Institute of Pathology and Neuropathology


Institute of Pathology and Neuropathology

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Schittenhelm J.,University of Tübingen | Schwab E.I.,University of Tübingen | Tatagiba M.,Institute of Pathology and Neuropathology | Meyermann R.,University of Tübingen | And 2 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013

Integrin inhibitors targeting αv series integrins are being tested for their therapeutic potential in patients with brain tumors, but pathologic studies have been limited by lack of antibodies suitable for immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded specimens. We compared the expression of αv integrins by IHC in brain tumor and normal human brain samples with gene expression data in a public database using new rabbit monoclonal antibodies against αvβ3, αvβ5, αvβ6, and αvβ8 complexes using both manual and automated microscopy analyses. Glial tumors usually shared an αvβ3-positive/ αvβ5-positive/αvβ8-positive/αvβ6-negative phenotype. In 94 WHO (World Health Organization) grade II astrocytomas, 85 anaplastic astrocytomas WHO grade III, and 324 glioblastomas from archival sources, expression of integrins generally increased with grade of malignancy. Integrins αvβ3 and αvβ5 were expressed in many glioma vessels; the intensity of vascular expression of αvβ3 increased with grade of malignancy, whereas αvβ8 was absent. Analysis of gene expression in an independent cohort showed a similar increase in integrin expression with tumor grade, particularly of ITGB3 and ITGB8; ITGB6 was not expressed, consistent with the IHC data. Parenchymal αvβ3 expression and ITGB3 gene overexpression in glioblastomas were associated with a poor prognosis, as revealed by survival analysis (Kaplan-Meier logrank, p = 0.016). Together, these data strengthen the rationale for anti-integrin treatment of glial tumors. © 2013 American Association of Neuropathologists, Inc.

Hindy N.E.,University of Duisburg - Essen | Bankfalvi A.,Institute of Pathology and Neuropathology | Herring A.,Institute of Pathology and Neuropathology | Siffert W.,University of Duisburg - Essen
Anticancer Research | Year: 2013

Aquaporin-1 (AQP1) is a water channel protein, widely expressed in epithelial and endothelial cells, known to be associated with invasion, angiogenesis, cell migration and formation of tumour oedema in several malignancies. We investigated the pattern of immunohistochemical expression of AQP1 in human astrocytomas and its role in tumour angiogenesis and infiltration. Immunohistochemical staining of AQP1 was performed in astrocytomas of grade II, III and IV. Intensity and pattern of expression were analysed. Nonneoplastic brain tissues served as control. There was a significant increase in the intensity of AQP1 expression from low-grade to high-grade astrocytomas (p<0.0001). Despite intense expression of AQP1 in astrocytoma grade IV, we observed strong regional differences. AQP1 up-regulation was predominantly located perivascularly, in areas of tumour infiltration, distant from the necrotic tumour core. AQP1 expression correlates with the grade of malignancy and is associated with angiogenesis, as well as with invasion of grade IV tumour in areas of tumour infiltration. Suppression of AQP1 expression could be a potential means of reducing invasion of glioma cells. © 2013 Anticancer Research.

Motomura K.,International Agency for Research on Cancer | Mittelbronn M.,Goethe University Frankfurt | Paulus W.,Institute of Neuropathology | Brokinkel B.,University of Munster | And 14 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013

ABSTRACT: Glioblastomas with a proneural expression signature are characterized by frequent IDH1 mutations (i.e. genetic hallmarks of secondary glioblastomas) and PDGFRA (platelet-derived growth factor receptor-α) amplification. Mutations in IDH1/2 are frequent and early genetic events in diffuse astrocytomas (World Health Organization grade II), precursor to secondary glioblastomas, but little is known about the role and timing of PDGFRA amplification in these tumors. We assessed PDGFRA gain in 342 low-grade diffuse gliomas by quantitative polymerase chain reaction. Gain in PDGFRA was detected in 27 (16.3%) of 166 diffuse astrocytomas, significantly more frequent than in oligodendrogliomas (3 [2.6%] of 115, p < 0.0001). Analyses using previously published data from our laboratory showed an inverse correlation between PDGFRA gain and IDH1/2 mutations (p = 0.018) or 1p/19q loss (p < 0.0001). The vast majority of diffuse astrocytomas showed IDH1/2 mutations and/or PDGFRA gain (154 [93%] of 166). Mean survival of diffuse astrocytoma patients with PDGFRA gain was 8.8 ± 1.6 years, similar to that with IDH1/2 mutations (7.8 ± 0.5 years) or TP53 mutations (7.6 ± 0.6 years) but significantly longer than those with MET gain (4.4 ± 0.7 years). Dual-color fluorescence in situ hybridization in 6 diffuse astrocytomas with PDGFRA/MET co-gain identified by quantitative polymerase chain reaction revealed that PDGFRA and MET were typically amplified in different tumor cell populations. Tumor cells with coamplification were also focally observed, suggesting intratumoral heterogeneity, even in diffuse astrocytomas. Copyright © 2012 by the American Association of Neuropathologists, Inc.

PubMed | University of Leipzig, Cardiac Pathology Unit, Institute of Pathology and Neuropathology, FNS Personal und Informationssysteme GmbH and 2 more.
Type: Comparative Study | Journal: Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology | Year: 2015

The present study aims to analyze the differences in ultrastructural changes between right ventricular myocardium in clinically determined grades of heart failure (HF) [New York Heart Association (NYHA) classes I-IV] and their value in the routine diagnostic setting.We investigated consecutive right ventricular endomyocardial biopsies of 12 patients presenting with HF (4911.2years; male=10) by light microscopy and ultrastructural morphometric analysis. The patients were divided into four groups according to their NYHA classes (NYHA I: n=1, II: n=2, III: n=8, IV: n=1). We used a stereological point counting method on electron micrographs to determine the volume, surface, and numerical density of cardiomyocyte myofibrils; z-lines; mitochondria; and cristae as required. Further, secondary parameters were calculated.Myofibrillar parameters increased between NYHA class I and II (P<.01), which matched with more pronounced cardiomyocyte hypertrophy on the light microscopic level. In NYHA classes III and IV, the myofibrillar parameters dropped, while parameters concerning the mitochondria and their cristae rose (P<.01). This resulted in an elevated mitochondria to myofibril ratio (P<.05) and correlated with histologically evident atrophic cardiomyocytes, perinuclear loss of myofibrils and dot-like perinuclear staining positive on peroxide acid shift.In this present study, right ventricular myocardial ultrastructure differed between patients diagnosed with HF of different degrees in distinct subcellular changes. These findings suggest that ultrastructural analysis, while correlated with histopathological features, adds to the diagnosis in the routine diagnostic setting, specifically in lower NYHA grades, in which only minor changes are observed histologically.

Pierscianek D.,International Agency for Research on Cancer | Kim Y.-H.,International Agency for Research on Cancer | Motomura K.,International Agency for Research on Cancer | Mittelbronn M.,Goethe University Frankfurt | And 11 more authors.
Brain Pathology | Year: 2013

Glioblastoma may develop rapidly without evidence for precursor lesions (primary glioblastomas), or progress from diffuse or anaplastic astrocytomas (secondary glioblastomas). Despite having distinct genetic profiles, these glioblastoma subtypes have similar histological features. We hypothesized that the highly malignant phenotype of glioblastoma may be attributable to genetic alterations that are common to both glioblastoma subtypes. In the present study, we first searched for commonly (>35%) amplified genes in glioblastomas with IDH1 mutation (a hallmark of secondary glioblastoma) and those without IDH1 mutation (typical for primary glioblastoma) in data from The Cancer Genome Atlas (TCGA). A total of 25 genes were identified, of which 21 were located at 7q31-34. We then screened 264 gliomas (70 glioblastomas, 112 diffuse astrocytomas, 82 oligodendrogliomas) for gain of the MET at 7q31.2 with quantitative polymerase chain reaction (PCR). MET gain was detected in primary glioblastomas (47%) and secondary glioblastomas (44%), suggesting that this genetic alteration plays a role in the pathogenesis of both glioblastoma subtypes. MET gain was also common in diffuse astrocytomas (38%), but less frequent in oligodendrogliomas (16%). MET gain in diffuse astrocytomas was associated with shorter survival (median, 43.0 vs. 70.7 months; P = 0.004), suggesting that MET gain is a useful prognostic marker for diffuse astrocytomas. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Radunz S.,Visceral and Transplantation Surgery | Hertel S.,Institute for Medical Informatics | Schmid K.W.,Institute of Pathology and Neuropathology | Heuer M.,Visceral and Transplantation Surgery | And 6 more authors.
Transplantation Proceedings | Year: 2010

The persistent shortage of organs for transplantation could be minimized by increasing the number of potential donors. The opinion of the staff of a university hospital toward organ donation is of special interest because they are directly involved in solid organ transplantation. In 2007, we conducted a first voluntary survey concerning organ donation among the staff of the university hospital of Essen. A short information campaign and further opinion poll among staff as well as visitors was performed in 2009 to compare professional and public attitudes toward organ donation. The first poll comprised 242 questionnaires showing 55% of the hospital staff carrying organ donor cards, particularly more women (60%) than men (46%). After this survey, an additional 19% of the hospital staff imagined they might carrying an organ donor card in the future. In the second survey, we analyzed 151 questionnaires, showing 66% of staff members carrying an organ donor card, an incidence significantly greater than among visitors (48%). The need for information regarding organ donation was greater among visitors (35%). However, 21% of the hospital staff still also need education concerning organ donation. More education and increased transparency of transplantation practice are necessary for hospital staff to act successfully as initiators. Hospital staff with positive attitudes toward organ donation may have a positive impact on the attitudes of the general public toward organ donation. © 2010 Elsevier Inc. All rights reserved.

PubMed | University of Barcelona, UH Alexandrovska, Rensselaer Polytechnic Institute, Institute of Pathology and Neuropathology and 3 more.
Type: | Journal: Neurobiology of aging | Year: 2016

Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimers disease with neuroradiologic features of Alzheimers disease, however, lacking amyloid- deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.

Harder A.,University of Munster | Wesemann M.,University of Munster | Hagel C.,Institute of Neuropathology | Schittenhelm J.,Institute of Pathology and Neuropathology | And 7 more authors.
American Journal of Surgical Pathology | Year: 2012

We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses. Copyright © 2012 by Lippincott Williams & Wilkins.

Noell S.,University of Tübingen | Wolburg-Buchholz K.,University of Tübingen | Mack A.F.,University of Tübingen | Ritz R.,University of Tübingen | And 5 more authors.
Cell and Tissue Research | Year: 2012

In human glioblastoma, the blood-brain barrier (BBB) is disturbed. According to our concept, the gliovascular relationships and thus the control of the BBB are essentially dependent on the polarity of astroglial cells. This polarity is characterized by the uneven distribution of the water channel protein aquaporin-4 (AQP4), dystroglycan and other molecules. Recently, we were able to show that the extracellular matrix component agrin is important for the construction and localization of the so-called orthogonal arrays of particles (OAPs), which consist in AQP4. Here, combining freeze-fracture electron microscopy, immunohistochemistry and Western blotting, we describe alterations of expression and distribution of AQP4, dystroglycan, agrin and the matrix metalloproteinases (MMP) 2, 3 and 9 in human primary glioblastomas (eight primary tumours, six recurrent tumours). Increase of MMP3- and MMP2/9 immunoreactivities went along with loss of agrin and dystroglycan respectively. On the protein level, AQP4 expression was increased in glioblastoma compared to control tissue. This was not accompanied by an increase of OAPs, suggesting that AQP4 can also occur without forming OAPs. The results underline our concept of the loss of glioma cell polarity as one of the factors responsible for the disturbance of the neurovascular unit and as an explanation for the formation of edemas in the glioblastoma. © Springer-Verlag 2012.

PubMed | University of Tübingen and Institute of Pathology and Neuropathology
Type: Journal Article | Journal: PloS one | Year: 2015

Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBP-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBP, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL.

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