Fitzgeraldconradsen0262

© 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.Background and purpose Current practice in re-irradiation (reRT) of previously treated high-grade gliomas (HGG) has generally been limited to small volume reRT with stereotactic procedures. Less evidence exists for large volume reRT involving treatment volumes equivalent to that used at initial diagnosis. The primary aim of this study was to investigate the outcome of large volume reRT delivered in combination with Bevacizumab (BEV) in patients with recurrent chemorefractory HGG. Methods and materials Patients with HGG managed with reRT were entered prospectively into a database. Clinicopathological features were recorded including timing of reRT, use of BEV and Dosimetric data. Median survival following reRT was the primary endpoint and association with clinicopathological factors was assessed with cox regression models. Results Sixty seven patients in total were managed with reRT, 51 patients had glioblastoma and 16 had anaplastic glioma. The median PTV was 145.3 cm3. Median OS post reRT was 7.8 months (95% CI 6.3-9.2 months) in the total cohort and 7.5 months (95% CI 6.6-8.3 months) for GBM patients. In multivariate analysis of the whole cohort, IDH1 mutation status (p = 0.041) and ECOG status prior to reRT ( less then 0.001) were significantly associated with OS. In terms of safety and toxicity, the majority of patients (66.5%) were ECOG 0-2 three months after treatment. In total, four episodes of suspected radiation necrosis occurred, all in patients treated without upfront BEV. Conclusion Large volume reRT with bevacizumab is a feasible late salvage option in patients with recurrent HGG and offers meaningful prolongation of survival with low toxicity. © 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.Background The combination of somatostatin receptor-directed peptide receptor radionuclide therapy (PRRT) in combination with external beam radiotherapy (EBRT) might prove a feasible treatment option in patients with advanced meningioma. Patients and methods From May 2010 to May 2011, 10 patients with unresectable meningioma (6 × WHO grade I, 2 × WHO grade II, 2 × WHO grading not available) were treated with one cycle of PRRT followed by EBRT. Long-term toxicity and efficacy were assessed according to Common Terminology Criteria for Adverse Events version 5.0 and magnetic resonance imaging-based Response Assessment in Neuro-Oncology Working Group criteria, respectively. Results During long-term follow-up of a median of 105.0 months (range, 38.2-111.4 m), combined PRRT and EBRT was well-tolerated with no severe acute or chronic toxicity. Kidney or bone marrow function was not affected in any patient. Combination of PRRT and EBRT resulted in disease stabilization in 7 of the 10 patients with a median progression-free survival of 107.7 months (range, 47.2-111.4 m) vs. 26.2 months (range, 13.8-75.9 m) for the patients with meningioma progression. Conclusions The combination of PRRT and EBRT is a feasible and safe therapeutic option in meningioma patients. In this pilot cohort, the multimodality treatment demonstrated good disease stabilization. © 2020 The Authors.Tyrosine kinase inhibitors (TKIs) induce autophagy in many types of cancer cells. We previously reported that gefitinib (GEF) and imatinib (IMA) induce autophagy in epidermal growth factor receptor (EGFR) knock-out A549 and non-BCR-ABL-expressing leukemia cell lines, respectively. This evidence suggests that TKI-induced autophagy is independent of the original target molecules. The present study compared the autophagy-inducing abilities of various TKIs, regardless of their targets, by quantitative autophagy flux assay. We established stable clones expressing the GFP-LC3-mCherry-LC3ΔG plasmid in A549, PC-9, and CAL 27 cell lines and assessed autophagy inducibility by monitoring the fluorescent ratios of GFP-LC3 to mCherry-LC3ΔG using an IncuCyte live cell imaging system during exposure to TKIs viz; GEF, osimertinib (OSI), lapatinib (LAP), lenvatinib (LEN), sorafenib (SOR), IMA, dasatinib (DAS), and tivantinib (TIV). Nemtabrutinib purchase Among these TKIs, DAS, GEF, and SOR exhibited prominent autophagy induction in A549 and PC-9 cells. In CAL 27 cells, IMA, SOR, and LEN, but not GEF, TIV, or OSI, exhibited autophagy induction. In the presence of azithromycin (AZM), which showed an inhibitory effect on autophagy flux, TKIs with prominent autophagy inducibility exhibited enhanced cytotoxicity via non-apoptotic cell death relative to effects of TKI alone. Therefore, autophagy inducibility of TKIs differed in the context of cancer cells. However, once induced, they appeared to have cytoprotective functions. Thus, blocking TKI-induced autophagy with AZM may improve the therapeutic effect of TKIs in cancer cells. © 2020 The Author(s).At the initial stage of carcinogenesis, when RasV12-transformed cells are surrounded by normal epithelial cells, RasV12 cells are apically extruded from epithelia through cell competition with the surrounding normal cells. In this study, we demonstrate that expression of cyclooxygenase (COX)-2 is upregulated in normal cells surrounding RasV12-transformed cells. Addition of COX inhibitor or COX-2-knockout promotes apical extrusion of RasV12 cells. Furthermore, production of Prostaglandin (PG) E2, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE2 suppresses apical extrusion of RasV12 cells. In a cell competition mouse model, expression of COX-2 is elevated in pancreatic epithelia harbouring RasV12-exressing cells, and the COX inhibitor ibuprofen promotes apical extrusion of RasV12 cells. Moreover, caerulein-induced chronic inflammation substantially suppresses apical elimination of RasV12 cells. These results indicate that intrinsically or extrinsically mediated inflammation can promote tumour initiation by diminishing cell competition between normal and transformed cells. © The Author(s) 2020.Comprehensive development is critical for gut macrophages being essential for the intestinal immune system. However, the underlying mechanisms of macrophage development in the colon remain elusive. To investigate the function of branched-chain amino acids in the development of gut macrophages, an inducible knock-out mouse model for the branched-chain amino acid transporter CD98hc in CX3CR1+ macrophages was generated. The relatively selective deletion of CD98hc in macrophage populations leads to attenuated severity of chemically-induced colitis that we assessed by clinical, endoscopic, and histological scoring. Single-cell RNA sequencing of colonic lamina propria macrophages revealed that conditional deletion of CD98hc alters the "monocyte waterfall"-development to MHC II+ macrophages. The change in the macrophage development after deletion of CD98hc is associated with increased apoptotic gene expression. Our results show that CD98hc deletion changes the development of colonic macrophages. © The Author(s) 2020.