Publications

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    ABSTRACT: Adenocarcinoma in situ (AIS) or high grade cervical glandular intraepithelial neoplasia comprises approximately one percent of cervical in situ lesions and is well accepted as precursor of invasive adenocarcinoma.(1) High-risk human papilloma virus infection has been demonstrated as the most important causative agent of AIS. At present, however, we still know far less about metabolic features of these lesions This article is protected by copyright. All rights reserved.
    Histopathology 09/2013;
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    ABSTRACT: AIB1 (amplified in breast cancer 1) is an estrogen receptorα (ERα) co-activator, known to be amplified and overexpressed in a fraction of breast cancers. It has been linked to prognosis and tamoxifen resistance. However, results have been ambiguous. The different functions of AIB1 in ERα-positive and -negative disease are poorly understood. Therefore, we analyzed the clinical significance of AIB1 in breast cancer with respect to ERα-status and characterized the subgroups. 2,197 breast carcinomas sampled on a pre-existing tissue microarray (TMA) were analyzed for AIB1 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results: AIB1 expression was detected in 60 % of the tumors. It was associated with tumor size (p = 0.003), high histological grade (p < 0.0001), poor disease-specific, and overall survival (p = 0.0018 and p = 0.003). There was a strong inverse relationship between AIB1 and ERα expression (p < 0.0001). AIB1 overexpression was associated with increased Ki67 labeling index (p < 0.0001), even if analyzed for different ER expression levels. AIB1 amplification was found in 11 % of the carcinomas. It was associated with high histological grade (p = 0.0012), lymph node involvement (p = 0.0163), and poor disease-specific survival (p = 0.0032) but not with overall survival (p = 0.1672) or ER status (p = 0.4456). If ER-positive tumors were stratified according to their AIB1 amplification status, there was a significant worse disease-specific survival in cases showing AIB1 amplification (p = 0.0017). AIB1 expression is associated with unfavorable prognosis and tumor phenotype. It seems to unfold its oncogenic potential at least in part independent from its role as an ERα co-activator. AIB1 has an impact on cell cycle regulation in ERα-positive as well as ERα-negative tumors. Furthermore, AIB1 amplification characterizes a subgroup of ERα-positive breast cancer with worse outcome. Therefore, AIB1 might be helpful to identify those ERα-positive breast cancers patients who are candidates for adjuvant chemotherapy.
    Breast Cancer Research and Treatment 01/2013;
  • Histopathology 01/2013;
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    ABSTRACT: Overexpression of anti-apoptotic Bcl-2 plays a role in prostate cancer progression, particularly in transformation to androgen-independent disease. Androgen-independent prostate cancers have been shown to harbor Bcl-2 gene copy number gains frequently suggesting that this genetic alteration might play a role in Bcl-2 overexpression. The relation of Bcl-2 overexpression and copy number gains or translocation of the BCL-2 gene in prostate cancer under hormone-naïve conditions is unknown. Prostate cancers of 3,261 hormone-naïve patients undergoing radical prostatectomy were arrayed in a TMA with one tissue core (diameter 0.6 mm) per tumor. Bcl-2 immunohistochemistry, analyzed for Bcl-2 expression level (negative, low, and high), was correlated with clinical, histopathological and molecular (Ki67, p53) tumor features, and biochemical failure. Cancers with high-level Bcl-2 expression were evaluated for genetic aberrations by fluorescence in situ hybridization (FISH). Bcl-2 expression was significantly up-regulated in tumors with aggressive phenotype as indicated by high Gleason score (P < 0.0001), advanced stage (P < 0.0001), and high proliferation index (P = 0.0114). The different Bcl-2 expression levels translated into significantly different survival curves showing better outcome for patients with lower Bcl-2 levels. The prognostic information obtained from the anti-apoptotic Bcl-2 was independent from the proliferation index (Ki67) of the cancer. FISH analysis detected no copy number gains or translocation of the Bcl-2 gene. Bcl-2 overexpression in prostate cancers under hormone-naïve conditions is not associated with increased copy numbers of the gene. This suggests that these frequently detected genetic alterations in androgen-independent tumors occur late in prostate cancer progression.
    The Prostate 10/2011; 72(9):991-7.
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    ABSTRACT: Die zielgerichtete Tumortherapie, die auf dem Verständnis der molekularen Grundlagen der malignen Transformation und der Tumorheterogenität basiert, stellt einen der wesentlichen Fortschritte in der Behandlung des Mammakarzinoms dar. Der Erfolg der zielgerichteten Therapien hängt mit der Auswahl der geeigneten Patienten zusammen. Derzeit anerkannte Prädiktoren sind der Hormonrezeptorstatus für eine endokrine Therapie und der HER2-Status für eine Anti-HER2-Therapie. Ihre qualitätsgesicherte Bestimmung ist Aufgabe der Pathologie. Aus heutiger Sicht ist der Nachweis des Zielmoleküls für sich allein allerdings keine optimale Voraussetzung für eine maßgeschneiderte Therapie. Mittels moderner Technologien wird derzeit versucht, molekulare Signaturen zu identifizieren, anhand derer Patienten für zielgerichtete Therapien ausgewählt werden können. Bislang sind die verfügbaren Genexpressions-Assays (RT-PCR- oder Microarray-basiert) aber noch nicht ausreichend validiert, um ihren Einsatz in der Routine empfehlen zu können. Die Förderung der Entwicklung und Konsolidierung gewebebasierter prädiktiver Testverfahren ist eine der wesentlichen zukünftigen Aufgaben der Pathologie. Targeted therapy based on the understanding of the molecular principles of malignant transformation and tumour heterogeneity has resulted in substantial progress in breast cancer therapy. The success of targeted therapy depends on the selection of patients. At present the hormone receptor and HER2-status are the generally accepted predictive markers of response to endocrine and anti-HER2 therapy, respectively. It is the role of pathology to assure standardization and quality control of the determination. However, simply knowing that the target exists is not optimal to tailor adjuvant therapy. Currently, newer technologies are aimed at identifying molecular signatures that characterize breast cancer patients who are most likely to respond to specific targeted therapies. So far, the available gene expression assays (RT-PCR or microarray-based) are not sufficiently validated to recommend routine use. The promotion of development and consolidation of tissue-based predictive assays is one of the primary future tasks of pathology.
    Der Gynäkologe 01/2009; 42(3):194-200.
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    ABSTRACT: Fibroblastlike stromal cells, which are always present as a component of giant cell tumor of bone (GCT), can be observed in both in vivo and cultured cell samples. Although they are assumed to trigger the cancer process in GCT, the histogenesis of GCT stromal cells is poorly understood. It is known that mesenchymal stem cells (MSCs) can develop to osteoblasts. Evidence has been presented that GCT stromal cells can also develop to osteoblasts. A connection between MSCs and GCT stromal cells was sought by using 2 different laboratory approaches. First, immunohistological analyses revealed that some of the same markers, detected by the SH2, SH3, and SH4 antibodies and the CD166 antigen, were found in GCT stromal cells as in the first developmental stages of osteoblast differentiation from the initial MSCs. These immunohistological findings could be confirmed by reverse transcriptase polymerase chain reaction. Second, cellular differentiation by morphology and lineage-specific staining offered evidence that not only osteoblasts, but also chondroblasts and adipocytes, could be cultured from stromal cells. The presented double approach indicates that GCT stromal cells can originate from MSCs.
    Human Pathlogy 11/2003; 34(10):983-93.