Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors.

INTRODUCTION: Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostatin analogues [SSAs]/dopamine agonists), underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin (MF) or SSAs. METHODS: Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, nonfunctioning pituitary tumors, and PitNET cell-lines (AtT20/GH3-cells). RESULTS: All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GH-releasing hormone-receptor/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects. CONCLUSION: Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs.

Is a second recombinant human thyrotropin stimulation test useful? The value of postsurgical undetectable stimulated thyroglobulin level at the time of remnant ablation on clinical outcome.

OBJECTIVE: The management of patients with differentiated thyroid cancer (DTC) has changed in recent years, and monitoring depends on the risk of persistent/recurrent disease. The objective was to assess the prognostic value of a single stimulated thyroglobulin (Tg) measured at the time of the first radioiodine therapy (Stim-Tg1), and the utility of a second stimulated Tg measurement performed 6-12 months later (Stim-Tg2). We also examined the role of neck ultrasound (US) in the early diagnosis of recurrence. DESIGN: This was a retrospective observational cohort study conducted in a tertiary referral hospital. Of 213 evaluated patients with DTC, 169 were finally included. METHODS: Measurement of Stim-Tg1, Stim-Tg2 and neck US. RESULTS: Stim-Tg1 was undetectable in 71 of 169 patients (42%). All of them (71/71) continued to have negative Stim-Tg2. Seventy of 71 had an excellent response to the first treatment. Sixty-eight of 71 had no evidence of disease after an average follow-up of 7·2 years. In patients with detectable Stim-Tg1 (98/169; 58%), Stim-Tg2 became negative in 40. The negative predictive value (NPV) of Stim-Tg1 was 0·96. The optimal Stim-Tg1 cut-off level for identifying persistence was 3·65 ng/ml. Recurrence was detected in 14 patients. Neck US was useful for identifying local recurrence (13/14; 92·85%). CONCLUSIONS: Stim-Tg1 is a reliable marker with a high NPV. A second stimulation test should be avoided in patients with negative Stim-Tg1. In patients with biochemical persistence, Stim-Tg2 is useful for confirming/ruling out final status. Neck US plays a valuable role in the early diagnosis of recurrence.

Relationship between nutritional treatment compliance and nutritional status improvements in patients with gastrointestinal impairment taking an oral peptide-based supplement.

OBJECTIVES: Compliance in outpatients with gastrointestinal (GI) malabsorption is key in nutritional treatment. The objective of this study was to assess compliance in patients with GI impairment and malnutrition taking a high-calorie, high-protein, peptide-based oral nutritional supplement (ONS-PBD). METHODS: A prospective, multicenter, observational study was conducted in 19 medical sites in Spain where ONS-PBD were prescribed as standard of care. Patients consumed ONS-PBD daily for 12 wk. Compliance was calculated as the percentage consumed of the prescribed amount of ONS per day. RESULTS: A total of 90 adult patients were included in the study, of whom 64 completed the 12-wk regimine. Mean compliance was 78.8% ± 24.5%. Risk of malnutrition decreased in 56.3% of patients at 12 wk, as measured with the malnutrition universal screening tool. A reduction in abdominal pain was observed and stool consistency improved, with a mean of 54.7% and 27.5%, respectively. Improvements in quality of life and a decrease in percentage of patients with severe functional impairment were observed. CONCLUSIONS: These data show that ONS-PBD compliance in malnourished patients with GI symptoms is high, reducing GI symptoms and improving patients' nutritional status.

Health care activity at the endocrinology and nutrition outpatient clinics of Castile-La Mancha (the AACENCAM study). / Actividad asistencial en las consultas de Endocrinología y Nutrición de Castilla-La Mancha (estudio AACENCAM).

INTRODUCTION: This study was promoted by Sociedad Castellano-Manchega de Endocrinología, Nutrición y Diabetes to ascertain the characteristics of patients seen at the outpatient clinics of endocrinology and nutrition of the Castilla-La Mancha Health Authority and the case mix of diagnoses. PATIENTS AND METHODS: This was a retrospective, cross-sectional study of the activity of the endocrinology and nutrition outpatient clinics of public hospitals of Castile-La Mancha during 2018. All visits made on 10% of the working days were analyzed. Data collected comprised patient age and sex, whether a first or subsequent had been made, and whether this was face-to-face or not, and up to five diagnoses per visit. RESULTS: A total of 10,709 visits with a subsequent/first visit ratio of 3.4 were analyzed. Patient age was 52.1 ± 18.2 years, and 67.1% were women. Type 2 diabetes mellitus, primary hypothyroidism, thyroid nodular disease, and obesity/overweight were the most common conditions recorded as first diagnosis, accounting for more than half of the total number of visits. Type 1 diabetes mellitus and thyroid cancer were the diagnoses in which the subsequent/first visit ratio was greater. Type 2 diabetes mellitus, obesity, and primary hypothyroidism accounted for almost half of the first visits. CONCLUSIONS: A wide variety of conditions were seen, some of which are among the most prevalent in the general population, while others are not so prevalent, but are complex and difficult to manage by other specialties. Improved knowledge and analysis of the data should allow for the identification of opportunities for improvement and for the implementation of specific actions.

Health care activity at the endocrinology and nutrition outpatient clinics of Castilla-La Mancha (the AACENCAM study).

INTRODUCTION: This study was promoted by Sociedad Castellano Manchega de Endocrinología, Nutrición y Diabetes to ascertain the characteristics of patients seen at the outpatient clinics of endocrinology and nutrition of the Castilla-La Mancha Health Authority and the case mix of diagnoses. PATIENTS AND METHODS: This was a retrospective, cross-sectional study of the activity of the endocrinology and nutrition outpatient clinics of public hospitals of Castile-La Mancha during 2018. All visits made on 10% of the working days were analyzed. Data collected comprised patient age and sex, whether a first or subsequent had been made, and whether this was face-to-face or not, and up to five diagnoses per visit. RESULTS: A total of 10,709 visits with a subsequent/first visit ratio of 3.4 were analyzed. Patient age was 52.1?±?18.2 years, and 67.1% were women. Type 2 diabetes mellitus, primary hypothyroidism, thyroid nodular disease, and obesity/overweight were the most common conditions recorded as first diagnosis, accounting for more than half of the total number of visits. Type 1 diabetes mellitus and thyroid cancer were the diagnoses in which the subsequent/first visit ratio was greater. Type 2 diabetes mellitus, obesity, and primary hypothyroidism accounted for almost half of the first visits. CONCLUSIONS: A wide variety of conditions were seen, some of which are among the most prevalent in the general population, while others are not so prevalent, but are complex and difficult to manage by other specialties. Improved knowledge and analysis of the data should allow for the identification of opportunities for improvement and for the implementation of specific actions.

Development of an index of complexity for outpatient endocrinology and nutrition clinics. / Desarrollo de un índice de complejidad en consultas externas de Endocrinología y Nutrición.

INTRODUCTION: The tools for analyzing the case-mix in outpatient clinics are scarce few and unsatisfactory. The objective of this study conducted by Sociedad Castellano Manchega de Endocrinología, Nutrición y Diabetes (SCAMEND) was to develop a tool that allows for analyzing the case-mix in outpatient endocrinology and nutrition clinics, considering bearing in mind the complexity of the conditions seen. MATERIAL AND METHODS: Using the Delphi method, the SCAMEND index of complexity in outpatient endocrinology and nutrition clinics (ISCCE-EyN) was developed by endocrinologists in two rounds, comparing the complexity of each condition being compared with that of a review visit of primary hypothyroidism. RESULTS: The first visits were considered more complex than the subsequent visits. Non-neoplastic thyroid disease and uncomplicated overweight/obesity were considered as the least complex diseases, while metabolic diseases, multiple endocrine neoplasia syndromes, and adrenal carcinoma were considered as the most complex. The degree of agreement was high in most of the diseases analyzed. CONCLUSIONS: This tool allows for analyzing the case-mix in outpatient endocrinology and nutrition clinics, based on the inherent complexity of the disease of the patient is reported. This tool may be used for comparisons between centers, to better allocate resources within a given service, or for self-evaluation.

A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.

Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms.

CONTEXT: Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients are resistant or poorly responsive to the main current medical treatments [i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists]. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known. OBJECTIVE: We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion. DESIGN: A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways. RESULTS: Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type-specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms. CONCLUSION: Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.

[Non-oropharyngeal dysphagia with frequent Emergency Room attendance]. / Disfagia no orofaríngea con alta frecuentación en Urgencias.

BACKGROUND: avoidant/restrictive food intake disorder (ARFID) is a new eating disorder category among eating disorders. Its recent incorporation explains the lack of studies evaluating the optimal treatment and follow-up of patients with this disorder. CASE REPORT: we present the case of a 20-year-old patient with 3-week dysphagia and 20% weight loss. After ruling out organic disorders, he was diagnosed with ARFID and required parenteral and tube feeding until the improvement of the eating disorder. DISCUSSION: in this patient, severe caloric malnutrition secondary to the eating disorder made it necessary to turn to the parenteral and enteral approach until the behavioral modification and progressive food exposure were effective. The absence of etiological treatment makes cognitive behavioral intervention, along with the correction of nutritional deficiencies, the preferred approach.

Introducción: el trastorno de evitación/restricción de la ingesta alimentaria es una nueva categoría diagnóstica en el espectro de trastornos de la alimentación. Su reciente aparición explica la falta de estudios que evalúen el tratamiento y seguimiento de pacientes con esta patología.Caso clínico: presentamos el caso de un paciente de 20 años con disfagia de tres semanas de evolución y pérdida del 20% de peso, diagnosticado de trastorno de evitación/restricción de la ingesta alimentaria tras descartar organicidad del proceso, con necesidad de nutrición parenteral y enteral como tratamiento nutricional hasta mejoría clínica.Discusión: en este paciente, la desnutrición calórica grave secundaria al trastorno alimentario hizo necesario recurrir al aporte parenteral y enteral hasta la modificación conductual y la reintroducción paulatina de la alimentación por vía oral. La ausencia de tratamiento etiológico hace que la terapia conductual junto con la corrección de los déficits nutricionales sean la base del manejo.

Disfagia no orofaríngea con alta frecuentación en urgencias / Non-oropharyngeal dysphagia with frequent Emergency Room attendance

Introducción: el trastorno de evitación/restricción de la ingesta alimentaria es una nueva categoría diagnóstica en el espectro de trastornos de la alimentación. Su reciente aparición explica la falta de estudios que evalúen el tratamiento y seguimiento de pacientes con esta patología. Caso clínico: presentamos el caso de un paciente de 20 años con disfagia de tres semanas de evolución y pérdida del 20% de peso, diagnosticado de trastorno de evitación/restricción de la ingesta alimentaria tras descartar organicidad del proceso, con necesidad de nutrición parenteral y enteral como tratamiento nutricional hasta mejoría clínica. Discusión: en este paciente, la desnutrición calórica grave secundaria al trastorno alimentario hizo necesario recurrir al aporte parenteral y enteral hasta la modificación conductual y la reintroducción paulatina de la alimentación por vía oral. La ausencia de tratamiento etiológico hace que la terapia conductual junto con la corrección de los déficits nutricionales sean la base del manejo

Background: avoidant/restrictive food intake disorder (ARFID) is a new eating disorder category among eating disorders. Its recent incorporation explains the lack of studies evaluating the optimal treatment and follow-up of patients with this disorder. Case report: we present the case of a 20-year-old patient with 3-week dysphagia and 20% weight loss. After ruling out organic disorders, he was diagnosed with ARFID and required parenteral and tube feeding until the improvement of the eating disorder. Discussion: in this patient, severe caloric malnutrition secondary to the eating disorder made it necessary to turn to the parenteral and enteral approach until the behavioral modification and progressive food exposure were effective. The absence of etiological treatment makes cognitive behavioral intervention, along with the correction of nutritional deficiencies, the preferred approach

Desarrollo de un índice de complejidad en consultas externas de Endocrinología y Nutrición / Development of an index of complexity for outpatient endocrinology and nutrition clinics

INTRODUCCIÓN: Las herramientas para analizar la casuística en consultas externas son escasas e insatisfactorias. El objetivo de este trabajo de la Sociedad Castellano Manchega de Endocrinología, Nutrición y Diabetes (SCAMEND) fue el desarrollo de una herramienta que permita analizar la casuística de las consultas externas de Endocrinología y Nutrición teniendo en cuenta la complejidad de la patología atendida. MATERIAL Y MÉTODOS: Se definió el Índice SCAMEND de Complejidad en Consultas Externas de Endocrinología y Nutrición (ISCCE-EyN) mediante método Delphi con dos rondas entre especialistas en Endocrinología y Nutrición, comparando la complejidad de cada patología con la de una revisión de hipotiroidismo primario. RESULTADOS: Las primeras visitas fueron consideradas más complejas que las visitas sucesivas. La patología tiroidea no neoplásica y el sobrepeso/obesidad sin complicaciones fueron consideradas las patologías menos complejas, mientras que las metabolopatías, los síndromes de neoplasias endocrinas múltiples y el carcinoma suprarrenal fueron consideradas las más complejas. El grado de consenso fue elevado en la mayoría de las patologías analizadas. CONCLUSIONES: Presentamos una herramienta que permite analizar la casuística de las consultas externas de Endocrinología y Nutrición teniendo en cuenta la complejidad inherente a la patología del paciente atendido. Esta herramienta puede servir para realizar comparaciones entre centros, para asignar mejores recursos dentro de un determinado servicio o para la autoevaluación

INTRODUCTION: The tools for analyzing the case-mix in outpatient clinics are scarce few and unsatisfactory. The objective of this study conducted by Sociedad Castellano Manchega de Endocrinología, Nutrición y Diabetes (SCAMEND) was to develop a tool that allows for analyzing the case-mix in outpatient endocrinology and nutrition clinics, considering bearing in mind the complexity of the conditions seen. MATERIAL AND METHODS: Using the Delphi method, the SCAMEND index of complexity in outpatient endocrinology and nutrition clinics (ISCCE-EyN) was developed by endocrinologists in two rounds, comparing the complexity of each condition being compared with that of a review visit of primary hypothyroidism. RESULTS: The first visits were considered more complex than the subsequent visits. Non-neoplastic thyroid disease and uncomplicated overweight/obesity were considered as the least complex diseases, while metabolic diseases, multiple endocrine neoplasia syndromes, and adrenal carcinoma were considered as the most complex. The degree of agreement was high in most of the diseases analyzed. CONCLUSIONS: This tool allows for analyzing the case-mix in outpatient endocrinology and nutrition clinics, based on the inherent complexity of the disease of the patient is reported. This tool may be used for comparisons between centers, to better allocate resources within a given service, or for self-evaluation