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  • 1
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    Thieme Verlag Stuttgart
    Gastroenterologie 1777-1781 
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  • 2
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; DISEASE ; NEW-YORK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; cell line ; TISSUE ; validation ; LINES ; MARKER ; TISSUES ; tumour ; CELL-LINES ; BREAST-CANCER ; TARGET ; immunohistochemistry ; gene expression ; affymetrix ; CELL-LINE ; LINE ; MARKERS ; CARCINOMAS ; adenocarcinoma ; OVEREXPRESSION ; PERIPHERAL-BLOOD ; GASTRIC-CANCER ; ADAM9 ; CDNA MICROARRAYS ; cell lines ; expression profiling ; HUMAN GENES ; K-RAS ; METALLOPROTEASE-DISINTEGRIN ; microarray hybridisation ; microdissection ; OLIGONUCLEOTIDE ARRAYS ; pancreatic cancer ; pancreatic carcinoma ; SERIAL ANALYSIS
    Abstract: In a search for new molecular markers of pancreatic ductal adenocarcinoma (PDAC), we compared the gene expression profiles of seven pancreatic carcinomas and one carcinoma of the papilla Vateri with those of duct cells from three non-neoplastic pancreatic tissues. In addition, the human pancreatic duct cell line and five PDAC cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2, HPAF) were examined. RNA was extracted from microdissected tissue or cultured cell lines and analysed using a custom-made Affymetrix Chip containing 3023 genes, of which 1000 were known to be tumour associated. Hierarchical clustering revealed 81 differentially expressed genes. Of all the genes, 26 were downregulated in PDAC and 14 were upregulated in PDAC. In PDAC cell lines versus normal pancreatic duct cells, 21 genes were downregulated and 20 were upregulated. Of these 81 differentially expressed genes, 15 represented human genes previously implicated in the tumourigenesis of PDAC. From the genes that were so far not known to be associated with PDAC tumorigenesis, we selected ADAM9 for further validation because of its distinct overexpression in tumour tissue. Using immunohistochemistry, the over-expressed gene, ADAM9, was present in 70% of the PDACs analysed. In conclusion, using microarray technology we were able to identify a set of genes whose aberrant expression was associated with PDAC and may be used to target the disease
    Type of Publication: Journal article published
    PubMed ID: 12942322
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  • 3
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; tumor ; carcinoma ; CELL-PROLIFERATION ; Germany ; PROTEINS ; DIFFERENTIATION ; EPITHELIA ; TISSUE ; prognosis ; LESIONS ; NEOPLASIA ; MUTATION ; p53 ; PCR ; RESECTION ; MUTATIONS ; CARCINOMAS ; adenocarcinoma ; ADENOCARCINOMAS ; intraepithelial neoplasia ; K-RAS ; Bcl-2 ; BCL-2 EXPRESSION ; GENE-MUTATIONS ; K-ras mutation ; LACKING ; pancreatic ductal carcinoma ; PanIN
    Abstract: Introduction: K-ras mutations are present in most ductal adenocarcinomas (DACs) of the pancreas and may also be found in ductal precursor lesions and even in normal ductal epithelium. The question is addressed whether mutated K-ras interferes with the regulation of apoptosis or proliferation. Methodology: In 50 Whipple resection specimens, tissue adjacent to DACs was histologically screened for ductal lesions that were classified as pancreatic intraepithelial neoplasia (PanIN) according to WHO criteria. PanIN lesions were microdissected and analyzed for K-ras mutations by means of a nested PCR. Apoptosis was identified by the TUNEL method. Proliferation and the expression of p53 and Bcl-2 were immunohistochemically determined. Results: On average, 30% of PanIN-1A and B lesions showed mutated K-ras. In PanIN-2 and PanIN-3 lesions, the rate of mutated K-ras increased to 45% and 56%, respectively. Apoptosis was present only in 2 of 26 PanIN-3 lesions. There was a gradual increase in proliferative activity from PanIN-1 to PanIN-3. p53 expression was found in 11% of PanIN-2 and 44% of PanIN-3 lesions. Bcl-2 expression was lacking in PanIN lesions of all grades. In invasive DACs, the apoptotic rate correlated with the degree of tumor differentiation and proliferation, with grade 3 carcinomas showing the highest apoptotic rate. Conclusion: In view of the discrepancy between the considerable rate of K-ras mutations in PanIN-1 and PanIN-2 lesions and the lack of apoptosis and Bcl-2 expression, coupled with very low p53 immunoreactivity, it is unlikely that mutated K-ras affects the apoptotic activity in low grade PanINs. Instead, K-ras mutations may have an effect on proliferation in PanIN-1 and PanIN-2
    Type of Publication: Journal article published
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  • 4
    Keywords: tumor ; Germany ; DIAGNOSIS ; imaging ; GENE ; TUMORS ; MARKER ; treatment ; MUTATION ; MARKERS ; MUTATIONS ; tomography ; adenocarcinoma ; sensitivity ; pathology ; COMPLICATIONS ; INITIATION ; COLONY-STIMULATING FACTOR ; GENE-MUTATIONS ; pancreas ; DUCTAL ADENOCARCINOMA ; methods ; pancreatic ; complication ; PHASE-I TRIAL ; FINE-NEEDLE-ASPIRATION ; K-RAS MUTATIONS ; technique ; CYSTIC LESIONS ; DEGUM INQUIRY ; ENDOSCOPIC ULTRASOUND ; endosonographically guided biopsy ; EUS-GUIDED FNA ; fine needle biopsy ; HIGH-SENSITIVITY ; indications ; MUCINOUS TUMORS ; NEEDLE BIOPSIES ; pancreas biopsy ; Sensitivity and Specificity
    Abstract: Pancreatic biopsy is an invasive diagnostic method that is only performed when all other diagnostic measures for establishing the diagnosis of a tumorous lesion of the pancreas have failed. Because of the advances in modern imaging techniques, fine needle biopsy of the pancreas guided by ultrasonography, computer tomography or endosonography has become a reliable method that allows the diagnosis of ductal adenocarcinoma or any of the other, rarer pancreatic tumors with high sensitivity and specificity. Complications are rare, particularly with the endosonographically guided biopsy. A new biopsy indication is the demonstration of certain markers or gene mutations that are needed for the initiation of special treatments, e.g. EGFR-Cetuximab
    Type of Publication: Journal article published
    PubMed ID: 15630570
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  • 5
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    Keywords: CELLS ; IN-VITRO ; BLOOD ; carcinoma ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; MODEL ; PERFUSION ; THERAPY ; VITRO ; VIVO ; BLOOD-FLOW ; pig ; TRANSPLANTATION ; animals ; blood flow ; FLOW ; EFFICACY ; chemotherapy ; DAMAGE ; arteries ; THERAPEUTIC EFFICACY ; CARCINOMAS ; ARTERY ; BODY ; pancreatic carcinoma ; FEASIBILITY ; DUCTAL CARCINOMA ; 2-DECHLOROETHYLIFOSFAMIDE ; 3-DECHLOROETHYLIFOSFAMIDE ; 4-HYDROXYIFOSFAMIDE ; angiographical targeting ; CARDIOPULMONARY BYPASS ; CYP2B1 ; FRACTIONATED INTRAVENOUS IFOSFAMIDE ; ifosfamide ; intra-arterial application ; pig pancreas
    Abstract: Background: The therapeutic efficacy of intratumoral instillation of genetically engineered, CYP2B1-expressing, microencapsulated cells in combination with ifosfamide had been previously demonstrated in xeno-grafted human pancreatic ductal carcinomas [Gene Ther 1998;5:1070-1078]. Prior to a clinical study, the feasibility of an intra-arterial application of microencapsulated cells to the pancreas and its consequences to the organ had to be evaluated. Material and Methods: Microencapsulated, CYP2B1-producing cells were instilled both in vivo (transfemoral angiographical access) and in vitro (perfusion model) in the splenic lobe of the pig pancreas. In vivo, animals were monitored clinically for 7 days, then treated with ifosfamide and sacrificed. In vitro, ifosfamide was administered intra-arterially. Results: In all animals, 100 microcapsules could be instilled safely via the femoral route without clinical, biochemical or histological signs of pancreatitis. Histological examination revealed partial obstruction of small arteries by the capsules, without causing any parenchymal damage. In vitro, instillation reduced blood flow by half. Ifosfamide, also in combination with the capsules, did not add any damage to the pancreas. Conclusion: Intra-arterial instillation of microencapsulated cells to the pig pancreas is feasible and safe. Neither pancreatitis, foreign body reactions nor circulatory disturbances were observed. Clinical application of this genetically enhanced chemotherapeutic method seems possible. Copyright (C) 2003 S. Karger AG, Basel and IAP
    Type of Publication: Journal article published
    PubMed ID: 12649565
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; carcinoma ; CELL ; Germany ; VITRO ; SYSTEM ; NEW-YORK ; POPULATION ; cell line ; DIFFERENTIATION ; LINES ; TIME ; MARKER ; ANTIGEN ; CELL-LINES ; polymorphism ; culture ; NO ; score ; ASSAY ; MEMBRANE ; NUMBER ; MUTATION ; CELL-LINE ; LINE ; MARKERS ; p53 ; TUMOR-SUPPRESSOR GENE ; immunocytochemistry ; intermediate filaments ; CARCINOEMBRYONIC ANTIGEN ; adenocarcinoma ; ESTABLISHMENT ; comparative studies ; cell lines ; K-RAS ; pancreatic carcinoma ; DUCTAL CARCINOMA ; LACKING ; pancreatic ductal carcinoma ; CELL POLARITY ; MUCIN ; EXOCRINE PANCREAS ; MUCINOUS NONCYSTIC CARCINOMA ; ultrastructure
    Abstract: There are a large number of stable pancreatic ductal carcinoma cell lines that are used by researchers worldwide. Detailed data about their differentiation status and growth features are, however, often lacking. We therefore attempted to classify commonly used pancreatic carcinoma cell lines according to defined cell biological criteria. Twelve pancreatic ductal adenocarcinoma cell lines were cultured as monolayers and spheroids and graded according to their ultrastructural features. The grading system was based on the integrity of membrane structures and on the presence of mucin granules, cell organelles, nuclear and cellular polymorphism, cell polarity, and lumen formation. On the basis of the resulting scores the cell lines were classified as well, moderately, or poorly differentiated. In addition, immunocytochemistry was performed for the markers cytokeratin 7, 8, 18, 19, carcinoembryonic antigen, MUC1 MUC2, MUC5, and MUC6. The population doubling time of monolayer cultures, determined by a tetrazolium salt based proliferation assay was correlated with the ultrastructural grade. The grading of the ultrastructural features of the monolayers, and particularly of the spheroids, revealed that Capan-1 and Capan-2 cells were well differentiated; Colo357, HPAF-2, Aspc-1, A818-4, BxPc3, and Panc89 cells were moderately differentiated and PancTu-1, Panc1, Pt45P1, and MiaPaCa-2 cells poorly differentiated. Membrane-bound MUC1 staining was a characteristic of well differentiated cell lines. The population doubling time of the monolayer cultures was related to the differentiation grade. No relationship was found between the p53, K-ras, DPC4/Smad4, or p16(INK4a) mutation status and the grade of differentiation. We conclude that the proposed ultrastructural grading system combined with the proliferative activity provides a basis for further comparative studies of pancreatic ductal adenocarcinoma cell lines
    Type of Publication: Journal article published
    PubMed ID: 12692724
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  • 8
    Abstract: OBJECTIVES: Autoimmune pancreatitis (AIP) is thought to be an immune-mediated inflammatory process, directed against the epithelial components of the pancreas. The objective was to identify novel markers of disease and to unravel the pathogenesis of AIP. METHODS: To explore key targets of the inflammatory process, we analyzed the expression of proteins at the RNA and protein level using genomics and proteomics, immunohistochemistry, western blot, and immunoassay. An animal model of AIP with LP-BM5 murine leukemia virus-infected mice was studied in parallel. RNA microarrays of pancreatic tissue from 12 patients with AIP were compared with those of 8 patients with non-AIP chronic pancreatitis. RESULTS: Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of the SPINK1 gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen. CONCLUSIONS: These data indicate that the immune-mediated process characterizing AIP involves pancreatic acinar cells and their secretory enzymes such as trypsin isoforms. Demonstration of trypsinogen autoantibodies may be helpful for the diagnosis of AIP.
    Type of Publication: Journal article published
    PubMed ID: 20407433
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  • 9
    Abstract: The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p 〈 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.
    Type of Publication: Journal article published
    PubMed ID: 28802189
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  • 10
    Keywords: CELLS ; CELL ; Germany ; DIAGNOSIS ; imaging ; DISEASE ; DISEASES ; DISTINCT ; PATIENT ; autoimmune diseases ; AUTOIMMUNE-DISEASE ; ASSOCIATION ; PLASMA ; NUMBER ; LYMPHOCYTES ; RESECTION ; CLINICAL PRESENTATION ; SERIES ; FREQUENT ; pathology ; AUTOANTIBODIES ; autoimmune pancreatitis ; BILE-DUCT ; chronic pancreatitis ; CROHNS-DISEASE ; DESTRUCTIVE CHRONIC-PANCREATITIS ; duct-destructive pancreatitis ; immune features ; lymphoplasmacytic pancreatitis ; PRIMARY BILIARY-CIRRHOSIS ; PRIMARY SCLEROSING CHOLANGITIS ; PSEUDOTUMOR ; RETROPERITONEAL FIBROSIS ; SJOGRENS-SYNDROME ; steroid ; STEROID-THERAPY
    Abstract: Introduction: In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjogren's disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. Aims: This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. Conclusions: As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis
    Type of Publication: Journal article published
    PubMed ID: 12826900
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