1,721,073 research outputs found
Growth hormone receptor variants and response to pegvisomant in monotherapy or in combination with somatostatin analogs in acromegalic patients: a multicenter study.
No full textAbstract
CONTEXT:
The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain.
OBJECTIVE:
The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects.
DESIGN AND SETTING:
A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals.
PATIENTS:
The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. INTERVENTION AND MAIN OUTCOME MEASURE: Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated.
RESULTS:
d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180.
CONCLUSIONS:
This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments
Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.
No full textBACKGROUND: The few epidemiological data available in literature on
neuroendocrine tumors (NET) are mainly based on Registry databases, missing
therefore details on their clinical and natural history. AIM: To investigate
epidemiology, clinical presentation, and natural history of NET. DESIGN AND
SETTING: A large national retrospective survey was conducted in 13 Italian
referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the
gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary
origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a
multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET,
33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly
differentiated carcinomas were <10%, all sporadic. The incidence of NET had a
linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis
was 60.0 +/- 16.4 yr, significantly anticipated in MEN1 patients (47.7 +/- 16.5
yr). Association with cigarette smoking and other non-NET cancer were more
prevalent than in the general Italian population. The first symptoms of the
disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the
diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most
common hormonal hypersecretions. An advanced tumor stage was found in 42%, more
frequently in the gut and thymus. No differences in the overall survival was
observed between T-NET and GEP-NET and between sporadic and MEN1-associated
tumors at 10 yr from diagnosis, while survival probability was dramatically
reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant
information on epidemiology, natural history, and clinico-pathological features
of NET, not available from the few published Register studies
A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome.
No full textAME position statement on adrenal incidentaloma.
Full text linkAbstract
OBJECTIVE:
To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice.
DESIGN:
A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l.
MANAGEMENT:
Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism
Transforming growth factor beta1: implications in adrenocortical tumorigenesis.
No full textAbstract
TGFbeta1, a multifunctional growth modulator, inhibits the proliferation of epithelial cells. TGFbeta1 signaling is dependent on the heterodimerization of the TGFbeta1 receptor II (TGFbeta1RII) with the TGFbeta1 receptor I (TGFbeta1RI). The cytoplasmic proteins Smads are the mediators of the TGFbeta1 signal. TGFbeta1 regulates adult and fetal adrenal growth and function. Previously we have shown by Northern analysis that TGFbeta1mRNA was well expressed in normal adrenal and in adrenocortical adenomas but reduced in carcinomas. To investigate whether TGFbeta1 receptors may act as tumor suppressors of adrenal tumorigenesis, 16 adenomas and 12 carcinomas were studied. We have used SSCP analysis to scan for inactivating mutations in carcinomas. All tumor samples were negative for somatic alterations of both genes. A competitive RT-PCR system was developed to compare the levels of expression of TGFbeta1, TGFbeta1R-I and TGFbeta1R-II, Smad-2 and Smad-4 genes in all tumors. In our study, we confirmed the presence of reduced levels of TGFbeta1 in carcinomas. On the contrary, Smad-4 gene levels were elevated in carcinomas when compared to that of adenomas. No significant differences were observed in gene expression of TGFbeta1RI and Smad-2. Our results suggest that mutations of TGFbeta1 receptors appear not to be involved in adrenal tumorigenesis. Adrenal carcinomas showed a significant reduction of the TGFbeta1 mRNA levels but on the contrary Smad 4 mRNA levels were significantly increased
Adrenal incidentaloma: an overview of hormonal data from the National Italian Study Group.
No full textAbstract
Adrenal masses are more and more frequently detected by adrenal ultrasound, computed tomography or nuclear magnetic resonance carried out for a reason other than the suspicion of adrenal disease (incidentalomas). The findings of an incidentaloma still leaves many diagnostic and therapeutic questions open. We report the results of a multicentric retrospective evaluation of patients with adrenal incidentalomas, performed by a Study Group of the Italian Society of Endocrinology. According to the definition of incidentaloma, exclusion criteria a priori were: severe or paroxysmal hypertension, frank hypokalemia and clinical signs of hypercortisolism or hyperandrogenism. 29 centers participated in the study and the data obtained by questionnaire were collected in 2 centers for final elaboration. Center 1 carried out the epidemiological and clinical evaluation. Basal and dynamic hormonal evaluation of 786 among the 1013 cases recruited were performed in our center (center 2). Functional studies included: diurnal rhythm of cortisol, urinary free cortisol (UFC), ACTH, DHEAS, 17-OH progesterone, testosterone, androstenedione, supine and upright plasma renin activity (PRA) and aldosterone, urinary aldosterone, urinary catecholamines and VMA. The hormonal dynamic evaluation included the overnight dexamethasone suppression test (1 mg), CRH test and ACTH test. In our study, 89% (702 patients) of adrenal incidentalomas were non-hypersecretory masses; 6.2% (49 patients) showed a preclinical Cushing's syndrome (PCS) (at least two altered parameters of pituitary-adrenal axis); 3.4% (27 patients) were pheochromocytomas; 0.89% (7 patients) were aldosteronomas. One tumor was a masculinizing adrenocortical carcinoma. Two hundred sixty patients underwent surgical exploration and the histological diagnosis showed: 138 adenomas (53%), 32 carcinomas (12%), 26 pheochromocytomas (10%). 16 myelolipomas (8%), 13 cystic lesions (5.5%), 7 tumors of neuronal lineage (3%). 12 metastases (4%), 13 others (5%). The 138 patients with adenomas had the following hormonal diagnosis: 103 nonfunctional adenomas (74%), 31 PCS (23%) and 4 cases of hyperaldosteronism (3%). In the patients with PCS an abnormal dexamethasone suppression test was found in 86% of cases (37/41 patients). Values for ACTH were low in 78% (32/41 patients). UFC was elevated in 64% of patients, the diurnal rhythm of cortisol evaluated in 14 patients was absent in 7. Only in 50% of cases DHEAS values (12/24 patients) were decreased, whereas they were normal in the other 50%. Interestingly, 8 patients with normal DHEAS and normal UFC showed nonsuppressible cortisol by dexamethasone test (1 mg). Blunted ACTH response to CRH was detected in 9 of 14 patients (64%). Thus our data suggest that the best parameter for evaluating subclinical hypercortisolism seems to be the overnight dexamethasone suppression test. In 27 patients with pheochromocytoma 24-hour urinary catecholamine and VMA levels were elevated in 86 and 46% of cases respectively. In 7 patients with hyperaldosteronism upright PRA was suppressed in 100% of cases and aldosterone plasma levels were elevated in 6 patients (86%); serum potassium level was slightly decreased in 60% of cases. In 86 of 138 histologically proven adenomas, DHEAS levels were: normal in 59% of patients, decreased in 36% and elevated in 4.6%, whereas in 22 of 32 cortical carcinomas evaluated. DHEAS levels were normal in 63% of cases, decreased in 18% and elevated 18%. Post-ACTH 17-OH progesterone levels were elevated in 52% (62/118 patients) of non-functioning adenomas and in 2 of 4 carcinomas. Not enough data are yet available postoperatively. In summary, endocrine evaluation can lead to the identification of a nonnegligible number of cases of clinically unsuspected pheochromocytomas and subtle hypercortisolism (about 3.4 and 6.2%, respectively of all adrenal incidentalomas), while cases of primary subclinical aldosteronism are rarely found. (ABSTRACT TRUNCATED
A venous thromboembolism risk assessment model for patients with Cushing's syndrome
No full textCushing’s syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a ‘CS-VTE score’ from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxi
Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in somatostatin analogue-naive patients with acromegaly.
Full text linkAbstract
OBJECTIVE:
To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4-8 weeks in somatostatin analogue-naïve patients with acromegaly.
DESIGN:
Open, non-comparative, phase III, multicenter clinical study.
METHODS:
Fifty-one patients (28 women, aged 19-78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if 5 microg/l every 4 weeks (group C, 19 patients). Treatment duration was 48-52 weeks. The primary objective was to control GH and IGF-I levels (GH<or=2.5 microg/l and IGF-I normalized for age/gender). Secondary objectives were to assess GH, IGF-I, and acid-labile subunit (ALS) decrease, improvement of clinical symptoms and quality of life (QoL).
RESULTS:
GH levels normalized in 32 patients (63%), similarly in de novo and post-op patients (72% vs 50%, p=0.48); in 100% of group A, in 73% of group B and in 21% of group C (p<0.0001). IGF-I levels normalized in 19 patients (37%), similarly in the de novo and post-op patients (33% vs 50%, p=0.48): in 65% of group A, 33% of group B, and in 16% of group C. Circulating GH levels decreased by 80+/-17%, IGF-I levels by 44+/-27%, and ALS by 30+/-17%. Symptoms (hyperhidrosis (68.6%), swelling (68.6%), asthenia (58.8%), spine arthralgia (54.9%), and paresthesias (52.9%) and QoL (from 9.1+/-7.9 to 6.1+/-6.6) significantly improved (p<0.001). No patient withdrew from the study because of adverse events (AE). The most frequent AE was diarrhea (76.2% of patients): at study end 16 mild and 1 moderate diarrhea were recorded. Gallstones developed in 12% of patients.
CONCLUSION:
ATG 120 mg in somatostatin-naïve patients with acromegaly controls GH secretion in 63% and IGF-I secretion in 37% during a 48-52 week period without any difference between de novo and post-op patients. The treatment was associated with improvement in clinical symptoms and QoL and with a good, safe profile
Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia.
No full textAbstract
BACKGROUND:
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors.
METHODS:
Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.
RESULTS:
Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.
CONCLUSION:
AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer
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