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Appendiceal neoplasms; Carcinoid tumor; Treatment outcome Neoplasias apendiculares; Tumor carcinoide; Resultado del tratamiento Neoplàsies apendiculars; Tumor carcinoide; Resultat del tractament Appendiceal neuroendocrine tumors (aNETs) are an uncommon neoplasm that is relatively indolent in most cases. They are typically diagnosed in younger patients than other neuroendocrine tumors and are often an incidental finding after an appendectomy. Although there are numerous clinical practice guidelines on management of aNETs, there is continues to be a dearth of evidence on optimal treatment. Management of these tumors is stratified according to risk of locoregional and distant metastasis. However, there is a lack of consensus regarding tumors that measure 1-2 cm. In these cases, some histopathological features such as size, tumor grade, presence of lymphovascular invasion, or mesoappendix infiltration must also be considered. Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease, except in the case of tumors smaller than 1 cm without additional risk factors. Somatostatin receptor scintigraphy or positron emission tomography with computed tomography should be considered in cases with suspected residual or distant disease. The main point of controversy is the indication for performing a completion right hemicolectomy after an initial appendectomy, based on the risk of lymph node metastases. The main factor considered is tumor size and 2 cm is the most common threshold for indicating a colectomy. Other factors such as mesoappendix infiltration, lymphovascular invasion, or tumor grade may also be considered. On the other hand, potential complications, and decreased quality of life after a hemicolectomy as well as the lack of evidence on benefits in terms of survival must be taken into consideration. In this review, we present data regarding the current indications, outcomes, and benefits of a colectomy.

A state of chronic inflammation is common in organs affected by autoimmune disorders, such as autoimmune thyroid diseases (AITD). Epithelial cells, such as thyroid follicular cells (TFCs), can experience a total or partial transition to a mesenchymal phenotype under these conditions. One of the major cytokines involved in this phenomenon is transforming growth factor beta (TGF-β), which, at the initial stages of autoimmune disorders, plays an immunosuppressive role. However, at chronic stages, TGF- β contributes to fibrosis and/or transition to mesenchymal phenotypes. The importance of primary cilia (PC) has grown in recent decades as they have been shown to play a key role in cell signaling and maintaining cell structure and function as mechanoreceptors. Deficiencies of PC can trigger epithelial–mesenchymal transition (EMT) and exacerbate autoimmune diseases. A set of EMT markers (E-cadherin, vimentin, α-SMA, and fibronectin) were evaluated in thyroid tissues from AITD patients and controls through RT-qPCR, immunohistochemistry (IHC), and western blot (WB). We established an in vitro TGF-β–stimulation assay in a human thyroid cell line to assess EMT and PC disruption. EMT markers were evaluated in this model using RT-qPCR and WB, and PC was evaluated with a time-course immunofluorescence assay. We found an increased expression of the mesenchymal markers α-SMA and fibronectin in TFCs in the thyroid glands of AITD patients. Furthermore, E-cadherin expression was maintained in these patients compared to the controls. The TGF-β-stimulation assay showed an increase in EMT markers, including vimentin, α-SMA, and fibronectin in thyroid cells, as well as a disruption of PC. The TFCs from the AITD patients experienced a partial transition to a mesenchymal phenotype, preserving epithelial characteristics associated with a disruption in PC, which might contribute to AITD pathogenesis.

Introduction: A small percentage of patients will develop a severe form of COVID-19 caused by SARS-CoV-2 infection. Thus, it is important to predict the potential outcomes identifying early markers of poor prognosis. In this context, we evaluated the association of SARS-CoV-2 infection with lipid abnormalities and their role in prognosis. Methods: Single-center, retrospective, observational study of COVID-19 patients admitted from March to October 2020. Clinical and laboratory data, comorbidities, and treatments for COVID-19 were evaluated. Main outcomes including intensive care unit (ICU) admission and mortality were analyzed with a multivariable Cox proportional hazards regression model. Results: We selected 1489 from a total of 2038 consecutive patients with confirmed COVID-19, who had a complete lipid profile before ICU admission. During the follow-up performed in 1109 patients, we observed a decrease in T-c, HDL-c, and LDL-c in 28.6%, 42.9%, and 30.4% of patients, respectively, and an increase in TG in 76.8%. The decrease of both T-c and HDL- c was correlated with a decrease in albumin levels (r = 0.39 and r = 0.37, respectively). Kaplan–Meier survival curves found an increased ICU admission in patients with lower T-c (HR 0.55, CI 0.36–0.86), HDL-c (HR 0.61, CI 0.45–0.84), and LDL-c (HR 0.85, CI 0.74–0.97). Higher values of T-c (HR 0.45, CI 0.36–0.57), HDL-c (HR 0.66, CI 0.54–0.81), and LDL-c (HR 0.86, CI 0.78–0.94) showed a protective effect on mortality. Conclusions: Abnormalities in lipid profile are a frequent complication of SARS-CoV-2 infection and might be related to morbidity and mortality. Funding: Proyectos de Investigación en Salud (FIS) and cofinanced by FEDER., This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PI16-02091 and PI19-00584 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid) and cofinanced by FEDER funds to M.M. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.

Objectives To evaluate disease activity status using the Acromegaly Disease Activity Tool (ACRODAT®) in a cohort of Spanish acromegaly patients, to assess the relationship between the level of disease activity according to both ACRODAT® and the physicians’ clinical evaluation, and to study the potential discrepancies in the perception of symptoms between physicians and patients. Design Multicenter, observational, descriptive and cross-sectional study. Methods Disease activity was assessed in adult patients with acromegaly under pharmacological treatment during at least 6 months using ACRODAT®. Results According to ACRODAT®, 48.2%, 31.8% and 20.0% of a total of 111 patients were classified as having a stable disease (S), mild disease activity (M-DA) and significant disease activity (S-DA) respectively. ACRODAT® classification of disease activity significantly correlated with physicians’ opinion, with a moderate inter-rater agreement and a specificity of 92.45% (PPV = 86.21%). No correlation was found between IGF-I levels and severity of symptoms or quality of life (QoL). A decision to take clinical action was significantly more frequent in S-DA and M-DA patients than S patients but no action was taken on 5 (22.7%) and 27 (77.1%) S-DA and M-DA patients, respectively Conclusions ACRODAT® detected disease activity in 51.8% of patients. Interestingly, although M-DA and S-DA patients were likely to be in the process of being controlled, action was not always taken on these patients. ACRODAT® is a validated and highly specific tool that may be useful to routinely monitor acromegaly and to identify patients with non-obvious disease activity by incorporating “patient-centred” parameters like symptoms and QoL to the clinical evaluation of acromegaly.

Normocalcemic primary hyperparathyroidism is an entity on which several issues about its clinical management remains unclear. This is reflected in the main current guidelines, where there are no evidence-based specific recommendations. Through an exhaustive review of current literature, a clinical management algorithm for these patients is proposed. We consider the diagnosis criteria, the differential diagnosis, the clinical manifestations, and the treatment indications. When indicated, we also review the preoperative locations techniques and the surgical approach. Finally, when surgical treatment is not indicated, the patient is not a candidate to surgery or refuse surgical management, we review the medical treatment options and the follow-up schemes.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >23 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P P P P SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.

REIPI-SEIMC COVID-19 group and COVID@HULP group., [Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality., [Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model., [Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p, [Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated., [Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

SARS‐CoV‐2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID‐19. We investigated whether the specific immune responses in the peripheral blood of 276 patients associated to severity and progression of COVID‐19. At admission, dramatic lymphopenia of T, B and NK cells associated to severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56‐CD16+ NK‐cells increased. Regarding humoral immunity, levels of IgM, IgA and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID‐19 patients, associating severity with an imbalanced humoral response and identifying new targets for therapeutic intervention., The study was funded by grants SAF2017-82886-R to FS-M from the Ministerio de Economía y Competitividad, and from “La Caixa Banking Foundation” (HR17-00016) to FS-M. Grant PI018/01163 to CMC and grant PI19/00549 to AA were funded by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain. SAF2017-82886-R, PI018/01163 and PI19/00549 grants were also cofunded by European Regional Development Fund, ERDF/FEDER. This work has been funded by grants Fondo Supera COVID (CRUE-Banco de Santander) to FSM, and “Ayuda Covid 2019” from Comunidad de Madrid.

The COVID-19 lockdown clearly affected the lifestyle of the population and entailed changes in their daily habits, which involved potential health consequences, especially on patients with Type 2 Diabetes Mellitus (T2DM). We aimed to examine the impact of the lockdown caused by COVID-19 pandemic on both nutrition and exercise habits, as well as the psychological effects in patients with T2DM, compared to their usual diet and physical activity level previous to the complete home confinement. We also intended to analyse any potential variables that may have influenced these lifestyle modifications. A Food Frequency Questionnaire (FFQ), Physical Activity Questionnaire (IPAQ), Food Craving Questionnaire-State (FCQ-S) and Food Craving Questionnaire-Trait (FCQ-T) were used. Our results showed an increase in vegetable, sugary food and snack consumption. An association between levels of foods cravings and snack consumption was also found. Data also showed a high percentage of physical inactivity before the COVID-19 lockdown, which was exacerbated during the home confinement. These findings emphasise the great importance to do further research with larger study samples to analyse and explore dietary habits and to develop public health policies to promote a healthy lifestyle in terms of diet and physical activity in these patients, especially after this strict period of lockdown, This work was supported by the lab of A.D., which is funded by the Spanish “Agencia Estatal de Investigación” and European FEDER Funds (PID2019-109369RB-I00). The lab of M.M. is funded by PI16-02091 and PI19-00584 (Instituto de Salud Carlos III (ISCIII) and TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), co-financed by FEDER funds

BackgroundSARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the pathogenesis and outcome of COVID-19. We aimed to investigate which specific responses from either cellular or humoral immunity associate to severity and progression of COVID-19.MethodsA cohort of 276 patients classified in mild, moderate and severe, was studied. Peripheral blood lymphocyte subpopulations were quantified by flow cytometry, and immunoglobulins and complement proteins by nephelometry.ResultsAt admission, dramatic lymphopenia of T, B and NK cells associated to severity. However, only the proportion of B cells increased, while T and NK cells appeared unaffected. Accordingly, the number of plasma cells and circulating follicular helper T cells (cTfh) increased, but levels of IgM, IgA and IgG were unaffected. When degrees of severity were considered, IgG was lower in severe patients, suggesting an IgG consumption by complement activation or antibody-dependent cellular cytotoxicity (ADCC). Activated CD56-CD16+ NK-cells, which mediate ADCC, were increased. Regarding complement, C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, compared to healthy donors. Moreover, IgG and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier.ConclusionOur study provides important clues to understand the immune response observed in COVID-19 patients, which is probably related to viral clearance, but also underlies its pathogenesis and severity. This study associates for the first time COVID-19 severity with an imbalanced humoral immune response characterized by excessive consumption of IgG and C4, identifying new targets for therapeutic intervention.

Context T regulatory type 1 (Tr1) cells are a subpopulation of T lymphocytes (CD4+CD49+LAG-3+IL-10+) that exert a considerable immunosuppressive effect. However, their possible role in autoimmune thyroid disease (AITD) has not been explored so far. Purpose To analyze the levels and function of Tr1 cells in peripheral blood and thyroid tissue of patients with AITD. Design Cases and controls, observational study. Setting Department of Endocrinology, Hospital Universitario de la Princesa, Madrid, Spain. Patients Thirty-eight patients with AITD (23 with Graves disease and 15 with Hashimoto thyroiditis) and 26 controls. Intervention Multiparametric flow cytometry and immunofluorescence techniques were used to analyze the levels in peripheral blood (n = 38) and thyroid mononuclear cells (n = 5). An in vitro assay of suppression of cellular activation and cytokine release was performed to study the function of Tr1 cells. Main outcome measure Levels and function of Tr1 cells in patients with AITD and controls. Results Levels of Tr1 cells were significantly diminished in peripheral blood from patients with AITD. Functional studies showed that Tr1 cells from patients with AITD exhibit a diminished suppressive function compared with healthy controls. Tr1 levels were associated with disease severity, including longer duration of the disease and ophthalmopathy activity, and with autoantibody titers. Conclusions The low levels of Tr1 cells and their diminished function may have a relevant role in the defective immune-regulatory function characteristic of patients with AITD.

To study the levels of pathogenic and non-pathogenic Th17 and Th22 cells in autoimmune thyroid disorders patients. Although Th17 cells seem to play an important role in the pathogenesis of thyroid autoimmune disorders, the specific subsets of these lymphocytes have not been analyzed in this condition. We assessed the levels of Th17 (pathogenic and non-pathogenic) and Th22 cells in peripheral blood and thyroid glands of autoimmune thyroid disorders patients (n = 26, 16 with Graves’ disease and 10 with Hashimoto’s thyroiditis) and 15 healthy controls by multi-parametric flow cytometry and immunofluorescence microscopy. We found increased levels of pathogenic Th17 lymphocytes and Th22 cells in peripheral blood from autoimmune thyroid disorders patients. In addition, these cells were detected in thyroid glands from HT patients. Furthermore, we found significant correlations between the levels of these cells and disease activity, disease duration, and the presence of ophthalmopathy. The increased levels of pathogenic Th17 lymphocytes and Th22 cells in autoimmune thyroid disorders suggest their involvement in the pathogenesis of this condition.

Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors., This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PIE13-0041, PI16-02091 and PI19-00584 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), GETNE G1707 and GCI1901 (funded by Grupo Español de Tumores Neuroendocrinos y Endocrinos) and cofinanced by FEDER funds to M.M. Proyectos de Investigación en Salud (FIS) PI19/01316-FEDER (funded by Instituto de Salud Carlos III), given to J.C.T. Grants from the Ministerio de Economia y Competitividad (SAF2016-76815 and SAF2017-90794-REDT), and Fundació La Marato de TV3 (534/C/2016) ceded to J.A.

Immune-mediated inflammatory disorders (IMID) are a group of diseases that present inflammation as a major pathogenic mechanism. They affect 15% of the population and pose a heavy socio-economic burden. Despite the growing knowledge on the etiopathogenesis of these diseases and the marked improvement in their management, there is a lack of predictive markers of IMID development or severity suitable for early diagnosis and adjustment of treatment intensity. The possibility that certain circulating miRNA profiles could be used as biomarkers of risk of development and/or severity of several autoimmune diseases has fuelled the interest in using them to improve the selection of successful treatments. The multi-pronged approach proposed here sought to reveal circulating miRNAs and miRNA signatures that could act as new predictive biomarkers of IMID development and severity. Our results showed that the circulating levels of miR-19b and miR-26b were significantly decreased (p < 0.001) in IMID patients compared to controls. Furthermore, receiver operating characteristic (ROC) curve analysis showed that these miRNAs were suitable discriminators capable to identify an IMID, with areas under the curve (AUC) of 0.85 and 0.83, respectively. In addition, we established that miR-19a and miR-143 were significantly increased in IMID patients with severe disease (p < 0.05). In summary, our findings identify two different miRNA signatures. One of them is associated with the presence of IMIDs and could lead to the development of tools for their early detection. The second signature is able to discriminate between mild and severe forms of these disorders and could be a putative tool to select patient candidates for a more intense treatment., This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PIE13-0041, PI16-02091 and PI19-00584 (funded by Ministerio de Economía y Competitividad (MINECO), Instituto de Salud Carlos III (ISCIII)), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12) to MM; also by grants RD16/0011/0012 and PI18/0371 from MINECO, ISCIII to IGA; PI17/01972 (MINECO, ISCIIII) to E. D; and Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Fundación BBVA a equipos de Investigación Científica 2018 and from “la Caixa Banking Foundation” under the project code HR17-00016 to F·S.M and cofinanced by FEDER funds

Introduction: ACRODAT® (Acromegaly Disease Activity Tool) is a new disease-specific tool intended to assist endocrinologists in evaluating disease activity in patients with acromegaly. ACRODAT® uses five disease-specific parameters (IGF-1, tumor status, comorbidities, symptoms and quality of life) to classify disease activity as stable (S), mild (M-DA), or significant (S-DA). Due to the recent development of the tool, its clinical application has not been studied yet. Aim: This study was aimed to evaluate disease activity status using ACRODAT® in a cohort of Spanish patients with acromegaly. Other secondary objectives were to assess the relationship between patient demographic characteristics and ACRODAT® disease categories; to analyze the correlation between classification of disease activity by ACRODAT® and by physician criteria and to study the potential discrepancies between symptoms perception between physicians and patients. Methodology: Multicenter, observational, descriptive, cross-sectional study in adult patients with acromegaly under pharmacological treatment during at least 6 months. Quality of life (QoL) was determined by the AcroQoL questionnaire. Severity of symptoms was quantified using PASQ questionnaire, fulfilled by patients (paPASQ) and by physicians (phPASQ). ACRODAT® tool was used to assess disease activity entering the data collected in the study. Results: 111 patients were included in the analysis with a mean age of 59.7 years (51.4% women). According to ACRODAT®, 48.2%, 31.8% and 20.0% of patients were classified as S, M-DA and S-DA respectively. Patients with S-DA were younger, had higher IGF-1 levels, worst QoL and less stable treatment than S patients. M-DA patients had higher IGF-1 levels (but lower than S-DA patients), more severe symptoms and worst QoL than S-patients. ACRODAT® classification of disease activity significantly correlated with physicians opinion, with a moderate inter-rater agreement and a specificity of 92.45% (PPV=86.21%). phPASQ significantly correlated with paPASQ with a substantial inter-rater agreement. No correlation was found between IGF-1 levels and PASQ or AcroQoL. Decision taken by physician was significantly more frequent in S-DA patients than S patients, but no action was taken in 5 (22.7%) S-DA patients. Conclusions: ACROVAL® detected disease activity in 51.8% of patients. Interestingly, although S-DA patients were likely to be in the process of being controlled, action was not always taken in these patients. This study demonstrated that ACRODAT® is a validated and highly specific tool that may be useful to identify patients with non-obvious disease activity by incorporating “patient-centered” parameters like PASQ and AcroQoL. 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.

Signaling lymphocytic activation molecule family 1 (SLAMF1) is a costimulatory receptor expressed by most immune cells. Its role in autoimmune thyroid disease (AITD) is not well known.To analyze the expression and function of the costimulatory receptor SLAMF1 in lymphocytes of patients with AITD.Cross-sectional, prospective, single-center study.Department of Endocrinology, Hospital Universitario de la Princesa, Madrid.Twenty-eight patients with AITD (17 with Graves disease and 11 with Hashimoto thyroiditis) and 21 controls.Multiparametric flow cytometry and immunofluorescence techniques to analyze the expression of SLAMF1 in peripheral blood (n = 28) and thyroid tissue (n = 5) mononuclear cells. Assay of inhibition of cellular proliferation to study the function of SLAMF1 in CD4+CD25+ T regulatory (Treg) cells.Expression levels and the function of SLAMF1 in lymphocytes in AITD patients and controls.Expression of SLAMF1 was significantly increased in peripheral blood CD4+, T helper 17, and CD19+ B cells from AITD patients. Immunofluorescence microscopy detected the presence of SLAMF1+ lymphocytes in thyroid inflammatory cell infiltrate. Functional studies showed that SLAMF1 engagement in Treg cells increased their suppressive function in healthy controls but not in AITD patients.The altered expression of SLAMF1, as well as its defective function observed in patients with AITD, may have a relevant role in the defective immune-regulatory function observed in this condition.

[Background] The mechanisms underlying autoimmune thyroid disease (AITD) remain elusive. Identification of such mechanisms would reveal novel and/or better therapeutic targets. Here, we use integrated analysis of miRNAs and mRNAs expression profiling to identify potential therapeutic targets involved in the mechanisms underlying AITD., [Methods] miRNA and mRNA from twenty fresh-frozen thyroid tissues (15 from AITD patients and 5 from healthy controls) were subjected to next-generation sequencing. An anti-correlated method revealed potential pathways and disease targets, including proteins involved in the formation of primary cilia. Thus, we examined the distribution and length of primary cilia in thyroid tissues from AITD and controls using immunofluorescence and scanning electron microscopy, and parsed cilia formation in thyroid cell lines in response to inflammatory stimuli in the presence of miRNA mimics., [Findings] We found that the expression of miR-21-5p, miR-146b-3p, miR-5571-3p and miR-6503-3p was anti-correlated with Enolase 4 (ENO4), in-turned planar cell polarity protein (INTU), kinesin family member 27 (KIF27), parkin co-regulated (PACRG) and serine/threonine kinase 36 (STK36) genes. Functional classification of these miRNA/mRNAs revealed that their differential expression was associated with cilia organization. We demonstrated that the number and length of primary cilia in thyroid tissues was significantly lower in AITD than in control (frequency of follicular ciliated cells in controls = 67.54% vs a mean of 22.74% and 21.61% in HT and GD respectively p = 0.0001, by one-way ANOVA test). In addition, pro-inflammatory cytokines (IFNγ and TNFα) and specific miRNA mimics for the newly identified target genes affected cilia appearance in thyroid cell lines., [Interpretation] Integrated miRNA/gene expression analysis has identified abnormal ciliogenesis as a novel susceptibility pathway that is involved in the pathogenesis of AITD. These results reflect that ciliogenesis plays a relevant role in AITD, and opens research pathways to design therapeutic targets in AITD., This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PIE13-0041 and PI16-02091 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), GETNE G1707 (funded by Grupo Español de Tumores Neuroendocrinos y Endocrinos) and cofinanced by FEDER funds to MM. We also acknowledge the service from the MiNa Laboratory at IMN, and funding from CM (project S2018/NMT-4291 TEC2SPACE), MINECO (project CSIC13-4E-1794) and EU (FEDER, FSE) to M.U.G. The funders had no role in study design, data collection, data analysis, interpretation or writing of the report.

The immune checkpoint based therapy targeting the programmed death-1 (PD-1) receptor and its PD-L1 ligand has recently been approved for the therapy of different malignant conditions, but not yet for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this context, we evaluated the expression of PD-1 and PD-L1 in GEP-NETs and its potential correlations with clinical outcomes. Expression of PD-1/PD-L1 was analyzed by immunohistochemistry in 116 GEP-NETs and 48 samples of peritumoral tissue. In addition, the expression of these molecules was assessed by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with GEP-NETs (n = 32) and healthy controls (n = 32) and in intratumoral mononuclear cells (TMCs) (n = 3). Expression of PD-L1 and PD-1 was detected by immunohistochemistry in 6% and 1% of tumor tissue samples, respectively, and in 8% of peritumoral tissue samples, for both markers. We also observed that PD-1 expression by TMCs was associated with metastatic disease at diagnosis, and the levels of circulating PD-1+ PBMCs were associated with progressive disease upon follow-ups. In addition, circulating PD-1+ PBMCs were significantly correlated with PD-L1 expression by tumor cells. Our data suggest that PD-1/PD-L1 is expressed in 1 to 8% of GEP-NETs, and that this feature is significantly associated with disease evolution (p

Context: Ustekinumab is a human IgG1 monoclonal antibody that targets interleukin (IL)-12 and IL-23, which may be useful in the treatment of autoimmune conditions such as psoriasis, psoriatic arthritis, and Crohn's disease. Hypophysitis is an immune-derived inflammatory condition of the pituitary gland that may lead to pituitary dysfunction. With the increasing use of immunotherapy, it is possible that this and other new immune-related adverse events (IRAEs) arise, although the mechanisms involved are still incompletely defined. Case description: A 35-year-old male, with a previous history of severe plaque-psoriasis who had started treatment with ustekinumab 4 months before, complained of progressive and persistent headache. Brain magnetic resonance imaging (MRI) was unremarkable. One year later, a new MRI was performed due to headache persistence, which revealed a homogenous and diffuse pituitary enlargement, with suprasellar extension and optic chiasm involvement, blurring of the pituitary stalk, absence of clear differentiation between the anterior and posterior lobes, and no signs of hemorrhage or adenomas. Endocrine evaluation was consistent with panhypopituitarism. Work-up of infiltrative and infectious diseases was negative. Follow-up MRI revealed an increase in the pituitary enlargement and transsphenoidal surgery was performed. Pathological findings revealed an intense fibrosis and a chronic inflammatory infiltrate, but no evidence of adenoma, granuloma, or acid fast bacilli. Immunohistochemical staining showed a combined T-cell (CD3+, CD4+) and B-cell (CD19+, CD20+) phenotype. Conclusion: We suggest a novel IRAE of ustekinumab, with full radiological and immunopathological iconography, which may be mediated by the complex interaction between different immunological processes, This work was supported by the grants from the Instituto de Salud Carlos III (Proyectos de Investigacion en Salud (FIS): PIE13-0041 and PI 16-02091) and co-financed by FEDER funds

Context Circulating microRNAs (miRNAs) are emerging as an interesting research area because of their potential role as novel biomarkers and therapeutic targets. Their involvement in autoimmune thyroid diseases (AITDs) has not been fully explored. Objective To compare the expression profile of miRNAs in thyroid tissue from patients with AITD and controls, using next-generation sequencing, further validated our findings in thyroid and serum samples. Design Twenty fresh-frozen thyroid tissues (15 from patients with AITD and 5 from controls) were used for miRNA next-generation sequencing. Thirty-six thyroid samples were recruited for the qRT-PCR validation test and 58 serum samples for further validation in peripheral blood. Results Expression of several miRNAs that had been previously associated with relevant immunological functions was significantly dysregulated. Specifically, eight differentially expressed miRNAs (miR-21-5p, miR-142-3p, miR-146a-5p, miR-146b-5p, miR-155-5p, miR-338-5p, miR-342-5p, and miR-766-3p) were confirmed using qRT-PCR in thyroid samples, and three had the same behavior in tissue and serum samples (miR-21-5p, miR-142-3p, and miR-146a-5p). Furthermore, when the expression of these miRNAs was assessed together with five additional ones previously related to AITD in peripheral blood, the expression of five (miR-Let7d-5p, miR-21-5p, miR-96-5p, miR-142-3p, and miR-301a-3p) was significantly expressed in AITD and, in patients with Graves disease (GD), was correlated with a higher severity of disease, including active ophthalmopathy, goiter, higher antibody titers, and/or higher recurrence rates. Conclusions The present findings identify a serum five-signature miRNA that could be an independent risk factor for developing AITD and a predisposition of a worse clinical picture in patients with GD.

In the era of predictive medicine, management of diseases is evolving into a more personal and individualized approach, as more data are available regarding clinical, biochemical, radiological, molecular, histopathological, and genetic aspects. In the particular setting of acromegaly, which is a rare, chronic, debilitating, and disfiguring disease, an optimized approach deems even more necessary, especially because of an associated increased morbidity and mortality, the impact on patients' quality of life, and the increased cost of frequently necessary life-long treatments. In this paper, we review the available studies that address potential genetic influences on acromegaly, their role in the outcome, and response to treatments, as well as their contribution to the risk of developing side effects. We focus mainly on pharmacogenetic factors involved during treatment with dopamine agonists, somatostatin analogs, and pegvisomant. Specifically, mutations in dopamine receptors, somatostatin receptors, growth hormone receptors, and metabolic pathways involved in growth hormone action; polymorphisms in the insulin-like growth factor and the insulin-like growth factor binding proteins; and polymorphisms in other genes that may determine differences in the frequency of developing adverse events.

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design: We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results: sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions: sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs., This work has received the following grants: Proyectos de Investigación en Salud (FIS) PI13-01414, and PIE-0041 (funded by Instituto de Salud Carlos III) and S2011/BMD-2328 TIRONET (funded by Comunidad de Madrid) (to MM). BIO-0139, CTS-5051, CTS-1406, PI-0369-2012, BFU2010-19300, BFU2013-43282-R, PI13/00651, CIBERobn and Ayuda Merck Serono 2013 (to RML and JPC). Fellowship CTS-5051 (to AIC). “Sara Borrell” program CD11/00276 (to MDG)

In the era of predictive medicine, management of diseases is evolving into a more personal and individualized approach, as more data are available regarding clinical, biochemical, radiological, molecular, histopathological, and genetic aspects. In the particular setting of acromegaly, which is a rare, chronic, debilitating, and disfiguring disease, an optimized approach deems even more necessary, especially because of an associated increased morbidity and mortality, the impact on patients' quality of life, and the increased cost of frequently necessary life-long treatments. In this paper, we review the available studies that address potential genetic influences on acromegaly, their role in the outcome, and response to treatments, as well as their contribution to the risk of developing side effects. We focus mainly on pharmacogenetic factors involved during treatment with dopamine agonists, somatostatin analogs, and pegvisomant. Specifically, mutations in dopamine receptors, somatostatin receptors, growth hormone receptors, and metabolic pathways involved in growth hormone action; polymorphisms in the insulin-like growth factor and the insulin-like growth factor binding proteins; and polymorphisms in other genes that may determine differences in the frequency of developing adverse events.

SummaryBackground Efficacy of the GH-receptor antagonist pegvisomant (PEG) has differed between preclinical and observational studies mainly due to dose adjustment and IGF-I normalization criteria. An escape phenomenon has also been described, but its definition and underlying causes have not been fully established. Objective To re-evaluate the outcomes of long-term PEG in a series of previously published patients and analyse the escape phenomenon. Methods We reviewed all patients with acromegaly resistant to SSA in whom PEG was started as monotherapy, who had been included in a previous publication. We prospectively evaluated 64 (56·3% women) from six tertiary care referral hospitals in Spain, for whom data as of June 2014 were available. Escape to PEG was defined as confirmed loss of biochemical control (IGF-I >1·2xULN), after at least 6 months of previous control with a stable dose of PEG. Results Patients were followed up for 13·0 (5·9–34·8) years since diagnosis, and 9·0 (4·1–10·4) years since the first administration of PEG. Fifty-one (89·5%) patients had an adequate IGF-I control at the last follow-up visit, 9 of them without treatment. Tumour growth was reported in 6 of 64 cases (9·4%), none of whom had received prior radiotherapy (P = 0·011). Seven patients died during follow-up. We found 16 escapes in 10 patients (15·6%). We identified potential underlying causes in 9 cases (tumour regrowth, previous treatment modifications, concomitant menopause and change in testosterone administration). The reason was unknown in 7 escapes, which occurred in 6 patients (9·4%). All patients, except one, achieved subsequent biochemical control after treatment adjustment. Conclusions We reassure the efficacy and safety of long-term PEG. An escape phenomenon may occur, but it can be overcome by adjusting therapy.

Introduction. Pituitary adenomas are the most frequent intracranial tumors. Surgical excision is the primary approach for these tumors, except for prolactinomas, and secondary hypopituitarism is its main complication.Aim: to assess the prevalence of postoperative hypopituitarism and analyze the risk factors involved in its development.Materials and methods. Ambispective multicenter observational study. Data were collected from The Molecular Registry of Pituitary Adenomas (REMAH). Univariate and multivariate analysis were performed in 128 patients with histologically confirmed adenomas who underwent transsphenoidal surgery between 2009 and 2015 in hospitals from Madrid, with more than one-month follow-up.Results. Postoperative hypopituitarism was found in 73.9% of cases (28.4% of new onset). Combined pituitary deficiency was the most frequently observed (46.3%), and hypoadrenalism the most frequent single postsurgical deficit (63.7%). Factors significantly associated with postoperative hypopituitarism in the univariate analysis were: previous hypopituitarism, larger tumor diameter, transsphenoidal endoscopic approach and presence of other postoperative complications (p

Introduction. Pituitary adenomas are the most frequent intracranial tumors of the central nervous system. Except for prolactinomas, surgery is the treatment of choice.Aim: to assess the percentage of patients with persistent disease after surgery and to identify independent predictors of persistent disease.Material and methods. Ambispective multicenter observational study. Data were collected from The Molecular Registry of Pituitary Adenomas (REMAH). Univariate and multivariate analysis were performed in 128 patients with histologically confirmed adenomas who underwent transsphenoidal surgery between 2009 and 2015 in hospitals from Madrid, with at least one month of follow-up.Results. During follow-up, persistent disease was observed in 50.8% of patients (radiological 30.7%, biochemical 2.4%, both 14.2%), especially in nonfunctioning tumors. Factors significantly associated with persistent disease in the univariate analysis were age, male gender, previous hypopituitarism, large tumor diameter and microscopic transsphenoidal surgery (p

Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/ progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value, This work has received the following grants: Proyectos de Investigación en Salud (FIS) PI13–01414, and PIE-0041 (funded by Instituto de Salud Carlos III) and S2011/BMD-2328 TIRONET (funded by Comunidad de Madrid) (to MM). BIO-0139, CTS-1406, PI-0639–2012 (funded by Junta de Andalucía), Proyectos de Investigación en Salud (FIS) PI13–00651 (funded by Instituto de Salud Carlos III), BFU2013–43282-R (funded by Ministerio de Economía y Competitividad), CIBERobn and Ayuda Merck Serono 2013 (to RML and JPC). Fellowship CTS-5051 (to AIC). “Sara Borrell” program CD11/00276 (to MDG)

Cabergoline is an ergot-derived dopamine D2 receptor agonist which may be effective for the medical management of acromegaly. Its efficacy in reducing growth hormone and IGF-I levels, as well as its antiproliferative and pro-apoptotic effects on pituitary tumor cells, has been observed in several studies. Cabergoline may be used alone or as an add-on therapy to patients who are partially resistant to somatostatin analogs (SSA), or who do not achieve complete control with maximum doses of pegvisomant (PEG). Additionally, the convenience of its oral administration, allowing better compliance, and its lower economic cost, in comparison with SSA and PEG, favor cabergoline as an attractive option for acromegalic patients, who frequently require long-life medical treatment to achieve disease control. The few adverse events observed with prolonged DA therapy, mainly regarding cardiac valve disease, are not frequent at the doses generally used in acromegaly.

Introduction. Evaluation of bone quality represents a clinical challenge. Analysis of bone mineral density (BMD) provides useful, but incomplete, information, and new tools are needed. Trabecular Bone Score (TBS) is emerging as a new surrogate marker of bone texture and microarchitecture and, may, therefore, be useful to potentially evaluate the risk of osteoporosis.Materials and methods. Retrospective study of 18 patients with primary hyperparathyroidism. Clinical, analytical and BMD data were collected form clinical records. TBS was calculated by reevaluating the already existing BMD images. Patients were classified into two different groups according to their treatment: 1) 10 patients who underwent surgery, in whom TBS was evaluated before (B-S) and after surgery (A-S), and 2) 8 patients who received standard medical treatment, in whom TBS was evaluated with a time-lapse of one year.Results. Basal age, body mass index (BMI), serum calcium, PTH and vitamin 25-OH-D levels, and T-Scores were not significantly different between the two groups. We observed a significant improvement of TBS one year after surgery in the first group (TBS B-S 1.24±0.13 vs TBS A-S 1.29±0.11,p=0.03). A subtle deterioration on TBS was observed one year after standard treatment in the second group (1.25±0.7 vs 1.22±0.7, p=0.29). Overall, surgical patients experienced a TBS increase 4.2%, whilst a decrease of 1.6% was observed in the second group (p=0.026)Conclusion. Bone microarchitecture, measured by TBS, improves after surgery in patients with primary hyperparathyroidism. This parameter seems promising in the evaluation of bone status in primary hyperparathyroidism. Larger and longer follow-up studies deem necessary to better evaluate the potential utilities of using TBS in the assessment of bone quality.

Introduction Patients with autoimmune thyroid disease (AITD) show defects in their immune-regulatory mechanisms. Herein we assessed the expression and function of galectin-1 and galectin-9 (Gal-1, Gal-9) in dendritic cells (DCs) from patients with AITD. Materials and Methods Peripheral blood samples from 25 patients with Graves’ disease (GD), 11 Hashimoto’s thyroiditis (HT), and 24 healthy subjects were studied. Thyroid tissue samples from 44 patients with AITD and 22 patients with goiter were also analyzed. Expression and function of Gal-1 and Gal-9 was assessed by quantitative RT-PCR, immunofluorescence and flow cytometry. Results A diminished expression of Gal-9, but not of Gal-1, by peripheral blood DCs was observed in GD patients, mainly in those with Graves´ ophthalmopathy, and a significant negative association between disease severity and Gal-9 expression was detected. In addition, the mRNA levels of Gal-9 and its ligand TIM-3 were increased in thyroid tissue from AITD patients and its expression was associated with the levels of Th1/Th12/Th17 cytokines. Immunofluorescence studies proved that intrathyroidal Gal-9 expression was confined to DCs and macrophages. Finally, in vitro functional assays showed that exogenous Gal-9 had a suppressive effect on the release of Th1/Th2/Th17 cytokines by DC/lymphocyte autologous co-cultures from both AITD patients and healthy controls. Conclusions The altered pattern of expression of Gal-9 in peripheral blood DCs from GD patients, its correlation with disease severity as well as its ability to suppress cytokine release suggest that Gal-9 could be involved in the pathogenesis of AITD, This work was supported by grants from the Fondo de Investigaciones Sanitarias (FISS) PI10/ 02521 and S2010/BMD-2328 TIRONET (Comunidad de Madrid), Spain (to MM) and the Fondo de Cooperación Internacional en Ciencia y Tecnología (FONCICYT) 95395, European Union-México (to RGA)