Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to ...assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly.
In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 μg/L and insulin-like growth factor 1 IGF-1 concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682.
Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6-26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1-31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 33% for treatment with 40 mg pasireotide, 19 31% with 60 mg pasireotide, and nine 14% with active control), diabetes (13 21%, 16 26%, and five 8%), and diarrhoea (ten 16%, 12 19%, and three 5%); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group.
Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues.
Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
Targeted treatment with somatostatin analogues (SA) in acromegaly and neuroendocrine neoplasms may have some benefits compared to curative treatments, because these agents decrease excessive hormone ...secretion and exert a tumor-suppressive effect. Monotherapy and combination therapy with SA is well tolerated and bears no risk of debilitating iatrogenic complications. In acromegaly caused by somatotropin producing pituitary tumor, first generation SA are treatment of choice after non-radical adenomectomy, as well as in the cases when patients reject surgery. Treatment efficacy depends on the pathomorphological types of somatotropic tumors, which are different in their receptor phenotype, clinical scenario and proliferative activity. The first generation SA are successfully used for medical treatment of other pituitary tumors (thyrotropic, corticotropic, gonadotropic, lactotropic with resistance to dopamine agonists), as well as for adjuvant therapy of neuroendocrine and non-endocrine neoplasms and elimination of various gastrointestinal disorders. The anti-secretory and anti-tumor effects of SA have been proven for gastroenteropancreatic tumors (carcinoid syndrome, vipomas, gastrinomas, insulinomas, glucagonomas, somatostatinomas). Targeted selection of patients for treatment with first generation SA based on the receptor phenotypes of malignant cells would facilitate more rapid achievement of biochemical remission, improvement of quality of life and survival.
Subject of Research. The transmitting channel of the laser location system, composed of a laser and its telescopic radiation expander, forms an output laser beam with specified geometric parameters. ...In particular, it can be a quasi- parallel beam or have a waist at a given distance. Method. The high-precision equipment setup is developed on the basis of geometrical optics methods providing the formation of a laser beam with preset geometrical parameters. The equipment setup is based on a mirror parabolic collimator and a matrix pyroelectric camera, which is located in its focal plane and is able to move along its axis. Flat diagonal mirrors are installed in such a way that they separate the laser beam coming out of the expander and direct it at the peripheral diametrically opposite collimator light zones. After reflection from the parabola, the beams converge at a sufficiently large angle convenient for further analysis. If the laser location system is aligned with the aim to reduce divergence, the matrix camera is positioned in the focal plane of the collimator. If the alignment is intended to create a waist of laser radiation at a given distance, then the matrix camera is placed at a certain distance from the focal plane. The alignment process is reduced to the registration of the gravity centers for the beams coming from parabola edges with their alternate overlapping. As soon as the difference in the beam coordinates becomes commensurate with the measurement error, the process is completed. Main Results. The technique involves the alignment of the telescopic expander together with the laser and eliminates errors associated with the installation of these two components relative to each other. During the operation, labor-intensive movements of the photodetector in space and subsequent calculations are not required, and fewer optical elements are used. Moreover, the effect of fluctuations in the laser radiation power is excluded. According to the proposed technique, a system is aligned consisting of a CO2 laser with divergence of 7.5 mrad and a telescopic expander with tenfold magnification. The obtained alignment accuracy amounts to 10 % of the laser radiation divergence value. It is shown that the main contribution to alignment accuracy is made by coordinate registration error of the image gravity centers, which largely depends on fluctuations in the laser radiation power. Practical Relevance. The proposed technique has a low labor intensity, sufficient accuracy for practical application and can be implemented in the laboratories of enterprises engaged in the production of laser location systems.
Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a ...large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
ObjectiveTo evaluate extended dosing intervals (EDIs) with lanreotide Autogel 120 mg in patients with acromegaly previously biochemically controlled with octreotide LAR 10 or 20 mg.Design and ...methodsPatients with acromegaly had received octreotide LAR 10 or 20 mg/4 weeks for ≥6 months and had normal IGF1 levels. Lanreotide Autogel 120 mg was administered every 6 weeks for 24 weeks (phase 1); depending on week-24 IGF1 levels, treatment was then administered every 4, 6 or 8 weeks for a further 24 weeks (phase 2). Hormone levels, patient-reported outcomes and adverse events were assessed. Primary endpoint: proportion of patients on 6- or 8-week EDIs with normal IGF1 levels at week 48 (study end).Results107/124 patients completed the study (15 withdrew from phase 1 and two from phase 2). Of 124 patients enrolled, 77.4% were allocated to 6- or 8-week EDIs in phase 2 and 75.8% (95% CI: 68.3–83.3) had normal IGF1 levels at week 48 with the EDI (primary analysis). A total of 88.7% (83.1–94.3) had normal IGF1 levels after 24 weeks with 6-weekly dosing. GH levels were ≤2.5 μg/l in >90% of patients after 24 and 48 weeks. Patient preferences for lanreotide Autogel 120 mg every 4, 6 or 8 weeks over octreotide LAR every 4 weeks were high.ConclusionsPatients with acromegaly achieving biochemical control with octreotide LAR 10 or 20 mg/4 weeks are possible candidates for lanreotide Autogel 120 mg EDIs. EDIs are effective and well received among such patients.
The transmitting channel of the laser location system, composed of a laser and its telescopic radiation expander, forms an output laser beam with specified geometric parameters. In particular, it can ...be a quasiparallel beam or have a waist at a given distance. Method. The high-precision equipment setup is developed on the basis of geometrical optics methods providing the formation of a laser beam with preset geometrical parameters. The equipment setup is based on a mirror parabolic collimator and a matrix pyroelectric camera, which is located in its focal plane and is able to move along its axis. Flat diagonal mirrors are installed in such a way that they separate the laser beam coming out of the expander and direct it at the peripheral diametrically opposite collimator light zones. After reflection from the parabola, the beams converge at a sufficiently large angle convenient for further analysis. If the laser location system is aligned with the aim to reduce divergence, the matrix camera is positioned in the focal plane of the collimator. If the alignment is intended to create a waist of laser radiation at a given distance, then the matrix camera is placed at a certain distance from the focal plane. The alignment process is reduced to the registration of the gravity centers for the beams coming from parabola edges with their alternate overlapping. As soon as the difference in the beam coordinates becomes commensurate with the measurement error, the process is completed. Main Results. The technique involves the alignment of the telescopic expander together with the laser and eliminates errors associated with the installation of these two components relative to each other. During the operation, labor-intensive movements of the photodetector in space and subsequent calculations are not required, and fewer optical elements are used. Moreover, the effect of fluctuations in the laser radiation power is excluded. According to the proposed technique, a system is aligned consisting of a CO2 laser with divergence of 7.5 mrad and a telescopic expander with tenfold magnification. The obtained alignment accuracy amounts to 10 % of the laser radiation divergence value. It is shown that the main contribution to alignment accuracy is made by coordinate registration error of the image gravity centers, which largely depends on fluctuations in the laser radiation power. Practical Relevance. The proposed technique has a low labor intensity, sufficient accuracy for practical application and can be implemented in the laboratories of enterprises engaged in the production of laser location systems.
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