Andrea Tannapfel

Publications of Andrea Tannapfel

• Effects of FTY720 and Rapamycin on Inflammation in Taurocholate-Induced Acute Pancreatitis in the Rat.

  Authors: Christophe A Müller, Orlin Belyaev, Wenzel Burr, Johanna Munding, Nicholas McArthur, Uwe Bergmann, Jens Werner, Andrea Tannapfel, Waldemar Uhl

  Pancreas. 04/2012;

  OBJECTIVES: This study aimed at T-cell inhibition by immunosuppressants to reduce cell damage and improve the course of severe acute pancreatitis (SAP). METHODS: A taurocholate-induced SAP was usedOBJECTIVES: This study aimed at T-cell inhibition by immunosuppressants to reduce cell damage and improve the course of severe acute pancreatitis (SAP). METHODS: A taurocholate-induced SAP was used and 5 groups were compared: (1) rapamycin + FTY720, (2) rapamycin, (3) FTY720, (4) cortisol, and (5) control: sodium chloride. Drugs were applied intravenously at SAP induction; 6 hours later, rats were killed. Interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor α, platelet-activating factor, amylase, and lipase were measured in serum and myeloperoxidase tissue activity in pancreas, kidney, lung, liver, and spleen. Edema, inflammation, and necrosis were histologically determined in pancreas. CD4/CD8 immunohistochemistry was performed. RESULTS: Inflammation was ameliorated in all 4 treated groups. Necrosis development was suppressed by FTY720, FTY720 + rapamycin, and cortisol. IL-6 and IL-10 were significantly lower in these groups. Amylase was higher in all treatment groups compared to the controls except for the cortisol group. Tumor necrosis factor α, lipase, and myeloperoxidase activity were not affected by therapy. CD4/CD8 cells were significantly less in FTY720-treated pancreata. CONCLUSION: Rapamycin and FTY720 ameliorated the severity of SAP, which may be due to early suppression of helper T cells. FTY720 reduced the development of pancreatic necrosis. The combination of both immunosuppressants did not show advantage to treatment with FTY720 alone.

• Comparison of a lightweight polypropylene mesh (Optilene® LP) and a large-pore knitted PTFE mesh (GORE® INFINIT® mesh)--Biocompatibility in a standardized endoscopic extraperitoneal hernia model.

  Authors: Dietmar A Jacob, Christine Schug-Pass, Florian Sommerer, Andrea Tannapfel, Hans Lippert, Ferdinand Köckerling

  Langenbeck's archives of surgery / Deutsche Gesellschaft für Chirurgie. 02/2012; 397(2):283-9.

  The use of a mesh with good biocompatibility properties is of decisive importance for the avoidance of recurrences and chronic pain in endoscopic hernia repair surgery. As we know from numerousThe use of a mesh with good biocompatibility properties is of decisive importance for the avoidance of recurrences and chronic pain in endoscopic hernia repair surgery. As we know from numerous experiments and clinical experience, large-pore, lightweight polypropylene meshes possess the best biocompatibility. However, large-pore meshes of different polymers may be used as well and might be an alternative solution. Utilizing a totally extraperitoneal technique in an established animal model, 20 domestic pigs were implanted with either a lightweight large-pore polypropylene (PP) mesh (Optilene® LP) or a medium-weight large-pore knitted polytetrafluorethylene (PTFE) mesh (GORE® INFINIT® mesh). After 94 days, the pigs were sacrificed and postmortem diagnostic laparoscopy was performed, followed by explantation of the specimens for macroscopic, histological and immunohistochemical evaluation. The mean mesh shrinkage rate was 14.2% for Optilene® LP vs. 24.7% for INFINIT® mesh (p = 0.017). The partial volume of the inflammatory cells was 11.2% for Optilene® LP vs. 13.9% for INFINIT (n.s.). CD68 was significantly higher for INFINIT (11.8% vs. 5.6%, p = 0.007). The markers of cell turnover, namely Ki67 and the apoptotic index, were comparable at 6.4% vs. 12.4% (n.s.) and 1.6% vs. 2.0% (n.s.). In the extracellular matrix, TGF-β was 35.4% for Optilene® LP and 31.0% for INFINIT® (n.s.). Collagen I (pos/300 μm) deposits were 117.8 and 114.9, respectively. In our experimental examinations, Optilene® LP and INFINIT® showed a comparable biocompatibility in terms of chronic inflammatory reaction; however, the shrinkage rate was significantly higher for INFINIT® after 3 months. The higher shrinkage rate of INFINIT® should be taken into account when choosing the mesh size for an adequate hernia overlap.

• CCR5 Deficiency Does Not Reduce Hypertensive End-Organ Damage in Mice.

  Authors: Christian Krebs, Christoph Fraune, Robin Schmidt-Haupt, Jan-Eric Turner, Ulf Panzer, Michael N Quang, Andrea Tannapfel, Joachim Velden, Rolf A Stahl, Ulrich O Wenzel

  American journal of hypertension. 01/2012;

  BackgroundCCR5 is expressed on infiltrating T cells in hypertensive mice and CCR5 antagonists reduce hypertension making CCR5 an interesting target in treatment of hypertension.MethodsTo evaluate theBackgroundCCR5 is expressed on infiltrating T cells in hypertensive mice and CCR5 antagonists reduce hypertension making CCR5 an interesting target in treatment of hypertension.MethodsTo evaluate the role of CCR5 in hypertensive renal and cardiac end-organ damage, we induced hypertension with desoxycorticosterone acetate (DOCA) and angiotensin II (Ang II) in wild-type (WT) and CCR5-deficient mice.ResultsCCR5 expression was increased in renal cortex and cardiac tissue as measured by quantitative PCR. Systolic blood pressure and renal function did not differ between hypertensive CCR5(-/-) and WT mice. DOCA + Ang II induced massive albuminuria and glomerular injury but no difference was found between CCR5(-/-) and WT mice. In addition, no difference was found for renal inflammation as measured by infiltrating T cells, macrophages, and CCL2 expression. The renal expression of the CCR5 ligands, CCL3, and CCL5 was increased in the kidney of hypertensive mice. For CCL3 the increase was significantly higher in CCR5(-/-) than in WT mice. DOCA + Ang II induced cardiac damage as assessed by heart weight, cardiac fibrosis as well as expression of fetal and matrix components but no significant difference was found between CCR5(-/-) and WT mice.ConclusionsCCR5 deficiency does not influence hypertensive renal and cardiac end-organ damage. Cells that infiltrate by expression of CCR5 are either not pathogenic or CCR5-positive leukocytes can migrate via alternative chemokine receptors. Beneficial effects of CCR5 antagonists in hypertension are most likely due to unspecific effects of the antagonists. Possibly, other chemokine receptors in concert with CCR5 are important for hypertensive injury.American Journal of Hypertension 2012; doi:10.1038/ajh.2011.243.

• TFAP2E-DKK4 and chemoresistance in colorectal cancer.

  Authors: Matthias P A Ebert, Marc Tänzer, Benjamin Balluff, Elke Burgermeister, Antje Karen Kretzschmar, David J Hughes, Reimo Tetzner, Catherine Lofton-Day, Robert Rosenberg, Anke C Reinacher-Schick [......] Ralf Hofheinz, Christoph Röcken, Gisela Keller, Rupert Langer, Katja Specht, Rainer Porschen, Jan Stöhlmacher-Williams, Tibor Schuster, Philipp Ströbel, Roland M Schmid

  The New England journal of medicine. 01/2012; 366(1):44-53.

  Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the geneChemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy. We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation. TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism. TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).

• Rare solid tumors of the pancreas as differential diagnosis of pancreatic adenocarcinoma.

  Authors: Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann

  JOP : Journal of the pancreas. 01/2012; 13(3):268-77.

  Rare solid tumors of the pancreas can be misinterpreted as primary pancreatic cancer. The aim of this study was to report our experience in the treatment of patients with rare tumor lesions of theRare solid tumors of the pancreas can be misinterpreted as primary pancreatic cancer. The aim of this study was to report our experience in the treatment of patients with rare tumor lesions of the pancreas and to discuss clinical and pathological characteristics in the context of the role of surgery. Data from patients of our prospective data-base with rare benign and malignant tumors of the pancreas, treated in our division from January 2004 to August 2010, were analyzed retrospectively. One-thousand and ninety-eight patients with solid tumors of the pancreas underwent pancreatic surgery. In 19 patients (10 women, 9 men) with a mean age of 57 years (range: 20-74 years) rare pancreatic tumors (metastasis, solid pseudopapillary tumor, teratoma, hemangioma, accessory spleen, lymphoepithelial cyst, hamartoma, sarcoidosis, yolk sac tumor) were the reason for surgical intervention. If rare benign and malignant pancreatic tumors, intrapancreatic metastasis, as well as pancreatic malformations or other abnormalities, present themselves as solid masses of the pancreas, they constitute an important differential diagnosis to primary pancreatic neoplasia, e.g. pancreatic ductal adenocarcinoma. Clinical imaging techniques cannot always rule out malignancy, thus operative exploration often remains the treatment of choice to provide the correct diagnosis and initiate adequate surgical therapy.

• The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ss-catenin signaling pathway.

  Authors: Johanna Munding, Wibke Ziebarth, Christian P Pox, Svetlana Ladigan, Markus Reiser, Dietrich Hüppe, Linda Brand, Wolff Schmiegel, Andrea Tannapfel, Anke C Reinacher-Schick

  Carcinogenesis. 12/2011; 33(3):637-43.

  Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk inSurveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.

• Histomorphological features of the pancreatic remnant as independent risk factors for postoperative pancreatic fistula: a matched-pairs analysis.

  Authors: Orlin Belyaev, Johanna Munding, Torsten Herzog, Dominique Suelberg, Andrea Tannapfel, Wolfgang E Schmidt, Christophe A Mueller, Waldemar Uhl

  Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 11/2011; 11(5):516-24.

  Postoperative pancreatic fistula (POPF) is a major complication after resective pancreatic surgery. This study aimed to identify histomorphological features of the pancreatic remnant as independentPostoperative pancreatic fistula (POPF) is a major complication after resective pancreatic surgery. This study aimed to identify histomorphological features of the pancreatic remnant as independent determinants for the development of POPF. Twenty-five patients, 3.6% of 696 resections over a period of 5 years, who developed POPF were matched for age, gender, diagnosis, comorbidities, surgeon and procedure with 25 controls without POPF. Pancreatic duct size and index, fibrosis grade, fat content, edema, and signs of chronic and acute inflammation were measured in frozen sections of the resection margin and were then compared. The POPF rate was 12.2 and 2.6% after distal pancreatectomy and pancreatoduodenectomy, respectively. The POPF group was characterized by a longer ICU and total postoperative stay, higher rate of reoperations and complications. Their pancreata were softer at palpation (88 vs. 56%). Their pancreatic duct was smaller (2.5 vs. 3.2 mm) and their pancreatic fat content higher (16 vs. 8%). High inter- and intralobular fat content, small duct size, low interlobular fibrosis grade and lack of signs of chronic pancreatitis were predictors of POPF development. A score including these parameters identified high-risk patients with a sensitivity of 92% and a specificity of 84%. Histomorphological features of the pancreatic remnant play an independent role as risk factors for the development of POPF. A simple histological score based on the frozen sections may already intraoperatively predict the risk of POPF development.

• Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma.

  Authors: Johanna B Munding, Alex T Adai, Abdelouahid Maghnouj, Aleksandra Urbanik, Hannah Zöllner, Sven T Liffers, Ansgar M Chromik, Waldemar Uhl, Anna E Szafranska-Schwarzbach, Andrea Tannapfel, Stephan A Hahn

  International journal of cancer. Journal international du cancer. 09/2011;

  Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis resulting from being diagnosed at an advanced stage. Accurate early diagnosis and new therapeutic modalities are thereforePancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis resulting from being diagnosed at an advanced stage. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. MicroRNAs (miRNAs), considered a new class of biomarkers and therapeutic targets, may be able to fulfill those needs. Combining tissue microdissection with global miRNA array analyses, cell type-specific miRNA expression profiles were generated for normal pancreatic ductal cells, acinar cells, PDAC cells derived from xenografts and also from macrodissected chronic pancreatitis (CP) tissues. We identified 78 miRNAs differentially expressed between ND and PDAC cells providing new insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development. Having filtered miRNAs which are upregulated in the three pairwise comparisons of PDAC vs. ND, PDAC vs. AZ and PDAC vs. CP, we identified 15 miRNA biomarker candidates including miR-135b. Using relative qRT-PCR to measure miR-135b normalized to miR-24 in 75 FFPE specimens (42 PDAC and 33 CP) covering a broad range of tumor content, we discriminated CP from PDAC with a sensitivity and specificity of 92.9% [95% CI=(80.5, 98.5)] and 93.4% [95% CI=(79.8, 99.3)], respectively. Furthermore, the area under the curve (AUC) value reached of 0.97 was accompanied by positive and negative predictive values of 95% and 91%, respectively. In conclusion, we report pancreatic cell-specific global miRNA profiles, which offer new candidate miRNAs to be exploited for functional studies in PDAC. Furthermore, we provide evidence that miRNAs are well-suited analytes for development of sensitive and specific aid-in-diagnosis tests for PDAC.

• MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B.

  Authors: Sven-T Liffers, Johanna B Munding, Markus Vogt, Jan D Kuhlmann, Berlinda Verdoodt, Sandeep Nambiar, Abdelouahid Maghnouj, Alireza Mirmohammadsadegh, Stephan A Hahn, Andrea Tannapfel

  Laboratory investigation; a journal of technical methods and pathology. 06/2011; 91(10):1472-9.

  MicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the presentMicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the present study, we investigated the transcription status of miRNA-148a (miR-148a) in human pancreatic ductal adenocarcinoma (PDAC) and its role in the regulation of the dual specificity protein phosphatase CDC25B. We observed that miR-148a exhibited a significant 4-fold down-regulation in PDAC as opposed to normal pancreatic ductal cells. In addition, we observed that stable lentiviral-mediated overexpression of miR-148a in the pancreatic cancer cell line IMIM-PC2, inhibited tumor cell growth and colony formation. Furthermore, CDC25B was identified as a potential target of miR-148a by in silico analysis using PicTar, Targetscan and miRanda in conjunction with gene ontology analysis. The proposed interaction between miR-148a and the 3' untranslated region (UTR) of CDC25B was verified by in-vitro luciferase assays. We demonstrate that the activity of a luciferase reporter containing the 3'UTR of CDC25B was repressed in the presence of miR-148a mimics, confirming that miR-148a targets the 3'UTR of CDC25B. Finally, CDC25B was down-regulated at the protein level in miR-148a overexpressing IMIM-PC2-cells, and in transiently transfected pancreatic cell lines (as detected by Western blot analysis), as well as in patient tumor samples (as detected by immunohistochemistry). In summary, we identified CDC25B as a novel miR-148a target which may confer a proliferative advantage in PDAC.

• Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy: a translational study of the AIO colorectal study group.

  Authors: Alexander Baraniskin, Johanna Munding, Karsten Schulmann, Dominik Meier, Rainer Porschen, Hendrik-Tobias Arkenau, Ullrich Graeven, Wolff Schmiegel, Andrea Tannapfel, Anke Reinacher-Schick

  Clinical colorectal cancer. 03/2011; 10(1):24-9.

  SMAD4 is a polypeptide with tumor suppressor function being investigated as a prognostic biomarker in Union Internationale Contre le Cancer stages II and III in previous studies, but its role as aSMAD4 is a polypeptide with tumor suppressor function being investigated as a prognostic biomarker in Union Internationale Contre le Cancer stages II and III in previous studies, but its role as a prognostic marker in stage IV colorectal cancer (CRC) is still undefined. We investigated the prognostic value of reduced SMAD4 expression in patients with metastatic (mCRC) under first-line oxaliplatin-containing combination chemotherapy. Tumor samples were obtained from patients who took part in a prospective randomized phase III chemotherapy trial of the Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society colorectal study group, comparing the use of capecitabine plus oxaliplatin with infusional 5-fluorouracil (5-FU) plus oxaliplatin as first-line therapy in mCRC. SMAD4 expression was determined by immunohistochemistry. Tumor tissues from 230 patients were obtained. Reduced SMAD4 expression was identified in 34% of samples. Patients with reduced nuclear SMAD4 expression in tumor tissue showed a shorter progression-free survival (PFS; 7.0 months vs. 8.9 months; P = .024) and overall survival (OS; 13.9 months vs. 17.8 months; P = .044) compared with patients retaining SMAD4 expression. The effect of SMAD4 expression on PFS and OS could be demonstrated in univariate and multivariate analyses. Our data demonstrate the importance of reduced SMAD4 expression in patients with mCRC receiving chemotherapy with oxaliplatin and 5-FU.

• Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas.

  Authors: Markus Vogt, Johanna Munding, Martha Grüner, Sven-Thorsten Liffers, Berlinda Verdoodt, Jennifer Hauk, Lars Steinstraesser, Andrea Tannapfel, Heiko Hermeking

  Virchows Archiv : an international journal of pathology. 01/2011; 458(3):313-22.

  The microRNA encoding genes miR-34a and miR-34b/c represent direct p53 target genes and possess tumor suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. WeThe microRNA encoding genes miR-34a and miR-34b/c represent direct p53 target genes and possess tumor suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. We previously reported that the miR-34a gene is subject to epigenetic inactivation by CpG methylation of its promoter region in primary prostate cancer and melanomas, and in 110 different cancer cell lines of diverse origin. Here we analyzed the methylation status of miR-34a and miR-34b/c in additional primary tumors of divergent sites. We found methylation of miR-34a or miR-34b/c in formalin-fixed, paraffin-embedded (FFPE) tumor samples from 178 patients with the following frequencies: colorectal cancer (74% miR-34a, 99% miR-34b/c; n = 114), pancreatic cancer (64%, 100%; n = 11), mammary cancer (60%, 90%; n = 10), ovarian cancer (62%, 69%; n = 13), urothelial cancer (71%, 57%; n = 7), and renal cell cancer (58%, 100%; n = 12). Furthermore, soft tissue sarcomas showed methylation of miR-34 gene promoters in FFPE samples (64%, 45%; n = 11), in explanted, cultured cells (53%, 40%; n = 40), and in frozen tissue samples (75%, 75%, n = 8). In the colorectal cancer samples a statistically significant correlation of miR-34a methylation and the absence of p53 mutation was detected. With the exception of sarcoma cell lines, the inactivation of miR-34a and miR-34b/c was concomitant in most cases. These results show that miR-34 inactivation is a common event in tumor formation, and suggest that CpG methylation of miR-34a and miR-34-b/c may have diagnostic value. The mutual exclusiveness of miR-34a methylation and p53 mutation indicates that miR-34a inactivation may substitute for loss of p53 function in cancer.

• Pathohistological diagnosis and differential diagnosis.

  Authors: Iris Tischoff, Matthias Neid, Volker Neumann, Andrea Tannapfel

  Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer. 01/2011; 189:57-78.

  Malignant mesothelioma is a rare aggressive tumour arising from mesothelial cells of the pleural and peritoneal cavity including pericardium and tunica vaginalis testis. Malignant mesothelioma occursMalignant mesothelioma is a rare aggressive tumour arising from mesothelial cells of the pleural and peritoneal cavity including pericardium and tunica vaginalis testis. Malignant mesothelioma occurs predominantly in men (>90%). Asbestos exposure is the best known and evaluated risk factor with a long latency period between exposure and onset of malignant mesothelioma ranging from 15 to 60 years. Exposure to erionite leads to higher incidences of mesothelioma and play an important role in environmental exposure (Turkey). Other possible risk factors are radiation, recurrent pleuritis/peritonitis and simian virus 40 (SV 40).Malignant pleural mesothelioma is most common, whereas malignant peritoneal mesothelioma accounts only for 6-10%. Infrequent sites of origin are the pericardium and tunica vaginalis in 1-2%.Malignant mesothelioma shows either diffuse growth pattern or occurs as a localised tumour mass. Diffuse type represents an aggressive tumour with poor prognosis and is incurable in most cases.According to the WHO classification, three histological subtypes are distinguished: epithelioid, sarcomatoid and biphasic malignant mesothelioma.Rare variants are desmoplastic type, a subtype of sarcomatoid mesothelioma, undifferentiated type and deciduoid type. Epithelioid type is the most frequent one, but biphasic malignant mesothelioma occurs in 30%. Pure sarcomatoid or biphasic type is seen less frequently in malignant peritoneal mesothelioma than in its pleural counterpart.Well-differentiated papillary mesothelioma is a generally non-invasive mesothelioma with low malignant potential that arises mostly in females in the peritoneal cavity. Histological type is an important prognostic marker. Longest survival is seen in patients with epithelioid malignant mesothelioma. Sarcomatoid subtype has the worst prognosis.Malignant mesothelioma shows macroscopical and microscopical similarities to benign lesions and other malignancies. Therefore, reactive mesothelial proliferations on the one hand and secondary tumours resembling mesothelial cells as well as benign or rare mesothelial tumours on the other hand have to be distinguished. Additional immunohistochemistry is essential in histopathological assessment using a marker panel of antibodies.

• Mesothelioma and analysis of tissue fiber content.

  Authors: Volker Neumann, Stefan Löseke, Andrea Tannapfel

  Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer. 01/2011; 189:79-95.

  The strong relationship between mesothelioma and asbestos exposure is well established. The analysis of lung asbestos burden by light and electron microscopy assisted to understand the increasedThe strong relationship between mesothelioma and asbestos exposure is well established. The analysis of lung asbestos burden by light and electron microscopy assisted to understand the increased incidence of mesothelioma in asbestos mining and consuming nations.The data on the occupational exposure to asbestos are important information for the purpose of compensation of occupational disease No. 4105 (asbestos-associated mesothelioma) in Germany.However, in many cases the patients have forgotten conditions of asbestos exposure or had no knowledge about the used materials with components of asbestos. Mineral fiber analysis can provide valuable information for the research of asbestos-associated diseases and for the assessment of exposure. Because of the variability of asbestos exposure and long latency periods, the analysis of asbestos lung content is a relevant method for identification of asbestos-associated diseases. Also, sources of secondary exposure, so called "bystander exposition" or environmental exposure can be examined by mineral fiber analysis.Household contacts to asbestos are known for ten patients (1987-2009) in the German mesothelioma register; these patients lived together with family members working in the asbestos manufacturing industry.Analysis of lung tissue for asbestos burden offers information on the past exposure. The predominant fiber-type identified by electron microscopy in patients with mesothelioma is amphibole asbestos (crocidolite or amosite). Latency times (mean 42.5 years) and mean age at the time of diagnose in patients with mesothelioma are increasing (65.5 years). The decrease of median asbestos burden of the lung in mesothelioma patients results in disease manifestation at a higher age.Lung dust analyses are a relevant method for the determination of causation in mesothelioma. Analysis of asbestos burden of the lung and of fiber type provides insights into the pathogenesis of malignant mesothelioma. The most important causal factor for the development of mesothelioma is still asbestos exposure.

• Endogenous hyperinsulinaemia in insulinoma patients is not associated with changes in beta-cell area and turnover in the tumor-adjacent pancreas.

  Authors: Chiara Montemurro, Christina U Köhler, Waldemar Uhl, Andrea Tannapfel, Wolfgang E Schmidt, Enzo Bonora, Juris J Meier

  Regulatory peptides. 12/2010; 165(2-3):180-5.

  Insulin therapy has been suggested to preserve beta-cell mass in patients with diabetes through the mechanisms of beta-cell rest as well as direct effects on beta-cell proliferation. However, dataInsulin therapy has been suggested to preserve beta-cell mass in patients with diabetes through the mechanisms of beta-cell rest as well as direct effects on beta-cell proliferation. However, data about the effects of hyperinsulinism on beta-cell mass and turnover in humans are sparse. Pancreatic tissue specimens from five patients with pancreatic insulinomas and ten non-diabetic control subjects were examined. Pancreatic sections were stained for insulin, Ki67 (replication) and TUNEL (apoptosis), and quantitative morphometric analyses were performed. Fractional beta-cell area was 1.11%±0.67% in the tumor-free pancreatic tissue of the insulinoma patients and 0.78%±0.26% in the control group (p=0.19). There also were no differences in islet size (p=0.62) or beta-cell nuclear diameter (p=0.20). Beta-cell replication and apoptosis were infrequently detected, without any measurable differences between the groups. There were also no differences in percentage of duct cells expressing insulin (p=0.47), a surrogate marker for islet neogenesis. Beta-cell area and turnover are not significantly altered in the proximity of intra-pancreatic insulinomas. Future in vivo studies, ideally employing larger animal models, are warranted to further evaluate the impact of exogenous insulin on beta-cell turnover.

• Appendiceal carcinoid tumor with lymph node metastasis in a child: case report and review of the literature.

  Authors: Grigore Cernaianu, Andrea Tannapfel, Joseph Nounla, Roberto Gonzalez-Vasquez, Thomas Wiesel, Ralf-Bodo Tröbs

  Journal of pediatric surgery. 11/2010; 45(11):e1-5.

  Most appendiceal carcinoids (ACs) in children present without lymph node metastasis. Lymph node metastasis is rarely present when primary tumor diameter exceeds 1 cm. We present the extraordinaryMost appendiceal carcinoids (ACs) in children present without lymph node metastasis. Lymph node metastasis is rarely present when primary tumor diameter exceeds 1 cm. We present the extraordinary case of an AC with a primary tumor diameter of 0.7 cm and infiltration of the mesentery, as well as 1 positive lymph node of the mesentery in a 14-year-old boy. Besides adding a rare case, we review the data published in the current literature on AC with lymph node metastasis in children and summarize up-to-date guidelines for diagnostic workup, therapy, and follow-up.

• [Gastrointestinal tract - pathology of early cancers].

  Authors: Iris Tischoff, Andrea Tannapfel

  Zentralblatt für Chirurgie. 10/2010; 135(5):385-8.

• Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas.

  Authors: Christina U Köhler, Marvin Olewinski, Andrea Tannapfel, Wolfgang E Schmidt, Helga Fritsch, Juris J Meier

  American journal of physiology. Endocrinology and metabolism. 10/2010; 300(1):E221-30.

  β-Cell regeneration declines with aging, but the molecular mechanisms controlling β-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins inβ-Cell regeneration declines with aging, but the molecular mechanisms controlling β-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins in prenatal and adult tissue and examined the association of these proteins with β-cell replication. Pancreatic tissue from a total of 20 human fetuses and adults was stained for Ki67, cyclin D3, p16 and p27, and insulin. The β-cellular expression of these cell cycle proteins was determined. The frequency of β-cell replication was lower in adult compared with prenatal β-cells (<0.5 vs. 3.4 ± 0.5%, respectively; P < 0.0001). p16 was sporadically expressed in prenatal β-cells (8.0 ± 1.1%) but highly enriched in adult β-cells (63.1 ± 5.2%, P < 0.0001). Likewise, the expression of p27 was much lower in prenatal β-cells (1.7 ± 0.4 vs. 44.1 ± 5.4%, respectively, P < 0.0001), and cyclin D3 expression increased from 24.2 ± 4.1 to 47.25 ± 5.0%, respectively (P < 0.001), with aging. The expression of all three proteins was significantly correlated with each other (P < 0.01 and r > 0.75, respectively). The strong expression of cyclin D3 in adult human β-cells and its correlation to p27 and p16 suggest a positive role in human β-cell cycle regulation. p16 and p27 appear to restrict β-cell replication with aging. The age dependency of cell cycle regulation in human β-cells might explain the reduced β-cell regeneration in adult humans.

• Proinsulin levels in patients with pancreatic diabetes are associated with functional changes in insulin secretion rather than pancreatic beta-cell area.

  Authors: Thomas G K Breuer, Bjoern A Menge, Matthias Banasch, Waldemar Uhl, Andrea Tannapfel, Wolfgang E Schmidt, Michael A Nauck, Juris J Meier

  European journal of endocrinology / European Federation of Endocrine Societies. 10/2010; 163(4):551-8.

  Hyperproinsulinaemia has been reported in patients with type 2 diabetes. It is unclear whether this is due to an intrinsic defect in β-cell function or secondary to the increased demand on theHyperproinsulinaemia has been reported in patients with type 2 diabetes. It is unclear whether this is due to an intrinsic defect in β-cell function or secondary to the increased demand on the β-cells. We investigated whether hyperproinsulinaemia is also present in patients with secondary diabetes, and whether proinsulin levels are associated with impaired β-cell area or function. Thirty-three patients with and without diabetes secondary to pancreatic diseases were studied prior to pancreatic surgery. Intact and total proinsulin levels were compared with the pancreatic β-cell area and measures of insulin secretion and action. Fasting concentrations of total and intact proinsulin were similar in patients with normal, impaired (including two cases of impaired fasting glucose) and diabetic glucose tolerance (P=0.58 and P=0.98 respectively). There were no differences in the total proinsulin/insulin or intact proinsulin/insulin ratio between the groups (P=0.23 and P=0.71 respectively). There was a weak inverse association between the total proinsulin/insulin ratio and pancreatic β-cell area (r(2)=0.14, P=0.032), whereas the intact proinsulin/insulin ratio and the intact and total proinsulin levels were unrelated to β-cell area. However, a strong inverse relationship between homeostasis model assessment index of β-cell function and both the total and the intact proinsulin/insulin ratio was found (r(2)=0.55 and r(2)=0.48 respectively). The association of insulin resistance (IR) with intact proinsulin was much weaker than the correlation with fasting insulin. Hyperproinsulinaemia is associated with defects in insulin secretion rather than a reduction in β-cell area. The weak association between intact proinsulin and IR argues against the usefulness of this parameter in clinical practice.

• [Effects of asbestos fiber dust exposure on lung function - a systematic review].

  Authors: Volker Neumann, Andrea Tannapfel

  Pneumologie (Stuttgart, Germany). 07/2010; 64(7):430-2; author reply 436-41.

• Validation of different replication markers for the detection of beta-cell proliferation in human pancreatic tissue.

  Authors: Christina U Köhler, Alexander Kreuter, Martha C Rozynkowski, Tim Rahmel, Waldemar Uhl, Andrea Tannapfel, Wolfgang E Schmidt, Juris J Meier

  Regulatory peptides. 06/2010; 162(1-3):115-21.

  Beta-cell-regeneration is considered as a future option for the therapy of diabetes, but the detection of beta-cell replication in human pancreas is still challenging. Therefore, the expression ofBeta-cell-regeneration is considered as a future option for the therapy of diabetes, but the detection of beta-cell replication in human pancreas is still challenging. Therefore, the expression of Ki67, PCNA and MCM-7 in human pancreatic tissue was quantified in order to validate their use as beta-cell replication markers. Human pancreatic tissue samples were stained for Ki67, PCNA, MCM7, insulin and nuclei, and the expression of replication markers was quantified. Co-expression of the markers was assessed by four-colour fluorescence-staining. All three markers could be detected in endocrine and exocrine tissue. There was a significant correlation between the expression frequencies of all three markers in the exocrine tissue (r>0.49, respectively) and in beta-cells (r>0.95, respectively). A subset of beta-cells with differential expression of the three replication markers was identified. Quantitative analyses revealed that only 36-55% of all exocrine cells expressed two markers at the same time. The expression of Ki67, MCM-7 and PCNA in adult human pancreas is highly correlated, but the labelling of individual cells differs between the markers. The analysis of a combination of markers, preferably MCM7 and Ki67, appears to yield the most reliable results for the determination of beta-cell replication and may allow for a differentiation of cell cycle stages.