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Manuel Maglione,
Benno Cardini,
Rupert Oberhuber,
Katrin Watschinger,
Marcel Jenny,
Johanna Gostner,
Martin Hermann, Peter Obrist,
Raimund Margreiter,
Johann Pratschke,
Gerald Brandacher,
Ernst R Werner
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ABSTRACT: Tetrahydrobiopterin has been shown to efficiently abrogate ischemia reperfusion injury (IRI). However, it is unclear, whether its beneficial action relies on cofactor activity of one of the five known tetrahydrobiopterin-dependent reactions or on its antioxidative capacity. We therefore compared tetrahydrobiopterin with the pterin derivate tetrahydroneopterin (similar biochemical properties, but no nitric oxide synthase cofactor activity) and the antioxidants vitamin C and 5-methyltetrahydrofolate. Donor mice were pretreated with tetrahydrobiopterin, tetrahydroneopterin, vitamin C, or 5-methyltetrahydrofolate. Pancreatic grafts were subjected to 16-h cold ischemia time and implanted in syngeneic recipients. Untreated and nontransplanted animals served as controls. Following 2-h reperfusion, microcirculation was analyzed by intravital fluorescence microscopy. Graft damage was assessed by histology and nitrotyrosine immunostaining, and tetrahydrobiopterin levels were determined by HPLC. Recipient survival served as ultimate readout. Prolonged cold ischemia time resulted in microcirculatory breakdown. Only tetrahydrobiopterin pretreatment succeeded to preserve the capillary net, whereas all other compounds showed no beneficial effects. Along with increased intragraft tetrahydrobiopterin levels during recovery and implantation, only tetrahydrobiopterin pretreatment led to significant reduction of IRI-related parenchymal damage enabling recipient survival. These results show a striking superiority of tetrahydrobiopterin in preventing lethal IRI compared with related compounds and suggest nitric oxide synthases as treatment target.
Transplant International 07/2012; 25(10):1084-1095. · 2.92 Impact Factor
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Michael C Haffner,
Johannes Laimer,
Alcides Chaux,
Georg Schäfer, Peter Obrist,
Andrea Brunner,
Irmgard E Kronberger,
Klaus Laimer,
Bora Gurel,
Johann-Benedikt Koller,
Christof Seifarth,
Bettina Zelger,
Helmut Klocker,
Michael Rasse,
Wolfgang Doppler,
Neil H Bander
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ABSTRACT: Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in prostate cancer as well as in the neo-vasculature of nonprostatic solid tumors. Here, we determined the expression pattern of PSMA in the vasculature of oral squamous cell carcinoma. Using a previously validated antibody, PSMA staining distribution and cyclooxygenase 2 (COX2) expression status was evaluated in a cohort of patients with squamous cell carcinoma of the oral cavity (n=96) using immunohistochemistry and was correlated with clinicopathological features as well as outcome. Twenty-four (25%) cases showed no detectable PSMA staining, 48 (50%) demonstrated positive immunoreactivity for PSMA in less than 50% of microvessels and 24 (25%) cases showed strong endothelial PSMA expression in more than 50% of tumor-associated microvessels. High endothelial PSMA expression was associated with greatly reduced survival (18.2 vs 77.3 months; P=0.0001) and maintained prognostic significance after adjusting for grade and stage in multivariate analysis (hazard ratio=2.19, P=0.007). Furthermore, we observed a strong association between endothelial PSMA and cancer cell-specific COX2 expression. In conclusion, we provide the first evidence for the prognostic significance of endothelial PSMA expression in oral squamous cell carcinoma and, suggest a potential interaction between arachidonic acid metabolites and endothelial PSMA expression in the tumor neo-vasculature.
Modern Pathology 03/2012; 25(8):1079-85. · 4.79 Impact Factor
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ABSTRACT: The eukaryotic translation initiation factor eIF3a is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. It is known to play an important role in general translation initiation as well as in the specific translational regulation of various gene products, among which many influence tumour development, progression, and the therapeutically important pathways of DNA damage repair. Therefore, beyond its role in protein synthesis, eIF3a is emerging as regulator in tumour pathogenesis and therapy response and, therefore, a potential tumor marker. By means of a tissue microarray (TMA) for histopathological and statistical assessment, we here show eIF3a expression in 103 cases of squamous cell carcinoma of the oral cavity (OSCC), representing tissues from 103 independent patients. A subset of the study cohort was treated with platinum based therapy. Our results show that the 170 kDa protein is upregulated in OSCC and correlates with good overall survival. Overexpressing tumors respond better to platinum-based chemotherapy, suggesting eIF3a as a putative predictive as well as prognostic tumor marker in OSCC.
Journal of Oncology 01/2012; 2012:901956.
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Klaus Laimer,
Birgit Troester,
Frank Kloss,
Georg Schafer, Peter Obrist,
Alexander Perathoner,
Johannes Laimer,
Gerald Brandacher,
Michael Rasse,
Raimund Margreiter,
Albert Amberger
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ABSTRACT: Indoleamine 2,3 dioxygenase (IDO) is a negative immune regulator and was found to be a prognostic marker in several tumor entities. In this study, we analysed IDO expression in oral squamous cell carcinoma (OSCC) regarding patient's prognosis. Additionally, expression of IDO like-1 gene (INDOL-1) was analysed. Tumor tissue from 88 patients with OSCC was analysed by immunohistochemistry for IDO expression. The influence of IDO expression on survival was studied by multivariate Cox regression, adjusting for established clinical prognostic parameters. Real time PCR of tumor samples was performed in a subgroup of patients to analyse mRNA expression of IDO and INDOL-1. IDO high-expression was observed in 44.2% of OSCC patients. No significant correlation was found between IDO expression and clinical stage, sex, age, tumor site, tumor size, metastasis or tumor grade. The median overall survival time was 3.1 years for patients with IDO low tumors, compared to 1.36 years for IDO high tumors (P=.028). Subset analysis of patients receiving adjuvant radio-chemotherapy showed a significant difference (P=.0046) in overall survival between IDO low tumors (3.35 years) and IDO high tumors (1.26 years). In contrast, the impact of IDO expression on survival time in patients without adjuvant therapy was not significant (P=.574). Interestingly, INDOL-1 was not expressed in OSCC. IDO high expression represents a significant negative prognostic factor in patients with OSCC, especially in those patients undergoing adjuvant radiochemotherapy. Our data support the suggestion, co-administration of small-molecule IDO inhibitors could represent a promising new strategy to increase the anti-tumor activity of radio-chemotherapy in patients with IDO positive OSCC.
Oral Oncology 03/2011; 47(5):352-7. · 2.86 Impact Factor
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ABSTRACT: Epithelial cell adhesion molecule (EpCAM) is a cell surface protein with oncogenic features that is expressed on healthy human epithelia and corresponding malignant tumours. EpCAM expression frequently correlates with more aggressive tumour behaviour and new EpCAM-specific therapeutic agents have recently been approved for clinical use in patients with cancer. However, no consensus exists on how and when to evaluate EpCAM expression in patients with cancer.
EpCAM expression was assessed by a well-established immunohistochemical staining protocol in 2291 primary tumour tissues and in 108 metastases using the EpCAM-specific antibody clone VU1D9. A total immunostaining score was calculated as the product of a proportion score and an intensity score. Four expression subgroups (no, weak, moderate and intense) were defined. As described previously, the term 'EpCAM overexpression' was reserved for tissues showing a total immunostaining score >4.
EpCAM was highly expressed in most tumours of gastrointestinal origin and in some carcinomas of the genitourinary tract. However, hepatocellular carcinomas, clear cell renal cell cancer, urothelial cancer and squamous cell cancers were frequently EpCAM negative. EpCAM expression in breast cancer depended on the histological subtype; lobular histology usually showed no or weak expression. Most metastases were EpCAM positive and they frequently reflected the expression phenotype of the primary tumour.
EpCAM expression was detected on adenocarcinomas of various primary sites. If EpCAM-specific antibodies are intended to be used in patients with cancer, we recommend prior immunohistochemical evaluation of EpCAM expression, particularly in patients with renal cell cancer, hepatocellular carcinoma, urothelial carcinoma, breast cancer and squamous cell carcinomas.
Journal of clinical pathology 03/2011; 64(5):415-20. · 2.43 Impact Factor
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Stefan Schneeberger,
Albert Amberger,
Julia Mandl,
Theresa Hautz,
Oliver Renz, Peter Obrist,
Hugo Meusburger,
Gerald Brandacher,
Walter Mark,
Daniela Strobl,
Jakob Troppmair,
Johann Pratschke,
Raimund Margreiter,
Andrey V Kuznetsov
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ABSTRACT: Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew→F344) and syngeneic (Lew→Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction.
Transplant International 12/2010; 23(12):1282-92. · 2.92 Impact Factor
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Robert Sucher,
Philipp Gehwolf,
Rupert Oberhuber,
Martin Hermann,
Christian Margreiter,
Ernst R Werner, Peter Obrist,
Stefan Schneeberger,
Robert Ollinger,
Raimund Margreiter,
Gerald Brandacher
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ABSTRACT: Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans.
Kidney International 02/2010; 77(8):681-9. · 6.61 Impact Factor
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Katrin Kienzl,
Bettina Sarg,
Georg Golderer, Peter Obrist,
Ernst R Werner,
Gabriele Werner-Felmayer,
Herbert Lindner,
Manuel Maglione,
Stefan Schneeberger,
Raimund Margreiter,
Gerald Brandacher
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ABSTRACT: Proteome analysis has emerged as a valuable tool for the study of large-scale protein expression profiles. Here, we applied this novel technology to identify specific biomarkers for acute cardiac allograft rejection.
Hearts of C57BL/10 mice were placed in fully major histocompatibility complex-mismatched C3H/He recipients. Syngeneic transplants served as controls. Intragraft protein expression analysis was performed using fluorescence two-dimensional difference gel electrophoresis on day 6 posttransplant. Spots of interest were subsequently subjected to nanospray ionization tandem mass spectrometry (MS/MS) for protein identification. In addition, expression of selected proteins was confirmed by Western blot analysis and by immunohistochemistry.
Two-dimensional difference gel electrophoresis enabled detection of 1541 protein spots. For 95 protein spots, the expression level during acute rejection differed by more than 1.5-fold from that observed in syngeneic grafts. Spots with significant differential regulation identified by tandem mass spectrometry were derived from peroxiredoxin 6, pyruvate kinase isozyme M2, coronin 1A, protein disulfide isomerase A3 precursor, and aconitate hydratase.
These identified proteins may constitute novel biomarkers of acute cardiac allograft rejection and might hold great potential as surrogate markers for monitoring in vivo alloimmune response.
Transplantation 09/2009; 88(4):553-60. · 4.00 Impact Factor
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ABSTRACT: Dendritic cells (DC) are the most potent antigen-presenting cells of the organism. They are specialized to capture, process, and present antigen via the MHC class II as well as the MHC class I pathways to CD4+ and CD8+ T cells, respectively. This results in T cell-mediated immune responses that are likely to counteract the generation and propagation of tumors in vivo. Therefore, we studied the distribution of dendritic cells in mammary Paget's disease. Paraffin-embedded samples of Paget's disease of the breast (n=27) and of disease-free epidermis of the nipple (n=10) were investigated immunohistochemically for the presence of dendritic cells, in particular of Langerhans cells, using antibodies against S-100, CD1a, and HLA-DR, as well as novel reagents against Langerin/CD207, DC-LAMP/CD208 and p55 (Fascin), the latter two being specific for mature dendritic cells. Paget samples presented a decrease of CD1a+, S-100+, and Langerin+ intraepidermal Langerhans cells in almost all cases. This was paralleled by a concentration of immature dendritic cells in the tumor-infiltrated tissue itself. Similar to infiltrating breast carcinoma we observed a marked increase of DC-LAMP+ and p55+ mature dendritic cells in the corial tissue beneath the tumor. These cells were almost always found in ribbon-like or nodular lymphocytic infiltrates. Moreover, rare mature dendritic cells were also found in the Paget cell-infiltrated epidermis of the nipple, i.e. in the tumorous lesion itself. These findings may indicate an effective ongoing anti-tumor immune response in this part of spreading breast cancer.
Cancer letters 11/2008; 272(2):206-20. · 4.86 Impact Factor
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ABSTRACT: 14-3-3sigma an intracellular phosphoserine binding protein regulates different cellular signalling processes and is involved in cancer development. In this study, we examined the expression of 14-3-3sigma and evaluated its clinical significance in OSCC. Tumour tissue from 95 OSCC patients was analysed for 14-3-3sigma and p53 expression, respectively. The correlation of these proteins with survival and clinical parameters was assessed. 14-3-3sigma high expression was observed in 44.2% of OSCC patients. A significant role of 14-3-3sigma expression on survival was shown by Kaplan-Meier analysis. Median survival time was 4.1years for patients with 14-3-3sigma low tumours, compared with 1.36years for 14-3-3sigma high tumours (P=.0021). Subset analysis in patients receiving adjuvant chemotherapy showed that the overall survival was significantly decreased in 14-3-3sigma high tumours than in 14-3-3sigma low tumours (P=.02). p53 expression was not significant in univariate analyses. In multivariate regression analysis, 14-3-3sigma expression emerged as a significant independent parameter (P=.003). These results provide evidence that 14-3-3sigma expression is involved in OSCC and, in contrast to p53 expression represents a new prognostic marker for OSCC and therapy response. Pending validation targeting 14-3-3sigma might also be a new opportunity to improve therapy.
Oral Oncology 08/2008; 45(2):127-34. · 2.86 Impact Factor
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ABSTRACT: Hepcidin, a small cationic liver derived peptide, is a master regulator of body iron homeostasis. Cytokines and iron availability have so far been identified as regulators of hepcidin expression. Herein, we investigated the functional role of Kupffer cells for hepcidin expression because of their vicinity to the hepatocytes and their importance for iron recycling via erythrophagocytosis. We investigated C57Bl6 mice and littermates, in which Kupffer cells were eliminated in vivo upon intravenous injection of liposome-encapsulated clodronate. Primary cultures of hepatocytes and Kupffer cells were used to study direct regulatory effects ex vivo. The in vivo depletion of Kupffer cells resulted in a significant increase in liver hepcidin expression, which was paralleled by a significant reduction in serum iron levels. The same pattern of regulation by Kupffer cell depletion was observed upon injection of bacterial lipopolysaccharide into mice and in primary (Hfe -/-) and in secondary iron-overloaded mice. Accordingly, the messenger ribonucleic acid (mRNA) concentrations of the hepcidin iron-sensing molecule hemojuvelin were not significantly changed upon Kupffer cell depletion. When primary hepatocytes were cocultivated with Kupffer cells or stimulated with a Kupffer cell-conditioned medium ex vivo, a significant reduction in hepatocyte hepcidin mRNA expression was observed. Our data suggest that Kupffer cells control body iron homeostasis by exerting negative regulatory signals toward hepcidin expression, which may be primarily referred to the secretion of yet unidentified hepcidin-suppressing molecules by Kupffer cells.
Journal of Molecular Medicine 07/2008; 86(7):825-35. · 4.67 Impact Factor
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ABSTRACT: This retrospective study was designed to investigate the prognostic significance of EpCAM expression in human oral squamous cell carcinoma on a long-term follow-up. EpCAM expression was examined immunohistochemically on a tissue microarray (TMA) of paraffin embedded tissue specimens from 77 consecutive patients who underwent surgical treatment for squamous cell carcinoma of the oral cavity in the period between 1980 and 1997 at the Department of Craniomaxillofacial and Oral Surgery, Innsbruck Medical University. High EpCAM expression was found in 17 (22.1%) of the tumor samples. Using Kaplan-Meier analysis no correlation of EpCAM overexpression was observed with conventional clinicopathologic features in this patient cohort. Taken together, these data suggest that EpCAM might become an attractive treatment target in a subgroup of patients with OSCC.
Oral Oncology 02/2008; 44(1):72-7. · 2.86 Impact Factor
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Andreas Jurgeit,
Chiara Berlato, Peter Obrist,
Christian Ploner,
Petra Massoner,
Judith Schmölzer,
Michael C Haffner,
Helmut Klocker,
Lukas A Huber,
Stephan Geley,
Wolfgang Doppler
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ABSTRACT: In addition to its extracellular function as a secreted protein, IGF-binding protein (IGFBP)-5 has been postulated to act as a signaling molecule in the nucleus. This study aims to assess the significance of this postulated nuclear localization. By confocal immunofluorescence microscopy, we detected IGFBP-5 in the vesicular compartment of mammary epithelial cells in culture, while no nuclear staining was observed. Immunohistochemistry performed on paraffin sections of the involuting mammary gland revealed IGFBP-5 positive staining of epithelial cells only outside the nucleus. To evaluate the contribution of reuptake of extracellular IGFBP-5, T47D cells were incubated with Alexa Fluor 647-labeled IGFBP-5. The protein was taken up into intracellular vesicles and again was neither detectable in the cytoplasm outside of vesicular structures nor in the nucleus. Quantification of the time and concentration dependence of uptake by immunoblotting revealed that the process was saturable at IGFBP-5 concentrations between 1 and 2 mum and partially reversible with 30% remaining in the cell after a 1-h chase. The observation of nuclear uptake of IGFBP-5 was restricted to artificial conditions such as expression of non-secreted forms of IGFBP-5 or selective permeabilization of the plasma membrane by digitonin.
Traffic 01/2008; 8(12):1815-28. · 4.92 Impact Factor
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ABSTRACT: For patients with squamous cell carcinoma of the oral cavity, both locoregional and distant recurrences are common, and an appropriate adjuvant treatment modality has yet to be defined. Thus, there is an urgent need to identify novel molecular markers with potential prognostic and/or predictive value to improve treatment outcome in these patients. This retrospective study was designed to investigate the predictive and/or prognostic value of STAT1 activation in squamous cell carcinoma of the oral cavity.
STAT1 expression and subcellular localization was examined immunohistochemically on a tissue microarray of paraffin-embedded tumor specimens from 89 patients who underwent surgical treatment in the period between 1980 and 1997. A nuclear staining score of greater than 35% was defined as high STAT1 activation.
According to study criteria, 18% of analyzed tumor samples exhibited high STAT1 activation. High STAT1 activation was associated with negative lymph node status. Moreover, in the subgroup of patients who received chemotherapy, high nuclear STAT1 staining in the tumor was associated with good prognosis.
This is the first report demonstrating the potential predictive value of STAT1 activation status in patients with squamous cell cancer of the oral cavity. If confirmed in large prospective trials, this molecular marker could help in guiding therapeutic decisions in these patients.
Cancer 08/2007; 110(2):326-33. · 4.77 Impact Factor
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ABSTRACT: Although various suture techniques for murine pancreas transplantation have been described, severe limitations have limited their widespread use. We therefore designed a surgical model for cervical heterotopic pancreas transplantation using a cuff technique.
C57BL6 mice were used as donor and recipient pairs. Recipients were rendered diabetic with streptozotocin and subsequently transplanted. The donor pancreas was isolated using a no-touch technique and then placed in the recipient's cervical region. Vascular anastomoses were completed by pulling the portal vein over the external jugular vein cuff and the donor aortic segment over the carotid cuff and fixed with an 8-0 ligature thereby facilitating a nonsuture technique. To test applicability of this model, graft microcirculation was evaluated by intravital microscopy after prolonged cold ischemia (16 h).
The immediate success rate was >90%. Donor operation lasted 40 +/- 5 min; dissection of recipient vessels lasted 20 +/- 4 min. Revascularization time was 4 to 6 min, resulting in a total pancreas ischemia time of 33 +/- 6 min. No thromboembolic complications on the cuff side were observed. Preoperative glucose levels were 518 +/- 59 mg/dl and returned to normal by postoperative day 1 (88 +/- 13 mg/dl). Histology on postoperative days 10 and 30 showed almost normal islet cell and acinar architecture of all grafts. In groups with prolonged cold ischemia, graft microcirculation was significantly reduced and paralleled by increased inflammation, interstitial edema, hemorrhage, acinar vacuolization, and focal areas of necrosis compared with nonischemic controls.
This new model may provide an excellent tool to further investigate the pathophysiology as well as novel therapeutic strategies of preservation, ischemia reperfusion injury, and graft pancreatitis.
Surgery 05/2007; 141(5):682-9. · 3.10 Impact Factor
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ABSTRACT: The role of iron in the pathogenesis of cardio-vascular disorders is still controversial. We studied the effects of iron perturbations on myocardial injury upon temporary ischemia/reperfusion. C57BL/6J male mice were injected with iron dextran for 2 weeks while controls received saline. Mice were then subjected to 30 min of myocardial ischemia and subsequent reperfusion for 6-24 h. Tissue damage was quantified histologically and by troponin T determination. The expressions of tumor necrosis factor-alpha (TNF-alpha), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were investigated in non-ischemic and ischemic regions of both groups. After myocardial ischemia and reperfusion, troponin T levels, as a marker of myocardial damage, were significantly reduced in iron-treated mice as compared to control mice (P < 0.05). Under the same conditions the infarction area and damage score were significantly lower in iron-treated animals. In parallel, TNF-alpha and SOD expressions were increased in infarcted regions of iron-treated mice as compared to controls, whereas myocardial iNOS expression was significantly lower in iron-treated mice. Although, iron challenge increased radical formation and TNF-alpha expression in vivo, this did not result in myocardial damage which may be linked to the parallel induction of SOD. Importantly, iron treatment inhibited iNOS expression. Since, an increased nitric oxide (NO) formation has been linked to cardiac damage after acute myocardial infarction, iron may exert short time cardio-protective effects after induction of ischemia/reperfusion via decreasing iNOS formation.
BioMetals 04/2007; 20(2):205-15. · 2.82 Impact Factor
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Klaus Laimer,
Gilbert Spizzo,
Guenther Gastl, Peter Obrist,
Thomas Brunhuber,
Dominic Fong,
Verena Barbieri,
Siegfried Jank,
Wolfgang Doppler,
Michael Rasse,
Burghard Norer
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ABSTRACT: This retrospective study was designed to investigate the prognostic significance of EGFR overexpression in human oral squamous cell carcinoma on a long-term follow-up. EGFR expression was examined immunohistochemically on a tissue microarray (TMA) of paraffin embedded tissue specimens from 109 patients who underwent surgical treatment for squamous cell carcinoma of the oral cavity and oropharynx in the period between 1980 and 1997. High EGFR expression was found in 80 (73.42%) of the tumour samples. Kaplan-Meier curves showed that EGFR overexpression was significantly related to decreased overall survival (p=0.05). Multivariate analysis showed that EGFR overexpression is an independent prognostic marker in these patients (p=0.02, RR 3.6). These results confirm that EGFR overexpression is an independent prognostic marker in patients with squamous cell carcinoma of the oral cavity and oropharynx. The EGFR antigen represents an attractive target for targeted therapies with monoclonal antibodies or specific tyrosine-kinase inhibitors in these patients.
Oral Oncology 03/2007; 43(2):193-8. · 2.86 Impact Factor
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Gilbert Spizzo,
Guenther Gastl, Peter Obrist,
Dominic Fong,
Margot Haun,
Kurt Grünewald,
Walther Parson,
Cordula Eichmann,
Simone Millinger,
Heidi Fiegl,
Raimund Margreiter,
Albert Amberger
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ABSTRACT: We examined the methylation status of the Ep-CAM promoter region of human breast cancer cell lines and breast cancer tissue using MethyLight technology and bisulfite sequencing. We found the promoter of Ep-CAM-negative breast cancer cell lines Hs 578T to be methylated to a higher degree as compared to positive cell lines MCF-7. Demethylation of cell lines was performed using 5-aza-2'-deoxycytidine. Ep-CAM RNA and protein expression could be partially restored by treating cells with 5-Aza-2'-deoxycytidine. In most primary breast cancer tissue, methylation of the Ep-CAM gene could be detected at a low level and no correlation was found with Ep-CAM protein expression in tumour tissue. Taken together, these data suggest that methylation of the Ep-CAM promoter is not a crucial mechanism for regulation of Ep-CAM expression in breast cancer. Thus, most important regulatory mechanisms have to be supposed in vivo.
Cancer Letters 03/2007; 246(1-2):253-61. · 4.24 Impact Factor
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ABSTRACT: Currently available clinical and molecular factors provide still an insufficient prognostic and predictive assessment for patients with epithelial ovarian cancer (EOC). To identify a potential molecular target and prognostic/predictive factor for EOC, we investigated in a retrospective study the prognostic value of Ep-CAM overexpression in EOC.
We assessed by immunohistochemistry the expression of the Ep-CAM antigen on tissue microarrays containing paraffin-embedded tissue samples of 199 patients with documented EOC. Patients were operated for ovarian cancer in the period between June 1980 and January 2000.
We observed a rate of Ep-CAM overexpression of 68.8%. Ep-CAM overexpression was significantly related to a decreased overall survival (P = 0.036). The prognostic power of Ep-CAM overexpression was particularly strong in patients with stage III and IV disease. In fact, in this subgroup, median overall survival was twofold higher in patients without as compared to patients with Ep-CAM overexpression (46 vs. 23 months, P < 0.01). Univariate analysis revealed a correlation with histologic grade. We observed a significantly higher rate of Ep-CAM overexpression (83.5%) in grade 3 tumors. Histologic subtypes associated with a higher rate of Ep-CAM overexpression were serous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, clear cell carcinoma, and endometrioid carcinoma. Cox regression analysis showed Ep-CAM overexpression to be an independent prognostic marker (P = 0.037, RR = 1.64).
This retrospective analysis demonstrates for the first time an independent prognostic value of Ep-CAM overexpression in patients with EOC. Ovarian cancer patients with Ep-CAM overexpressing tumors are frequent and would qualify for treatment with Ep-CAM-specific immunotherapeutic approaches.
Gynecologic Oncology 11/2006; 103(2):483-8. · 3.89 Impact Factor
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ABSTRACT: The incidence of distant metastasis in head and neck cancer and especially in salivary gland cancer is relatively low in comparison to other malignancies. However, the presence of distant metastasis heralds a poor prognosis in head and neck cancer, with a median survival of 4.3-7.3 months. Treatment of these patients is usually performed in a palliative setting. Patients with malignant salivary gland tumors should have an X-ray or CT scan of the chest at their initial assessment to exclude the possibility of distant metastasis. The likelihood of developing distant metastasis is associated with high-grade tumors, such as adenoid cystic carcinoma, salivary duct carcinoma, high-grade mucoepidermoid carcinoma and tumors located in the submandibular gland, posterior tongue and pharyngeal tumors. A lower risk of developing distant metastasis is known for all other histological entities of salivary gland tumors. Nevertheless all patients who have a histologically confirmed malignant salivary gland tumor should have lifelong follow-up. On the basis of a clinical case regarding a patient with metastatic parotid gland cancer we present a review of the literature.
Acta Oto-Laryngologica 05/2006; 126(4):340-5. · 1.08 Impact Factor
