K W Schmid

University Hospital Essen, Essen, North Rhine-Westphalia, Germany

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Publications (568)1607.29 Total impact

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    ABSTRACT: Context: Multiple endocrine neoplasia (MEN) 2 is usually caused by missense mutations in the proto-oncogene RET. Objective: To determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 and with medullary thyroid carcinoma (MTC) six years later. Methods: Exome and Sanger sequencing from leukocyte DNA. Wild-type RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay. Results: Exome sequencing revealed a 6 nucleotide/2 amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared to wild type RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway (pERK1/2) and the PI3K pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation fourfold compared to wild-type RET. Conclusion: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6 bp deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We, therefore, recommend to screen the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.
    No preview · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Within the pulmonary tumors there is a subset of tumors with neuroendocrine differentiation divided into pulmonary carcinoids and high-grade carcinomas. The rising impact of molecular pathology in routine diagnostics calls for reliable biomarkers which differentiate those subgroups and thereby may influence the subsequent clinical management of those patients. Methods: The study is based on a collective of 70 representative, formalin-fixed, paraffin embedded pulmonary neuroendocrine lung tumors (17 TC, 17 AC, 19 LCNEC, and 17 SCLC) to retrospectively identify biomarkers by sequencing. Using the Illumina TruSeq Amplicon - Cancer Panel on the MiSeq Personal Sequencer, the samples were screened for alterations in 48 genes including 221 mutational hotspots. Results: After filtering about 26.000 variants and applying strict algorithms we have limited the amount to 342 variants in total splitted on 175 different mutations. 61 of these are predicted to influence protein structure and functionality. The most frequent mutated genes were FLT3, TP53 and APC. We found statistical correlation between frequency or mutation status of the samples with diverse clinical parameters. Variants within the PIK3CA locus are strongly associated with AC and SCLC (p=0.0061). A high statistical significance between TP53 variants and tumor type (p< 0.0001) as well lymph node invasion (p=0.0013) were detected. Furthermore, the number of mutations in APC (p=0.0433), BRAF (p=0.0468) and STK11 (p=0.0144) were associated with lymph-node invasion. Analogously, the occurrence of mutations in ATM, FLT3, MET, KRAS and RB1 showed statistical significance to PFS and again FWXB7 was significant for OS. Conclusions: Pulmonary carcinoids and neuroendocrine carcinomas of the lung show clear differences in their mutational status. A better understanding of the biology of NELC may improve their clinical management.
    Full-text · Article · Dec 2015 · British Journal of Cancer
  • Kurt Werner Schmid
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    ABSTRACT: The human thyroid gland contains less than 0.01-0.1 % calcitonin producing and secreting C cells, which in men are almost exclusively situated in an intrafollicular location; the vast majority of C cells are embryologically derived of remnants of the ultimobranchial body and ultimately of the neural crest, a small subset, however, is presumed to originate from endodermal stem cells. Thyroid tumours with C cell differentiation have been named medullary thyroid carcinoma (MTC); calcitonin is also produced and secreted by MTC which makes this peptide hormone a very useful serum marker both for early detection and clinical follow-up of patients with MTC. About 70-80 % of MTC are sporadic tumours, whereas 20-30 % are familial MTC which are autosomal-dominant inherited and caused by germline mutations of the RET proto-oncogene located on chromosome 10. This article summarizes the histological, immunhistochemical and molecular genetic features of C cells, C-cell hyperplasia (CCH) and MTC, emphasizing the role of diagnostic pathology.
    No preview · Article · Oct 2015 · Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer
  • S Ting · S Synoracki · A Bockisch · D Führer · K W Schmid
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    ABSTRACT: The cytological evaluation of fine needle biopsies (FNB) of the thyroid gland crucially depends on a close cooperation between clinicians and cytopathologists. Scintigraphy, sonography as well as clinical data and patient history are necessary for a correct interpretation of the indications for FNB; moreover, these data are of outstanding importance for cytopathologists for the correct interpretation of the cytomorphological findings. This overview describes the present standards in the acquisition, technical workup and cytopathological interpretation of thyroid gland tissue obtained by FNB, particularly focusing on the rapidly growing relevance of additional molecular pathological investigations to increase the diagnostic accuracy of thyroid FNB.
    No preview · Article · Oct 2015 · Der Pathologe
  • K W Schmid
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    ABSTRACT: The different biological features of the various major entities of thyroid cancer, e.g. papillary, follicular, poorly differentiated, anaplastic and medullary, depend to a large extent on their different metastatic spread. Papillary thyroid cancer (PTC) has a propensity for cervical lymphatic spread that occurs in 20-50 % of patients whereas distant metastasis occurs in < 5 % of cases. Cervical lymphadenopathy may be the first symptom particularly of (micro) PTC. In contrast follicular thyroid cancer (FTC) has a marked propensity for vascular but not lymphatic invasion and 10-20 % of FTC develop distant metastases. At the time of diagnosis approximately one third of medullary thyroid cancer (MTC) cases show lymph node metastases, in 10-15 % distant metastases and 25 % develop metastases during the course of the disease. Poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) spread via both lymphatic and vascular invasion. Thus distant metastases are relatively uncommon in DTC and when they occur, long-term stable disease is the typical clinical course. The major sites of distant metastases are the lungs and bone. Metastases to the brain, breasts, liver, kidneys, muscle and skin are relatively rare or even rare. The thyroid gland itself can be a site of metastases from a variety of other tumors. In autopsy series of patients with disseminated cancer disease, metastases to the thyroid gland were found in up to 10 % of cases. Metastases from other primary tumors to the thyroid gland have been reported in 1.4-3 % of patients who have surgery for suspected cancer of the thyroid gland. The most common primary cancers that metastasize to the thyroid gland are renal cell (48.1 %), colorectal (10.4 %), lung (8.3 %) and breast cancer (7.8 %) and surprisingly often sarcomas (4.0 %).
    No preview · Article · Sep 2015 · Der Pathologe
  • V Tiedje · S Ting · H Dralle · K W Schmid · D Führer
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    ABSTRACT: Medullary thyroid carcinoma (MTC) is a very rare malignancy, which arises from parafollicular C cells and accounts for 3-5 % of all thyroid cancers. MTC represents a neuroendocrine tumor with a biology that differs considerably from differentiated thyroid cancer. Presence of a RET proto-oncogene germline mutation indicates hereditary C cell disease in the context of multiple endocrine neoplasia type 2 and hence a special treatment algorithm is required. Cure of MTC is only possible through surgery. Calcitonin screening is advocated for early MTC diagnosis and preoperative MTC management stratification. In case of surgically incurable persistent MTC, estimation of calcitonin and CEA doubling time is crucial to assess tumor biology and is complemented by multimodal imaging to assess tumor burden. Treatment decisions in incurable MTC must be carefully balanced with treatment-related morbidity, since MTC may take an indolent course over years.
    No preview · Article · Sep 2015 · Der Internist
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    ABSTRACT: CLAUDIN-1 belongs to the family of transmembrane tight junction proteins tightening the paracellular cleft of epithelial cells. In human malignancies, CLAUDIN-1 is often dysregulated and located in subcellular compartments, particularly in the nucleus where it may influence cellular behaviour. Here, we studied CLAUDIN-1 in relation to the biological characteristics of follicular thyroid cancer (FTC). CLAUDIN-1 immuno-staining showed loss of membrane expression and increased nuclear CLAUDIN-1 localization in FTC metastases. CLAUDIN-1 function was further investigated in two different follicular thyroid carcinoma cell lines, FTC-133 isolated from a regional lymph node metastasis and FTC-238 derived from a lung metastasis. In both cell lines CLAUDIN-1 expression was demonstrated in the cell nuclei with a significantly higher protein expression in FTC-238 compared to FTC-133 cells. Interestingly, in vitro scratch assay revealed enriched nuclear CLAUDIN-1 expression near the scratch. Furthermore, the increase of the pathogenic character of FTC-133 cells by RASV12 transfection was associated with elevated CLAUDIN-1 expression and enhanced cell migration, invasion and proliferation. Likewise over-expression of nuclear CLAUDIN-1 in FTC-133 cells resulted in increased cell migration and invasion. Conversely, CLAUDIN-1 down-regulation in FTC-238 cells by siRNA resulted in decreased cell migration and invasion and was accompanied by reduced phospho PKC expression. Moreover, activation and inhibition of PKC resulted in CLAUDIN-1 up- and downregulation in FTC cells respectively. These data suggest an impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness, which could potentially be influenced by PKC activity.
    No preview · Article · Jul 2015 · Endocrine Related Cancer
  • K.W. Schmid · D. Führer
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    ABSTRACT: Background The diagnostics and differential diagnosis of tumors of the thyroid glands are still challenging. Molecular genetic insights are increasingly allowing a better definition of the various tumor entities. Objectives The role of molecular pathology in preoperative (e.g. fine needle biopsies) and postoperative diagnostics of thyroid tumors as well as an aid to decision making in targeted therapies of advanced stage thyroid cancer. Material and methods A comprehensive summary based on relevant scientific and review articles in the literature. Results The traditional differentiation of thyroid carcinomas into four major groups (i.e. papillary, follicular, medullary and anaplastic carcinomas) based on morphology and clinical features is strongly supported by distinct genetic alterations in these four groups and with very little overlap. However, the morphologically and biologically relevant entity of poorly differentiated thyroid carcinoma still lacks a genetic definition. Molecular testing has been successfully included in the evaluation of fine needle thyroid biopsies. Currently available targeted therapies are based on genetic alterations, which are usually demonstrated by pathologists. In the future molecular pathology will most likely become an important tool in the decision-making process of targeted therapies in advanced and aggressive thyroid carcinomas. Conclusion Molecular pathology has become an integral part of the diagnostic routine in the preoperative and postoperative evaluation, particularly of papillary thyroid carcinoma.
    No preview · Article · Jul 2015 · Der Onkologe
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    ABSTRACT: Positive surgical margins (PSM) after radical prostatectomy have been shown to be associated with impaired outcome. In pT3pN0 patients with PSM either immediate radiotherapy or clinical and biological monitoring followed by salvage radiotherapy is recommended by the latest guidelines of the European Association of Urology. A retrospective, multicenter study of eight urological centers was conducted on 536 prostatectomy patients with pT3aN0/NxR1 tumors and no neoadjuvant/adjuvant therapy. A pathological re-review of all prostate specimens was performed. Association of clinical and pathological features with biochemical recurrence (BCR) was analyzed using univariate and multivariate analysis. With 48months median follow-up, BCR occurred in 39.7%. Preoperative PSA value, performance of pelvic lymph node dissection and Gleason score were significantly associated with BCR. In multivariate analysis, Gleason score was the only independent prognostic factor (p<0.001) for BCR. Five-year BCR-free survival rates were 74%, 70%, 38%, and 51% with Gleason score 6, 3+4=7a, 4+3=7b, and 8-10, respectively. In pT3aN0/NxR1 patients with no adjuvant/neoadjuvant treatment, Gleason Score permits independent prediction of the risk for BCR. These findings could help to estimate and discuss the individual risk for BCR with our patients on an individual basis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Radiotherapy and Oncology
  • S Synoracki · S Ting · U Siebolts · H Dralle · O Koperek · K W Schmid
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    ABSTRACT: The goal of evaluation of intraoperative frozen sections of the thyroid gland is to achieve a definitive diagnosis which determines the subsequent surgical management as fast as possible; however, due to the specific methodological situation of thyroid frozen sections evaluation a conclusive diagnosis can be made in only some of the cases. If no conclusive histological diagnosis is possible during the operation, subsequent privileged processing of the specimen allows a final diagnosis at the latest within 48 h in almost all remaining cases. Applying this strategy, both pathologists and surgeons require a high level of communication and knowledge regarding the specific diagnostic and therapeutic peculiarities of thyroid malignancies because different surgical strategies must be employed depending on the histological tumor subtype.
    No preview · Article · Jun 2015 · Der Pathologe
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    ABSTRACT: This study aimed to link expression patterns of AQP1, AQP5, Bcl-2 and p16 to clinicopathological characteristics of oro-hypopharyngeal squamous cell carcinomas. Immunohistochemical expression of AQP1, AQP5, Bcl-2 and p16 was investigated in 107 consecutive oro-hypopharyngeal squamous cell carcinoma cases. Molecular interrelationship and correlations with clinicopathological parameters and survival were computed. AQP1 was expressed exclusively by a subgroup of basaloid-like squamous cell carcinomas. AQP5 was detected in 25.2 per cent of the samples, showing significant association with the absence of p16 and Bcl-2 (p = 0.018; p = 0.010). In multivariate analysis, overexpression of p16 was significantly correlated with favourable overall survival (p = 0.014). AQP5 defined a subset of patients with Bcl-2-negative and p16-negative tumours with a poor clinical outcome. AQP1 was found to be a marker of a subgroup of aggressive basaloid-like squamous cell carcinomas. These findings suggest that AQP1 and AQP5 are interesting candidates for further studies on risk group classification and personalised treatment of oro-hypopharyngeal squamous cell carcinomas.
    No preview · Article · Jun 2015 · The Journal of Laryngology & Otology
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    ABSTRACT: Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is mainly linked to asbestos exposure. E3 ubiquitin ligase (MDM2) overexpression was found in approximately 20% of MPM, and this was significantly associated with decreased overall survival and poor response to treatment. MDM2 is a negative regulator of P53 leading to strongly decreased P53 activity and stability. Nutlin-3A (a cis-imidazoline analogue) is a potent and selective MDM2 inhibitor preventing MDM2-P53-interaction. Material and methods: 134 MPM patients from two German locations (Berlin and Essen) were selected for IHC- and/or qPCR-based analysis of the expression of P53, MDM2 and P14/ARF. The effect of MDM2 inhibition via Nutlin-3A and standard first line therapy were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, NCI-H2452) representing the expression profiles of P53 and MDM2 as identified in the patient collectives. Results: In both MPM collectives, MDM2 expression was identified as prognostic marker. For the patients from Essen data for response to treatment were available and MDM2 was identified as predictive marker. In in vitro experiments, Nutlin-3A plus cisplatin showed an up to 9.75 times higher reduction of cell viability and up to 5 times higher induction of apoptosis compared to the first line therapy. Conclusion: Our study demonstrates that Nutlin-3A is associated with a significant induction of apoptosis and reduction of cell viability in MPM cell lines and is more potent than the conventional regimens. Thus, Nutlin-3A may be proposed as a promising substance for a targeted therapy in a subgroup of MPM patients with MDM2 overexpression.
    No preview · Conference Paper · May 2015
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    S. Ting · S.T. Schmid · S. Synoracki · K.W. Schmid

    Preview · Article · May 2015 · Der Pathologe
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    ABSTRACT: Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC.Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.
    Full-text · Article · May 2015 · Oncotarget

  • No preview · Article · May 2015 · Oral Oncology
  • S Synoracki · S T Schmid · S Ting · K W Schmid
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    ABSTRACT: All tumours with C cell differentiation are designated as medullary carcinomas (MTC). MTC occur sporadically (75-80 %) or hereditary (20-25 %), the latter being part of the multiple endocrine neoplasia type 2. Familial MTC, which is commonly preceded by "neoplastic" C cell hyperplasia, is caused by autosomal-dominant inherited germ line mutation of the RET-protooncogene; dependent on the codon affected by the mutation, patients show substantially different clinical courses. Due to its morphological heterogeneity, the immunohistochemical demonstration of calcitonin is mandatory for the diagnosis of MTC. For early diagnosis of MTC calcitonin screening has been introduced in Germany and Austria approx. 10 years ago in patients with thyroid nodules; however, an increased calcitonin serum level may also be caused by "non-MEN2-associated" C cell, which is not regarded as a precursor of sporadic MTC. Very rarely tumours may show a mixed C cell-follicular cell differentiation.
    No preview · Article · Apr 2015 · Der Pathologe
  • S Ting · S Synoracki · K W Schmid
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    ABSTRACT: The C cells (parafollicular) of the human thyroid gland are predominantly located within the thyroid follicles, are of neuroendocrine origin and produce and secrete the peptide hormone calcitonin. Calcitonin is clinically utilized as a screening marker to detect occult medullary thyroid carcinoma (MTC) as well as in the follow-up of patients with MTC. An increase in the number of C cells is designated as C cell hyperplasia (CCH). Neoplastic CCH is caused by an autosomal dominant inherited mutation of the RET protooncogene, which develops into invasive familial MTC in the setting of multiple endocrine neoplasia (MEN) type 2 depending on the location of the mutation in the RET gene with a high variation in latency. According to the current state of knowledge CCH without a germline mutation in the RET protooncogene, designated as non-MEN2-associated CCH, seems to be unrelated to the development of sporadic MTC.
    No preview · Article · Apr 2015 · Der Pathologe
  • S-Y Sheu-Grabellus · K W Schmid
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    ABSTRACT: The diagnostic histopathology of parathyroid glands comprises mostly benign diseases associated with primary, secondary and rarely tertiary hyperparathyroidism. Parathyroid adenoma and hyperplasia are the most common diagnoses, whereas parathyroid carcinomas and atypical adenomas are exceptional causes of hyperparathyroidism, the latter being purely a diagnosis by exclusion. This article deals with the major histopathological criteria of the various diagnoses with special emphasis on the clinical manifestation.
    No preview · Article · Apr 2015 · Der Pathologe
  • Vera Tiedje · Denise Zwanziger · Saskia Ting · Kurt Werner Schmid · Dagmar Führer
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    ABSTRACT: The molecular pathogenesis of thyroid tumors has been an evolving field in the past years. The constitutive activation of intracellular tyrosine kinases has been identified as a hallmark of thyroid cancer. The activation of MAPK and PI3K pathways through somatic gene mutations or gene rearrangements seem to play a pivotal role in the pathogenesis of follicular-cell-derived tumors. In poorly differentiated tumors and anaplastic tumors often an accumulation of genetic alterations from differentiated thyroid cancer but also novel gene mutations can be observed. The C-cell-derived medullary thyroid cancer evolves through the constitutive activation of the RET kinase, either through germline RET mutations or somatic RET and RAS mutations. The better knowledge of the molecular pathogenesis allowed the development of targeted therapies in thyroid cancer patients. The identification of molecular response markers to tyrosine kinase inhibitor therapy is desirable. © Georg Thieme Verlag KG Stuttgart · New York.
    No preview · Article · Apr 2015 · DMW - Deutsche Medizinische Wochenschrift
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    ABSTRACT: Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Apr 2015 · EMBO Molecular Medicine

Publication Stats

10k Citations
1,607.29 Total Impact Points

Institutions

  • 2003-2015
    • University Hospital Essen
      • • Institute of Pathology and Neuropathology
      • • Klinik für Urologie
      Essen, North Rhine-Westphalia, Germany
  • 2001-2015
    • University of Duisburg-Essen
      • • Faculty of Medicine
      • • Department of Internal and Integrative Medicine
      • • Institut für Psychologie
      • • Institut für Katholische Theologie
      Essen, North Rhine-Westphalia, Germany
  • 2011
    • University of Texas Southwestern Medical Center
      • Department of Internal Medicine
      Dallas, Texas, United States
  • 2008-2010
    • Katholisches Klinikum Essen
      Essen, North Rhine-Westphalia, Germany
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
  • 2009
    • University of Bergen
      • Department of Surgical Sciences
      Bergen, Hordaland Fylke, Norway
  • 2007
    • University of Leipzig
      Leipzig, Saxony, Germany
  • 1992-2007
    • University of Münster
      • • Gerhard-Domagk-Institute of Pathology
      • • Department of General and Visceral Surgery
      • • Institute of Experimental Pathology
      Münster, North Rhine-Westphalia, Germany
  • 1986-2006
    • University of Innsbruck
      • • Institut für Psychologie
      • • Institute of Biochemistry
      • • Department of Pharmacology
      Innsbruck, Tyrol, Austria
  • 1987-1997
    • University of Wales
      • College of Medicine
      Cardiff, Wales, United Kingdom
  • 1996
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 1995
    • Otto-von-Guericke-Universität Magdeburg
      • Institut für Pathologie
      Magdeburg, Saxony-Anhalt, Germany
  • 1988
    • IST Austria
      Klosterneuberg, Lower Austria, Austria