Utility of circulating serum miRNA profiles to evaluate the potential risk and severity of immune-mediated inflammatory disorders.

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.

Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach?

Obesity and its associated comorbidities entail a significantly increased cardiovascular mortality. Therefore, approaching obesity control must include among its aims the reduction of the associated comorbidities and the higher cardiovascular mortality risk and not only weight loss. Many observational studies indicate that bariatric surgery (BS) is associated with a better long-term survival than standard care. Furthermore, in general, these epidemiological studies included patients who underwent gastric bypass (GB), not biliopancreatic diversion/duodenal switch (BPD/DS), so the potential additional benefit of this latter technique remains unknown. In this regard, in theory, derivative techniques are usually associated to a higher rate of long-term improvement of metabolic comorbidities, so their potential impact on cardiovascular morbidity and mortality could be even greater than what has been published up to date. In 2007, our group proposed a simplification of the bariatric technique based on the duodenal switch, which we termed "single anastomosis duodeno-ileal bypass with sleeve gastrectomy" or SADI-S. In this review, and 10 years later, we describe some of the main results of those patients who underwent this procedure, specifically regarding their outcome on metabolic comorbidities and cardiovascular risk. Considering the findings presented in this review, in which a significant improvement of all metabolic comorbidities was observed, we may confidently suggest that SADI-S seems comparable to a BPD/DS procedure in the mid-term outcome. After all, the SADI-S procedure was conceived as a simplified version of the BPD/DS technique and not necessarily intended to maximize the improvement of cardiovascular and metabolic comorbidities, which is already sufficiently optimal. In this regard, in our experience, we have encountered a new satisfactory result, which combines more pros than cons. In fact, as we have seen, after a follow-up of 3 years, the outcomes of weight loss and improvement of blood pressure, lipid profile, and insulin resistance seem to be better with SADI-S than with Roux-en-Y gastric bypass (RYGB), and this difference may be probably still relevant in the long-term evaluation. SUMMARY: Mid-term follow-up of patients who underwent SADI-S has proven that this procedure seems, at least, as effective as other malabsorptive techniques such as BPD/DS and significantly reduces the four main cardiovascular risk factors to a higher extent than RYGB. One of the main advantages inherent to this intervention modality is that it truly simplifies any of the prior derivative procedures and that it may be specifically adapted and individualized to each patient, according to his BMI and associated metabolic comorbidities.

Long-term treatment with pegvisomant for acromegaly: a 10-year experience.

BACKGROUND: 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.

Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy.

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance. Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed. Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

A Simplified Screening Model to Predict the Risk of Gestational Diabetes Mellitus in Caucasian and Latin American Pregnant Women.

The pathophysiology of gestational diabetes mellitus (GDM) comprises clinical and genetic factors. In fact, GDM is associated with several single nucleotide polymorphisms (SNPs). This study aimed to build a prediction model of GDM combining clinical and genetic risk factors. A total of 1588 pregnant women from the San Carlos Cohort participated in the present study, including 1069 (67.3%) Caucasian (CAU) and 519 (32.7%) Latin American (LAT) individuals, and 255 (16.1%) had GDM. The incidence of GDM was similar in both groups (16.1% CAU and 16.0% LAT). Genotyping was performed via IPLEX Mass ARRAY PCR, selecting 110 SNPs based on literature references. SNPs showing the strongest likelihood of developing GDM were rs10830963, rs7651090, and rs1371614 in CAU and rs1387153 and rs9368222 in LAT. Clinical variables, including age, pre-pregnancy body mass index, and fasting plasma glucose (FPG) at 12 gestational weeks, predicted the risk of GDM (AUC 0.648, 95% CI 0.601-0.695 in CAU; AUC 0.688, 95% CI 0.628-9.748 in LAT), and adding SNPs modestly improved prediction (AUC 0.722, 95%CI 0.680-0.764 in CAU; AUC 0.769, 95% CI 0.711-0.826 in LAT). In conclusion, adding genetic variants enhanced the prediction model of GDM risk in CAU and LAT pregnant women.

Early Mediterranean-Based Nutritional Intervention Reduces the Rate of Gestational Diabetes in Overweight and Obese Pregnant Women: A Post-Hoc Analysis of the San Carlos Gestational Prevention Study.

Obesity is a risk factor for the development of gestational diabetes mellitus (GDM). However, the most optimal type of nutritional intervention to prevent GDM in high-risk women is not clearly defined. This study investigates if nutritional treatment based on the Mediterranean diet (MedDiet) before the 12th gestational week (GW) in women at high risk due to a body mass index (BMI) ≥ 25 kg/m2 reduces the rate of GDM and metabolic syndrome (MetS) at 3 years postpartum. We performed a post-hoc analysis of the San Carlos Gestational Prevention Study. A total of 735 women with BMI ≥ 25 kg/m2 were evaluated between 2015 and 2018, with 246 in the standard diet control group (CG) and 489 in the MedDiet intervention group (IG). The rate of GDM was significantly lower in IG compared to CG (25.1% vs. 31.7%), relative risk (95% confidence interval), and 0.89 (0.78-0.99); p = 0.037. Postnatal follow-up was completed by 141 women in CG (57%) and 312 women in IG (64%). At 3 years postpartum, we observed a reduction in the rates of impaired fasting glucose (IFG) (0.51 (0.28-0.92); p = 0.019), obesity (0.51 (0.28-0.92); p = 0.041), waist circumference (WC) ≥ 89.5 cm (0.54 (0.31-0.94); p = 0.022), and MetS (0.56 (0.33-0.94); p = 0.003). MedDiet reduces the rate of GDM and postpartum MetS in women with BMI) ≥ 25 kg/m2, suggesting that its implementation should be routinely recommended from the first GWs.

Which criteria should be used to define type 2 diabetes remission after bariatric surgery?

BACKGROUND: Comparison of diabetes remission rates after bariatric surgery using two different models of criteria. METHODS: Retrospective analysis of data from 110 patients with type 2 diabetes and morbid obesity who underwent bariatric surgery, preoperatively and at 18-month follow-up. Comparison of two models of remission: 1) 2009 consensus statement criteria; 2) simple criteria using ADA's HbA1c diabetes diagnostic cut-off values. RESULTS: Patients' mean ± SD preoperative characteristics were: age 53.3 ± 9.5 years, BMI 43.6 ± 5.5 kg/m(2), HbA1c 7.9 ± 1.8%, duration of diabetes 7.6 ± 7.5 years. 44.5% of patients with previous insulin therapy. With 2009 consensus statement criteria: complete, partial and no remission in 50%, 12.7% and 37.3%, respectively; with HbA1c criteria: 50%, 15% and 34.5% in the analogous categories (p=0.673). CONCLUSIONS: We suggest a simpler approach to evaluate diabetes remission after bariatric surgery, following the rationale of the definition of diabetes itself.

Cognitive dysfunction in patients with primary adrenal insufficiency: A systematic review.

Addison's disease (AD) entails a chronic insufficient production of gluco- and mineralocorticoids. Fatigue and decreased quality of life are frequently reported symptoms, but little is known about its effects on cognition. This study aims to explore the existence of cognitive impairment in patients with AD and the influence of treatment regimens. We conducted a systematic review. Inclusion criteria were met by 10 articles, most of them ranked as intermediate quality. Three studies analyzed the relationship between AD and cognitive impairment; one explored the effect of delaying treatment showing no effect on cognitive performance, and another one studied the effect of fludrocortisone treatment. Episodic memory was the most frequent cognitive domain impaired across studies, in comparison to healthy controls. Two papers investigated the relationship between impaired sleep quality and poor cognitive performance. Two studies related cognitive impairments with hypocortisolism-derived brain neuroglycopenia. Two studies investigated the effect of DHEA substitution. In conclusion, patients exhibit a moderately reduced performance in verbal learning. The pathophysiology of this impairment is likely multifactorial. Future studies should include larger sample sizes, the use of comprehensive and multi-domain neuropsychological and behavioral protocols, and neuroimaging.

Impact of Treatment with GLP1 Receptor Agonists, Liraglutide 3.0 mg and Semaglutide 1.0 mg, While on a Waiting List for Bariatric Surgery.

BACKGROUND: Weight loss before undergoing metabolic and bariatric surgery (MBS) has been suggested to reduce perioperative complications, although with controversial results. The objective of this study is to evaluate the impact of treatment with GLP1-R agonists (liraglutide 3.0 mg and semaglutide 1.0 mg) on preoperative weight loss and patients' decisions regarding MBS while on a surgical waiting list. MATERIALS AND METHODS: One hundred and two patients on a waiting list for MBS started treatment with GLP1-RA for at least 6 months. Changes in weight at 26 and 52 weeks, the number of patients achieving >5% weight loss, and patients' decisions regarding MBS were evaluated. RESULTS: After 52 weeks, patients lost 16.9 ± 7.2% of weight with semaglutide 1.0 mg and 16.1 ± 5.8% of weight with liraglutide 3.0 mg. All patients lost ≥5% of initial weight, 84.7% lost ≥10%, 54.6% lost ≥15%, and 27.5% reached ≥20%. A total of 68.6% of participants were satisfied with the achieved weight loss and withdrew from the waiting list for MBS. A threshold of >15.1% weight loss had the greatest sensitivity and specificity for the final decision regarding undergoing MBS. CONCLUSIONS: Losing >15% of initial weight after 52 weeks of treatment with liraglutide 3.0 mg or semaglutide 1.0 mg during the waiting list for MBS impacts patients' decisions regarding the final acceptance or rejection of the procedure.

Mixed Meal Tolerance Test Versus Continuous Glucose Monitoring for an Effective Diagnosis of Persistent Post-Bariatric Hypoglycemia.

Gastric bypass determines an increase in incretin secretion and glucose excursions throughout the day and may sometimes entail the development of severe post-bariatric hypoglycemia (PBH). However, there is no consensus on the gold standard method for its diagnosis. In this study, we evaluated the usefulness of a mixed meal tolerance test (MMTT) and continuous glucose monitoring (CGM) for the diagnosis of PBH, defined as glucose levels <54 mg/dL (3.0 mmol/L). We found that hypoglycemia occurred in 60% of patients after the MMTT and in 75% during CGM, and it was predominantly asymptomatic. The MMTT confirmed the diagnosis of PBH in 88.9%of patients in whom surgery had been performed more than three years ago, in comparison to 36.4% in cases with a shorter postsurgical duration. CGM diagnosed nocturnal asymptomatic hypoglycemia in 70% of patients, and daytime postprandial hypoglycemia in 25% of cases. The mean duration of asymptomatic hypoglycemia was more than 30 min a day. Patients with ≥2% of their CGM readings with hypoglycemia exhibited a higher degree of glucose variability than those with <1% of the time in hypoglycemia. Our results show that the MMTT may be a useful dynamic test to confirm the occurrence of hypoglycemia in a large number of patients with persistent and recurrent PBH during long-term follow-up after gastric bypass. CGM, on its part, helps identify hypoglycemia in the real-world setting, especially nocturnal asymptomatic hypoglycemia, bringing to light that PBH is not always postprandial.

Axonal neuropathy, long limbs and bumpy tongue: think of MEN2B.

INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. METHODS: A 14-year-old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot-Marie-Tooth syndrome). RESULTS: Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. CONCLUSIONS: Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis.

Seasonality of month of birth in patients with autoimmune endocrine diseases: A systematic review.

BACKGROUND: Exposure to seasonal environmental factors during gestation or early in the postnatal period could influence the development of autoimmunity, determining a seasonality in the month of birth (MOB). There are studies evaluating this potential seasonality in patients with type 1 diabetes (T1D), autoimmune thyroid diseases (AITD), and Addison's disease (ADD), but results have been controversial. METHODS: Systematic review according to PRISMA guidelines, using PubMed, Web of Science and WorldCat databases (2005-2020) of studies that explored the association between the seasonality of the MOB and T1D, AITD and ADD. Information on sex and age, location, methodology and internal quality, seasonal patterns, hypotheses and other factors proposed to explain seasonality were extracted. Differences in season and month of birth were further discussed. RESULTS: The initial search retrieved 300 articles, and after further screening, 11 articles fulfilled inclusion criteria and were finally selected and reviewed. 73% found a seasonal pattern and 64% showed birth peaks in spring and/or summer. Hashimoto's thyroiditis and women exhibited a higher seasonality. Ultraviolet radiation, Vitamin D levels and viral infections were identified as influencing factors. CONCLUSIONS: The effect of certain seasonal factors during foetal development, reflected by the seasonal differences in the MOB, could contribute to the development of endocrine autoimmune diseases in predisposed patients. Further research is needed to elucidate the mechanisms underlying the observed seasonality.

Gestational weight gain influences neonatal outcomes in women with obesity and gestational diabetes.

INTRODUCTION: Obesity and gestational diabetes mellitus (GDM) are associated with an increased risk of perinatal complications and obesity in the offspring. However, the impact of gestational weight gain (GWG) on maternal and foetal outcomes is controversial. PATIENTS AND METHODS: Retrospective study of 220 women with GDM and pre-pregnancy body mass index (BMI)>30kg/m2. Pregnant women were classified according to the Institute of Medicine (IOM) recommendations regarding their prior BMI and GWG. We evaluated the impact of GWG on perinatal and obstetric outcomes. RESULTS: Mean maternal age was 34.7±5.3 years. Pre-pregnancy obesity was classified as class I in 55.3% of the cases, class II in 32.0% and class III in 12.7%. GWG was adequate (5-9kg) in 24.2%, insufficient (<5kg) in 41.8% and excessive (>9kg) in 34.2%. Birth weight was within normal range in 81.9%, 3.6% were small for gestational age (microsomia) and 14.4% were large for gestational age (macrosomia). Insufficient GWG was associated with a higher rate of microsomal offspring, excessive GWG was associated to macrosomia and adequate GWG with normal birth weight. CONCLUSION: GWG in women with pre-pregnancy obesity and GDM impacts neonatal birthweight. Insufficient GWG is associated with microsomia and excessive GWG is associated with macrosomia. Women with adequate GWG according to the IOM guidelines obtained better perinatal outcomes.

Genetic variants for prediction of gestational diabetes mellitus and modulation of susceptibility by a nutritional intervention based on a Mediterranean diet.

Hypothesis: Gestational diabetes mellitus (GDM) entails a complex underlying pathogenesis, with a specific genetic background and the effect of environmental factors. This study examines the link between a set of single nucleotide polymorphisms (SNPs) associated with diabetes and the development of GDM in pregnant women with different ethnicities, and evaluates its potential modulation with a clinical intervention based on a Mediterranean diet. Methods: 2418 women from our hospital-based cohort of pregnant women screened for GDM from January 2015 to November 2017 (the San Carlos Cohort, randomized controlled trial for the prevention of GDM ISRCTN84389045 and real-world study ISRCTN13389832) were assessed for evaluation. Diagnosis of GDM was made according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Genotyping was performed by IPLEX MassARRAY PCR using the Agena platform (Agena Bioscience, SanDiego, CA). 110 SNPs were selected for analysis based on selected literature references. Statistical analyses regarding patients' characteristics were performed in SPSS (Chicago, IL, USA) version 24.0. Genetic association tests were performed using PLINK v.1.9 and 2.0 software. Bioinformatics analysis, with mapping of SNPs was performed using STRING, version 11.5. Results: Quality controls retrieved a total 98 SNPs and 1573 samples, 272 (17.3%) with GDM and 1301 (82.7%) without GDM. 1104 (70.2%) were Caucasian (CAU) and 469 (29.8%) Hispanic (HIS). 415 (26.4%) were from the control group (CG), 418 (26.6%) from the nutritional intervention group (IG) and 740 (47.0%) from the real-world group (RW). 40 SNPs (40.8%) presented some kind of significant association with GDM in at least one of the genetic tests considered. The nutritional intervention presented a significant association with GDM, regardless of the variant considered. In CAU, variants rs4402960, rs7651090, IGF2BP2; rs1387153, rs10830963, MTNR1B; rs17676067, GLP2R; rs1371614, DPYSL5; rs5215, KCNJ1; and rs2293941, PDX1 were significantly associated with an increased risk of GDM, whilst rs780094, GCKR; rs7607980, COBLL1; rs3746750, SLC17A9; rs6048205, FOXA2; rs7041847, rs7034200, rs10814916, GLIS3; rs3783347, WARS; and rs1805087, MTR, were significantly associated with a decreased risk of GDM, In HIS, variants significantly associated with increased risk of GDM were rs9368222, CDKAL1; rs2302593, GIPR; rs10885122, ADRA2A; rs1387153, MTNR1B; rs737288, BACE2; rs1371614, DPYSL5; and rs2293941, PDX1, whilst rs340874, PROX1; rs2943634, IRS1; rs7041847, GLIS3; rs780094, GCKR; rs563694, G6PC2; and rs11605924, CRY2 were significantly associated with decreased risk for GDM. Conclusions: We identify a core set of SNPs in their association with diabetes and GDM in a large cohort of patients from two main ethnicities from a single center. Identification of these genetic variants, even in the setting of a nutritional intervention, deems useful to design preventive and therapeutic strategies.

Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies.

Immunotherapy is an effective treatment in advanced cancer, although predictors of response are limited. We studied whether excess weight influences the efficacy outcomes of immunotherapy. We have also evaluated the combined prognostic effect of excess weight and immune-related adverse events (irAEs). Efficacy of anti-PD-1 treatment was evaluated with both objective radiological response (ORR) rate and progression-free survival (PFS), and toxicity with irAEs. We studied the association between excess weight and ORR, PFS or irAEs. 132 patients diagnosed with advanced cancer were included. Median body mass index (BMI) was 24.9 kg/m2. 64 patients had normal weight (BMI<25 kg/m2), and 64 patients had excess weight (BMI≥25 kg/m2). Four patients had underweight and were excluded from further analysis. ORR was achieved in 50 patients (38.0%), median PFS was 6 months. 44 patients developed irAEs (33.3%). ORR was higher in excess weight patients than in patients with normal weight (51.6% vs 25.0%; OR 3.45, p = .0009). PFS was improved in patients with excess weight (7.25 months vs 4 months, HR 1.72, p = .01). The incidence of IrAEs was not different in patients with excess weight (54.5% vs 43.2%, p = .21). When high BMI and irAEs were combined, we observed a marked prognostic trend in ORR rate (87.5% vs 6.2%; OR 161.0, p < .00001), and in PFS (14 months vs 3 months; HR 5.89, p < .0001). Excess weight patients with advanced cancer that receive single-agent anti-PD-1 antibody therapy exhibit a significantly improved clinical outcome compared with normal BMI patients. This association was especially marked when BMI and irAEs were considered combined.

Bringing Cardiovascular Comorbidities in Acromegaly to an Update. How Should We Diagnose and Manage Them?

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.

Nivolumab-induced thyroid dysfunction in patients with lung cancer.

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.

Integrated miRNA and mRNA expression profiling identifies novel targets and pathological mechanisms in autoimmune thyroid diseases.

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.

Treatment of adult growth hormone deficiency with human recombinant growth hormone: an update on current evidence and critical review of advantages and pitfalls.

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.

Is receptor profiling useful for predicting pituitary therapy?

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.