Wessel, Bambi

BACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patientʼs individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ . We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ. METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High–molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge. EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone. DISCUSSION: Limited mechanistic feedback from individual patientsʼ gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.

Caring for the growing elderly population will require specialty and subspecialty physicians who have not completed geriatric medicine fellowship training to participate actively in patient care. To meet this workforce demand, a sustainable approach to integrating geriatrics into specialty and subspecialty graduate medical education training is needed. This article describes the use of a geriatrics education team ( GET ) model to develop, implement, and sustain specialty‐specific geriatrics curricula using a systematic process of team formation and needs assessment through evaluation, with a unique focus on developing curricular interventions that are meaningful to each specialty and satisfy training, scholarship, and regulatory requirements. The GET model and associated results from 15 specialty residency and fellowship training programs over a 4‐year period include 93% curriculum sustainability after initial implementation, more than half of the programs introducing additional geriatrics education, and more than 80% of specialty GET s fulfilling their scholarship requirements through their curriculum dissemination. Win–wins and barriers encountered in using the GET model, along with the model's efficacy in curriculum development, sustainability, and dissemination, are summarized.