Exth-33. rage inhibitor (ttp488) as an alternative to dexamethasone for managing cerebral edema following brain tumor surgery

BACKGROUND Cerebral edema (CE) commonly occurs after neurosurgical procedures and contributes to patient morbidity and neurological deterioration. Corticosteroids alleviate brain edema during the perioperative period, but they impose several undesirable side effects and interfere with immunotherapies in patients with malignant brain tumors. OBJECTIVE To assess the anti-inflammatory effects of TTP488 (inhibitor of receptor for advanced glycation end products) on CE formation following tumor resection in glioma models. METHODS Mice harboring orthotopic CT-2A gliomas were randomly assigned to three groups and underwent tumor resection. TTP488, dexamethasone, and vehicle were administered perioperatively (day -4 pre-op to day 7 post-op) and post-operative neurological function was examined. CE was assessed on serial brain MRIs over a 7-day period, and using manual segmentation techniques, tumor-related volumes were calculated. In a separate survival experiment, the effect of each drug on anti-PD-1 immunotherapy response was measured. RESULTS In each group, CE peaked on post-operative day 2 and gradually diminished by day 7. On post-operative day one, mice treated with TTP488 showed a marked reduction in CE compared to those treated with either dexamethasone or vehicle with mean CE volumes of 1.75±1.08%, 2.69±0.77%, and 3.87±1.07%, respectively (P=0.02, TTP488 vs vehicle). Furthermore, the TTP488 group had better functional recovery scores (P=0.04) and wound healing (dehiscence, P=0.00003) compared to the vehicle group. Interestingly, unlike dexamethasone, TTP488 did not abrogate the efficacy of immunotherapy in the CT-2A glioma model. CONCLUSION TTP488 was as effective as dexamethasone in alleviating CE caused by tumor resection and did not interfere with the efficacy of immunotherapy. TTP488 could potentially be an alternative to dexamethasone in the perioperative management of patients undergoing tumor resection or other neurosurgical interventions.