22 results on '"Hauschke, D."'
Search Results
2. Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders
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Jost WH, Benecke R, Hauschke D, Jankovic J, Kaňovský P, Roggenkämper P, Simpson DM, and Comella CL
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Wolfgang H Jost,1 Reiner Benecke,2 Dieter Hauschke,3 Joseph Jankovic,4 Petr Kaňovský,5 Peter Roggenkämper,6 David M Simpson,7 Cynthia L Comella81Department of Neurology, University of Freiburg, Freiburg, Germany; 2Clinic and Policlinic for Neurology, University of Rostock, Rostock, Germany; 3Institute of Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany; 4Department of Neurology, Baylor College of Medicine, Houston, TX, USA; 5Department of Neurology, Palacky University Olomouc, Faculty of Medicine and Dentistry and University Hospital, Olomouc, Czech Republic; 6University Eye Clinic of Bonn, Bonn, Germany; 7Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8Rush University Medical Center, Chicago, IL, USABackground: IncobotulinumtoxinA (Xeomin®) is a purified botulinum neurotoxin type A formulation, free from complexing proteins, with proven efficacy and good tolerability for the treatment of neurological conditions such as blepharospasm, cervical dystonia (CD), and post-stroke spasticity of the upper limb. This article provides a comprehensive overview of incobotulinumtoxinA based on randomized controlled trials and prospective clinical studies.Summary: IncobotulinumtoxinA provides clinical efficacy in treating blepharospasm, CD, and upper-limb post-stroke spasticity based on randomized, double-blind, placebo-controlled trials with open-label extension periods (total study duration up to 89 weeks). Adverse events were generally mild or moderate. The most frequent adverse events, probably related to the injections, included eyelid ptosis and dry eye in the treatment of blepharospasm, dysphagia, neck pain, and muscular weakness in patients with CD, and injection site pain and muscular weakness when used for treating spasticity. In blepharospasm and CD, incobotulinumtoxinA was investigated in clinical trials permitting flexible intertreatment intervals based on the individual patient’s clinical need; the safety profile of intervals shorter than 12 weeks was comparable to intervals of 12 weeks and longer. There were no cases of newly formed neutralizing antibodies during the Phase III and IV incobotulinumtoxinA trials. Phase III head-to-head trials of incobotulinumtoxinA versus onabotulinumtoxinA for the treatment of blepharospasm and CD have demonstrated therapeutic equivalence of both formulations. Additional Phase III trials of incobotulinumtoxinA in conditions such as lower-limb spasticity, spasticity in children with cerebral palsy, and sialorrhea in various neurological disorders are ongoing.Conclusion: IncobotulinumtoxinA is an effective, well-tolerated botulinum neurotoxin type A formulation. Data from randomized clinical trials and further observational studies are expected to help physicians to optimize treatment by tailoring the choice of formulation, dose, and treatment intervals to the patient’s clinical needs.Keywords: blepharospasm, botulinum toxin, cervical dystonia, incobotulinumtoxinA, spasticity, Xeomin
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- 2015
3. OPTIMIZED AFTERCARE IN THE FIRST YEAR AFTER LIVING KIDNEY TRANSPLANTATION WITH THE SUPPORT OF TELEMONITORING - A SINGLE CENTER EXPERIENCE: V087
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Hils, S., Schmid, A., Bogatyreva, L., Hauschke, D., and Pisarski, P.
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- 2015
4. Methods for Generalized Evidence Synthesis
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Bender, R, Herrmann, KH, Jensen, K, Hauschke, D, Leverkus, F, Friede, T, Bender, R, Herrmann, KH, Jensen, K, Hauschke, D, Leverkus, F, and Friede, T
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- 2017
5. Oesophageal Doppler guided goal-directed haemodynamic therapy in thoracic surgery - a single centre randomized parallel-arm trial
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Kaufmann, K.B., primary, Stein, L, additional, Bogatyreva, L, additional, Ulbrich, F, additional, Kaifi, J.T., additional, Hauschke, D, additional, Loop, T, additional, and Goebel, U, additional
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- 2017
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6. 'Evidence Based Medicine' auf Patientenebene
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Hauschke, D, Knoerzer, D, Bender, R, and Leverkus, F
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Frederick Klauschen: Applied systems medicine for therapy prediction and clinical trial design in personalized oncology Thomas Metcalfe: Precision Medicine Approaches in Oncology - Implications for Trial Design and Regulatory Frameworks Klaus Jung & Tim Beißbarth: Identification of biomarkers[zum vollständigen Text gelangen Sie über die oben angegebene URL], GMDS 2015; 60. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)
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- 2015
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7. Workshop der AG ATF: Subgruppenanalysen auch unter dem Fokus der Nutzenbewertung
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Hauschke, D, Bender, R, Leverkus, F, Hauschke, D, Bender, R, and Leverkus, F
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- 2016
8. Results of a randomized controlled trial analyzing telemedically supported case management in the first year after living donor kidney transplantation - a budget impact analysis from the healthcare perspective.
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Kaier K, Hils S, Fetzer S, Hehn P, Schmid A, Hauschke D, Bogatyreva L, Jänigen B, and Pisarski P
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ᅟ: We analyze one-year costs and savings of a telemedically supported case management program after kidney transplantation from the perspective of the German Healthcare System. Recipients of living donor kidney transplantation (N = 46) were randomly allocated to either (1) standard aftercare or (2) standard aftercare plus additional telemedically supported case management. A range of cost figures of each patient's medical service utilization were calculated at month 3, 6 and 12 and analyzed using two-part regression models. In comparison to standard aftercare, patients receiving telemedically supported case management are associated with substantial lower costs related to unscheduled hospitalizations (mean difference: €3,417.46 per patient for the entire one-year period, p = 0.003). Taking all cost figures into account, patients receiving standard aftercare are associated, on average, with one-year medical service utilization costs of €10,449.28, while patients receiving telemedically supported case management are associated with €5,504.21 of costs (mean difference: € 4,945.07 per patient, p < 0.001). With estimated expenditures of €3,001.5 for telemedically supported case management of a single patient, we determined a mean difference of €1,943.57, but this result is not statistically significant (p = 0.128). Sensitivity analyses show that the program becomes cost-neutral at around ten participating patients, and was beneficial starting at 15 patients. Routine implementation of telemedically supported case management in German medium and high-volume transplant centers would result in annual cost savings of €791,033 for the German healthcare system. Patients with telemedically supported case management showed a lower utilization of medical services as well as better medical outcomes. Therefore, such programs should be implemented in medium and high-volume transplant centers., Trial Registration: DRKS00007634 ( http://www.drks.de/DRKS00007634 ).
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- 2017
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9. Anti-Phosphohistone H3-Positive Mitoses Are Linked to Pathological Response in Neoadjuvantly Treated Breast Cancer.
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Timme S, Sillem M, Bronsert P, Bogatyreva L, Hauschke D, Zur Hausen A, Werner M, and Stickeler E
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Background: We evaluated breast cancer (BC) core biopsies taken before neoadjuvant chemotherapy (NACT) by immunohistochemistry using anti-phosphohistone H3 (PHH3) antibody to determine mitosis, and correlated the results to clinicopathological data and histopathological regression of resected tumor specimens after NACT., Methods: 72 patients with either triple-negative (TN) or luminal type BC received NACT with epirubicin/cyclophosphamide (EC) and Taxotere®. Tumor regression was analyzed in resected specimens; pathological complete response (pCR) was achieved in 22.2%. Immunohistochemistry with PHH3 was performed on biopsy samples taken before treatment, and mitotic figures were evaluated in 10 high-power fields (HPF)., Results: PHH3-detected mitoses correlated significantly with tumor grading (p = 0.001). TNBC showed > 10 PHH3-positive mitoses/10 HPF significantly more frequently than luminal type BC (p = 0.003). Tumors with > 10 PHH3-positive mitoses/10 HPF achieved pCR significantly more often than those with ≤ 10 PHH3-positive mitoses/10 HPF (p = 0.031). Even luminal type BC with > 10 PHH3-positive mitoses/10 HPF was associated significantly with pCR compared to luminal type BC with ≤ 10 PHH3-positive mitoses/10 HPF (p = 0.016)., Conclusion: NACT with EC and Taxotere is suitable for strong proliferating TNBC and luminal BC (> 10 PHH3-positive mitoses/10 HPF). Immunohistochemical determination of mitoses using anti-PHH3 antibody is a simple and robust method for predicting therapy response to NACT in BC tissue.
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- 2017
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10. Randomized Comparison of Oral P2Y 12 -Receptor Inhibitor Loading Strategies for Transitioning From Cangrelor: The ExcelsiorLOAD2 Trial.
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Hochholzer W, Kleiner P, Younas I, Valina CM, Löffelhardt N, Amann M, Bömicke T, Ferenc M, Hauschke D, Trenk D, Neumann FJ, and Stratz C
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- Adenosine administration & dosage, Adenosine adverse effects, Adenosine Monophosphate administration & dosage, Adenosine Monophosphate adverse effects, Administration, Oral, Aged, Blood Platelets metabolism, Clopidogrel, Coronary Disease blood, Coronary Disease diagnostic imaging, Female, Germany, Humans, Infusions, Intravenous, Male, Middle Aged, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors adverse effects, Platelet Function Tests, Prasugrel Hydrochloride adverse effects, Prospective Studies, Purinergic P2Y Receptor Antagonists adverse effects, Receptors, Purinergic P2Y12 blood, Receptors, Purinergic P2Y12 drug effects, Stents, Ticagrelor, Ticlopidine administration & dosage, Ticlopidine adverse effects, Time Factors, Treatment Outcome, Adenosine analogs & derivatives, Adenosine Monophosphate analogs & derivatives, Blood Platelets drug effects, Coronary Disease therapy, Drug Substitution, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention instrumentation, Platelet Aggregation Inhibitors administration & dosage, Prasugrel Hydrochloride administration & dosage, Purinergic P2Y Receptor Antagonists administration & dosage, Ticlopidine analogs & derivatives
- Abstract
Objectives: This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor., Background: Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition., Methods: This trial randomized 110 P2Y
12 -receptor blocker-naive patients undergoing PCI with use of cangrelor to loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). The primary endpoint was the proportion of patients without high on-treatment platelet reactivity 1 h after stopping cangrelor., Results: The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups., Conclusions: Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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11. Tissue microarray technique is applicable to bone marrow biopsies of myeloproliferative neoplasms.
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Limberger KA, Bogatyreva L, Todorova R, Herde B, Hauschke D, Pahl HL, Werner M, and Aumann K
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- Adult, Aged, Aged, 80 and over, Biopsy, Humans, Middle Aged, Young Adult, Bone Marrow pathology, Myeloproliferative Disorders pathology, Tissue Array Analysis
- Abstract
Tissue microarray (TMA) technique is an established high-throughput method to analyze multiple tissue specimens in parallel. However, in order to obtain reliable results from immunohistochemical analyses of TMA blocks, cell composition of TMA spots must correspond to whole tissue sections (WTS) particularly in tissues with a heterogeneous cell composition as it is the case in myeloproliferative neoplasms (MPN). The aim of this study was to validate TMA of bone marrow biopsies from MPN patients. TMAs of MPN bone marrow biopsies (ET: n = 26, PV: n = 26, and PMF: n = 29) were compiled in triplicates and MPN-specific histological parameters were assessed. Results of TMA spots were compared with WTS' results using the intra-class correlation coefficient (ICC). Immunohistochemical NFE2 and calreticulin stainings of the TMA with quantitative evaluation were performed. TMA construction was technically successful with a loss of 10 % of all spots. ICC calculation revealed high to moderate correlations of TMA with WTS, especially the parameters that are typically affected in MPN tissue, e.g. cellularity of hematopoiesis (ICC 0.62-0.89), number of megakaryocytes (ICC 0.50-0.71), micro-vessel density (ICC 0.56-0.91), or grade of myelofibrosis (ICC 0.56-0.89). Results of NFE2 and calreticulin immunohistochemistry of MPN TMAs are consistent with previously published data. Overall, our results show moderate to good correlation between histological data of WTS and TMA spots illustrating that the TMA technique is applicable to bone marrow biopsies of MPN patients. However, TMA construction in triplicates is necessary to reach sufficient correlation. MPN TMAs can be applied for serial immunohistochemical surveys of archived tissues to assess the mutation status or to further sub-classify MPN cases.
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- 2017
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12. Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice.
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Machado V, Gilsbach R, Das R, Schober A, Bogatyreva L, Hauschke D, Krieglstein K, Unsicker K, and Spittau B
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- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration & dosage, Animals, Biomarkers metabolism, Cell Proliferation, Cytokines metabolism, Growth Differentiation Factor 15 metabolism, Inflammation Mediators metabolism, Mice, Neuroglia metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Dopaminergic Neurons metabolism, Growth Differentiation Factor 15 deficiency, Neostriatum metabolism, Neostriatum pathology, Substantia Nigra metabolism, Substantia Nigra pathology
- Abstract
Growth/differentiation factor-15 (Gdf-15) is a member of the transforming growth factor-β (Tgf-β) superfamily and has been shown to be a potent neurotrophic factor for midbrain dopaminergic (DAergic) neurons both in vitro and in vivo. Gdf-15 has also been shown to be involved in inflammatory processes. The aim of this study was to identify the role of endogenous Gdf-15 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease (PD) by comparing Gdf-15 (+/+) and Gdf-15 (-/-) mice. At 4 days and 14 days post-MPTP administration, both Gdf-15 (+/+) and Gdf-15 (-/-) mice showed a similar decline in DAergic neuron numbers and in striatal dopamine (DA) levels. This was followed by a comparable restorative phase at 90 days and 120 days, indicating that the absence of Gdf-15 does not affect the susceptibility or the recovery capacity of the nigrostriatal system after MPTP administration. The MPTP-induced microglial and astrocytic response was not significantly altered between the two genotypes. However, pro-inflammatory and anti-inflammatory cytokine profiling revealed the differential expression of markers in Gdf-15 (+/+) and Gdf-15 (-/-) mice after MPTP administration. Thus, the MPTP mouse model fails to uncover a major role of endogenous Gdf-15 in the protection of MPTP-lesioned nigrostriatal DAergic neurons, in contrast to its capacity to protect the 6-hydroxydopamine-intoxicated nigrostriatal system.
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- 2016
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13. Bacterial Contamination of the Anesthesia Workplace and Efficiency of Routine Cleaning Procedures: A Prospective Cohort Study.
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Goebel U, Gebele N, Ebner W, Dettenkofer M, Bürkle H, Hauschke D, and Schulz-Stübner S
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- Bacterial Load, Colony Count, Microbial, Cross Infection microbiology, Efficiency, Environmental Monitoring methods, Humans, Prospective Studies, Time Factors, Time and Motion Studies, Workforce, Anesthesiology, Cross Infection prevention & control, Decontamination methods, Equipment Contamination prevention & control, Housekeeping, Hospital, Nurse Anesthetists, Operating Rooms, Workplace
- Abstract
In this prospective cohort study, 200 decontamination (cleaning and disinfection) procedures of the anesthesia workplace either by anesthesia nurses or by specially trained housekeeping staff were monitored. Time used by housekeeping staff was shorter (1.2 ± 0.1 vs 2.6 ± 0.2 minutes on average, data are mean ± SEM; P < 0.0001) with less visible marker spots (14.4 ± 0.68 [55%] vs 17.3 ± 0.75 [66.7%] on average, data are mean ± SEM; P = 0.0041), and the bacterial load showed a decrease (≅67%, P < 0.0001) compared with anesthesia nurses. Specially trained housekeeping staff outperformed anesthesia nurses in cleaning the anesthesia workplace. Specific training for anesthesia workplace cleaning is supported by these findings.
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- 2016
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14. In vitro and in vivo effects of a recombinant anti-PSMA immunotoxin in combination with docetaxel against prostate cancer.
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Michalska M, Schultze-Seemann S, Bogatyreva L, Hauschke D, Wetterauer U, and Wolf P
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- Animals, Cell Line, Tumor, Docetaxel, Humans, Male, Mice, Mice, SCID, Single-Chain Antibodies pharmacology, Taxoids pharmacology, Xenograft Model Antitumor Assays, Antigens, Surface pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Glutamate Carboxypeptidase II pharmacology, Immunotoxins pharmacology, Prostatic Neoplasms
- Abstract
Docetaxel (DOC) is used for the first-line treatment of castration resistant prostate cancer (CPRC). However, the therapeutic effects are limited, only about one half of patients respond to the therapy and severe side effects possibly lead to discontinuation of treatment. Therefore, actual research is focused on the development of new DOC-based combination treatments. In this study we investigated the antitumor effects of a recombinant immunotoxin targeting the prostate specific membrane antigen (PSMA) in combination with DOC in vitro and in vivo. The immunotoxin consists of an anti-PSMA single chain antibody fragment (scFv) as binding and a truncated form of Pseudomonas aeruginosa Exotoxin A (PE40) as toxin domain. The immunotoxin induced apoptosis and specifically reduced the viability of androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cells. A synergistic cytotoxic activity was observed in combination with DOC with IC50 values in the low picomolar or even femtomolar range. Moreover, combination treatment resulted in an enhanced antitumor activity in a C4-2 SCID mouse xenograft model. This highlights the immunotoxin as a promising therapeutic agent for a future DOC-based combination therapy of CPRC., Competing Interests: The authors declare no conflicts of interest.
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- 2016
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15. Structured reporting ensures complete content and quick detection of essential data in pathology reports of oncological breast resection specimens.
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Aumann K, Niermann K, Asberger J, Wellner U, Bronsert P, Erbes T, Hauschke D, Stickeler E, Gitsch G, Kayser G, and Werner M
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- Female, Humans, Neoplasm Grading, Pathology, Surgical, Tumor Burden, Breast Neoplasms pathology, Research Report standards
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There is increasing evidence that not only the way of data acquisition but also the design of data visualization (i.e., the format) has impact on the quality of pathology reports. Therefore, we investigated the correlation between the format of pathology reports and the amount as well as the detection time of transmitted data. All reports of oncological breast resection specimens referred to the Institute for Surgical Pathology, University Medical Center Freiburg, between 2003 and 2011 (n = 4181) were classified into descriptive reports (DR, n = 856), structured reports (SR, n = 2455), or template-based synoptic reports (TBSR, n = 870). The reports were screened regarding the content of nine organ-specific essential data. The amount of recorded essential data per report was summarized in an essential data score (EDS) and the format types were statistically compared regarding their EDS. Additionally, we measured the time a gynecologist needed to detect all nine essential data within a subset of reports and compared the format types regarding the detection times statistically. A full-score EDS of 9 was seen in 28.4 % of all reports, in 4 % of DRs, in 21.4 % of SRs, and in 72.3 % of TBSRs (p < 0.0001). Median EDS of DRs was 7, of SRs 8, and of TBSRs 9 (p < 0.0001). Data regarding tumor localization, tumor size, specific grading, angioinvasion, hormone receptor status, and additional findings were mentioned more frequently in TBSRs compared to other format type reports with a statistically highly significant difference (p < 0.0001). Mean data detection time decreased significantly from 26 to 20 and 14 s in DRs, SRs, and TBSRs, respectively. Our results clearly show that due to the use of TBSRs reporting of oncological breast resection specimens are improved regarding the content of essential data and the clarity of the data layout resulting in a rapid detection of essential data by clinicians.
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- 2016
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16. Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity.
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Ahrens TD, Timme S, Ostendorp J, Bogatyreva L, Hoeppner J, Hopt UT, Hauschke D, Werner M, and Lassmann S
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- Adult, Aged, Aged, 80 and over, Carrier Proteins physiology, Cell Line, Tumor, Epigenesis, Genetic, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, Female, Humans, Male, Middle Aged, Reactive Oxygen Species metabolism, Thioredoxin Reductase 1 physiology, Azacitidine therapeutic use, Esophageal Neoplasms drug therapy, Histone Deacetylase Inhibitors therapeutic use, Thioredoxins physiology
- Abstract
We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (P<0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (P<0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n=19) and esophageal adenomcarcinomas (EAC, n=16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P=0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P=0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.
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- 2016
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17. Histone modifiers and marks define heterogeneous groups of colorectal carcinomas and affect responses to HDAC inhibitors in vitro.
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Lutz L, Fitzner IC, Ahrens T, Geißler AL, Makowiec F, Hopt UT, Bogatyreva L, Hauschke D, Werner M, and Lassmann S
- Abstract
Little is known about histone modifiers and histone marks in colorectal cancers (CRC). The present study therefore addressed the role of histone acetylation and histone deacetylases (HDAC) in CRCs in situ and in vitro. Immunohistochemistry of primary CRCs (n=47) revealed that selected histone marks were frequently present (H3K4me3: 100%; H3K9me3: 77%; H3K9ac: 75%), partially displayed intratumoral heterogeneity (H3K9me3; H3K9ac) and were significantly linked to higher pT category (H3K9me3: p=0.023; H3K9ac: p=0.028). Furthermore, also HDAC1 (62%), HDAC2 (100%) and HDAC3 (72%) expression was frequent, revealing four CRC types: cases expressing 1) HDAC1, HDAC2 and HDAC3 (49%), 2) HDAC2 and HDAC3 (30%), 3) HDAC1 and HDAC2 (10.5%) and 4) exclusively HDAC2 (10.5%). Correlation to clinico-pathological parameters (pT, pN, G, MSI status) revealed that heterogeneous HDAC1 expression correlated with lymph node status (p=0.012). HDAC expression in situ was partially reflected by six CRC cell lines, with similar expression of all three HDACs (DLD1, LS174T), preferential HDAC2 and HDAC3 expression (SW480, Caco2) or lower HDAC2 and HDAC3 expression (HCT116, HT29). HDAC activity was variably higher in HCT116, HT29, DLD1 and SW480 compared to LS174T and Caco2 cells. Treatment with broad (SAHA) and specific (MS-275; FK228) HDAC inhibitors (HDACi) caused loss of cell viability in predominantly MSIpositive CRC cells (HCT116, LS174T, DLD1; SAHA, MS-275 and in part FK228). In contrast, MSI-negative CRC cells (Caco2, HT29, SW480) were resistant, except for high doses of FK228 (Caco2, HT29). Cell viability patterns were not linked to different efficacies of HDACi on reduction of HDAC activity or histone acetylation, p21 expression and/or induction of DNA damage (γH2A-X levels). In summary, this study reveals inter- and intra-tumoral heterogeneity of histone marks and HDAC expression in CRCs. This is reflected by diverse HDACi responses in vitro, which do not follow known modes of action. Together, this implies further exploitation of histone alterations in CRC for molecular classification and/or novel treatment options.
- Published
- 2016
18. Randomized Comparison of Different Thienopyridine Loading Strategies in Patients Undergoing Elective Coronary Intervention: The ExcelsiorLOAD Trial.
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Hochholzer W, Amann M, Titov A, Younas I, Löffelhardt N, Riede F, Potocnik C, Stratz C, Hauschke D, Trenk D, Neumann FJ, and Valina CM
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- Aged, Blood Platelets drug effects, Clopidogrel, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Prospective Studies, Ticlopidine administration & dosage, Percutaneous Coronary Intervention, Platelet Activation drug effects, Platelet Aggregation Inhibitors administration & dosage, Prasugrel Hydrochloride administration & dosage, Premedication, Ticlopidine analogs & derivatives
- Abstract
Objectives: This randomized trial investigated to what extent loading with prasugrel can provide a more rapid peri-interventional antiplatelet effect than clopidogrel 600 mg., Background: Effective platelet inhibition at the start of a percutaneous coronary intervention (PCI) reduces the risk of ischemic complications. With clopidogrel administered immediately before a PCI, effective platelet inhibition is delayed by 2 h. Prasugrel has the potential of shortening this period., Methods: We randomly assigned 300 P2Y12 receptor blocker-naive patients undergoing an elective PCI to loading with clopidogrel 600 mg, prasugrel 30 mg, or prasugrel 60 mg immediately before the PCI. Platelet function was assessed serially by impedance aggregometry. The primary endpoint was the proportion of patients with high on-treatment platelet reactivity at 60 min after loading defined as ≥468 aggregation units × minute (Multiplate Analyzer, Roche Diagnostics, Mannheim, Germany)., Results: The 3 groups were well balanced with respect to clinical and angiographic characteristics. At 60 min, 33% of the patients assigned to prasugrel 60 mg, 37% of patients assigned to prasugrel 30 mg, but 55% of those assigned to clopidogrel had high on-treatment platelet reactivity (p < 0.001). At any time point starting from 30 min, prasugrel 60 mg achieved significantly lower platelet reactivity than clopidogrel. Platelet reactivity at 60 min after prasugrel was not significantly different from that at 120 min after clopidogrel (p = 0.18). Prasugrel 30 mg had an intermediate effect. The 30-day incidence of bleeding events was not different among the 3 groups., Conclusions: From 30 min onward, prasugrel 60 mg achieved a stronger platelet inhibition than clopidogrel loading in stable patients undergoing a PCI. Compared with clopidogrel, prasugrel 60 mg was associated with a twice as fast onset of platelet inhibition. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate-Advanced Loading Strategies [ExcelsiorLOAD]; DRKS00006102)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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19. Methodological aspects of the benefit assessment of medical interventions.
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Hauschke D and Schmoor C
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- Humans, Biometry, Controlled Clinical Trials as Topic
- Published
- 2016
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20. Aurora B expression and histone variant H1.4S27 phosphorylation are no longer coordinated during metaphase in aneuploid colorectal carcinomas.
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Sijare F, Geißler AL, Fichter CD, Hergeth SP, Bogatyreva L, Hauschke D, Schneider R, Werner M, and Lassmann S
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- Aneuploidy, Fluorescent Antibody Technique, Humans, In Situ Hybridization, Fluorescence, Metaphase, Microsatellite Instability, Phosphorylation, Adenocarcinoma enzymology, Adenocarcinoma genetics, Aurora Kinase B biosynthesis, Colorectal Neoplasms enzymology, Colorectal Neoplasms genetics, Histones metabolism
- Abstract
Experimental model systems identified phosphorylation of linker histone variant H1.4 at Ser 27 (H1.4S27p) as a novel mitotic mark set by Aurora B kinase. Here, we examined expression of Aurora B and H1.4S27p in colorectal carcinoma (CRC) cell lines (HCT116, DLD1, Caco-2, HT29) and tissue specimens (n = 36), in relation to microsatellite instability (MSI) status and ploidy. In vitro, Aurora B (pro-/meta-/anaphase) and H1.4S27p (pro-/metaphase) were localized in mitotic figures. The proportion of labeled mitoses was significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora B, these differences were not associated with an altered Aurora B gene copy number (FISH) or messenger RNA (mRNA) expression level (qRT-PCR). Moreover, Aurora B expression and H1.4S27 phosphorylation were no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity for Aurora B or H1.4S27p did not correlate with T- or N-stage, grade, or MSI status. However, metaphase labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was significantly correlated with H1.4S27p-positive metaphases in MSI (p = 0.010) or diploid (p = 0.003) CRCs. Finally, combined classification of MSI status and ploidy revealed a significant positive correlation of Aurora B with H1.4S27p in metaphases of diploid/MSI (p = 0.010) and diploid/microsatellite-stable (MSS; p = 0.031) but not of aneuploid/MSS (p = 0.458) CRCs. The present study underlines the functional link of Aurora B expression and H1.4S27p during specific phases of mitosis in diploid and/or MSI-positive CRCs in vitro and in situ. Importantly, the study shows that the coordination between Aurora B expression and phosphorylation of H1.4 at Ser 27 is lost in cycling aneuploid CRC cells.
- Published
- 2015
- Full Text
- View/download PDF
21. Therapeutic polo-like kinase 1 inhibition results in mitotic arrest and subsequent cell death of blasts in the bone marrow of AML patients and has similar effects in non-neoplastic cell lines.
- Author
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Münch C, Dragoi D, Frey AV, Thurig K, Lübbert M, Wäsch R, Bogatyreva L, Hauschke D, Lassmann S, Werner M, and May AM
- Subjects
- Aged, Aged, 80 and over, Antimitotic Agents pharmacology, Blast Crisis drug therapy, Blast Crisis enzymology, Blast Crisis pathology, Blotting, Western, Bone Marrow enzymology, Bone Marrow pathology, Cell Cycle Proteins metabolism, Cell Proliferation drug effects, Female, Humans, Immunoenzyme Techniques, Leukemia, Myeloid, Acute enzymology, Male, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Polo-Like Kinase 1, Apoptosis drug effects, Bone Marrow drug effects, Cell Cycle Proteins antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Mitosis drug effects, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Pteridines pharmacology
- Abstract
Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer.
- Author
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Fichter CD, Timme S, Braun JA, Gudernatsch V, Schöpflin A, Bogatyreva L, Geddert H, Faller G, Klimstra D, Tang L, Hauschke D, Werner M, and Lassmann S
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Antibodies, Monoclonal, Humanized pharmacology, Antibody-Dependent Cell Cytotoxicity, Apoptosis drug effects, Blotting, Western, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Cycle Checkpoints drug effects, Cell Proliferation drug effects, ErbB Receptors metabolism, Erlotinib Hydrochloride, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, Fluorescent Antibody Technique, Gefitinib, Gene Expression Regulation, Neoplastic, Humans, Immunoenzyme Techniques, Protein Multimerization, Quinazolines pharmacology, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 metabolism, Tumor Cells, Cultured, Adenocarcinoma drug therapy, Carcinoma, Squamous Cell drug therapy, ErbB Receptors antagonists & inhibitors, Esophageal Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-3 antagonists & inhibitors
- Abstract
Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n = 110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p = 0.088) and HER2 (34.4%; p < 0.001) with HER3 (91.5%; p < 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK-GT-4), lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs., (© 2014 UICC.)
- Published
- 2014
- Full Text
- View/download PDF
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