Thomas Fillies

Publications of Thomas Fillies

• Analysis of differentially expressed proteins in oral squamous cell carcinoma by MALDI-TOF MS.

  Authors: Uta J E Thiel, Ralph Feltens, Boris Adryan, Rita Gieringer, Christoph Brochhausen, Robert Schuon, Thomas Fillies, Franz Grus, Wolf J Mann, Juergen Brieger

  Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 12/2010; 40(5):369-79.

  To explore the presence of differentially expressed proteins in OSCC for discrimination of tumour and normal mucosa to establish potential biomarkers and therapeutic targets. Paired protein samplesTo explore the presence of differentially expressed proteins in OSCC for discrimination of tumour and normal mucosa to establish potential biomarkers and therapeutic targets. Paired protein samples of 12 individuals (tongue cancer and non-cancerous mucosa) were separated by two-dimensional polyacrylamid gel electrophoresis. The protein patterns were compared pairwise and protein spots were quantified. We identified about 70 regulated proteins which we subsequently identified by MALDI-TOF mass spectrometry. Cancerous and non-cancerous tissues could be most precisely distinguished by a panel of proteins. They include the heat shock proteins (hsp)70 and 90, keratins (ck) 5, 6, 13, 14, 16, 17 and 19, beta globin, alpha-2-actin, stratifin, tropomyosin, calreticulin precursor, beta-2-tubulin, galectin7, thioredoxin, involucrin, adenylyl-cyclase-associated protein, disulfide isomerase-associated protein, thyrosine 3-monooxygenase, MYL2 and the s100 calcium binding protein. MYL3, cardiac muscle alpha actin 1 proprotein and transferrin were under-represented in OSCC. Six biomarkers, ck6 und ck13, beta globin, alpha-2-actin, hsp70 and hsp90 discriminated best between cancerous and non-cancerous oral tissues. All over-expressed proteins were analysed by STRING-analysis to highlight experimentally determined and computationally predicted interactions between the proteins. Especially involucrin, hsp70, calreticulin precursor, stratifin, (ck) 5, 6, 14, 19, tyrosine 3-monooxygenase, beta-2-tubulin and disulfide isomerase associated protein showed multiple relations. We identified six proteins which are differentially expressed in most OSCC compared to healthy tissues. Of those, by string analysis, multiple interaction partners are assumed for hsp70. This protein is supposed to be the most promising candidate as marker molecule and target for OSCC therapy.

• Cytokeratin alteration in oral leukoplakia and oral squamous cell carcinoma.

  Authors: Thomas Fillies, Mirco Jogschies, Johannes Kleinheinz, Burkhard Brandt, Ulrich Joos, Horst Buerger

  Oncology reports. 09/2007; 18(3):639-43.

  Intermediate filaments are involved in cell migration and intracellular signal transduction pathways. In a variety of organs, the expression of distinct intermediary filaments are further associatedIntermediate filaments are involved in cell migration and intracellular signal transduction pathways. In a variety of organs, the expression of distinct intermediary filaments are further associated with distinct steps of malignant transformation. In this study, we seeked to define the cytokeratin (Ck) expression pattern in oral leukoplakia and oral squamous cell carcinoma (OSCC). One hundred and ninety-two patients with OSCC, 117 patients with oral leukoplakia without dysplasia (OL) and 23 with oral leukoplakia with dysplasia (squamous intraepithelial neoplasia) (OLD) of the oral cavity were investigated for the immunohistochemical expression of Ck 5-6, Ck 8/18, Ck 1 Ck 10, Ck 14, Ck 19 using the tissue microarray technique. Correlations between clinical features and the expression of cytokeratins were evaluated statistically by chi2 tests. The expression of Ck 8/18, Ck 19 and Ck 1 was seen in 3.1% (Ck 8/18), 12.5% (Ck 19), 75.4% (Ck 1) of all leukoplakias, 1.0% (Ck 8/18), 9.4% (Ck 19), 76.8% (Ck 1) in OL, 13.0% (Ck 8/18), 27.3% (Ck 19), 68.4% (Ck 1) in OLD and was significantly associated with the degree of dysplasia (Ck 8/18 p<0.01; Ck 19 p<0.01; Ck 1 p<0.01) and the acquisition of invasive growth properties. The highest frequencies were observed in invasive squamous cell carcinomas. The expression of Ck 8/18 and Ck 19 in transformed oral lesions can be regarded as an early feature in the pathogenesis of invasive OSCC. However, the aberrant expression of Ck 8/18 and Ck 19 in an even higher frequency in invasive carcinomas characterizes the expression of typical glandular cytokeratins as a general progression marker in squamous cell carcinomas. These results can be interpreted as first hints that oral leukoplakias with an expression of Ck 8/18 or 19 independent of dysplasia, should be resected totally since they might indicate an increased progression potential.

• Cell cycle regulating proteins p21 and p27 in prognosis of oral squamous cell carcinomas.

  Authors: Thomas Fillies, Mike Woltering, Burkhard Brandt, Jean-Paul Van Diest, Richard Werkmeister, Ulrich Joos, Horst Buerger

  Oncology reports. 03/2007; 17(2):355-9.

  Cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs), such as p21 and p27, exert a direct control on the cell cycle. p21 and p27 are negative regulators of cyclin-dependentCyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs), such as p21 and p27, exert a direct control on the cell cycle. p21 and p27 are negative regulators of cyclin-dependent kinases and in this function they are negative check-point regulators of the cell cycle. We therefore aimed to evaluate p21 and p27 expression in oral squamous cell carcinomas (OSSC) to determine the value as a prognostic marker. One hundred and ninety-two patients with histologically proven, surgically treated squamous cell carcinoma of the oral cavity were eligible for the study and investigated for the expression of p21 and p27 by means of tissue microarrays (TMAs). Immunohistochemical screening under identical condition were carried out with antibodies against p21 and p27. Correlations between clinical features and the expression of the respective antibodies were evaluated statistically by Kaplan-Meier curves, log-rank and chi(2) tests. The expression of p21 correlated significantly with an increased prognosis in the log-rang test (p=0.01). No significant correlation was found between the expression of p27 and the overall survival rate. In multivariate Cox analysis, p27 was indicated as independent predictor of survival prognosis in the subgroup of nodal positive carcinomas, p27 positive tumours showed a significantly better survival prognosis (p=0.03). p21 and p27 in carcinoma of oral cavity seem to be predictive parameter in regulation and prognosis of squamous cell carcinomas. A p21 negative subgroup of OSCC may benefit from additional radio or radiochemotherapy.

• Perioperative complications in infant cleft repair.

  Authors: Thomas Fillies, Christoph Homann, Ulrich Meyer, Alexander Reich, Ulrich Joos, Richard Werkmeister

  Head & face medicine. 02/2007; 3:9.

  BACKGROUND: Cleft surgery in infants includes special risks due to the kind of the malformation. These risks can be attributed in part to the age and the weight of the patient. Whereas a lot ofBACKGROUND: Cleft surgery in infants includes special risks due to the kind of the malformation. These risks can be attributed in part to the age and the weight of the patient. Whereas a lot of studies investigated the long-term facial outcome of cleft surgery depending on the age at operation, less is known about the complications arising during a cleft surgery in early infancy. METHODS: We investigated the incidence and severity of perioperative complications in 174 infants undergoing primary cleft surgery. The severity and the complications were recorded during the intraoperative and the early postoperative period according to the classification by Cohen. RESULTS: Our study revealed that minor complications occurred in 50 patients. Severe complications were observed during 13 operations. There was no fatal complication in the perioperative period. The risk of complications was found to be directly correlated to the body weight at the time of the surgery. Most of the problems appeared intraoperatively, but they were also followed by complications immediately after the extubation. CONCLUSION: In conclusion, cleft surgery in infancy is accompanied by frequent and sometimes severe perioperative complications that may be attributed to this special surgical field.

• Cytokeratin 8/18 expression indicates a poor prognosis in squamous cell carcinomas of the oral cavity.

  Authors: Thomas Fillies, Richard Werkmeister, Jens Packeisen, Burkhard Brandt, Philippe Morin, Dieter Weingart, Ulrich Joos, Horst Buerger

  BMC cancer. 02/2006; 6:10.

  BACKGROUND: Intermediary filaments are involved in cell motility and cancer progression. In a variety of organs, the expression of distinct intermediary filaments are associated with patientBACKGROUND: Intermediary filaments are involved in cell motility and cancer progression. In a variety of organs, the expression of distinct intermediary filaments are associated with patient prognosis. In this study, we seeked to define the prognostic potential of cytokeratin and vimentin expression patterns in squamous cell carcinomas (SCC's) of the oral cavity. METHODS: 308 patients with histologically proven and surgically treated squamous cell carcinomas of the oral cavity were investigated for the immunohistochemical expression of a variety of intermediary filaments including high- and low-molecular weight cytokeratins (Ck's), such as Ck 5/6, Ck 8/18, Ck 1, CK 10, Ck 14, Ck 19 and vimentin, using the tissue microarray technique. Correlations between clinical features and the expression of Cytokeratins and vimentin were evaluated statistically by Kaplan-Meier curves and multivariate Cox regression analysis. RESULTS: The expression of Ck 8/18 and Ck 19 were overall significantly correlated with a poor clinical prognosis (Ck 8/18 p = 0.04; Ck19 p < 0.01). These findings could also be reproduced for Ck 8/18 in primary nodal-negative SCC's and held true in multivariate-analysis. No significant correlation with patient prognosis could be found for the expression of the other cytokeratins and for vimentin. CONCLUSION: The expression of Ck 8/18 in SCC's of the oral cavity is an independent prognostic marker and indicates a decreased overall and progression free survival. These results provide an extended knowledge about the role of intermediary filament expression patterns in SCC's.

• Vascular basis of mucosal color.

  Authors: Johannes Kleinheinz, André Büchter, Thomas Fillies, Ulrich Joos

  Head & face medicine. 09/2005; 1:4.

  BACKGROUND: Besides the color of the teeth the color of the alveolar gingiva plays a crucial role in esthetic rehabilitation in dento-alveolar treatment. Whereas nowadays the color of the teeth canBACKGROUND: Besides the color of the teeth the color of the alveolar gingiva plays a crucial role in esthetic rehabilitation in dento-alveolar treatment. Whereas nowadays the color of the teeth can be determined exactly and individually, the specific influence of the red color of the gingiva on treatment has not been assessed yet. The aim of this study was to evaluate the vascularization as the basis for gingival esthetics. METHODS: Standardized photographs of defined areas of the alveolar gingiva in operated and non-operated patients were taken and assigned to groups with same characteristics after color comparisons. In addition, histologic and immunohistologic analyses of gingival specimens were performed for qualitative and quantitative assessment of vessels and vascularization. Finally, colors and number of vessels were correlated. RESULTS: Our results demonstrated three different constellations of colors of the alveolar gingiva in healthy patients. The operated patients could not be grouped because of disparate depiction. There was a clear correlation between color and vessel number in the alveolar gingiva. CONCLUSION: Our investigations revealed the connections between vascularization and gingival color. Recommendations for specific change or even selection of colors based on the results cannot be given, but the importance of vascularly based incision lines was demonstrated.

• Relationship between lower wisdom tooth position and cyst development, deep abscess formation and mandibular angle fracture.

  Authors: Richard Werkmeister, Thomas Fillies, Ulrich Joos, Koord Smolka

  Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 07/2005; 33(3):164-8.

  AIM: There is an ongoing controversy about indications for prophylactic removal of third molars. The purpose of this retrospective study was to clarify the risk of preservation of lower third molars.AIM: There is an ongoing controversy about indications for prophylactic removal of third molars. The purpose of this retrospective study was to clarify the risk of preservation of lower third molars. MATERIAL AND METHOD: In a 5-year period, 316 patients were registered who had received in-patient treatment for deep abscess formation, cyst formation or mandibular angle fracture in relation to lower third molars. A radiological analysis (panoramic radiographs) was performed to determine whether major pathological changes associated with lower wisdom teeth are related to their position. Third molar positions were studied in this in-patient group and in an out-patient group. The latter consisted of 300 consecutive patients with prophylactically removed impacted third molars without any pathology. The relationship between the positions and the different pathological changes associated with impacted lower wisdom teeth was analysed statistically using a new 'position score'. RESULTS: The study revealed that the highest 'position scores' corresponding to a leading aberrant position correlated significantly with cyst formation. Lower scores corresponding to moderately aberrant or slightly irregular position were found with angle fractures, abscess formation, and in the control group as a whole. CONCLUSION: This study indicates that prophylactic third molar surgery for teeth with high and strongly elevated 'position scores' is appropriate in order to prevent cyst formation or mandibular angle fractures in a population at risk for facial trauma. In addition to other factors, 'position score' data could be useful for development of a model for predicting severe complications related to (removal of) impacted lower wisdom teeth.

• A clinical phase I/II trial of rhIL-4 applied topically in patients with oral squamous cell carcinomas to assess safety and therapeutic activity.

  Authors: Richard Werkmeister, Thomas Fillies, Christoph Gaertner, Ulrich Joos, Wolfgang E Berdel

  Oncology reports. 04/2005; 13(3):449-52.

  Besides its immunoregulatory effects, interleukin-4 (IL-4) has growth inhibitory activity on cells from human solid tumors, and IL-4 receptors are present on tumor cells including cells from head andBesides its immunoregulatory effects, interleukin-4 (IL-4) has growth inhibitory activity on cells from human solid tumors, and IL-4 receptors are present on tumor cells including cells from head and neck squamous cell carcinomas. We have conducted a phase I/II trial in patients with oral squamous cell carcinomas of T(4), N(+) (1 exception) stage to assess safety and therapeutic activity of recombinant human (rh) IL-4 applying the drug intratumorally 3 times a week with dose escalation for a duration of 4 weeks. A total of 7 patients entered the study using doses of 1, 3, and 5 microg/kg. There was no reduction of tumor size with 1 patient showing clear progression of the tumor after 4 weeks of treatment. This, and the observation of limiting toxicity occurring as local pain at the injection site, led to study termination. Therefore, rhIL-4 cannot be recommended as an antitumor drug in this disease using monotherapy with the schedules applied in this trial.

• HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor

  Authors: Thomas Fillies, Richard Werkmeister, van Diest Paul, Burkhard Brandt, Ulrich Joos, Horst Buerger

  BMC Cancer. 01/2005;

  Abstract Background Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, which plays a central role in biologic processes under hypoxic conditions, especially concerning tumourAbstract Background Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, which plays a central role in biologic processes under hypoxic conditions, especially concerning tumour angiogenesis. HIF-1α is the relevant, oxygen-dependent subunit and its overexpression has been associated with a poor prognosis in a variety of malignant tumours. Therefore, HIF-1α expression in early stage oral carcinomas was evaluated in relation to established clinico-pathological features in order to determine its value as a prognostic marker. Methods 85 patients with histologically proven surgically treated T1/2 squamous cell carcinoma (SCC) of the oral floor were eligible for the study. Tumor specimens were investigated by means of tissue micro arrays (TMAs) and immunohistochemistry for the expression of HIF-1. Correlations between clinical features and the expression of HIF-1 were evaluated by Kaplan-Meier curves, log-rank tests and multivariate Cox regression analysis. Results HIF-1α was frequently overexpressed in a probably non-hypoxia related fashion. The expression of HIF-1α was related with a significantly improved 5-year survival rate (p < 0.01) and a significantly increased disease free period (p = 0.01) independent from nodal status and tumour size. In primary node negative T1/T2 SCC of the oral floor, absence of HIF-1α expression specified a subgroup of high-risk patients (p < 0.05). Conclusion HIF-1α overexpression is an indicator of favourable prognosis in T1 and T2 SCC of the oral floor. Node negative patients lacking HIF-1α expression may therefore be considered for adjuvant radiotherapy.

• HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor.

  Authors: Thomas Fillies, Richard Werkmeister, Paul J van Diest, Burkhard Brandt, Ulrich Joos, Horst Buerger

  BMC cancer. 01/2005; 5:84.

  BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, which plays a central role in biologic processes under hypoxic conditions, especially concerning tumour angiogenesis.BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, which plays a central role in biologic processes under hypoxic conditions, especially concerning tumour angiogenesis. HIF-1alpha is the relevant, oxygen-dependent subunit and its overexpression has been associated with a poor prognosis in a variety of malignant tumours. Therefore, HIF-1alpha expression in early stage oral carcinomas was evaluated in relation to established clinico-pathological features in order to determine its value as a prognostic marker. METHODS: 85 patients with histologically proven surgically treated T1/2 squamous cell carcinoma (SCC) of the oral floor were eligible for the study. Tumor specimens were investigated by means of tissue micro arrays (TMAs) and immunohistochemistry for the expression of HIF-1. Correlations between clinical features and the expression of HIF-1 were evaluated by Kaplan-Meier curves, log-rank tests and multivariate Cox regression analysis. RESULTS: HIF-1alpha was frequently overexpressed in a probably non-hypoxia related fashion. The expression of HIF-1alpha was related with a significantly improved 5-year survival rate (p < 0.01) and a significantly increased disease free period (p = 0.01) independent from nodal status and tumour size. In primary node negative T1/T2 SCC of the oral floor, absence of HIF-1alpha expression specified a subgroup of high-risk patients (p < 0.05). CONCLUSION: HIF-1alpha overexpression is an indicator of favourable prognosis in T1 and T2 SCC of the oral floor. Node negative patients lacking HIF-1alpha expression may therefore be considered for adjuvant radiotherapy.

• Early tissue reaction at the interface of immediately loaded dental implants.

  Authors: Ulrich Meyer, Hans-Peter Wiesmann, Thomas Fillies, Ulrich Joos

  The International journal of oral & maxillofacial implants. 18(4):489-99.

  PURPOSE: The treatment of patients with early or immediately loaded dental implants has renewed interest in the behavior of osteoblasts at the implant surface under load. A newly designed dentalPURPOSE: The treatment of patients with early or immediately loaded dental implants has renewed interest in the behavior of osteoblasts at the implant surface under load. A newly designed dental implant indicated for immediate loading was tested in vivo for early stages of osteoblast behavior at the implant surface. MATERIALS AND METHODS: Thirty-two implants were placed in the mandibles of 8 minipigs. Half of the implants (n = 16) were immediately loaded under occlusal contacts, and implants placed in non-occlusal relations served as a control. RESULTS: All implants, except 1 that showed signs of tissue infection, healed uneventfully and were stable throughout the experimental period. Ultrastructural analysis of mandibular specimens revealed an intimate attachment of osteoblasts to the material surface beginning as early as day 1. Application of either occlusal or non-occlusal load did not alter the phenotypic morphology of the attached osteoblasts. Transmission electron microscopy and x-ray diffraction analysis demonstrated a direct contact of bone-like minerals over the whole implant surface with no signs of crestal hard tissue alteration. Electron diffraction analysis showed a slight release of titanium from the implant side. DISCUSSION: These results indicate that immediate loading of specially designed dental implants can be performed without disruption of the titanium/bone interface or disturbance of osteoblast physiology in the early loading phase. CONCLUSION: Immediate loading protocols can be performed without disturbance of normal bone biology.