Altmann K.,Johannes Gutenberg University Mainz |
Hermanns P.,Johannes Gutenberg University Mainz |
Muhlenberg R.,HELIOS Klinikum |
Fricke-Otto S.,HELIOS Klinikum |
And 2 more authors.
Experimental and Clinical Endocrinology and Diabetes | Year: 2013
Congenital hypothyroidism occurs with a prevalence of approximately 1:3 500. Defects in thyroid hormone synthesis which lead to goitrous hypothyroidism account for 10-15% of these cases. Several genetic defects have been characterized and mutations in the thyroid peroxidase (TPO) gene are the most common cause for dyshormonogenesis. So far, more than 80 mutations in the TPO gene have been described, resulting in a variable decrease in TPO bioactivity. Clinically TPO defects manifest with congenital primary goitrous hypothyroidism. We here present 2 children with congenital primary hypothyroidism, who were identified to have compound heterozygous TPO mutations. They both shared the same novel mutation in the TPO gene (C756R) in exon 13. One case presented with an apparently dominant inheritance of thyroid dyshormonogenesis. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York ISSN 0947-7349.
PubMed | Klinikum Chemnitz, Ludwig Maximilians University of Munich, University of Greifswald, Practice for Hematology and Medical Oncology and 6 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016
To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab.CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated.Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results.In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab.NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.
Sandrock-Lang K.,Albert Ludwigs University of Freiburg |
Wentzell R.,Lukaskrankenhaus |
Santoso S.,Justus Liebig University |
Zieger B.,Albert Ludwigs University of Freiburg
Hamostaseologie | Year: 2015
Inherited platelet disorders may be the cause of bleeding symptoms of varying severity as platelets fail to fulfil their haemostatic role after vessel injury. Platelet disorders may be difficult to diagnose (and are likely to be misdiagnosed) and raise problems in therapy and management. This review explores the clinical and molecular genetic phenotype of several inherited disorders. Inherited platelet disorders can be classified according to their platelet defects: Receptor defects (adhesion or aggregation), secretion disorder, and cytoskeleton defects. The best characterized platelet receptor defects are Glanzmann thrombasthenia (integrin αIIbα3 defect) and Bernard-Soulier syndrome (defect of GPIb/IX/V). Detailed case reports of patients suffering from Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS) showing the bleeding diathesis as well as investigation of platelet aggregation/ agglutination and platelet receptor expression will complement this review. In addition, Hermansky-Pudlak syndrome (HPS) as an important defect of δ-granule secretion is extensively described together with a case report of a patient suffering from HPS type 1. © Schattauer 2016.
Kahraman D.,University of Cologne |
Goretzki P.E.,Lukaskrankenhaus |
Szangolies M.,Rontgeninstitut Mechernich |
Schade H.,Kreiskrankenhaus Mechernich |
And 2 more authors.
Experimental and Clinical Endocrinology and Diabetes | Year: 2011
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare catecholamine-secreting neuroendocrine tumors arising from chromaffin tissue and can occur within the adrenal medulla (PHEO) or extra-adrenal sites (PGL). The most common site for PGL is the organ of Zuckerkandl, extra-adrenal chromaffin tissue near the origin of the inferior mesenteric artery.We here present 2 patients with extra-adrenal PGL in the organ of Zuckerkandl, located by iodine-123-metaiodobenzylguanadine (123I-MIBG) scintigraphy and thereafter treated surgically or with iodine-131-metaiodobenzylguanadine ( 131I-MIBG). First, in a 15-year-old boy with clinical suspicion of PHEO, the diagnosis was established by biochemical evaluation and confirmed by further imaging studies, including CT and 123I-MIBG, as PGL in the Zuckerkandl organ. The tumor was completely resected by laparotomy. Second, in a 70-year-old woman presenting with progressive hypertension and palpitations, MR and 123I-MIBG revealed a singular tumor lesion with abnormal 123I-MIBG uptake in the Zuckerkandl organ. Due to severe general vascular disease, surgery was not performed and instead the patient underwent 131I-MIBG therapy. The patient showed a good symptomatic response with improvement of symptoms and no relevant side-effects of therapy. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.
Gencer D.,University of Heidelberg |
Al-Batran S.-E.,Klinik fur Onkologie und Hamatologie Am Krankenhaus Nordwest |
Dada R.,Universitatsklinikum Aachen Hamatologie Onkologie |
Hunerliturkoglu A.-N.,Lukaskrankenhaus |
And 7 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013
Purpose: Little is known about the use of first-line chemotherapy in clinical practice in patients with advanced esophagogastric adenocarcinoma, and no data have been published regarding potential obstacles for the implementation of molecular testing for targeted agents in this patient group. Here, we sought to evaluate factors influencing treatment decisions with special focus on the implementation of HER2 testing during the first year after trastuzumab market approval in Germany. Methods: A total of 754 patients undergoing treatment decisions for palliative first-line therapy in 2010 were documented using Therapiemonitor®. Drug use and intensity of first-line treatment were analyzed. Data on HER2 testing and test algorithm are described, and variables influencing HER2 testing were selected using bivariate analysis. Significant factors were included in a multivariate logistic regression analysis. Results: Compared with previous years, treatment intensity has further increased. The use of chemotherapy triplets rose from 10.1 % in 2006 to 60.3 % in 2010. In 2010, 49.1 % of patients were tested for HER2 and in 52.2 % of these patients the currently proposed test algorithm was used. Using multivariate logistic regression analysis age ≥67 years and "initiating institution: practice" were found to negatively impact the likelihood of HER2 testing, while treatment goal "prevention of progression", multiple metastases and a Karnofsky status >80 % showed positive correlation with HER2 testing. Conclusion: The tendency to use more intensive first-line chemotherapy regimens in patients with advanced esophagogastric adenocarcinoma continued in 2010. Only a minority of patients had an access to the appropriate molecular diagnostics and therefore to treatment with trastuzumab. The access was limited due to the preselection following individual, clinical and institutional factors. © 2012 Springer-Verlag Berlin Heidelberg.
Reuschenbach M.,University of Heidelberg |
Reuschenbach M.,German Cancer Research Center |
Roos J.,Lukaskrankenhaus |
Panayotopoulos D.,Heinrich Heine University Düsseldorf |
And 10 more authors.
Journal of Lower Genital Tract Disease | Year: 2013
Objective. The incidence of vulvar squamous cell carcinomas located between the clitoris and urethra in young women is rising in distinct geographic regions, but characteristics of the tumors indicating certain carcinogenic mechanisms are unknown. The present study aimed at characterizing these vulvar cancers for their human papillomavirus (HPV), p16INK4a, and p53 status, revealing potential pathways of carcinogenesis. Materials and Methods. Squamous cell vulvar cancers of the anterior fourchette were retrospectively collected from 8 German hospitals, with additional squamous cell cancers located at other sites of the vulva from 2 of the hospitals. All tumors were analyzed for HPV DNA by polymerase chain reaction and for p16INK4a and p53 expression by immunohistochemistry. Results. Potentially HPV-associated tumors (HPV and p16INK4a positive, 21.4% [27/126] of the anterior fourchette and 27.7% [13/47] from other locations), p53- overexpressing tumors (35.7% [45/126] and 29.8% [14/47]), and a third group (HPV/p16 negative/p53 not overexpressed, 42.9% [54/126] and 42.6% [20/47]) were observed among tumors from the anterior fourchette as well as among vulvar cancers from other locations. Women with vulvar cancers of the anterior fourchette were of young age irrespective of the HPV/p16INK4a/p53 status. Conclusions. Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general. © 2013, American Society for Colposcopy and Cervical Pathology.
Kleinbongard P.,University of Duisburg - Essen |
Konorza T.,University of Duisburg - Essen |
Bose D.,University of Duisburg - Essen |
Baars T.,University of Duisburg - Essen |
And 3 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012
The interventional implantation of a stent into an atherosclerotic coronary artery is a unique and paradigmatic scenario of plaque rupture in humans. The use of protection devices not only prevents the released plaque particles and the superimposed thrombotic material from being washed and embolized into the coronary microcirculation of the individual patient, but permits also the retrieval and ex vivo analysis of particulate plaque debris and soluble substances. The particulate debris comprises typical cholesterol crystals, foam cells, hyalin material and calcium deposits from the atheroma as well as platelets and coagulation material; soluble substances include vasoconstrictors, such as serotonin and thromboxane, as well as inflammatory mediators, such as TNFα which amplifies vasoconstriction by inducing endothelial dysfunction. The vasoconstriction observed in a bioassay ex vivo correlates to clinical symptoms, angiographic stenosis and plaque burden, as assessed by intravascular ultrasound. The release of TNFα into the aspirate correlates to restenosis. Detailed analysis of the human coronary aspirate may promote a better understanding of the pathophysiology of the vulnerable atherosclerotic plaque and help to better antagonize the microvascular consequences of coronary microembolization, including the no reflow phenomenon. This article is part of a Special Issue entitled "Coronary Blood Flow.". © 2011 Elsevier Ltd.
Bruns I.,Heinrich Heine University Düsseldorf |
Cadeddu R.-P.,Heinrich Heine University Düsseldorf |
Brueckmann I.,German Cancer Research Center |
Frobel J.,Heinrich Heine University Düsseldorf |
And 19 more authors.
Blood | Year: 2012
Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyteerythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGF- signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term selfrenewal were impaired as a consequence of activated TGF- signaling. In accordance, TGF- levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGF- signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myelomafree NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations. © 2012 by The American Society of Hematology.
Reunert J.,Universitatsklinikum Munster |
Wentzell R.,Lukaskrankenhaus |
Walter M.,Charité - Medical University of Berlin |
Jakubiczka S.,University Hospital Magdeburg |
And 4 more authors.
European Journal of Human Genetics | Year: 2012
Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C > T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G > A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria. © 2012 Macmillan Publishers Limited All rights reserved.
Johannsen M.,Charité - Medical University of Berlin |
Staehler M.,Universitatsklinikum Grosshadern |
Ohlmann C.-H.,Universitatsklinikum Saarland |
Florcken A.,Charité - Medical University of Berlin |
And 7 more authors.
Annals of Oncology | Year: 2011
Background: It is unknown if discontinuation of targeted therapy (TT) and readministration in case of recurrence is feasible in patients with metastatic renal cell carcinoma (mRCC) in which complete response (CR) is achieved by TT alone or no evidence of disease (NED) with additional resection of residual metastases. Patients and methods: Patients in whom TT was discontinued after CR to TT alone or NED after additional metastasectomy were included in this retrospective analysis. Outcome criteria evaluated were time off TT, recurrence of metastases and response to re-exposure to TT. Univariate and multivariate analyses were carried out to identify variables potentially predictive of outcome. Results: In 36 patients with CR or NED under TT with sunitinib (22), sorafenib (11), bevacizumab/interferon (2) and temsirolimus (1), TT was discontinued. Recurrence was observed in 24 patients (66.7%). Re-exposure to TT was effective in 86.9% of these cases. Twelve patients (33.3%) remained recurrence free at a median follow-up of 12 months (range 3-31). Median time off TT was 7 months (range 1-31). Factors that correlate with outcome could not be identified. Conclusions: In the majority of patients with mRCC and CR or NED, discontinuation of TT was followed by recurrence, but re-exposure to TT was effective. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.