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P Schirmacher

Publications and source records attributed to P Schirmacher.

At least 19 recordsLinked to original sources
PubMed2007

[The morphologic variants of KSHV/HHV 8-associated lymphoproliferations].

KSHV/HHV 8 infection is associated with primary effusion lymphoma, multicentric Castleman disease (MCD) and MCD-associated plasmablastic lymphoma. We report the case of an HIV-infected male with Kaposi sarcoma, MCD in the lymph node and development of a KSHV/HHV 8-associated plasmablastic lymphoma in the liver. Immunohistochemistry revealed an HHV 8 infection of plasmablasts showing cytoplasmic IgM/lambda expression. To the best of our knowledge, liver infiltration by a MCD-associated HHV 8 positive plasmablastic lymphoma has not been documented previously. The differential diagnosis is discussed.

Adult↗
PubMed2006

Dysregulation of growth factor signaling in human hepatocellular carcinoma.

Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.

Carcinoma, Hepatocellular↗
PubMed2006

Molecular characterisation of non-absorptive and absorptive enterocytes in human small intestine.

BACKGROUND AND AIMS: Perturbation of differentiation of the crypt-villus axis of the human small intestine is associated with several intestinal disorders of clinical importance. At present, differentiation of small intestinal enterocytes in the crypt-villus axis is not well characterised. SUBJECTS AND METHODS: Expression profiling of microdissected enterocytes lining the upper part of crypts or the middle of villi was performed using the Affymetrix X3P arrays and several methods for confirmation. RESULTS: A total of 978 differentially expressed sequences representing 778 unique UniGene IDs were found and categorised into four functional groups. In enterocytes lining the upper part of crypts, cell cycle promoting genes and transcription/translation related genes were predominantly expressed, whereas in enterocytes lining the middle of villi, high expression of cell cycle inhibiting genes, metabolism related genes, and vesicle/transport related genes was found. CONCLUSION: Two types of enterocytes were dissected at the molecular level, the non-absorptive enterocyte located in the upper part of crypts and the absorptive enterocyte found in the middle of villi. These data improve our knowledge about the physiology of the crypt-villus architecture in human small intestine and provide new insights into pathophysiological phenomena, such as villus atrophy, which is clinically important.

Adult↗
PubMed2006

Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) rarely affects people under 40. OBJECTIVES: To determine whether the clinical, pathomorphological and genetic features of PDAC occurring in young patients (<or=40 years) differ from those in elderly patients. METHODS: Clinical and pathomorphological data were obtained from seven patients presenting with PDAC, with age ranging from 35 to 40 years of age (mean 38 years). All tumours were characterised by using immunohistochemistry and molecular genetics. RESULTS: All seven patients were women and lacked an association to cancer-predisposing genetic syndromes. Four patients were smokers and one had non-hereditary chronic pancreatitis. Pathomorphologically, tumours in three patients displayed moderate differentiation and four showed poor differentiation including one adenosquamous carcinoma. All tumours showed overexpression of transforming growth factor beta1 and loss or significant reduction of Smad4. Accumulation of p53 and overexpression of epidermal growth factor receptor (EGFR) were seen in five and four patients, respectively. No expression of p16, oestrogen hormone receptor or progesterone receptor was found. Mismatch repair gene products (MutL homologue 1 (MLH1), MSH2 and MSH6) were expressed in all tumours. Mutational analyses showed K-ras mutations in only three of the seven tumours. CONCLUSION: A large clinical, pathomorphological and genetic overlap of PDAC in young patients aged under 40 is seen with that in elderly patients. The existence of yet undefined initiating events of pancreatic carcinogenesis is suggested by the low rate of K-ras mutations, in at least a subgroup of young patients.

Adult↗
PubMed2006

c-myc amplifications in primary breast carcinomas and their local recurrences.

OBJECTIVE: To evaluate the role of c-myc oncogene amplifications in the progression of invasive breast carcinomas. METHODS: c-myc gene copy number was evaluated in a series of 49 primary breast carcinomas and the corresponding local recurrences using fluorescence in situ hybridisation. RESULTS: 11 of the primary carcinomas (22%) harboured c-myc amplifications; these tumours typically were hormone receptor negative and occurred in younger patients (43 v 53 years). At the time of relapse, six additional tumours had acquired a c-myc amplification. The mean recurrence-free survival was 24 months; c-myc amplified tumours relapsed significantly earlier than carcinomas without amplification (18 v 27 months). Univariate analysis showed a worse overall survival in these patients. CONCLUSIONS: While c-myc amplifications can be observed in early stage breast cancer, especially in younger patients, they often occur later in tumour development and appear to be associated with disease progression.

Adenocarcinoma↗
PubMed2006

Tenascin C and annexin II expression in the process of pancreatic carcinogenesis.

Tenascin C (TNC) is a component of the provisional extracellular matrix (ECM) that characterizes solid tumours. Cell surface annexin II is a high-affinity receptor for large TNC splice variants. The aim of this study was to analyse whether TNC and annexin II play a role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a rich ECM populated by pancreatic stellate cells, which play a crucial role in pancreatic desmoplasia. The mRNA and protein levels of TNC and of annexin II were analysed in pancreatic tissues by DNA array, quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemistry. TNC large splice variants were detected by RT-PCR. Enzyme linked immunosorbent assay (ELISA) was used to measure TNC levels in serum and culture supernatants. TNC and annexin II mRNA levels were significantly higher in pancreatic cancer tissues than in the normal pancreas. TNC expression was detected with increased frequency in the progression from PanIN-1 lesions to PDAC, and a parallel switch from cytoplasmic to cell surface expression of annexin II was observed. Large TNC transcripts were found in pancreatic cancer and in chronic pancreatitis, but not in the normal pancreas. TNC expression was demonstrated in pancreatic stellate cells, where it could be induced by tumour necrosis factor alpha (TNFalpha), transforming growth factor beta1 (TGF-beta1) and by cancer cell supernatants supplemented with TGF-beta1. In conclusion, the expression of TNC and cell surface annexin II increases in the progression from low-grade PanIN lesions to pancreatic cancer. Pancreatic stellate cells are identified as a source of TNC in pancreatic tissues, possibly under the influence of soluble factors released by the tumour cells.

Adenocarcinoma↗
PubMed2006

[Malignant lymphomas of the liver: new diagnostic algorithms].

Primary hepatic lymphomas represent rare neoplasms, which are partly observed in association with chronic viral hepatitis, immunosuppression and autoimmune diseases. In contrast, secondary hepatic lymphomas are much more frequent and represent disseminated disease. Lymphomas involving the liver include, with decreasing frequency, diffuse large B-cell lymphoma, small lymphocytic lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma, follicular lymphoma and extranodal marginal zone B-cell lymphoma. Many B-cell lymphomas in the liver reveal a characteristic infiltration pattern allowing a rapid and cost-effective diagnosis based on focused immunohistochemical analyses. In contrast, most T-cell lymphomas show a more diverse morphology, which is sometimes difficult to differentiate from a reactive condition. Therefore, additional molecular analyses are frequently necessary. The differential diagnosis includes hepatitis and inflammatory bile duct diseases, undifferentiated carcinoma, inflammatory myofibroblastic tumor as well as histiocytic and dendritic cell neoplasms.

Algorithms↗
PubMed2006

[Primary sarcomas and sarcoma metastases in the liver: morphological and molecular aspects].

The considerable progress made in radiology, in surgical management with curative intent, and in the identification of molecularly targeted small molecules, such as the tyrosine kinase inhibitor imatinib mesylate, in the treatment of gastrointestinal stromal tumors has greatly influenced the treatment of sarcoma manifestations within the liver. This requires not only the unequivocal pathomorphological differentiation of sarcomas from other tumor entities, e. g. spindle cell dedifferentiated/pleomorphic carcinomas, aggressive non-Hodgkin lymphomas or amelanotic malignant melanomas, but also an accurate subtyping of this complex group of tumors. Additionally to macroscopic and histological findings, the recognition of characteristic immunophenotypic constellations and, at least in some types of sarcoma, the identification of molecular signatures, have greatly expanded the diagnostic tools in pathology.

Diagnosis, Differential↗
PubMed2006

Interstitial fibrosis in the heart: differences in extracellular matrix proteins and matrix metalloproteinases in end-stage dilated, ischaemic and valvular cardiomyopathy.

AIMS: To investigate whether or not there are differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs) in end-stage heart failure underlying different cardiomyopathies. METHODS AND RESULTS: Thirty-nine explanted human hearts were investigated: 15 with dilated cardiomyopathy (DCM), 17 with ischaemic cardiomyopathy (ICM) and seven with valvular cardiomyopathy (VCM). Transmural samples from four different sites were investigated. Frozen sections were processed for immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities were determined. All ECM components were expressed more frequently in DCM than in ICM. Comparing ICM with VCM, all proteins were found more frequently in VCM than in ICM except for type III collagen, which was significantly more frequent in ICM. Comparing DCM and VCM, VCM showed significantly higher volume densities for type III collagen and laminin. MMPs showed only slight variations between the cardiomyopathies. CONCLUSION: The distribution of ECM proteins differs between DCM, ICM and VCM, which suggests that they can be morphologically discriminated by interstitial fibrosis, especially by their expression of matrix proteins.

Adult↗
PubMed2006

Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions.

AIMS: The differential diagnosis of benign hepatic lesions and well-differentiated hepatocellular carcinomas can be a challenge, especially in small biopsy specimens. Recently, novel proteins expressed by the neovasculature in hepatocellular carcinoma (HCC) have been identified. The aim of this study was to compare the expression of podocalyxin-like protein 1 (PODXL1), a CD34-related sialomucin, in HCC and benign liver tumours or tumour-like lesions. METHODS AND RESULTS: Vascular marker expression was examined using tissue microarrays as well as standard paraffin sections from formalin fixed paraffin-embedded liver tissue samples. Expression of PODXL1 was compared with anti-CD34, CD31 and von Willebrand factor VIII staining by immunohistochemistry. PODXL1 is expressed in tumour-associated microvasculature endothelial cells in HCC, as well as in capillarized sinusoidal endothelium of focal nodular hyperplasia (FNH) and hepatic adenoma. Expression in cirrhotic nodules correlates with CD34 and highlights endothelium in the inflow area. In dysplastic nodules CD34 and PODXL1 are not or only focally expressed. CONCLUSIONS: Expression patterns of CD34 and PODXL1 are almost identical in primary hepatic tumours and tumour-like lesions. The presence of CD34+ and PODXL1+ sinusoidal endothelial cells aids in the diagnosis of HCC. Sinusoidal expression of PODXL1 is also seen in a less diffuse pattern in FNH and adenoma.

Antigens, CD34↗
PubMed2005

Coeliac disease is associated with impaired expression of acyl-CoA-synthetase 5.

BACKGROUND AND AIMS: Coeliac disease and other disorders of the small intestine are associated with disturbances in mucosal architecture. The most severe injury to tissue architecture is villus atrophy. In coeliac disease, molecules reflecting the state of the villus architecture are not well characterized at present. MATERIALS AND METHODS: Expression of acyl-CoA-synthetase 5 (ACS5) was studied in unaffected human small/large intestinal tissue and in coeliac disease using several methods including molecular techniques, as well as an in situ approach using a novel established monoclonal antibody directed against human ACS5. RESULTS: Strong expression, synthesis, and enzymatic activity of ACS5 were found in normal small intestinal mucosa compared with unaffected colon mucosa. In normal small intestine, ACS5 preferentially located to the epithelium covering villi. In coeliac disease, expression of ACS5 was regularly associated with differentiation of villi. Thus, ACS5 was found in the villus epithelium of the small intestine with coeliac disease of Marsh grades I, II, IIIa, or IIIb respectively. In Marsh grade IIIc coeliac disease lesions, strong expression of ACS5 was detectable neither in the surface epithelium nor in the epithelium lining hyperplastic crypts. CONCLUSION: These data suggest that ACS5 is a very suitable marker molecule for the detection of villus atrophy in the small intestine.

Adolescent↗
PubMed2005

Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade--results of an explorative CGH meta-analysis.

All available comparative genomic hybridisation (CGH) analyses (n=31, until 12/2003) of human hepatocellular carcinomas (HCCs; n=785) and premalignant dysplastic nodules (DNs; n=30) were compiled and correlated with clinical and histological parameters. The most prominent amplifications of genomic material were present in 1q (57.1%), 8q (46.6%), 6p (22.3%), and 17q (22.2%), while losses were most prevalent in 8p (38%), 16q (35.9%), 4q (34.3%), 17p (32.1%), and 13q (26.2%). Deletions of 4q, 16q, 13q, and 8p positively correlated with hepatitis B virus aetiology, while losses of 8p were more frequently found in hepatitis C virus-negative cases. In poorly differentiated HCCs, 13q and 4q were significantly under-represented. Moreover, gains of 1q were positively correlated with the occurrence of all other high-frequency alterations in HCCs. In DNs, amplifications were most frequently present in 1q and 8q, while deletions occurred in 8p, 17p, 5p, 13q, 14q, and 16q. In conclusion, aetiology and dedifferentiation correlate with specific genomic alterations in human HCCs. Gains of 1q appear to be rather early events that may predispose to further chromosomal abnormalities. Thus, explorative CGH meta-analysis generates novel and testable hypotheses regarding the cause and functional significance of genomic alterations in human HCCs.

Allelic Imbalance↗
PubMed2005

Liver-specific expression of interferon gamma following adenoviral gene transfer controls hepatitis B virus replication in mice.

Interferons control viral replication and the growth of some malignant tumors. Since systemic application may cause severe adverse effects, tissue-specific expression is an attractive alternative. Liver-directed interferon gene therapy offers promising applications such as chronic viral hepatitis B or C or hepatocellular carcinoma and thus needs testing in vivo in suitable animal models. We therefore used the Tet-On system to regulate gene expression in adenoviral vectors, and studied the effect of liver-specific and regulated interferon gamma expression in a mouse model of chronic hepatitis B virus (HBV) infection. In a first generation adenoviral vector, genes encoding for firefly luciferase and interferons alpha, beta or gamma, respectively, were coexpressed under control of the bidirectional tetracycline-regulated promoter P(tet)bi. Liver-specific promoters driving expression of the reverse tetracycline controlled transactivator ensured local expression in the livers of HBV transgenic mice. Following gene transfer, we demonstrated low background, tight regulation and a 1000-fold induction of gene expression by doxycycline. Both genes within the bidirectional transcription unit were expressed simultaneously, and in a liver-specific fashion in cell culture and in living mice. Doxycycline-dependent interferon gamma expression effectively controlled HBV replication in mice, but did not eliminate HBV transcripts. This system will help to study the effects of local cytokine expression in mouse disease models in detail.

Adenoviridae↗
PubMed2005

Expression of acyl-CoA synthetase 5 in human endometrium and in endometrioid adenocarcinomas.

AIM: Fatty acid metabolism of the endometrium is important for tissue homeostasis in the proliferative and secretory phase of the menstrual cycle. The enzyme acyl-CoA synthetase 5 (ACS5) plays a crucial role in fatty acid metabolism, mainly through the generation of multifunctional long-chain-fatty-acid-CoA esters. The aim of the present study was to characterize expression and localization of ACS5 in the normal human endometrium and in endometrioid adenocarcinomas. METHODS AND RESULTS: Expression of ACS5 in the human endometrium was investigated by in situ techniques (immunohistochemistry, mRNA in situ hybridization) and a molecular approach (reverse transcriptase-polymerase chain reaction, Western blot). ACS5 protein and mRNA were localized to the epithelium of the human endometrium. Here, ACS5 expression was found throughout the menstrual cycle as well as in the postmenopausal endometrium. Notably, in endometrioid adenocarcinomas, the ACS5 molecule was found abundantly in well-differentiated tumours, but not in poorly differentiated adenocarcinomas. CONCLUSIONS: The abundance of ACS5 in the endometrial epithelium throughout the menstrual cycle provides support for its role in the regulation of tissue homeostasis. With regard to its value for histopathological diagnosis, immunohistochemical characterization of endometrioid adenocarcinomas shows that a decrease in ACS5 expression correlates with tumour dedifferentiation.

Adult↗
PubMed2005

Characterization of metaplastic and heterotopic epithelia in the human gastrointestinal tract by the expression pattern of acyl-CoA synthetase 5.

Metaplastic and heterotopic epithelia are frequently found in the human intestine. The recently cloned human acyl-CoA synthetase 5 (ACS5) is a key enzyme in providing cytosolic acyl-CoA thioesters. The aim of the study was to identify and to locate the expression of ACS5 in the gastric body and the small intestine with metaplasia or heterotopia by different methods. In the normal gastrointestinal tract, ACS5 was predominantly found in the villus epithelium of the small intestine, but not in the gastric mucosa. Of note, strong expression of ACS5 was also detectable in intestinal metaplasia of the stomach. Inversely, ACS5 expression could neither be detected in heterotopic gastric mucosa of the corpus type nor in gastric, pseudopyloric, or antral metaplasia of the small intestine. In conclusion, our data implicate that ACS5 is a suitable differentiating marker molecule in the gastrointestinal tract.

Adult↗