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Frank Edelmann,
Rolf Wachter,
Albrecht G Schmidt,
Elisabeth Kraigher-Krainer,
Caterina Colantonio,
Wolfram Kamke,
André Duvinage,
Raoul Stahrenberg,
Kathleen Durstewitz, Markus Löffler,
Hans-Dirk Düngen,
Carsten Tschöpe,
Christoph Herrmann-Lingen,
Martin Halle,
Gerd Hasenfuss,
Götz Gelbrich,
Burkert Pieske
[show abstract]
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ABSTRACT: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression.
To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction.
The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction.
Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up.
The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months.
Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations.
In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations.
clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.
JAMA The Journal of the American Medical Association 02/2013; 309(8):781-91. · 30.03 Impact Factor
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Christina Heemann,
Markus Kreuz,
Irene Stoller,
Nils Schoof,
Frederike von Bonin,
Marita Ziepert, Markus Löffler,
Wolfram Jung,
Michael Pfreundschuh,
Lorenz Trümper,
Dieter Kube
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ABSTRACT: Peripheral T-cell non-Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.
Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.
Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99-3.14 with P = 0.056]. A protective role of IL-10-1087A, -824T, and -597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92-4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22-5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.
Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs.
Clinical Cancer Research 05/2012; 18(13):3637-47. · 7.74 Impact Factor
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Frank Edelmann,
Götz Gelbrich,
Hans-Dirk Düngen,
Stefan Fröhling,
Rolf Wachter,
Raoul Stahrenberg,
Lutz Binder,
Agnieszka Töpper,
Diana Jahandar Lashki,
Silja Schwarz,
Christoph Herrmann-Lingen, Markus Löffler,
Gerd Hasenfuss,
Martin Halle,
Burkert Pieske
[show abstract]
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ABSTRACT: We sought to determine whether structured exercise training (ET) improves maximal exercise capacity, left ventricular diastolic function, and quality of life (QoL) in patients with heart failure with preserved ejection fraction (HFpEF).
Nearly one-half of patients with heart failure experience HFpEF, but effective therapeutic strategies are sparse.
A total of 64 patients (age 65 ± 7 years, 56% female) with HFpEF were prospectively randomized (2:1) to supervised endurance/resistance training in addition to usual care (ET, n = 44) or to usual care alone (UC) (n = 20). The primary endpoint was the change in peak Vo(2) after 3 months. Secondary endpoints included effects on cardiac structure, diastolic function, and QoL.
Peak Vo(2) increased (16.1 ± 4.9 ml/min/kg to 18.7 ± 5.4 ml/min/kg; p < 0.001) with ET and remained unchanged (16.7 ± 4.7 ml/min/kg to 16.0 ± 6.0 ml/min/kg; p = NS) with UC. The mean benefit of ET was 3.3 ml/min/kg (95% confidence interval [CI]: 1.8 to 4.8, p < 0.001). E/e' (mean difference of changes: -3.2, 95% CI: -4.3 to -2.1, p < 0.001) and left atrial volume index (milliliters per square meter) decreased with ET and remained unchanged with UC (-4.0, 95% CI: -5.9 to -2.2, p < 0.001). The physical functioning score (36-Item Short-Form Health Survey) improved with ET and remained unchanged with UC (15, 95% CI: 7 to 24, p < 0.001). The ET-induced decrease of E/e' was associated with 38% gain in peak Vo(2) and 50% of the improvement in physical functioning score.
Exercise training improves exercise capacity and physical dimensions of QoL in HFpEF. This benefit is associated with atrial reverse remodeling and improved left ventricular diastolic function. (Exercise Training in Diastolic Heart Failure-Pilot Study: A Prospective, Randomised, Controlled Study to Determine the Effects of Physical Training on Exercise Capacity and Quality of Life [Ex-DHF-P]; ISRCTN42524037).
Journal of the American College of Cardiology 10/2011; 58(17):1780-91. · 14.16 Impact Factor
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ABSTRACT: Parallel high-throughput microarray and sequencing experiments produce vast quantities of multidimensional data which must be arranged and analyzed in a concerted way. One approach to addressing this challenge is the machine learning technique known as self organizing maps (SOMs). SOMs enable a parallel sample- and gene-centered view of genomic data combined with strong visualization and second-level analysis capabilities. The paper aims at bridging the gap between the potency of SOM-machine learning to reduce dimension of high-dimensional data on one hand and practical applications with special emphasis on gene expression analysis on the other hand.
The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories (adipose, endocrine, homeostasis, digestion, exocrine, epithelium, sexual reproduction, muscle, immune system and nervous tissues). SOM mapping reduces the dimension of expression data from ten of thousands of genes to a few thousand metagenes, each representing a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of genes related to specific molecular processes in the respective tissue. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering are better represented and provide better signal-to-noise ratios if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues broadly into three clusters containing nervous, immune system and the remaining tissues.
The SOM technique provides a more intuitive and informative global view of the behavior of a few well-defined modules of correlated and differentially expressed genes than the separate discovery of the expression levels of hundreds or thousands of individual genes. The program is available as R-package 'oposSOM'.
BMC Bioinformatics 01/2011; 12:306. · 2.75 Impact Factor
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ABSTRACT: Basal cell carcinoma (BCC) is the most common malignant skin cancer. For a deeper insight into the specific growth patterns of the tumorous tissue in BCC, we have focused on the development of a novel automated image-processing chain for 3D reconstruction of BCC using histopathological serial sections. For fully automatic delineation of the tumor within the tissue, we apply a fuzzy c-means segmentation method. We used a novel multi-grid form of the non-linear registration introduced by Braumann and Kuska in 2005 effectively suppressing registration runs into local minima (possibly caused by diffuse nature of the tumor). Our method was successfully applied in a proof-of-principle study for automated reconstruction.
Experimental Dermatology 07/2010; 19(7):689-91. · 3.54 Impact Factor
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ABSTRACT: Healthcare and medical research in Germany are heading to more interconnected systems. New initiatives are funded by the German government to encourage the development of Integrated Research and Treatment Centers (IFB). Within an IFB new organizational structures and infrastructures for interdisciplinary, translational and trans-sectoral working relationship between existing rigid separated sectors are intended and needed. This paper describes how an IT-infrastructure of an IFB could look like, what major challenges have to be solved and what methods can be used to plan such a complex IT-infrastructure in the field of healthcare. By means of project management, system analyses, process models, 3LGM<sup>2</sup>-models and resource plans an appropriate concept with different views is created. This concept supports the information management in its enterprise architecture planning activities and implies a first step of implementing a connected healthcare and medical research platform.
Studies in health technology and informatics 01/2010; 160(Pt 2):1319-23.
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Biomedical Image Registration, 4th International Workshop, WBIR 2010, Lübeck, Germany, July 11-13, 2010. Proceedings; 01/2010
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Heinz-Wolfram Bernd,
Marita Ziepert,
Christoph Thorns,
Wolfram Klapper,
Hans-Heinrich Wacker,
Michael Hummel,
Harald Stein,
Martin-Leo Hansmann,
German Ott,
Andreas Rosenwald,
Hans-Konrad Müller-Hermelink,
Thomas F E Barth,
Peter Möller,
Sergio B Cogliatti,
Michael Pfreundschuh,
Norbert Schmitz,
Lorenz Trümper,
Silvia Höller, Markus Löffler,
Alfred C Feller
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ABSTRACT: Research on prognostically relevant immunohistochemical markers in diffuse large B-cell lymphomas has mostly been performed on retrospectively collected clinical data. This is also true for immunohistochemical classifiers that are thought to reflect the cell-of-origin subclassification of gene expression studies. In order to obtain deeper insight into the heterogeneous prognosis of diffuse large B-cell lymphomas and to validate a previously published immunohistochemical classifier, we analyzed data from a large set of cases from prospective clinical trials with long-term follow-up.
We performed morphological and extensive immunohistochemical analyses in 414 cases of diffuse large B-cell lymphoma from two prospective randomized clinical trials (NHL-B1/B2, Germany). Classification into germinal center and non-germinal center subtypes of B-cell lymphoma was based on the expression pattern of CD10, BCL6, and IRF4. Multivariate analyses were performed adjusting for the factors in the International Prognostic Index.
Analyzing 20 different epitopes on tissue microarrays, expression of HLA-DR, presence of CD23(+) follicular dendritic cell meshworks, and monotypic light chain expression emerged as International Prognostic Index-independent markers of superior overall survival. Immunoblastic morphology was found to be related to poor event-free survival. The non-germinal center subtype, according to the three-epitope classifier (CD10, BCL6, and IRF4) did not have prognostic relevance when adjusted for International Prognostic Index factors (relative risk=1.2, p=0.328 for overall survival; and relative risk=1.1, p=0.644 for event-free survival).
The previously reported International Prognostic Index-independent prognostic value of stratification into germinal center/non-germinal center B-cell lymphoma using the expression pattern of CD10, BCL6, and IRF4 was not reproducible in our series. However, other markers and the morphological subtype appear to be of prognostic value.
Haematologica 11/2009; 94(11):1569-80. · 6.42 Impact Factor
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Felix Mehrhof, Markus Löffler,
Götz Gelbrich,
Cemil Ozcelik,
Maximilian Posch,
Hans-Werner Hense,
Ulrich Keil,
Thomas Scheffold,
Heribert Schunkert,
Christiane Angermann, [......],
Uwe Siebert,
Jürgen Wasem,
Anja Neumann,
Alexander Göhler,
Stefan D Anker,
Friedrich Köhler,
Martin Möckel,
Karl-Josef Osterziel,
Rainer Dietz,
Mathias Rauchhaus
[show abstract]
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ABSTRACT: Heart failure (HF) has been identified as one of the most threatening diseases for the western civilisation, posing a risk to health for a rising number of patients. Acknowledging the medical problem of HF to be both economically and socially threatening the German Federal Ministry of Research and Education (BMBF) initiated a nationwide research network aiming to find new ways in prevention, alleviation and treatment of the widespread disease. The "Competence Network Heart Failure" (CNHF), initiated in 2003, bundles the scientific expertise in a large-scale research network; its aims are the coordination of basic and applied clinical research as well as dissemination of findings into clinical practice in order to consolidate and perpetuate the achieved improvements. The scope of this paper is to introduce the CNHF and to provide an overview of the tasks and hitherto attained achievements to a broad spectrum of health care providers.
International journal of cardiology 09/2009; 145(1):135-8. · 7.08 Impact Factor
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Andreas Engert,
Volker Diehl,
Jeremy Franklin,
Andreas Lohri,
Bernd Dörken,
Wolf-Dieter Ludwig,
Peter Koch,
Mathias Hänel,
Michael Pfreundschuh,
Martin Wilhelm,
Lorenz Trümper,
Walter-Erich Aulitzky,
Martin Bentz,
Mathias Rummel,
Orhan Sezer,
Hans-Konrad Müller-Hermelink,
Dirk Hasenclever, Markus Löffler
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ABSTRACT: The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up.
Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated.
Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively.
The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.
Journal of Clinical Oncology 08/2009; 27(27):4548-54. · 18.37 Impact Factor
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ABSTRACT: The planning of case report forms (CRFs) in clinical trials or databases in registers is mostly an informal process starting from scratch involving domain experts, biometricians, and documentation specialists. The Telematikplattform für Medizinische Forschungsnetze, an umbrella organization for medical research in Germany, aims at supporting and improving this process with a metadata repository, covering the variables and value lists used in databases of registers and trials. The use cases for the metadata repository range from a specification of case report forms to the harmonization of variable collections, variables, and value lists through a formal review. The warehouse used for the storage of the metadata should at least fulfill the definition of part 3 "Registry metamodel and basic attributes" of ISO/IEC 11179 Information technology - Metadata registries. An implementation of the metadata repository should offer an import and export of metadata in the Operational Data Model standard of the Clinical Data Interchange Standards Consortium. It will facilitate the creation of CRFs and data models, improve the quality of CRFs and data models, support the harmonization of variables and value lists, and support the mapping of metadata and data.
Studies in health technology and informatics 02/2009; 150:409-13.
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Dieter Kube,
Thanh-Duc Hua,
Frederike von Bonin,
Nils Schoof,
Samira Zeynalova,
Marita Klöss,
Daniela Gocht,
Bernd Potthoff,
Mladen Tzvetkov,
Jürgen Brockmöller, Markus Löffler,
Michael Pfreundschuh,
Lorenz Trümper
[show abstract]
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ABSTRACT: Current chemotherapy can achieve high response rates in aggressive non-Hodgkin's lymphoma (NHL), but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis whether interleukin-10 (IL-10) polymorphisms predict clinical outcome, leukocytopenia, or infectivity during therapy. IL-10 was chosen because immune alterations are a major risk factor for NHL, and IL-10 is a cytokine involved in inflammatory processes associated with clinical outcome.
Five hundred patients with aggressive NHL treated with CHOP/CHOEP were analyzed for IL-10 gene polymorphisms, including distal loci -7400InDel, -6752AT (rs6676671), and -6208CG (rs10494879) in comparison with proximal loci -3538AT (rs1800890), -1087AG (rs1800896), and -597AC (rs1800872) according to the incidence and outcome of the lymphoma.
No differences in allele frequencies or haplotypes were found comparing a cohort of patients with aggressive NHL/diffuse large B-cell lymphoma with a healthy control group. Patients with aggressive NHL characterized by IL-10(-7400DelDel) had shorter overall survival periods compared with the other genotypes (P = 0.004). The 3-year rate is 43.4% for IL-10(-7400DelDel) and 73.4% for IL-10(-7400InIn) and IL-10(-7400InDel) together. A significant increased risk for event-free survival is found for carriers of the genotype IL-10(-6752TT-6208CC-3538AA) (P = 0.047). Multivariate analysis of IL-10(-7400) gene variation in relation to overall survival adjusted to international prognostic index revealed a relative risk of 1.9 for carriers of IL-10(-7400DelDel) (P = 0.037). No associations were found analyzing diffuse large B-cell lymphoma patients separately.
Our results indicate that IL-10 gene variations could be associated to the clinical course of aggressive NHL, which points out the importance of host factors and respective genetic elements for treatment response.
Clinical Cancer Research 07/2008; 14(12):3777-84. · 7.74 Impact Factor
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Gunnar Elke,
Dirk Schädler,
Christoph Engel,
Holger Bogatsch,
Inez Frerichs,
Maximilian Ragaller,
Jens Scholz,
Frank M Brunkhorst, Markus Löffler,
Konrad Reinhart,
Norbert Weiler
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ABSTRACT: To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany.
Nationwide prospective, observational, cross-sectional, 1-day point-prevalence study.
The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size.
Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference).
None.
Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29-3.37).
Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.
Critical care medicine 07/2008; 36(6):1762-7. · 6.37 Impact Factor
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Judith Dierlamm,
Eva M Murga Penas,
Stefan Bentink,
Swen Wessendorf,
Hilmar Berger,
Michael Hummel,
Wolfram Klapper,
Dido Lenze,
Andreas Rosenwald,
Eugenia Haralambieva,
German Ott,
Sergio B Cogliatti,
Peter Möller,
Carsten Schwaenen,
Harald Stein, Markus Löffler,
Rainer Spang,
Lorenz Trümper,
Reiner Siebert
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ABSTRACT: The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma.
We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling.
A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p<0.001). Cases with 18q21/MALT1 gain more frequently showed an activated B-cell-like (ABC) gene expression signature (65%) than a germinal center B-cell-like (GCB) one (23%) (p<0.001). Ninety-eight genes including MALT1, BCL2, and some selected nuclear factor-kappaB target genes were differentially expressed between the two genetic groups of diffuse large B-cell lymphoma. By global testing of each chromosome, we identified 33 genes, all located on chromosome 18q, which were differentially expressed between the two genetic groups independently of the ABC/GCB status. In multivariate analysis, the 18q21/MALT1 status represented an independent negative prognostic factor for overall survival (p=0.03).
In diffuse large B-cell lymphoma, gain of 18q21 including MALT1 is significantly associated with differential expression of genes located on 18q, the ABC gene expression subtype, increased BCL2 gene and protein expression and might indicate an unfavorable prognosis.
Haematologica 05/2008; 93(5):688-96. · 6.42 Impact Factor
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Bildverarbeitung für die Medizin 2008, Algorithmen, Systeme, Anwendungen, Proceedings des Workshops vom 6. bis 8. April 2008 in Berlin; 01/2008
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ABSTRACT: Malignant growth and invasiveness of cancers is a function of both intratumoral and stromal factors. The accessibility to nutrients, oxygen and growth factors, the stromal composition, and the interference with the immune system all shape the tumor invasion front. A recent study has shown a prognostic difference with respect to different invasion patterns analyzed on histological specimens of cervical cancers. The present study analyzes the spatial organization of a cervical cancer and the relation of the tumor invasion front and the infiltration with CD3(+) T-cells.
From a cervical squamous cell carcinoma specimen, 84 serial sections were performed and three interleaving series were stained with hematoxylin/eosin and immunohistochemistry directed against the cervical carcinoma biomarker p16(INK4a) and the T-cell marker CD3. Sections were passed through an image processing chain to obtain a reconstructed and segmented tissue volume. For local tumor invasion front analysis the mean curvature was used, which in turn was related to the respective local minimum tumor to T-cell distance as well to a T-cell originated diffusing substance's concentration at the tumor surface.
Spatial models of the tumor tissue and the infiltrating T-cells were computed. The overall discrete compactness of the tumor invasion front was 0.89, corresponding to a pathological assessment of diffuse infiltration. The comparison of the tumor invasion front with the density of T-cell infiltration revealed an increased smoothening in regions with high T-cell infiltration.
We could demonstrate the spatial organization of a cervical cancer and model the interaction between infiltrating T-cells with the tumor invasion front shape. Increased smoothening in regions with high T-cell infiltration suggests that T-cells may have an influence on the shaping of the tumor invasion front, e.g., by attacking tumor cells displaying specific antigens. The applied technique allows visualization of the spatial organization of tissues and could be extended to analyze multiple stains on alternating sections.
Cytometry Part A 06/2007; 71(5):327-33. · 3.73 Impact Factor
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Till Neumann,
Stefan Esser,
Anja Potthoff,
Sabine Pankuweit,
Anja Neumann,
Frank Breuckmann,
Katrin Neuhaus,
Jana Kondratieva,
Thomas Buck,
Thomas Müller-Tasch, [......],
Wolfgang Herzog,
Burkert Pieske,
Mathias Rauchhaus, Markus Löffler,
Bernhard Maisch,
Andreas Mügge,
Jürgen Wasem,
Guido Gerken,
Norbert H Brockmeyer,
Raimund Erbel
[show abstract]
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ABSTRACT: HIV infection is a global public health issue that is frequently associated with cardiac involvement. However, myocardial dysfunction and heart failure are often clinically occult or attributed incorrectly to other non-cardiac disease processes even a heightened awareness and knowledge for these cardiac diseases in HIV-infected patients may lead to earlier detection and a reduction in morbidity and mortality. The present study evaluates the frequency and clinical course of myocardial dysfunction and heart failure in a HIV-infected population.
The HIV-HEART (HIV-infection and HEART disease) study is a prospective, long-term cohort study. The study is designed and powered to define prevalence and natural history of chronic heart failure. Following a pilot-study of 105 HIV-infected subjects the HIV-HEART trial will contain 802 HIV-infected males and females with and without antiretroviral therapy in an urban population. HIV-HEART is performed by using non-invasive techniques for the quantification of exercise intolerance and ventricular dysfunction, including concentration of B-type natriretic peptide (BNP), transthoracal echocardiography and endurance testing. Patients with BNP >100 pg/ml achieve a magnetic resonance tomography of the heart for characterization of myocardial dysfunction and type of cardiomyopathy. To determine incidence and natural history of myocardial dysfunction and heart failure, a 2 year follow-up started in September 2006.
The HIV-HEART study will define the significance of myocardial dysfunction and heart failure in a HIV-infected urban population and classify appropriate methods for identifying high-risk patients, the basis for risk stratification and therapy.
European journal of medical research 06/2007; 12(6):243-8. · 1.13 Impact Factor
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Bildverarbeitung für die Medizin 2006, Algorithmen, Systeme, Anwendungen, Proceedings des Workshops vom 19. - 21. März 2006 in Hamburg; 01/2006
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ABSTRACT: The analysis of the three-dimensional (3-D) structure of tumoral invasion fronts of carcinoma of the uterine cervix is the prerequisite for understanding their architectural-functional relationship. The variation range of the invasion patterns known so far reaches from a smooth tumor-host boundary surface to more diffusely spreading patterns, which all are supposed to have a different prognostic relevance. As a very decisive limitation of previous studies, all morphological assessments just could be done verbally referring to single histological sections. Therefore, the intention of this paper is to get an objective quantification of tumor invasion based on 3-D reconstructed tumoral tissue data. The image processing chain introduced here is capable to reconstruct selected parts of tumor invasion fronts from histological serial sections of remarkable extent (90-500 slices). While potentially gaining good accuracy and reasonably high resolution, microtome cutting of large serial sections especially may induce severe artifacts like distortions, folds, fissures or gaps. Starting from stacks of digitized transmitted light color images, an overall of three registration steps are the main parts of the presented algorithm. By this, we achieved the most detailed 3-D reconstruction of the invasion of solid tumors so far. Once reconstructed, the invasion front of the segmented tumor is quantified using discrete compactness.
IEEE Transactions on Medical Imaging 11/2005; 24(10):1286-307. · 3.64 Impact Factor
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ABSTRACT: One goal in modern medicine is to increase the treatment quality. A major step towards this aim is to support the execution of standardized, guideline-based clinical protocols, which are used in many medical domains, e.g., for oncological chemotherapies. Standardized chemotherapy protocols contain detailed and structured therapy plans describing the single therapy steps (e.g., examinations or drug applications). Therefore, workflow management systems offer good support for these processes. However, the treatment of a particular patient often requires modifications due to unexpected infections, toxicities, or social factors. The modifications are described in the treatment protocol but not as part of the standard process. To be able to further execute the therapy workflows in case of exceptions running workflows have to be adapted dynamically. Furthermore, the physician should be supported by automated exception detection and decision support for derivation of necessary modifications. The AdaptFlow prototype offers the required support for the field of oncological chemotherapies by enhancing a workflow system with dynamic workflow adaptation and rule based decision support for exception detection and handling.
Studies in health technology and informatics 01/2004; 101:113-7.
