Thymoma and Thymic Carcinoma: Molecular Pathology and Targeted Therapy

Abstract:Thymomas and thymic carcinomas (TC) are rare epithelial tumors of the thymus. Although most thymomas have organotypic features (i.e., resemble the normal thymus), TC are morphologically undistinguishable from carcinomas in other organs. Apart from their different morphology, TC and thymomas differ also in functional terms (TC, in contrast to thymomas, have lost the capacity to promote the maturation of intratumorous lymphocytes), have different genetic features (discussed in this review), a different immunoprofile (most TC overexpress c-KIT, whereas thymomas are consistently negative), and different clinical features (TC, in contrast to thymomas, are not associated with paraneoplastic myasthenia gravis). Thus, although all the data suggest that the biology of thymomas and TC is different, in clinical practice, their therapeutic management up to now is identical. In the age of personalized medicine, the time may have come to think this over. We will briefly review the molecular genetics of malignant thymic tumors, summarize the current status of targeted therapies with an emphasis on the multitargeted kinase inhibitors sunitinib and sorafenib, and try to outline some future directions

Generalizability of an Identification Approach for Machine Control Signals in Brownfield Production Environments

Digital transformation has been a central aspect of optimizing processes in manufacturing companies for several years now. A basic prerequisite of successful transformation is the vertical integration of all machines and machine tools to capture data at all levels. This can create further applications that enable more sustainable and resource-saving processes. At the same time cost- and quality-optimizing analyses such as failure detection, predictive maintenance or general process optimization represent major incentives for companies. While the necessary interfaces are now integrated in state-of-the-art machine tools, companies with older legacy machines face the problem that no such interfaces are readily available. Brownfield machine tools feature outdated technology that does not allow direct networking connectivity without further effort. To participate in the technological progress, a system was developed that allows to extract machine control signals from machine tools and identify them automatically as time series. This is compatible with several communication protocols (e.g., OPC UA) to be as universally applicable as possible. Since machine control signals are often not interpretable for the user due to different naming conventions, the extracted time series are analyzed by machine learning and analytical rule bases, these are based on expert knowledge, and assign a specific signal type in each case. With regard to a cross-machine generalization capability, several aspects have to be considered. Due to different data sources, the identification system must still function reliably with varying sampling frequency. Another challenge is the diversity of different types of machines and production equipment. Therefore, this publication investigates the different influences of data sources and machine types on the machine control signal identification system

End-to-end Learning for Image-based Detection of Molecular Alterations in Digital Pathology

Current approaches for classification of whole slide images (WSI) in digital pathology predominantly utilize a two-stage learning pipeline. The first stage identifies areas of interest (e.g. tumor tissue), while the second stage processes cropped tiles from these areas in a supervised fashion. During inference, a large number of tiles are combined into a unified prediction for the entire slide. A major drawback of such approaches is the requirement for task-specific auxiliary labels which are not acquired in clinical routine. We propose a novel learning pipeline for WSI classification that is trainable end-to-end and does not require any auxiliary annotations. We apply our approach to predict molecular alterations for a number of different use-cases, including detection of microsatellite instability in colorectal tumors and prediction of specific mutations for colon, lung, and breast cancer cases from The Cancer Genome Atlas. Results reach AUC scores of up to 94% and are shown to be competitive with state of the art two-stage pipelines. We believe our approach can facilitate future research in digital pathology and contribute to solve a large range of problems around the prediction of cancer phenotypes, hopefully enabling personalized therapies for more patients in future.Comment: MICCAI 2022; 8.5 Pages, 4 Figure

O6-methylguanine-DNA methyltransferase (MGMT) Promoter methylation is a rare event in soft tissue sarcoma

BACKGROUND: Gene silencing of O6-methylguanine–DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide. FINDINGS: Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%. CONCLUSION: MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide

Perioperative and Oncological Outcome of Laparoscopic Resection of Gastrointestinal Stromal Tumour (GIST) of the Stomach

Background. Surgery remains the only curative treatment for gastrointestinal stromal tumour (GIST). Resection needs to ensure tumour-free margins while lymphadenectomy is not required. Thus, partial gastric resection is the treatment of choice for small gastric GISTs. Evidence on whether performing resection laparoscopically compromises outcome is limited. Methods. We compiled patients undergoing laparoscopic resection of suspected gastric GIST between 2003 and 2007. Follow-up was performed to obtain information on tumour recurrence. Results. Laparoscopic resection with free margins was performed in 21/22 patients. Histology confirmed GIST in 17 cases, 4 tumours were benign neoplasms. Median operation time and postoperative stay for GIST patients were 130 (range 80–201) mins and 7 (range 5–95) days. Two patients experienced stapler line leakage necessitating surgical revision. After median follow-up of 18 (range 1–53) months, no recurrence occurred. Conclusions. Laparoscopic resection of gastric GISTs yields good perioperative outcomes. Oncologic outcome needs to be assessed with longer follow-up. For posterior lesions, special precaution is needed. Laparoscopic resection could become standard for circumscribed gastric GISTs if necessary precautions for oncological procedures are observed

Pathomechanisms of Paraneoplastic Myasthenia Gravis

Thymic T cell development is characterized by sequential selection processes to ensure generation of a self-tolerant, immuncompetent mature T cell repertoire. Malfunction of any of these selection processes may potentially result in either immunodeficiency or autoimmunity. Myasthenia gravis (MG) is a typical autoimmune manifestation of thymic epithelial tumors (thymomas) and is related to the capacity of these tumors to generate and export mature T cells. Analysis of the factors that lead to autoimmunization in thymomas will help to understand the mechanisms that prevent MG under physiological conditions in humans. In a comparison of MG(+) and MG(-) thymomas, we could show that only thymomas capable of generating mature CD45RA+CD4+ T cells are associated with MG (p< 0.0001), while terminal thymopoiesis was abrogated in MG(-) thymomas. In particular, acquisition of the CD27+CD45RA+ phenotype appears to be a critical checkpoint of late T cell development in the human thymus and may play an important role in the prevention of autoimmunity. Moreover, MG(-) thymomas were virtually depleted of regulatory (CD4+CD25+) T cells (regT), while regT were readily detectable in MG(+) thymomas, albeit at significantly reduced numbers compared to control thymuses. Thus, in MG(+) thymoma patients, thymectomy apparently also results in removal of a regulatory T cell pool and may explain the frequent temporary postoperative deterioration of MG in these patients

Molecular analysis of desmoid tumors with a high-density single-nucleotide polymorphism array identifies new molecular candidate lesions

Background: Desmoid tumors are neoplastic proliferations of connective tissues. The mutation status of the gene coding for catenin (cadherin-associated protein) beta 1 (CTNNB1) and trisomy 8 on the chromosomal level have been described to have prognostic relevance. Patients and Methods: In order to elucidate new molecular mechanisms underlying these tumors, we carried out a molecular analysis with a genome-wide human high-density single-nucleotide polymorphism (SNP) array, in 9 patients. Results: Single samples showed numerical aberrations on chromosomes (Chrs) 20 and 6 with either trisomy 20 or monosomy 6. No trisomy 8 could be detected. Recurrent heterozygous deletions were found in Chr 5q (including the APC gene locus, n = 3) and Chr 8p23 (n = 4, containing coding regions for the potential tumor suppressor gene CSMD1). This novel deletion in 8p23 showed an association with local recurrence. In addition, structural chromosomal changes (gain of Chrs 8 and 20) were found in a minority of cases. Conclusion: The genomic alteration affecting the candidate gene CSMD1 could be important in the development of desmoid tumors

Mesenchymal tumours of the mediastinum—part II

This is the second part of a two-part review on soft tissue tumours which may be encountered in the mediastinum. This review is based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart and provides an updated overview of mesenchymal tumours that have been reported in the mediastinum