Development of an experimental model to study the pathophysiology of cerebral salt wasting following subarachnoid hemorrhage.

Hyponatremia is frequent following cranial -neurosurgery or acute brain injury like subarachnoid hemorrhage (SAH), and increases mortality by 30%. The patho-physiology is not understood nor does a causal therapy exist. Since clinical trials are potentially dangerous in this very ill population, we examined whether an established rat model allows studying cerebral salt wasting (CSW) following SAH. The daily urine sodium excretion as well as plasma sodium, osmolality and antidiuretic hormone (ADH) levels were measured for 10 days. Following the injection of 300 µl of blood into the great cistern (SAH(severe)), natriuresis peaked twice (days 1 and 3-5, p < 0.05) resulting in a plasma sodium nadir (day 1 - 133.9 mmol/L, day 5 - 132.6 mmol/L), while following the injection of 300 µL saline (ICP(control)), natriuresis occurred delayed on days 4-5 (p < 0.05). Following double SAH (200 µL twice, 24 h apart), a natriuresis on day 4 resulted in a hyponatremia (131.7 mmol/L, p = 0.025). Neither SAH(mild) (100 µL), the injection of hemolyzed blood (100 µL) or hypertonic saline (200 µL) replicated the effect. The immediate release of ADH (32.23 ± 34.87 pg/mL) following SAH(severe) normalized over the next few days. We conclude that first, the rat model of SAH is suitable for studying CSW, second the increase in intracranial pressure generates the delayed hyponatremia, and third, the ADH release does not mediate natriuresis.

Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary Adenomas and Carcinomas-A German Survey.

CONTEXT: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. OBJECTIVE: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. DESIGN AND SUBJECTS: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. RESULTS: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. CONCLUSION: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.