26 research outputs found
Differential effects of short- and long-term treatment with mepolizumab on eosinophil kinetics in blood and sputum in eosinophilic asthma
Mepolizumab (anti-IL-5) is a successful biological for treatment of T2/eosinophilic asthma by blocking the IL-5-eosinophil axis. The kinetics of human eosinophils in blood and sputum was determined to better understand the underlying mechanism(s). Pulse-chase labeling was performed with 6,6-2H2-glucose in patients with asthma after short term (4 days) and long term (84 days) treatment with mepolizumab (n = 10) or placebo (n = 10). The retention time of eosinophils in sputum was longer than in blood. Treatment with mepolizumab induced a fast and long-lasting eosinopenia with no reduction of eosinophil progenitors. The retention time of eosinophils in blood was delayed only after short-term treatment. This leads to the hypothesis that IL-5 increases the number of IL-5-responsive progenitors and potentiates homing to the tissues, leading to reactive eosinophilia. Long-term treatment is associated with low numbers of IL-5-independent eosinophils in blood and tissues. Therefore, long-term treatment with mepolizumab restores the kinetics of eosinophils as normally found in homeostasis
Peptide receptor radionuclide therapy in patients with medullary thyroid carcinoma: predictors and pitfalls
Background: For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with
tyrosine kinase inhibitors result in grade 3–4 adverse events in a large number of patients. Peptide Receptor
Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well
tolerated, but evidence on its effectivity is very limited.
Methods: Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with
progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical 111InDTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm.
Results: Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable
disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable
disease were characterized by a combination of both a high uptake on 111In-DTPA-octreotide scan (uptake grade ≥
3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry.
Retrospective evaluation of historical 111In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low
uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in
the remaining 4/35 (11%).
Conclusions: PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake
on 111In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high
uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC
patients.
Keywords: Thyroid cancer, medullary, Peptide receptor radionuclide therapy, Lutetium, Receptors, somatostati
Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing's syndrome
Context: Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop. Objective: Investigation of regulation of steroidogenesis in a case of PPNAD with virilization. Materials and methods : A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroid
Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies
Context: A 56-yr-old woman presented with acromegaly, a pulmonary mass, and elevated levels of GHRH, GH, and IGF-I. Histological examination revealed a bronchial carcinoid with positive staining for GHRH. Somatostatin analogs (SAs) can play an important role in the treatment of neuroendocrine tumors, dependent on the somatostatin receptor subtype (sst) expression pattern. The sst pattern in bronchial carcinoids and effects of SAs have not been extensively investigated, particularly not for the recently developed universal SA SOM230 (Pasireotide) that has high affinity for sst(1, 2, 3,) and (5). Objective: Our objective was to investigate the in vivo response of a GHRH-producing bronchial carcinoid to octreotide (OCT), its sst-expression profile, and in vitro responses to different SAs, including SOM230. Methods: In vivo, 50 mu g OCT was administered, and plasma GH and GHRH responses were determined. In vitro, the expression of ssts was analyzed by quantitative PCR. Furthermore, the effects of SOM230 and OCT on GHRH secretion were evaluated in primary cell cultures of the carcinoid tissue. Results: In vivo, OCT administration fully suppressed GH and GHRH levels. In vitro, sst1 mRNA was most abundant, followed by sst(2) and sst(5). Both SOM230 and OCT inhibited GHRH production dose dependently (SOM230 100 nM vs. control, P = 0.01; OCT 110 nM vs. control, P = 0.05). Conclusions: In this case of a GHRH-producing bronchial carcinoid, we demonstrated that SOM230 was a potent inhibitor of GHRH production in vitro and was at least equally potent compared with OCT. Therefore, SOM230 may be a potential therapeutic agent to control GHRH secretion in ectopic acromegaly. (J Clin Endocrinol Metab 94: 428-433, 2009