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BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of solid tumors. However, although ICIs are better tolerated than conventional chemotherapy, their use is associated with a peculiar toxicity profile, related to the enhancement of the immune response, affecting several organs. Among immune-related adverse events (irAEs), up to 10% involve the endocrine system. Most of them are represented by thyroid disorders (hypothyroidism and hyperthyroidism), mainly correlated to the use of anti-PD-1 and/or anti-PD-L1 agents. Less common endocrine irAEs include hypophysitis, adrenalitis, and metabolic irAEs. A deeper understanding of endocrine toxicities is a critical goal for both oncologists and endocrinologists. A strict collaboration between these specialists is mandatory for early recognition and proper treatment of these patients. In this review we will provide a comprehensive overview of endocrine and metabolic adverse events of ICIs, with particular interest in the pathogenesis, predisposing factors and clinical presentation of these irAEs, and their impact on clinical outcomes of patients. Furthermore, we will summarize the most recent studies and recommendations on the clinical approach to immune-related endocrinopathies with the purpose to optimize the diagnostic algorithm, and to help both oncologists and endocrinologists to improve the therapeutic management of these unique types of irAEs, in a real-life scenario.

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients’ gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

Objective To date, no systematic reviews and meta-analysis on the global epidemiology of acromegaly are available in the literature. The aims of this study are to provide a systematic review and a meta-analysis of the global epidemiology of acromegaly and to evaluate the quality of study reporting for the identified studies. Methods MEDLINE, EMBASE and The Cochrane Library databases were searched for studies assessing the epidemiology of acromegaly from inception until 31 January 2020. We included original observational studies written in English, reporting acromegaly prevalence and/or incidence for a well-defined geographic area. Two reviewers independently extracted data and performed quality assessments. Prevalence and incidence pooled estimates were derived by performing a random-effects meta-analysis. Results A total of 32 studies were included in the systematic review, and 22 of them were included in the meta-analysis. The pooled prevalence of acromegaly was 5.9 (95% CI: 4.4–7.9) per 100 000 persons, while the incidence rate (IR) was 0.38 (95% CI: 0.32–0.44) cases per 100 000 person-years. For both prevalence and IR, considerable between-study heterogeneity was found (I2 = 99.3 and 86.0%, respectively). The quality of study reporting was rated as the medium for 20 studies and low for 12 studies. Conclusions Although the largest amount of heterogeneity was due to the high precision of the studies’ estimates, data source and geographic area could represent relevant study-level factors which could explain about 50% of the total between-study variability. Large-scale high-quality studies on the epidemiology of acromegaly are warranted to help the public health system in making decisions.

Background Pituitary metastases are rare, often deriving from lung or breast cancer owing to the upper vena cava proximity. Pituitary metastases can manifest with signs and symptoms of pituitary tumors, consequent to mass effect (headache, visual impairment) and/or hormonal alterations (hyperprolactinemia, hypopituitarism, and diabetes insipidus). Immune checkpoint inhibitors burst immunity against tumors, significantly increasing patients’ survival, but their autoimmune side effects frequently involve the skin, the gastrointestinal tract, and the endocrine glands (pituitary, thyroid, pancreas). Case presentation A 77-year-old Caucasian man had undergone trans-nasal sphenoidal surgery for a nonsecreting pituitary macroadenoma in 2001, without remnant or endocrine deficits. In 2016, he was operated for a shoulder melanoma. In February 2018, imaging evaluation demonstrated metastases in lung, liver, and femur. Therefore, treatment with pembrolizumab (anti-programmed death 1) was scheduled in May 2018, but, before starting this therapy, a brain computed tomography performed for a sudden loss of consciousness detected a sellar mass of 17 × 12 mm, which extended to the pituitary stalk and compressed the optic chiasma. Focused magnetic resonance imaging confirmed the size and characteristics of the lesion, while emergency evaluation of the hormonal profile demonstrated an impairment of adrenal and thyroid function. The pituitary lesion demonstrated a remarkable shrinkage (8 × 6 mm), which was confirmed by subsequent imaging evaluations. Conclusions This is the first case reporting on effectiveness of immune checkpoint inhibitors in a patient with pituitary metastasis from a melanoma.

Introduction: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported. Evidence acquisition: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated. Evidence synthesis: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis. Conclusions: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.

Hashimoto’s thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. 500 HT patients (467 F, 33 M; median age 41 years, range 14–69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took l-thyroxine. Exclusion criteria: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P

Advanced glycation end products (AGEs) are increased in conditions of oxidative stress and promote inflammation by interacting with their receptor RAGE on cell membrane. By contrast, the soluble receptor sRAGE exerts protective effects by competing with RAGE for ligand binding. AGEs/sRAGEs interaction is involved in the pathogenesis of several diseases related to oxidative stress. In the present study, we evaluated the AGEs/sRAGEs oxidative balance in Hashimoto’ thyroiditis (HT). We measured the levels of sRAGE, by ELISA, and AGEs, by spectrophotometric method, in the serum of 50 HT patients (5 M, 45 F; mean age 38.5 ± 12 years) and 50 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. Serum sRAGEs were significantly lower (median 424 vs 738 pg/ml; p = 0.001) and AGEs higher (205 vs 114 AU/g prot; p = 0.001) in HT patients compared to controls, and the two parameters were inversely correlated (p = 0.016). Accordingly, the AGEs/sRAGEs ratio was threefold higher in HT patients than controls (0.48 vs 0.15; p = 0.0001). In regression analysis models, serum TPO-Ab were the main predictors for AGEs and sRAGEs levels and AGEs/sRAGEs ratio (p

Background: There is a growing awareness that nutritional habits may influence risk of several inflammatory and immune-mediated disorders, including autoimmune diseases, through various mechanisms. The aim of the present study was to investigate dietary habits and their relationship with redox homeostasis in the setting of thyroid autoimmunity. Materials and Methods: Two hundred subjects (173 females and 27 males; median age, 37 years) were enrolled. None were under any pharmacological treatment. Exclusion criteria were any infectious/inflammatory/autoimmune comorbidity, kidney failure, diabetes, and cancer. In each subject, serum thyrotropin (TSH), free thyroxine, antithyroid antibodies, and circulating oxidative stress markers were measured. A questionnaire on dietary habits, evaluating the intake frequencies of food groups and adherence to the Mediterranean diet, was submitted to each participant. Results: Among the 200 recruited subjects, 81 (71 females and 10 males) were diagnosed with euthyroid Hashimoto's thyroiditis (HT); the remaining 119 (102 females and 17 males) served as controls. In questionnaires, HT subjects reported higher intake frequencies of animal foods (meat, p = 0.0001; fish, p = 0.0001; dairy products, p = 0.004) compared with controls, who reported higher intake frequencies of plant foods (legumes, p = 0.001; fruits and vegetables, p = 0.030; nuts, p = 0.0005). The number of subjects who preferentially consumed poultry instead of red/processed meat was lower in HT subjects than in controls (p = 0.0141). In logistic regression analysis, meat consumption was associated with increased odds ratio of developing thyroid autoimmunity, while the Mediterranean diet traits were protective. In HT subjects, serum advanced glycation end products (markers of oxidative stress) were significantly higher (p = 0.0001) than in controls, while the activity of glutathione peroxidase and thioredoxin reductase, as well as total plasma antioxidant activity, were lower (p = 0.020, p = 0.023, and p = 0.002, respectively), indicating a condition of oxidative stress. Stepwise regression models demonstrated a significant dependence of oxidative stress parameters on consumption of animal foods, mainly meat. Conclusions: The present study suggests a protective effect of low intake of animal foods toward thyroid autoimmunity and a positive influence of such nutritional patterns on redox balance and potentially on oxidative stress-related disorders.

Background: folliculogenesis is a strictly regulated process that may be affected by endocrine disrupting chemicals (EDCs) through sometimes not so clear molecular mechanisms. Methods: we conducted a multicentric observational study involving six fertility centers across Italy, prospectively recruiting 122 women attending a fertility treatment. Recruited women had age ≤42 years, and normal ovarian reserve. Blood and follicular fluid samples were taken for EDCs measurement using liquid chromatography tandem mass spectrometry and each woman completed an epidemiological questionnaire. Results: The main EDCs found were monobutyl phthalate (MBP) (median blood: 8.96 ng/mL, follicular fluid 6.43 ng/mL), monoethylhexyl phthalate (MEHP) (median blood: 9.16 ng/mL, follicular fluid 7.68 ng/mL) and bisphenol A (BPA) (median blood: 1.89 ng/mL, follicular fluid 1.86 ng/mL). We found that serum MBP concentration was significantly associated with the considered area (p < 0.001, adj. mean: 7.61 ng/mL, 14.40 ng/mL, 13.56 ng/mL; Area 1: Milan–Turin, Area 2: Rome–Naples; Area 3: Catania–Bari, respectively) but negatively with home plastic food packaging (p = 0.004). Follicular MBP was associated with irregular cycles (p = 0.019). No association was detected between EDCs and eating habits and other clinical and epidemiological features. Conclusions: This study represents the first Italian biomonitoring of plastic EDCs in follicular fluid, laying the basis for future prospective evaluation on oocyte quality before assisted reproduction techniques (ART).

Sensors are tools for detecting, recognizing, and recording signals from the surrounding environment. They provide measurable information on chemical or physical changes, and thus are widely used in diagnosis, environment monitoring, food quality checks, or process control. Polymers are versatile materials that find a broad range of applications in sensory devices for the biomedical sector and beyond. Sensory materials are expected to exhibit a measurable change of properties in the presence of an analyte or a stimulus, characterized by high sensitivity and selectivity of the signal. Signal parameters can be tuned by material features connected with the restriction of macromolecule shape by crosslinking or folding. Gels are crosslinked, three-dimensional networks that can form cavities of different sizes and forms, which can be adapted to trap particular analytes. A higher level of structural control can be achieved by foldamers, which are macromolecules that can attain well-defined conformation in solution. By increasing control over the three-dimensional structure, we can improve the selectivity of polymer materials, which is one of the crucial requirements for sensors. Here, we discuss various examples of polymer gels and foldamer-based sensor systems. We have classified and described applied polymer materials and used sensing techniques. Finally, we deliberated the necessity and potential of further exploration of the field towards the increased selectivity of sensory devices.

Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

// Alfredo Campenni 1 , Luca Giovanella 2 , Salvatore Antonio Pignata 1 , Antonio Vento 1 , Angela Alibrandi 4 , Letterio Sturiale 1 , Riccardo Laudicella 1 , Alessio Danilo Comis 1 , Rossella Filice 1 , Giuseppe Giuffrida 3 , Maria Elena Stipo 1 , Salvatore Giovinazzo 3 , Francesco Trimarchi 5 , Rosaria Maddalena Ruggeri 3 and Sergio Baldari 1 1 Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, Nuclear Medicine Unit, University of Messina, Messina, Italy 2 Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland 3 Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, Messina, Italy 4 Department of Economical, Business and Environmental Sciences and Quantitative Methods, University of Messina, Messina, Italy 5 Accademia Peloritana dei Pericolanti, University of Messina, Messina, Italy Correspondence to: Alfredo Campenni, email: acampenni@unime.it Keywords: differentiated thyroid cancer; 131-radioiodine treatment; 131-radioiodine thyroid remnant ablation; thyroglobulin; post-therapy whole body scintigraphy Received: December 11, 2017 Accepted: February 26, 2018 Published: April 03, 2018 ABSTRACT Background: Differentiated thyroid cancer (DTC) work-up is based on (near)total-thyroidectomy plus thyroid remnant ablation (TRA) with 131-radioiodine in many patients, and long-life follow-up. 131 I-post therapy whole body scan (pT-WBS) and serum thyroglobulin (Tg) are used in identifying metastatic patients. Some authors have evaluated the possibility of using post-surgical Tg (ps-Tg) values in deciding for or against TRA. The aim of our study was to verify the diagnostic accuracy of 131 I-pT-WBS and SPECT/CT imaging (post-therapeutic imaging) compared to serum Tg levels in detecting metastases in early stage of DTC patients. Results: Post-therapeutic imaging revealed metastases in 82 out of 570 (14.4%) patients. Metastases were successively confirmed by other diagnostic tools or by histology (sensitivity and PPV = 100%). Seventy-three out of 82 patients (90.2%) showed ps-Tg levels ≤1 ng/ml. In fifty-four per cent of patients, serum Tg levels at TRA remained ≤1 ng/ml. Conclusion: In conclusion, ps-Tg levels cannot be used in deciding for or against TRA. In early stage of DTC, post-therapeutic imaging ( 131 I-pT-WBS and SPECT/CT) is an accurate method of detecting metastases, also in patients with stimulated serum Tg values ≤1 ng/ml Methods: We retrospectively reviewed the records of 570 consecutive patients affected by pT1-pT3 DTC (F = 450, M = 120), referred to our Nuclear Medicine Units in the last five years to perform TRA after (near)-total-thyroidectomy.All patients underwent TRA 3-4 months after thyroid surgery either in euthyroid or in hypothyroid state. Serum Tg values evaluated in post-surgical period and at TRA were matched with post-therapeutic imaging results.

SUMMARY Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. On the contrary, primary thyroid lymphoma (PTL) is a rare disease, accounting for 2% to 5% of all thyroid malignancies. Despite several cases in which both PTC and PTL arise in the setting of Hashimoto's thyroiditis (HT), the coexistence of both tumors in HT patients is very rare. Herein we report the case of a 66-year-old woman with long-standing nodular HT under replacement therapy, who presented with a fast, painless enlargement in the right anterior side of the neck. Thyroid ultrasonography demonstrated increased growth of a hypoechoic nodule in the right lobe measuring 32 × 20 mm. A total thyroidectomy was performed, and histology revealed a diffuse large B-cell lymphoma (DLBCL) on a background of florid HT. Moreover, a unifocal papillary microcarcinoma, classical variant (7 mm, pT1aNxMx), was discovered. The patient was then treated with chemotherapy for the PTL, but she did not undergo radioactive iodine ablation treatment for the microPTC as per guidelines. Two years after surgery, the patient had no evidence of recurrence of either malignancy. This rare case highlights the importance of monitoring HT patients with nodular lesions, especially if they have long-standing disease. In addition, PTL should be considered for differential diagnosis in elder HT patients who present with sudden thyroid enlargement.

Objective Hashimoto’s thyroiditis (HT), the most common autoimmune thyroid disease at any age, is often associated with other autoimmune diseases. The present study was aimed to describe the type and frequency of non-thyroidal autoimmune diseases (NTADs) in HT patients and to delineate the clinical pattern of diseases clustering in pediatric/adolescent and adult age. Design Cross-sectional study. Methods 1053 newly diagnosed HT patients (500 adults (467 F, mean age 40.2 ± 13.7 years) and 553 children/adolescents (449 F, mean age 11.1 ± 3.0 years)) were evaluated for common NTADs by means of careful recording of medical history, physical examination and assessment of selected autoantibody profiles. Results The prevalence of associated NTADs was significantly higher in adults than that in pediatric/adolescent HT patients (P P P Conclusions Age at HT presentation may influence autoimmune diseases clustering, favoring the association of specific NTADs in different ages of life. Moreover, the association between HT and NTADs increases with age and occurs most frequently in adults.

The endocrine system is interested by several autoimmune diseases, characterized by different impact and severity, according to the organs involved. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders, while hypophysitis, adrenalitis (90% of cases of primary hypocortisolism or Addison's disease), POF and hypoparathyroidism represent quite rare conditions. Autoimmune endocrine diseases can also coexist in the same individuals and cluster in families. Some of these associations are nosologically codified in the so-called autoimmune polyglandular syndromes, but autoimmune endocrinopathies can also be accompanied by other non-endocrine autoimmune disorders (i.e. connective tissue, skin or gastrointestinal diseases). Pathophysiology generally results from a complex interplay among genetic predisposition and environmental/endogenous factors. In the diagnostic process, measurement of organ-specific autoantibodies, both with a causative role or as an epiphenomenon, is often fundamental and integrates the assessment of hormone axes and the targeted imaging studies.

The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment.This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology.The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score6), 38.6% medium (6 to8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers.Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment.AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography.

Over the last years, there have been several reports on the occurrence of acute liver damage (ALD) in patients affected with Graves’ ophthalmopathy (GO) receiving intravenous glucocorticoids (ivGCs). This article is aimed at reviewing the literature on this specific topic and reporting two new cases of ALD occurring in GO patients while on ivGCs. The terms “glucocorticoid therapy” and “Graves’ Ophthalmopathy”/“Graves’ Orbitopathy”/”Thyroid eye disease” were used both separately and in conjunction with the terms “liver disease,” “liver damage,” “hepatotoxicity,” “liver failure,” to search MEDLINE for articles published since the first report of ALD in 2000 and up to 2015. ALD [defined as an increase in alanine aminotransferase (ALT) >300 U/L] during or after completion of ivGCs has been so far reported in 17 fully documented cases. Overall, one-half of those patients were diagnosed as having autoimmune hepatitis (AIH) and in the vast majority of the remaining cases a diagnosis of methylprednisolone(MP)-induced hepatotoxicity was suspected. The clinical course of liver injury varied from asymptomatic hypertransaminasemia in the vast majority of patients to fatal hepatic failure in four patients receiving higher (>8 g) cumulative doses of MP. The overall risk of ALD is relatively low (~1 %), and seems higher using a single dose >0.5 g and a cumulative dose >8.5 g MP. Whenever ivGC treatment is required, serum liver enzymes, viral hepatitis markers, and autoantibodies related to AIH should be obtained prior to ivGC administration. Liver function should be monitored during ivGC and up to 6 months after the end of treatment. Prolonging observation after 6 months is likely unnecessary, since all cases of ALD so far reported always occurred well within this term.

Aims To describe atrial fibrillation (AF) management in member countries of the European Society of Cardiology (ESC) and to verify cardiology practices against guidelines. Methods and results Among 182 hospitals in 35 countries, 5333 ambulant and hospitalized AF patients were enrolled, in 2003 and 2004. AF was primary or secondary diagnosis, and was confirmed on ECG in the preceding 12 months. Clinical type of AF was reported to be first detected in 978, paroxysmal in 1517, persistent in 1167, and permanent in 1547 patients. Concomitant diseases were present in 90% of all patients, causing risk factors for stroke to be also highly prevalent (86%). As many as 69% of patients were symptomatic at the time of the survey; among asymptomatic patients, 54% were previously experienced symptoms. Oral anticoagulation was prescribed in 67 and 49% of eligible and ineligible patients, respectively. A rhythm control strategy was applied in 67% of currently symptomatic patients and in 44% of patients who never experienced symptoms. Conclusion This survey provides a unique snapshot of current AF management in ESC member countries. Discordance between guidelines and practice was found regarding several issues on stroke prevention and antiarrhythmic therapy.

The term Marine-Lenhart syndrome describes the association between Graves’ disease and autonomously functioning thyroid nodules (AFTN), such as toxic adenoma or toxic multinodular goiter. The two diseases may coexist or may be present at different moments in the same patient. In the literature, there are many reports on the development of Graves’ disease after radioiodine treatment for AFTN, but very little information may be found on the occurrence of AFTN after radioiodine therapy for Graves’ disease. We describe here the case of a female patient with Graves’ disease who was successfully treated with radioiodine for Graves’ disease, returning to normal thyroid function. Three years later, biochemical analysis and ultrasound examination identified a thyroid nodule that progressively increased in size. The 99mTc-pertechnetate scintigraphy showed avid uptake in the right lobule, which corresponded to a nodular lesion consistent with AFTN.

Technetium-99m (Tc-99m)-tetrofosmin is a radio isotope that has been shown to be an accurate alternative to thallium-201 for detecting coronary artery disease. However, its prognostic value is less well determined. To this end, 459 consecutive patients (mean age 58 +/- 10 years) with suspected or known coronary artery disease underwent exercise single-photon emission tomography Tc-99m-tetrofosmin scintigraphy. Follow-up, defined as the time from scanning until a soft event (revascularization procedures), a hard event (myocardial infarction and cardiac death), or patient response, lasted up to 78 months (median 38). An ischemic scintigraphic perfusion score, which takes into account both the extent and severity of reversible perfusion defects, was calculated to estimate the severity of perfusion abnormalities. Patients with normal scans were at low risk of events (yearly hard event rate 0.5% and soft event rate 0.9%). The rate of outcomes increased significantly with abnormal scans (yearly hard event rate 4.9% and soft event rate 10.3%). Statistical analysis using the Kaplan-Meyer survival curves showed a significant difference in event-free survival between patients with normal and abnormal scans. With use of Cox proportional-hazards analysis, after adjusting for prescan information, nuclear data provided incremental prognostic value for hard events (clinical and exercise data vs nuclear data; chi-square = 15.5 vs 33.4, p

Background. Technetium 99m-labeled myocardial agents have been proposed as an alternative to thallium 201. The aim of this study was to assess retrospectively the accuracy of exercise myocardial 99mTc-tetrofosmin scintigraphy with tomographic imaging (SPECT) in a large group population in the evaluation of coronary artery disease. Furthermore we evaluated the relation between the severity of scintigraphic impaired myocardial perfusion and the angiographic coronary artery stenoses in patients without myocardial infarction and with stenosis localized exclusively in the proximal segment of the 3 main coronary arteries. Methods and Results. The study group consisted of 235 consecutive patients, 204 (87%) of whom were men, with a mean age of 57 ± 10 years, and with suspected or known coronary artery disease, who underwent 99mTc-tetrofosmin SPECT and coronary angiography. Furthermore, 61 patients in a low-likelihood group for coronary artery disease were also studied. Significant disease was defined by ≥50% luminal coronary artery stenosis in ≥1 native coronary artery or major branch or in a saphenous vein graft or arterial mammary graft. The overall sensitivity was 95%, specificity was 76%, and predictive accuracy was 95%. The normalcy rate for the low-likelihood group was 93%. Sensitivity was 71% for the left anterior descending artery, 61% for the left circumflex artery, and 73% for the right coronary artery. Specificity was 94% for the left anterior descending artery, 96% for the left circumflex artery, and 91% for the right coronary artery. Predictive accuracy was 79% for the left anterior descending artery, 78% for the left circumflex artery, and 81% for the right coronary artery. In patients without myocardial infarction linear regression analysis between scintigraphy and angiography showed a significant correlation in patients with severe proximal coronary artery stenosis (r = 0.53, P < .002), but not in those with moderate proximal stenosis (r = 0.31, P = NS). Conclusions. This study shows that 99mTc-tetrofosmin SPECT is accurate in the detection of coronary artery disease. The relation of the severity of scintigraphic impaired myocardial perfusion and angiographic coronary artery stenosis, however, may differ significantly in patients with proximal stenosis of different severity.

Tetrofosmin is a new technetium 99m-labeled myocardial perfusion agent that has demonstrated favorable imaging characteristics in recent clinical trials. However, it is not certain whether 99mTc-tetrofosmin compared with thallium 201 would underestimate myocardial viability in regions with left ventricular dysfunction.To this end 15 patients (mean age 52+/-7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 35%+/-8%) documented on angiography underwent both quantitative rest-redistribution 201Tl and rest 99mTc-tetrofosmin single photon emission computed tomography imaging. RESULTS; Of 240 total segments on rest-redistribution 201Tl protocol 139 (58%) segments had irreversible 201Tl defects. Of these segments 79 (57%) had only mild to moderate reduction of 201Tl uptake (51% to 85% of normal uptake), whereas the remaining 60 (43%) had severely reduced tracer uptake (or = 50% of normal uptake). On 99mTc-tetrofosmin protocol 180 (75%) segments had abnormal 99mTc-tetrofosmin uptake; of these segments 120 (67%) had mild to moderate reduction of 99mTc-tetrofosmin uptake, whereas 60 (33%) had severely reduced activity. Among hypokinetic regions concordance between 201Tl and 99mTc-tetrofosmin regarding myocardial viability with a cutoff point of 50% of peak activity was obtained in 28 (90%) of 31 segments (K' = 0.80), leaving only 3 of 31 regions discordant (p = NS). Similarly, among akinetic or dyskinetic regions concordance between the two tracers regarding myocardial viability was achieved in 54 (93%) regions (K' = 0.75), leaving only 4 of the 58 regions discordant (p = NS).These data show that when the severity of uptake was considered within abnormal segments, a similar amount of 201Tl viable regions were observed by 99mTc-tetrofosmin. Thus these two agents may provide comparable information about myocardial viability when quantitative analysis of defect severity is performed.

Purpose: This multicenter study was carried out to compare the efficacy of intrauterine insemination (IUI) and intraperitoneal insemination (IPI) associated with multiple follicular development as treatment for unexplained infertility. Method: A total of 205 couples completed the trial. Sixty-seven couples underwent treatment with IPI (group A) and 138 couples underwent treatment with IUI (group B). Results: Clinical pregnancy was obtained in 23 couples in group A (pregnancy rate: 34.3%) and in 36 couples in group B (pregnancy rate: 26.1%). No significant difference was observed between group A and group B. As for the evolution of pregnancies and the incidence of twin pregnancies, no significant difference was observed between the two groups. Conclusions: Because IUI and IPI allow us to obtain same results and IPI is more invasive than IUI, the latter technique can be considered the method of choice and IPI should be used when IUI is difficult to perform, as in the presence of a tight cervical canal.

A randomised crossover study was conducted to compare the efficacy and tolerability of amlodipine with that of slow release nifedipine in patients with stable exertional angina. After a 1 -week drug washout phase, 48 patients were treated for 4 weeks with amlodipine (5 to 10mg once daily) or slow release nifedipine (20 to 40mg twice daily) and then crossed over to the alternative regimen; dosages were titrated to response within the dose range allowed. Both drugs were effective in controlling cardiac ischaemia, as evidenced by a reduced incidence of anginal episodes (reported by patients and observed with Holter monitoring) and increased exercise tolerance. From the results of bicycle stress tests, both drugs appeared to reduce myocardial oxygen consumption during dynamic exercise by limiting the increase in heart rate; these findings were also confirmed by heart rate and systolic blood pressure determinations. Patients who received amlodipine during the second treatment phase showed arterial pressures similar to those achieved with slow release nifedipine, but heart rates were lower. In contrast, patients treated with amlodipine during the first phase experienced a further reduction in blood pressure and an increase in heart rate when subsequently treated with nifedipine; however, these results require additional confirmation. The incidence of adverse events was also lower during treatment with amlodipine than with nifedipine. In conclusion, amlodipine has an efficacy and tolerability profile that is at least as good as that of slow release nifedipine in the treatment of patients with stable angina pectoris.