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A Tannapfel

Publications and source records attributed to A Tannapfel.

At least 55 records · Page 3Linked to original sources
PubMed2003

Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.

BACKGROUND: The Raf/MEK/ERK (mitogen activated protein kinase-MAPK) signal transduction cascade is an important mediator of a number of cellular fates, including growth, proliferation, and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. AIMS: The aim of this study was to elucidate a possible function of BRAF in liver tumours. METHODS: Mutations of BRAF and KRAS were evaluated in 25 hepatocellular carcinomas (HCC) and in 69 cholangiocarcinomas (CC) by direct DNA sequencing analyses after microdissection. The presence of active intermediates of the MAPK pathway was assessed immunohistochemically. The results obtained were correlated with histopathological variables and patient survival. RESULTS: Activating BRAF missense mutations were identified in 15/69 CC (22%) and in one case of tumour surrounding liver. KRAS mutations were found in 31 of 69 (45%) CC examined and in two cases of tumour surrounding non-neoplastic liver tissue. In HCC, neither BRAF nor KRAS mutations were detected. All 31 CC with KRAS mutations had an intact BRAF gene. We failed to observe a correlation between BRAF or KRAS mutations and histopathological factors or prognosis of patients. CONCLUSIONS: Our data indicate that BRAF gene mutations are a relatively common event in CC but not in HCC. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway, either by RAS or BRAF mutation, was detected in approximately 62% of all CC and is therefore one of the most frequent defects in cholangiocellular carcinogenesis.

Base Sequence↗
PubMed2003

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

In a 59-year-old patient, thyroid follicular cancer was diagnosed in two right-sided toxic thyroid nodules, which had presented clinically as unilateral thyroid autonomy. In addition, the patient had histologically proven lung metastases of thyroid cancer; however, these failed to exhibit iodine uptake and were resistant to radioiodine treatment. The functional activity of the thyroid nodules prompted us to screen for TSH receptor (TSHR) mutations, and the histological diagnosis of follicular carcinoma led us to search for the PAX8-PPARgamma1 rearrangement and mutations in the ras genes. Each thyroid nodule harboured a different TSHR mutation (large nodule, Asp633Tyr; small nodule, Phe631Ile). Presence of both mutations in one sample suggestive of local invasion of a thyroid carcinoma could not be demonstrated, although several specimens from different nodule locations were screened. Only the wild-type TSHR sequence was identified in the histologically normal left thyroid lobe, and no genetic alterations were found in the other investigated genes. No TSHR mutations were detected in the pulmonary metastases. This is the first case report of a patient with toxic follicular thyroid carcinoma harbouring two different TSHR mutations and presenting with non-functional lung metastases.

Adenocarcinoma, Follicular↗
PubMed2002

Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients.

Adenocarcinoma↗
PubMed2002

Carcinogen-specific mutation pattern in the p53 tumour suppressor gene in UV radiation-induced basal cell carcinoma.

OBJECTIVES: Basal cell carcinoma (BCC) is mainly caused by high and long-term UV radiation. UV radiation causes DNA damage in various genes. Mutations of the p53 tumour suppressor gene have been identified in a wide variety of human cancers. The aim of the study was to analyse specific p53 mutations in BCCs in workers exposed to high and long-term UV radiation. METHODS: The mutation pattern of the p53 tumour suppressor gene was analysed in tissue from 12 patients with UV-related BCC. All patients had a suspected occupational disease notified within the period 1995-1999. As a control, 20 BCC skin samples removed from areas definitively unexposed to sunlight were analysed. The specific mutations were determined by direct sequencing of codon 4 to 9 of the p53 gene in carcinomatous and adjacent non-neoplastic tissue after microdissection. Immunohistochemical analysis was performed to detect p53 protein. RESULTS: p53 mutations were detected in 7/12 cases (58%). Point mutations were found in six cases (50%). In one case a deletion of 24 base pairs was observed. The most frequent mutations we found were CC-->TT base-pair changes in four and C-->T mutations in two cases. Within the control group specific p53 mutations were found in 11 cases (55%) without any C-->T predominance. No case showed CC-->TT mutations. CONCLUSIONS: Mutations of the p53 tumour suppressor gene in UV-associated BCC are frequent events. A predominance of C-->T mutations and tandem CC-->TT base-pair changes were observed in the sunlight-exposed cases only supporting the idea of site-directed mutagenesis by UV radiation in human BCC.

Base Sequence↗
PubMed2002

[Parapharyngeal space-occupying lesions. Differential diagnosis based on case examples].

INTRODUCTION: Parapharyngeal tumors account for only 0.8% of all head and neck tumors which often presents the problem of preoperative diagnosis. Up to 80% of parapharyngeal tumors are benign. PATIENTS: Starting November 1995 to March 2001, 16 patients with parapharyngeal tumors and 1 retropharyngeal abscess were treated. The median age was 54 years. Only 2 patients demonstrated peripheral nerve lesions preoperatively. RESULTS: 17 tumors and the retropharyngeal abscess were excised via transcervical approach, with an extension by parotidectomy and temporary mandibular split in 1 case. Histological entities were pleomorphic adenomas in 5 cases, a ganglioneurinoma, neurinoma of the vagal nerve and metastasis of a squamous cell carcinoma in 2 patients each, furthermore neuroblastoma, extramedullary plasmocytoma, T-cell lymphoma, and hemangioma in 1 patient each. CONCLUSIONS: We demonstrate the differential diagnosis of parapharyngeal tumors as well as their diagnostic and therapeutic management. The tumors should be excised by a transcervical approach to protect cervical vessels and nerves, which is limited by a transoral approach.

Adolescent↗
PubMed2002

[Prognostic factors in head-neck carcinomas].

Squamous cell carcinoma of the head and neck is one of the most common human cancers with an unchanged high rate of mortality despite improved diagnostic and therapeutic methods of the past twenty years. Latest advances of molecular biological methods contributed to the understanding of the multistep process of carcinogenesis. Genetic instability, dysregulation of cell cycle and apoptosis as well as changes of oncogenes and tumor suppressor genes are involved in carcinogenesis. So far, molecular markers do not fulfill the desired requirement of clinical relevance concerning early detection of cancer, estimation of prognosis and individualized therapy regimens in potential risk patients. With the establishment of the UICC TNM staging system first prognostic statements were made possible, which showed a positive correlation between tumor stage and prognosis. There is, however, a need of clinical and/or molecular parameters that reliably predict individual prognosis and results of individualized therapy. We discuss parameters that have been associated with prognosis of head and neck squamous cell carcinoma so far.

Biomarkers, Tumor↗
PubMed2002

INK4a-ARF alterations in liver cell adenoma.

BACKGROUND: The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), whose functions are inactivated in many human cancers. AIMS: To evaluate p14(ARF) and p16(INK4a) alterations in liver cell adenoma. METHODS: After microdissection, DNA from 25 liver cell adenomas and corresponding normal liver tissue were analysed for INK4-ARF inactivation by DNA sequence analysis, methylation specific polymerase chain reaction, restriction enzyme related-polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INK4a) were assessed by differential PCR. RESULTS: Methylation of p14(ARF) was found in 3/25 cases (12%) and alterations in p16(INK4a) occurred in 6/25 liver cell adenomas (24%) which correlated with loss of mRNA transcription. We failed to detect microdeletions or specific mutations of both exons. p16(INK4a) methylation appeared in the context of an unmethylated p14(ARF) promoter in six cases. In normal liver tissue, p14(ARF) or p16(INK4a) alterations were not observed. CONCLUSIONS: Our data suggest that p14(ARF) methylation occurs independently of p16(INK4a) alterations in liver cell adenomas. Furthermore, methylation of p14(ARF) and p16(INK4a) may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.

Adenoma, Liver Cell↗
PubMed2002

Carcinogen-induced site-specific mutagenesis and genetic susceptibility in squamous cell carcinoma of the head and neck.

Tobacco and alcohol have been identified as the most important risk factors for squamous cell carcinomas of the head and neck (HNSCC). Especially for tobacco, some of the carcinogen-induced mutations that trigger transformation have been identified. Much attempt has been made to show a relationship between the mutations of growth regulatory genes, i.e. tumor suppressor- or oncogenes, and the exposure to specific exogeneous mutagens. One of the best examined genes - harboring the most DNA damages (DNA adducts) - caused by xenobiotics is p53. This tumor suppressor gene is an important regulator of cell cycle and apoptosis and is mutated in 40-60% of all HNSCC. Further studies link specific mutations of the ras oncogene to definite carcinogens. The question of why these mutations lead to cancer in some smokers but not in others, i.e. the individual's susceptibility to external carcinogens, remains unclear. One possibility is the individual's ability (or non-ability) of detoxifying carcinogenic xenobiotics or repairing the DNA damages they caused. There are several known polymorphisms of enzymes involved in detoxification as well as in DNA repair - which might explain the interindividual variable susceptibility to HNSCC in smokers and drinkers. However, the results of several examined polymorphisms are diverse or even controversial. The diversity might be due to ethnical differences, study populations, tumor localizations as well as intratumoral heterogeneity. In this review, we attempt to discuss the carcinogen-specific mutations as well as the genetic polymorphisms, which may transfer an enhanced susceptibility to suffer HNSCC.

Alcohol Drinking↗
PubMed2001

INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas.

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.

Adult↗
PubMed2001

Alloreactivity of natural killer cells in allogeneic liver transplantation.

BACKGROUND: The cytolytic attack of natural killer (NK) cells is blocked by recognition of the idiotypic phenotype of certain polymorphisms in HLA class I molecules, specifically by HLA-C alleles (Asn77, Lys80 or Ser77, Asn80) or HLA-Bw4 allotypes. Because liver allograft rejection is associated closer with mismatch in HLA class I than class II, we investigated the role of NK cells in acute hepatic allograft rejection in vivo/in vitro. METHODS: The HLA pattern was typed with serological and polymerase chain reaction (PCR) techniques. In 31 liver transplantations, mononuclear cells from donor spleen and peripheral blood of recipients (before/after transplantation) were cultured in mixed lymphocyte cultures (MLC). MLC-derived effector cells were analyzed by flow cytometry and tested in 51Cr-release assays. RESULTS: Patients with NK allospecific constellations tended to have higher numbers of NK cells in peripheral blood during the first 4 weeks after transplantation, and patients' lymphocytes stimulated with donor cells had a significantly higher cytotoxic activity on days 14 and 21 compared with patients without NK allospecificity. However, acute rejection occurred with similar frequency in both groups (31% with allospecific constellations vs. 40% without). Moreover, acute rejection episodes were not associated with an increase in NK cells in vivo or enhanced cytotoxicity of NK cells to donor target cells. CONCLUSIONS: Under standard immunosuppressive therapy, NK allospecific constellations did not seem play a major role in acute hepatic allograft rejection. Strategies to prevent or treat NK allospecific constellations after liver transplantation are not likely to reduce the incidence or severity of acute allograft rejection.

Acute Disease↗
PubMed2001

Arterialization of the portal vein in liver transplantation: a new microsurgical model in the rat.

BACKGROUND: A preexisting thrombosis of the portal vein and the deep splanchnic bed can make it extremely difficult to reestablish the portal blood flow in orthotopic liver transplantation in man. Complete arterialization of the liver transplant, including the donor portal vein, might be a viable therapeutic option. A new rat transplantation model is described, in which the liver is completely arterialized. METHODS: The outflow of the portal blood in the recipient was secured via a portocaval shunt. Hepatectomy was then performed and the liver transplant placed in orthotopic position. An interposed aortic segment was used for direct arterialization of the donor portal vein. RESULTS: The laboratory parameters determined in the serum at the end of the observation period of 28 days revealed normal functioning of the transplant. The histological examinations showed largely normal cellular architecture, with no signs of necrosis, but incipient fibrosis. CONCLUSIONS: Using this new surgical technique in the rat liver transplantation model, long-term morphological and functional changes in a completely arterialized liver graft, and the regenerative capability of liver tissue perfused in this way, can be investigated.

Anastomosis, Surgical↗
PubMed2001

Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G --> A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC.

Adult↗
PubMed2001

Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer.

The tumour-suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. This study investigated the status of p53 and its two homologues in multiple simultaneous gastric carcinomas. Expression and mutation of p53, p73 and p63 including the two major isotypes TAp63 and black triangleNp63, were examined by direct DNA-sequencing, in situ hybridization, western blotting and immunohistochemistry in 68 gastric carcinomas of 32 patients. The results obtained were correlated with pathohistological stage (according to UICC(16)) and several other histopathological factors and finally with patient survival. p53 mutations were detected in 23/68 carcinomas (34%) from 18 patients with a discordant mutation pattern. Independently of p53 mutation status, p73 transcripts and protein expression were found in 33/68 carcinomas from 24 patients. p63 positivity was found in 21 patients; 25 out of 68 tumours expressed p63. The number of cells containing p63 and their distribution depend on the degree of tumour differentiation. High grade carcinomas of the diffuse type exhibited a significantly higher p63 expression. In intestinal metaplasia and atrophic gastritis, an increase of TAp63 and black triangleNp63 staining was also observed. Specific mutations of p73 or p63 causing amino acid substitutions were not identified. Neither p53, p73 nor p63 were related to prognosis. p73 and p63 have rarely been found to be mutated in gastric carcinomas, but both proteins were expressed in only a subset of tumours. The status of these p53 homologues was discordant in all patients with multiple simultaneous gastric carcinomas. The increased expression of p63 (TAp63 and black triangleNp63) in less well differentiated gastric carcinomas may indicate that p63 can act to promote neoplastic growth in the gastric epithelium.

DNA Mutational Analysis↗