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Staging in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.There is a concern that as a result of COVID-19 there will be a shortage of ventilators for patients requiring respiratory support. This concern has resulted in significant debate about whether it is appropriate to withdraw ventilation from one patient in order to provide it to another patient who may benefit more. The current advice available to doctors appears to be inconsistent, with some suggesting withdrawal of treatment is more serious than withholding, while others suggest that this distinction should not be made. We argue that there is no ethically relevant difference between withdrawing and withholding treatment and that suggesting otherwise may have problematic consequences. If doctors are discouraged from withdrawing treatment, concern about a future shortage may make them reluctant to provide ventilation to patients who are unlikely to have a successful outcome. This may result in underutilisation of available resources. A national policy is urgently required to provide doctors with guidance about how patients should be prioritised to ensure the maximum benefit is derived from limited resources.Pilocytic astrocytomas (PAs) as well as other pediatric low-grade gliomas (pLGGs) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are KIAA1549BRAF fusions, BRAFV600E and NF1 mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for pre-clinical testing of MAPKi in pLGGs with the goal to identify novel MAPK pathway suppressing synergistic drug combinations. A reporter plasmid (pDIPZ) with a MAPK-responsive ELK-1-binding element driving the expression of destabilized firefly luciferase was generated and packaged using a lentiviral vector system. Pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively, were stably transfected. Modulation of the MAPK pathway activity by MAPKi was measured using the luciferase reporter and validated by detection of phosphorylated protein levels. A screen of a MAPKi library was performed and synergy of selected combinations was calculated. Screening of a MAPKi library revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and next-generation RAF inhibitors. Combination treatments with different MAPKi classes showed synergistic effects in BRAF fusion as well as BRAFV600E mutation backgrounds. We here report a novel reporter assay for medium- to high-throughput pre-clinical drug testing in pLGG cell lines. The assay confirmed MEK, ERK and next-generation RAF inhibitors as potential treatment approaches for KIAA1549BRAF and BRAFV600E mutated pLGGs. In addition, the assay revealed that combination treatments synergistically suppressed MAPK pathway activity.Glycosylation is a complex multi-enzyme related process which is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface specific glycotopes that can be targeted by antibodies. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization. It recognizes CA6, a Mucin-1 (MUC1) associated sialoglycotope that is highly detected in breast, ovarian, lung and bladder carcinomas. SAR566658 antibody drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative drug, DM4. SAR566658 binds to tumor cells with sub-nanomolar affinity, allowing good ADC internalization and intracellular delivery of DM4, resulting in tumor cell death (IC50 from 1 to 7.3 nM). SAR566658 showed in vivo anti-tumor efficacy against CA6 positive human pancreas, cervix, bladder and ovary tumor xenografts and against 3 breast patient-derived xenografts (PDX). Tumor regression was observed in all tumor models with minimal effective dose correlating with CA6 expression. SAR566658 displayed better efficacy than standard of care non-targeted tubulin binders. click here This data supports the development of SAR566658 in patients with CA6 expressing tumors.Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44+/CD24-, ALDH activity, or by tumor sphere formation. In vivo, upregulation of EMP2 promoted tumor growth while knockdown reduced the ALDHhigh CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1a, a transcription factor previously shown to regulate the self-renewal of ALDHhigh CSC. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSC, reducing the ALDH+ population and blocking their tumor initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor initiating cells providing a rationale for the continued development of EMP2 targeting agents.
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