Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie

Berlin, Germany

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie

Berlin, Germany
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Horsch D.,Klinik fur Innere Medizin | Schmid K.W.,Universitatsklinikum Essen | Anlauf M.,Heinrich Heine University Düsseldorf | Anlauf M.,Institute For Pathologie Und Zytologie Giessen Limburg Wetzlar | And 16 more authors.
Oncology Research and Treatment | Year: 2014

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium 'Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract. © 2014 S. Karger GmbH, Freiburg.

Lange C.M.,University of Lausanne | Lange C.M.,Goethe University Frankfurt | Bibert S.,University of Lausanne | Kutalik Z.,University of Lausanne | And 17 more authors.
PLoS ONE | Year: 2012

Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome. © 2012 Lange et al.

Lange C.M.,University of Lausanne | Lange C.M.,Goethe University Frankfurt | Miki D.,RIKEN | Miki D.,Hiroshima University | And 24 more authors.
PLoS ONE | Year: 2013

Background:Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).Methodology/Principal Findings:Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.Conclusions/Significance:Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis. © 2013 Lange et al.

Amano M.,Hokkaido University | Eriksson H.,Karolinska Institutet | Manning J.C.,Ludwig Maximilians University of Munich | Detjen K.M.,Medizinische Klinik Mit Schwerpunkt Hepatologie und Gastroenterologie | And 4 more authors.
FEBS Journal | Year: 2012

Tumour suppressor p16INK4a is known to exert cell-cycle control via cyclin-dependent kinases. An emerging aspect of its functionality is the orchestrated modulation of N/O-glycosylation and galectin expression to induce anoikis in human Capan-1 pancreatic carcinoma cells. Using chemoselective N/O-glycan enrichment technology (glycoblotting) and product characterization, we first verified a substantial decrease in sialylation. Tests combining genetic (i.e. transfection with α2,6-sialyltransferase-specific cDNA) or metabolic (i.e. medium supplementation with N-acetylmannosamine to track down a bottleneck in sialic acid biosynthesis) engineering with cytofluorometric analysis of lectin binding indicated a role of limited substrate availability, especially for α2,6-sialylation, which switches off reactivity for anoikis-triggering homodimeric galectin-1. Quantitative MS analysis of protein level changes confirmed an enhanced galectin-1 presence along with an influence on glycosyltransferases (β1,4-galactosyltransferase-IV, α2,3-sialyltransferase-I) and detected p16INK4a-dependent down-regulation of two enzymes in the biosynthesis pathway for sialic acid [i.e. the bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and N-acetylneuraminic acid 9-phosphate synthase] (P < 0.001). By contrast, quantitative assessment for the presence of nuclear CMP-N-acetylneuraminic acid synthase (which is responsible for providing the donor for enzymatic sialylation that also acts as feedback inhibitor of the epimerase activity of GNE) revealed a trend for an increase. Partial restoration of sialylation in GNE-transfected cells supports the implied role of sialic acid availability for the glycophenotype. Fittingly, the extent of anoikis was reduced in double-transfected (p16INK4a/GNE) cells. Thus, a second means of modulating cell reactivity to the growth effector galectin-1 is established in addition to the common route of altering α2,6- sialyltransferase expression: regulating enzymes of the pathway for sialic acid biosynthesis. The tumor suppressor p16INK4a, a well-known control element of the cell cycle, also increases susceptibility to anoikis. Toward this end, an effector lectin (galectin-1) is upregulated and glycosylation reprogrammed. 2,6-Sialylation, which precludes galectin-1 reactivity, is decreased by downregulation sialic acid biosynthesis at the level of expression of two enzymes of this pathway in tandem. © 2012 The Authors Journal compilation © 2012 FEBS.

Baur A.D.J.,Charité - Medical University of Berlin | Kunz F.,Charité - Medical University of Berlin | Schwenke C.,Scossis Statistical Consulting | Pschowski R.,Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie | And 3 more authors.
Journal of Computer Assisted Tomography | Year: 2016

Purpose The aim of this study was to evaluate signs of right-sided heart dysfunction on staging computed tomography (CT) as indirect indicators of carcinoid heart disease. Patients and Methods Patients with functionally active neuroendocrine neoplasm and different grades of tricuspid valve regurgitation (TR) were identified. Two readers independently reviewed contrast-enhanced staging CT performed within 90 days before or after echocardiography. Logistic regression and receiver operating analyses were used to asses the predictive value of right ventricle-left ventricle ratio (RV-LV ratio), ventricular septal bowing, retrograde contrast filling of the hepatic veins during contrast injection, and time to aortal enhancement greater than 100 Hounsfield units during bolus tracking for TR. Results Forty-four examinations were evaluated (11 with TR = 0, 16 with TR = 1, 9 with TR = 2, and 8 with TR = 3). Right ventricle-LV ratio was found to predict TR less than or equal to 1 versus TR greater than 1 (P = 0.0188) and TR less than or equal to 1 versus TR equals 2 (P = 0.0082). A prolonged time to aortal enhancement greater than 100 Hounsfield units during bolus tracking predicted TR less than or equal to 1 versus TR greater than 1 (P = 0.0077). Area under the curve for RV-LV ratio was 0.86 when differentiating TR less than or equal to 1 versus TR equals 2. With a cutoff of 1.07, sensitivity was 0.89, and specificity was 0.72. Conclusions In patients with functionally active neuroendocrine neoplasm, an RV-LV ratio of more than 1.07 predicted TR with a relatively high sensitivity and moderate specificity and thus could serve as an indicator of subclinical carcinoid heart disease on routine staging CT. © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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