Search

Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology(AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence and only those classified as “critical” were considered in the formulation of recommendations. Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Introduction: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. Methods: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” have been considered in the systematic review of evidence and only those classified as “critical” have been considered in the formulation of recommendations. Results: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the first-choice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. Conclusion: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Background: Direct locoregional treatments were recently proposed for the local control of cervical and distant metastasis of thyroid cancer, but data on their use as part of a multimodality approach for primary thyroid tumors are poor. In this feasibility study, laser ablation (LTA) was successfully used for the initial debulking of unresectable radioiodine-refractory thyroid cancer in sequential therapy with Tyrosine-Kinase Inhibitors (TKI). Case Presentation: A 69-year-old woman underwent partial resection of papillary thyroid cancer with extensive tracheal infiltration. Post-treatment whole-body scan (131I, 8140 MBq) showed the absence of cervical thyroid uptake. The patient experienced a rapid increase in her cervical mass associated with dysphonia, dyspnea, and dysphagia. Due to a concomitant severe hypertensive state and cardiac failure, the patient was treated with LTA after a multidisciplinary consultation. After local anesthesia, two 300 nm optic fibers were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were performed with a diode-laser source. LTA resulted in rapid cancer debulking, and mass volume decreased from 23.9 to 7.5 mL resulting in significant improvement of pressure symptoms. Three months later, the patient was started on lenvatinib due to the initial regrowth of the tumor mass. The cervical tumor burden was controlled by TKI for 20 months when a rapid disease progression occurred, and the patient died. Discussion: Locally advanced, unresectable, and radioiodine-refractory thyroid tumors can be managed with a novel multimodality approach. The initial debulking with LTA of the locally aggressive disease results in rapid control of the tumor burden threatening patients’ life and is effectively followed by long-term control with TKI treatment. Conclusion: Based on this experience, sequential multimodality treatment with an initial locally directed laser ablation procedure followed by TKI therapy may be considered as a salvage option in patients with unresectable and rapidly progressive RR thyroid tumors.

Carcinomas of the thyroid with Ewing family tumor elements (CEFTEs) are small cell thyroid tumors characterized by epithelial differentiation and EWSR1-FLI1 rearrangements. In contrast to primary thyroid Ewing sarcomas, these rare tumors have a favorable prognosis. CEFTEs may co-exist with papillary thyroid carcinoma (PTC) foci and are thought to arise from either PTCs or main cells of solid cell nests (SCN). Due to their rare occurrence, characteristic clinical presentations, preoperatory sonographic (US) findings, and fine-needle aspiration (FNA) cytologic features were ill-defined until now. We report a case of a 40-year-old male who was referred to the thyroid clinic for a progressively enlarging, hard, painless, cervical mass. US examination revealed a hypoechoic nodule with lobulated margins and scant intranodular vascular signals of the right thyroid lobe. Evidence of extracapsular spread was not identified. FNA provided a Bethesda V cytology classification on conventional smears. Repeat FNA sampling with the use of a CytoFoam Core allowed a preoperative diagnosis consistent with undifferentiated thyroid carcinoma. Total thyroidectomy without lymph node dissection was performed. Histologic examination with subsequent molecular studies provided the diagnosis of papillary carcinoma of the thyroid with Ewing family tumour elements (CEFTEs). No additional treatment was rendered and the patient showed no evidence of local or distant disease by clinical examination, US, and (18)FDG-TAC/PET after 6 months of follow-up. This is the first reported case of CEFTE with complete clinical, US, cytologic, and immunohistochemical preoperatory assessment.

Background: Outcomes of high-intensity focused ultrasound (HIFU), as a non-surgical treatment option for benign symptomatic thyroid nodules, has mainly been based on single-center studies and short-term follow-up. Therefore, we assessed the safety, and long-term efficacy of HIFU in benign thyroid nodules among four centers with expertise in thyroid mini-invasive procedures. Patients and methods: Retrospective three year follow-up study in four European centers, treating solid benign thyroid nodules causing pressure symptoms and/or cosmetic concerns. Nodule volume reduction was assessed at 1, 3, 6, 12, 24, and 36 months post-treatment. Technical efficacy, defined as a volume reduction rate (VVR) >50% was evaluated at 6, 12, 24 and 36 months. Predictive factors of efficacy were assessed using logistic models. Complications and side effects were classified according to the Interventional Radiology Guidelines and changes in local symptoms were scored on a visual-analog scale. Results: Sixty-five patients (mean age 51.1 ± 14.0 years; 86.2% women) with a single thyroid nodule and a mean baseline nodule volume of 9.8 ± 10.3 mL were treated with a mean energy of 7.1 ± 3.1 kJ (range: 2.0 to 15.5 kJ). Median nodule volume reduction was 31.5% (IQR: −38.6% to −23.1%) at 12 months and 31.9% (IQR: −36.4% to −16.1%) at 36 months. Technical efficacy was obtained in 17.2% of cases at 6 months, 17.8% at 12 months, 3.4% at 24 months, and 7.4% at 36 months. The number of treated pixels and the mean energy delivered were positively correlated to VRR at 1, 6 and 12 months. The risk of treatment failure decreased by 4.3% for each additional unit of energy delivered. The procedure duration was inversely correlated with treatment failure (OR 1.043, 95% CI: 1.011–1.083; p = 0.014). Improvement of cervical pressure symptoms or cosmetic complaints were observed in less than 15% of the cases at 12, 24 and 36 months. Horner’s syndrome occurred in one case (1.5%) and minor complications, not requiring treatment, in three (4.6%) patients. No change in thyroid function was registered. Conclusions: HIFU carried a low risk of complications. A single treatment resulted in a 30–35% thyroid nodule volume decrease within one year, reduction that remained stable for 2 years. Outcomes varied significantly between centers with different HIFU expertise. Focus on improved HIFU technology, adequate training, and appropriate selection of patients is needed to achieve efficacy comparable to other thermal ablation procedures.

IntroductionObesity is a global pandemic and is cause of serious concern in all regions of the world. It is important to raise the attention of health care professionals in order to provide early treatment of patients with obesity. Obesity management, however, varies greatly amongst endocrinologists with respect to attitudes to diagnosis and treatment. Aim of this study was to identify practices and needs of Italian endocrinologists with respect to people with obesity.MethodsIn this study, all members of the Italian Association of Clinical Endocrinologists (AME) were invited to participate in a web-based survey concerning the management of obesity.ResultsThe response rate was 24.1% (542/2248). Nutritional and obesity problems were reported as major areas of interest by 29.4% of the participants. A large proportion of patients seeking an endocrine consultation for other reasons are affected by obesity, but one in five respondents addressed the issue in 25% or less of the cases, while one in three always dealt with the problem. Obesity was managed personally/within a dedicated team by 42.6% of participants, while the remainders referred the patient to a dietician/nutritionist or a 2nd level center for obesity therapy. Metformin was used in a median of 30% of the patients (Interquartile range: 10-50) and liraglutide in 10% of the cases (IQR 0-30), while orlistat (median 0%; IQR 0-10) and naltrexone/bupropion (median 0%; IQR 0-5) were seldom prescribed. Cost of therapy was considered as the major limitation to the use of anti-obesity drugs, affecting adherence to long-term treatment. According to 41.9% of respondents, psychological support should be offered to all patients with obesity. Finally, 56% of participants believe that the availability of new drugs will increase the number of patients candidate to drug therapy.DiscussionIn conclusion, it is of primary importance to raise the awareness of endocrinologists towards the problem of obesity and increase their confidence in managing this pathological condition.

Cartilaginous bone tumors represent a wide variety of neoplasms ranging from benign to extremely aggressive malignant lesions. Unlike other tumors, the biopsy cannot easily predict the histological grade, sometimes not allowing choosing the best therapeutic approach. The aim of the study was to evaluate the ability of 18F-FDG PET/CT to differentiate enchondroma from chondrosarcoma and to predict the histological grade as compared to biopsy. 18F-FDG PET/CT of 95 patients with chondroid lesions were retrospectively evaluated. The best SUVmax cutoff to predict the post-surgical histological grade were correlated to those of biopsy and to several radiologic aggressiveness features, which were summarized in the parameter “Radiologic Aggressiveness Score” (AgSCORE). A concordance between the preoperative biopsy and the definitive histological grade was observed overall in 78.3% of patients, the lowest accuracy (58.6%) being in the identification of intermediate/high-grade chondrosarcoma (G2/G3). The best SUVmax cutoff was 2.6 to discriminate enchondroma vs. low-grade chondrosarcoma (sensitivity 0.68, specificity 0.86), 3.7 to differentiate low-grade vs. intermediate/high-grade chondrosarcoma (sensitivity 0.83, specificity 0.84) and 7.7 to differentiate intermediate/high-grade vs. dedifferentiated chondrosarcoma (sensitivity 0.92, specificity 0.9). The AgSCORE also showed a high accuracy to differentiate between G1 and G2/G3 chondrosarcoma (cutoff = 4; sensitivity 0.76; specificity 0.89). An even higher accuracy was observed in those cases in which both SUVmax and AgSCORE cutoff were concordant. Results in this large series of patients suggest a potential role of 18F-FDG PET/CT for histological grading of cartilaginous tumors, thus helping the orthopedic surgeon towards the most appropriate surgical procedure.

The high complexity of multimodality treatment frequently results in undertreatment of elderly sarcoma patients, and this may be one of the factors that influence their prognosis. We describe the real-life approach to a population of patients aged over 70 with both soft tissue (STS) and bone sarcomas (BS) followed by our Sarcoma Disease Management Team from 2012 to 2017. One-hundred and twenty-three patients with a median age of 77 years (range: 70&ndash, 92) were identified. STS were the most common histological subtypes (94%) and the grade was high in 79/123 patients (64%). At diagnosis, 88% of patients had localized disease (LD) and 12% were metastatic (MD). Overall, 96% of patients with LD underwent surgery, 46/54 (85%) with high grade STS patients underwent complementary radiotherapy, and 10/54 (19%) received adjuvant treatments. Twelve out of 33 patients who relapsed (36%) underwent local therapies. Seventeen (52%) and eight (24%) patients were treated with first-line and second-line medical treatments, respectively. Tolerability to systemic treatments was fairly good. Overall, 21% of the patients with advanced disease were candidates for best supportive care alone. Our case series of elderly patients with both STS and BS shows that personalized multidisciplinary treatment can nevertheless be offered to this frail population in order to control the evolution of disease.

Background. Short-term interventions based on very low-calorie ketogenic diets (VLCKDs) and meal replacements may be prescribed to selected overweight or obese patients. Few, inconsistent data are available on protein intake from various sources on body weight, composition of gut microbiota and metabolic outcomes in these patients. Aim. To compare efficacy, safety and effect on microbiota composition of short-term isocaloric very low-calorie ketogenic diets encompassing whey, vegetable or animal proteins, in obese patients with insulin resistance. Materials and Methods. 48 obese patients (19 males and 29 females) with HOMA-index ≥ 2.5, age mean: 55.2 years (range: 45-73), BMI mean 35.9 kg/m2 (range: 30.2 - 46.4) were randomly assigned to three isocaloric VLCKD regimens (≤800 kcal/day) containing either whey, plant or animal proteins for 45 days, with assessments of anthropometric indexes, blood and urine chemistry, body composition, muscle strength, taxonomic composition of the gut microbiome. Results. A significant reduction of body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, total and LDL cholesterol was observed in all the patients, regardless the dietary protein source. Patients fed with whey proteins and vegetable proteins had a more pronounced decrease of visceral adipose tissue (VAT) compared with the group fed with animal proteins. The markers of renal function slightly worsened in the group fed with animal proteins. A decrease in relative abundance of Firmicutes and an increase of Bacteroidetes was observed after VLCKDs. This pattern was less pronounced in patients consuming animal proteins. Conclusions. VLCKDs lead to significant weight loss and a striking improvement of the metabolic parameters over a short period of time. VLCKDs based on whey or vegetable proteins induce a larger reduction of VAT, have a safer profile and determine a healthier microbiota composition compared to those containing animal proteins.

Background. Direct loco-regional treatments are considered for local control of cervical metastasis of thyroid cancer. In our feasibility study, laser ablation was employed for initial debulking of an unresectable radioiodine-refractory thyroid cancer in a combined treatment with tyrosin kinase inhibitors (TKI). Clinical case. On June 2016, a 69-year-old woman underwent partial resection of a papillary thyroid cancer with extensive tracheal infiltration. On August 2016, whole body scan performed after 131-I treatment (8140 MBq) demonstrated nearly absent thyroid bed uptake. Due to progressive increase of the cervical mass, the patient experienced dysphonia and dysphagia and, after multidisciplinary consultation, was treated with laser ablation (LTA). After local anesthesia, two 300 nm fiberoptics were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were peformed with a diode-laser source. LTA resulted in rapid mass volume decrease (28 x12 x16 mm, 2.8 mL, vs 52 x 29 x 29 mm, 22.7 mL) and improvement of pressure symptoms that lasted 6 months. In May 2017, due to initial regrowth of the tumor mass, the patient started therapy with Lenvatinib, at 10-24 mg/day. The cervical tumor burden remained controlled until April 2019, when occurred rapid disease progression and death of the patient. Discussion. These preliminary results suggest that locally-advanced unresectable and radioiodine-refractory thyroid tumors can be managed with preliminary LTA mass debulking, for rapid control of local disease, followed by long-term TKI treatment. References. Mauri G et al. Cardiovasc Intervent Radiol. 2016 Jul; 39(7):1023-30; Park KW et al. Ann Surg Oncol 2011; 18:2564-2568. Schlumberger M et al. NEJM 2015 12; 372(7):621-30.

Context We compared the efficacy, safety, and effect of 45-day isocaloric very-low-calorie ketogenic diets (VLCKDs) incorporating whey, vegetable, or animal protein on the microbiota in patients with obesity and insulin resistance to test the hypothesis that protein source may modulate the response to VLCKD interventions. Subjects and Methods Forty-eight patients with obesity (19 males and 29 females, homeostatic model assessment (HOMA) index ≥ 2.5, aged 56.2 ± 6.1 years, body mass index [BMI] 35.9 ± 4.1 kg/m2) were randomly assigned to three 45-day isocaloric VLCKD regimens (≤800 kcal/day) containing whey, plant, or animal protein. Anthropometric indexes; blood and urine chemistry, including parameters of kidney, liver, glucose, and lipid metabolism; body composition; muscle strength; and taxonomic composition of the gut microbiome were assessed. Adverse events were also recorded. Results Body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, and total and low-density lipoprotein cholesterol decreased in all patients. Patients who consumed whey protein had a more pronounced improvement in muscle strength. The markers of renal function worsened slightly in the animal protein group. A decrease in the relative abundance of Firmicutes and an increase in Bacteroidetes were observed after the consumption of VLCKDs. This pattern was less pronounced in patients consuming animal protein. Conclusions VLCKDs led to significant weight loss and a striking improvement in metabolic parameters over a 45-day period. VLCKDs based on whey or vegetable protein have a safer profile and result in a healthier microbiota composition than those containing animal proteins. VLCKDs incorporating whey protein are more effective in maintaining muscle performance.

Background: Single-center trials demonstrated moderate-substantial level of interobserver agreement in the evaluation of ultrasound (US) features of thyroid nodules. Multicenter studies on US agreement, however, are scanty, and data on intraobserver agreement are poor. Aim of the study was to assess inter- and intraobserver agreement between different thyroid centers and different specialists. Methods: A blinded analysis of 100 electronically recorded thyroid nodule US images was conducted in three large-volume thyroid centers by seven radiologists and endocrinologists. The evaluation was repeated after randomization 4 months later. The following US characteristics were evaluated: composition, echogenicity, margins, intranodular echogenic spots, vascularity, and shape. Thyroid nodules were also classified according to AACE/ACE/AME, EU-TIRADS, ATA, and ACR-TIRADS US classifications. Intra- and interobserver agreement was calculated using cross-tabulation expressed as mean Cohen's Kappa. Results: Interobserver agreement for US features: K-coefficient was 0.53 for composition, 0.47 for echogenicity, 0.46 for intranodular vascularity, and 0.33 for margins of the nodules. For echogenic foci, the K-coefficient was 0.47 for microcalcifications, 0.38 for macrocalcifications, 0.11 for the subcategory comet-tail artifacts, and 0.42 for shape. Operators resulted uncertain on hyperechoic foci definition in 16% of cases and described them as "hyperechoic foci of uncertain significance." Interobserver Cohen-K for US classification systems was 0.44 for AACE, 0.42 for ACR-TIRADS, 0.39 EU-TIRADS, and 0.34 for ATA. Intraobserver agreement: the K-coefficient for nodule US features was 0.62 for intranodular vascularity, 0.58 for composition, 0.60 for echogenicity, 0.54 for macrocalcifications, 0.55 for microcalcifications, 0.47 for comet tails, 0.39 for margins, and 0.35 for shape. Intraobserver Cohen-K for US classification systems was 0.54 for AACE, 0.49 for ACR-TIRADS, 0.38 for ATA, and 0.33 for EU-TIRADS. Conclusions: Intraobserver reproducibility for thyroid nodule US reporting and US classification systems appears fairly adequate, while the interobserver agreement between different centers is lower than that assessed in single-center trials. Reporting and rating ability of thyroid US examiners still appear not consistent. An unified lexicon of thyroid US features, a simplified method of classification, and a dedicated training in the description of thyroid US findings may increase the observers' agreement and the predictive value of US classification systems in real world practice.

To assess the efficacy, safety, and pain benefits of imaging-guided laser ablation (IGLA) in patients with radioiodine-refractory (RR) bone metastases from differentiated thyroid carcinoma (DTC). The institutional medical records of patients with bone metastases from DTC treated with laser ablation (LA) were reviewed retrospectively. Local response, complications, and effects on pain relief were investigated. Six osteolytic lesions in five patients (one male, four females; mean age 65.4 ± 5.1 years, range 58–72) were treated with IGLA. All lesions were osteolytic and all have had previous treatments with high-dose radioiodine therapy followed by external radiotherapy (EBRT). All patients assumed opioid analgesics for severe pain. Overall, the lesions (mean size 5.8 ± 3.2 cm; median 5.0 cm, range 3.0–12.0 cm) underwent nine IGLA sessions (mean 1.8 ± 0.4 sessions; median 2.0 sessions, range 1–2). In four (80%) out five lesions, cross-sectional imaging showed a nearly complete response (CR) while the largest lesion was ablated by 80%. Pain changes were assessed with the Brief Pain Inventory-Short Form, that was administered before IGLA and during a 6-month follow-up. Patients experienced significant reduction in worst pain, average pain, and pain interference. Following IGLA, the average daily opioid requirement rapidly and progressively decreased. Treatments were well-tolerated and no major complications occurred. IGLA is an effective and safe debulking procedure and provides significant pain relief in patients suffering from DTC bone metastases that are not responsive to standard treatments. So, IGLA could be considered as part of a multimodality management of advanced thyroid cancer with RR metastatic skeletal involvement.

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets. Published version

Background: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease. Very low-calorie ketogenic diets (VLCKD) represent a feasible treatment as they induce profound weight loss and insulin resistance (IR) improvement. Despite the recognized benefits on NAFLD deriving from pharmacological administration of fibroblast growth factor 21 (FGF21), whose endogenous counterpart is a marker of liver injury, little is known about its physiology in humans. Aim: To identify predictors of NAFLD improvement as reflected by the reduction of the non-invasive screening tool hepatic steatosis index (HSI) in obese patients undergoing a weight loss program. Methods: Sixty-five obese patients underwent a 90-day dietary program consisting of a VLCKD followed by a hypocaloric low carbohydrate diet (LCD). Anthropometric parameters, body composition, and blood and urine chemistry were assessed. Results: Unlike most parameters improving mainly during the VLCKD, the deepest HSI change was observed after the LCD (p = 0.02 and p &lt, 0.0001, respectively). Baseline HOMA-IR and serum FGF21 were found to be positive (R = 0.414, p = 0009) and negative (R = 0.364, p = 0.04) independent predictors of HSI reduction, respectively. Conclusions: We suggest that patients with IR and NAFLD derive greater benefit from a VLCKD, and we propose a possible role of human FGF21 in mediating NAFLD amelioration following nutritional manipulation.

Background: In sarcopenic obese subjects it is essential to reduce body weight and to preserve lean mass, in order to avoid a worsening of muscle function (1). Several studies have shown that leucine supplementation can be useful to improve skeletal muscle mass in sarcopenic patients (2). Aim: Evaluate the effectiveness of a short-term low calorie diet (LCD) combined with combined supplementation with whey protein, leucine and vitamin D on weight loss, lean mass and muscle strength in sarcopenic, obese, hyperinsulinemic and menopause women. Materials and methods: 16 female with mean age: 58.1 years (range: 47–69 years), BMI 37.6 Kg/m2 (range: 31,7 - 44,1 Kg/m2), HOMA-index ≥ 2.5, were assigned to an LCD regimen (1000 kcal/day) with supplementation of 18 g protein, 4 g leucine and 5 mcg vitamin D for 45 days. Anthropometric indexes, blood and urine chemistry, body composition by DEXA, muscle strength by handgrip test and Short Physical Performance Battery (SPPB) were assessed at baseline and at the end of the treatment. Results: A significant reduction of BMI (35,7 vs 37,6 Kg/m2), waist circumference (102,4 vs 107 cm), HOMA index (2,3 vs 4,8) and fasting insulin (10,4 vs 17,4 μIU/ml) was observed in all patients. Women preserved total lean body mass (57 vs 55 %) and improved significantly muscle strength, as measured by handgrip (22,2 vs 18,6 Kg) and SPPB (8,9 vs 7,5). Conclusion: We conclude that LCD with adequate protein intake and a supplementation with whey protein, leucine and vitamin D should be promoted to maintain muscle mass and improve muscle strength in menopause women with sarcopenic obesity. References: 1. Batsis JA, Villareal DT. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018 Sep;14(9):513–5372. Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, McMurdo ME, Mets T, Seal C, Wijers SL, Ceda GP, De Vito G, Donders G, Drey M, Greig C, Holmbäck U, Narici M, McPhee J, Poggiogalle E, Power D, Scafoglieri A, Schultz R, Sieber CC, Cederholm T. Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2015 Sep 1;16(9)

Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 drugs, is an area in increasing development for its efficacy and advantages in the treatment of advanced metastatic melanoma. In fact, immunotherapy has been the target of several and recent studies in different types of cancer, namely in melanoma, a globally growing threat. Contributing to the increasing incidence of this cancer is climate change, particularly global warming of the past century, which has increased the tendency to spend more time outdoors and, consequently, exposure to sunlight and ultraviolet radiation. Among the most relevant risk factors for melanoma is the increase in ultraviolet radiation due to ozone layer depletion, one of the main factors responsible for the incidence of new cases. Anti-PD-1 agents like Nivolumab and Pembrolizumab allow a more effective treatment, enhancing the duration of the responses to therapy and prolonging the survival of the patient. However, recent studies about safety and tolerability have stated that, although these drugs present less adverse effects and toxicity, they may lead to specific autoimmune-mediated adverse events. Overall, immunotherapy with anti-PD-1 agents represents a highly promising area in the treatment of some types of cancer such as melanoma.

Surgery is the traditional treatment for thyroid nodules that keep growing over time and are associated with local symptoms. Yet, the direct and indirect expenses due to thyroidectomy and its long-term consequences, the risk of temporary or permanent complications, and the potential adverse influence on the quality of life are important concerns. Due to these considerations, a few image-guided minimally invasive procedures have been proposed for an office-based treatment of nodules that even if benign thyroid nodules are symptomatic or cause cosmetic concern. Among these techniques, US-guided laser thermal ablation (LA) is the most thoroughly assessed and is currently an easy accessible procedure in several thyroid specialized centers in Europe and Asia.

Background: Single-center trials have demonstrated an acceptable level of inter-observer agreement in the evaluation of the ultrasound (US) features of thyroid nodules, but limited data are available about the consistency in the assessment of US findings among different thyroid centers. Aim of the study: to assess the inter-observer agreement between different thyroid centers and among different specialists in the evaluation of the main US features of thyroid nodules. Materials and methods A blinded retrospective analysis of 100 electronically-recorded US images was conducted in three large-volume thyroid centers by seven qualified thyroid imaging experts, two radiologist and five endocrinologists. The following US features were evaluated: composition (solid, predominantly solid, predominantly cystic, and cystic); echogenicity (hyperechoic, isoechoic, mildly and deeply hypoechoic); margins (well-defined, ill-defined, microlobulated, and spiculated); calcifications (absent, microscopic, macroscopic, eggshell); hyperechoic foci of uncertain significance; comet-tail artifacts; vascularity (no vascular signals, perinodular and/or slight intranodular flow, and marked intranodular flow). Thyroid nodules were also classified according to four major US classification systems: AACE/ACE/AME, EU-TIRADS, ATA and ACR. The inter-observer agreement was calculated using cross-tabulation expressed in Cohen's Kappa. Kappa values were evaluated, according to Landis and Koch, as follows: 0-0.20 poor, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.80 substantial, and 0.81-1.0 almost perfect agreement. A sub-analysis assessed how many times and how many operators evaluated as suspicious for malignancy the US features of each nodule. Results: The inter-observer agreement resulted in a K-correlation coefficient of 34.5%, 44.0%, 42.3% and 38.8% for the ATA, AACE/ACE/AME, ACR, and EU-TIRADS classification systems, respectively. The interobserver agreement for the main thyroid nodule US findings resulted as follows: composition 53.2%; echogenicity 46.9%; margins 33.2%; comet-tail 10.6%, microcalcifications 46.8%; macrocalcifications 37.7%; eggshell calcifications 64.9%; intranodular vascularity 45.9%. Conclusion: The level of agreement among different thyroid centers in the description of suspicious US features in thyroid nodules ranged from fair to moderate, with the lowest level of consistency for the characteristics of margins and the presence of comet-tails. A similar range of variability was demonstrated also for the four US classification systems. An universally accepted lexicon of thyroid US features and a dedicated training in thyroid US findings definition are needed to improve the inter-observer agreement and the predictive value of US classification systems in real world practice.

Surgery is the standard treatment for cervical metastases of medullary thyroid cancer (MTC) diagnosed after initial surgical treatment. Repeated neck dissections, however, carry an elevated risk of complications, have an adverse impact on the quality of life, and sometimes do not achieve cure of the disease Clinical case: In a patient who had undergone two cervical neck dissections complicated by accessory nerve injury, an US-guided laser ablation (LA) of a lymph node metastasis of MTC was performed. LA was performed with two treatments during a five month period. The procedure was carried out with one optical fiber and an energy delivery of 3300 and 360 Joules. Treatments were well tolerated and resulted in complete structural and biochemical cure during a 12 month follow-up. No major complication was registered.LA is a promising tool for the management of relapsing cervical metastases that are localized in non- critical areas and are characterized by low progression rate. Advantages of LA are the outpatient setting, the absence of general anesthesia, the tolerability and the safety of the procedure. Thus, LA may be considered as an alternative approach to surgery or active surveillance for the management of local recurrences of MTC in selected patients.

Context: Sirtuins (SIRTs) are NAD+-dependent deacetylases, cellular sensors to detect energy availability, and modulate metabolic processes. SIRT1, the most studied family member, influences a number of tissues including adipose tissue. Expression and activity of SIRT1 reduce with weight gain and increase in conditions of starvation. Objective: To focus on SIRT1 plasma concentrations in different conditions of adiposity and to correlate SIRT1 with fat content and distribution, energy homeostasis and inflammation in under-weight, normal-weight, and obese individuals. Materials and Methods: 21 patients with anorexia nervosa, 26 normal-weight and 75 patients with obesity were evaluated. Body fat composition by dual-energy X-ray absorptiometry, ultrasound liver adiposity, echocardiographic epicardial fat thickness (EFT), inflammatory (ESR, CRP, and fibrinogen), and metabolic (FPG, insulin, LDL- and HDL-cholesterol, triglycerides) parameters, calculated basal metabolic rate (BMR) and plasma SIRT1 (ELISA) were measured. Results: SIRT1 was significantly higher in anorexic patients compared to normal-weight and obese patients (3.27 ± 2.98, 2.27 ± 1.13, and 1.36 ± 1.31 ng/ml, respectively). Linear regression models for each predictor variable adjusted for age and sex showed that SIRT1 concentration was inversely and significantly correlated with EFT, fat mass %, liver fat content, BMR, weight, BMI, WC, LDL-cholesterol, insulin, ESR. Stepwise multiple regression analysis revealed that age and EFT were the best independent correlates of SIRT1 (β = −0.026 ± 0.011, p = 0.025, and β = −0.516 ± 0.083, p < 0.001, respectively). Conclusions: Plasma SIRT1 shows a continuous pattern that inversely follows the whole spectrum of adiposity. SIRT1 significantly associates with EFT, a strong index of visceral fat phenotype, better than other indexes of adiposity studied here.

Purpose Recombinant human TSH (rhTSH) is currently used in follow-up of patients affected by differentiated thyroid cancer (DTC). Age, sex, weight, body mass index, body surface area (BSA) and renal function are known factors affecting serum TSH peak levels, but the proper rhTSH dose to deliver to single patient remains elusive. In this study, the correlations of basal metabolic rates with serum TSH peak following rhTSH administration were investigated. Methods We evaluated 221 patients affected by thyroid cancer that received a standard dose rhTSH. Blood samples were collected at pre-established time points. Data on body weight, height, and BSA were collected. The Mifflin-St Jeor and Fleisch equations were used to assess basal metabolism. Results The median value (range) of serum TSH peaks was 142 ± 53 μU/ml. Serum TSH peaks were significantly lower in males than in females (p = 0.04). TSH values also increased with age. Data showed a significant decrease of TSH peak levels at day 3 from the administration of rhTSH when basal metabolic rates increased (p = 0.002 and p = 0.009, respectively). Similar findings were observed at day 5 (p = 0.004 and p = 0.04, respectively). A multivariate analysis of several factors revealed that patients’ basal metabolism (obtained using the Mifflin-St Jeor but not Fleisch equation) predicts serum TSH level peak at day 3 (p

Il carcinoma della mammella e la prima neoplasia e la seconda causa di morte per cancro nella donna. Amenorrea, menopausa o infertilita sono legate ai trattamenti citotossici. La valutazione della funzione ovarica e importante per le future finalita riproduttive, per la scelta della ormonoterapia adiuvante ottimale e per il trattamento dell’eventuale menopausa chemio-indotta. L’ormone anti-Mulleriano e uno dei piu interessanti fattori predittivi per studiare la funzione ovarica di queste pazienti.

Context British Thyroid Association (BTA), American Thyroid Association (ATA), and American Association of Clinical Endocrinologists (AACE/ACE/AME) recommend for thyroid nodules an ultrasound (US)-based stratification of risk of malignancy. Aim of our study was to assess the diagnostic accuracy of US classification systems and their reliability for indication to fine-needle aspiration (FNA). Design Prospective study on 987 thyroid nodules consecutively referred for FNA. US images were independently reviewed by four experts for assignment of malignancy risk. Cytologically benign nodules had confirmation with a second FNA, whereas Bethesda class IV, V, and VI nodules were operated upon. Class III nodules had surgery or follow-up on the basis of clinical, immunocytochemical, and US features. Results BTA: Malignancy rate was 2.8% in benign, 10.0% in indeterminate, 51.3% in suspicion, and 80.9% in malignant US class. Sensitivity was 0.74, specificity was 0.92, and accuracy was 0.89. ATA: Malignancy rate was 0.0% in benign, 2.2% in very low suspicion, 3.0% in low suspicion, 5.8% in intermediate, and 55.0% in high suspicion US class. Sensitivity was 0.81, specificity was 0.87, and accuracy was 0.86. AACE/ACE/AME: Malignancy rate was 1.1% in low-risk, 4.4% in intermediate-risk, and 54.9% in high-risk US class. Sensitivity was 0.82, specificity was 0.87, and accuracy was 0.86. K correlation coefficient was 78.9%, 76.9%, and 82.0% for BTA, ATA, and AACE/ACE/AME classifications. Conclusions Classification systems had elevated predictive value of malignancy in high-risk classes. ATA and AACE/ACE/AME systems were effective for ruling out indication to FNA in low-US-risk nodules. A similar diagnostic accuracy and a substantial interobserver agreement was provided by the three- and the five-category classifications.

Background Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms. Methods Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2-positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing. Results A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases. Conclusions These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0410-3) contains supplementary material, which is available to authorized users.

Sirtuins (SIRTs), ubiquitous deacetylases, are main regulators of energy homeostasis and metabolism. SIRT1 has a positive impact on obesity, diabetes mellitus, liver steatosis, and other metabolic disorders. Lean subjects have higher expression of SIRT1 in the adipose tissue compared to obese. However, it is not known whether weight loss associates with changes in blood SIRT1. We evaluated the effect of weight loss on circulating SIRT1, metabolic parameters, and body composition.Thirty-two obese subjects were studied before and 6 months after BioEnterics® Intragastric Balloon (BIB®) [22 patients, BMI 41.82 ± 6.28 kg/m(2)] or hypocaloric diet [10 patients, BMI 38.95 ± 6.90 kg/m(2)]. Plasma SIRT1, body composition, measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL cholesterol, triglycerides), and inflammation markers (ESR, CRP, fibrinogen) were recorded.SIRT1 levels showed a significant increase, together with a significant reduction of BMI, excess body weight, and total fat mass either after BIB or diet intervention. The percent excess body weight loss was 33.73 ± 19.06 and 22.08 ± 11.62 % after BIB and diet, respectively, a trend toward a metabolic and inflammatory amelioration was observed with both treatments. Negative correlation between SIRT1 and % fat mass (BIB, ρ = -0.537, p = 0.017; diet, ρ = -0.638, p = 0.047) was also seen.The reduction of fat mass associates with increased plasma SIRT1 indicating that, besides tissue levels, circulating SIRT1 is stimulated by a negative caloric balance. The rise of plasma SIRT1 may represent a parameter associating with fat loss rather than weight lowering regardless of the weight reduction system method used.

Sirtuins (SIRTs) are master metabolic regulators with protective roles against obesity and obesity-associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) and type-2 diabetes. We aimed to ascertain whether there is a relationship between serum SIRT1 and liver steatosis severity in obese patients. Seventy-two obese patients (BMI ≥ 30 kg/m(2)), 18 males and 54 females, mean age 39.66 ± 12.34 years, with ultrasonographic evidence of NAFLD, were studied. BMI, transaminases, insulin, HOMA-index, HbA1c, body composition (DXA), plasma SIRT1 levels (ELISA) and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were evaluated. Thirty healthy lean patients were included as controls. SIRT1 was significantly lower in severe liver steatosis obese group compared to the mild steatosis group, both had lower SIRT1 plasma values compared to control lean patients (P = 0.0001). SIRT1 showed an inverse correlation with liver steatosis and HbA1c in univariate analysis (ρ = -0.386; P = 0.001; ρ = -0.300; P = 0.01, respectively). Multiple linear regression analysis showed that liver steatosis was the independent correlate of SIRT1 even after adjustment for potentially relevant variables (β = -0.442; P = 0.003). Serum SIRT1 might be a novel clinical/biochemical parameter associated with fat liver infiltration. Further studies in larger cohorts are warranted.

To investigate safety, compliance, and efficacy, on weight loss and cardiovascular risk factors of a multi- phasic dietary intervention based on meal replacements, including a period of very low calorie diet (VLCD) in a population of obese patients. Anthropometric parameters, blood tests (including insulin), dual-energy-X-ray absorp- tiometry (DXA), and questionnaires for the assessment of safety and compliance before and after (phase I) a 30-day VLCD, 700 kcal/day, normoproteic, 50 g/day carbohy- drate, four meal replacements; (phase II) a 30-day low calorie diet (LCD), 820 kcal/day, three meal replacements plus a protein plate; (phase III) 60-day LCD, 1,100 kcal/ day, two meal replacements plus two protein plates and reintroduction of small amounts of carbohydrates; (phase IV) 60-day hypocaloric balanced diet (HBD), 1,200 kcal/ day, one meal replacement, two protein plates and the reintroduction of carbohydrates. 24 patients (17 females, 7 males, mean BMI 33.8 ± 3.2 kg/m 2 , mean age 35.1 ± 10.2 years) completed the study. The average weight loss was 15.4 ± 6.7 %, with a significant reduction of fat mass (from 32.8 ± 4.7 to 26.1 ± 6.3 % p \ 0.05) and a relative increase of lean mass (from 61.9 ± 4.8 to 67.1 ± 5.9 % p \ 0.05). An improvement of metabolic parameters and no variations of the liver and kidney functions were found. A high safety profile and an excel- lent dietary compliance were seen. The VLCD dietary program and the replacement dietary system described here is an effective, safe, and well-tolerated treatment for weight control.

Background The 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area. Methods and Findings We retrospectively analyzed 6454 patients who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found 18F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with 18F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected. Conclusions This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of 18F-FDG-detected BAT.

Stefania Mariani,1 Daniela Fiore,1 Laura Varone,2 Sabrina Basciani,1 Agnese Persichetti,1 Mikiko Watanabe,1 Maurizio Saponara,3 Giovanni Spera,1 Costanzo Moretti,4 Lucio Gnessi11Department of Experimental Medicine, Section of Medical Physiopathology and Endocrinology, Sapienza University of Rome, Italy; 2Department of Environmental Biology, Sapienza University of Rome, Italy; 3Department of Otolaryngology, Audiology and Phonation, Sapienza University of Rome, Italy; 4Division of Endocrinology, Department of System Medicine, Section of Reproductive Endocrinology University of TorVergata, Fatebenefratelli Hospital "San Giovanni Calibita" Rome, ItalyContext: Obesity and its co-morbidities may adversely affect bone mineral density (BMD). Obstructive sleep apnea (OSA) is a major complication of obesity. To date, the effects of OSA on BMD in obese patients have been poorly studied.Objective: To examine whether the severity of OSA independently correlates with BMD in obese patients.Methods: One hundred and fifteen obese subjects with OSA (Apnea/Hypopnea Index [AHI] ≥5 events per hour) were included in the study. BMD was measured at lumbar spine, total hip, and femoral neck by dual energy X-ray absorptiometry. Body mass index, lean mass, and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were also evaluated.Results: BMD did not differ among obese individuals regardless of OSA severity. Correlation coefficient analysis for all the covariates showed a lack of association between AHI and BMD that was strongly influenced by age and weight.Conclusion: Our study does not support an independent association between AHI and BMD in obese patients. Controlled studies involving a greater number of patients are warranted.Keywords: obesity, polysomnography, metabolic syndrome