ObjectiveTo describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity ...and mortality in a nationwide survey of Italian acromegalic patients.DesignRetrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months.ResultsA total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87–1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34–2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality.ConclusionsPretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.
Objective
This study aimed to assess the long-term outcome of patients with acromegaly.
Design
This is a multicenter, retrospective, observational study which extends the mean observation period of a ...previously reported cohort of Italian patients with acromegaly to 15 years of follow-up.
Methods
Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population.
Results
A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4–2.0,
p
< 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1–1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population.
Conclusions
Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.
Purpose
The main purpose of this study was to investigate the effects of 12 months of rhPTH (1–84) (Natpar
®
) treatment in a cohort of patients selected according to the indications of ...hypoparathyroidism guidelines. The use of recombinant human PTH (1–84) rhPTH (1–84) is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy.
Methods
It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations.
Results
Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1–84) for 12 months. At 12 months of rhPTH (1–84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1–84) treatment compared to baseline (
p
= 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (
p
= 0.014). No severe adverse events were described.
Conclusions
Biochemical and clinical results confirm the efficacy and safety of rhPTH (1–84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.
This paper quantitatively assesses the negative impact of land discontinuity on the development of a railway network on an island. This implicit cost of insularity is because an insular railway ...network only serves the territory in which it is located while the same network on a mainland also serves other regions. We apply this idea to the case of a simplified Italian railway network and we implement it through a simulation model. The simulation results highlight the strong negative effect of land discontinuity: whereas the railway lines located on the island of Sardinia are the least profitable under the factual scenario, their relative profitability is significantly boosted in every counterfactual scenario where the land discontinuity is artificially removed.
ContextHepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the ...UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome.ObjectiveTo determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.Design and settingMulticenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.PatientsA total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.InterventionsClinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.ResultsNo differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found.ConclusionsUGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.
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.
Background
Anti-pituitary antibodies (APA) were described in patients with Type 1 Diabetes (T1D) but their prevalence and relevance remain controversial.
Materials and methods
We evaluated the APA ...prevalence in Sardinian sera from 100 T1D patients, 70 Type 2 Diabetes (T2D) patients and 62 healthy controls, using indirect immunofluorescence on bovine pituitary sections. To compare two different substrates, we tested using bovine sections, further T1D patient sera (
n
= 11, from Pisa) previously analysed for APA on monkey sections, while some T1D Sardinian patient sera (
n
= 22) were tested on monkey sections. According to preliminary experiments, positivity were considered ≥1:200 and ≥1:20 for bovine and monkey substrates, respectively.
Results and discussion
Using bovine sections, APA were detected in 7/100 Sardinian T1D patients (at 1:200 titer) and in none of the other Sardinian sera tested. When the T1D sera from Pisa were tested on bovine and the T1D Sardinian sera were tested on monkey, none of these sera showed corresponding positivity for APA. Pituitary hormone dysfunctions were not found in the 7 APA-positive Sardinian T1D patients. The present study shows that the presence of APA at low-titer is highly related to T1D but not associated with any pituitary dysfunction while the animal species used as substrate appears crucial.
Conclusion
Further studies are needed to ascertain whether APA detected by different animal species may have different pathological relevance in T1D and/or whether APA in the long run may predict future anterior pituitary dysfunction.
Background:
Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The ...question whether these therapies modify control and progression of diabetes once present is still open.
Aim:
Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes.
Methods:
Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters.
Results:
Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9–7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%).
Conclusions:
Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.
Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The ...mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, TaqI A1-/TaqI B1-/HphI T-/NcoI T- haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.
This paper analyses the empirical relationship between growth, country size and tourism specialization by using a data set covering the period 1980–2003. It finds that tourism countries are small and ...grow significantly faster than all the other subgroups considered in the analysis. Tourism appears to be an independent determining factor for growth: controlling for initial per capita income and for trade openness does not weaken the positive correlation between tourism specialization and growth. Another finding of the paper is that small states are fast growing only when they are highly specialized in tourism. In contrast with some previous conclusions in the literature, smallness per se is not good for growth.
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