Browsing by Author "Marx, A."

Myasthenia gravis (MG) in thymoma patients depends critically on intraturnorous generation and export of mature autoreactive CD4(+) T cells. Why non-MG thymomas fail to produce CD4(+) T cells is unknown. We studied three single-nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4(CTLA4) gene in thymoma patients, nonthymoma early-onset MG patients, and control subjects. Surprisingly, the CTLA4(high) geno- type +49A/A, which is protective against several autoimmune diseases, exerted a prominent predisposing effect to paraneoplastic MG in thymoma patients. The unusual disease association with a CTLA4(high) genotype implies a unique pathogenesis of paraneoplastic MG, with high CTLA4 levels possibly supporting the nontolerogenic selection of CD4(+) T cells in MG-associated thymomas.

Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intratumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in 'central' tolerance in both humans and mice. However, while inactivating AIRE mutations result in the lautoirnmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable tools to test conclusions drawn from mouse models. Here we show, in a large series, that similar to 95% of thymoma patients are 'chimeric'; expression of AIRE and major AIRE-related autoantigens (eg insulin) were undetectable in their tumours but maintained in their remnant thymic tissue and lymph nodes. Notably, despite the AIRE-deficient thymopoiesis in thymomas, disorders and autoantibodies typical of APS-1 were distinctly uncommon in these patients. The one striking similarity was in the recently observed neutralizing anti-type I interferon (IFN) antibodies, which are found at diagnosis in 100% of patients with APS-1 and in similar to 60% of patients with thymomas, as we show here. We conclude that APS-1 type autoantigens must be protected from autoimmunity by mechanisms that do not extend to the muscle autoantigens so frequently targeted in thymoma patients but so rarely recognized in APS-1. Thus our findings argue strongly for a tolerogenic function of AIRE beyond its role in negative T-cell selection in human thymopoiesis, and/or for specific autoimmunization against muscle in thymomas. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Soft tissue sarcomas are a rare and heterogeneous group of tumors. Surgery clearly remains the standard therapy of non-metastatic soft tissue sarcoma. A pretreatment biopsy is necessary to determine the histology and grade of soft tissue sarcomas and to diagnose entities that can be treated by targeted therapies, such as dermatofibrosarcoma protuberans or alveolar soft tissue sarcoma once they are in a metastatic stage. Nevertheless, locally advanced disease requires multimodal treatment and interdisciplinary treatment decisions. Limb sarcoma of borderline resectability (encasement of vessels, invasion of joints or close proximity to motor nerves) may profit from isolated limb perfusion with recombinant tumor necrosis factor and melphalan. Preoperative chemotherapy may be applied in locally advanced high grade tumors when clear resection margins are difficult to achieve. Deep wave hyperthermia has proven to be a useful addition to systemic chemotherapy in such a neoadjuvant setting. Also preoperative radiation therapy has proven to be effective in controlling locally advanced sarcoma despite higher perioperative morbidity which pays off in the long run by better limb function. Postoperative adjuvant external beam irradiation therapy with the best available technique is recommended for any tumor larger than 5 cm with (FNLCC) grades 2 and 3 (American Joint Committee on Cancer stage IIb/III). Given all these therapeutic options, it is absolutely crucial that interdisciplinary decision-making starts early in the therapeutic process. Patients are often seen first by the surgeon. For an optimal treatment surgeons need to know the efficacy and toxicity of the multimodal treatment options described.

The (La0.7Sr0.3MnO3)(0.95):(MgO)(0.05) nanocomposite system (LSMO:MgO) shows a low-field magnetoresistance up to 30% at low temperatures. The low-frequency 1/f-noise was investigated extensively to characterize the LSMO/MgO interface. The noise was found to be independent of both an applied magnetic field and the bias current. Furthermore, the temperature dependence of the noise level shows a maximum which can be connected to the temperature dependence of the resistance. The measured noise level is comparable to epitaxial manganite systems without doped grain boundaries. This suggests that the quality of the coherent LSMO/MgO interfaces where the low-frequency noise is predominantly generated is very high. (c) 2005 American Institute of Physics.

Mesenchymal neoplasms of the thymus and mediastinum account for only 2 % of neoplasms of the mediastinum and are therefore very rare. With very few exceptions the histology, immunohistochemistry and (based on current knowledge) molecular biology of mediastinal soft tissue tumors are not different from their counterparts in other organs. Characteristic features are more concerned with clinical epidemiological and therapeutic aspects as well as the multitude of possible differential diagnoses. With the exception of organ-specific tumors, such as gastrointestinal stromal tumors (GIST), virtually all entities encountered in peripheral soft tissues can also arise in the mediastinum. Primary mediastinal soft tissue sarcomas (STS) must be distinguished from secondary radiation-induced STS after irradiation, e. g. for breast cancer and Hodgkin's lymphoma and from STS arising as somatic type malignancies in mediastinal germ cell tumors.

Thymic carcinomas (TC) are approximately 10 times less prevalent than thymomas but of high clinical relevance because they are more aggressive, less frequently resectable than thymomas and usually refractory to classical and targeted long-term treatment approaches. Furthermore, in children and adolescents TC are more frequent than thymomas and particularly in this age group, germ cell tumors need to be a differential diagnostic consideration. In diagnostic terms pathologists face two challenges: a), the distinction between thymic carcinomas and thymomas with a similar appearance and b), the distinction between TC and histologically similar metastases and tumor extensions from other primary tumors. Overcoming these diagnostic challenges is the focus of the new WHO classification of thymic epithelial tumors. The objectives of this review are to highlight novel aspects of the WHO classification of thymic carcinomas and to address therapeutically relevant diagnostic pitfalls.

Thymomas are rare tumors but are one of the most common mediastinal neoplasms in adults and exhibit an enormous variability in histological, biological and genetic features. The morphological spectrum within a given entity is enormous and some tumors with histological patterns of more than one entity are more common than pure histological subtypes. Due to a lack of subtype-specific markers classification of thymomas often requires complex diagnostic algorithms. The refined presentation including the definition of obligatory and optional features and of diagnostic immunohistochemical profiles, is the focus of the new World Health Organization (WHO) classification of thymomas, aiming at improving diagnostic reproducibility. This review highlights novel aspects of the WHO classification of thymomas and addresses typical differential diagnostic challenges with a focus on diagnostic pitfalls.