Torsten Reichert - Academia.edu (original) (raw)

Papers by Torsten Reichert

Carcinogenesis, 2015

Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is inv... more Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is involved in oral squamous cell carcinoma (OSCC) and glioblastoma progression. The NC11 domain of collagen XVI has been described previously with a strong implication in physiological processes. We detected the non-collagenous (NC) 11-domain in supernatants of OSCC cells after recombinant expression of full-length collagen XVI and in sera from OSCC patients and healthy individuals. Stable expression of NC11-green fluorescent protein (GFP) fusion protein in OSCC cells initiated proliferation control and block of anchorage-independent growth. Moreover, the NC11 domain triggered the generation of tubular-like net structures on laminin-rich matrix in contrast to mock-GFP control cells and cells expressing full-length collagen XVI. Taqman® quantitative PCR and diaminobenzidine staining in 2D- and 3D cell culture revealed a significantly increased gene and protein expression of VEGFR1, VEGFR2 and uPAR in recombinant NC11-GFP-expressing cells. Specific VEGF receptor inhibition with Axitinib or fetal calf serum heat inactivation prevented formation of tubular-like net structures. Accordantly, NC11-GFP coated culture slides led to an increase of focal adhesion contact formation and the upregulation of VEGFR1 and uPAR in three different non-transfected OSCC cell lines. In summary, we suggest that the NC11 domain of collagen XVI is a potential biomarker for OSCC and triggers vasculogenic mimicry via upregulation of endothelial receptors VEGFR1, VEGFR2 and uPAR in 2D- and 3D OSCC cell culture conditions.

Der MKG-Chirurg, 2011

ABSTRACT Die periapikale ossäre Dysplasie aus der Gruppe der ossären Dysplasien stellt eine Erkra... more ABSTRACT Die periapikale ossäre Dysplasie aus der Gruppe der ossären Dysplasien stellt eine Erkrankung dysplastischer Genese dar, die überwiegend bei Frauen im mittleren Alter vornehmlich im Bereich der Unterkieferfrontzähne manifest wird. Diese zeigen bei erhaltener Vitalität der betroffenen Zähne im Initialstadium periapikal lokalisierte Osteolysen, die sukzessive mineralisieren und schlussendlich als röntgendichte Strukturen mit transluzentem Randsaum imponieren. Eine differenzialdiagnostische Abgrenzung muss vor allem zur Parodontitis apicalis chronica erfolgen, um eine nicht indizierte Trepanation oder Extraktion des Zahnes zu unterlassen. Da die periapikale ossäre Dysplasie einen selbstlimitierenden Krankheitsverlauf zeigt, kann auf eine weitere Therapie zugunsten regelmäßiger klinisch-radiologischer Verlaufskontrollen verzichtet werden.

Trials, 2009

Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. Howe... more Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation. The present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients ...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2002

We have reported earlier that T cells found in the tumor microenvironment of head and neck cancer... more We have reported earlier that T cells found in the tumor microenvironment of head and neck cancer showed evidence of apoptosis as well as decreased expression of signaling molecules. In this prospective study, spontaneous apoptosis in tumor-infiltrating lymphocytes (TILs) and in paired circulating peripheral blood lymphocytes (PBLs) was evaluated in 28 patients with oral carcinoma and correlated with zeta-chain expression and anti-CD3 antibody-induced proliferation of the PBL obtained from each patient. In addition, expression of CD3, CD4, and CD8 molecules on TIL and Fas ligand (FasL) on the tumor was studied by immunohistochemistry. Soluble FasL was measured in the patients' sera. PBL obtained from 20 age-matched normal donors was used as a control. Reduced zeta-chain expression was observed in TIL-T of 9 of 28 patients and in PBL-T of 12 of 28 patients. Low zeta expression in autologous TIL-T and PBL-T was correlated (P < 0.0012), and it was associated with high levels of ...

Head & Face Medicine, 2008

Background: With the 2005 WHO classification of salivary gland tumours and its increasingly recog... more Background: With the 2005 WHO classification of salivary gland tumours and its increasingly recognized diagnostic entities, the frequency of adenocarcinoma (NOS) has decreased significantly.

Head & Face Medicine, 2008

A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells with aggressive... more A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells with aggressive clinical behaviour and poor prognosis. Diagnosis is often delayed due to its variable and often benign clinical appearance. This case presents a 64-year-old man with a six-month-history of a recurrent diffuse and erythematous painless swelling below the left eye. Several resections with intraoperatively negative resection margins followed, but positive margins were repeatedly detected later on permanent sections. Histopathologic examination of the specimen diagnosed a cutaneous angiosarcoma. Neither, finally achieved negative margins on permanent sections, nor a following chemotherapy could prevent the recurrence of the disease after five months and the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s dead 21 months after the first diagnosis. The case elucidates the current diagnostic and therapeutic dilemma of this entity, which shows an unfavourable clinical course in spite of multimodal therapy.

The immunological response to solid tumours is insufficient. Therefore, tumour specific antigens ... more The immunological response to solid tumours is insufficient. Therefore, tumour specific antigens have been explored to facilitate the activation of the immune system. The cancer/ testis antigen class of MAGE-A antigens is a possible target for vaccination. Their differential expression profiles also modulate the course of the cancer disease and its response to antineoplastic drugs.

PLoS ONE, 2014

Collagen XVI belongs to the family of fibril-associated collagens with interrupted triple helices... more Collagen XVI belongs to the family of fibril-associated collagens with interrupted triple helices (FACIT). It is overexpressed during the progression of oral squamous cell carcinoma (OSCC). The present data show a strong collagen XVI-dependent induction of MMP9 and an increase in OSCC cell invasion. We found activated integrin-linked kinase (ILK) in a complex with kindlin-1 and activation of protein kinase B (PKB/Akt) to be responsible for MMP9 induction. Inhibition of the formation of focal adhesions reduced MMP9 expression. Moreover, collagen XVI overexpressing OSCC cell clones (COLXVI cell clones) transfected with vectors containing different MMP9 promoter fragments adjacent to a luciferase reporter revealed an increase in luciferase signal dependent on AP-1 binding sites. Deletion of the AP-1 binding site 98 bp upstream of the reported transcription start site and inhibition of AP-1 with Tanshinone IIA resulted in decreased MMP9 expression. The AP-1 subunit JunB showed differential expression between COLXVI cell clones and mock control cells. Additionally, mass spectrometric analysis of immunoprecipitates revealed that c-Fos interacted strongly with dyskerin in COLXVI cell clones compared to mock controls.

Zeitschrift für Gastroenterologie, 2013

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal ro... more P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.

Journal of Leukocyte Biology, 2004

Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin... more Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precur-

Journal of Cranio-Maxillofacial Surgery, 2013

Introduction: Head and neck melanoma compromises a group of aggressive tumours with varying clini... more Introduction: Head and neck melanoma compromises a group of aggressive tumours with varying clinical courses. This analysis was performed to find anatomic and clinicopathological parameters predictive for lymph node metastasis and overall survival. Material and methods: Data and outcome of 246 patients with a malignant melanoma in the head and neck region were retrospectively analyzed for predictive parameters. Results: Lentigo maligna melanoma (n ¼ 115) was the most frequent histology, followed by superficial spreading (n ¼ 63) and nodular melanoma (n ¼ 52). More than half of the melanomas (n ¼ 138) were in the face. Tumours of the face and anterior scalp metastasized to lymph nodes of the neck and parotid gland, whereas tumours of the posterior scalp and neck also metastasized to the nuchal region. Advanced Clark level, presence of tumour ulceration and younger age were the strongest predictors of lymph node metastasis in multivariate regression analysis (p < 0.05), but anatomic site, histological subtype and tumour thickness were also associated with lymph node metastasis. Lymph node metastases, distant metastases, ulceration, nodular subtype and non-facial site of origin were the strongest negative prognostic parameters for disease-specific overall survival (p < 0.05). In contrast, the width of resection margin (<1 cm vs. 1e2 cm vs. >2 cm) did not correlate with tumour recurrence and overall survival (p > 0.05). Conclusion: Histological subtype diagnosis, anatomic site of origin as well as the established factors tumour thickness, ulceration and depth of invasion are prognostic indicators of cervical lymph node metastasis and overall survival. A resection margin of at least 1 cm seems sufficient in head and neck melanoma. The status of sentinel lymph node biopsy and neck dissection has to be proven within the next years.

International Journal of Cancer, 2009

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carc... more Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used for therapy of recurrent or metastatic disease; however, their mode of action is not completely understood. To investigate the immunological effects of anti-EGFR mAb, we generated a three-dimensional spheroid model of EGFR-expressing SCCHN and used this model to study the effect of anti-EGFR mAb on leukocyte migration toward tumors. Pretreatment with the blocking anti-EGFR mAb EMD 72000, its F(ab 0 )2 fragments or an EGFR tyrosine kinase inhibitor led to substantially increased leukocyte infiltration into EGFR overexpressing tumor spheroids, but not into those with low EGFR expression. Nonblocking anti-EGFR mAb or fibroblast-specific mAb did not affect leukocyte infiltration, suggesting that the observed increase in leukocyte infiltration depends on interference with EGFR activation. Using a human cytokine macroarray, we demonstrated that the blockade of EGFR by anti-EGFR mAb in EGFR-overexpressing SCCHN cells leads to differential expression of several cytokines and chemokines, including the chemokine MCP-1/CCL-2. The significant upregulation of MCP-1/CCL2 on exposure to anti-EGFR mAb was confirmed by quantitative PCR and enzyme-linked immunospot analyses. Moreover, blocking anti-MCP-1 antibody inhibited leukocyte migration toward tumor cells induced by anti-EGFR mAb, pointing to an important role of MCP-1/CCL2 in anti-EGFR mAb-induced leukocyte migration. Our findings demonstrate that anti-EGFR mAb induces leukocyte infiltration to tumor spheroids by upregulating chemokine expression. This novel mechanism for anti-EGFR mAb action may contribute to the antitumor effects of anti-EGFR mAb in vivo.

ELECTROPHORESIS, 2009

Recently, there has been an increased interest in unravelling the molecular mechanisms and cellul... more Recently, there has been an increased interest in unravelling the molecular mechanisms and cellular pathways controlling the differentiation and proliferation of human stem cell lines. Proteome analysis has proven to be an effective approach to comprehensive analysis of the regulatory network of differentiation. In the present study we applied 2-DE combined with capillary-LC-MS/MS analysis to profile differentially regulated proteins upon differentiation of dental follicle precursor cells (DFPCs). Out of 115 differentially regulated proteins, glutamine synthetase, lysosomal proteinase cathepsin B proteins, plastin 3 T-isoform, beta-actin, superoxide dismutases, and transgelin were found to be highly up-regulated, whereas cofilin-1, pro-alpha 1 collagen, destrin, prolyl 4-hydrolase and dihydrolipoamide dehydrogenase were found to be highly down-regulated. The group of up-regulated proteins is associated with actin-bundling and defence against oxidative cellular stress, whereas down-regulated proteins were associated with collagen biosynthesis. Bioinformatic analyses of the entire data set confirmed these findings that represent significant steps towards the understanding of DFPC differentiation. The bioinformatic analyses suggest that proteins associated with cell cycle progression and protein metabolism were down-regulated and proteins involved in catabolism, cell motility and biological quality were up-regulated. These results display the general physiological state of DFPCs before and after osteogenic differentiation. We also identified regulatory proteins, such as the transcription factors TP53 and Sp-1, associated with the differentiation process. Further studies will investigate the impact of identified regulatory proteins for cell proliferation and osteogenic differentiation in DFPCs.

Differentiation, 2012

P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecu... more P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecules. In the normal oral epithelium it shows a strong expression in the basal cell layer which gradually decreases in the suprabasal cell layers. The exact role of P-cadherin during the development and homeostasis of the oral epithelium has not been elucidated, yet. Here, we show for the first time that P-cadherin controls differentiation by regulating cytokeratin (CK) 1/10 expression in primary oral keratinocytes (POK) from normal, but interestingly not in POKs from oral squamous cell carcinoma (OSCC) tissue. SiRNA knockdown of P-cadherin in normal POKs revealed a strong upregulation of CK1/10 expression on mRNA and protein level. In contrast, E-cadherin knockdown in normal oral keratinocytes did not show any influence on CK1/10 expression. Moreover, in comparison with normal control keratinocytes normal oral keratinocytes with reduced P-cadherin expression displayed an enhanced expression and a stronger nuclear staining of C/EBP-beta, a well-known regulator of CK1/10 expression in keratinocytes. Furthermore, after P-cadherin knockdown in normal POKs the promoter activity of a C/EBP-responsive luciferase construct was significantly higher than in normal POKs with regular P-cadherin expression. Additionally, we noticed a proliferation advantage in normal oral keratinocytes in contrast to keratinocytes with diminished P-cadherin expression. However, the inverted effect was seen in tumor derived primary oral keratinocytes. In summary, we show that P-cadherin contributes to the keratinocyte differentiation in the oral epithelium by influencing the CK1 and CK10 expression via C/EBP-beta-mediated signaling in normal but not in tumor derived oral keratinocytes from OSCC patients.

Clinical Oral Implants Research, 2014

The aim of this study was to compare crestal bone-level changes, soft tissue parameters and impla... more The aim of this study was to compare crestal bone-level changes, soft tissue parameters and implant success and survival between small-diameter implants made of titanium/zirconium (TiZr) alloy or of Grade IV titanium (Ti) in edentulous mandibles restored with removable overdentures. This was a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann bone-level implants (diameter 3.3 mm), one of Ti Grade IV (control) and one of TiZr (test), in the interforaminal region. Implants were loaded after 6-8 weeks and removable Locator-retained overdentures were placed within 2 weeks of loading. Modified plaque and sulcus bleeding indices, radiographic bone level, and implant survival and success were evaluated up to 36 months. Of 91 treated patients, 75 completed the three-year follow-up. Three implants were lost (two control and one test implant). The survival rates were 98.7% and 97.3%, and the mean marginal bone level change was -0.78 ± 0.75 and -0.60 ± 0.71 mm for TiZr and Ti Grade IV implants. Most patients had a plaque score of 0 or 1 (54% for test and 51.7% for control), and a sulcus bleeding score of 0 (46.1% for test and 44.9% for control). No significant differences were found between the two implant types for bone-level change, soft tissue parameters, survival and success. After 36 months, similar outcomes were found between Ti Grade IV and TiZr implants. The results confirm that the results seen at 12 months continue over time.

Clinical Implant Dentistry and Related Research, 2012

The use of endosseous dental implants has become common practice for the rehabilitation of edentu... more The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two-implant overdenture has been recommended as the standard of care. The use of small-diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. This randomized, controlled, double-blind, multicenter study investigated in a split-mouth model whether small-diameter implants made from Titanium-13Zirconium alloy (TiZr, Roxolid™) perform at least as well as Titanium Grade IV implants. Patients with an edentulous mandible received one TiZr and one Ti Grade IV small-diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double-blinded. Outcome measures included change in radiological peri-implant bone level from surgery to 12 months post-insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Of 91 treated patients, 87 were available for the 12-month follow-up. Peri-implant bone level change (-0.3 ± 0.5 mm vs -0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. This study confirms that TiZr small-diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.

Head & Face Medicine, 2008

Background: acantholytic squamous cell carcinomas (ASCC) and intraoral angiosarcoma share similar... more Background: acantholytic squamous cell carcinomas (ASCC) and intraoral angiosarcoma share similar histopathological features. Aim of this study was to find marker for a clear distinction.

Carcinogenesis, 2015

Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is inv... more Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is involved in oral squamous cell carcinoma (OSCC) and glioblastoma progression. The NC11 domain of collagen XVI has been described previously with a strong implication in physiological processes. We detected the non-collagenous (NC) 11-domain in supernatants of OSCC cells after recombinant expression of full-length collagen XVI and in sera from OSCC patients and healthy individuals. Stable expression of NC11-green fluorescent protein (GFP) fusion protein in OSCC cells initiated proliferation control and block of anchorage-independent growth. Moreover, the NC11 domain triggered the generation of tubular-like net structures on laminin-rich matrix in contrast to mock-GFP control cells and cells expressing full-length collagen XVI. Taqman® quantitative PCR and diaminobenzidine staining in 2D- and 3D cell culture revealed a significantly increased gene and protein expression of VEGFR1, VEGFR2 and uPAR in recombinant NC11-GFP-expressing cells. Specific VEGF receptor inhibition with Axitinib or fetal calf serum heat inactivation prevented formation of tubular-like net structures. Accordantly, NC11-GFP coated culture slides led to an increase of focal adhesion contact formation and the upregulation of VEGFR1 and uPAR in three different non-transfected OSCC cell lines. In summary, we suggest that the NC11 domain of collagen XVI is a potential biomarker for OSCC and triggers vasculogenic mimicry via upregulation of endothelial receptors VEGFR1, VEGFR2 and uPAR in 2D- and 3D OSCC cell culture conditions.

Der MKG-Chirurg, 2011

ABSTRACT Die periapikale ossäre Dysplasie aus der Gruppe der ossären Dysplasien stellt eine Erkra... more ABSTRACT Die periapikale ossäre Dysplasie aus der Gruppe der ossären Dysplasien stellt eine Erkrankung dysplastischer Genese dar, die überwiegend bei Frauen im mittleren Alter vornehmlich im Bereich der Unterkieferfrontzähne manifest wird. Diese zeigen bei erhaltener Vitalität der betroffenen Zähne im Initialstadium periapikal lokalisierte Osteolysen, die sukzessive mineralisieren und schlussendlich als röntgendichte Strukturen mit transluzentem Randsaum imponieren. Eine differenzialdiagnostische Abgrenzung muss vor allem zur Parodontitis apicalis chronica erfolgen, um eine nicht indizierte Trepanation oder Extraktion des Zahnes zu unterlassen. Da die periapikale ossäre Dysplasie einen selbstlimitierenden Krankheitsverlauf zeigt, kann auf eine weitere Therapie zugunsten regelmäßiger klinisch-radiologischer Verlaufskontrollen verzichtet werden.

Trials, 2009

Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. Howe... more Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation. The present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients ...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2002

We have reported earlier that T cells found in the tumor microenvironment of head and neck cancer... more We have reported earlier that T cells found in the tumor microenvironment of head and neck cancer showed evidence of apoptosis as well as decreased expression of signaling molecules. In this prospective study, spontaneous apoptosis in tumor-infiltrating lymphocytes (TILs) and in paired circulating peripheral blood lymphocytes (PBLs) was evaluated in 28 patients with oral carcinoma and correlated with zeta-chain expression and anti-CD3 antibody-induced proliferation of the PBL obtained from each patient. In addition, expression of CD3, CD4, and CD8 molecules on TIL and Fas ligand (FasL) on the tumor was studied by immunohistochemistry. Soluble FasL was measured in the patients' sera. PBL obtained from 20 age-matched normal donors was used as a control. Reduced zeta-chain expression was observed in TIL-T of 9 of 28 patients and in PBL-T of 12 of 28 patients. Low zeta expression in autologous TIL-T and PBL-T was correlated (P < 0.0012), and it was associated with high levels of ...

Head & Face Medicine, 2008

Background: With the 2005 WHO classification of salivary gland tumours and its increasingly recog... more Background: With the 2005 WHO classification of salivary gland tumours and its increasingly recognized diagnostic entities, the frequency of adenocarcinoma (NOS) has decreased significantly.

Head & Face Medicine, 2008

A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells with aggressive... more A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells with aggressive clinical behaviour and poor prognosis. Diagnosis is often delayed due to its variable and often benign clinical appearance. This case presents a 64-year-old man with a six-month-history of a recurrent diffuse and erythematous painless swelling below the left eye. Several resections with intraoperatively negative resection margins followed, but positive margins were repeatedly detected later on permanent sections. Histopathologic examination of the specimen diagnosed a cutaneous angiosarcoma. Neither, finally achieved negative margins on permanent sections, nor a following chemotherapy could prevent the recurrence of the disease after five months and the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s dead 21 months after the first diagnosis. The case elucidates the current diagnostic and therapeutic dilemma of this entity, which shows an unfavourable clinical course in spite of multimodal therapy.

The immunological response to solid tumours is insufficient. Therefore, tumour specific antigens ... more The immunological response to solid tumours is insufficient. Therefore, tumour specific antigens have been explored to facilitate the activation of the immune system. The cancer/ testis antigen class of MAGE-A antigens is a possible target for vaccination. Their differential expression profiles also modulate the course of the cancer disease and its response to antineoplastic drugs.

PLoS ONE, 2014

Collagen XVI belongs to the family of fibril-associated collagens with interrupted triple helices... more Collagen XVI belongs to the family of fibril-associated collagens with interrupted triple helices (FACIT). It is overexpressed during the progression of oral squamous cell carcinoma (OSCC). The present data show a strong collagen XVI-dependent induction of MMP9 and an increase in OSCC cell invasion. We found activated integrin-linked kinase (ILK) in a complex with kindlin-1 and activation of protein kinase B (PKB/Akt) to be responsible for MMP9 induction. Inhibition of the formation of focal adhesions reduced MMP9 expression. Moreover, collagen XVI overexpressing OSCC cell clones (COLXVI cell clones) transfected with vectors containing different MMP9 promoter fragments adjacent to a luciferase reporter revealed an increase in luciferase signal dependent on AP-1 binding sites. Deletion of the AP-1 binding site 98 bp upstream of the reported transcription start site and inhibition of AP-1 with Tanshinone IIA resulted in decreased MMP9 expression. The AP-1 subunit JunB showed differential expression between COLXVI cell clones and mock control cells. Additionally, mass spectrometric analysis of immunoprecipitates revealed that c-Fos interacted strongly with dyskerin in COLXVI cell clones compared to mock controls.

Zeitschrift für Gastroenterologie, 2013

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal ro... more P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.

Journal of Leukocyte Biology, 2004

Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin... more Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precur-

Journal of Cranio-Maxillofacial Surgery, 2013

Introduction: Head and neck melanoma compromises a group of aggressive tumours with varying clini... more Introduction: Head and neck melanoma compromises a group of aggressive tumours with varying clinical courses. This analysis was performed to find anatomic and clinicopathological parameters predictive for lymph node metastasis and overall survival. Material and methods: Data and outcome of 246 patients with a malignant melanoma in the head and neck region were retrospectively analyzed for predictive parameters. Results: Lentigo maligna melanoma (n ¼ 115) was the most frequent histology, followed by superficial spreading (n ¼ 63) and nodular melanoma (n ¼ 52). More than half of the melanomas (n ¼ 138) were in the face. Tumours of the face and anterior scalp metastasized to lymph nodes of the neck and parotid gland, whereas tumours of the posterior scalp and neck also metastasized to the nuchal region. Advanced Clark level, presence of tumour ulceration and younger age were the strongest predictors of lymph node metastasis in multivariate regression analysis (p < 0.05), but anatomic site, histological subtype and tumour thickness were also associated with lymph node metastasis. Lymph node metastases, distant metastases, ulceration, nodular subtype and non-facial site of origin were the strongest negative prognostic parameters for disease-specific overall survival (p < 0.05). In contrast, the width of resection margin (<1 cm vs. 1e2 cm vs. >2 cm) did not correlate with tumour recurrence and overall survival (p > 0.05). Conclusion: Histological subtype diagnosis, anatomic site of origin as well as the established factors tumour thickness, ulceration and depth of invasion are prognostic indicators of cervical lymph node metastasis and overall survival. A resection margin of at least 1 cm seems sufficient in head and neck melanoma. The status of sentinel lymph node biopsy and neck dissection has to be proven within the next years.

International Journal of Cancer, 2009

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carc... more Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used for therapy of recurrent or metastatic disease; however, their mode of action is not completely understood. To investigate the immunological effects of anti-EGFR mAb, we generated a three-dimensional spheroid model of EGFR-expressing SCCHN and used this model to study the effect of anti-EGFR mAb on leukocyte migration toward tumors. Pretreatment with the blocking anti-EGFR mAb EMD 72000, its F(ab 0 )2 fragments or an EGFR tyrosine kinase inhibitor led to substantially increased leukocyte infiltration into EGFR overexpressing tumor spheroids, but not into those with low EGFR expression. Nonblocking anti-EGFR mAb or fibroblast-specific mAb did not affect leukocyte infiltration, suggesting that the observed increase in leukocyte infiltration depends on interference with EGFR activation. Using a human cytokine macroarray, we demonstrated that the blockade of EGFR by anti-EGFR mAb in EGFR-overexpressing SCCHN cells leads to differential expression of several cytokines and chemokines, including the chemokine MCP-1/CCL-2. The significant upregulation of MCP-1/CCL2 on exposure to anti-EGFR mAb was confirmed by quantitative PCR and enzyme-linked immunospot analyses. Moreover, blocking anti-MCP-1 antibody inhibited leukocyte migration toward tumor cells induced by anti-EGFR mAb, pointing to an important role of MCP-1/CCL2 in anti-EGFR mAb-induced leukocyte migration. Our findings demonstrate that anti-EGFR mAb induces leukocyte infiltration to tumor spheroids by upregulating chemokine expression. This novel mechanism for anti-EGFR mAb action may contribute to the antitumor effects of anti-EGFR mAb in vivo.

ELECTROPHORESIS, 2009

Recently, there has been an increased interest in unravelling the molecular mechanisms and cellul... more Recently, there has been an increased interest in unravelling the molecular mechanisms and cellular pathways controlling the differentiation and proliferation of human stem cell lines. Proteome analysis has proven to be an effective approach to comprehensive analysis of the regulatory network of differentiation. In the present study we applied 2-DE combined with capillary-LC-MS/MS analysis to profile differentially regulated proteins upon differentiation of dental follicle precursor cells (DFPCs). Out of 115 differentially regulated proteins, glutamine synthetase, lysosomal proteinase cathepsin B proteins, plastin 3 T-isoform, beta-actin, superoxide dismutases, and transgelin were found to be highly up-regulated, whereas cofilin-1, pro-alpha 1 collagen, destrin, prolyl 4-hydrolase and dihydrolipoamide dehydrogenase were found to be highly down-regulated. The group of up-regulated proteins is associated with actin-bundling and defence against oxidative cellular stress, whereas down-regulated proteins were associated with collagen biosynthesis. Bioinformatic analyses of the entire data set confirmed these findings that represent significant steps towards the understanding of DFPC differentiation. The bioinformatic analyses suggest that proteins associated with cell cycle progression and protein metabolism were down-regulated and proteins involved in catabolism, cell motility and biological quality were up-regulated. These results display the general physiological state of DFPCs before and after osteogenic differentiation. We also identified regulatory proteins, such as the transcription factors TP53 and Sp-1, associated with the differentiation process. Further studies will investigate the impact of identified regulatory proteins for cell proliferation and osteogenic differentiation in DFPCs.

Differentiation, 2012

P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecu... more P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecules. In the normal oral epithelium it shows a strong expression in the basal cell layer which gradually decreases in the suprabasal cell layers. The exact role of P-cadherin during the development and homeostasis of the oral epithelium has not been elucidated, yet. Here, we show for the first time that P-cadherin controls differentiation by regulating cytokeratin (CK) 1/10 expression in primary oral keratinocytes (POK) from normal, but interestingly not in POKs from oral squamous cell carcinoma (OSCC) tissue. SiRNA knockdown of P-cadherin in normal POKs revealed a strong upregulation of CK1/10 expression on mRNA and protein level. In contrast, E-cadherin knockdown in normal oral keratinocytes did not show any influence on CK1/10 expression. Moreover, in comparison with normal control keratinocytes normal oral keratinocytes with reduced P-cadherin expression displayed an enhanced expression and a stronger nuclear staining of C/EBP-beta, a well-known regulator of CK1/10 expression in keratinocytes. Furthermore, after P-cadherin knockdown in normal POKs the promoter activity of a C/EBP-responsive luciferase construct was significantly higher than in normal POKs with regular P-cadherin expression. Additionally, we noticed a proliferation advantage in normal oral keratinocytes in contrast to keratinocytes with diminished P-cadherin expression. However, the inverted effect was seen in tumor derived primary oral keratinocytes. In summary, we show that P-cadherin contributes to the keratinocyte differentiation in the oral epithelium by influencing the CK1 and CK10 expression via C/EBP-beta-mediated signaling in normal but not in tumor derived oral keratinocytes from OSCC patients.

Clinical Oral Implants Research, 2014

The aim of this study was to compare crestal bone-level changes, soft tissue parameters and impla... more The aim of this study was to compare crestal bone-level changes, soft tissue parameters and implant success and survival between small-diameter implants made of titanium/zirconium (TiZr) alloy or of Grade IV titanium (Ti) in edentulous mandibles restored with removable overdentures. This was a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann bone-level implants (diameter 3.3 mm), one of Ti Grade IV (control) and one of TiZr (test), in the interforaminal region. Implants were loaded after 6-8 weeks and removable Locator-retained overdentures were placed within 2 weeks of loading. Modified plaque and sulcus bleeding indices, radiographic bone level, and implant survival and success were evaluated up to 36 months. Of 91 treated patients, 75 completed the three-year follow-up. Three implants were lost (two control and one test implant). The survival rates were 98.7% and 97.3%, and the mean marginal bone level change was -0.78 ± 0.75 and -0.60 ± 0.71 mm for TiZr and Ti Grade IV implants. Most patients had a plaque score of 0 or 1 (54% for test and 51.7% for control), and a sulcus bleeding score of 0 (46.1% for test and 44.9% for control). No significant differences were found between the two implant types for bone-level change, soft tissue parameters, survival and success. After 36 months, similar outcomes were found between Ti Grade IV and TiZr implants. The results confirm that the results seen at 12 months continue over time.

Clinical Implant Dentistry and Related Research, 2012

The use of endosseous dental implants has become common practice for the rehabilitation of edentu... more The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two-implant overdenture has been recommended as the standard of care. The use of small-diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. This randomized, controlled, double-blind, multicenter study investigated in a split-mouth model whether small-diameter implants made from Titanium-13Zirconium alloy (TiZr, Roxolid™) perform at least as well as Titanium Grade IV implants. Patients with an edentulous mandible received one TiZr and one Ti Grade IV small-diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double-blinded. Outcome measures included change in radiological peri-implant bone level from surgery to 12 months post-insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Of 91 treated patients, 87 were available for the 12-month follow-up. Peri-implant bone level change (-0.3 ± 0.5 mm vs -0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. This study confirms that TiZr small-diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.

Head & Face Medicine, 2008

Background: acantholytic squamous cell carcinomas (ASCC) and intraoral angiosarcoma share similar... more Background: acantholytic squamous cell carcinomas (ASCC) and intraoral angiosarcoma share similar histopathological features. Aim of this study was to find marker for a clear distinction.