Safety of long-term treatment with Pegvisomant: analysis of Spanish patients included in global ACROSTUDY.

PURPOSE: To evaluate the long-term safety of Pegvisomant (PEG) in the Spanish cohort of ACROSTUDY. METHODS: As of July 2013, 199 Spanish patients were included in ACROSTUDY, a global non interventional safety PEG surveillance study. Patients were observed for safety, biochemical outcome and magnetic resonance imaging evaluations. RESULTS: PEG was administered during an average period of 6.7 ± 2.1 years and a mean daily dose of 15.5 ± 7.5 mg. 48.2% of patients received PEG monotherapy. 90.9% of patients had received other medical treatment before PEG start. 195 adverse events (AEs) were reported in 88 patients (44.2%), and serious AEs were described in 31 patients (15.6%). There were no cases of liver tests >10 ULN, or permanent liver damage. Tumor size changes were locally reported in 61 cases (33.5%), with increases observed in 11 patients (6%). In acromegalic patients with diabetes mellitus a decrease in fasting serum glucose value was reported, reaching statistical significance after 1 and 4 years of treatment (-24.6 and -25.9 mg/dl, p = 0.04). After 60 months, normal or lower limit of normal (LLN) IGF-I levels were found in 67.9% of patients. 85.5% of patients showed an IGF-I normal or

Update on prognostic factors in acromegaly: Is a risk score possible?

Certain clinical conditions and markers have recently been demonstrated to modify the natural history of acromegaly in affected patients. Thus, some clinical, histological, radiological and molecular factors are associated with more aggressive pituitary tumors that have higher biochemical activity, higher tumor volumes and decreased tumoral and biochemical responses to current therapies. However, these factors do not seem to have an equal influence on the prognosis of patients with acromegaly. We present a review of the factors that influence the clinical course of patients with acromegaly and propose a risk value for each factor that will allow prognostic scoring for affected patients by considering a combination of these factors.

Influence of the exon 3 deletion of GH receptor and IGF-I level at diagnosis on the efficacy and safety of treatment with somatotropin in adults with GH deficiency.

PURPOSE: The treatment of adults with GH deficiency (GHD) with human recombinant growth hormone has interindividual variability and several factors influence it. The aims of this study were : 1-to analyze the GH receptor (GHR) genotype in terms of exon 3 deletion GHR (d3-GHR) in adults with GHD; 2-to assess the effects of d3-GHR on initial IGF-I levels; 3-to evaluate whether d3-GHR and/or initial IGF-I levels were associated with adverse effects and/or treatment discontinuation. METHODS: Forty-four adult patients with GHD were included. Demographic, clinical and biochemical characteristics were retrospectively evaluated at baseline and 6 months, 1 and 3 years after the initiation of treatment. d3-GHR was analyzed in 35 patients. RESULTS: 37.1% of patients were d3-GHR carriers (31.4% heterozygous, 5.7% homozygous). IGF-I at baseline was low in 64% of patients and was not related to d3-GHR status. There was no association between the d3-GHR allele and baseline IGF-I (p = 0.14). Although adverse events were more frequent in the d3-GHR carriers (30.7 vs. 18.2% in fl/fl) and in patients with normal IGF-I levels at diagnosis (43.7 vs. 17.8% in patients with low IGF-I levels), this association was not statistically significant. d3-GHR status was not related to the incidence of adverse events (p = 0.4) or treatment discontinuation (p = 0.47). Baseline IGF-I levels were neither associated with adverse events (p = 0.08) nor treatment discontinuation (p = 0.75). CONCLUSIONS: The d3-GHR allele was not related to baseline levels of IGF-I. Neither d3-GHR nor baseline IGF-I level was related to adverse events or treatment discontinuation.

Epidemiology, mortality rate and survival in a homogeneous population of hypopituitary patients.

INTRODUCTION: Hypopituitarism is associated with higher prevalence of cardiovascular risk factors and premature death. Furthermore, some clinical and therapeutic features of hypopituitarism have been associated with a worse prognosis. OBJECTIVE: We reviewed, retrospectively, a large series of adult patients with hypopituitarism using stringent epidemiological criteria. Prevalence, association with cardiovascular risk factors, mortality and survival have been analysed. DESIGN AND METHODS: Two hundred and nine adult hypopituitary patients (56·9% females) from a population of 405 218 inhabitants, followed for 10 years. RESULTS: Prevalence of hypopituitarism at the end of the study was 37·5 cases/100 000 inhabitants. Incidence of hypopituitarism was 2·07 cases/100 000 inhabitants and year. Thirty-two patients died during the period of the study. Standardized mortality rate (SMR) was 8·05, higher in males (8·92 vs 7·34) and in younger patients (84·93 vs 5·26). Diagnosis of acromegaly (P = 0·033), previous radiotherapy (P = 0·02), higher BMI (P = 0·04), diabetes mellitus (P = 0·03) and cancer (P < 0·0001) were associated with mortality. A lower survival was associated with older age at diagnosis, nontumoural causes, previous radiotherapy, diabetes mellitus with poor metabolic control and malignant disease. CONCLUSIONS: Prevalence of hypopituitarism was 37·5 cases/100 000 inhabitants, and annual incidence was 2·07 cases/100 000 inhabitants. SMR was 8 times higher in hypopituitarism than in general population and was also higher in males and younger patients. Reduced survival was significantly related to cancer, nontumoural causes of hypopituitarism, older age at diagnosis, previous radiotherapy and diabetes mellitus with poor metabolic control.

Pegvisomant and cabergoline combination therapy in acromegaly.

Combination with cabergoline may offer additional benefits to acromegalic patients on pegvisomant monotherapy. We evaluated the safety and efficacy profile of this combination and investigated the determinants of response. An observational, retrospective, cross-sectional study. Fourteen acromegalic patients (9 females), who were partially resistant to somatostatin analogs and on pegvisomant monotherapy. Cabergoline was added because of the presence of persistent mildly increased IGF-I. The mean follow-up time was 18.3 ± 10.4 months. The efficacy and safety profile was assessed. The influence of clinical and biochemical characteristics on treatment efficacy was studied. IGF-I levels returned to normal in 4 patients (28%) at the end of the study. In addition, some decline in IGF-I levels was observed in a further 5 patients. The % IGF-I decreased from 158 ± 64% to 124 ± 44% (p = 0.001). The average change in IGF-I was -18 ± 27% (range -67 to +24%). Lower baseline IGF-I (p = 0.007), female gender (p = 0.013), lower body weight (p = 0.031), and higher prolactin (PRL) levels (p = 0.007) were associated with a better response to combination therapy. There were no significant severe adverse events. Significant tumour shrinkage was observed in 1 patient. Combination therapy with pegvisomant and cabergoline could provide better control of IGF-I in some patients with acromegaly. Baseline IGF-I levels, female gender, body weight, and PRL levels affect the response to this combination therapy.

Pituitary surgery in elderly patients: a safe and effective procedure.

PURPOSE: The incidence of pituitary adenoma (PA) increases with age. Transsphenoidal surgery (TSS) in elderly patients is often considered to have greater risk compared to the younger population. The aim of this study is to compare surgical results, evolution and postoperative complications between elderly and young patients undergoing TSS. METHODS: Retrospective review of patients undergoing TSS between 2011 and 2018 in our institution. Patients were divided into two cohorts: elderly (≥65 years) and non-elderly (<65 years). Characteristics and outcomes of both groups were compared at diagnosis, before surgery and for an average of 5.9 years of postoperative follow-up. RESULTS: One hundred and twenty-five patients were included, 53 patients were ≥65 years (42%). The elderly patients were more likely to have non-functioning PA (NFPA) (90.5% vs. 45.8%, p: <0.01), a higher proportion of macroadenomas (92.4% vs. 77.8%, p = 0.029) and greater extrasellar extension (88.7% vs. 68.1%, p = 0.007). The elderly group also had more compressive symptoms (54.7% vs. 34.7%, p = 0.035) and hypopituitarism (66% vs. 47.2%, p = 0.029). Overall, surgical and endocrinological outcomes between the two groups were similar. Inpatient mortality in the elderly group was 1.8%. Regarding long-term outcomes, elderly patients had more postoperative hypopituitarism (67.9% vs. 45.8%, p = 0.03) with no differences in permanent diabetes insipidus, less residual tumours (24.5% vs. 40.3%, p = 0.019) and a higher rate of remission after surgery (71.7% vs. 52.8%, p = 0.034). When only NFPA cases were compared, the only significant difference was a higher frequency of macroadenomas in the elderly group. CONCLUSIONS: Our results support the safety and efficacy of TSS in elderly patients with PA. Age should not be considered an exclusion criterion for TSS given that successful results can be achieved if an experienced pituitary team is available.

Rewiring of the apoptotic TGF-ß-SMAD/NFκB pathway through an oncogenic function of p27 in human papillary thyroid cancer.

Papillary thyroid carcinoma (PTC), the most frequent thyroid cancer, is characterized by low proliferation but no apoptosis, presenting frequent lymph-node metastasis. Papillary thyroid carcinoma overexpress transforming growth factor-beta (TGF-ß). In human cells, TGF-ß has two opposing actions: antitumoral through pro-apoptotic and cytostatic activities, and pro-tumoral promoting growth and metastasis. The switch converting TGF-ß from a tumor-suppressor to tumor-promoter has not been identified. In the current study, we have quantified a parallel upregulation of TGF-ß and nuclear p27, a CDK2 inhibitor, in samples from PTC. We established primary cultures from follicular epithelium in human homeostatic conditions (h7H medium). TGF-ß-dependent cytostasis occurred in normal and cancer cells through p15/CDKN2B induction. However, TGF-ß induced apoptosis in normal and benign but not in carcinoma cultures. In normal thyroid cells, TGF-ß/SMAD repressed the p27/CDKN1B gene, activating CDK2-dependent SMAD3 phosphorylation to induce p50 NFκB-dependent BAX upregulation and apoptosis. In thyroid cancer cells, oncogene activation prevented TGF-ß/SMAD-dependent p27 repression, and CDK2/SMAD3 phosphorylation, leading to p65 NFκB upregulation which repressed BAX, induced cyclin D1 and promoted TGF-ß-dependent growth. In PTC samples from patients, upregulation of TGF-ß, p27, p65 and cyclin D1 mRNA were significantly correlated, while the expression of the isoform BAX-ß, exclusively transcribed in apoptotic cells, was negatively correlated. Additionally, combined ERK and p65 NFκB inhibitors reduced p27 expression and potentiated apoptosis in thyroid cancer cells while not affecting survival in normal thyroid cells. Our results therefore suggest that the oncoprotein p27 reorganizes the effects of TGF-ß in thyroid cancer, explaining the slow proliferation but lack of apoptosis and metastatic behavior of PTC.

[Thyrotropin-producing adenoma of the hypophysis]. / Adenoma hipofisario productor de tirotropina.

A patient with a thyrotropin (TSH) secreting pituitary adenoma had hyperthyroidism with high levels of thyroid hormones and inadequate TSH secretion. After the challenge with thyrotropin releasing hormone (TRH), TSH level did not change. The normalization of plasma levels of thyroid hormones with antithyroid drugs was followed by an important increase in TSH levels. The adenoma was resected by the transphenoidal route and the diagnosis was confirmed by immunohistochemical study. Inadequate TSH secretion persisted after surgery, and radiation therapy with lineal accelerator was attempted. At present, one year after radiation therapy, inadequate TSH secretion requiring antithyroid drugs persists. We describe this clinical picture and briefly discuss the literature.

Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study.

CONTEXT: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

Anterior pituitary function in Cushing's syndrome: study of 36 patients.

We studied the anterior pituitary function in 36 patients (25 females and 11 males, mean age: 35 years) with untreated Cushing's syndrome by simultaneous triple stimulus with insulin, TRH and LHRH. Thirty-one patients (86%) had Cushing's disease and five (14%) had an adrenal adenoma. We observed a lack of response of GH to hypoglycemia in 88%, TSH to TRH in 91%, LH to LHRH in 30%, FSH to LHRH in 12% and PRL to TRH in 6% of the patients. Low-to-normal total thyroxine (T4) values were obtained in 37%, with low triiodothyronine levels in 87%. The free-T4 index was normal in all patients. Total testosterone was low in only one adult man, while estradiol and progesterone were low in 45% and 15% of premenopausal women, respectively. We observed no differences in either axis among patients with Cushing's syndrome of different etiologies. Nor was there any statistical difference between the frequency of alteration of each axis and the levels of urinary free cortisol or the duration of the disease. We conclude that hypercortisolism is responsible for the abnormalities in anterior pituitary function in Cushing's syndrome.