Opioid Use Is Associated With Higher Health Care Costs and Emergency Encounters in Inflammatory Bowel Disease.

BACKGROUND: We aimed to examine opioid use among adult patients with inflammatory bowel disease (IBD) in the United States and the impact of extended opioid use on emergency health care services and health care costs among patients. METHODS: We conducted a retrospective cohort study using medical claims data from the Truven Health MarketScan research databases, consisting of patients across the United States with employer-based health insurance. Subjects with IBD were identified in 2009. The occurrence of an emergent encounter in 2010 and health care costs were assessed. RESULTS: There were 76,171 subjects with 35,993 emergent encounters among the study population, for an overall rate of 0.47 per patient-year. However, these encounters were confined to 6.9% of patients overall. The median total charges per patient in 2010 were $5372. Extended opioid use in 2009 was associated with a higher odds of an emergent encounter in 2010 (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.67-1.98), higher incidence rate of emergent encounters (incidence rate ratio, 2.07; 95% CI, 1.91-2.24), and higher odds of being in the top quartile of cost in 2010 (OR, 1.90; 95% CI, 1.79-2.02). Depression was a strong predictor of extended opioid use (OR, 2.64; 95% CI, 2.49-2.81; P < 0.001). CONCLUSIONS: Extended opioid use among patients with IBD is an important predictor of emergent encounters and is associated with higher total health care costs. Psychosocial comorbidities are significant predictors of extended opioid use in patients with IBD.

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation.

Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood-brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1-eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival.Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32-46. ©2017 AACR.

MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma.

Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts poor survival in glioblastoma multiforme. In established and patient-derived cell lines, pharmacologic MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E, a crucial effector for MNK-induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis. When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacologic MNK inhibition targets mesenchymal glioblastoma multiforme and its GSC population. IMPLICATIONS: These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of glioblastoma multiforme. Mol Cancer Res; 14(10); 984-93. ©2016 AACR.