Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.

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Objective: To contribute evidence for the reliability, construct validity and responsiveness of the PROMIS-29 profile questionnaire as a measure of recovery after pancreatic surgery. Summary Background Data: PROMIS questionnaires have been recommended to evaluate post-discharge recovery after surgery. Evidence supporting their measurement properties in pancreatic surgery is missing. Methods: An observational validation study designed according to the COSMIN checklist was conducted including data from a prospective clinical trial. Patients undergoing pancreatectomy completed PROMIS-29 preoperatively and on postoperative days (PODs) 15, 30, 90, 180. Reliability was assessed by internal consistency using Cronbach’s alpha. Construct validity was assessed by known-groups comparison. Responsiveness was evaluated hypothesizing that scores would be higher (1) preoperatively versus POD15, (2) on POD30 versus POD15, (3) on POD90 versus POD30, and (4) on POD180 versus POD90. Results: Overall, 510 patients were included in the study. Reliability was good to excellent (alpha values ranged from 0.82 to 0.97). Data supported 4 of 5 hypotheses tested for construct validity for five domains (physical function, anxiety, depression, fatigue and ability to participate in social roles) at most time points. Responsiveness hypotheses 1, 2, 3 were supported by the data for physical function, fatigue, sleep disturbance, pain interference and ability to participate in social roles domains. Conclusion: PROMIS had excellent reliability, discriminated between most groups expected to have different recovery trajectories and was responsive to the expected trajectory of recovery up to 90 days after surgery. Our findings support the use of PROMIS-29 profile as a patient reported outcome measure of post-discharge recovery after pancreatectomy.