Thymic Carcinoma: Is it a Separate Entity? From Molecular to Clinical Evidence

The second edition of the World Health Organization (WHO) classification of thymic tumors (2004) has resumed the previous separation of thymic carcinomas (TCs) from thymomas. This "reseparation" was mainly based on new genetic data. Consequently, it is no longer recommended to label TCs as type C thymomas. TCs are very heterogeneous and comprise squamous, basaloid cell, mucoepidermoid, neuroendocrine, and many other subtypes. They resemble morphologic mimics in other organs and are labeled accordingly. However, only thymic squamous cell carcinomas (TSCCs) and lymphoepithelioma-like carcinomas are relatively common. For TSCCs, quite specific immunohistochemical markers (eg, CD5, CD70, CD117, CD205, FOXN1) and chromosomal gains and losses have been defined that help to distinguish TSCCs not only from malignant thymomas but also from pulmonary squamous cell carcinomas. Recognition of these differences is clinically important, because the prognosis of TSCC is better compared with the other TC subtypes and also compared with lung tumors. Considering the need to treat advanced TC more effectively, disparate findings in predictive molecular markers (eg, KIT mutations in TSCC, but not in thymomas) suggest that targeted treatments will have to be different in thymomas and TC. Preliminary data from single case collections and small treatment trials support this prediction

The urokinase-system - role of cell proliferation and apoptosis

The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are involved in the control of extracellular matrix turnover, cell migration, invasion and cell signalling leading to a variety of different responses, under both physiological and pathological conditions. The urokinase receptor, binding to the growth factor-like domain of uPA, directs membrane-associated extracellular proteolysis and signals through transmembrane proteins, thus regulating tissue regeneration, angiogenesis, cancer growth and metastasis. Since these physiological and pathophysiological processes of the uPA-system are known, less informations concerning uPA-induced cell proliferation and anti-apoptotic effects of the uPAsystem are available. Recent studies show a close relationship of the uPA-system and cell proliferation/ apoptosis. uPA is responsible for the activation and release of different growth factors and modulates the cell proliferation/apoptosis ratio through the dynamic control of cell-matrix interactions. This article focuses on the important role of the uPA/uPAR-system for cell proliferation and apoptosis

The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes

The thymus plays distinct roles in the pathogenesis of the different Myasthenia gravis (MG) subtypes. Inflammatory, neoplastic and age-related alterations of the thymus are of pivotal relevance for the initiation of antiacetylcholine receptor (AChR) autoimmunity in early onset MG, thymoma-associated MG and, likely, late onset MG, respectively. By contrast the thymus is presumably not related to MG that is due to autoantibodies to the muscle specific kinase, MuSK. Finally, the role of the thymus is still obscure in MG defined by antibodies against the agrin receptor LRP4 and in MG without all of the above autoantibdies (triple sero-negative MG) since these MG subtypes have been described only recently and thymectomy has not been their standard treatment This review aims to give an update on intrathymic mechanisms of tolerance breakdown in MG, including abnormal T cell selection and activation, the role of thymic myoid cells, the autoimmune regulator (AIRE) and regulatory T cells. (C) 2013 Elsevier B.V. All rights reserved

Effects of Different Milk-Tube Guidance Settings and Teat-Cup Types on the Dynamics of Teat-End Vacuum and Vacuum Fluctuations During Machine Milking

The objective of this study was to determine the effects of milk tube guidance setting and teat cup type on the dynamics of teat-end vacuum and vacuum fluctuations in quarter individual milking systems. In order to meet this objective, a series of wet tests was conducted in the laboratory. Different teat cups; AMS, BIO and RVS along with the milk tube guidance settings namely: direct tube, half-half tube and Y-piece tube system with varying tube inside diameters were tested at different water flow rates. The data obtained from the wet-test measurements were used to calculate the teat-end vacuum and vacuum fluctuation at the teat-old in b and d- phase. From the study conducted, it was found that the teat-end vacuum in BIO is always between the range of 32 and 42 kPa as recommended by DIN ISO 5707 (2010a) at any flow rate for all three types of connections. The teat-end vacuum for RVS was between 32-42 kPa range if the flow rate varies between 4 and 6 L min(-1) for both, the direct and the half-half connection. The Y-piece connection meets DIN ISO 5707 (2010a) requirements once the flow rate changes between 2 and 6 L min(-1). The findings about milk tube inside diameter indicated that the use of 14 or 16 mm milk tube diameter for BIO will provide better teat-end vacuum if the recommended value of 10 mm is used. On the other hand, the use of 16 mm milk tube diameter was found to be appropriate for AMS as recommended by the manufacturer. For the RVS, the appropriate milk tube diameter should be 14 mm when statistical differences in b and d-phase are examined from the point of teat-end vacuum and vacuum fluctuations

Tumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: prognostic impact

Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor PAI-1, play a key role in tumor invasion and metastasis. uPA and PAI-1 were the first novel tumor biological factors to be validated at the highest level of evidence regarding their clinical utility in breast cancer. Their antigens are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA- and PAI-1 in their primary tumor tissue have significantly better survival than patients with high levels of either factor. However, it is unclear whether it is their (relative) levels in the tumor stroma or in the tumor cells themselves that is most relevant to patient outcome. This missing knowledge leads to an uncertainty concerning the management of breast cancer tissue specimens. It is unclear how much tumor stroma is allowed in one tumor tissue specimen for an adequate assessment of the patients' outcome. This is the first study in which tumor cells and stromal tissue of invasive breast carcinomas (n=60) were separated by laser capture microdissection followed by ELISA-based determination of the uPA-, uPAR- and PAI-1-levels. In addition, we have assessed uPA-, uPAR- and PAI-1 distribution in formalin-fixed, paraffin-embedded breast cancer specimens (n=60) by immunohistochemistry. The uPA-, uPAR- and PAI-1 in tumor stroma only, tumor cells only and not separated tumor tissue did not show any significant differences in protein-levels determined by ELISA. Cox regression analysis showed that patients with high uPA-, high uPAR-, and/or high PAI-1-levels, as compared to patients with low levels of either factor, showed a significantly shorter relapse-free survival and overall survival (p=0.000001). These results suggest that a strong expression of uPA, uPAR and PAI-1 in the tumor stroma, as well as in tumor cells, have the same impact on the clinical behaviour of breast cancer. Conclusion: When using uPA- and PAI-1 levels as prognostic and predictive factors in breast cancer the quantity of tumor stroma in the tumor tissue specimen is not relevant for the assessment of the patients' outcome

Thymoma related myasthenia gravis in humans and potential animal models

Thymoma-associated Myasthenia gravis (TAMG) is one of the anti-acetylcholine receptor MG (AChR-MG) sub-types. 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. (C) 2015 Elsevier Inc. All rights reserved

Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer

Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients

Choroidal metastases from thymic carcinoma during pregnancy: Case Report

BACKGROUND: Rare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma. CASE PRESENTATION: A 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma. CONCLUSIONS: Choroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses

Optimized expression-based microdissection of formalin-fixed lung cancer tissue

Analysis of specific DNA alterations in precision medicine of tumors is crucially important for molecular targeted treatments. Lung cancer is a prototypic example and one of the leading causes of cancer-related deaths worldwide. One major technical problem of detecting DNA alterations in tissue samples is cellular heterogeneity, that is, mixture of tumor and normal cells. Microdissection is an important tool to enrich tumor cells from heterogeneous tissue samples. However, conventional laser capture microdissection has several disadvantages like user-dependent selection of regions of interest (ROI), high costs for dissection systems and long processing times. ROI selection in expression-based microdissection (xMD) directly relies on cancer cell-specific immunostaining. Whole-slide irradiation leads to localized energy absorption at the sites of most intensive staining and melting of a membrane covering the slide, so that tumor cells can be isolated by removing the complete membrane. In this study, we optimized xMD of lung cancer tissue by enhancing staining intensity of tumor cell-specific immunostaining and processing of the stained samples. This optimized procedure did not alter DNA quality and resulted in enrichment of mutated EGFR DNA from lung adenocarcinoma specimens after xMD. We here also introduce a quality control protocol based on digital whole-slide scanning and image analysis before and after xMD to quantify selectivity and efficiency of the procedure. In summary, this study provides a workflow for xMD, adapted and tested for lung cancer tissue that can be used for lung tumor cell dissection before diagnostic or investigatory analyses