Stendal, Germany
Stendal, Germany

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Daniels M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Lurkin I.,Erasmus University Rotterdam | Pauli R.,Institute of Pathology | Erbstosser E.,Institute of Pathology | And 16 more authors.
Cancer Letters | Year: 2011

Pathogenetic pathways of gastrointestinal stromal tumors (GIST) lacking mutations in KIT and PDGFRA (∼15%) are still poorly studied. Nearly nothing is known about PI3K alterations in GISTs and only a few GISTs with BRAF mutations have been reported. BRAF mutations (V600E) were found in 3/87 tumors (3.5%) concomitantly were wild type for KIT and PDGFRA. No mutations were detected in KRAS, NRAS, and FGFR3. For the first-time we demonstrated a PIK3CA mutation (H1047L) simultaneously occurring with a 15-bp deletion in KIT exon 11 in one tumor. We suggest that BRAF mutations are of pathogenetic significance in wild type GISTs. The PI3K pathway should be assessed in future studies. © 2011 Elsevier Ireland Ltd.


Pelz A.-F.,Otto Von Guericke University of Magdeburg | Agaimy A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Daniels M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Evert M.,Otto Von Guericke University of Magdeburg | And 12 more authors.
Human Pathology | Year: 2011

Rectal gastrointestinal stromal tumors are rare. To date, 12 gastrointestinal stromal tumors have been reported as pelvic vaginal masses. We describe a rectovaginal tumor in a 39-year-old woman. The tumor frequently recurred after multiple surgical excisions and interrupted imatinib treatment without metastasizing. Magnetic resonance tomography demonstrated a partial response under imatinib. The patient was alive with stable disease under imatinib 44 months from initial diagnosis. Molecular analysis showed a somatic 6-base pair deletion in exon 11 of c-KIT (W557-K558del) in both the primary tumor and the third recurrence; the recurrence had an additional exon 17 mutation (N822K). Comparative genomic hybridization analysis of the primary tumor showed loss of 14q and gain of 1q. Recurrence showed complete loss of nuclear p16 expression. Molecular studies and p16 status confirmed the typical characteristics of gastrointestinal stromal tumors with an aggressive phenotype underscoring the need for a special interdisciplinary treatment and for achieving complete local excision with free margins. © 2011 Elsevier Inc. All rights reserved.


Kornfeld J.-W.,University of Hamburg | Kornfeld J.-W.,University of Cologne | Meder S.,University of Hamburg | Wohlberg M.,University of Hamburg | And 6 more authors.
British Journal of Cancer | Year: 2011

Background:TACE/ADAM17 is a transmembranous protease that cleaves membrane-bound growth factors like EGFR ligands. TACE-dependent proteolysis is regulated by its inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP3). This study analyses the role of TACE and TIMP3 mRNA expression in squamous cell carcinomas of the head and neck (HNSCCs).Methods:We analysed TACE and TIMP3 mRNA expression in HNSCCs from 106 patients by RNA in situ hybridisation.Results: TACE mRNA was upregulated in HNSCCs compared with dysplastic (P0.05) and normal epithelia (P0.001), with strong hybridisation signals in 21.9% of invasive tumour tissues and 4.5% of dysplasia. Elevated mRNA levels were accompanied by increased amounts of TACE protein in HNSCCs. TIMP3 mRNA expression in HNSCC-associated stroma was significantly higher than in the stroma adjacent to dysplastic or normal epithelia. Expression of TACE mRNA in HNSCCs was associated with tumour stage (P0.019) and regional lymph node metastasis (P0.009). Furthermore, levels of TACE mRNA in HNSCCs correlated with the expression of TIMP3 mRNA in HNSCC-associated stroma. Concomitantly, patients expressing high levels of TACE and TIMP3 mRNA showed significantly reduced overall survival compared with those with low mRNA levels.Conclusion:Our results indicate an important role of TACE and TIMP3 during development and progression of HNSCCs. © 2011 Cancer Research UK All rights reserved.


Riethdorf S.,University of Hamburg | Frey S.,University of Hamburg | Santjer S.,University of Hamburg | Stoupiec M.,University of Hamburg | And 8 more authors.
International Journal of Cancer | Year: 2016

The transcription factor grainyhead-like 2 (GRHL2) plays a crucial role in various developmental processes. Although GRHL2 recently has attracted considerable interest in that it could be identified as a novel suppressor of the epithelial-to-mesenchymal transition, evidence is emerging that GRHL2 also exhibits tumour-promoting activities. Aim of the present study therefore was to help defining the relevance of GRHL2 for human cancers by performing a comprehensive immunohistochemical analysis of GRHL2 expression in normal (n = 608) and (n = 3,143) tumour tissues using tissue microarrays. Consistent with its accepted role in epithelial morphogenesis, GRHL2 expression preferentially but not exclusively was observed in epithelial cells. Regenerative and proliferating epithelial cells with stem cell features showed a strong GRHL2 expression. Highly complex GRHL2 expression patterns indicative of both reduced and elevated GRHL2 expression in tumours, possibly reflecting potential tumour-suppressing as well as oncogenic functions of GRHL2 in distinct human tumours, were observed. A dysregulation of GRHL2 expression for the first time was found in tumours of non-epithelial origin (e.g., astrocytomas, melanomas). We also report GRHL2 copy number gains which, however, did not necessarily translate into increased GRHL2 expression levels in cancer cells. Results obtained by meta-analysis of gene expression microarray data in conjunction with functional assays demonstrating a direct regulation of HER3 expression further point to a potential therapeutic relevance of GRHL2 in ovarian cancer. Hopefully, the results presented in this study may pave the way for a better understanding of the yet largely unknown function of GRHL2 in the initiation, progression and also therapy of cancers. What's new? Transcription factor "grainyhead-like 2" (GRHL2) acts as a tumour suppressor in breast cancer, but it may have tumour-promoting activities in other cancers. In this study using immunohistochemistry and tissue microarrays, the authors found that GRHL2 expression is dysregulated in a broad range of malignant tumours, including astrocytoma, melanoma, breast and ovarian cancers. These results indicate that GRHL2 may offer a potential therapeutic target, and further studies should enhance our understanding of its role in numerous types of cancer. © 2015 UICC.


PubMed | Practice of Pathology and University of Hamburg
Type: Journal Article | Journal: International journal of cancer | Year: 2016

The transcription factor grainyhead-like 2 (GRHL2) plays a crucial role in various developmental processes. Although GRHL2 recently has attracted considerable interest in that it could be identified as a novel suppressor of the epithelial-to-mesenchymal transition, evidence is emerging that GRHL2 also exhibits tumour-promoting activities. Aim of the present study therefore was to help defining the relevance of GRHL2 for human cancers by performing a comprehensive immunohistochemical analysis of GRHL2 expression in normal (n = 608) and (n = 3,143) tumour tissues using tissue microarrays. Consistent with its accepted role in epithelial morphogenesis, GRHL2 expression preferentially but not exclusively was observed in epithelial cells. Regenerative and proliferating epithelial cells with stem cell features showed a strong GRHL2 expression. Highly complex GRHL2 expression patterns indicative of both reduced and elevated GRHL2 expression in tumours, possibly reflecting potential tumour-suppressing as well as oncogenic functions of GRHL2 in distinct human tumours, were observed. A dysregulation of GRHL2 expression for the first time was found in tumours of non-epithelial origin (e.g., astrocytomas, melanomas). We also report GRHL2 copy number gains which, however, did not necessarily translate into increased GRHL2 expression levels in cancer cells. Results obtained by meta-analysis of gene expression microarray data in conjunction with functional assays demonstrating a direct regulation of HER3 expression further point to a potential therapeutic relevance of GRHL2 in ovarian cancer. Hopefully, the results presented in this study may pave the way for a better understanding of the yet largely unknown function of GRHL2 in the initiation, progression and also therapy of cancers.


Reifschneider O.,University of Munster | Wehe C.A.,University of Munster | Diebold K.,Practice of Pathology | Becker C.,Practice of Oral and Maxillofacial Surgery | And 3 more authors.
Journal of Analytical Atomic Spectrometry | Year: 2013

Haematoxylin and eosin are frequently used histological stains ("H & E-stains") for the visualization of tissue structures, which is particularly important for the diagnosis of various diseases including cancer. These stains contain aluminum and bromine in their chemical structures, thus providing access for their visualization by means of ICP-MS imaging. Different tissues including appendix, lymph nodes, Fallopian tube and esophageal tumor were investigated. By means of this novel approach, orthogonal data in comparison to optical micrographs, commonly used by the pathologist, were obtained. Hence, different entities of the parallel or serial tissue sections can now be allocated to the manifold set of elemental information acquired by LA-ICP-MS. In surgically removed and H & E-stained human tissues, the images of aluminum and bromine with resolution down to 10 μm were generated. In addition, elemental distribution maps of carbon, aluminum, bromine and platinum in unstained and stained human esophageal tumor sections after Cisplatin therapy were generated, showing a further expanding the capabilities of this technique. As both stained and unstained samples showed a similar platinum distribution, integrity of the platinum distribution after the staining process could be verified. In addition, no significant background of aluminum or bromine in unstained samples was observed, showing the successful reduction of polyatomic, isobaric interferences by utilization of a collision/reaction cell. This journal is © The Royal Society of Chemistry.


Herdering C.,University of Munster | Wehe C.A.,University of Munster | Reifschneider O.,University of Munster | Raj I.,The Interdisciplinary Center | And 6 more authors.
Rapid Communications in Mass Spectrometry | Year: 2013

RATIONALE Biological functions of metals are not only specified by the element itself, but also by its chemical form and by its organ, cell and subcellular location. The developed laser ablation based setup enables spatially resolved analysis with simultaneous elemental and molecular mass spectrometry (MS) and promises therefore localization, identification and quantification of metal or heteroelement-containing species in biological samples such as tissue sections. METHODS A UV laser ablation (LA) system is hyphenated in parallel both with an elemental and a molecular mass spectrometer via flow splitted transfer lines to simultaneously obtain data from both of the mass spectrometers. Elemental MS was performed using inductively coupled plasma (ICP)-MS, whereas atmospheric pressure chemical ionization (APCI)-MS with an orbitrap mass analyzer was utilized for molecular MS. RESULTS Simultaneous elemental and molecular MS imaging with high lateral resolution down to 25 μm was presented for the staining agents eosin Y and haematoxylin as well as for the chemotherapy drug cisplatin in thin tissue sections. For molecular MS, target compounds were identified by their exact masses and by characteristic fragment ions. CONCLUSIONS The first simultaneous elemental and molecular MS imaging approach based on laser ablation sampling was introduced for spatially resolved speciation analysis. The combination of the advantages of LA-ICP-MS such as low detection limits and high spatial resolution with information on the chemical identity promises not only localization of metals, but also identification of metal species in biological samples. Therefore, this novel technique opens up new possibilities to address complex challenges in life science research. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.

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