Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia.

The worldwide prevalence and incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and of NENs, in general, have been increasing recently. While valuing the considerable progress made in the treatment strategies for GEP-NEN in recent years, patients with advanced, metastasized disease still have a poor prognosis, which calls for urgent novel therapies. The immune system plays a dual role: both host-protecting and "tumor-promoting." Hence, immunotherapy is potentially a powerful weapon to help NEN patients. However, although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Studies led to their approval in NEN of the lung and Merkel cell carcinoma, whereas results in other settings have not been so encouraging. Oncolytic viruses can selectively infect and destroy cancer cells, acting as an in situ cancer vaccine. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype. Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to checkpoint inhibitors alone. Future efforts should focus on finding the best way to include immunotherapy in the GEP-NEN treatment scenario. In this context, this study aims at providing a comprehensive generalized review of the immune checkpoint blockade and the oncolytic virotherapy use in GEP-NENs that might improve GEP-NEN treatment strategies.

Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS).

PURPOSE: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. METHODS: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. RESULTS: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). CONCLUSIONS: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer.

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways' inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways' inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.

Lipidomics biomarkers in women with polycystic ovary syndrome (PCOS) using ultra-high performance liquid chromatography-quadrupole time of flight electrospray in a positive ionization mode mass spectrometry.

Polycystic ovary syndrome (PCOS), characterized by oligo-anovulation and androgen excess is considered a high-risk condition for metabolic disorders. Herein, untargeted metabolomics analysis was applied to women with PCOS, aiming to provide deeper insights into lipidomics biomarkers signature of PCOS, for better diagnosis and management. This was a cross-sectional study in which 15 Caucasian women with PCOS and 15 Caucasian healthy, age-matched women were enrolled. Lipidomics analysis was performed using Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Electrospray Mass Spectrometry. Partial Least Squares Discriminant Analysis retrieved the most important discriminative metabolites. Significantly increased levels of triacylglycerol (18:2/18:2/0-18:0) in addition to cholestane-3beta, 5alpha, 6beta-triol (18:0/0:0) and cholestane-5alpha (18:1/0:0) appeared as valuable variables to differentiate subjects with PCOS from controls. Acyl-carnitine 2-hydroxylauroylcarnitine was significantly elevated in PCOS in opposition to decreased phosphocholines metabolites (18:1/18:4, 18:3/18:2), to suggest a metabolic pattern linked to lipid peroxidation. A high fat intake or reduced fat energy consumption during nighttime due to diminished ability to switch to lipid oxidation during fasting time possibly contribute to hypertriglyceridemia found in PCOS. Furthermore, inflammatory mediators including metabolites of the prostaglandin (PG) E2 pathway and oxo-leukotrienes (LT) were increased in patients with PCOS. Potential lipidomics biomarkers were identified that could stratify between women with PCOS and healthy controls. The results show particular alterations in acylglycerols, PGs and LTs and phosphocholines and carnitine metabolites. The lipidomics profiles of PCOS indicate a higher risk of developing metabolic diseases.

MicroRNA Expression Profiling-Potential Molecular Discrimination of Papillary Thyroid Carcinoma Subtypes.

Recent research has revealed the importance of miRNAs in the diagnosis and clinical evolution of papillary thyroid cancer (PTC). We aim to identify a specific miRNA profile that could differentiate between specific subtypes of PTC. METHODS: In this cross-sectional study, total RNA was extracted from paraffin-embedded tissues of 43 patients, 17 with an infiltrative follicular variant of PTC (iFVPTC) and 26 with a conventional variant of PTC (cPTC). Nine miRNAs were evaluated using qRT-PCR technology and specific miRNA assays. RESULTS: We found specific patterns for cPTC and iFVPTC, such as miRNA altered in both types of tumours (miR-146b-5p, miR-181a-5p, miR-221-3p, miR-21-5p and miR-222-3p) and two miRNAs significantly expressed only in cPTC (miR-20b-5p, miR-21-5p). The iFVPTC group presented strong and moderate correlations between miRNA expression and clinical data. miR-221-3p, miR-195-5p, miR-181-5p, miR-146b-5p and miR-222 were correlated with age, tumour size (TS) or lymph node metastases (N), while only miR-20b-5p, miR-195-5p and miR-181-5p were correlated with TS, N and age in the cPTC group. CONCLUSIONS: The present study allowed the identification of a signature of two miRNAs to confirm miRNA differences between the two histological subtypes of TC. Our results provide advances in the molecular diagnosis of TC and could help to improve the diagnostic performance of already existing molecular classifiers.

Metabolomics in acromegaly: a systematic review.

The therapeutic response heterogeneity in acromegaly persists, despite the medical-surgical advances of recent years. Thus, personalized medicine implementation, which focuses on each patient, is justified. Metabolomics would decipher the molecular mechanisms underlying the therapeutic response heterogeneity. Identification of altered metabolic pathways would open new horizons in the therapeutic management of acromegaly. This research aimed to evaluate the metabolomic profile in acromegaly and metabolomics' contributions to understanding disease pathogenesis. A systematic review was carried out by querying four electronic databases and evaluating patients with acromegaly through metabolomic techniques. In all, 21 studies containing 362 patients were eligible. Choline, the ubiquitous metabolite identified in growth hormone (GH)-secreting pituitary adenomas (Pas) by in vivo magnetic resonance spectroscopy (MRS), negatively correlated with somatostatin receptors type 2 expression and positively correlated with magnetic resonance imaging T2 signal and Ki-67 index. Moreover, elevated choline and choline/creatine ratio differentiated between sparsely and densely granulated GH-secreting PAs. MRS detected low hepatic lipid content in active acromegaly, which increased after disease control. The panel of metabolites of acromegaly deciphered by mass spectrometry (MS)-based techniques mainly included amino acids (especially branched-chain amino acids and taurine), glyceric acid, and lipids. The most altered pathways in acromegaly were the metabolism of glucose (particularly the downregulation of the pentose phosphate pathway), linoleic acid, sphingolipids, glycerophospholipids, arginine/proline, and taurine/hypotaurine. Matrix-assisted laser desorption/ionization coupled with MS imaging confirmed the functional nature of GH-secreting PAs and accurately discriminated PAs from healthy pituitary tissue.

Xanthogranuloma of the Sellar Region: A Comprehensive Review of Neuroimaging in a Rare Inflammatory Entity.

Xanthogranuloma of the sellar region is a rare chronic inflammatory lesion resulting from secondary hemorrhage, inflammation, infarction, and necrosis of an existing Rathke's cleft cyst, craniopharyngioma, or pituitary adenoma. Sellar xanthogranulomas are challenging to differentiate from other cystic lesions preoperatively due to the lack of characteristic imaging features. We performed a literature overview of the clinical and paraclinical features, treatment options, and long-term outcomes of patients with sellar xanthogranuloma, focusing on the preoperative radiological diagnosis. The hyperintense signal in both T1- and T2-weighted sequences, cystic or partially cystic morphology, ovoid shape, sellar epicenter, intra- and suprasellar location, intratumoral calcifications, linear rim contrast enhancement, and the absence of cavernous sinus invasion suggest xanthogranuloma in the preoperative differential diagnosis. An endoscopic endonasal gross total resection without radiotherapy is the preferred first-line treatment. Given the low rate of recurrence rate and low chance of endocrinological recovery, a mass reduction with decompression of the optic apparatus may represent an appropriate surgical goal. Identifying the xanthogranulomas' mutational profile could complement histopathological diagnosis and give insight into their histo-pathogenesis. A better preoperative neuroimagistic diagnosis of sellar xanthogranulomas and differentiation from lesions with a poorer prognosis, such as craniopharyngioma, would result in an optimal personalized surgical approach.

Spontaneous remission of Cushing's disease: A systematic review.

Spontaneous remission is rare in Cushing's disease. We describe one illustrative case and provide a systematic review of cases previously reported in the literature. Case report: A 51-year-old woman diagnosed with Cushing's disease underwent 9 months' isolated metyrapone treatment. Two months after end of treatment, she was admitted with acute kidney failure. After another 4 months, in June 2020, there was no evidence of hypercortisolism, either clinically or biochemically, or of hypocortisolism. At the time of writing, 1 year later, she was still in remission. Cases reported in the literature: 23 patients were reported, including the present case. 87% were female with a median age of 32 years. Ten of those with radiologically visible tumors had microadenoma (44%) and 7 had macroadenoma (30%). Mean time from diagnosis to spontaneous remission was 5 months, and was shorter in macroadenoma (1 month) than in microadenoma (13.5 months). Treatments before spontaneous remission were: no treatment (65%), steroidogenesis enzyme inhibitors (22%), bilateral adrenalectomy and adrenal autotransplantation (5%), partial bilateral adrenalectomy (4%), and incomplete pituitary surgery (4%). Pituitary tumor apoplexy was the most frequently incriminated event (91%), radiologically documented in 43% of patients. Mean remission during follow-up was 28 months (range, 6-130 months). Recurrence occurred in 39% (n=9) of patients. Although several mechanisms responsible for this phenomenon have been proposed, clinical or subclinical pituitary tumor apoplexy, the latter sometimes presenting atypically, seems to be the most frequently incriminated event. Doctors should be aware of this, and regular follow-up is mandatory due to its unpredictability.

Rationale for therapeutic decision-making in locally advanced and metastatic radioactive iodine (RAI)-refractory differentiated thyroid cancer, starting from a clinical case.

Iodine uptake and organification are the hallmarks of thyroid cells differentiation. The loss of these characteristics in thyroid cancer leads to radioactive iodine refractoriness, a rare condition that bears a low survival rate and poor prognosis. We present a 52-year-old patient presenting dry cough and dyspnea in the supine position. Imaging examinations revealed a thyroid nodule with a high suspicion of malignancy in the right thyroid lobe, multiple laterocervical and mediastinal lymph nodes, lung, bone, and brain metastases. Fine needle aspiration cytologic features have advocated for papillary thyroid cancer (PTC). The patient underwent total thyroidectomy and selective lymphadenectomy. Subsequently, the patient received suppressive treatment with levothyroxine and four courses of radioactive iodine therapy. In addition, to treat bone and brain metastases, the patient experienced external radiotherapy and glucocorticoid therapy. Despite this rigorous therapeutic management, the patient obtained an incomplete structural and functional response. Although the last two posttherapeutic 131I whole-body scans were negative, the patient had elevated stimulated thyroglobulin levels and loco-regional recurrence by thyroid ultrasound. This aspect would suggest that thyroid cells become unable to uptake 131I, most likely through the emergence of new genetic mutations in the cancer cells. In conclusion, our patient's case suggests a 131I-refractory PTC, requiring the initiation of novel targeted systemic agents such as tyrosine kinase inhibitors, in order to improve structural and functional outcomes of radioactive iodine therapy and to afford prolonged progression-free survival advantage.

Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

Background: Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules (ITNs). Previous test versions, Thyroseq v2 and Afirma Gene Expression Classifier (GEC), have proven shortcomings in malignancy detection performance. Objective: This study aimed to evaluate the diagnostic performance of the established Thyroseq v3, Afirma Gene Sequencing Classifier (GSC), and microRNA-based assays versus prior iterations in ITNs, in light of "rule-in" and "rule-out" concepts. It further analyzed the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification and Bethesda cytological subtypes on the performance of molecular tests. Methods: Pubmed, Scopus, and Web of Science were the databases used for the present research, a process that lasted until September 2020. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and area under the curve (AUC) for each panel. The conducted sensitivity analyses addressed different Bethesda categories and NIFTP thresholds. Results: A total of 40 eligible studies were included with 7,831 ITNs from 7,565 patients. Thyroseq v3 showed the best overall performance (AUC 0.95; 95% confidence interval: 0.93-0.97), followed by Afirma GSC (AUC 0.90; 0.87-0.92) and Thyroseq v2 (AUC 0.88; 0.85-0.90). In terms of "rule-out" abilities Thyroseq v3 (NLR 0.02; 95%CI: 0.0-2.69) surpassed Afirma GEC (NLR 0.18; 95%CI: 0.10-0.33). Thyroseq v2 (PLR 3.5; 95%CI: 2.2-5.5) and Thyroseq v3 (PLR 2.8; 95%CI: 1.2-6.3) achieved superior "rule-in" properties compared to Afirma GSC (PLR 1.9; 95%CI: 1.3-2.8). Evidence for Thyroseq v3 seems to have higher quality, notwithstanding the paucity of studies. Both Afirma GEC and Thyroseq v2 performance have been affected by NIFTP reclassification. ThyGenNEXT/ThyraMIR and RosettaGX show prominent preliminary results. Conclusion: The newly emerged tests, Thyroseq v3 and Afirma GSC, designed for a "rule-in" purpose, have been proved to outperform in abilities to rule out malignancy, thus surpassing previous tests no longer available, Thyroseq 2 and Afirma GEC. However, Thyroseq v2 still ranks as the best rule-in molecular test. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, identifier CRD42020212531.

Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma.

Intracranial germinomas are rare tumours, usually affecting male paediatric patients. They frequently develop in the pineal and suprasellar regions, causing endocrinological disturbances, visual deficits, and increased intracranial pressure. The diagnosis is established on magnetic resonance imaging (MRI), serum and cerebrospinal fluid (CSF) markers, and tumour stereotactic biopsy. Imaging techniques, such as susceptibility-weighted imaging (SWI), T2* (T2-star) gradient echo (GRE) or arterial spin labelling based perfusion-weighted MRI (ASL-PWI) facilitate the diagnosis. Germinomas are highly radiosensitive tumours, with survival rates >90% in the context of chemoradiotherapy. However, patients with resistant disease have limited therapeutic options and poor survival. The aim of this review is to highlight the genetic, epigenetic, and immunologic features, which could provide the basis for targeted therapy. Intracranial germinomas present genetic and epigenetic alterations (chromosomal aberrations, KIT, MAPK and PI3K pathways mutations, DNA hypomethylation, miRNA dysregulation) that may represent targets for therapy. Tyrosine kinase and mTOR inhibitors warrant further investigation in these cases. Immune markers, PD-1 (programmed cell death protein 1) and PD-L1 (programmed death-ligand 1), are expressed in germinomas, representing potential targets for immune checkpoint inhibitors. Resistant cases should benefit from a personalized management: genetic and immunological testing and enrolment in trials evaluating targeted therapies in intracranial germinomas.

The Prognostic Value of MicroRNAs in Thyroid Cancers-A Systematic Review and Meta-Analysis.

Thyroid cancer (TC) includes various phenotypes, from indolent to highly aggressive cancer. The limitations of the current prognostication systems to predict the recurrence risk and the variability in expression of the genes involved in the thyroid carcinogenesis uncover the need for new prognostic biomarkers by taking into account potential epigenetic differences. We aimed to summarize the current knowledge regarding the prognostic impact of microRNAs (miRNAs) in TC. A literature search was conducted in PubMed, Embase, Scopus, and Web of Science databases. Both upregulated and downregulated miRNAs are significantly correlated with worse overall survival (hazard ratio (HR) = 5.94, 95% CI: 2.73-12.90, p < 0.001; HR = 0.51, 95% CI: 0.26-0.96, p = 0.048) disease/recurrence-free survival (HR = 1.58, 95% CI: 1.08-2.32, p = 0.003; HR = 0.37, 95%, CI: 0.24-0.60, p < 0.001). Sensitivity analysis revealed a significant association between the higher expression of miR-146b, miR-221, and miR-222 and the recurrence of papillary TC (OR = 9.11, 95% CI 3.00 to 27.52; p < 0.001; OR = 3.88, 95% CI 1.34 to 11.19, p < 0.001; OR = 6.56, 95% CI 2.75 to 15.64, p < 0.001). This research identified that miR-146b, miR-221, and miR-222 could serve as potential prognostic biomarkers in TC, particularly in PTC. Further studies are needed to strengthen these findings and sustain its clinical applicability.

Selenoproteins in human body: focus on thyroid pathophysiology.

Selenium (Se) has a multilevel, complex and dynamic effect on the human body as a major component of selenocysteine, incorporated into selenoproteins, which include the selenocysteine-containing enzymes iodothyronine deiodinases. At the thyroid level, these proteins play an essential role in antioxidant protection and hormone metabolism. This is a narrative review based on PubMed/Medline database research regarding thyroid physiology and conditions with Se and Se-protein interferences. In humans, Se-dependent enzyme functions are best expressed through optimal Se intake, although there is gap in our knowledge concerning the precise mechanisms underlying the interrelation. There is a good level of evidence linking low serum Se to autoimmune thyroid diseases and, to a lesser extent, differentiated thyroid cancer. However, when it comes to routine supplementation, the results are heterogeneous, except in the case of mild Graves' orbitopathy. Autoimmune hypothyroidism is associated with a state of higher oxidative stress, but not all studies found an improvement of thyroid function after Se was introduced as antioxidant support. Meanwhile, no routine supplementation is recommended. Low Se intake is correlated with an increased risk of developing antithyroid antibodies, its supplementation decreasing their titres; there is also a potential reduction in levothyroxine replacement dose required for hypothyroidism and/or the possibility that it prevents progression of subclinical hypothyroidism, although not all studies agree. In thyroid-associated orbitopathy, euthyroidism is more rapidly achieved if the micronutrient is added to traditional drugs, while controls appear to benefit from the microelement only if they are deficient; thus, a basal assay of Se appears advisable to better select patients who need substitution. Clearly, further Se status biomarkers are required. Future introduction of individual supplementation algorithms based on baseline micronutrient levels, underlying or at-risk clinical conditions, and perhaps selenoprotein gene polymorphisms is envisaged.

Prevalence and predictors of non-alcoholic fatty liver disease as defined by the fatty liver index in a type 2 diabetes population.

BACKGROUND AND AIMS: We aimed to study the prevalence and the predictive factors of non-alcoholic fatty liver disease (NAFLD) defined by the fatty liver index (FLI) in type 2 diabetic patients (T2DM). METHODS: Three hundred and eighty-one T2DM outpatients who regularly attended a Consulting Clinic in Cluj were retrospectivelly included. FLI, a surrogate steatosis biomarker based on body mass index (BMI), waist circumference (WC), triglycerides (TGL) and gammaglutamyl-transferase (GGT) was used to assess NAFLD in all patients. Anthropometric and biochemical parameters were measured. Hepatic steatosis (HS) was evaluated by ultrasonography. RESULTS: NAFLD-FLI (defined as FLI>60) was correlated with HS evaluated by ultrasound (r=0.28; p<0.001). NAFLD-FLI was detected in 79% of T2DM. The prevalence of obesity in NAFLD-FLI patients was 80%. Of the patients with normal alanine aminotransferase (ALAT), 73.8 % had NAFLD. At univariate analysis, NAFLD-FLI was correlated with age (r= -0.14; p=0.007), sex (r=0.20; p<0.001), LDL cholesterol (r=0.12; p=0.032), HDL cholesterol (r = -0.13; p=0.015), ALAT (r=0.20; p<0.001) and ASAT (r=0.19; p<0.001). At multiple regression analysis, sex, ALAT and LDL-cholesterol were independent predictors of NAFLD-FLI. After logistic regression model, ALAT, LDL-cholesterol, HOMA-IR were good independent predictors of NAFLD-FLI. CONCLUSIONS: NAFLD-FLI could be useful to identify NAFLD in T2DM patients. Subjects with T2DM had a high prevalence of NADLD-FLI even with normal ALAT levels. Our findings showed that sex, ALAT, LDL cholesterol and IR were significant and independent factors associated with the presence of NAFLD in T2DM subjects.

Challenges of thyroid cancer management in amiodarone-treated patients: a case report.

Thyroid carcinoma (TC) is the most common endocrine malignancy. Although the overall prognosis for patients with TC is good, up to 20-30% of patients have recurrent or persistent disease after conventional therapy by surgical resection and radioactive iodine (RAI). Amiodarone is a highly efficient anti-arrhythmic drug with a very long half-life, so it may interfere with RAI many months after the drug withdrawal. This case report mirrors the challenges of thyroid cancer management in an amiodarone-treated patient.

Age, abdominal obesity, and glycated hemoglobin are associated with carotid atherosclerosis in type 2 diabetes patients with nonalcoholic fatty liver disease.

AIM: The aim of this study was to evaluate the impact of clinical parameters and indices of body composition on the relation between non-alcoholic fatty liver disease (NAFLD) and carotid intima-media thickness (cIMT), in a type 2 diabetes mellitus population (T2DM). MATERIAL AND METHODS: We retrospectively enrolled 336 T2DM outpatients who regularly attended Regina Maria Clinic in Cluj. Clinical, anthropometric and biochemical parameters were measured. Ultrasonography (US) was used to assess hepatic steatosis (HS) in all patients and cIMT in 146 subjects. Body composition was assessed by bioelectric impedance (BIA, InBody 720) in all patients. RESULTS: cIMT was correlated with age (r=0.25; p=0.004), systolic blood pressure (r=0.18; p=0.041), glycated haemoglobin A1C (HbA1C, r=0.20; p=0.04), and with coronary artery disease (r=0.20; p=0.007). HS did not correlate with cIMT (r=0.04; p=0.64). cIMT was correlated with visceral fatty area (VFA, r=0.18; p=0.014) but not with other indices of body composition. Homeostasis model assessment for insulin resistance (HOMA-IR) was not correlated with cIMT (r=0.17; p=0.086). After multivariate analysis, age, HbA1c, and VFA were good independent predictors of cIMT (r=0.45; p < 0.001). CONCLUSIONS: These results are suggestive that in T2DM patients, fatty liver is not a direct mediator of early carotid atherosclerosis. Our data indicate that visceral fat accumulation and HbA1C are determinant factors of cIMT sugesting that controlling abdominal obesity and hyperglicemia might reduce atherosclerotic disease risk in NAFLD-T2DM subjects.

Association between body composition and bone mineral density in healthy, non-obese, young Romanian adults and effects of menopause.

INTRODUCTION: The link between bone mass and body composition is widely recognized, but the mechanism remains unclear. Most studies enrolled subjects irrespective of their body weight and only few works were selectively performed on healthy subjects with body mass index (BMI) within normal limits. MATERIAL AND METHODS: We aimed to determine the relevance of body composition parameters to bone mass in healthy, young and non-obese Romanian volunteers (n=42) and in postmenopausal women (n=20) and to establish the effects of menopausal transition. Both bone mineral density (BMD) and body composition were assessed using whole-body dual X-ray absorptiometry (DXA). OUTCOMES: Despite normal mean BMI, large variability of the whole-body fat mass (FM) content was noted, ranging between 18.6-49.7% in women and 22-40.3% in men. Fat mass was not related to bone density; in contrast, BMD at all sites was positively associated to fat-free mass (FFM) in young non-obese women (r=0.34-0.53). In women, the trunk fat mass/leg fat mass ratio was significantly predicted by age (p=0.001), explaining about 20% of the pattern variability. Menopausal status appeared not to significantly influence whole-body fat or FM distribution. A tendency towards a higher trunk FM/legs FM ratio was observed after menopause, but lost after age-adjustment. CONCLUSION: In non-obese subjects, even of young age, the FM content and distribution is highly variable. FFM mass appears to be the main composition contributor to bone mass, at least in young, healthy, non-obese women. Menopause is not associated to major changes of whole-body fat and trunk adipose tissue, although a significant decrease in peripheral FM content and a tendency towards an age-dependent central redistribution of adiposity is noticed.