Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2015-001703-32.

Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n ¼ 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n ¼ 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro, inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer.

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Recently, SOX2 has been identified as a potential lineage-specific oncogene in lung squamous cell carcinomas. Since head and neck squamous cell carcinomas (HNSCC) are morphologically and clinically highly related to lung squamous cell carcinomas, we hypothesized that SOX2 also plays an oncogenic role in this tumor entity. We assembled a cohort of 496 patients with HNSCC, including 253 metastases and 135 recurrences. SOX2 amplification (FISH) and SOX2 protein expression (immunohistochemistry) were correlated with molecular and clinicopathological parameters. In order to investigate the functional role of SOX2 in human HNSCC, SOX2 knockdown and overexpression in SCC-25 cells were generated by lentiviral constructs and subjected to cell cycle analysis, proliferation and apoptosis assays. Furthermore, SOX2 expression was correlated with the expression of proliferation and apoptosis-related proteins in primary HNSCC samples. SOX2 amplification was detected in 21% of primary HNSCC and mostly observed in a concordant manner between primary tumors and corresponding metastatic tissues. Overall, SOX2 amplification resulted in protein overexpression and was mutually exclusive with human papillomavirus infection. SOX2 protein overexpression was associated with clinicopathological parameters of worse outcome. Functionally, SOX2 induced the expression of the antiapoptotic protein BCL-2 and enhanced resistance to apoptosis-inducing agents including cisplatin, indicating SOX2 as a mediator of therapy resistance in human HNSCC. Targeting SOX2 and related molecular downstream pathways such as BCL-2 may enhance therapy efficacy in SOX2-expressing HNSCC.

Prostate cancer is mostly diagnosed at an early stage; however, some tumors are diagnosed in a metastatic stage as cancer of unknown primary origin. In order to allow specific treatment in the case of prostate cancer presenting as cancer of unknown primary origin, it is important to determine the tumor origin. Prostate-specific antigen is used as a diagnostic marker for prostate cancer but the expression declines with progression to castration-resistant prostate cancer. Aim of this study was to identify the most informative marker constellation, which is able to detect metastatic prostate cancer at high sensitivity. The widely used prostate cancer markers such as prostate-specific antigen, prostate-specific acid phosphatase, androgen receptor, prostate-specific membrane antigen, prostein, and ETS-related gene were investigated for their sensitivity to detect prostatic origin of metastases. Expression of prostate-specific antigen, prostate-specific acid phosphatase, androgen receptor, prostate-specific membrane antigen, prostein, and ETS-related gene was determined on archived tissue specimens consisting of benign prostatic tissue (n ¼ 9), primary prostate cancer (n ¼ 79), lymph node metastases (n ¼ 58), and distant metastases (n ¼ 39) using immunohistochemistry. The staining intensity was categorized as negative (0), weak (1), moderate (2), and strong (3). All markers except ETS-related gene were able to detect at least 70% of lymph node metastases and distant metastases, with prostate-specific antigen, androgen receptor, and prostate-specific membrane antigen having the highest sensitivity (97%, 91%, and 94%, respectively). A further increase of the sensitivity up to 98% and 100% could be achieved by the combination of prostate-specific antigen, prostate-specific membrane antigen, or androgen receptor for lymph node metastases and for distant metastases, respectively. The same sensitivity could be reached by combining prostate-specific membrane antigen and prostein. Our data show that a combined staining of at least two prostate markers should be utilized to identify metastases as originating from prostate cancer. Modern Pathology (2015) 28, 138-145; doi:10.1038/modpathol.2014 published online 13 June 2014 Prostate cancer is the most commonly diagnosed non-epidermal cancer and second-most common cancer-related cause of death in men in the western world. 1 The patients' death is often caused by the development of castration-resistant prostate cancer. Most prostate cancers are detected early in a localized stage; however, in some cases, metastases can be the first manifestation of a prostate cancer. 2 Unlike other carcinomas, hormone-sensitive prostate cancer responds to hormonal therapy and therefore the identification of the tumor origin is important in order to allow specific treatment. Male patients with a metastatic adenocarcinoma are routinely assessed for prostatic origin using prostate-specific immunohistochemistry markers like prostate-specific antigen (PSA). 3 PSA is highly expressed in benign prosta...