Unita di Endocrinologia

Matera, Italy

Unita di Endocrinologia

Matera, Italy

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Pasquali D.,The Second University of Naples | Circelli L.,University of Sannio | Faggiano A.,IRCCS Fondazione SDN | Pancione M.,University of Sannio | And 10 more authors.
European Journal of Endocrinology | Year: 2011

Context: CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet. Objective and design: We screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age- and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission. Results: The T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients. Conclusions: Collectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker. © 2011 European Society of Endocrinology.


Durante C.,University of Rome La Sapienza | Costante G.,University of Catanzaro | Lucisano G.,Center for Outcomes Research and Clinical Epidemiology | Lucisano G.,University of Bari | And 10 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed. OBJECTIVE To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed. MAIN OUTCOMES AND MEASURES Baseline nodule growth (primary end point)was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20%or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up. RESULTS Nodule growth occurred in 153 patients (15.4%[95%CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1%[95%CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9mm(95%CI, 4.2-5.5 mm), from 13.2 mm(95%CI, 12.1-14.2 mm) to 18.1mm(95%CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95%CI 1.4-3.4] for 2 nodules; OR, 3.2 [95%CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95%CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2mL (OR, 2.9 [95%CI, 1.7-4.9] for volumes >0.2 to <1mL and OR, 3.0 [95%CI, 1.8-5.1] for volumes≥1 mL), and male sex (OR, 1.7 [95%CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95%CI 0.3-0.9]). In 184 individuals (18.5%[95%CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3%[95%CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3%[95%CI, 7.5%-11.1%]), with detection of one cancer. CONCLUSIONS AND RELEVANCE Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules. Copyright © 2015 American Medical Association. All rights reserved.


PubMed | Unita Operativa Semplice Dipartimentale di Endocrinologia, University of Bari, University of Perugia, Unita di Endocrinologia and 6 more.
Type: Journal Article | Journal: JAMA | Year: 2015

Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed.To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size.Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up.Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes >0.2 to <1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes 1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer.Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules.


Durante C.,University of Rome La Sapienza | Montesano T.,University of Rome La Sapienza | Torlontano M.,Instituto Of Ricovero E Cura A Carattere Scientifico | Attard M.,Cervello | And 13 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: The current use of life-long follow-up in patients with papillary thyroid cancer (PTC) is based largelyonthe study of individuals diagnosed and treated in the latter half of the 20th century when recurrence rates were approximately 20% and relapses detected up to 20-30 years after surgery. Since then, however, diagnosis, treatment, and postoperative monitoring of PTC patients have evolved significantly. Objectives: The objective of the study was to identify times to PTC recurrence and rates by which these relapses occurred in a more recent patient cohort. Patients and Design: We retrospectively analyzed follow-up data for 1020 PTC patients consecutively diagnosed in 1990-2008 in 8 Italian hospital centers for thyroid disease. Patients underwent thyroidectomy, with or without radioiodine ablation of residual thyroid tissue and were followed up with periodic serum thyroglobulin assays and neck sonography. Results: At the initial posttreatment (≤12 months) examination, 948 patients had no structural/functional evidence of disease. During follow-up (5.1-20.4 years; median 10.4 years), recurrence (cervical lymph nodes, thyroid bed) was diagnosed in 13 (1.4%) of these patients. All relapses occurred 8 or fewer years after treatment (10 within the first 5 years, 6 within the first 3 years). Recurrence was unrelated to the use/omission of postoperative radioiodine ablation. Conclusion: In PTC patients whose initial treatment produces disease remission (no structural evidence of disease), recurrent disease is rare, and it usually occurs during the early postoperative period. The picture of recurrence timing during the follow-up provides a foundation for the design of more cost-effective surveillance protocols for PTC patients. Copyright © 2013 by The Endocrine Society.


Lamartina L.,University of Rome La Sapienza | Montesano T.,University of Rome La Sapienza | Trulli F.,University of Rome La Sapienza | Attard M.,Cervello | And 10 more authors.
Endocrine | Year: 2015

Papillary thyroid cancer (PTC) patients treated with thyroidectomy and radioiodine remnant ablation (RRA) often have detectable TSH-stimulated thyroglobulin (Tg) levels without localizable disease after primary treatment. To assess the value of repeat stimulated Tg assays in these patients’ follow-up, we retrospectively analyzed 86 cases followed in 5 Italian thyroid-cancer referral centers. We enrolled 86 patients with PTCs treated with total/near-total thyroidectomy plus RRA between January 1,1990 and January 31, 2006. In all cases, the initial postoperative visit revealed stimulated serum Tg ≥1 ng/mL, negative Tg antibodies, and no structural evidence of disease. None received empiric radioiodine therapy. Follow-up (median: 9.6 years) included neck ultrasound and basal Tg assays (yearly) and at least 1 repeat stimulated Tg assay. Of the 86 patients analyzed (initial risk: low 63 %, intermediate 35 %, high 2 %), one (1 %) had ultrasound-detected lymph node disease and persistently elevated stimulated Tg levels at 3 years. In 17 (20 %), imaging findings were consistently negative, but the final stimulated Tg levels was still >1 ng/mL (median 2.07 ng/mL, range 1.02–4.7). The other 68 (80 %) appeared disease-free (persistently negative imaging findings with stimulated Tg levels ≤1 ng/mL). Mean intervals between first and final stimulated Tg assays were similar (5.2 and 4.8 years) in subgroups with versus without Tg normalization. Reclassification as disease-free was significantly more common when initial stimulated Tg levels were indeterminate (<10 ng/mL). In unselected PTC cohorts with incomplete/indeterminate biochemical responses to thyroidectomy and RRA, periodic remeasurement of stimulated Tg allows most patients to be classified as disease-free. © 2015 Springer Science+Business Media New York


Adami S.,University of Verona | Romagnoli E.,University of Rome La Sapienza | Carnevale V.,University of Rome La Sapienza | Scillitani A.,Unita di Endocrinologia | And 5 more authors.
Reumatismo | Year: 2011

The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has elaborated the following guidelines about the definition, prevention and treatment of inadequate vitamin D status. The highlights are presented here. • Daily vitamin D allowance ranges from 1,500 IU (healthy adults) to 2,300 IU (elderly with low calcium intake). Since the average Italian diet includes around 300 IU/day, subjects with no effective sun exposure should be supplemented with 1,200-2,000 IU vitamin D per day. • The serum 25-hydroxy-vitamin D [25(OH)D] levels represents the most accurate way to assess vitamin D repletion, even though there are still no standardized assay methods. • Conditions of "deficiency" and "insufficiency" are defined by the following ranges of 25(OH)D levels: less than 20 ng/ml and 20-30 ng/ml, respectively. • In Italy, approximately 50% of young healthy subjects have vitamin D insufficiency during the winter months. The prevalence of deficiency increases with ageing, affecting almost all elderly subjects not on vitamin D supplements. • When a condition of deficiency has been identified, a cumulative dose of 300,000-1,000,000 IU, over 1-4 weeks is recommended. • In subjects recently treated for deficiency-insufficiency, a maintenance dose of 800-2,000 IU/day (or weekly equivalent) is recommended. In patients on daily doses over 1,000 IU, 25(OH)D levels should be checked regularly (e.g. once every two years). • The highest tolerated daily dose has been identified as 4,000 IU/day. • Vitamin D supplementation should be carefully monitored in patients at higher risk of vitamin D intoxication (granulomatosis) or with primary hyperparathyroidism. • In pregnant women, vitamin D supplements should be given as in non-pregnant women, but bolus administration (i.e.: single dose >25,000 IU) should be avoided.


Durante C.,University of Rome La Sapienza | Attard M.,Cervello | Torlontano M.,Instituto Of Ricovero E Cura A Carattere Scientifico | Ronga G.,University of Rome La Sapienza | And 14 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Most papillary thyroid microcarcinomas (PTMCs; ≤ 1 cm diameter) are indolent low-risk tumors, but some cases behave more aggressively. Controversies have thus arisen over the optimum postoperative surveillance of PTMC patients. Objectives: We tested the hypothesis that clinical criteria could be used to identify PTMC patients with very low mortality/recurrence risks and attempted to define the best strategy for their management and long-term surveillance. Design: We retrospectively analyzed data from 312 consecutively diagnosed PTMC patients with T1N0M0 stage disease, no family history of thyroid cancer, no history of head-neck irradiation, unifocal PTMC, no extracapsular involvement, and classic papillary histotypes. Additional inclusion criteria were complete follow-up data from surgery to at least 5 yr after diagnosis. All 312 had undergone (near) total thyroidectomy [with radioactive iodine (RAI) remnant ablation in 137 (44%) - RAI group] and were followed up yearly with cervical ultrasonography and serum thyroglobulin, TSH, and thyroglobulin antibody assays. Results: During follow-up (5-23 yr, median 6.7 yr), there were no deaths due to thyroid cancer or reoperations. The first (6-12 months after surgery) and last postoperative cervical sonograms were negative in all cases. Final serum thyroglobulin levels were undetectable (<1 ng/ml) in all RAI patients and almost all (93%) of non-RAI patients. Conclusion: Accurate risk stratification can allow safe follow-up of most PTMC patients with a less intensive, more cost-effective protocol. Cervical ultrasonography is the mainstay of this protocol, and negative findings at the first postoperative examination are highly predictive of positive outcomes. Copyright © 2010 by The Endocrine Society.


Manco M.,Instituto Of Ricovero E Cura A Carattere Scientifico | Miraglia Del Giudice E.,The Second University of Naples | Spreghini M.R.,Unita di Dietologia Clinica | Cappa M.,Unita di Endocrinologia | And 5 more authors.
Acta Diabetologica | Year: 2012

Adults with normal glucose tolerance (NGT) but exaggerated plasma glucose excursion at 1 h (1HPG) following the oral glucose tolerance test (OGTT) have significantly higher risk of developing impaired glucose tolerance (IGT) or diabetes. Aim of the study will be to characterize the metabolic phenotype of NGT obese youth according to values of 1HPG. To accomplish this aim, obese patients (N = 1,454; 761 men; 79 IGT; BMI z-score 2.56 ± 0.16 SDS; age 11 ± 0.7 years) from two data sets were analyzed. In all patients, empirical parameters of insulin metabolism were calculated in fasting condition and following an OGTT (1.75 mg of glucose per kilogram/ body weight). Receiver-operating characteristic (ROC) analysis was performed in the first group (training set, N = 920) to establish the cutoff value of 1HPG best identifying IGT. The second set (validation set, N = 534) served to verify the goodness of the model and the identified cutoff values. 1HPG ≥ 132.5 mg/dl identified IGT with 80.8% sensitivity and 74.3% specificity in the training set (AUC 0.855, 95% CI 0.808-0.902, P<0.0001), and 70.3% sensitivity and 80% specificity in the validation set (AUC 0.81, 95% CI 0.713-0.907, P<0.0001), respectively. NGT patients with 1HPG ≥ 132.5 mg/dl had a metabolic phenotype (triglycerides, insulin action, and secretion) that was in between those of NGT patients with 1HPG below the threshold and IGT patients (P<0.0001 for all the comparisons). 1HPG ≥ 132.5 mg/dl seems to be associated with increased metabolic risk in obese youth, identifying patients with lower insulin sensitivity, early secretion, and higher total insulin secretion than in obese mates with lower 1HPG. © Springer-Verlag 2011.


Sponziello M.,University of Rome La Sapienza | Lavarone E.,University of Udine | Pegolo E.,University of Udine | Di Loreto C.,University of Udine | And 8 more authors.
Endocrinology | Year: 2013

Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-γ, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.


De Filippis T.,Instituto Of Ricevero E Cura A Carattere Scientifico Irccs | Marelli F.,Instituto Of Ricevero E Cura A Carattere Scientifico Irccs | Nebbia G.,Clinica Pediatrica de Marchi | Porazzi P.,Instituto Of Ricevero E Cura A Carattere Scientifico Irccs | And 17 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2016

Context: The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. Objective: Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. Design, Settings, and Patients: A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academicandpublic hospitals. TheJAG1variantswerestudied in vitroandin the zebrafish. Results:Wereport a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. Conclusions: clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH. © 2016 by the Endocrine Society.

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