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

Mesenchymal tumours of the mediastinum—part I

The mediastinum is an anatomically defined space in which organs and major blood vessels reside with surrounding soft tissue elements. The thymus is an important organ in the mediastinum, and many of the masses encountered in the mediastinum are related to this organ. Most neoplasms diagnosed in the mediastinum are epithelial tumours (thymomas and thymic carcinomas), lymphomas or germ cell tumours. In contrast, soft tissue tumours of the mediastinum are rare. In 1963, Pachter and Lattes systematically reviewed soft tissue pathology of the mediastinum, covering the hitherto described [2, 226, 227] In this review, based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart, we provide an updated overview of mesenchymal tumours that may be encountered in the mediastinum

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor <it>(VEGF-R</it>) and Transketolase-like-1 (<it>TKTL1</it>) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of <it>VEGFR-1</it>, <it>VEGFR-2 </it>and <it>TKTL1 </it>in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab.</p> <p>Methods</p> <p>Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR.</p> <p>Results</p> <p>Significantly higher expression of <it>VEGFR-1/2 </it>was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High <it>TKTL1 </it>expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers.</p> <p>Conclusion</p> <p>High <it>TKTL-1 </it>expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.</p

Analysis of single nucleotide polymorphisms in the FAS and CTLA-4 genes of peripheral T-cell lymphomas

Angioimmunoblastic T-cell lymphoma (AILT) represents a subset of T-cell lymphomas but resembles an autoimmune disease in many of its clinical aspects. Despite the phenotype of effector T-cells and high expression of FAS and CTLA-4 receptor molecules, tumor cells fail to undergo apoptosis. We investigated single nucleotide polymorphisms (SNPs) of the FAS and CTLA-4 genes in 94 peripheral T-cell lymphomas. Although allelic frequencies of some FAS SNPs were enriched in AILT cases, none of these occurred at a different frequency compared to healthy individuals. Therefore, SNPs in these genes are not associated with the apoptotic defect and autoimmune phenomena in AILT

Benchmarking whole exome sequencing in the German Network for Personalized Medicine

Introduction Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis. Methods To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics investigating somatic and germline variants, copy-number alteration (CNA), and different complex biomarkers. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. In addition, all raw data were re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability. Results The mean positive percentage agreement (PPA) of somatic variant calling was 76% and positive predictive value (PPV) 89% compared a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88% for all and 97% for clinically relevant variants. CNA calls were concordant for 82% of genomic regions. Calls of homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94%, 93%, and 93% respectively. Variability of CNAs and complex biomarkers did not increase considerably using the central pipeline and was hence attributed to wet-lab differences. Conclusion Continuous optimization of bioinformatic workflows and participating in round robin tests are recommend

Activating CBL mutations are associated with a distinct MDS/MPN phenotype

Activating point mutations in CBL have recently been identified in diverse subtypes of myeloid neoplasms. Because detailed clinical and hematological characteristics of CBL-mutated cases is lacking, we screened 156 BCR-ABL and JAK2 V617F negative patients with myeloproliferative neoplasms (MPN) and overlap syndromes between myelodysplastic syndrome (MDS) and MPN (MPS/MPN) for mutations in exons 8 and 9 of CBL by denaturing high-performance liquid chromatography and direct sequencing. CBL mutations were identified in 16/156 patients (10 %), of which five also carried mutations in EZH2 (n?=?3) and TET2 (n?=?2). Comprehensive clinical and hematological characteristics were available from 13/16 patients (81 %). In addition to splenomegaly (77 %), striking common hematological features were CML-like left-shifted leukocytosis (85 %) with monocytosis (85 %), anemia (100 %), and thrombocytopenia (62 %). Thrombocytosis was not observed in any patient. Relevant bone marrow features (n?=?12) included hypercellularity (92 %) with marked granulopoiesis (92 %), nonclustered microlobulated megakaryocytes (83 %), and marrow fibrosis (83 %). Nine deaths (progression to secondary acute myeloid leukemia/blast phase, n?=?7; cytopenia complications, n?=?2) were recorded. Three-year survival rate was 27 %, possibly indicating poor prognosis of CBL mutated MDS/MPN patients. <br/

TFAP2E-DKK4 and chemoresistance in colorectal cancer

Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy