Cost-Effectiveness of Vedolizumab as a First-Line Advanced Therapy Versus Adalimumab Treatment Sequences for Ulcerative Colitis in Italy.

BACKGROUND: Today, there are many treatment options available for the management of ulcerative colitis, creating challenges in selecting the most efficacious and cost-effective treatment sequences. Treatments in the anti-tumor necrosis factor alpha (TNFα) therapeutic class, as well as vedolizumab, are widely used and endorsed as first-line options according to treatment guidelines. The aim of this study was to compare treatment sequences involving vedolizumab and the anti-TNFα treatment adalimumab in terms of cost-effectiveness in the treatment of moderately to severely active ulcerative colitis in Italy. METHODS: A cost-effectiveness model comparing treatment sequences within the Italian National Health Service in terms of costs and quality-adjusted life years (QALYs) with a lifetime horizon was developed. The analysis focused on the relative positioning of vedolizumab and adalimumab, leveraging the results of the landmark head-to-head VARSITY clinical trial as key inputs. The robustness of the results was investigated through a range of sensitivity and scenario analyses. RESULTS: The strategy of vedolizumab as a first-line advanced therapy followed by adalimumab was associated with higher costs and health benefits compared with first-line adalimumab followed by vedolizumab. The incremental cost-effectiveness ratio was €16,146/QALY, which was found to be robust to changes to inputs associated with areas of high uncertainty. CONCLUSION: This economic evaluation estimated a 94% probability that vedolizumab as a first-line advanced therapy is cost-effective at a threshold of €33,004/QALY when compared with first-line adalimumab sequences. Using clinical trial evidence to inform the efficacy of second-line treatments estimated that the effectiveness of anti-TNFα treatments is not substantially reduced by vedolizumab exposure.

From genotype to apricot fruit quality: the antioxidant properties contribution.

Apricot fruit (Prunus armeniaca L.) quality strictly relates to the eating quality of fresh produce. Since consumers are more and more interested in healthy food, and apricot germplasm shows a wide choice of new selections and cultivars, apricot nutraceutical properties are under evaluation in order to select outstanding genotypes, which may link breeding and marketing. In the present study, 18 apricot genotypes of the Italian and international germplasm were evaluated over three years according to pomological, total antioxidant and total phenols attributes using principal component and hierarchical cluster analyses. The antioxidant capacity ranged from 1.24 to 11.47 µmolTE gFW⁻¹ and total phenols from 0.22 to 1.58 mgGAE gFW⁻¹. Four outstanding genotypes stood out as healthy food for fresh consumption which may also be introduced in breeding programs to produce new cultivars with improved nutraceutical values in addition to fruit qualitative attributes.

Pomological and nutraceutical properties in apricot fruit: cultivation systems and cold storage fruit management.

We have investigated the effect of cultivation systems and fruit post-harvest management on the antioxidant properties of apricot fruits. Trees of five cultivars 'Tyrinthos', 'Cafona', 'Bella d'Italia', 'Vitillo' and 'Pellecchiella' were cultivated under integrated and organic systems. Fruits were collected at full maturity stage and analyzed either immediately or after storage at 4+/-0.5 degrees C and 85% of relative humidity for seven and 14 days. The main pomological traits (weight, colour, flesh firmness, total soluble sugars, titratable acidity) and antioxidant properties were analyzed. The total antioxidant capacity (TAC by TEAC method), total phenols content (TP by Folin-Ciocalteu method) and carotenoid content by HPLC-DAD were monitored. Cultivar characterization by principal component analysis (PCA) indicated a large variability on pomological and antioxidant properties of apricot fruits. 'Bella d'Italia' showed better TAC and TP values compared to the other cultivars. ANOVA interactions between cultivar and cultivation system (organic/integrated) were found for the antioxidant properties. These interactions may help to select a set of genotypes with better performances under organic system, which in our study might be indicated in 'Cafona' and 'Bella d'Italia'.

Eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increased rate of vertebral fractures.

OBJECTIVE: Subclinical hypercortisolism (SH) is suggested to exert a deleterious effect on bone. This effect and the role of gonadal status in male subjects are not fully elucidated. We evaluated bone mineral density (BMD) and prevalence of vertebral fractures in eugonadal male subjects with adrenal incidentalomas (AI) and without SH. DESIGN: This 12-month observational multicentre study was performed between January and December 2006 on inpatient basis in three referral Italian centres. PATIENTS: Eighty-eight consecutive eugonadal male patients with AI and 90 matched control subjects were studied. MEASUREMENTS: All subjects underwent the determination of BMD by dual-energy X-ray absorptiometry at lumbar spine (LS) and femoral neck (FN), and spinal radiograph. In AI patients SH was diagnosed in the presence of two of the following: urinary free cortisol > 193.1 nmol/l, cortisol after 1 mg dexamethasone suppression test > 82.8 nmol/l, ACTH levels < 2.2 pmol/l. RESULTS: As compared to patients without SH (SH-, n = 66) and controls, patients with SH (SH+, n = 22) had lower BMD at LS (Z-score: SH+, -1.04 +/- 1.84; SH-, 0.19 +/- 1.34, Controls 0.20 +/- 1.28, P = 0.001 and FN (Z-score: SH+, -0.63 +/- 1.01; SH-, 0.01 +/- 1.01, Controls 0.26 +/- 1.06, P = 0.002) and higher prevalence of fractures (SH+, 72.7%; SH-, 21.2%, Controls 20.0%, P = 0.0001). Multivariable analyses showed that SH was associated to BMD at LS (beta = -0.378, P = 0.0001) and vertebral fractures (OR = 7.81, 95% CI 1.96-31.17, P = 0.004). CONCLUSION: In eugonadal male patients with AI, SH is associated with low BMD and high prevalence of vertebral fractures.

Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data.

OBJECTIVE: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. METHODS: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. RESULTS: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. CONCLUSIONS: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

Economic evaluation of spondyloarthritis: economic impact of diagnostic delay in Italy.

BACKGROUND AND AIM: Spondyloarthritis (SpA) is a disease that normally affects the axial skeleton. It progressively leads to overall stiffness up to severe postural deformity of rachis and functional impotence. The objective of the study was to quantify, through an economic model, the impact of specialized testing and pharmacological treatments carried out by the National Health Service (NHS) in normal clinical practice, before the patient is diagnosed with SpA in Italy. In line with the analysis objective, the chosen perspective is that of the NHS. METHOD: The study was conducted by analyzing the Health Search Database - IMS Health Longitudinal Patient Database, from which newly diagnosed SpA patients were identified over the period 1 January 2007 to 31 December 2013. The use of specialist health care services and pharmacological treatments provided to the patients before the final SpA diagnosis were estimated. RESULTS: Through a retrospective analysis of the Health Search Database, 1,084 subjects (aged 25-45 years) were identified. These patients produced an expense of approximately €153,000 in the 3 years prior to a confirmed SpA diagnosis, in terms of specialist check-ups and drugs, presumably not appropriately used due to a lack of diagnosis. If we assume that the Health Search Database is a representative sample of the Italian population, it may be estimated that, in the 3 years prior to SpA diagnosis, over €5.4 million was largely unduly spent in Italy to examine and manage 38,232 newly diagnosed SpA patients, between 2010 and 2013. CONCLUSION: The costs due to the delay in SpA diagnosis were quantified for the first time in Italy. For this reason, this work represents a contribution for national and regional decision makers to understand the current clinical practice and the economic consequences of a diagnostic delay in the short and medium term.

Diabetic foot management: multidisciplinary approach for advanced lesion rescue.

The diabetic foot is a complication of diabetes affecting 15% of diabetics in their lives. It is associated to diabetic neuropathy and peripheral vascular disease and its incidence has increased. The ulceration is the initial cause of a dramatic process leading, if not correctly treated, to amputations. Both neuropathy, neuro-ischemia and infections have a role in determining healing or worsening of the lesions and 85% of all amputations in diabetic patients are preceded by a foot ulceration deteriorating to a severe gangrene or infection. The different causative agents and the different clinical presentations of diabetic foot ask a multidisciplinary approach in order to address treatments to the final goals, the prevention of the amputations and the maintenance of a functional foot able with weight-bearing ability. Many professional figures, diabetologists, surgeons (both general and vascular and orthopedics), interventional radiologists, infectious diseases specialists, specialized nurses, podiatrists, orthotic technicians, are called to apply their knowledges to the diabetic patients affected by diabetic foot in a virtuous circle leading to reach the goals, with the imperative action of the multidisciplinary team. The so organized center will allow both a correct and rapid diagnosis, the use in ambulatorial environments of modern tools, or the hospitalization in multitasking wards, in which all the complications and the necessary treatments are possible, both in emergencies or in elective way, considering both revascularizations and surgery.

Economic burden of schizophrenia in Italy: a probabilistic cost of illness analysis.

OBJECTIVES: Schizophrenia is a chronic, debilitating psychiatric disease with highly variable treatment pathways and consequent economic impacts on resource utilisation. The aim of the study was to estimate the economic burden of schizophrenia in Italy for both the societal and Italian National Healthcare perspective. METHODS: A probabilistic cost of illness model was applied. A systematic literature review was carried out to identify epidemiological and economic data. Direct costs were calculated in terms of drugs, hospitalisations, specialist services, residential and semiresidential facilities. Indirect costs were calculated on the basis of patients' and caregivers' loss of productivity. In addition, the impact of disability compensation was taken into account using a database from the Italian National Social Security Institute -Italy (INPS). RESULTS: Overall, 303 913 prevalent patients with schizophrenia were estimated. Of these, 212 739 (70%) were diagnosed and 175 382 (82%) were treated with antipsychotics. The total economic burden was estimated at €2.7 billion (95% CI €1771.93 to €3988.65), 50.5% due to indirect costs and 49.5% to direct costs. Drugs corresponded to 10% of direct costs and hospitalisations (including residential and semiresidential facilities) accounted for 81%. CONCLUSIONS: This study highlighted that indirect costs and hospitalisations (including residential and semiresidential facilities) play a major role within the expenses associated with schizophrenia in Italy, and this may be considered as a tool for public decision-makers.

Direct and Indirect Costs of Immunoglobulin Replacement Therapy in Patients with Common Variable Immunodeficiency (CVID) and X-Linked Agammaglobulinemia (XLA) in Italy.

BACKGROUND: In Italy, there is scarce evidence on the epidemiological and economic burden induced by primary antibody deficiencies. OBJECTIVE: The aim of this study was to elaborate the available epidemiological and cost data in order to estimate the annual expenditure induced by the management of patients affected by the common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) requiring immunoglobulin (Ig) replacement therapy. METHODS: A probabilistic cost-of-illness model was developed to estimate the number of patients with CVID and XLA, and the economic burden associated with their therapy in terms of direct or indirect costs. A systematic literature review was carried out to reveal both epidemiological and economic data. Furthermore, a probabilistic sensitivity analysis with 5000 Monte Carlo simulations was performed. RESULTS: The epidemiological model allowed us to estimate the number of prevalent patients affected by XLA and CVID in Italy in 2017, corresponding to 1885 (95% confidence interval [CI] 944-3145) and 133 (95% CI 115-152) patients, respectively. The estimated total expenditure for the treatment and management of patients with CVID and XLA requiring Ig replacement therapy amounts to €42.68 million (95% CI €14.38-€86.1 million). CONCLUSIONS: This information provides a comprehensive perspective of the economic issues, and facilitates better-informed public health decision making, in the management of CVID and XLA in Italy.

Cigarette smoking is associated with low glomerular filtration rate in male patients with type 2 diabetes.

OBJECTIVE: The relationship between cigarette smoking and renal dysfunction in diabetes has predominantly been documented in patients with type 1 diabetes. The aim of the present study was to explore the relationship between cigarette smoking and glomerular filtration rate (GFR) in a large cross-sectional study carried out in male subjects with type 2 diabetes. The role of metabolic syndrome in modulating this relationship was also investigated. RESEARCH DESIGN AND METHODS: One hundred fifty-eight current smokers and 158 never smokers with type 2 diabetes were consecutively recruited. Low GFR was defined as GFR <60 ml/min per 1.73 m(2). RESULTS: The proportion of patients affected by low GFR was significantly higher in current smokers (20.9 vs. 12.0%, P = 0.03). The adjusted risk (odds ratio [OR]) of low GFR in current smokers was 2.20 (95% CI 1.14-4.26, P = 0.02) and markedly higher in patients from the first tertile of disease duration (4.27 [1.26-14.40], P = 0.02). When metabolic syndrome was added to the statistical model exploring the relationship between smoking and low GFR, the risk of low GFR showed a small change, although it did not become any more significant (1.84 [0.98-3.45], P = 0.06). Current smokers showed even higher free oxygen radical test unit values (560.0 +/- 91.5 vs. 442.7 +/- 87.2, P < 0.0001). CONCLUSIONS: In a large population of male patients with type 2 diabetes, the risk of low GFR is markedly enhanced by smoking and is at least partially mediated by metabolic syndrome.

Early Treatment in HIV Patients: A Cost-Utility Analysis from the Italian Perspective.

BACKGROUND AND OBJECTIVE: Highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections and mortality. Several recent studies show early antiretroviral therapy reduces the risk of AIDS and HIV-related disease. The aim of this study was to perform an economic analysis to estimate the cost-utility of early antiretroviral therapy in Italy for managing HIV-infected patients. METHODS: The incremental cost-utility analysis was carried out to quantify the benefits of the early-treatment approach in HIV subjects. A Markov simulation model including direct costs and health outcomes was developed from a third-party (Italian National Healthcare Service) payer's perspective for four CD4 strata. 5000 Monte Carlo simulations were performed on two distinct scenarios: Standard of care (SoC) in which 30% of patients started HAART with a CD4 count ≥500 cells/mm(3) versus the early-treatment scenario (ETS), where the number of patients starting HAART with a CD4 count ≥500 cells/mm(3) increased to 70%. A systematic literature review was carried out to identify epidemiological and economic data, which were subsequently used to inform the model. In addition, a one-way probabilistic sensitivity analysis was performed in order to measure the relationship between the effectiveness of the treatments and the number of patients to undergo early treatment. RESULTS: The model shows, in terms of the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) gained, that early treatment appeared to be the most cost-effective option compared to SoC (ICER = €13,625) over a time horizon of 10 years. The cost effectiveness of ETS is more sustainable as it extends the time horizon analysis (ICER = €7526 per QALY to 20 years and €8382 per QALY to 30 years). The one-way sensitivity analysis on the main variables confirmed the robustness of the model for the early-treatment approach. CONCLUSION: Our model represents a tool for policy makers and health-care professionals to provide information on the cost effectiveness of the early-treatment approach in HIV-infected patients in Italy. Starting HAART earlier keeps HIV-infected patients in better health and reduces the incidence of AIDS- and non-AIDS-related events, generating a gain in terms of both patients' health and correct resource allocation.

Early Treatment in HCV: Is it a Cost-Utility Option from the Italian Perspective?

BACKGROUND AND OBJECTIVE: In Italy, the Italian Pharmaceutical Agency (AIFA) criteria used F3-F4 fibrosis stages as the threshold to prioritise the treatment with interferon (IFN)-free regimens, while in genotype 1 chronic hepatitis C (G1 CHC) patients with fibrosis of liver stage 2, an approach with pegylated interferon (PEG-IFN)-based triple therapy with simeprevir was suggested. The key clinical question is whether, in an era of financial constraints, the application of a universal IFN-free strategy in naïve G1 CHC patients is feasible within a short time horizon. The aim of this study is to perform an economic analysis to estimate the cost-utility of the early innovative therapy in Italy for managing hepatitis C virus (HCV)-infected patients. METHODS: The incremental cost-utility analysis was carried out to quantify the benefits of the early treatment approach in HCV subjects. A Markov simulation model including direct and indirect costs and health outcomes was developed from an Italian National Healthcare Service and societal perspective. A total of 5000 Monte Carlo simulations were performed on two distinct scenarios: standard of care (SoC) which includes 14,000 genotype 1 patients in Italy treated with innovative interferon-free regimens in the fibrosis of liver stages 3 and 4 (F3-F4) versus early-treatment scenario (ETS) where 2000 patients were additionally treated with simeprevir plus PEG-IFN and ribavirin in the fibrosis stage 2 (F2) (based on Italian Medicines Agency AIFA reimbursement criteria). A systematic literature review was carried out to identify epidemiological and economic data, which were subsequently used to inform the model. Furthermore, a one-way probabilistic sensitivity was performed to measure the relationship between the main parameters of the model and the cost-utility results. RESULTS: The model shows that, in terms of incremental cost-effectiveness ratio (ICER) per quality adjusted life year (QALY) gained, ETS appeared to be the most cost-utility option compared with both perspective societal (ICER = EUR11,396) and NHS (ICER = EUR14,733) over a time period of 10 years. The cost-utility of ETS is more sustainable as it extends the time period analysis [ICER = EUR 6778 per QALY to 20 years and EUR4474 per QALY to 30 years]. From the societal perspective, the ETS represents the dominant option at a time horizon of 30 years. If we consider the sub-group population of treated patients [16,000 patients of which 2000 not treated in the SoC, the ETS scenario was dominant after only 5 years and the cost-utility at 2 years of simulation. The one-way sensitivity analysis on the main variables confirmed the robustness of the model for the early-treatment approach. CONCLUSION: Our model represents a tool for policy makers and health-care professionals, and provided information on the cost-utility of the early-treatment approach in HCV-infected patients in Italy. Starting innovative treatment regimens earlier keeps HCV-infected patients in better health and reduces the incidence of HCV-related events; generating a gain both in terms of health of the patients and correct resource allocation.

The PPARγ2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus.

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus.

[Direct and indirect costs associated with respiratory allergic diseases in Italy. A probabilistic cost of illness study]. / Costi diretti e indiretti associati a malattie allergiche respiratorie in Italia. Uno studio probabilistico di cost of illness.

BACKGROUND: The respiratory allergies, including allergic rhinitis and allergic asthma, represent a substantial medical and economic burden worldwide. Despite their dimension and huge economic-social burden, no data are available on the costs associated with the management of respiratory allergic diseases in Italy. The objective of this study was to estimate the average annual cost incurred by the National Health Service (NHS), as well as society, due to respiratory allergies and their main co-morbidities in Italy. METHODS: A probabilistic prevalence-based cost of illness model was developed to estimate an aggregate measure of the economic burden associated with respiratory allergies and their main co-morbidities in terms of direct and indirect costs. A systematic literature review was performed in order to identify both the cost per case (expressed in present value) and the number of affected patients, by applying an incidence-based estimation method. Direct costs were estimated multiplying the hospitalization, drugs and management costs derived by the literature with the Italian epidemiological data. Indirect costs were calculated based on lost productivity according to the human capital approach. Furthermore, a one-way and probabilistic sensitivity analysis with 5,000 Monte Carlo simulations were performed, in order to test the robustness of the results and define the proper 95% Confidence Interval (CI). RESULTS: Overall, the total economic burden associated with respiratory allergies and their main co-morbidities was € 7.33 billion (95% CI: € 5.99-€ 8.82). A percentage of 27.5% was associated with indirect costs (€ 2.02; 95% CI: € 1.72-€ 2.34 billion) and 72.5% with direct costs (€ 5.32; 95% CI: € 4.04-€ 6.77 billion). In allergic asthma, allergic rhinitis, combined allergic rhinitis and asthma, turbinate hypertrophy and allergic conjunctivitis, the model estimate an average annual economic burden of € 1,35 (95% CI: € 1,14-€ 1,58) billion, € 1,72 (95% CI: € 1,14-€ 2,43) billion, € 1,62 billion (€ 0,91-€ 2,53) billion, € 0,12 (€ 0,07-€ 0,17) billion, € 0,46 (€ 0,16-€ 0,92) billion respectively. CONCLUSIONS: To our knowledge, this is the first study in which direct costs (incurred by NHS) and indirect ones (incurred by the society) were taken into account to estimate the overall burden associated with respiratory allergies and their main co-morbidities in our Country. In conclusion, this work may be considered an efficient tool for public decision-makers to correctly understand the economic aspects involved by the management and treatment of respiratory allergies-induced diseases in Italy.

Over-supplementation of vitamin D in two patients with primary hyperparathyroidism.

OBJECTIVE: To describe the biochemical effects of an over-supplementation of vitamin D3 in two patients with primary hyperparathyroidism (PHPT). DESIGN: Two patients (A and B) with PHPT took erroneously 2,400,000 U (300,000 U/day for 8 days) and 4,500,000 U (300,000 U/day for 15 days) of cholecalciferol, respectively. They were followed for 4 months and ionized calcium, creatinine, PTH, 25 hydroxy-vitamin D, 1,25(OH)2D and urinary calcium/creatinine levels were measured. Finally, the patients were operated on and a parathyroid adenoma was removed in both. RESULTS: One week after the last dose of vitamin D, serum ionized calcium (iCa) rose from 1.35 to 1.41 mMol/L (n.r. 1.14-1.31) for patient A, and from 1.43 to 1.62 for patient B, while fasting urinary Calcium/Creatinine (uCa/Cr) augmented from 0.31 to 0.50 mg/mg, and from 0.32 to 0.55, respectively. During the follow-up, the average levels of iCa were 1.37 ± 0.03 and 1.48 ± 0.07 mMol/L, while those of uCa/Cr were 0.29 ± 0.13 and 0.32 ± 0.13, both iCa and uCa/Cr levels returning to baseline values within 4 months. CONCLUSIONS: The unintentional over-supplementation of vitamin D in the two PHPT patients caused a moderate and temporary increase of hypercalcemia and hypercalciuria and was not associated with clinical signs of toxicity.

CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort.

OBJECTIVE: To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort. METHODS: Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) (n = 15), atypical adenoma (AA) (n = 14) and typical adenoma (TA) (n = 17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive. RESULTS: Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors. Median follow up times were 88 months for CA, 76 months for AA, and 104 months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma. CONCLUSIONS: Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210 months.

Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study.

CONTEXT: Effects of vitamin D repletion in young people with low vitamin D status have not been investigated so far. OBJECTIVE: We evaluated the effect of a single massive dose of cholecalciferol on calcium metabolism at 3, 15, and 30 d, compared to baseline. DESIGN AND SETTING: We conducted a prospective intervention study in an ambulatory care setting. PARTICIPANTS: Forty-eight young subjects with vitamin D deficiency participated in the study. INTERVENTION: A single oral dose of 600,000 IU of cholecalciferol was administered to each subject. MAIN OUTCOME MEASURES: We evaluated serum changes of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, calcium, and PTH induced by a single load of cholecalciferol. RESULTS: The 25(OH)D level was 15.8 ± 6.5 ng/ml at baseline and became 77.2 ± 30.5 ng/ml at 3 d (P < 0.001) and 62.4 ± 26.1 ng/ml at 30 d (P < 0.001). PTH levels concomitantly decreased from 53.0 ± 20.1 to 38.6 ± 17.2 pg/ml at 3 d and to 43.4 ± 14.0 pg/ml at 30 d (P < 0.001 for both). The trends were maintained in a subgroup followed up to 90 d (P < 0.001). Mean serum Ca and P significantly increased compared to baseline, whereas serum Mg decreased at 3 d. 1,25-Dihydroxyvitamin D significantly increased from 46.8 ± 18.9 to 97.8 ± 38.3 pg/ml at 3 d (P < 0.001) and to 59.5 ± 27.3 pg/ml at 60 d (P < 0.05). CONCLUSIONS: A single oral dose of 600,000 IU of cholecalciferol rapidly enhances 25(OH)D and reduces PTH in young people with vitamin D deficiency.

Sporadic and MEN1-related primary hyperparathyroidism: differences in clinical expression and severity.

Primary hyperparathyroidism (PHPT) is a common endocrine disease that is associated with multiple endocrine neoplasia type 1 (MEN1) in approximately 2% of PHPT cases. Lack of a family history and other specific expressions may lead to underestimated MEN1 prevalence in PHPT. The aim of this study was to identify clinical or biochemical features predictive of MEN1 and to compare the severity of the disease in MEN1-related versus sporadic PHPT (sPHPT). We performed a 36-mo cross-sectional observational study in three tertiary referral centers on an outpatient basis on 469 consecutive patients with sporadic PHPT and 64 with MEN1-related PHPT. Serum calcium, phosphate, PTH, 25(OH)D(3), and creatinine clearance were measured, and ultrasound examination of the urinary tract/urography was performed in all patients. In 432 patients, BMD was measured at the lumbar spine (LS) and femoral neck (FN). MEN1 patients showed lower BMD Z-scores at the LS (-1.33 +/- 1.23 versus -0.74 +/- 1.4, p = 0.008) and FN (-1.13 +/- 0.96 versus -0.6 +/- 1.07, p = 0.002) and lower phosphate (2.38 +/- 0.52 versus 2.56 +/- 0.45 mg/dl, p = 0.003) and PTH (113.8 +/- 69.5 versus 173.7 +/- 135 pg/ml, p = 0.001) levels than sPHPT patients. Considering probands only, the presence of MEN1 was more frequently associated with PTH values in the normal range (OR, 3.01; 95% CI, 1.07-8.50; p = 0.037) and younger age (OR, 1.61; 95% CI, 1.28-2.02; p = 0.0001). A combination of PTH values in the normal range plus age <50 yr was strongly associated with MEN1 presence (OR, 13.51; 95% CI, 3.62-50.00; p = 0.0001). In conclusion, MEN1-related PHPT patients show more severe bone but similar kidney involvement despite a milder biochemical presentation compared with their sPHPT counterparts. Normal PTH levels and young age are associated with MEN1 presence.

Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study.

CONTEXT: In patients with adrenal incidentalomas and subclinical hypercortisolism (SH), the factors influencing bone and the prevalence of vertebral fractures are debated. Spinal deformity index (SDI), which reflects bone quality, has never been evaluated. OBJECTIVE: The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures. DESIGN: This was a retrospective, multicenter study. SETTING: The study was conducted on an in- and outpatient basis. PATIENTS: Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females). MAIN OUTCOME MEASURE: Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20-25%), 2 (25-40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 microg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 microg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter). RESULTS: BMD was significantly lower in SH+ than SH- patients and controls (lumbar spine -0.73 +/- 1.43, 0.17 +/- 1.33, 0.12 +/- 1.21, respectively; femoral neck -0.37 +/- 1.06, 0.07 +/- 1.09, 0.17 +/- 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 +/- 0.68, 0.39 +/- 0.93, 1.35 +/- 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94-13.41, P = 0.0001; beta = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender. CONCLUSION: SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI.