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    • In conclusion this first in human phase

    2018-11-13

    In conclusion, this first-in-human phase I study of VEDT was designed to establish the BED of VEDT for future investigations of the clinical activity of VEDT. VEDT is distinguished from other tocotrienols by its consistently superior anticancer activity in preclinical models. Although there are no approved agents for pancreatic cancer prevention, the dismal natural history of pancreatic cancer and increasing recognition of high-risk individuals warrants the investigation of promising agents like VEDT from preclinical studies (Husain et al., 2013a). Here, we have shown that VEDT use in untreated patients with pancreatic cancer and high-risk premalignant tumors was associated with selective induction of apoptosis in neoplastic xpo 1 without toxicity. These results, as well as efficacy data of VEDT in preclinical studies, encourage our further exploration of VEDT as an alternative treatment for patients at risk of pancreatic cancer. Additional considerations of VEDT include its use in treatment of early-stage disease to prevent or delay relapse, as well as combining VEDT with chemotherapy and other targeted agents.
    Contributors
    Role of the Funding Source The study was supported in part by the National Cancer Institute Grant 1RO1 CA-129227-01A1. Our study also received valuable assistance from Translational Research Core, Biostatistics Core, and Analytic Microscopy Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center, supported under NIH Grant P30-CA76292. The sponsor of the study had no role in the study design, data collection, data analyses, data interpretation, or writing of the report.
    Potential Conflicts of Interest
    Acknowledgments
    Introduction Pancreatitis is a prevalent inflammatory disorder of the pancreas that is associated with high mortality and is a source of significant global socioeconomic burden. (Lankisch et al., 2015; Yadav and Lowenfels, 2013) The annual incidence of acute pancreatitis (AP) ranges from 13 to 45 per 100,000 population (Lankisch et al., 2015), mainly based on studies from high-income countries. Among patients treated in US hospitals in 2009, AP was the most frequent discharge diagnosis in gastrointestinal disease and hepatology, the second highest cause of all hospital stays, the largest contributor to aggregate costs, and the fifth leading cause of in-hospital deaths (Lankisch et al., 2015; Peery et al., 2012). Chronic pancreatitis (CP) leads to progressive replacement of pancreatic parenchyma with fibrotic tissue (Braganza et al., 2011). CP is less prevalent than AP, with annual prevalence rates ranging between 5 and 12 per 100,000 (Yadav and Lowenfels, 2013; Braganza et al., 2011). CP is associated with a spectrum of chronic endocrine and exocrine pancreatic insufficiencies, manifesting in malnutrition, diabetes mellitus, disability, medical costs, and quality of life loss (Yadav and Lowenfels, 2013; Braganza et al., 2011). Alcohol consumption is considered one of the major causative agents for pancreatitis (Lankisch et al., 2015; Irving et al., 2009); after gallstones, alcohol is the second major leading cause of AP and the most common cause of CP (Yadav and Lowenfels, 2013; Yadav and Lowenfels, 2006). In 2009, a systematic review and meta-analysis on the association between alcohol consumption and pancreatitis (Irving et al., 2009), based on data from six studies, found a monotonically increasing dose–response relationship between average alcohol consumption and pancreatitis. Since then, a number of original studies were published (Kume et al., 2015; Gonzalez-Perez et al., 2010; Yang et al., 2014; Lai et al., 2011; Lembke et al., 2011; Lin et al., 2014) which have led to recent summaries on etiological and pathobiological aspects of different subtypes of pancreatitis (Lankisch et al., 2015; Yadav and Lowenfels, 2013), which allow for more in-depth analyses of the risk relationships. In particular, these new studies allow for differentiation of dose–response relationships by type of pancreatitis (acute vs. chronic) and by sex. This differentiation is important, as the biological mechanisms underlying are different — gallstones are the primary cause of AP, along with factors associated with biliary disease and choledocholithiasis, such as obesity and hypertriglyceridemia, whereas they play a negligible role in CP, except in cases where AP progresses into CP (Yadav and Lowenfels, 2013). On the other hand, CP is associated primarily with the impact of chronic toxic influences that makes alcohol use the most common causative agent for CP (Yadav and Lowenfels, 2013). Consequently, while AP and CP are still seen on a continuum of clinical manifestations of one inflammatory disease (Whitcomb, 2004; Mitchell et al., 2003), the progression and outcomes of CP and AP significantly differ (Lankisch et al., 2015; Yadav and Lowenfels, 2013).