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2.
EBioMedicine ; 50: 329-342, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735554

RESUMO

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. FUNDING: Instituto de Salud Carlos III, Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Ministerio de Economía y Empresa and FEDER.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31606735

RESUMO

OBJECTIVE: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. PARTICIPANTS: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based Consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. CONSENSUS PROCESS: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. CONCLUSIONS: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

4.
Endocrine ; 66(3): 650-659, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31473918

RESUMO

OBJECTIVE: To study the differences in the cardiometabolic profile between patients with non-functioning adrenal incidentalomas (NFAI) and incidentalomas with autonomous cortisol secretion (ACS). METHODS: A total of 149 patients with adrenal incidentalomas were retrospectively evaluated and followed-up for a mean time of 34.6 months at Departments of Endocrinology and Metabolic Diseases Units of four tertiary Spanish hospitals. Patients were grouped as NFAI or ACS adenomas based on two cutoffs in the dexamethasone suppression test (DST): 3.0 µg/dl (NFAIDST3 or ACSDST3) and 1.8 µg/dl (ACSDST1.8 and NFAIDST1.8). RESULTS: The mean age of both groups was 62.0 (10.31) and was similar in ACS and NFAI. The prevalence of diabetes, high blood pressure, cardiovascular, and cerebrovascular disease was higher in ACS than in NFAI, but differences only reached statistical significance for cerebrovascular disease using the 3.0 µg/dl cutoff (15.8% vs 2.3%, p = 0.01) and for diabetes using the 1.8 µg/dl cutoff (38.0% vs 22.0%, p = 0.04). No differences were found in the prevalence of dyslipidemia. The prevalence of obesity was lower in patients with ACS than in NFAI 26.3% vs 39.2%, p = 0.18 (NFAIDST3 vs ACSDST3) and 32.1% vs 40.6%, p = 0.56 (ACSDST1.8 vs NFAIDST1.8), but the differences did not reach statistical significance. Maximum adenoma diameter (R-squared = 0.15, p < 0.001) and cerebrovascular disease (OR = 1.59, p = 0.04) were the only parameters that could be predicted by the DST. The DST was an inadequate predictor of clinical (systolic and diastolic blood pressure, body mass index), hormonal (DHEAS, ACTH, UFC, and basal serum cortisol), biochemical (glucose, cholesterol, LDL, HDL, and triglycerides), and other radiological (laterality, lipid content) parameters. Throughout the follow-up, patients did not develop overt Cushing's Syndrome; three NFAIDST3 developed ACSDST3, eight NFAIDST1.8 developed ACSDST1.8, and one NFAIDST1.8 progressed to ACSDST3. In both groups (NFAI and ACS) the metabolic profile remained stable. CONCLUSIONS: Our data suggest higher prevalence of diabetes and cerebrovascular disease in ACS patients compared with NFAI. However, probably because of the small sample size, the differences only reached statistical significance using the cutoffs of 1.8 µg/dl for diabetes and 3.0 µg/dl for cerebrovascular disease. Patients with ACS and NFAI rarely progress to more aggressive forms of hypercortisolism, and the metabolic profile usually remains stable during the follow-up.

5.
J Clin Oncol ; 37(28): 2571-2580, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390276

RESUMO

PURPOSE: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS: We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS: We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION: The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30930848

RESUMO

Patients with acromegaly frequently develop cardiovascular comorbidities, which significantly affect their morbidity and contribute to an increased all-cause mortality. In this regard, the most frequent complications that these patients may encounter include hypertension, cardiomyopathy, heart valve disease, arrhythmias, atherosclerosis, and coronary artery disease. The specific underlying mechanisms involved in the pathophysiology of these comorbidities are not always fully understood, but uncontrolled GH/IGF-I excess, age, prolonged disease duration, and coexistence of other cardio-vascular risk factors have been identified as significant influencing predisposing factors. It is important that clinicians bear in mind the potential development of cardiovascular comorbidities in acromegalic patients, in order to promptly tackle them, and avoid the progression of cardiac abnormalities. In many cases, this approach may be performed using straightforward screening tools, which will guide us for further diagnosis and management of cardiovascular complications. This article focuses on those cardiovascular comorbidities that are most frequently encountered in acromegalic patients, describes their pathophysiology, and suggests some recommendations for an early and optimal diagnosis, management and treatment.

7.
Endocrine ; 64(1): 1-13, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30847651

RESUMO

Adrenal incidentalomas (AI) are one of the most frequent reasons for consultation in Endocrinology, as they are present in 3-10% of the general population. Up to 20% of them may have autonomous cortisol secretion (ACS), a term that refers to AI carriers with biochemical evidence of excess cortisol, but without the "specific" clinical signs of Cushing's syndrome. As ACS is associated with an increased risk of diabetes, obesity, high blood pressure (HBP), osteoporosis, cardiovascular events, and global mortality; its correct identification is of great importance. There are different laboratory assays to detect ACS, but all of them have some limitations. The dexamethasone suppression test is the most accepted for screening. However, there is no consensus on the cutoff point that should be used. Low levels of ACTH and DHEA-S and high urinary free cortisol are also associated with ACS, but in isolation they are of little value to establish the diagnosis. Considering its clinical implications and the lack of consensus in the diagnosis and in which is the most appropriate management of these patients, this review offers a quick reference guide of ACS, presenting an exhaustive review of the topic: its definition, epidemiology, diagnosis, clinical implications, treatment, and follow-up.

8.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(1): 26-34, ene. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-175790

RESUMO

Background: Nivolumab is an anti-cancer monoclonal antibody that inhibits PD1 and modulates T-cell response. It has been shown to significantly improve survival in several types of cancer, but clinical trials have also reported an increased risk of developing immune-related adverse events (IRAEs). Endocrine IRAEs may be particularly relevant. Objective: To comprehensively evaluate the clinical presentation of endocrine IRAEs in patients with lung cancer treated with nivolumab. Potential risk factors are analyzed, and strategies for IRAE management are proposed. Methods: Forty consecutive patients treated with nivolumab for advanced non-small cell lung cancer (NSCLC) were studied, paying particular attention to development of endocrine IRAEs (thyroid, hypophyseal, adrenal, or pancreatic) and clinical outcome. Results: Thyroid function changes were found in 9 patients (22.5%), of which six developed hypothyroidism and three had hyperthyroidism after a median of 3.8 and 2.3 cycles of nivolumab respectively. Only one patient had thyroid-related symptoms. Thyroid autoimmunity was negative in all cases. Hyperthyroid patients showed no uptake in iodine scintigraphy, and their hormone values returned to normal in less than six months. Nivolumab was discontinued for toxicity in one patient. One patient with hyperthyroidism also developed autoimmune diabetes, and one patient with hypothyroidism also had hypogonadism. After a median follow-up of 7.6 months, 25 patients (62.5%) showed response to nivolumab. Univariate and multivariate analyses showed no differences between patients who developed thyroid changes and those who did not. Conclusions: Thyroid changes after treatment with nivolumab are common and warrant active laboratory monitoring. The underlying mechanisms and their relevance deserve further research


Introducción: Nivolumab es un anticuerpo monoclonal que ejerce acción anti-tumoral mediante la inhibición de PD1 y modulación de la respuesta de las células T. Ha demostrado un aumento significativo en la supervivencia de distintos tipos de cáncer, pero también se ha reportado un incremento en el riesgo de desarrollar eventos adversos relacionados con la inmunidad (IRAEs). Los IRAEs endocrinos son particularmente relevantes. Objetivos: Evaluar de forma detallada la presentación clínica de los IRAEs endocrinos en pacientes con cáncer de pulmón refractario tratados con nivolumab. Se analizan potenciales factores de riesgo y se proponen estrategias para su manejo. Material y métodos: Se estudiaron 40 pacientes consecutivos con cáncer de pulmón de células no pequeñas (NSCLC) tratados con nivolumab. Se realizó el seguimiento prestando especial atención al desarrollo de los IRAEs endocrinos (tiroides, hipófisis, adrenal o páncreas) y su evolución clínica. Resultados: Se detectaron alteraciones de la función tiroidea en 9 casos (22,5%): 6 hipotiroidismo y 3 hipertiroidismo, tras una mediana de 3,8 y 2,3 ciclos de nivolumab, respectivamente. Solo un paciente desarrolló síntomas relacionados. La autoinmunidad tiroidea fue negativa en todos los casos. La gammagrafía fue negativa en todos los casos de hipertiroidismo y los valores hormonales volvieron a la normalidad en menos de 6 meses. Se suspendió nivolumab en un caso debido a toxicidad. Uno de los pacientes con hipertiroidismo también desarrolló diabetes autoinmune, y uno de los pacientes con hipotiroidismo también presentaba hipogonadismo. Tras una mediana de seguimiento de 7,6 meses, 25 pacientes (62,5%) presentaron respuesta favorable al nivolumab. El análisis uni y multivariante no mostró diferencias entre los pacientes que desarrollaron alteraciones tiroideas y los que no. Conclusiones: Las alteraciones tiroideas tras el tratamiento con nivolumab son frecuentes y requieren una vigilancia activa. Los mecanismos subyacentes y su relevancia aún no se conocen en profundidad


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Glândula Tireoide/fisiopatologia , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glândula Tireoide , Fatores de Risco , Doenças Autoimunes/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/complicações , Tireoidite Autoimune
9.
Minerva Endocrinol ; 44(2): 169-175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30531695

RESUMO

Acromegaly is a chronic disorder usually diagnosed late in the disease evolution, leading to substantial morbidity and mortality related to this long period of undiagnosed state as well as the difficulty in achieving normalization of GH hypersecretion and controlling tumor mass. First generation somatostatin analogues (SSA) are accepted as the first-line medical therapy or as second-line therapy in patients undergoing unsuccessful surgery. However, because a high percentage of patients experience SSA treatment failure, the inclusion of biomarkers associated with a successful or non-successful response to these drug (as well as to all classes of medical therapy) is necessary to better guide the choice of treatment, potentially allowing for a quicker achievement of disease control. The current treatment algorithms for acromegaly are based upon a "trial and error" approach with additional treatment options provided when disease is not controlled. In many other diseases, their therapeutic algorithms have been evolving towards personalizing treatment with medication that best matches individual disease characteristics, using biomarkers that identify therapeutic response, thus allowing the personalization of the therapy. It is time to introduce this approach to acromegaly treatment algorithms. This paper reviews the potential tools for doing so.


Assuntos
Acromegalia/tratamento farmacológico , Medicina de Precisão , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Padrões de Prática Médica
10.
Endocrinol Diabetes Nutr ; 66(1): 26-34, 2019 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29910159

RESUMO

BACKGROUND: Nivolumab is an anti-cancer monoclonal antibody that inhibits PD1 and modulates T-cell response. It has been shown to significantly improve survival in several types of cancer, but clinical trials have also reported an increased risk of developing immune-related adverse events (IRAEs). Endocrine IRAEs may be particularly relevant. OBJECTIVE: To comprehensively evaluate the clinical presentation of endocrine IRAEs in patients with lung cancer treated with nivolumab. Potential risk factors are analyzed, and strategies for IRAE management are proposed. METHODS: Forty consecutive patients treated with nivolumab for advanced non-small cell lung cancer (NSCLC) were studied, paying particular attention to development of endocrine IRAEs (thyroid, hypophyseal, adrenal, or pancreatic) and clinical outcome. RESULTS: Thyroid function changes were found in 9 patients (22.5%), of which six developed hypothyroidism and three had hyperthyroidism after a median of 3.8 and 2.3 cycles of nivolumab respectively. Only one patient had thyroid-related symptoms. Thyroid autoimmunity was negative in all cases. Hyperthyroid patients showed no uptake in iodine scintigraphy, and their hormone values returned to normal in less than six months. Nivolumab was discontinued for toxicity in one patient. One patient with hyperthyroidism also developed autoimmune diabetes, and one patient with hypothyroidism also had hypogonadism. After a median follow-up of 7.6 months, 25 patients (62.5%) showed response to nivolumab. Univariate and multivariate analyses showed no differences between patients who developed thyroid changes and those who did not. CONCLUSIONS: Thyroid changes after treatment with nivolumab are common and warrant active laboratory monitoring. The underlying mechanisms and their relevance deserve further research.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
11.
Sci Rep ; 8(1): 17812, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546030

RESUMO

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 < 0.01).


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais , Proteínas de Neoplasias/biossíntese , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Receptor de Morte Celular Programada 1/biossíntese , Neoplasias Gástricas , Adulto , Idoso , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
12.
Cancer Treat Rev ; 70: 209-222, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30292979

RESUMO

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms regarding their molecular biology, clinical behaviour, prognosis and response to therapy. Several attempts to establish robust predictive biomarkers have failed. Neither tissue markers nor blood borne ones have proven to be successful yet. Circulating tumour cells (CTCs) as "liquid biopsies" could provide prognostic information at the time a therapeutic decision needs to be made and could be an attractive tool for tumour monitoring throughout the treatment period. However, "liquid biopsies" are far from becoming the standard biomarker in NETs. Promising results have been presented over the last few years using a novel biomarker candidate, a multianalyte algorithm analysis PCR-based test (NETest). New technologies will open the field to different ways of approaching the biomarker conundrum in NETs. However, the complications derived from being a heterogeneous group of malignancies will remain with us forever. In summary, there is an unmet need to incorporate new biomarker candidates into clinical research trials to obtain a robust prospective validation under the most demanding scenario.


Assuntos
Algoritmos , Biomarcadores Tumorais/análise , Células Neoplásicas Circulantes/patologia , Tumores Neuroendócrinos/patologia , Receptores de Peptídeos/química , Serotonina/metabolismo , Somatostatina/análogos & derivados , Humanos , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/efeitos da radiação , Tumores Neuroendócrinos/terapia , Compostos Radiofarmacêuticos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Somatostatina/uso terapêutico
13.
Endocrinol. diabetes nutr. (Ed. impr.) ; 65(8): 428-437, oct. 2018.
Artigo em Espanhol | IBECS | ID: ibc-176283

RESUMO

Objetivos: Buscar consenso sobre cuestiones que pueden generar dudas en el manejo de la acromegalia en España. Método: Grupos nominales y Delphi. Se seleccionaron 4 expertos que definieron cuestiones relevantes en el manejo de la acromegalia sobre las que se formularon distintas aseveraciones y recomendaciones. Posteriormente, se eligió un grupo de 30 expertos adicionales con el que se determinó el grado de acuerdo con las mismas en 2 rondas Delphi. Se establecieron las siguientes categorías de respuesta: 1) totalmente en desacuerdo; 2) básicamente en desacuerdo; 3) básicamente de acuerdo; y 4) totalmente de acuerdo. Se definió acuerdo si, en la segunda ronda Delphi≥70% de las respuestas estaban en las categorías 1 y 2 (consenso con el desacuerdo) o 3 y 4 (consenso con el acuerdo). Resultados: Se generaron aseveraciones y recomendaciones sobre diversos aspectos de la práctica clínica incluyendo: 1) instrumentos de utilidad en la individualización del tratamiento (marcadores predictivos de respuesta, técnicas de imagen, etc.); 2) perfiles clínicos y comorbilidades en la individualización del tratamiento; 3) papel del paciente en la toma de decisiones terapéuticas; y 4) acceso al tratamiento (accesibilidad y equidad). La primera ronda Delphi incluyó 35 aseveraciones, en 6 se alcanzó consenso, 2 fueron eliminadas y 2 reformuladas. En la segunda se incluyeron 27 y se alcanzó consenso en 24 (22 en el acuerdo, 2 en el desacuerdo) y 3 se eliminaron. Conclusiones: Este documento pretende resolver algunos interrogantes clínicos habituales y facilitar la toma de decisiones en el manejo de la acromegalia


Objectives: To seek a consensus on issues that may generate doubts in management of acromegaly in Spain. Method: Nominal groups and Delphi. Four experts defined relevant issues in management of acromegaly and generated different assertions and recommendations. Subsequently, a group of 30 additional experts was selected to test agreement with the assertions through two Delphi rounds. The following response categories were established: 1) Totally disagree; 2) Basically disagree; 3) Basically agree; 4) Totally agree. Agreement was defined as ≥70% of answers in categories 1 and 2 (consensus with the disagreement) or 3 and 4 (consensus with the agreement) in the second Delphi round. Results: Assertions covers various aspects of clinical practice, including: 1) Useful instruments in individualization of treatment (response predictive markers, imaging techniques, etc.); 2) Clinical profiles and relevant comorbidities in treatment individualization; 3) Role of patient in treatment decision-making; 4) Access to treatments (accessibility and equity). The first Delphi round included 35 assertions. Consensus was reached on six of these assertions, two were eliminated, and two were reformulated. Of the 27 assertions included in the second round, consensus was reached on 24 (22 in the agreement, two in the disagreement) and three were eliminated. Conclusions: This document is intended to solve some common clinical questions and to facilitate decision making in the management of patients with acromegaly


Assuntos
Humanos , Acromegalia/tratamento farmacológico , Tomada de Decisão Clínica , Somatostatina/uso terapêutico , Acromegalia/fisiopatologia , Biomarcadores , Comorbidade , Participação do Paciente , Pesquisa Qualitativa , Conferências de Consenso como Assunto
14.
Endocrinol Diabetes Nutr ; 65(8): 428-437, 2018 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30244765

RESUMO

OBJECTIVES: To seek a consensus on issues that may generate doubts in management of acromegaly in Spain. METHOD: Nominal groups and Delphi. Four experts defined relevant issues in management of acromegaly and generated different assertions and recommendations. Subsequently, a group of 30 additional experts was selected to test agreement with the assertions through two Delphi rounds. The following response categories were established: 1) Totally disagree; 2) Basically disagree; 3) Basically agree; 4) Totally agree. Agreement was defined as ≥70% of answers in categories 1 and 2 (consensus with the disagreement) or 3 and 4 (consensus with the agreement) in the second Delphi round. RESULTS: Assertions covers various aspects of clinical practice, including: 1) Useful instruments in individualization of treatment (response predictive markers, imaging techniques, etc.); 2) Clinical profiles and relevant comorbidities in treatment individualization; 3) Role of patient in treatment decision-making; 4) Access to treatments (accessibility and equity). The first Delphi round included 35 assertions. Consensus was reached on six of these assertions, two were eliminated, and two were reformulated. Of the 27 assertions included in the second round, consensus was reached on 24 (22 in the agreement, two in the disagreement) and three were eliminated. CONCLUSIONS: This document is intended to solve some common clinical questions and to facilitate decision making in the management of patients with acromegaly.


Assuntos
Acromegalia/terapia , Acromegalia/complicações , Técnica Delfos , Humanos , Guias de Prática Clínica como Assunto , Medicina de Precisão
15.
Eur J Endocrinol ; 179(5): D15-D25, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30139823

RESUMO

Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients' treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the Aryl hydrocarbon receptor interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.


Assuntos
Agonistas de Dopamina/uso terapêutico , Hipófise/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Receptores Dopaminérgicos/metabolismo , Receptores de Somatostatina/metabolismo , Agonistas de Dopamina/administração & dosagem , Humanos , Hipófise/efeitos dos fármacos , Neoplasias Hipofisárias/metabolismo
16.
J Clin Endocrinol Metab ; 103(9): 3359-3367, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982465

RESUMO

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.


Assuntos
Doença de Graves/sangue , Doença de Hashimoto/sangue , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Tireoidite Autoimune/sangue , Adulto , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Imunofluorescência , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Glândula Tireoide/imunologia , Tireoidite Autoimune/imunologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-29593650

RESUMO

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.

18.
Endocrine ; 60(2): 203-218, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29417370

RESUMO

Adult-onset growth-hormone (GH) deficiency (GHD) is a rare disorder, which most commonly results from pituitary or peripituitary tumors and their treatment, and is characterized by alterations in body composition, carbohydrate and lipid metabolism, bone mineral density, cardiovascular risk profile and quality of life, all of which may contribute to an increased morbidity and mortality. Since recombinant human GH (rhGH) became available in 1985, several studies have provided evidence of its beneficial effects, despite the potential risk of developing adverse effects, and much clinical experience has been accumulated. However, in adults, the precise therapeutic role of GH replacement therapy and the individual response to it remains highly variable and is still a matter of debate. In this article, we present a critical review of the available evidence on rhGH replacement therapy in GHD adults, emphasizing the pitfalls clinicians encounter in the diagnosis of GHD and monitoring of rhGH replacement therapy. We will cover all the relevant aspects regarding the potential usefulness of GH treatment, including the hot topic of mortality.


Assuntos
Hormônio do Crescimento/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Doenças da Hipófise/tratamento farmacológico , Idade de Início , Biomarcadores , Humanos , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/mortalidade , Resultado do Tratamento
19.
Oncologist ; 23(4): 422-432, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29330208

RESUMO

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs. SUBJECTS, MATERIALS, AND METHODS: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3. RESULTS: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%). CONCLUSION: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index. IMPLICATIONS FOR PRACTICE: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.


Assuntos
Carcinoma Neuroendócrino/classificação , Carcinoma Neuroendócrino/patologia , Neoplasias Intestinais/classificação , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/patologia , Sistema de Registros/estatística & dados numéricos , Neoplasias Gástricas/classificação , Neoplasias Gástricas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/mortalidade , Diferenciação Celular , Criança , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/mortalidade , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Espanha , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Organização Mundial da Saúde , Adulto Jovem
20.
J Clin Endocrinol Metab ; 103(3): 1139-1150, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325052

RESUMO

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.


Assuntos
MicroRNAs/análise , Índice de Gravidade de Doença , Glândula Tireoide/metabolismo , Tireoidite Autoimune/genética , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Doença de Graves/genética , Doença de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Glândula Tireoide/patologia , Tireoidite Autoimune/patologia
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