K Mann

University of Duisburg-Essen, Essen, North Rhine-Westphalia, Germany

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Publications (463)1530.76 Total impact

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    ABSTRACT: Patients with dedifferentiated or anaplastic thyroid carcinomas currently lack appropriate treatment options. Kinase inhibitors are among the most promising new agents as alternative strategies. The BRAF- and multi-kinase inhibitor, sorafenib, has already shown antitumor effects in thyroid carcinoma patients in a phase III clinical trial. In this study we aim to better characterize molecular effects and efficacy of sorafenib against thyroid carcinoma cells with various histological origins and different BRAF mutational status. Analysis of different signaling pathways affected by sorafenib may contribute to assist a more specific therapy choice with fewer side effects. Twelve thyroid carcinoma cell lines derived from anaplastic, follicular and papillary thyroid carcinomas with wildtype or mutationally activated BRAF were treated with sorafenib. Growth inhibition, cell cycle arrest, cell death induction and inhibition of intracellular signaling pathways were then comprehensively analyzed. Cell viability was analyzed by MTT assay, and the cell cycle was assessed by flow cytometry after propidium iodide staining. Cell death was assessed by lactate dehydrogenase liberation assays, caspase activity assays and subG1 peak determinations. Inhibition of intracellular pathways was analyzed in dot blot and western blot analyses. Sorafenib inhibited proliferation of all thyroid carcinoma cell lines tested with IC50 values ranging between 1.85 and 4.2 μM. Cells derived from papillary carcinoma harboring the mutant BRAF (V600E) allele were slightly more sensitive to sorafenib than those harboring wildtype BRAF. Cell cycle analyses and caspase assays showed a sorafenib-dependent induction of apoptosis in all cell lines, whereas increased lactate dehydrogenase release suggested cell membrane disruption. Sorafenib treatment caused a rapid inhibition of various MAP kinases in addition to inhibiting AKT and receptor tyrosine kinases. Sorafenib inhibited multiple intracellular signaling pathways in thyroid carcinoma cells, which resulted in cell cycle arrest and the initiation of apoptosis. Sorafenib was effective against all thyroid carcinoma cell lines regardless of their tumor subtype origin or BRAF status, confirming that sorafenib is therapeutically beneficial for patients with any subtype of dedifferentiated thyroid cancer. Inhibition of single intracellular targets of sorafenib in thyroid carcinoma cells may allow the development of more specific therapeutic intervention with less side effects.
    BMC Cancer 12/2015; 15(1):184. DOI:10.1186/s12885-015-1186-0 · 3.36 Impact Factor
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    ABSTRACT: Background: The indirubin derivative 7-bromoindirubin-3'-oxime (7BIO) has already shown anticancer properties by causing cell death in some tumour cell lines and may be a new therapeutic option for treatment-resistant tumour cells. Since dedifferentiated and anaplastic thyroid carcinomas do not take up radioiodine and are insensitive to chemotherapeutic treatment and external radiation, direct cell death induction in these tumour cells may be a promising approach. We thus investigated the effect of 7BIO on thyroid carcinoma cell lines of different histological origins and characterized the type of cell death induction by 7BIO. Methods: Cell viability was measured with MTT assay. Cell death was analysed by caspase 3/7 activity, lactate dehydrogenase liberation, caspase cleavage products, DNA fragmentation, cell cycle phase distribution and LC3B analysis. Results: After 7BIO treatment, cell viability was reduced in all 14 thyroid carcinoma cell lines investigated. Treated cells showed DNA fragmentation, cell cycle arrest and lactate dehydrogenase liberation but no LC3B cleavage. Caspase activation following 7BIO treatment was found in five of six cell lines investigated. Interestingly, inhibition of caspases had no effect on viability of the cells after 7BIO incubation. Conclusions: Our results indicate that 7BIO efficiently killed dedifferentiated thyroid carcinoma cells. It induced a non-classical kind of cell death that was caspase-independent and includes DNA fragmentation. 7BIO and related indirubin components thus may have value as a new therapeutic option for dedifferentiated thyroid cancer irrespective of the exact target molecules and the kind of cell death they induce.
    Cancer Cell International 10/2015; 15(1):97. DOI:10.1186/s12935-015-0251-8 · 2.77 Impact Factor
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    ABSTRACT: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.
    Pituitary 07/2015; 18(6). DOI:10.1007/s11102-015-0673-2 · 3.20 Impact Factor
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    ABSTRACT: Background: The evasion of cell death is one of the hallmarks of cancer, contributing to both tumor progression and resistance to therapy. Dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to conventional anticancer treatments and patients with these tumors are difficult to treat. BH3 mimetics are a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and promote cell death. The purpose of this study was to analyze the molecular effects of the BH3 mimetic GX15-070 on thyroid carcinoma cell lines and to characterize cell death induced by GX15-070. Methods: A total of 17 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with GX15-070. Cell viability was measured with MTT assay while cell cycle phase distribution and subG1 peaks were determined after propidium iodide staining. We assessed cell death via the caspase 3/7 activity, caspase cleavage products, lactate dehydrogenase (LDH) liberation assays, and a LC3 analysis by western blot. Ultrastructural changes were analysed by electron microscopy of GX15-070-treated cells. Results: After GX15-070 treatment, the number of viable cells was decreased in all cell lines examined, with IC50 values ranging from 48nM to 3.25 μM. We observed biochemical markers of autophagic cell death and necrosis like LC3 conversion and LDH release after the GX15-070 treatment. Electron microscopy revealed several common characteristic ultrastructural changes like swelling of mitochondria, dilatation of rough endoplasmic reticulum, membrane blebbing and formation of vacuoles. GX15-070 treatment induced DNA fragmentation detected by subG1-peak induction and an arrest in G1 phase of the cell cycle. Caspase activation after GX15-070 incubation was detected but had no effect on viability of cells. Conclusions: With these experiments we demonstrated the efficacy of the BH3 mimetic drug GX15-070 acting against dedifferentiated thyroid carcinoma cells of various histological origins by the induction of cell death. GX15-070-treated cells underwent non-classical cell death with signs of apoptosis, autophagy and necrosis in parallel. GX15-07 and related compounds thus may be a new therapeutic option for dedifferentiated thyroid carcinoma of various histological subtypes.
    Journal of Experimental & Clinical Cancer Research 07/2015; 34(1):69. DOI:10.1186/s13046-015-0186-x · 4.43 Impact Factor

  • Journal of the American College of Cardiology 03/2015; 65(10):A1498. DOI:10.1016/S0735-1097(15)61498-X · 16.50 Impact Factor
  • T Deutschbein · K Mann · S Petersenn ·
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    ABSTRACT: Measurement of sex steroids is required to evaluate gonadal function, but normative data are lacking (especially for estimates of physiologically active testosterone). Using modern immunoassays, this study established sex-specific reference ranges (2.5% and 97.5% percentiles) for total testosterone (TOT), bioactive testosterone Vermeulen (BTV), free androgen index (FAI), free testosterone Sartorius (FTS), free testosterone Vermeulen (FTV), and sex hormone binding globulin (SHBG). In the comparative study, subjects were grouped by age (18-30; 31-50; >50 years), BMI (<25; 25-30; >30 kg/m(2)), and sex. Study participants were selected in such a way that each group comprised 12 subjects (e. g., 12 males between 18 and 30 years with a BMI of <25 kg/m(2), and so on), resulting in a total of 216 controls (108 males, 108 females; age: 40.3±1.0; BMI: 27.8±0.4). Multiple stepwise regression analyses were performed (covariates: age, BMI, sex), and sex-specific reference ranges were applied to 50 males (age: 46.1±2.3; BMI: 27.4±0.7) with suspected hypogonadism. Regression analysis identified the strongest predictor of each parameter apart from sex, resulting in age-specific (males: FAI, SHBG, BTV, FTV; females: TOT, FTS, SHBG), BMI-specific (males: TOT, FTS; females: FAI, BTV, FTV) and overall cutoffs for both sexes. In male patients, overall agreement between the results derived from the estimates (i. e., BTV, FTS, FTV) was high (with discordant results in only 4%). In summary, if both the endocrine workup and the clinical presentation were taken into account, the newly established reference ranges allowed reliable identification of hypogonadal males. © Georg Thieme Verlag KG Stuttgart · New York.
    Hormone and Metabolic Research 01/2015; 47(11). DOI:10.1055/s-0034-1395569 · 2.12 Impact Factor
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    ABSTRACT: The thyrotropin receptor-cAMP pathway is central in growth regulation of thyroid cells and thyroid tumorigenesis, and it regulates expression of thyroid specific genes. Recently, 2 new protein kinase A-independent cAMP effectors named EPAC1 and 2 were described that activate additional intracellular pathways. The aim of our study was to investigate the role of EPAC proteins in growth regulation of thyroid cells and thyroid carcinomas. EPAC1 expression was investigated immunohistochemically in tissues of various thyroid tumors. Utilizing MTT assay, the effect of EPAC stimulation on proliferation in thyroid carcinoma cells and in non-transformed rat FRTL5 cells was investigated. The activation of intracellular signaling pathways was examined by RAP pull-down assay and Western blots. EPAC1 expression was strong in non-oxyphilic follicular thyroid adenomas and carcinomas and in follicular papillary thyroid carcinomas. It was moderate in oxyphilic follicular tumors and classical and tall cell papillary carcinomas. In contrast, EPAC1 expression was low in poorly differentiated carcinomas and very low in anaplastic carcinomas. Thyroid carcinoma cell lines showed no or very weak EPAC1 expression and exhibited no growth-promoting effect after EPAC stimulation. Non-transformed rat FRTL5 cells were growth-stimulated by an EPAC-specific cAMP-analogue and showed EPAC-dependent activation of RAP, ERK, and p70S6 kinase. EPAC1 expression and cellular response to EPAC activation in rat FRTL5 cells reflect cellular responses to cAMP and TSH stimulation in non-transformed thyroid cells. In undifferentiated thyroid carcinomas, loss of EPAC1 expression may be in accordance with the loss of thyroid-specific functions and the loss of responsiveness of the TSHR-cAMP pathway.
    Hormone and Metabolic Research 11/2014; 47(03). DOI:10.1055/s-0034-1390484 · 2.12 Impact Factor
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    ABSTRACT: Thyroid dysfunction may impair fertility, course of pregnancy and fetal development. Physiological alterations of thyroid function parameters, that occur during pregnancy need to be distinguished from pathophysiological states of hypo- and hyperthyroidism. We performed a literature search (PubMed 1990-2013) and review relevant publications as well as consensus and practice guidelines of international thyroid/endocrine societies. Interpretation of thyroid function values in pregnancy must be based on trimester-specific TSH and T4 ranges. Alterations in thyroid function are present in up to 15% of pregnancies (0.4% overt hypothyroidism, 0.1-0.4% hyperthyroidism) and may lead to preventable complications in the pregnant woman and the fetus. Hypothyroidism is associated with an increased risk for abortion, premature delivery and stillbirth, besides impairment of neurocognitive development. The latter has also been shown in situations of grave iodine deficiency. In addition to new-born screening directed at early recognition of congenital hypothyroidism (incidence 0.03%), universal screening of all pregnant women should be implemented in health care guidelines. Newly diagnosed overt hypothyroidism in a pregnant woman requires immediate levothyroxine substitution at adequate doses. In subclinical hypothyroidism thyroid hormone replacement should be considered. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Pregnancy causes a number of, that need to be of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn.
    DMW - Deutsche Medizinische Wochenschrift 10/2014; 139(42):2148-2152. DOI:10.1055/s-0034-1387300 · 0.54 Impact Factor
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    ABSTRACT: Objective: Malignant phaeochromocytomas are rare and highly aggressive tumours. This retrospective study evaluated the outcome of combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (also known as CVD regimen). Methods: Patients with histologically and radiologically confirmed malignant phaeochromocytoma who were treated with the CVD regimen for progressive disease were retrospectively identified from chart review. Treatment cycles were usually repeated at 21-day intervals, with cyclophosphamide (750 mg/m(2) ), vincristine (1·4 mg/m(2) ) and dacarbazine (600 mg/m(2) ) on day 1, and dacarbazine only (600 mg/m(2) ) on day 2. The main outcome measures were best response during treatment and progression-free survival. Results: Eight patients (4 males; median age 55·5 (range 31-77) years) with progressive disease underwent a median of 6 (range 3-11) cycles. Best treatment responses were as follows: partial response, n = 2 (25%); stable disease, n = 3 (38%); and progressive disease, n = 3 (38%). The median progression-free survival was 5·4 (range 2·5-26·8) months. After the initial administration of 6 cycles, two patients received a second course of chemotherapy with another 6 cycles after new progressive disease had been detected. Subsequently, these patients were progression-free for another 6·0 and 6·4 months. Mild gastrointestinal symptoms and fatigue were the most common adverse events. Conclusion: Although objective tumour response rates were lower than previously reported in small series, the CVD regimen allowed disease stabilization for a substantial period of time and may therefore be considered as a treatment option in advanced stages. To improve disease outcome, however, new therapeutic approaches and larger multicentre studies are needed.
    Clinical Endocrinology 08/2014; 82(1). DOI:10.1111/cen.12590 · 3.46 Impact Factor
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    ABSTRACT: Preceding studies have indicated that aberrant expression levels rather than genetic changes of GADD45γ, MEG3, and p8 gene might play a role in the pathogenesis of pituitary adenomas. We analysed their expression in various normal human tissues and in different pituitary tumour types, and investigated GADD45γ mutations in a subset of adenomas. Absolute quantification by real-time RT-PCR was performed in 24 normal tissues as well as in 34 nonfunctioning, 24 somatotroph, 12 corticotroph adenomas, 4 prolactinomas, 1 FSHoma, and in 6 normal pituitaries. Furthermore, we investigated the relationship between clinical data and gene expression. A subset was screened for GADD45γ mutations by single strand conformation polymorphism analysis (SSCP) and sequencing. All normal human tissues expressed GADD45γ, MEG3, and p8 mRNA. For GADD45γ, significantly lower expression levels were found in nonfunctioning adenomas compared with normal pituitary and somatotroph adenomas. P8 and MEG3 mRNA levels were significantly lower in nonfunctioning and corticotroph adenomas compared with normal pituitary. Expression of GADD45γ was significantly higher in pituitary adenomas of female patients. No mutation was found in the GADD45γ gene. GADD45γ, MEG3, and p8 appear to have physiological functions in a variety of human tissues. GADD45γ, MEG3, and P8 may be involved in the pathogenesis of nonfunctioning and corticotroph pituitary tumours. Female gender seems to predispose to slightly higher GADD45γ expression in pituitary adenomas. Mutations of the GADD45γ are unlikely to be involved in the pathogenesis of pituitary adenomas.
    Hormone and Metabolic Research 08/2014; 46(9):644-50. DOI:10.1055/s-0034-1383566 · 2.12 Impact Factor
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    ABSTRACT: Objective: Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients. Design: Of 514 acromegalic patients treated with pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes. Results: Under treatment with pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, P=0.04) for IGF1. Diabetic patients normalised for IGF1 required higher pegvisomant doses (18.9 vs 15.5 mg pegvisomant/day, P<0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg pegvisomant/day, P=0.11). Conclusions: Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.
    European Journal of Endocrinology 07/2014; 171(1):59-68. DOI:10.1530/EJE-13-0438 · 4.07 Impact Factor
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    ABSTRACT: We present a case of a patient suffering from metastatic differentiated thyroid carcinoma (DTC) and insufficient endogenous TSH production suspicious of secondary hypothyroidism. The use of recombinant human TSH (rhTSH) enabled us to administer a therapeutic activity of radioactive iodine (RAI) under maximal TSH-stimulation, achieving a marked decrease in thyroglobulin accompanied by a clinical improvement.
    Journal of endocrinological investigation 07/2014; 23(7):473-5. DOI:10.1007/BF03343758 · 1.45 Impact Factor
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    ABSTRACT: Background: Medullary thyroid cancer (MTC) is a rare tumor entity. The contents of best supportive care (BSC) have not been defined in advanced MTC. The objective of this work is to describe the epidemiology, the treatment patterns with respect to symptom management, as well as palliative treatment and associated costs. Method: A Delphi panel with 9 clinical experts experienced in treating MTC was conducted to obtain details on the epidemiology of MTC and to gain insights into the therapeutic options considered for BSC in advanced MTC in Germany. Unit costs were applied to the described resources from the perspective of the German National Healthcare System in 2011. Results: The annual incidence of MTC in Germany was estimated at about 220. 32% of all patients were estimated to have aggressive/symptomatic MTC, with an estimated mean survival of 36.7 months (median: 36 months). The core element of BSC is relief of symptoms to maintain quality of life. The total mean cost of BSC per patient/year was estimated at € 9,248, lifetime cost at € 28,283. Conclusion: There was consistent agreement within the panel on the epidemiology of MTC and on the structure of the provided therapeutic measures for BSC in advanced MTC, also defining the management of symptoms as a crucial goal of treatment.
    Oncology Research and Treatment 05/2014; 37(6):316-22. DOI:10.1159/000362613
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    ABSTRACT: We determined the prognostic value of transient increases in high-sensitive serum troponin I (hsTnI) during a marathon and its association with traditional cardiovascular risk factors and imaging-based risk markers for incident coronary events and all-cause mortality in recreational marathon runners. Baseline data of 108 marathon runners, 864 age-matched controls and 216 age- and risk factor-matched controls from the general population were recorded and their coronary event rates and all-cause mortality after 6 ± 1 years determined. hsTnI was measured in 74 marathon finishers before and after the race. Other potential predictors for coronary events, i.e., Framingham Risk Score (FRS), coronary artery calcium (CAC) and presence of myocardial fibrosis as measured by magnetic resonance imaging-based late gadolinium enhancement (LGE), were also assessed. An increase beyond the 99 % hsTnI-threshold, i.e., 0.04 μg/L, was observed in 36.5 % of runners. FRS, CAC, or prevalent LGE did not predict hsTnI values above or increases in hsTnI beyond the median after the race, nor did they predict future events. However, runners with versus without LGE had higher hsTnI values after the race (median (Q1/Q3), 0.08 μg/L (0.04/0.09) versus 0.03 μg/L (0.02/0.06), p = 0.039), and higher increases in hsTnI values during the race (median (Q1/Q3), 0.05 μg/L (0.03/0.08) versus 0.02 μg/L (0.01/0.05), p = 0.0496). Runners had a similar cumulative event rate as age-matched or age- and risk factor-matched controls, i.e., 6.5 versus 5.0 % or 4.6 %, respectively. Event rates in runners with CAC scores <100, 100-399, and ≥400 were 1.5, 12.0, and 21.4 % (p = 0.002 for trend) and not different from either control group. Runners with coronary events had a higher prevalence of LGE than runners without events (57 versus 8 %, p = 0.003). All-cause mortality was similar in marathon runners (3/108, 2.8 %) and controls (26/864, 3.0 % or 5/216, 2.4 %, respectively). Recreational marathon runners with prevalent myocardial fibrosis develop higher hsTnI values during the race than those without. Increasing coronary artery calcium scores and prevalent myocardial fibrosis, but not increases in hsTnI are associated with higher coronary event rates. All-cause mortality in marathon runners is similar to that in risk factor-matched controls.
    Archiv für Kreislaufforschung 01/2014; 109(1):391. DOI:10.1007/s00395-013-0391-8 · 5.41 Impact Factor
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    ABSTRACT: Background Coronary artery calcium (CAC) indicates coronary atherosclerosis and can be present in very early stages of the disease. The conversion from no CAC to any CAC reflects an important step of the disease process as cardiovascular risk is increased in persons even with mildly elevated CAC. We sought to identify risk factors that determined incident CAC>0 in men and women from an unselected general population with a special focus on the role of smoking. Methods All 4814 persons that were initially studied in the Heinz Nixdorf Recall Study were invited to participate in the follow-up examination after 5.1±0.3 years. All traditional Framingham risk factors were quantified using standard techniques. Smokers were categorized in never, former and present smokers. The CAC scores were measured from EBCT using the Agatston method. Results Overall, out of 342 men and 919 women with zero CAC at baseline, 107 (31.3%) men and 210 (22.9%) women had CAC>0 at second examination. In multivariable analysis, age (OR estimate per 5 years: 1.34 (95%CI: 1.21-1.47)), LDL cholesterol (per 10 mg/dl: 1.05 (95%CI: 1.01-1.10)), systolic blood pressure (per 10 mmHg: 1.19 (95%CI: 1.11-1.28)) and current smoking (1.49 (95%CI: 1.04-2.15)) were independent predictors of CAC onset. The probability of CAC onset steadily increased with age from 23.3% (men) and 15.3% (women) at age 45-49 years to 66.7% (men) and 42.9% (women) at age 70-74 years. The difference in age-dependent conversion rates was quantified by years between reaching a given level of CAC onset probability. We found a consistent pattern with respect to smoking status: presently (formerly) smoking middle-aged men convert to positive CAC 10 (5) years earlier than never smokers, for women (middle-aged to elderly) this time span is 8 (5) years. Conclusion Several traditional CVD risk factors are associated with CAC onset during 5 years follow-up. CAC onset is accelerated by approximately 10 (5) years for present (former) compared to never smokers.
    Atherosclerosis 11/2013; 232(2). DOI:10.1016/j.atherosclerosis.2013.11.045 · 3.99 Impact Factor
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    ABSTRACT: Background: Coronary atherosclerosis can be detected by computed tomography. The amount of coronary artery calcification (CAC) is related to cardiovascular risk factors, the strength of the gender specific relation between lipoprotein parameters and CAC has not extensively been studied. Especially, the role of routinely determined lipoproteins in contrast to less common and computed lipid parameters (e.g. ratios) remains to be clarified. Methods and results: The study cohort (n = 3956, 52% women, age 45-75 years) was randomly selected from three cities of a German metropolitan area. Lipoproteins-low-and high density lipoprotein (LDL-C/HDL-C), total cholesterol, apolipoprotein A-1 and B (apoA-1/apoB) as well as lipoprotein (a) (Lp(a)) were measured, while non-HDL-C was calculated. All participants received an electron-beam computed tomography (EBCT) for quantification of CAC. Adjusted for age and cardiovascular risk factors, CAC increased by a factor of 1.97 (1.51-2.57, 95% CI) and 1.94 (1.53-2.45, 95% CI) comparing the fourth to the first quartile of LDL-C for men and women, respectively. This association with LDL-C was also found after dichotomization of CAC at thresholds >0, ≥ 100 and ≥ 400. The best association of CAC was, however, found to be apoB and the second best was non HDL-C, in both men and women. For apoB, the model including all risk factors reached an explained variance for CAC of 20.2% in men and of 21.6% in women. When using LDL-C as a given parameter according to the current practice and advice, HDL-C in men and apoB in women provided an additional but small benefit. Conclusion: ApoB showed the best association with CAC compared to all other tested lipoproteins. Neither the ratio LDL-C/HDL-C nor apoB/apoA-1, or Lp(a) revealed a closer association with CAC. While lipoproteins are related to CAC more closely in women than in men, their association with CAC is, however, not particularly strong. Our results may influence primary and secondary prevention advices in order to improve detection of subclinical atherosclerosis, for which lipoprotein parameters can only play a minor role.
    Atherosclerosis 05/2013; 229(2). DOI:10.1016/j.atherosclerosis.2013.04.015 · 3.99 Impact Factor

  • Experimental and Clinical Endocrinology & Diabetes 03/2013; 121(03). DOI:10.1055/s-0033-1336743 · 1.56 Impact Factor

  • Experimental and Clinical Endocrinology & Diabetes 03/2013; 121(03). DOI:10.1055/s-0033-1336682 · 1.56 Impact Factor
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    ABSTRACT: Coronary risk factors in patients with acromegaly after first-line transsphenoidal surgery (TSS) or first-line somatostatine analogue (SSA) treatment have rarely been examined. Aim of this study was an evaluation of cardiovascular risk factors and left ventricular hypertrophy (LVH) in 3 different patient groups with treatment naïve, active (ACT), first-line medically controlled (MED) and first-line surgically treated (SUR) acromegaly and a calculation of the Framingham Weibull Risk Score (FS).Retrospective comparative matched case-control study.40 acromegalic patients (cases aged 45-74 years, 23 men) were matched with respect to age and gender to 200 controls from the general population. 13 patients had treatment-naïve acromegaly (ACT), 12 patients were SSA treated (MED) and 15 patients were operated by TSS (SUR). Coronary risk factors were assessed after 12 months of treatment by interviews and direct laboratory measurements. Only patients normalized for IGF-I in MED and SUR group were included. FS and odds ratios (OR) from multiple conditional logistic regression (matched for age and gender, adjusted for BMI) were calculated.Compared to matched controls ACT patients had higher HbA1c levels (6.9±1.4 vs. 5.5±0.7% (p<0.0001)) and an increased prevalence of left ventricular hypertrophy (LVH) (30.8 vs. 3.2% (p=0.007). MED and SUR groups were similar for gender, age, disease duration and IGF-I levels at diagnosis. Compared to matched controls, MED patients had a significantly increased diastolic blood pressure (89±9 vs. 79±11 mmHg (p=0.001), prevalence of LVH (41.7 vs. 1.7% (p<0.0001), prevalence of diabetes mellitus (33.3 vs. 10.0% (p=0.03)), higher HbA1c levels (6.8±1.3 vs. 5.5±0.7% (p=0.0005)) and a higher FS (21.2±9.7 vs. 12.4±7.7% (p=0.002), OR 1.11 [1.02-1.21] (p=0.01)) while in the SUR group only higher prevalences of LVH (40.0 vs. 4.1% (p<0.0001)) and HbA1c levels (6.4±1.2 vs. 5.5±0.8% (p=0.006)) were found compared to controls.When comparing treatment naive, medically treated and surgically cured patients with acromegaly to age- and gender-matched subjects from the general population, we have found an increased cardiovascular risk in patients at 12 months after first-line SSA treatment but not in patients after first-line surgery.
    Experimental and Clinical Endocrinology & Diabetes 01/2013; 121(2). DOI:10.1055/s-0032-1314811 · 1.56 Impact Factor
  • D Graf · B Helmich-Kapp · S Graf · F Veit · N Lehmann · K Mann ·
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    ABSTRACT: Background: The American (ATA) and the European Thyroid Association (ETA) recommend a thyroid scintiscan for the detection of a suspected autonomy only when serum thyrotropin (TSH) levels are low or suppressed. If ultrasound reveals a thyroid nodule > 1.0 cm and TSH is normal, a fine-needle biopsy is recommended without a preceding scintiscan as the next step. The aim of this prospective study was to evaluate the incidence of reduced or suppressed TSH in 100 autonomous adenoma > 1.0 cm and to clarify, if normal TSH does substantially exclude a focal autonomy. When the study was conducted no data of German patients were available. Patients and methods: An unselected group of 496 patients with a nodular goiter was continuously screened by scintiscan in order to detect 100 autonomous adenoma > 1.0 cm for the study. The following investigations were carried out: ultrasound, scintiscan and laboratory tests (fT3, fT4, TSH, TPO-antibodies). The reference range of TSH was 0.4 to 4.0 µU/ml. Results: 21% of patients (100/476) with a nodular goiter had a focal autonomy. 32 % (32/100) of autonomous adenoma revealed a reduced (< 0.4 µU/ml) or completely suppressed TSH, while in 68 % (68/100) normal TSH level were found. Conclusion: In Germany autonomous adenoma are still frequent (21 % of all thyroid nodules). Most of them (68 %) reveal normal TSH levels. Our data demonstrate, that there is no relevant connection between TSH level and autonomous adenoma detected by scintiscan. In most cases, TSH is not able to discriminate, whether a nodule is autonomous or not. Biopsy of undetected autonomous nodules should not be performed, as they often show cytological features of follicular neoplasias. In thyroid nodules > 1.0 cm a scintiscan should routinely be performed in primary diagnostics to avoid unnecessary fine-needle biopsy of autonomous adenoma.
    DMW - Deutsche Medizinische Wochenschrift 10/2012; 137(41):2089-92. DOI:10.1055/s-0032-1305324 · 0.54 Impact Factor

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9k Citations
1,530.76 Total Impact Points


  • 1995-2015
    • University of Duisburg-Essen
      • • Faculty of Medicine
      • • Department of Internal and Integrative Medicine
      Essen, North Rhine-Westphalia, Germany
    • University Hospital Essen
      • • Institute of Medical Computer Science, Biometry and Epidemiology
      • • Institute of Pathology and Neuropathology
      • • Institute of Pharmacology
      • • Clinic for Endocrinology
      Essen, North Rhine-Westphalia, Germany
  • 2012
    • Katholisches Klinikum Essen
      Essen, North Rhine-Westphalia, Germany
  • 2009
    • University of Cologne
      • Rhenish Institute for Environmental Research
      Köln, North Rhine-Westphalia, Germany
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
    • Endokrinologikum Hamburg
      Hamburg, Hamburg, Germany
  • 2005
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2004
    • Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V.
      Essen, North Rhine-Westphalia, Germany
  • 2001
    • Clinic for Minimally Invasive Surgery
      Berlín, Berlin, Germany
  • 1994
    • Austrian Academy of Sciences
      • Institute for Biomedical Aging Research
      Wien, Vienna, Austria
  • 1990-1994
    • Ludwig-Maximilian-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 1979-1988
    • University Hospital München
      München, Bavaria, Germany