Philipp Ströbel

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany

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Publications (193)855.08 Total impact

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    ABSTRACT: Thymoma-associated Myasthenia gravis (TAMG) is one of the anti-acetylcholine receptor MG (AChR-MG) subtypes. The clinico-pathological features of TAMG and its pathogenesis are described here in comparison with pathogenetic models suggested for the more common non-thymoma AChR-MG subtypes, early onset MG and late onset MG. Emphasis is put on the role of abnormal intratumorous T cell selection and activation, lack of intratumorous myoid cells and regulatory T cells as well as deficient expression of the autoimmune regulator (AIRE) by neoplastic thymic epithelial cells. We review spontaneous and genetically engineered thymoma models in a spectrum of animals and the extensive clinical and immunological overlap between canine, feline and human TAMG. Finally, limitations and perspectives of the transplantation of human and murine thymoma tissue into nude mice, as potential models for TAMG, are addressed. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 02/2015; DOI:10.1016/j.expneurol.2015.02.010 · 4.62 Impact Factor
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    ABSTRACT: The rarity of thymomas and lack of multi-institutional studies have hampered therapeutic progress for decades. To overcome this, the members of the International Thymic Malignancy Interest Group created a worldwide retrospective database. This database was analyzed regarding the demographic and geographic distribution of thymomas and the impact of different variables on survival and recurrence. This study analyzed 4221 thymomas diagnosed between 1983 and 2012 with World Health Organization histotype information from the International Thymic Malignancy Interest Group database. Associations to survival and recurrence were studied by univariate and multivariate analyses. Type B2 thymoma is the most common (28%) and type A the least common (12%) histotypes. They are significantly more frequent in Europe and the United States than Asia. Type A and AB occur at significantly higher age than other thymomas (64 and 57 years, respectively). There are no differences in gender distribution. Stage is lower in type A (90% in stages I-II) and AB than B1 to B3 thymomas (38% of type B3 in stage III). In univariate analysis, recurrence is significantly less frequent among stage I/II tumors, in type A and AB (recurrence rates, 1-2%) than B1 to B3 thymomas (2-7%). Multivariate analysis reveals an impact of age, stage, and resection status on survival and recurrence, whereas for histology there is only a significant impact on recurrence. New findings are (1) geographic differences such as a lower incidence of type A and B2 thymoma in Asia; and (2) impact of stage and histology, the latter partially limited to early stage disease, on recurrence.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2015; 10(2):367-372. DOI:10.1097/JTO.0000000000000393 · 5.80 Impact Factor
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    ABSTRACT: Lymphovascular invasion (LVI) represents a surrogate marker for micrometastatic urothelial carcinoma of the bladder (UCB).
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    ABSTRACT: Plakophilins 1 and 3 (PKP1/3) are members of the arm-repeat family of catenin proteins and serve as structural components of desmosomes important for cell-cell-adhesion. In addition, PKP1/3 occur as soluble proteins outside of desmosomes, yet their role in the cytoplasm is not known so far. We found that cytoplasmic PKP1/3 were co-precipitated with the RNA-binding proteins FXR1, G3BP, PABPC1 and UPF1 and these PKP1/3 complexes also comprised desmoplakin and PKP2 mRNAs. Moreover, we showed that the interaction of PKP1/3 with G3BP, PABPC1 and UPF1 but not with FXR1 was RNase-sensitive. To address the cytoplasmic function of PKP1/3 we performed gain and loss of function studies. Both PKP1 and PKP3 knock down cell lines showed reduced protein and mRNA levels for desmoplakin and PKP2. Whereas global rates of translation were unaffected, desmoplakin and PKP2 mRNA were destabilized. Furthermore, binding of PKP1/3 to FXR1 was RNA-independent, and both PKP3 and FXR1 stabilized PKP2 mRNA. Our results demonstrate that cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression.
    Molecular and Cellular Biology 09/2014; 34(23). DOI:10.1128/MCB.00766-14 · 5.04 Impact Factor
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    ABSTRACT: Stage classification is an important underpinning of management of patients with cancer, and rests on a combination of three components: T for tumor extent, N for nodal involvement, and M for more distant metastases. This article details an initiative to develop proposals for the first official stage classification system for thymic malignancies for the 8th edition of the stage classification manuals. Specifically, the results of analysis of a large database and the considerations leading to the proposed N and M components are described. Nodal involvement is divided into an anterior (N1) and a deep (N2) category. Metastases can involve pleural or pericardial nodules (M1a) or intraparenchymal pulmonary nodules or metastases to distant sites (M1b).
    Journal of Thoracic Oncology 09/2014; 9(9):S81-7. · 5.80 Impact Factor
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    ABSTRACT: Thymic neuroendocrine tumors (TNET) are rare primary epithelial neoplasms of the thymus. This study aimed to determine clinically relevant parameters for their classification and for therapeutic decisions. We performed a comprehensive histological, clinical, and genetic study of 73 TNET cases (13 thymic typical carcinoids [TTC], 40 thymic atypical carcinoids [TAC], and 20 high-grade neuroendocrine carcinomas [HGNEC] of the thymus), contributed by multiple institutions. The mean number of chromosomal imbalances per tumor was 0.8 in TTC (31% aberrant cases) versus 1.1 in TAC (44% aberrant cases) versus 4.7 in HGNEC (75% aberrant cases). Gains of 8q24 (MYC gene locus) were the most frequent alteration and one of the overlapping features between carcinoids and HGNEC. The 5-year survival rates for TTC, TAC, and HGNEC were 100, 60, and 30%. The 10-year survival rates for TTC and TAC were 50 and 30% (P = 0.002). Predictive mitotic cut-off values for TTC versus TAC were 2.5 per 10 high-power fields (HPF; indicating a higher death rate, P = 0.062) and 15 per 10 HPF (indicating higher risk of recurrence, P = 0.036) for separating HGNEC from TAC. We conclude that the current histopathologic classifications of TNET reflect tumor biology and provide important information for therapeutic management. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 09/2014; 53(9). DOI:10.1002/gcc.22183 · 3.84 Impact Factor
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    ABSTRACT: Despite longstanding recognition of thymic epithelial neoplasms, there is no official American Joint Committee on Cancer/Union for International Cancer Control stage classification. This article summarizes proposals for classification of the T component of stage classification for use in the 8th edition of the tumor, node, metastasis classification for malignant tumors. This represents the output of the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group Staging and Prognostics Factor Committee, which assembled and analyzed a worldwide database of 10,808 patients with thymic malignancies from 105 sites. The committee proposes division of the T component into four categories, representing levels of invasion. T1 includes tumors localized to the thymus and anterior mediastinal fat, regardless of capsular invasion, up to and including infiltration through the mediastinal pleura. Invasion of the pericardium is designated as T2. T3 includes tumors with direct involvement of a group of mediastinal structures either singly or in combination: lung, brachiocephalic vein, superior vena cava, chest wall, and phrenic nerve. Invasion of more central structures constitutes T4: aorta and arch vessels, intrapericardial pulmonary artery, myocardium, trachea, and esophagus. Size did not emerge as a useful descriptor for stage classification. This classification of T categories, combined with a classification of N and M categories, provides a basis for a robust tumor, node, metastasis classification system for the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control stage classification.
    Journal of Thoracic Oncology 09/2014; 9(9):S73-80. · 5.80 Impact Factor
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    ABSTRACT: A universal and consistent stage classification system, which describes the anatomic extent of a cancer, provides a foundation for communication and collaboration. Thymic epithelial malignancies have seen little progress, in part because of the lack of an official system. The International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group assembled a large retrospective database, a multispecialty international committee and carried out extensive analysis to develop proposals for the 8th edition of the stage classification manuals. This tumor, node, metastasis (TNM)-based system is applicable to all types of thymic epithelial malignancies. This article summarizes the proposed definitions of the T, N, and M components and describes how these are combined into stage groups. This represents a major step forward for thymic malignancies.
    Journal of Thoracic Oncology 09/2014; 9(9):S65-72. · 5.80 Impact Factor
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    ABSTRACT: Pancreatic undifferentiated carcinoma is a heterogeneous group of neoplasms, including pleomorphic giant cell, sarcomatoid, round cell, and rhabdoid carcinomas, the molecular profiles of which have so far been insufficiently characterized. We studied 14 undifferentiated carcinomas with prominent rhabdoid cells, occurring as advanced tumors in seven females and seven males aged 44-96 years (mean: 65 years). Histologically, 10 tumors qualified as pleomorphic giant cell and 4 as monomorphic anaplastic carcinomas. A glandular component, either in the primary or in the metastases, was seen in 5 out of 14 tumors (4 out of 10 pleomorphic giant cell and 1 out of 4 monomorphic anaplastic subtypes, respectively). Osteoclast-like giant cells were absent. Immunohistochemistry revealed coexpression of cytokeratin and vimentin, and loss of membranous β-catenin and E-cadherin staining in the majority of cases. Nuclear SMARCB1 (INI1) expression was lost in 4 out of 14 cases (28%), representing all 4 tumors of the monomorphic anaplastic subtype. FISH and mutation testing of KRAS revealed KRAS amplification in 5 out of 13 (38%) and exon 2 mutations in 6 out of 11 (54%) successfully analyzed cases. A strong correlation was found between KRAS alterations (mutation and/or copy number changes) and intact SMARCB1 expression (7 out of 8; 87%). On the other hand, loss of SMARCB1 expression correlated with the absence of KRAS alterations (3 out of 5 cases; 60%). The results suggest that rhabdoid phenotype in pancreatic undifferentiated rhabdoid carcinomas has a heterogeneous genetic background. SMARCB1 loss is restricted to the anaplastic monomorphic subtype and correlates with the absence of KRAS alterations, whereas the pleomorphic giant cell subtype is characterized by KRAS alterations and intact SMARCB1 expression. Recognition and appropriate subtyping of these rare variants might become necessary for future therapeutic strategies.Modern Pathology advance online publication, 8 August 2014; doi:10.1038/modpathol.2014.100.
    Modern Pathology 08/2014; DOI:10.1038/modpathol.2014.100 · 6.36 Impact Factor
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    ABSTRACT: AimsThe current WHO classification of thymic epithelial neoplasms describes types A and AB thymomas as behaving “like benign neoplasms”. However, recent published data suggests that rare cases may exhibit more aggressive behavior. The aim of this study is to assess the frequency of atypical cases, together with determining whether atypia is associated with more advanced disease.Methods and Results121 thymomas (type A (n=68); type AB (n=53)) were retrospectively reviewed for “atypical” features (nuclear pleomorphism, mitotic activity and necrosis). Logistic regression was utilised to ascertain the association with increasing Masoaka-Koga stage. Where available, follow-up data were also reviewed. There were 72 stage I, 42 stage II, 5 stage III and 2 stage IV tumours. Only the presence of necrosis showed a significant association with increased stage on univariate and multivariate analysis. Nuclear atypia and increased mitotic activity were not associated with increasing stage of disease.Conclusion Our data support the concept of there being a more aggressive atypical variant of both type A and AB thymoma and suggests that the presence of necrosis could be used to predict aggressive behaviour.This article is protected by copyright. All rights reserved.
    Histopathology 08/2014; 66(6). DOI:10.1111/his.12512 · 3.30 Impact Factor
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    ABSTRACT: CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.
    Diagnostic Pathology 06/2014; 9(1):116. DOI:10.1186/1746-1596-9-116 · 2.41 Impact Factor
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    ABSTRACT: BACKGROUND: CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid. METHODS: We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-α and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets. RESULTS: Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-α gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene. CONCLUSIONS: All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-α gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016.
    Diagnostic Pathology 06/2014; Diagn Pathol(9):116. · 2.41 Impact Factor
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    ABSTRACT: Due to its profound therapeutic consequences, the distinction between thymoma and T-lymphoblastic lymphoma in needle biopsies is one of the most challenging in mediastinal pathology. One essential diagnostic criterion favouring thymoma is the demonstration of increased numbers of keratin-positive epithelial cells by immunohistochemistry. Loss of keratin expression in neoplastic epithelial cells could lead to detrimental misdiagnoses. We here describe a series of 14 thymic epithelial tumours (11 type B2 and B3 thymomas, 3 thymic carcinomas) with loss of expression of one or more keratins. Cases were analysed for expression of various keratins and desmosomal proteins by immunohistochemistry and immunofluorescence and compared with 45 unselected type B thymomas and 24 thymic carcinomas arranged in a multitissue histological array. All 14 cases showed highly reduced expression of at least one keratin, three cases were completely negative for all keratins studied. Of the 14 cases, 13 showed strong nuclear expression of p63. Expression of desmosomal proteins was preserved, suggesting intact cell contact structures. Loss of expression of broad-spectrum-keratins and K19 was observed in 3 and 5 % of unselected thymomas and in 30 and 60 % of thymic carcinomas. A proportion of keratin-depleted thymomas contained giant cells, reminiscent of thymic nurse cells. Loss of keratin expression in type B2 and B3 thymomas is an important diagnostic pitfall in the differential diagnosis with T-lymphoblastic lymphoma and can be expected in 5 % of cases. A panel of epithelial markers including p63 is warranted to ensure correct diagnosis of keratin-negative mediastinal tumours.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2014; 465(3). DOI:10.1007/s00428-014-1606-6 · 2.56 Impact Factor
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    ABSTRACT: Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs) and pulmonary chondromas in a patient. In contrast to Carney-Stratakis Syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase complex (SDH) subunits A, B, C or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of the SDH subunit C (SDHC) in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the succinate dehydrogenase complex as a plausible alternate mechanism of tumorigenesis in CT.
    Endocrine Related Cancer 05/2014; 21(4). DOI:10.1530/ERC-14-0254 · 4.91 Impact Factor
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    ABSTRACT: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2014; 9(5):596-611. DOI:10.1097/JTO.0000000000000154 · 5.80 Impact Factor
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    ABSTRACT: A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer (PCa) is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high risk PCa, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness and apoptosis in PCa at least partially via STAT1/STAT3 mediated activation of the JAK/STAT signalling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signalling pathway. miR-221 expression sensitized PCa cells for IFN-γ mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk PCa.
    Cancer Research 03/2014; 74(9). DOI:10.1158/0008-5472.CAN-13-1606 · 9.28 Impact Factor
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    ABSTRACT: SERS microscopy is a novel staining technique in immunohistochemistry, which is based on antibodies labeled with functionalized noble metal colloids called SERS labels or nanotags for optical detection. Conventional covalent bioconjugation of these SERS labels cannot prevent blocking of the antigen recognition sites of the antibody. We present a rational chemical design for SERS label-antibody conjugates which addresses this issue. Highly sensitive, silica-coated gold nanoparticle clusters as SERS labels are non-covalently conjugated to primary antibodies by using the chimeric protein A/G, which selectively recognizes the Fc part of antibodies and therefore prevents blocking of the antigen recognition sites. In proof-of-concept two-color imaging experiments for the co-localization of p63 and PSA on non-neoplastic prostate tissue FFPE specimens, we demonstrate the specificity and signal brightness of these rationally designed primary antibody-protein A/G-gold nanocluster conjugates.
    Nanoscale 01/2014; 6(4). DOI:10.1039/c3nr05890e · 6.74 Impact Factor
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    ABSTRACT: To evaluate the expression of multiple lymph-specific markers and to test its association with histopathological characteristics and clinical outcomes in patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy (RC). Vascular endothelial growth factor-C and -D (VEGF-C/-D), its receptor VEGF receptor-3 (VEGFR-3), and chemokine receptor type 7 (CCR7) expressions were assessed by immunohistochemistry in RC specimens of 119 patients. Semiquantitative analyses of marker expressions were correlated with clinical and pathological characteristics. Univariable and multivariable analyses were performed to identify predictors of disease-specific survival (DSS) and recurrence free survival (RFS). VEGF-C, VEGF-D, VEGFR-3, and CCR7 were overexpressed in 37.8%, 26.2%, 50.4%, and 23.5% of UCB samples, respectively. VEGF-D overexpression was significantly associated with a positive lymph node status (pN+). On univariable analysis, a higher pT stage, pN+, the presence of lymphovascular invasion (LVI) and vascular invasion (VI) (all P<0.001), and overexpressions of VEGF-D (P = 0.049) and VEGFR-3 (P = 0.032) were significantly associated with reduced DSS. On multivariable analysis, pT stage (P = 0.002) and pN+status (P = 0.009) were identified as independent predictors of reduced DSS. In a subgroup of patients without lymph node metastasis (pN0; n = 75), pT stage (P = 0.043) and VEGFR-3 overexpression (P = 0.008) were independent predictors of reduced DSS. Lymph-specific markers are frequently overexpressed in UCB. VEGF-D overexpression is associated with the presence of lymphatic metastasis. In patients without lymph node metastasis at the time of RC, an assessment of VEGFR-3 expression may improve the identification of high-risk patients. These findings require prospective validation to determine the potential benefit of more aggressive adjuvant treatment.
    Urologic Oncology 01/2014; 32(1):54.e9-54.e17. DOI:10.1016/j.urolonc.2013.08.031 · 3.36 Impact Factor
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    ABSTRACT: The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.
    Frontiers in Oncology 12/2013; 3:316. DOI:10.3389/fonc.2013.00316

Publication Stats

3k Citations
855.08 Total Impact Points

Institutions

  • 2013–2015
    • Georg-August-Universität Göttingen
      • Faculty of Medicine
      Göttingen, Lower Saxony, Germany
    • Universitair Medisch Centrum Groningen
      Groningen, Groningen, Netherlands
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2014
    • Universitätsmedizin Göttingen
      Göttingen, Lower Saxony, Germany
  • 2008–2013
    • Universität Heidelberg
      • • Department of Pathology
      • • Institute of Pathology (Heidelberg)
      • • Institute of Papyrology
      Heidelburg, Baden-Württemberg, Germany
  • 1999–2013
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany
  • 2012
    • Universitätsklinikum Freiburg
      • Department of General and Visceral Surgery
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2007–2012
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2010–2011
    • Universitätsmedizin Mannheim
      Mannheim, Baden-Württemberg, Germany
    • University of Münster
      • Department of Urology
      Muenster, North Rhine-Westphalia, Germany
  • 2008–2011
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2009–2010
    • Pathologisches Institut Bremerhaven
      Bremerhaven, Bremen, Germany
    • Université Victor Segalen Bordeaux 2
      Burdeos, Aquitaine, France
  • 2004
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
    • Central Military Hospital Koblenz
      Coblenz, Rheinland-Pfalz, Germany
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany