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Background: Death from pancreatic ductal adenocarcinoma (PDAC) is rising across the world and PDAC is predicted to be the second most common cause of cancer death in the USA by 2030. Development of effective biotherapies for PDAC are hampered by late presentation, a low number of differentially expressed molecular targets and a tumor-promoting microenvironment that forms both a physical, collagen-rich barrier and is also immunosuppressive. In 2017 Pancreatic Cancer UK awarded its first Grand Challenge Programme award to tackle this problem. The team plan to combine the use of novel CAR T cells with strategies to overcome the barriers presented by the tumor microenvironment. In advance of publication of those data this review seeks to highlight the key problems in effective CAR T cell therapy of PDAC and to describe pre-clinical and clinical progress in CAR T bio-therapeutics., (Copyright © 2020. Published by Elsevier B.V.)

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10 -8 ). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Background: There is little knowledge of the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) and whether their prescription varies between countries., Objective: To describe prescription practices of NSAIDs in equids in the United Kingdom (UK), United States of America (USA) and Canada., Study Design: Descriptive observational study., Methods: Free-text electronic medical records from 141,543 equids from 10 equine practices in the UK, 255,777 equids from 7 equine practices with 20 branches from the USA and 2 practices with 7 branches from Canada were evaluated. A validated text-mining technique was used to describe the proportion of equids prescribed NSAIDs at least once in these countries. The choice of NSAIDs in orthopaedic and colic cases was evaluated., Results: The prescription of NSAIDs is more common in the USA (42.4%) and Canada (34.2%) than in the UK (28.6%). Phenylbutazone and flunixin meglumine were the drugs mostly prescribed in all countries. While flunixin meglumine was most prescribed with colic cases in all countries, a proportion received phenylbutazone despite this drug being licensed for use only with musculoskeletal disease. Phenylbutazone was the most commonly prescribed drug in cases with orthopaedic disease followed by flunixin meglumine in all countries. Only a small proportion of cases received meloxicam, ketoprofen or firocoxib., Main Limitations: The retrospective design might have resulted in an unknown number of incomplete records, particularly in the reporting of colic and orthopaedic disease. Although the data set is large, the relatively small number of practices recruited from each country may introduce bias., Conclusions: Clinical practice can differ between countries although the influence of individual practitioners and practice-specific policy on apparent intercountry differences requires further research. Despite several other NSAIDs being available and a substantial effort being made to evaluate their efficacy, the prescription of NSAIDs other than phenylbutazone and flunixin meglumine remains rather limited., (© 2018 EVJ Ltd.)

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking 'how can we effectively treat cancer?', we do not capture the complexity of a disease encompassing >200 different cancer types - many consisting of multiple subtypes - with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.