Atypical PKCiota Contributes to Poor Prognosis Through Loss of Apical-basal Polarity and Cyclin E Overexpression in Ovarian Cancer

We show that atypical PKCι, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCι protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCι DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCι proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCι protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCι as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCι is a novel target for therapy

Intranasal fentanyl spray versus intravenous opioids for the treatment of severe pain in patients with cancer in the emergency department setting: A randomized controlled trial.

ObjectiveIntranasal fentanyl (INF) quickly and noninvasively relieves severe pain, whereas intravenous hydromorphone (IVH) reliably treats severe cancer pain but requires vascular access. The trial evaluated the efficacy of INF relative to IVH for treating cancer patients with severe pain in an emergency department (ED) setting.MethodsWe randomized 82 patients from a comprehensive cancer center ED to receive INF (n = 42) or IVH (n = 40). Eligible patients reported severe pain at randomization (≥7, scale: 0 "none" to 10 "worst pain"). We conducted non-inferiority comparisons (non-inferiority margin = 0.9) of pain change from treatment initiation (T0) to one hour later (T60). T0 pain ratings were unavailable; therefore, we estimated T0 pain by comparing 1) T60 ratings, assuming similar group T0 ratings; 2) pain change, estimating T0 pain = randomization ratings, and 3) pain change, with T0 pain = 10 (IVH group) or T0 pain = randomization rating (INF group).ResultsAt T60, the upper 90% confidence limit (CL) of the mean log-transformed pain ratings for the INF group exceeded the mean IVH group rating by 0.16 points (>pain). Substituting randomization ratings for T0 pain, the lower 90% CL of mean pain change in the INF group extended 0.32 points below (ConclusionsTwo of three analyses supported non-inferiority of INF versus IVH, while one analysis was inconclusive. Compared to IVH, INF had the advantage of shorter time to administration.Trial registrationClinicalTrials.gov Identifier: NCT02459964