular basis in this family, we tested for linkage of the disease to known adHGF loci. A maximal multipoint logarithm of the odds score of 3.91 was obtained with marker D2S390 (θ∈=∈0) at the GINGF3 locus on chromosome 2p23.3-p22.3, and linkage to other known loci was excluded. Sequencing two candidate genes, ALK and C2orf18, and a single nucleotide polymorphisms array analysis did not reveal a mutation or copy number variation in a patient from the family. We refined the GINGF3 locus to a 6.56-cM, 8.27-Mb region containing 112 known and hypothetical genes, and our data and a search of the literature suggest that GINGF3 is a major adHGF locus. © 2009 The Author(s).


PubMed | University of Hamburg, Heart Center Munich Bogenhausen, Isar Heart Center Munich, Hospital Coburg and 4 more.
Type: Journal Article | Journal: Journal of electrocardiology | Year: 2016

This investigation addresses procedural characteristics of catheter ablation in patients with atrial fibrillation (AF) and sinus bradycardia.From the prospective, multi-center German Ablation Registry 1073 patients with sinus rhythm at the time of AF ablation were divided into two groups according to heart rate at start of procedure (A, <60 beats per minute (bpm), n=197; B, 60-99bpm, n=876).Acute procedural success was high (98%) and similar between groups. Procedure duration and energy application time were increased in group A (180min vs. 155min and 2561s vs. 1879s, respectively). Major complications were more frequent in group A (2.2% vs. 0.5%), and a greater proportion of these patients was discharged under antiarrhythmic medication (64% vs. 52%).Catheter ablation of AF with concomitant sinus bradycardia is associated with high procedural efficacy, longer procedure- and energy application durations, and a slightly elevated complication rate.


PubMed | University of Tübingen, Hannover Medical School, University Hospital Mainz, University of Zürich and 7 more.
Type: Comparative Study | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism.A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation.With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis 2 was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis 2 were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis 2 more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment.Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

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