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Systematic Cavernous Sinus Exploration Combined With Early Hormonal Assessment in Cushing Disease. BACKGROUND AND OBJECTIVES: Unrecognized cavernous sinus (CS) invasion by adenomas is a major factor in surgical failure and recurrence of Cushing disease (CD), and pituitary adenomas. Exploration of the CS during trans-sphenoidal surgery (TSS) and resection of the involved medial wall of CS (medial wall of the CS) can achieve apparent gross total resection. However, novel strategies are needed to identify patients with occult tumor residuals and direct them to early radiotherapy. We developed the normalized early postoperative value (NEPV) of adrenocorticotropic hormone (ACTH) and cortisol as potential early predictors of remission. In this study, we integrate exploration of CS and NEPV into a clinical decision-making strategy in CD. METHODS: We analyzed data from 315 patients (2012-2023) undergoing TSS by a single surgeon for CD. Surgical approaches included sublabial TSS, CS exploration, and medial wall resection based on preoperative imaging or intraoperative findings. Postoperative cortisol and ACTH levels were assessed at extubation and every 6 hours postoperatively for 72 hours before corticosteroid replacement. RESULTS: CS exploration was performed in 50 patients (33 female; median age 26.5 years) because of preoperative MRI findings (n = 37) or intraoperative findings (n = 13). Adenoma adherence (n = 18, 36%) or invasion (n = 32, 64%) of the medial wall was observed. Thirteen patients with subtotal resection were recommended for radiation. Among 37 patients with gross total resection, 12 (29.7%) received radiotherapy because of elevated postoperative hormone levels, including persistent hypercortisolemia (n = 5), elevated NEPV ACTH (n = 5), or cortisol (n = 5). No recurrence occurred in these 12 patients. Transient cranial neuropathies (<90 days) were observed in 4 patients, with no arterial injuries reported. CONCLUSION: Preoperative MRI often underestimates CS invasion. CS exploration and medial wall resection are safe and effective for durable remission. An integrated strategy, using intraoperative findings and postoperative biochemical monitoring, may guide effective adjuvant therapy in CD.