ABSTRACT
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/metabolism , Trifluoperazine/pharmacology , Trifluoperazine/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Temozolomide/pharmacology , Chemoradiotherapy , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
BACKGROUND: Iatrogenic internal carotid artery (ICA) injury is a catastrophic complication in open skull base surgery. There is a lack of information regarding the most appropriate techniques on how to manage this complication. OBJECTIVE: To highlight the difficulties encountered when an ICA injury arises intraoperatively and discuss the role and the potential pitfalls of the crushed muscle patch in the management of an ICA injury during open skull base surgery. METHODS: In this technical video, we demonstrate the management of intraoperative ICA injury, which occurred during the resection of a diffuse planum sphenoidale meningioma via a left pterional craniotomy. RESULTS: When isolation of the defect with temporary clips failed, we opted for a crushed muscle graft to plug the defect. Hemostasis was achieved, but because of prolonged pressure application and "overpacking," the parent vessel was occluded. CONCLUSION: The crushed muscle patch can be easily applied; however, care must be taken not to "overpack" and occlude the ICA.
