Adherence and long-term outcomes of therapy in paediatric patients in Greece using the easypod™ electromechanical device for growth hormone treatment: The phase IV multicentre easypod™ connect observational study (ECOS).

BACKGROUND: The easypod™ injection device allows automatic recording and transmission of adherence data from patients receiving recombinant human growth hormone (rhGH [Saizen®]) to treat growth disorders. This analysis aimed to evaluate the adherence of Saizen® administered via easypod™ in a cohort of Greek patients from the easypod™ connect observational study (ECOS). METHODS: The phase IV, open-label, multicentre, observational, and longitudinal ECOS study (EMR200104-520, NCT01363674) enrolled patients treated for a minimum of 6 months and up to 3 years. The primary endpoint was to assess the mean rate of adherence to treatment at different time points, where good adherence was defined as ≥85%. Change in height, height standard deviation score (SDS), height velocity and height velocity SDS were evaluated after 1 year of treatment as secondary endpoints, together with the impact of adherence on growth outcomes using the Spearman's product moment. RESULTS: Of the 180 patients enrolled, 86 were included in the analysis. The mean adherence to Saizen®, as recorded via easypod™, was high at each individual time point, and was maintained at 95.5% after 1 year of treatment. Clinically meaningful positive changes were also noted for all of the secondary endpoints (median increase in height = 7.25 cm, height SDS = 0.32, median height velocity = 7.62 cm/year and height velocity SDS = 1.65). However, no significant correlation was noted between adherence and growth outcomes. CONCLUSIONS: rhGH replacement therapy using Saizen® with easypod™ led to full compliance to the treatment in a representative Greek population from ECOS, and provided additional insights on how the easypod™ device can assist physicians in monitoring adherence and help to optimise linear growth in paediatric patients with growth disorders.

Pediatric growth hormone therapy in Greece: analysis of the Hellenic cohort of the GeNeSIS study.

PURPOSE: To describe the data from the Greek cohort of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). METHODS: GeNeSIS was a prospective, open-label, multinational, observational study collecting information on clinical outcomes and treatment safety of children with growth disorders treated with growth hormone (GH), according to national indications. After informed consent, 305 patients (143 females), including 255 patients with growth hormone deficiency (GHD) and 30 with Turner syndrome (TS), from eight investigational sites, were enrolled in Greece. Demographic data, treatment efficacy, and adverse events were reported at the discretion of attending physicians. RESULTS: Treatment with GH was undertaken for 247/255 patients with GHD and 29/30 with TS. The majority of patients treated with GHD (73.7%) and TS (84%) with recorded Tanner stage were prepubertal at enrolment. Among patients treated with GHD and TS, 70.45% and 55% were GH-naïve at study entry, respectively. Height standard deviation score (SDS), height velocity SDS, and height SDS-target height SDS numerically improved during the 4-year observation period. The effect of GH treatment was more prominent in the first year of treatment, especially in the GHD group. CONCLUSIONS: In the Greek cohort of GeNeSIS, GHD is the most frequent indication for GH treatment, followed by TS. While the latter is diagnosed somewhat earlier, GH treatment is not as efficacious as for patients with GHD. No major safety issues were reported during follow-up. The results, which are in accordance with the international literature, should be interpreted in the context of observational studies.

Leptin levels in patients with thalassemia major.

AIM: Patients with thalassemia major often present endocrine abnormalities due to dysfunction in their hypothalamic-pituitary axis. Leptin, an adipocyte derived hormone, primarily acts in hypothalamus and its deficiency in the ob/ob mouse results in persistent immaturity of its hypothalamic-pituitary function. The aim of the study was to evaluate leptin levels in thalassemic patients. METHODS: The study involved 33 adult patients (11 males), mean age (SD) 19.3 years (4.4) and a group of 12 prepubertal boys, mean age (SD): 7 years (1.7) with homozygous beta-thalassemia. RESULTS: Mean (SD) leptin concentration was 3.2 (3.3) ng/mL in thalassemic males and 8.6 (3.3) ng/mL in thalassemic females; values significantly lower than matched normal subjects. In the group of prepubertal thalassemic children, leptin levels were also lower compared with matched healthy children, although the difference was not statistically significant. CONCLUSIONS: In conclusion, low leptin levels were observed in thalassemic patients, which may be due to a toxic effect of iron to adipocytes.

Tumor necrosis factor-alpha levels in short children.

Growth hormone has been suggested to modulate the release of cytokines, such as tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1). Moreover, TNFalpha synthesis has been shown to be decreased in hypophysectomized rodents. The aim of this study was to evaluate the influence of GH status on TNFalpha levels in a group of 44 short prepubertal children. Among them, 13 children aged 9.8 +/- 3.5 years were growth hormone (GH) deficient and the other 31 short children had normal growth velocity, normal GH response to provocative testing, and did not suffer from any chronic disease, thus this group was diagnosed as having idiopathic short stature (ISS). A group of 40 age- and sex-matched healthy children was used as controls. No significant differences in basal TNFalpha levels (pg/ml) were found between the GH deficient, ISS children and healthy controls. Furthermore, there was no correlation between TNFalpha and basal serum concentrations of GH or peak GH levels after stimulation. Similarly, TNFalpha values did not correlate with either IGF-I or IGFBP-3 serum concentrations.

Gonadal function in young patients successfully treated for Hodgkin disease.

BACKGROUND: Gonadal function in pediatric and young adult survivors of Hodgkin disease is not very well defined. This study evaluates the outcome following the Multiple Drug Protocol (MDP) and the results are compared to the published experience. PROCEDURE: Ovarian and testicular function was assessed in 65 patients (36 males) with Hodgkin disease in first or second complete remission after treatment with either radiation (RT, n = 13), chemotherapy (CT, n = 9), or both (n = 43). Chemotherapy consisted of six cycles of the MDP (doxorubicin, procarbazine, prednisone, vincristine, and cyclophosphamide). Median age at diagnosis was 13.1 years (range, 2.4-22.6) and median age at evaluation was 22.6 years (range, 15.1-33.7), which was 6.7 years (range, 2.0-19.8) after the completion of all treatments. For the purpose of analysis, patients were divided into three groups: group A, patients who received only RT that did not include the pelvis (8 females, 5 males); group B, patients who received CT but no pelvic RT (15 females, 25 males); and group C, patients who received CT plus pelvic RT (6 females, 6 males). RESULTS: All patients progressed spontaneously through puberty and evaluable patients were found to be sexually mature (Tanner stage IV and V). Serum follicle stimulating hormone (FSH) was increased in 0/5, 13/25, and 5/6 and testicular volume was decreased in 1/3, 4/11, and 2/3 group A, B, and C male patients, respectively. Leydig cell dysfunction was uncommon; 91% and 88% of males had normal serum concentrations of luteinizing hormone (LH) and testosterone, respectively. FSH and LH were increased in 0/8, 3/15, and 2/6 group A, B, and C female patients, respectively, at last follow-up, indicating a 17% prevalence of ovarian dysfunction. Serial data in seven females whose initial levels of FSH/LH were elevated revealed normalization in four. Six females delivered eight normal children. CONCLUSIONS: The majority of males who received CT +/- RT have evidence of germ cell dysfunction, while Leydig cell function is unaffected in most. In females, although abnormal function early after the end of treatment was observed, ovarian function remained or returned to normal in most young women. Thus, in females the results of hormone testing performed early after treatment may not be predictive of their eventual reproductive potential.

Reproductive health in patients with beta-thalassemia.

Homozygous transfusion-dependent beta-thalassemia patients manifest cardiac, hepatic, endocrine, and metabolic disorders attributable to chronic anoxia and iron overload. Short stature, delayed sexual maturation, diabetes mellitus, hypothyroidism, hypoparathyroidism, and metabolic bone disease can and should be diagnosed as early as possible so that the intervention can be fruitful. Primary or secondary amenorrhea is due primarily to pituitary gonadotrope hemosiderosis, as attested by pathology data and the demonstration in vivo of nonstimulable follicle-stimulating hormone and luteinizing hormone release and secretion after the exogenous administration of gonadotropin-releasing hormone or its agonistic analogs. Ovulation can be achieved with the use of exogenous gonadotropins provided that the ovary has no siderosis (as seen in neglected patients) or damage induced by drugs used for bone marrow transplantation. Once pregnancy is achieved, it should be considered high risk and be dealt with or cared for by an expert team to ensure a successful outcome.

Dehydroepiandrosterone in morbidly obese adolescents: effects on weight, body composition, lipids, and insulin resistance.

The hormone dehydroepiandrosterone (DHEA) has been reported to have beneficial effects on obesity, diabetes mellitus, and serum lipids in animal studies, but results in human studies are less clear. We conducted a randomized double-blind placebo-controlled trial to determine the effects of DHEA treatment on obesity and related physiologic conditions in adolescents and young adults. In this 10-week study, 13 morbidly obese subjects received a placebo for 2 weeks. After this run-in period, patients were randomized, with seven subjects (mean age, 15.5 years; body mass index [BMI, derived by dividing body weight in kilograms by height in meters squared], 48.2 +/- 9.7 [mean +/- SD]) receiving DHEA 40 mg sublingually twice daily for 8 weeks and six subjects (mean age, 18.0 years; BMI, 52.9 +/- 14) receiving placebo. Variables measured included body weight, body composition, resting metabolic rate (RMR), serum lipid levels, insulin sensitivity, and serum steroid levels. Treatment with DHEA resulted in a statistically significant increase in plasma DHEA and DHEA sulfate (DHEAS) concentrations (P < .01). Testosterone (T) levels were significantly increased in females who received DHEA. DHEA administration had no effect on body weight, sense of well-being, or any other measured variables. These findings suggest that DHEA 40 mg administered sublingually twice daily for 8 weeks has no positive effect on body weight, body composition, serum lipids, or insulin sensitivity in extremely obese adolescents and young adults.

Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy--a clinical research center study.

Muscle weakness and wasting in myotonic dystrophy (MyD) are believed to be due to a decrease in muscle protein synthesis, secondary to insulin resistance. A 4-month, randomized, double blind, placebo-controlled trial was undertaken to assess whether recombinant human insulin-like growth factor I (rhIGF-I) may overcome the insulin resistance. Patients received either 5 mg rhIGF-I (n = 7) or placebo (n = 9), sc, twice daily. Glucose metabolism was assessed by stable label iv glucose tolerance test, amino acid metabolism by L-[13C] leucine turnover, body composition by dual energy x-ray absorptiometry and N excretion, and muscle response by manual muscle strength and neuromuscular function. In the treated group, the insulin sensitivity index, insulin action, and glucose disposal all increased (P < 0.05). Leucine flux and leucine incorporation into protein increased (P < 0.05), and the rate of leucine oxidation to leucine turnover decreased (P < 0.05), findings indicative of increased protein synthesis. Body weight and lean body mass increased, whereas percent body fat decreased (P < 0.05). An increase in manual muscle strength of 0.42 +/- 0.30 (P < 0.02) and in neuromuscular function of 17.5 +/- 11.7 (P < 0.02) occurred in the four patients who received a rhIGF-I dose greater than 70 micrograms/kg, whereas a more modest response occurred in the three patients who received a dose less than 70 micrograms/kg. Two patients showed dramatic improvement. Long term rhIGF-I therapy appears to cause metabolic and muscle improvement in optimally treated MyD patients.

Rhabdoid tumor of the kidney with humoral hypercalcemia and parathyroid hormone-related protein production.

This is a report of a 7-month-old infant with malignant rhabdoid tumor of the kidney (RTK). The patient (pt) demonstrated clinical and biochemical evidence of humoral hypercalcemia of malignancy (HHM). The hypercalcemia responded promptly to calcitonin treatment and tumor removal. Despite aggressive surgery and chemotherapy, the patient expired four months after diagnosis. The primary tumor displayed adenylate cyclase-stimulating activity (ACSA) indicating the production of parathyroid hormone-related protein (PTHrP) by the primary tumor. This is the first report of ACSA documented in a pt with RTK.

Increased energy expenditure in a patient with diencephalic syndrome.

Total energy expenditure, measured in an infant with diencephalic syndrome with doubly labeled water, was 30% to 50% higher than that reported for other healthy infants whose energy expenditure was measured by the same technique and 13% higher than the patient's energy intake. This result suggests that the weight loss and cachexia of the diencephalic syndrome are the result of abnormally increased energy expenditure.