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Purpose: Osteopathy is an emerging complication of acromegaly characterized by increased bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). In somatostatin analog (SSA)- resistant patients (pts), Pegvisomant (PegV) and Pasireotide LAR (Pasi) are used for acromegaly treatment, but their effect on skeletal health is still not defined. Methods: In a longitudinal international multicenter study, we evaluated incidence of radiological VFs in 55 pts (29F/26M), mean age 44.1 yrs (SD: 17) with acromegaly resistant to first line SSA. Results: At the study entry, prevalent VFs (lumbar, thoracic) were identified in 23 pts (41.8%): 42 mild and 3 moderate (Genant score) VF. Mean spine Z-score was -0.4 (-0.6 in PegV, -0.2 in Pasi group, respectively; p=0.49). Biochemical acromegaly control was reached in 22 / 31 pts on Peg-V (71%) and in 16/24 pts on Pasi (66.7%). During the follow-up (mean 89.9 months for PegV group and 50.5 months for Pasi group), incident VFs were detected in 16 pts (29.1%). Occurrence of incident VFs was associated with the presence of pre-existing VFs (p=0.009), persistence of active acromegaly (p=0.009) and with higher median value of serum IGF-I during follow-up (p=0.04). There were no significant differences in age, gender, initial treatment choice and changes in lumbar spine BMD. Incident VFs occurred in 7/9 pts not contolled on Peg-V and 2/8 pts not controlled on Pasi. Among pts with active disease at last visit, incident VFs occurred less frequently in pts on treatment with Pasi (25%) compared to Peg-V (77.8%), p=0.03, independently of the IGF-I values (p=0.9). In pts who reached acromegaly biochemical control, 5/17 (22.7%) on Peg-V and 2/14 (12.5%) pts on Pasi had incident VFs, p=0.4. In pts on Peg-V, factors associated with incident VFs during follow-up were persistence of active acromegaly and higher values of IGF-I (median IGF x ULN: 0.5 IQR:1.8 vs 2.6 IQR: 2.2 p=0.02). In pts treated with Pasi, we did not find any factors associated with incident VFs. Furthermore, in pts with biochemically controlled acromegaly, no factor was associated with incident VFs which occurred less frequently in pts treated with Pasi. Conclusion: Our data confirm that active acromegaly is the main determinant of VFs and show for the first time that pts with biochemically active disease treated with Pasi had lower risk of incident VFs vs those treated with Peg-V. Conversely, no significant drug-related differences in incident VFs in pts with controlled acromegaly were observed. Additional studies on larger populations and with longer follow-up are needed to confirm our data and disclose the mechanisms underlying our findings. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Purpose: Pituitary adenomas are in most of cases benign lesions. However, in around 25% of cases they can show aggressive behavior, such invasiveness of pituitary region surrounding structures, progressive or rapid increase in size or evolvement in pituitary carcinoma. In recent years, 68Ga-peptides and 18F-FDG PET/CT have been applied in the functional assessment of residual pituitary adenomas. Methods: We retrospectively reviewed our series of patients submitted to 68Ga-peptides and/or 18F-FDG PET-CT for evaluating residual pituitary adenomas after primary surgery. Results: Sixteen patients underwent 68Ga-peptides and/or 18F-FDG PET/CT in the period 2012-2018 at our Institution. A total of 15 68Ga-peptides PET/CT scans and 8 18F-FDG PET/CT scans were performed. Fourteen patients had pituitary adenoma, and two pituitary carcinoma. Nine patients were affected by not-secreting (null cell) pituitary adenoma; 3 patients by Cushing disease; 3 patients by acromegaly and a single patients by prolactinoma. All patients underwent partial removal of the pituitary adenoma, as all cases invaded the cavernous sinus. Mean Ki67 was 4% (SD: 3). Positivity at 68Ga-peptides PET/CT was detected in 10 patients. Positivity at 18F-FDG PET/CT was detected in 6 patients. Six patients were submitted to both PET/CT scans: 4 showed concordant results and two were positive only at 68Ga-peptide PET/CT. Nine patients with residual tumor positive at 68Ga-peptides PET/CT were treated with long-acting somatostatin analogues (L-SSA). Progression of the residual adenoma was observed in 9 patients: 6 were positive at 68Ga-peptide PET/CT and 5 were positive at FDG PET/CT. 5 patients were on treatment with L-SSA. Mean follow-up was 37.8 months (DS:30). The only determinant of progression disease was the Ki67: in patients with progression of pituitary adenoma, mean Ki67 was 5% (SD: 3, p=0.05) and in patients with stable disease its mean value was 1.5% (SD:1.5). Conclusion: 68Ga-peptides and 18F-FDG PET/CT can be useful for functional evaluation of residual pituitary adenomas after primary surgery and in scheduling the therapeutic management. In any case, the main determinant of disease progression is represented by the Ki67 index. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Objective Changes in bile flow after bariatric surgery may beneficially modulate secretion of insulin and incretins, leading to diabetes remission. However, the exact mechanism(s) involved is still unclear. Here, we propose an alternative method to investigate the relationship between alterations in physiological bile flow and insulin and incretin secretion by studying changes in gut-pancreatic function in extrahepatic cholestasis in nondiabetic humans. Methods To pursue this aim, 58 nondiabetic patients with recent diagnosis of periampullary tumors underwent an oral glucose tolerance test (OGTT), and a subgroup of 16 patients also underwent 4-hour mixed meal tests and hyperinsulinemic-euglycemic clamps. Results The analysis of the entire cohort revealed a strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as a marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during the OGTT. Altered bile flow elicited a markedly greater increase in glucagon and glucagon-like peptide 1 (GLP-1) secretion at fasting state, and following the meal, both glucagon and GLP-1 levels remained increased over time. Conversely, Glucose-dependent insulinotropic polypeptide (GIP) levels were comparable at the fasting state, whereas the increase following meal ingestion was significantly blunted with high bilirubin levels. We reveal strong correlations between total bilirubin and glucagon and GLP-1 levels. Conclusions Our findings suggest that acute extrahepatic cholestasis determines major impairment in enteroendocrine gut-pancreatic secretory function. The altered bile flow may determine a direct deleterious effect on β-cell function, perhaps mediated by the impairment of incretin hormone function.

Purpose: The testis-sparing surgery (TSS) is surgical technique accepted for small testicular masses (STMs). Frozen section examination (FSE) is an essential assessment at the time of TSS. The aim of this study is to measure the maximum distance of the foci of ITGCN from STMs. Methods: In our hospital between June 2010 and October 2017 a total of 68 patients with STM underwent a TSS. All the testis specimens were totally embedded and processed via the whole-mount method and a diagnosis of germ cell tumor with GCNIS were made. The distance between STMs and GCNIS were calculated by two pathologists directly on the slides considering for the third dimension the number of the paraffin blocks in which the foci of GCNIS were found. Results: The STMs were classic seminoma in 62 out 68 cases, embryonal carcinoma in 4 cases, while in 2 case a diagnose of mixed germ cell tumor were made. The size of the STMs was between 0.5 and 2 cm and the foci of GCNIS were observed in seminiferous tubules very closed to SMTs or as skip lesions in the surrounding testicular parenchyma, dispersed in normal testis. In 48 out of 68 cases (70.5%) foci of GCNIS were at the distance from SMTS of 1.5 cm or below and in 60 out of 68 cases (88%) at the distance of 2 cm or below The distance of GCNIS from the STMs was not related to the histological subtype of the germ cell tumor, while there is a linear correlation between size of the STMs and the distance of foci of GCNIS (p = 0.0105; r = 0.9167). Conclusion: Our data showed that foci of ITGCN were not observed beyond 2.5 cm from the STM. In particular we demonstrated that exist a linear correlation between size of STMs and distance of the foci of GCNIS from STMs (p = 0.0105; r = 0.9167). In conclusion mapping the tissue around the tumor not randomly but in targeted areas could reduce the false negative biopsies of the testis with GCNIS, increasing the radicality of the TSS procedure.

Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans—from the normal state, progressing to insulin resistance to overt T2D—to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.

Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-&alpha, alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs.

The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N-terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.

Problem A significant increased expression/activation of one of the most well-characterized inflammasomes, the NAcht leucine-rich-repeat protein-3 (NALP-3), in the endometrium from idiopathic recurrent pregnancy loss women (RPL) has been previously found by our research group. We therefore, suggested this event as being one of the molecular mechanisms altering endometrial inflammatory status during early pregnancy. In the present research, we attempt to investigate whether molecules with anti-inflammatory activity, alpha-lipoic acid (ALA), and/or myoinositol affect the endometrial NALP-3 expression and activation. Method of study Women with a history of idiopathic RPL (n = 30) were included in the study and compared to a control group (n = 15). Endometrial tissues were collected by hysteroscopy during the mid-luteal phase. RPL women underwent a three-month prescription of tablets containing ALA plus myoinositol (Sinopol® ). After treatment, hysteroscopic biopsies were repeated in RPL patients. Inflammasome expression was evaluated by immunohistochemical and Western blot analysis. NALP-3 activation was studied by quantifying the secretion of both caspase-1 and interleukin (IL)-1s and IL-18 through ELISA. In ex vivo experiments, the effects of each molecule on endometrial inflammasome were studied. Results Sinopol® significantly reduced the RPL endometrial inflammasome expression and activation. ALA, but not myoinositol, significantly reduced the endometrial inflammasome expression and activity. Conclusion Our data suggest a role for ALA on RPL inflammasome. Understanding the mechanisms involved in RPL and the observation that specific molecules are able to interfere with such complex at the endometrium might provide new rational design approaches to a personalized evaluation of endometrial status and, ultimately, a targeted medicine.

Context The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging. Design We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs). Results In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group. Conclusion Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).

Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes.

Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-&beta, levels and enhanced ER-&beta, activity were detected in endometriotic tissues. It is well known that ER-&beta, interacts with components of the cytoplasmic inflammasome-3 (NALP-3), the NALP-3 activation increases interleukin (IL)-1&beta, and IL-18, enhancing cellular adhesion and proliferation. Otherwise, the inhibition of ER-&beta, activity suppresses the ectopic lesions growth. The present study aims to investigate the potential effect of &alpha, lipoic acid (ALA) on NALP-3 and ER-&beta, expression using a western blot analysis, NALP-3-induced cytokines production by ELISA, migration and invasion of immortalized epithelial (12Z) and stromal endometriotic cells (22B) using a 3D culture invasion assay, and matrix-metalloprotease (MMPs) activity using gelatin zymography. ALA significantly reduces ER-&beta, NALP-3 protein expression/activity and the secretion of IL-1&beta, and IL-18 in both 12Z and 22B cells. ALA treatment reduces cellular adhesion and invasion via a lower expression of adhesion molecules and MMPs activities. These results provide convincing evidence that ALA might inhibit endometriosis progression.

Somatostatin analogs (SSAs), which were initially used to control hormonal syndromes associated with neuroendocrine neoplasms (NENs), have been successfully proposed as antiproliferative agents, able to control tumor growth in patients affected by gastroenteropancreatic (GEP)-NENs. The development of long-acting formulations of SSAs which require only weekly or monthly injections can improve patient compliance. In particular, lanreotide (LAN) Autogel®, which is a viscous aqueous formulation supplied in ready-to-use prefilled syringes, can be administered every 28-56 days. Since its introduction in the clinical practice, several studies evaluated the clinical utility of LAN Autogel in the medical treatment of GEP-NENs. Although there is no evidence of an overall survival benefit, these studies confirm the efficacy of LAN Autogel in terms of benefit in progression-free survival, and in more than half of cases, a reduction of tumor markers can be observed during treatment with this drug. Moreover, LAN Autogel is widely recognized to be effective in controlling tumor-related symptoms in the majority of patients affected by GEP tumors, especially in patients affected by carcinoid syndrome, improving considerably patients' quality of life.

BACKGROUND Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) represents a challenge for the diagnosis and management of thyroid carcinoma. Some authors have proposed histological criteria that are able to distinguish NIFTPs from invasive follicular variant of papillary thyroid carcinoma (I-FVPTC). Hence, NIFTPs may have repercussions in the diagnostic categories on fine-needle aspiration. In the current study, the authors evaluated the criteria for NIFTPs on liquid-based cytology samples. METHODS The authors recorded all 61 liquid-based cytology samples proved to be histological FVPTC between January 2013 and March 2016 and analyzed the architectural, cytoplasmic, and nuclear parameters. They compared them with a cohort of 40 PTC cases and 20 follicular adenoma cases. RESULTS The authors reported 37 NIFTP cases and 24 I-FVPTC cases at histology. The cytological diagnoses of follicular nodules in the NIFTP cases were twice those found in the I-FVPTC cases (54.1% vs 29.2%). The number of positive for malignancy cases among the NIFTPs were approximately half those of I-FVPTC cases. When compared with I-FVPTCs, 70% of the NIFTP cases demonstrated a nuclear size .05). A predominant microfollicular pattern was recognized in both NIFTPs and I-FVPTCs (97.3% vs 100%). CONCLUSIONS The majority of NIFTPs appear to be devoid of nuclear pseudoinclusions and papillary structures, thereby allowing the inclusion in the follicular nodule cases. Nuclear size and microfollicular clusters may suggest the discrimination between NIFTPs and I-FVPCs. Cancer Cytopathol 2016. © 2016 American Cancer Society.

The main goals of the symposium entitled “Thyroid Fine-Needle Aspiration: New Classifications and New Interpretations” are the presentation and discussion of the thyroid fine-needle aspiration terminologies most commonly used, an analysis of their respective advantages and limitations, and a statement of how ancillary techniques could reduce the number of indeterminate cases.

The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors.

In Diabetes Mellitus the loss of capacity to regulate immunity, the reduction of pulmonary functions and the pro-thrombotic state determine the severity of COVID-19.

Prostate cancer (PCa) is a sex-steroid hormone-dependent cancer in which estrogens play a critical role in both initiation and progression. Recently, several long non-coding RNAs (lncRNAs) have been associated with PCa and are supposedly playing a pivotal role in the biology and progression of this type of cancer. In this review, we focused on some lncRNAs that are known for their androgen and estrogen transcriptional responsiveness in PCa. Specifically, we summarized recent pieces of evidence about lncRNAs NEAT1, H19, MALAT1, and HOTAIR, in estrogen signaling, emphasizing their role in PCa progression and the acquisition of a castration-resistant phenotype. Here, the reader will find information about lncRNAs present in estrogen-dependent transcriptional complexes. The potential role of lncRNA/estrogen signaling as a novel pathway for PCa treatment will be discussed.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.

In recent years, extended scientific works shed light on the important role played by the endometrium in early pregnancy. This review examines our current knowledge about the delicate balance between microbial and cellular immune agents at endometrial level: All of them might affect endometrial receptivity. In contrast to the classical thinking of human endometrium as a sterile tissue, several recent studies have drawn attention to a resident population of microorganisms, which reaches only a 30% of concordance with those of the cervical-vaginal flora. At present, the understanding of the microbiome in relation to human reproduction is in its infancy and further studies are needed to clarify the activity of endometrial microbiome and the possible effects of a "reproductive tract dysbiosis" on fertility. Moreover, in the human endometrium, there is a complex system works preventing the risk of infection as well as enabling, when pregnancy occurs, the acceptance of the blastocyst. In this way, the endometrium plays a central role in the uterine immune surveillance. A better understanding of the different agents that may affect endometrial receptivity would improve the diagnosis and treatment of obstetric complications related to defective implantation and placentation.

INTRODUCTION Several authors have underlined the limits of morphological analysis mostly in the diagnosis of follicular neoplasms (FN). The application of ancillary techniques, including immunocytochemistry (ICC) and molecular testing, contributes to a better definition of the risk of malignancy (ROM) and management of FN. According to literature, the application of models, including the evaluation of ICC, somatic mutations (ie, BRAFV600E ), micro RNA analysis is proposed for FNs. This study discusses the validation of a diagnostic algorithm in FN with a special focus on the role of morphology then followed by ancillary techniques. METHODS From June 2014 to January 2016, we enrolled 37 FNs with histological follow-up. In the same reference period, 20 benign nodules and 20 positive for malignancy were selected as control. ICC, BRAFV600E mutation and miR-375 were carried out on LBC. RESULTS The 37 FNs included 14 atypia of undetermined significance/follicular lesion of undetermined significance and 23 FN. Specifically, atypia of undetermined significance/follicular lesion of undetermined significance resulted in three goitres, 10 follicular adenomas and one NIFTP whereas FN/suspicious for FN by seven follicular adenomas and 16 malignancies (nine non-invasive follicular thyroid neoplasms with papillary-like nuclear features, two invasive follicular variant of papillary thyroid carcinoma [PTC] and five PTC). The 20 positive for malignancy samples included two invasive follicular variant of PTC, 16 PTCs and two medullary carcinomas. The morphological features of BRAFV600E mutation (nuclear features of PTC and moderate/abundant eosinophilic cytoplasms) were associated with 100% ROM. In the wild type cases, ROM was 83.3% in presence of a concordant positive ICC panel whilst significantly lower (10.5%) in a negative concordant ICC. High expression values of MirR-375 provided 100% ROM. CONCLUSIONS The adoption of an algorithm might represent the best choice for the correct diagnosis of FNs. The morphological detection of BRAFV600E represents the first step for the identification of malignant FNs. A significant reduction of unnecessary thyroidectomies is the goal of this application.

Male accessory gland infection/inflammation (MAGI) is a frequent disease, mostly with a chronic course, involving 1 or more sexual accessory glands. Majority of the MAGIs remain asymptomatic, thereby leading to a dilemma whether to treat these patients or not. It is moreover noteworthy that the diagnosis of MAGI is difficult, since patients are frequently asymptomatic and semen samples or prostatic secretions are often free from bacteria. As a consequence the identification of novel and reliable markers of inflammation in seminal plasma is an open challenge. If leukocytospermia and polymorphonuclear elastase and the analysis of the secretory products of male accessory glands have been widely used in the past, their diagnostic significance is discussed. Some cytokines (IL-6 and IL-8) and protein markers (suPAR) have been reported in the last years as the most promising markers for the diagnosis and the follow-up of MAGI. Recent advances in proteomic techniques undoubtedly represent a real promise in the future for the identification of novel markers of MAGI. This article provides an overview of key seminal biomarkers of MAGI, including the novel perspectives of the putative markers deriving by the most recent proteomic approaches.

The original version of the article contained an error in the results section of the Abstract. The vertebral fractures (VFs) odds ratio is incorrectly published as 61.0 and the correct value is 6.10.

Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field. The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

A large body of evidence recently highlighted the involvement of long non-coding RNAs (lncRNAs) in cardiovascular disease [1] and some dysregulated lncRNAs have been associated with diabetic cardiomyopathy [2, 3, 4, 5]. Among them, a higher expression of the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been observed in diabetic cardiomyopathy [6, 7]. However, a clear understanding of the molecular mechanisms leading to pathological regulation of lncRNAs in diabetic cardiomyopathy is still missing. Our prior work by Barbati et al. [8], established that, in the presence of high glucose, nitric oxide (NO) signaling derangement might alter the epigenetic landscape of cardiac cells, both in vitro and in vivo, via transcription factor CREM activation. Aim The present study is aimed at investigating the role of high glucose (HG) and NO pathway in the regulation of MALAT1 in the heart of mice after 6 months of prolonged hyperglycemia and in two cellular models of cardiomyocytes exposed to HG.

Thyroid ultrasonography (US) is the gold standard for thyroid imaging and its widespread use is due to an optimal spatial resolution for superficial anatomic structures, a low cost and the lack of health risks. Thyroid US is a pivotal tool for the diagnosis and follow-up of autoimmune thyroid diseases, for assessing nodule size and echostructure and defining the risk of malignancy in thyroid nodules. The main limitation of US is the poor reproducibility, due to the variable experience of the operators and the different performance and settings of the equipments. Aim of this consensus statement is to standardize the report of thyroid US through the definition of common minimum requirements and a correct terminology. US patterns of autoimmune thyroid diseases are defined. US signs of malignancy in thyroid nodules are classified and scored in each nodule. We also propose a simplified nodule risk stratification, based on the predictive value of each US sign, classified and scored according to the strength of association with malignancy, but also to the estimated reproducibility among different operators. © 2018, Italian Society of Endocrinology (SIE).

Purpose: Acromegalic osteopathy is an emerging complication of acromegaly characterized by increase in bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). Somatostatin receptor ligands (SRLs) and pegvisomant (PegV) are used for treatment of acromegaly and there is evidence that both drugs may exert direct effects on peripheral targets regardless of biochemical control of disease. However, whether or not SRLs and PegV may directly influence skeletal health its is unknown. Methods: In this longitudinal study, we evaluated the incidence of radiological VFs in 83 patients (48 females, 35 males; median age 47 years, range 18–80 years) who were treated with SRLs alone (42 cases), PegV alone (6 cases) or in combination with SRLs (35 cases) for median period of 82 months (range 36–126). PegV was given when acromegaly was not controlled by SRLs alone. Results: During the follow-up, 29 patients (34.9%) developed incident VFs. In patients receiving PegV due to active disease during SRL therapy, incidence of VFs decreased significantly from 43.9 to 26.8% (p = 0.039). When acromegaly was controlled by PegV, the incidence of VFs was slightly but not significantly lower as compared to that observed in patients with biochemical control of disease by SRLs (10.0 vs. 26.7%; p = 0.09). In the multivariate logistic regression analysis, incident VFs were independently predicted by pre-existing VFs (odds ratio 61.0; p = 0.009), duration of active acromegaly (odds ratio 1.01; p = 0.05) and mean serum IGF-I during the follow-up (odds ratio 5.26; p = 0.03), regardless of the therapeutic regimen (odds ratio 1.05; p = 0.94). Conclusions: PegV and SRLs had comparable effects on VF risk in acromegaly. The activity of disease was the main determinant of VFs independently of the drug used to control acromegaly.

Nucleoporin 153 (Nup153), key regulator of nuclear import/export, has been recently associated to oncogenic properties in pancreatic and breast tumour cells modulating either cell motility and migration or gene expression by chromatin association. In the present work, we have characterized the role of Nup153 in a cellular model of prostate cancer (PCa). The analysis of several immortalized cell lines derived from freshly explants of prostate cancer specimens showed that Nup153 protein was higher and present in multimeric complexes with eNOS and ERbeta as compared to normal/hyperplastic prostate epithelial cells. This phenomenon was enhanced in the presence of 17beta-estradiol (E2, 10-7M). Further experiments revealed that eNOS and ERbeta were present in a DNA binding complexes associated with Nup153 promoter as demonstrated by ChIPs. Notably, after Nup153 depletion (siNup153), a reduction of migration capacity and colony formation in primary tumor-derived and metastatic PCa cells was observed. In addition, eNOS and ERbeta nuclear localization was lost upon siNup 153 regardless of E2 treatment, suggesting that Nup153 is a key regulator of prostate cancer cell function and of the nuclear translocation of these proteins in response to hormone stimulus. Taken altogether our findings indicate that in PCa cells: i. the expression and function of Nup153 is modulated by estrogen signaling; ii. Nup153 contributes to cell migration and proliferation; iii. Nup153 regulates the nuclear translocation of eNOS and ERbeta by forming a multimeric complex. Our findings unveil Nup153 as a novel component of the estrogen-dependent multimeric complex, thus representing a potential therapeutic candidate in prostate cancer.

The original version of this article unfortunately contained a mistake in Figure 1. There is a typo in the word "osteoclastogenesis" and the word "activity" is missing in the same entity. It should be "osteoclastogenesis" instead of "osteoclestogenesis".

Adrenal incidentalomas constitute a common clinical problem with an overall prevalence of around 2-3%, but are more common with advancing age being present in 10% of those aged 70 years. The majority of these lesions are benign adrenocortical adenomas (80%), characterized in 10-40% of the cases by autonomous cortisol hypersecretion, and in 1-10% by aldosterone hypersecretion. Several observational studies have shown that autonomous cortisol and aldosterone hypersecretion are more prevalent than expected in patients with osteopenia and osteoporosis: these patients have accelerated bone loss and an increased incidence of vertebral fractures. In contrast to glucocorticoid action, the effects of aldosterone on bone are less well understood. Recent data, demonstrating a concomitant co-secretion of glucocorticoid metabolites in patients with primary aldosteronism, could explain some of the metabolic abnormalities seen in patients with aldosterone hypersecretion. In clinical practice, patients with unexplained osteoporosis, particularly when associated with other features such as impaired glucose tolerance or hypertension, should be investigated for the possible presence of autonomous cortisol or aldosterone secretion due to an adrenal adenoma. Randomized intervention studies are needed, however, to investigate the optimum interventions for osteoporosis and other co-morbidities in these patients.

Purpose: The aim of this study was to generate immortalized human anterior pituitary adenoma cells. Reliable cell models for the study of human pituitary adenomas are as yet lacking and studies performed so far used repeated passaging of freshly excised adenomas, with the attendant limitations due to limited survival in culture, early senescence, and poor reproducibility. Methods Results: We devised a technique based upon repeated co-transfections of two retroviral vectors, one carrying the catalytic subunit of human telomerase, hTERT, the other SV40 large T antigen. This approach extended the lifespan of cells derived from a human growth hormone-secreting adenoma up to 18 months while retaining morphology of primary cells, growth hormone synthesis and growth hormone secretion. Conclusions: Our attempt represents the first demonstration of successful lifespan extension of human growth hormone-secreting pituitary adenoma cells via co-transfection of hTERT and SV40T and paves the way to future attempts to obtain stable cell lines.

Objective The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes. Methods Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI > 25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet + either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic-euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention. Results Body weight in both groups decreased significantly (−7.5% in the vitamin D group and −10% in the placebo group; P

Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function. Cancer Res; 75(21); 4560–72. ©2015 AACR.

Objective In fine needle aspiration cytology (FNAC), the category of benign thyroid lesions (BTL), which constitutes 65–70% of all thyroid FNAC, and can be correctly diagnosed by morphology alone, is an important entity. A diagnosis of BTL denotes a lesion managed with follow-up unless found in conjunction with compressive symptoms. Although this diagnosis can be quite simple, there are cases in which the scant cellular or colloid component may pose diagnostic issues. Herein, we describe the experiences of evaluating BTL at two large academic institutions. We evaluated the clinical importance of a correct diagnosis of BTL to define the exact inherent risk of a false-negative result (FNR). Methods From January 2008 through to June 2013, 506 (3.6%) out of 15 850 patients with BTL underwent surgery. All nodules were sampled under sonographic guidance (US) and processed either with liquid-based cytology (LBC), Diff-Quik® smears or alcohol-Papanicolaou staining methods. Results The histological follow-up of 506 BTL series included 493 benign and 13 malignant lesions. The latter group included four follicular carcinomas (FC), two classic variants of papillary thyroid carcinoma (PTC), one macrofollicular PTC and six follicular variants of PTC (FVPC). The malignancy rate for the BTL category was 2.5%. Conclusions When diagnosed by expert cytopathologists, BTL represents a robust diagnosis and might reduce the number of FNR. Additional diagnostic experience and a large case series could enable cytopathologists to recognise all the morphological entities of BTL. An important additional aid is the extensive sampling of the lesions to reduce issues related to a low cellularity.

BACKGROUND Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAFV600E) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAFV600E represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle-shaped nuclei) anti-BRAFV600E antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC). METHODS Between January 2013 and June 2014, there were 150 cytologic samples with surgical follow-up at the authors' institution. BRAF mutations, which were identified using liquid-based cytology, were classified into wild-type BRAF, BRAFV600E, and uncommon BRAF mutations. All clinicopathologic correlations between BRAF and FVPCs were analyzed. RESULTS Forty-four of 150 samples were identified as benign histologic lesions, and the authors focused on the 106 cytologic samples from patients who had malignant outcomes (60 PTCs and 46 FVPCs). The series included 16 follicular neoplasms, 36 samples diagnosed as suspicious of malignancy, and 54 samples diagnosed as positive for malignancy. The BRAFV600E mutation was detected in 17.4% of FVPCs and in 66.6% of PTCs, whereas uncommon BRAF mutations were detected only in FVPCs. Plump pink cells and VE1 expression were not identified in samples that had uncommon BRAF mutations. VE1 immunocytochemistry yielded positive results in all 36 samples that had the BRAFV600E mutation. CONCLUSIONS Uncommon BRAF mutations were observed only in FVPCs and were linked to less aggressive behavior. Negative/weak VE1 expression was observed in both wild-type and uncommon BRAF mutations. The current investigation did not reveal any plump cells or morphologic BRAF findings in samples that had uncommon BRAF mutations. In the authors' experience, BRAF mutations detected by DNA methods were more accurate in identifying FVPCs. Cancer (Cancer Cytopathol) 2015;123:593–602. © 2015 American Cancer Society.

Well-differentiated carcinoma (WDC) accounts for up to 90% of all thyroid cancers. The presence of a minor poorly differentiated (PD) component (mainly insular pattern) might represent an additional critical parameter for patients' prognosis and outcome. The role of both CXCR4 (a chemokine inducing cytoskeletal rearrangement and cell adhesion) and BRAF mutation have been studied in WDC (mainly papillary thyroid cancer and its variants), highlighting their critical role in tumor progression, local infiltration, and metastases. We discussed the clonal heterogeneity through the prognostic role of CXCR4 and BRAF mutation in WDC with a minor PD/insular component. Of our 16 WDC cases with a PD/insular component, up to 40% underwent surgery. The cases were subclassified according to the PD percentage as (1)

The current approach for calculating the starting dose of levothyroxine (LT4) after total thyroidectomy is based on the patient's body weight (BW). The aim of the study was to identify the major predictive factors of LT4 requirement and to elaborate a new method to improve the accuracy of the LT4 starting dose after total thyroidectomy.The study consists of two parts. The first part consisted of the retrospective identification of 92 adult patients (retrospective cohort) who had undergone a total thyroidectomy for benign disease and who had begun LT4 treatment at a dose of 1.6 μg/kg/day. Adjustments to optimize the LT4 dose were then performed at the post-surgery follow-up on the basis of serum thyrotropin (TSH) levels. The results of this retrospective analysis were used to formulate a nomogram for a proper calculation of the LT4 starting dose that was then used prospectively in the second part of the study on 31 consecutive patients (prospective cohort).At the first follow-up, 37 (40%) patients from the retrospective cohort were euthyroid. Univariate analysis indicated significant correlations between the optimal dose of LT4 and BW, body mass index (BMI), age, preoperative mean corpuscular volume, and free triiodothyronine (fT3). The optimal dose of LT4, analyzed for BMI and age, showed an inverse relationship with these two parameters, and ranged from 1.4 to 1.8 μg/kg/day. In the prospective cohort, the use of an age- and BMI-related nomogram improved the prediction of the optimal LT4 starting dose, with 68% of patients being euthyroid at the first follow-up compared to 41% of patients reported to have reached euthyroid state using the best strategy proposed in the literature.This study confirms that BW is not the only variable for predicting LT4 requirement, as it decreases with the increase in age and BMI, probably due to the relative decrease of lean body mass. A new correlation between optimal dose and presurgical levels of fT3 and mean corpuscular volume was observed. We propose an easy and more efficient method of calculating LT4 starting dose after total thyroidectomy for benign disease.

Objective To study the efficacy of low-dose SKA Progesterone and IL-10 in modulating the inflammatory pathway in endometriosis. Design Experimental basic science study. Setting Reproductive biology laboratory. Models Immortalized human endometriotic epithelial cells (12Z) derived from active red peritoneal lesions, immortalized human endometriotic stromal cells (22B) derived from active red peritoneal lesions and immortalized human endometrial cell line T-Hesc (ATCC collection). Methods Cells were treated with SKA-Progesterone and SKA-IL10 at low doses (10 pg/ml and 10 fg/ml respectively). Medroxyprogesterone 17-acetate (MPA) was used at a dose of 10 μM as reference treatment. Main outcome measure(s) Modulation of HSD17B1 levels by WB analysis after low-dose SKA Progesterone and MPA; Modulation of IKBα protein levels and NF-kB p65 nuclear levels by WB analysis after low-dose SKA-Progesterone, low-dose SKA-IL10, low-dose SKA-Progesterone and low-dose SKA-IL10 (combined treatment), MPA. Results Low-dose SKA Progesterone was effective in the inhibition of HSD17B1 expression in endometriotic epithelial (12Z) and stromal (22B) cell lines. Low-dose of SKA Progesterone and low-dose of SKA-IL10 inhibit NF-kB p65 nuclear localization and DNA binding in endometriotic epithelial (12Z) cells, stromal (22B) cells line and in endometrial cell line T-Hesc. The combined treatment showed an additive effect, namely increasing the inhibition of nuclear localization of NF-kB p65 and DNA binding as result of single treatments. Conclusion Our data suggest that the use of a combination of low-dose SKA Progesterone and IL-10 may represent an opportunity for the development of new therapies in the clinical management of endometriosis.

Chronic glucocorticoid (GC) treatment represents a widely-prescribed therapy for several diseases in consideration of both anti-inflammatory and immunosuppressive activity but, if used at high doses for prolonged periods, it can determine the systemic effects characteristic of Cushing’s syndrome. In addition to signs and symptoms of hypercortisolism, patients on chronic GC therapy are at risk to develop tertiary adrenal insufficiency after the reduction or the withdrawal of corticosteroids or during acute stress. This effect is mediated by the negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis, which mainly involves corticotropin-release hormone (CRH), which represents the most important driver of adrenocorticotropic hormone (ACTH) release. In fact, after withdrawal of chronic GC treatment, reactivation of CRH secretion is a necessary prerequisite for the recovery of the HPA axis. In addition to the well-known factors which regulate the degree of inhibition of the HPA during synthetic GC therapy (type of compound, method of administration, cumulative dose, duration of the treatment, concomitant drugs which can increase the bioavailability of GCs), there is a considerable variation in individual physiology, probably related to different genetic profiles which regulate GC receptor activity. This may represent an interesting basis for possible future research fields.