Successful treatment of Cushing's disease using yttrium-90 rods.

Interstitial irradiation using yttrium-90 (90Y) rods implanted by needle into the pituitary gland was used as primary treatment in 16 patients with pituitary dependent Cushing''s disease. Clinical and biochemical remission was observed within three or six months in 13 and in the remaining three after a supplementary implant. There was no perioperative morbidity. Follow-up from the time of definitive operation ranged from six to 123 months (mean 39). No recurrence has been observed. The return of a normal diurnal cortisol rhythm has been observed in 10/12 patients studied after remission. Some form of long-term pituitary hormone replacement therapy was required in only the six patients who had received the largest irradiation dose. Implantation of 90Y is safe and effective treatment for patients with Cushing''s disease, comparing favourably with selective trans-sphenoidal pituitary surgery.     

Uptake of yttrium-90 into lipid vesicles

Abstract

Lipid vesicles may be safely and efficiently loaded with therapeutic dose levels of the beta emitter yttrium-90 (⁹⁰Y) by using the ability of the cation ionophore A23187 to transport yttrium across the lipid bilayer where it is chelated on the vesicle interior by diethylenetriamine pentaacetic acid (DTPA). For 100 nm diameter vesicles composed of diplamitoylphosphatidylcholine (DPPC) and cholesterol (Choi), DPPC/Chol (1:1), containing 15 mM DTPA with 40 nmoles of external yttrium, total uptake was > 95% of added yttrium within 5 min at 50° using 0.4 ng of ionophore per nmole of lipid. Background binding in these neutral vesicles accounts for less than 0.1% of the yttrium associated with the vesicles. Important operational parameters were the amount of ionophore (> 0.2 μg of ionophore per μmole of lipid was required) and also the temperature (for DPPC/Chol (1:1) vesicles uptake at 40° was essentially background but was > 95% at 50°). The presence of the polymer polyethylene glycol (PEG) on the membrane surface had no effect upon yttrium uptake. Once entrapped, vesicles did not leak any contents for several days at room temperature.     

Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment

A woman affected by Cushing's disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson's syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15-80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 x 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson's syndrome in the presence of a pituitary macroadenoma.     

Feasibility of outpatient management after intra-articular yttrium-90: comparison of two regimens.

In a study comparing two regimens of treatment after intra-articular irradiation of the knee with yttrium-90 one group of patients was allocated to bed rest for 48 hours in hospital and the other to mobilisation at home. Initially a Robert-Jones orthopaedic bandage was applied to the knee in all patients, serving as a semi-rigid splint, but as loss of isotope from the knee was appreciable in the mobilised patients, subsequent patients were sent home with the knee in a plaster-of-Paris cylinder. No difference in extra-articular spread or chromosomal damage was found between the patients sent home with their knee in a rigid splint and those treated by bed rest. Clinical outcome at three months was satisfactory in all three groups. These results show that rigid splinting is essential in reducing extra-articular spread of the isotope but that bed rest is not necessary. Increases in intra-articular pressure associated with quadriceps muscle activity combined with flexion of the knee may be the most important factor affecting extra-articular spread of isotope.     

Asymmetrical radical formation in D- and L-alanines irradiated with yttrium-90 beta-rays.

Radical formation in 90Y-beta-irradiated D- and L-alanines was studied using ESR. It was observed that the relative radical concentration by beta-irradiation was distinguishably (13.9-21.5%) more in D-alanine than in L-alanine. Discussion was made on the possible mechanisms for the observed results.     

Evaluation of two regimens to immobilise the knee after injections of yttrium-90.

Two regimens to immobilise the knee after injection were compared in patients receiving intra-articular yttrium-90 for persistent synovitis of the knee, the patients being randomly allocated to receive either complete bed rest or full mobilisation with the affected knee in a firm splint. There was no difference in the percentage of the radioisotope retained in the knee or in that taken up by other tissues between the two regimens. It is concluded that after intra-articular injections of yttrium-90 strict bed rest in hospital is unnecessary.     

ACTH secretion during sleep in a patient with Nelson's syndrome.

Plasma ACTH determinations were made by radioimmunoassay, every 10 min for 8 hours during sleep in a patient with Nelson's syndrome. The plasma ACTH concentrations were relatively stable, fluctuating in a narrow range. It is strongly suggested that the pituitary tumor itself was secreting ACTH in an autonomous manner and it is concluded that a neuronally initiated program of ACTH secretion, was absent in the present patient with Nelson's syndrome.     

Effect of an oral serotonin antagonist,ketanserin, on plasma ACTH concentrations in Nelson's syndrome.

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson''s syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing''s disease and who had Nelson''s syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson''s syndrome. These results show that it is not indicated in these patients.     

An approach to the mechanism of the asymmetrical radical formation in yttrium-90-beta-irradiated D- and L-alanines

Several attempts were made to investigate the mechanism of the asymmetrical radical formation in yttrium-90-beta-irradiated D- and L-alanines which was reported in the preceding paper (1). The experiments demonstrated that the magnitude of the asymmetry was dependent on beta-ray dose, namely the lower the dose the larger the observed difference was, and that no difference could be detected when the alanines were irradiated in aqueous state. The results in the present study seem to that different interaction between the crystal structure of the two enantiomers and polarized beta-rays may be responsible for the observed phenomenon.