Publications by authors named "Stefano Mariotti"

69 Publications

Iodoprophylaxis and thyroid autoimmunity: an update.

Immunol Res 2021 Apr 29. Epub 2021 Apr 29.

Department of Internal Medicine and Medical Specialties (DiMI), Genoa University, Viale Benedetto XV, 6 I-16132, Genova, Italy.

Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12026-021-09192-6DOI Listing
April 2021

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

Thyroid 2021 02 22;31(2):224-232. Epub 2020 Oct 22.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2020.0276DOI Listing
February 2021

Embolization of iliac metastasis during lenvatinib treatment in patient with advanced Hürthle cell thyroid carcinoma.

Future Oncol 2019 Aug 6;15(24s):35-40. Epub 2019 Aug 6.

Department of Medical Sciences & Public Health, Postgraduate School of Endocrinology & Metabolic Diseases, University of Cagliari, Cagliari, Italy.

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2019-0184DOI Listing
August 2019

Intertriginous and Seborrheic Dermatitis-Like Lesions in an Endocrine Patient: Answer.

Am J Dermatopathol 2019 Jun;41(6):457-458

Unit of Dermatology, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001055DOI Listing
June 2019

The Aging Thyroid: A Reappraisal Within the Geroscience Integrated Perspective.

Endocr Rev 2019 10;40(5):1250-1270

Istituto Auxologico Italiano, Laboratorio Sperimentale di Ricerche di Neuroendocrinologia Geriatrica ed Oncologica, Milan, Italy.

The thyroid plays a crucial and pervasive role in physiology (metabolism, thermogenesis, and immunity, among others) and its aging and related changes in thyroid hormone production contribute to the common occurrence of thyroid diseases in elderly and to age-associated changes in other organs and systems. We address the complexity of thyroid aging following the basic suggestions of geroscience. This integrative new perspective identifies a few basic molecular mechanisms or "pillars" (inflammation, adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, and epigenetic modifications) as a unifying conceptual framework to understand the aging process and age-associated diseases. Within this scenario, we review available data on the presence and role in the thyroid of alterations of such mechanistic pillars, paying particular attention to (i) inflammation, focusing on cellular senescence and age-associated dysbiosis (alteration of gut microbiota); (ii) telomere shortening as an example of macromolecular damage; (iii) proteasomal function, including mitophagy and autophagy; (iv) stem cells and cell renewal; (v) energy metabolism and mitochondrial dysfunction; and (vi) age-related epigenetic changes, focusing on DNA methylation. Overall, the study of these topics in the thyroid is in its infancy and deserves much more attention. Finally, thyroid function in centenarians as a model of healthy aging is reviewed within the framework of possible adaptive mechanisms involving the thyroid to attain longevity. Accordingly, the concept of "thyroid biography" is proposed to grasp the complex combination of factors (including endocrine disruptors and lifestyle habits) impinging lifelong on thyroid function at the individual level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/er.2018-00170DOI Listing
October 2019

Cancer immunotherapy-associated hypophysitis.

Semin Oncol 2018 06 21;45(3):181-186. Epub 2018 Oct 21.

Department of Radiology, University Hospital of Cagliari, Cagliari, Italy. Electronic address:

Side effects of immune checkpoint blockade are often said to be infrequent and usually mild. The uniqueness of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if immunotherapy is used at earlier stages of neoplastic disease. Immune-related hypophysitis is one of these observed endocrine adverse events. It is often difficult to diagnose, sometimes occurring without specific symptoms. It can lead to irreversibly altered functioning of diverse endocrine glands. Radiographically, the differential diagnosis of hypophysitis includes pituitary apoplexy and primary and secondary neoplastic lesions. Immune-related hypophysitis is most common with single-agent anti-CTLA-4, followed by the combination of anti-CTLA-4 and anti-PD-1, while occurs infrequently when anti-PD-1 or anti-PD-L1 agents are administered alone. Hypophysitis with immune checkpoint blockade requires early recognition, diagnosis, and treatment. Patients can present with headache, visual disturbances or other endocrine-related syndromes or they can be asymptomatic. The manifestation of symptoms should prompt blood analysis and magnetic resonance imaging of the brain. Imaging is important to exclude secondary meningeal or parenchymal lesions. Management should include discontinuation of the immune checkpoint blockade, initiation of corticosteroid therapy and eventually hormone replacement therapy. Hypophysitis impacts treatment of the disease and usually requires long-term management of this irreversible side effect. A multidisciplinary team approach is merited to insure the correct diagnosis and management of immune-related hypophysitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.seminoncol.2018.09.002DOI Listing
June 2018

Reduction of Total Brain and Cerebellum Volumes Associated With Neuronal Autoantibodies in Patients With APECED.

J Clin Endocrinol Metab 2019 01;104(1):150-162

NEF Laboratory, Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy.

Context: In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoantibodies (AutoAbs) labeling brain neurons were reported; conversely, brain MRI alterations associated with these AutoAbs were never reported.

Objectives: To describe brain alterations in APECED and to correlate them with AutoAbs against glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH), and 5-tryptophan hydroxylase (5-HT) neurons.

Design And Participants: Fourteen Sardinian patients with APECED and age-matched control subjects were recruited for MRI analysis and blood sampling to detect AutoAbs to GAD, TH, and 5-HT neurons by using rat brain sections. The majority of patients (n = 12) were investigated for AutoAbs a decade earlier, and 7 of 12 were positive for AutoAbs to GAD and TH neurons.

Main Outcomes: Patients with APECED had smaller cerebellum and gray matter volumes, with a ventricular enlargement and a total cerebrospinal fluid (CSF) increase, compared with controls (P < 0.01). In 11 of 14 patients, brain abnormalities were associated with AutoAbs to GAD or TH neurons (titer 1:100 to 15,000) that had persisted for 10 years in 7 of 11 patients. AutoAbs to 5-HT neurons were revealed in all patients with AutoAbs to TH neurons. A decrease in whole brain and cerebellum volumes (P = 0.028) was associated with AutoAbs to GAD neurons, and a CSF increase was associated with AutoAbs to GAD and TH/5-HT neurons (P < 0.05). HLA alleles did not appear to be involved in neuronal autoimmunity.

Conclusions: Brain alterations and neuronal AutoAbs were observed in 78.6% of Sardinian patients with APECED, suggesting a brain autoimmune reaction. Prolonged clinical follow-up must be conducted for the possible appearance of clinical neurologic consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2018-01313DOI Listing
January 2019

Heterogeneity of Thyroid Function and Impact of Peripheral Thyroxine Deiodination in Centenarians and Semi-Supercentenarians: Association With Functional Status and Mortality.

J Gerontol A Biol Sci Med Sci 2019 05;74(6):802-810

Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Italy.

Thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) were evaluated in a population of 672 well-characterized Italian subjects (age range: 52-113 years), including an unprecedented number of centenarians, semi-supercentenarians, as well as centenarian's offspring and age-matched elderly (CENT, 105+, CENTOFF, and CTRL, respectively). The results show that FT3 level and FT3/FT4 ratio decrease while FT4 and TSH increase in an age-dependent manner. In CENT/105+, higher FT4 level, and lower FT3/FT4 ratio are associated with an impaired functional status and an increased mortality. A cluster analysis identified three clusters of CENT/105+ based on their FT3, FT4, and TSH levels. Cluster 3, characterized by lower FT3 and TSH and higher FT4, shows the worst health status and the shortest survival. Thus, the age-related changes of thyroid hormones extend to the most advanced age, and CENT/105+ are highly heterogeneous regarding thyroid function. This heterogeneity is related to different health, functional and cognitive status, as well as with survival/mortality in CENT/105+. Finally, we investigated a remarkable number of CENT/105+ showing a thyroid profile suggestive of non-thyroidal illness syndrome (NTIS) (excluded from the previous analysis). NTIS CENT/105+ are characterized by a worse functional and cognitive status and an increased mortality with respect to CENT/105+ without NTIS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/gly194DOI Listing
May 2019

Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study.

Clin Colorectal Cancer 2018 09 8;17(3):e601-e615. Epub 2018 Jun 8.

Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy. Electronic address:

Background: The impact of free triiodothyronine (FT)/free thyroxine (FT) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT/FT ratio in patients with advanced cancer. We evaluated the impact of FT/FT ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib.

Methods: Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT, FT, and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT/FT ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari.

Results: In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT/FT ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models.

Conclusions: High baseline FT/FT ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2018.05.013DOI Listing
September 2018

Intertriginous and Seborrheic Dermatitis-Like Lesions in an Endocrine Patient: Challenge.

Am J Dermatopathol 2019 Jun;41(6):e55-e56

Unit of Dermatology, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001054DOI Listing
June 2019

Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features.

PLoS One 2017 16;12(10):e0186485. Epub 2017 Oct 16.

University Hospital of Pisa, Endocrine Unit 2, Pisa, Italy.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186485PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643132PMC
November 2017

Thyroid Autoimmunity and Thyroid Cancer: Review Focused on Cytological Studies.

Eur Thyroid J 2017 Jul 24;6(4):178-186. Epub 2017 Apr 24.

Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

The association between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) has been originally suggested by retrospective pathological studies and has recently been re-evaluated and proposed on the basis of several fine-needle aspiration cytology (FNAC) studies. In FNAC studies, the association between HT and PTC is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands. Most of the pathological studies found a high prevalence rate of PTC in HT. In most FNAC studies, the risk ratio of PTC in HT patients was evaluated using multivariate statistical analysis: increased TSH levels represented the main and common independent risk factor of malignancy, although it resulted not consistently related to HT. On the other hand, several studies provided a positive relationship between ATA and PTC, particularly with TgAb. Two recent FNAC studies from the same referral center clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between PTC and ATA and diffuse LTI at histology. These studies are consistent with the hypothesis that autoimmune thyroid inflammation and increased serum TSH concentration may be involved in thyroid tumor growth. The complex relationship between HT and PTC, which involves immunological/hormonal pathogenic links, needs to be further investigated with prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000468928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567004PMC
July 2017

Metabolomic profile in hyperthyroid patients before and after antithyroid drug treatment: Correlation with thyroid hormone and TSH concentration.

Int J Biochem Cell Biol 2017 12 4;93:119-128. Epub 2017 Aug 4.

Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Cagliari, Italy.

Hyperthyroidism (HT) is characterized by an intense metabolic impact which affects the lipid, carbohydrate and amino acids metabolism, with increased resting energy expenditure and thermogenesis. Metabolomics is a new comprehensive technique that allows to capture an instant metabolic picture of an organism, reflecting peculiar molecular and pathophysiological states. The aim of the present prospective study was to identify a distinct metabolomic profile in HT patients using H NMR spectroscopy before and after antithyroid drug treatment. This prospective study included 15 patients (10 female, 5 male) who were newly diagnosed hyperthyroidism. A nuclear magnetic resonance (H NMR) based analysis was performed on plasma samples from the same patients at diagnosis (HypT) and when they achieved euthyroidism (HypT). The case groups were compared with a control group of 26 healthy volunteers (C). Multivariate statistical analysis was performed with Partial Least Squares-Discriminant Analysis (PLS-DA). PLS-DA identified a distinct metabolic profile between C and untreated hyperthyroid patients (RX 0.638, RY 0.932, Q 0.783). Interestingly, a significant difference was also found between C and euthyroid patients after treatment (RX 0.510, RY 0.838, Q 0.607), while similar cluster emerged comparing HypTvs HypT patients. This study shows that metabolomic profile is deeply influenced by hyperthyroidism and this alteration persists after normalization of thyrotropin (TSH) and free thyroid hormone (FT3, FT4) concentration. This suggests that TSH, FT3 and FT4 assays may not be insufficient to detect long lasting peripheral effects of the thyroid hormones action. Further studies are needed to clarify whether and to what extent the evaluation of metabolomics profile may provide relevant information in the clinical management of hyperthyroidism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biocel.2017.07.024DOI Listing
December 2017

Aggressive differentiated thyroid cancer with multiple metastases and NRAS and TERT promoter mutations: A case report.

Oncol Lett 2017 Aug 16;14(2):2186-2190. Epub 2017 Jun 16.

Endocrinology Unit, Department of Medical Sciences 'M. Aresu', University of Cagliari and University Hospital of Cagliari, I-09042 Cagliari, Italy.

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of advanced differentiated thyroid carcinoma (DTC). Resistance to sorafenib may appear under treatment and may be associated with increased aggressiveness of the neoplasia. The present study reports the case of a 65-year-old male who underwent total thyroidectomy for a follicular thyroid carcinoma, Hürthle cell variant, in February 2005. Until January 2010, the patient received four consecutive I doses (total dose, 612 mCi) for increased serum thyroglobulin (Tg) and initial faint lung uptake (which eventually became undetectable). Subsequently, the patient developed several sequential bone (humerus, rib and skull), adrenal and lung metastases, the majority of which were surgically removed. Histological examination in all cases revealed evidence of DTC metastases that were strongly positive for Tg, as revealed by immunohistochemistry. In March 2014, sorafenib therapy was initiated, but it was discontinued 10 months later to allow an undelayable prostatectomy. Immediately upon surgery, the patient developed a large metastatic lesion in the right gluteal muscle, whose biopsy revealed undifferentiated neoplasia of epithelial origin, and the patient succumbed shortly afterwards. An extensive comparative search for biochemical and molecular markers was performed on all available tissues (primary tumor, and differentiated and undifferentiated metastases). The primary tumor and all the available metastases exhibited the same molecular oncogenic markers (namely, the RAS mutation p.Q61R and the telomerase promoter mutation C228T). In addition, the undifferentiated metastasis exhibited a p53 mutation. The present study reports a case of a sudden acceleration of DTC metastatic progression following sorafenib discontinuation, which could have been due to the emergence of sorafenib-resistant undifferentiated p53-positive tumor cell clones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2017.6395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530175PMC
August 2017

Assessment of eating disorders with the diabetes eating problems survey - revised (DEPS-R) in a representative sample of insulin-treated diabetic patients: a validation study in Italy.

BMC Psychiatry 2017 07 19;17(1):262. Epub 2017 Jul 19.

Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.

Background: The purpose of the study was to evaluate in a sample of insulin-treated diabetic patients, with type 1 or type 2 diabetes, the psychometric characteristics of the Italian version of the DEPS-R scale, a diabetes-specific self-report questionnaire used to analyze disordered eating behaviors.

Methods: The study was performed on 211 consecutive insulin-treated diabetic patients attending two specialist centers. Lifetime prevalence of eating disorders (EDs) according to DSM-IV and DSM-5 criteria were assessed by means of the Module H of the Structured Clinical Interview for DSM IV Axis I Disorder and the Module H modified, according to DSM-5 criteria. The following questionnaires were administered: DEPS-R and the Eating Disorder Inventory - 3 (EDI-3). Test/retest reproducibility was assessed on a subgroup of 70 patients. The factorial structure, internal consistency, test-retest reliability and concurrent validity of DEPS-R were assessed.

Results: Overall, 21.8% of the sample met criteria for at least one DSM-5 diagnosis of ED. A "clinical risk" of ED was observed in 13.3% of the sample. Females displayed higher scores at DEPS-R, a higher percentage of at least one diagnosis of ED and a higher clinical risk for ED. A high level of reproducibility and homogeneity of the scale were revealed. A significant correlation was detected between DEPS-R and the 3 ED risk scales of EDI-3.

Conclusions: The data confirmed the overall reliability and validity of the scale. In view of the significance and implications of EDs in diabetic patients, it should be conducted a more extensive investigation of the phenomenon by means of evaluation instruments of demonstrated validity and reliability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12888-017-1434-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518128PMC
July 2017

Regorafenib-induced hypothyroidism and cancer-related fatigue: is there a potential link?

Eur J Endocrinol 2017 Jul 3;177(1):85-92. Epub 2017 May 3.

Endocrinology Unit.

Objective: Thyroid dysfunction has been reported during Regorafenib (Reg) administration, but no detailed study is presently available.

Design: Prospective, observational cohort study. Patients with documented metastatic colorectal cancer and progression of disease during or within 3 months after the last standard therapy, with no evidence and history of previous thyroid disease were enrolled.

Methods: Twenty-five consecutive patients were evaluated before and 8-50 weeks after initiating Reg therapy by monthly clinical, ultrasound and laboratory (thyrotropin (TSH), free thyroxine (fT4), antithyroglobulin (TgAb) and antithyroid peroxidase (TPOAb)) evaluation.

Results: Thirteen/25 patients (52%) became hypothyroid (TSH: 12.5 ± 4.01 IU/L, range: 4.6-22.0) within 5 months of therapy. TPOAb became detectable (99-155 IU/mL) in 2/25 (8%) patients. Thyroid volume progressively decreased (from 8.6  2.2 mL to 4.9 ± 2.4 mL after 5 months of Reg therapy,  < 0.0001). The progression-free survival (PFS) was longer in patients developing hypothyroidism (43 weeks) than in those remaining euthyroid (17 weeks,  < 0.01). Fatigue (the most common general serious Reg adverse event) was associated with hypothyroidism severity and reversed after levothyroxine therapy (L-T4).

Conclusions: Reg rapidly causes hypothyroidism in about 50% of patients and in a minority of them also triggers thyroid autoimmunity. Reg-induced hypothyroidism was strictly related to fatigue, easily reversed by L-T4 administration and associated to longer survival. These results suggest that prompt recognition of hypothyroidism in patients with severe fatigue may prevent unnecessary Reg dose reduction or withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-17-0231DOI Listing
July 2017

Off-target effects and clinical outcome in metastatic colorectal cancer patients receiving regorafenib: The TRIBUTE analysis.

Sci Rep 2017 04 5;7:45703. Epub 2017 Apr 5.

Medical Oncology, University Hospital and University of Cagliari, Cagliari, Italy.

Regorafenib is an orally administered multikinase inhibitor indicated for the treatment of heavily pretreated metastatic colorectal cancer patients with good performance status, albeit less than 50% treated patients achieve disease stabilisation or better at the first radiological evaluation. In addition to that a particularly broad spectrum of toxicities (experienced as G3 or more NCI CTCAE graded by 50% of patients treated) have led to reconsider its widespread use in the majority of patients. We retrospectively collected data about the magnitude of off-target effects experienced during the first 8-weeks of regorafenib monotherapy and analysed their correlation with overall survival, progression free survival and disease control rate. Our findings suggest that skin rash (Exp (B): 0.52, p = 0.0133) or hypothyroidism (Exp (B): 0.11, p = 0.0349) were significantly correlated with improved overall survival at multivariate regression analysis. It was also demonstrated a statistically significant role of diarrhea as predictor of improved survival but its independent prognostic role was lost at multivariate analysis (Exp (B): 0.63, p = 0.162). This is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, however sample size limitations and the retrospective nature of our analysis prevent us from drawing definitive conclusions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep45703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380985PMC
April 2017

The birth and rise of a craniopharyngioma: the radiological evolution of an incidental craniopharyngioma detected on serial MRI during medical treatment of a macroprolactinoma.

Clin Case Rep 2017 Jan 20;5(1):14-17. Epub 2016 Nov 20.

Radiology Department of Medical Sciences University of Cagliari Cagliari Italy.

This case demonstrates the rare coexistence of a prolactinoma with craniopharyngioma and documents its radiological growth. This case suggests that patients with pituitary neoplasms should be followed closely and although prolactinomas can often be managed medically, a coexistent other lesion may require surgery for histological assessment and to reduce mass effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224775PMC
January 2017

Hypothyroidism and Thyroid Autoimmunity as a Prognostic Biomarker of Better Response in Metastatic Cancer Long-Term Survivors Treated with Sunitinib.

Thyroid 2016 09 11;26(9):1336-7. Epub 2016 Jul 11.

1 Endocrinology Unit, Department of Medical Sciences "M. Aresu," University of Cagliari , Cagliari, Italy .

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2016.0159DOI Listing
September 2016

VGF Peptide Profiles in Type 2 Diabetic Patients' Plasma and in Obese Mice.

PLoS One 2015 12;10(11):e0142333. Epub 2015 Nov 12.

Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy.

To address the possible involvement of VGF peptides in obesity and diabetes, we studied type 2 diabetes (T2D) and obese patients, and high-fat diet induced obese mice. Two VGF peptides (NAPP-19 and QQET-30) were identified in human plasma by HPLC-ESI-MS. The VGF C-terminus, the above two cleaved peptides, and the TLQP-21 related peptide/s were studied using ELISA and immunohistochemistry. In euglycemic patients, plasma NAPPE and TLQP like peptides were significantly reduced with obesity (74±10 vs. 167±28, and 92±10 vs. 191±19 pmol/ml, mean+SEM, n = 10 and 6, obese vs. normal BMI, respectively, p<0.03). Upon a standard glucose load, a distinct response was shown for VGF C-terminus, TLQP and QQET-like (ERVW immunoreactive) peptides in euglycemic normal BMI patients, but was virtually abolished in euglycemic obese, and in T2D patients independently of BMI. High-fat diet induced obese mice showed reduced plasma VGF C-terminus, NAPPE and QQET-like (ERVW) peptide/s (3±0.2 vs. 4.6±0.3, 22±3.5 vs. 34±1.3, and 48±7 vs. 100±7 pmol/ml, mean+SEM, n = 8/group, obese vs. slim, respectively, p<0.03), with a loss of the response to glucose for all VGF peptides studied. In immunohistochemistry, TLQP and/or VGF C-terminus antibodies labelled VGF containing perikarya in mouse celiac ganglia, pancreatic islet cells and thin beaded nerve fibres in brown adipose tissues, with fewer in white adipose tissue. Upon the glucose load, tyrosine hydroxylase and VGF C-terminus immunoreactive axons became apparent in pancreatic islets of slim animals, but not in obese animals. Alltogether, a significant loss of VGF peptide immunoreactivity and/or their response to glucose was demonstrated in obese patients, with or without T2D, in parallel with a similar loss in high-fat diet induced obese mice. An involvement of VGF in metabolic regulations, including those of brown and/or white adipose tissues is underlined, and may point out specific VGF peptides as potential targets for diagnosis and/or treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643017PMC
June 2016

Thyroid Dysfunction in Patients with Metastatic Carcinoma Treated with Sunitinib: Is Thyroid Autoimmunity Involved?

Thyroid 2015 Nov 14;25(11):1255-61. Epub 2015 Oct 14.

1 Endocrinology Unit, University of Cagliari , Cagliari, Italy .

Background: Sunitinib is a tyrosine kinase inhibitor (TKI) inducing thyroid dysfunction, but the precise mechanism(s) involved remains to be explained, including the role of thyroid autoimmunity. The objective of this study was to evaluate thyroid function, parameters of autoimmunity, and thyroid ultrasound findings in patients with metastatic cancer and normal thyroid function/autoimmunity before the initiation of sunitinib therapy. This was a prospective, observational cohort study.

Methods: Twenty-seven patients with metastatic carcinomas at comparable tumor stages were evaluated over 12-18 months after initiating therapy with sunitinib given at a daily oral dose of 50 mg for four weeks (ON), followed by one to two weeks off therapy (OFF). Serum thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and antithyroglobulin (TgAb), and antithyroid peroxidase (TPOAb) autoantibodies were measured in all cases. Thyroid morphology and volume were evaluated by echo-color Doppler ultrasound.

Results: A total of 16/27 patients (60%) became hypothyroid (TSH range 7-114 mIU/L) within 30-120 days of therapy. The thyroid volume decreased in 24/27 (89%) patients (from M = 14.6 mL, SD = 6.4 mL to M = 3.8 mL, SD = 2.6 mL after 12 months; p < 0.001), together with the appearance of mild to severe hypoechogenicity. TPOAb (40-3000 IU/mL) became detectable in 7/27 (25%) patients, and TPOAb-positive patients displayed a higher degree of hypothyroidism and volume reduction. The progression-free survival (PFS) was significantly longer in patients developing TPOAb (10.8 months) than in the other group of patients (5.8 months).

Conclusions: These data confirm the thyroid inhibitory effect of sunitinib, in keeping with the key role of kinases in controlling thyroid function and growth. However, the novel appearance of TPOAb in a subgroup of patients with more severe hypothyroidism and longer survival indicates that sunitinib may also trigger/exacerbate thyroid autoimmunity contributing to thyroid failure. The development of TPOAb was associated with a longer PFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2015.0170DOI Listing
November 2015

Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study.

Acta Diabetol 2016 Feb 22;53(1):73-9. Epub 2015 Apr 22.

Department of Medical Sciences "Mario Aresu", University of Cagliari, AOU, SS 554, Monserrato, Cagliari, Italy.

Aims: Stable genetic background makes individuals from the Mediterranean island of Sardinia ideal to define the predictive power of islet-related autoantibodies (IRAs): glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase-like antibodies (IA-2A), islet cell antibodies (ICA) to identify T1DM progressors. The aims of the present study were: (1) determination of IRAs reference limits in healthy non-diabetic Sardinian schoolchildren (SSc). (2) Predictive power evaluation of IRAs as single or combined determination to identify islet to identify T1DM progressors.

Methods: Between 1986 and 1994, 8448 SSc were tested for IRAs. All were followed up for 10 years. The predictive power of single or combination of IRAs was determined as hazard ratio (HR), sensitivity, specificity, area under the ROC curve, negative and positive predictive value (NPV, PPV).

Results: All 43 progressors to T1DM, but three showed at least one autoantibody positivity. HR for any single-autoantibody positivity was 55.3 times greater when compared to SSc negative for all IRAs. Any single autoantibody performed at least 64.9 % sensitivity with PPV always lower than 16 %. The best performing combination was ICA, plus IA-2A (showing 52.6 % sensitivity, 99.8 % specificity, 0.76 area under the ROC curve, 51.3 % PPV and 99.8 % NPV.

Conclusions: Determination of IRAs reference limits in healthy SSc by standard statistical methods is crucial to establish the power of IRAs as progression markers to T1DM. Our data offer a solid rationale for future testing of ICA and IA-2A as routine laboratory markers to identify individuals at high risk of T1DM in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00592-015-0751-yDOI Listing
February 2016

Is the incidence of differentiated thyroid cancer increased in patients with thyrotropin-secreting adenomas? Report of three cases from a large consecutive series.

Thyroid 2015 Apr 9;25(4):417-24. Epub 2015 Mar 9.

1 Pituitary Unit, Department of Neurosurgery, Istituto Scientifico San Raffaele, Università Vita-Salute , Milan, Italy .

Background: Patients with a thyrotropin-secreting pituitary adenoma (TSHoma) are exposed to unregulated and inappropriately high levels of thyrotropin (TSH). Given the rarity of this condition, it is not known whether this chronic TSH stimulation of the thyroid gland might represent a risk factor for the development of differentiated thyroid cancer (DTC). We analyzed the incidence of DTC in a large cohort of patients with TSHomas.

Methods: The study population consisted of all consecutive patients who underwent neurosurgery for a TSHoma between 1990 and 2013. Criteria for the diagnosis of TSHoma in patients without previous thyroid ablative procedures included elevated free thyroid hormones and normal/high serum TSH concentrations, presence of a lesion at magnetic resonance imaging (MRI), and abnormal response of TSH to at least one dynamic test. Patients who had received thyroid ablative procedures were required to have a pituitary lesion on MRI and TSH levels not suppressed while on levothyroxine therapy at doses causing elevation of free thyroid hormone levels.

Results: Sixty-two patients (32 females, 30 males) underwent surgery for a TSHoma at our center. Among them, 3 patients had a coexistent diagnosis of DTC with an estimated incidence of 4.8%. In 2 patients, DTC was diagnosed during the evaluation for suspected TSH-dependent hyperthyroidism, whereas in the third patient, diagnosis of DTC preceded the detection of the pituitary tumor.

Conclusions: The elevated incidence of DTC in patients with TSHoma suggests a possible role of TSH hypersecretion in the development of thyroid tumors. A formal high-resolution ultrasound of the thyroid is recommended in patients diagnosed with a TSHoma, especially if a long history of the pituitary tumor is suspected. Moreover, suspicion about the presence of TSHoma should be raised by the lack of suppression of TSH levels despite adequate doses of levothyroxine after thyroidectomy for DTC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2014.0222DOI Listing
April 2015

Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4).

Endocr Connect 2015 03 21;4(1):1-8. Epub 2014 Nov 21.

F Cetani, Department of Clinical and Experimental Medicine, University of Pisa, Endocrine Unit 2, University Hospital of Pisa, Pisa, Italy

Inactivating germline mutations of the CDKN1B gene, encoding for the nuclear cyclin-dependent kinase inhibitor p27kip1 protein, have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to in vitro characterize the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by multiglandular primary hyperparathyroidism and gastro-entero-pancreatic tumors. We carried out subcellular localization experiments transfecting into eukaryotic HeLa and GH3 cell lines plasmid vectors expressing the CDKN1B wild type (wt) or mutant cDNA. Western blot studies showed that fusion proteins were expressed at equal levels. The mutated protein was shorter compared to the wt protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells wt p27 localized in the nucleus whereas the p27_S125X protein was retained in the cytoplasm predicting the loss of tumor suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, since wt and mutant alleles were both present by sequencing the somatic DNA. Immunohistochemistry showed a complete loss of nuclear p27 expression in the parathyroid adenoma removed by the patient at the second surgery. In conclusion, our study confirms the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-14-0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713151PMC
March 2015

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

PLoS Genet 2014 Feb 27;10(2):e1004123. Epub 2014 Feb 27.

Department of Endocrinology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937134PMC
February 2014

Optimizing detection of RET and PPARg rearrangements in thyroid neoplastic cells using a home-brew tetracolor probe.

Cancer Cytopathol 2014 May 7;122(5):377-85. Epub 2014 Feb 7.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

Background: Fluorescence in situ hybridization (FISH) to identify specific DNA target sequences in the nuclei of nondividing cells of numerous solid neoplasms has contributed to the introduction of molecular cytogenetics as a useful adjunct to cytology, leading recently to the "marriage" of the 2 disciplines. Numerous cancer molecular markers can now be investigated using different technical approaches, at both the gene and expression levels, in biopsies of various suspected cancers, including differentiated thyroid carcinoma. The limited amount of bioptic material is often insufficient to carry out multiple tests, and optimizing handling of the biopsy is desirable.

Methods: We have developed a home-brew tetracolor break-apart probe able to simultaneously identify the 2 most common genetic alterations in differentiated thyroid carcinoma: RET/PTC variants in papillary thyroid carcinoma and PAX8/PPARg fusion and variants in follicular thyroid carcinoma.

Results: The probe had 100% specificity, 99.5% sensitivity, and ≥ 3% cutoff. The probe was tested on RET/PTC and PAX8/PPARg RT-PCR positive controls, and feasibility was assessed in 368 thyroid nodule fine-needle aspirations (FNA). In the latter analysis, 24 FNAs had split RET signal, and 9 had split PPARg signal. FISH analysis of available surgically removed nodules confirmed the sensitivity of FISH in detecting abnormal clones and oligoclones.

Conclusions: The home-brew tetracolor probe showed high feasibility, optimizing the use of the biological material in relation to the available molecular tests and maximizing the FISH experimental and slide-scoring times. This probe may be considered an alternative to RT-PCR when recovery and quality of RNA amplification from FNA are insufficient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.21397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231233PMC
May 2014

Differentiated thyroid cancer: indications and extent of central neck dissection--our experience.

Int J Surg Oncol 2013 26;2013:625193. Epub 2013 Sep 26.

Department of Surgical Sciences, University of Cagliari, 09100 Cagliari, Italy.

The aim of this retrospective study was to determine the rate of metastases in the central neck compartment and examine the morbidity and rate of recurrence in patients with differentiated thyroid cancer treated with or without a central neck dissection. Two hundred and fifteen patients undergoing total thyroidectomy with preoperative diagnosis of differentiated thyroid cancer, in the absence of suspicious nodes, were divided in two groups: those who underwent a thyroidectomy only (group A; n = 169) and those who also received a central neck dissection (group B; n = 46). Five cases (2.32%) of nodal recurrence were observed: 3 in group A and 2 in group B. Tumor histology was associated with a risk of recurrence: Hürthle cell-variant and tall cell-variant carcinomas were associated with a high risk of recurrence. Multifocality and extrathyroidal invasion also presented a higher risk, while smaller tumors were at lower risk. The results of this study suggest that prophylactic central neck dissection should be reserved for high-risk patients only. A wider use of immunocytochemical and genetic markers to improve preoperative diagnosis and the development of methods for the intraoperative identification of metastatic lymph nodes will be useful in the future for the improved selection of patients for central neck dissections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/625193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804149PMC
July 2014

Assessing RET/PTC in thyroid nodule fine-needle aspirates: the FISH point of view.

Endocr Relat Cancer 2013 Aug 27;20(4):527-36. Epub 2013 Jun 27.

Department of Biomedical Sciences, M. Aresu Surgical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (Cagliari), Italy.

RET/PTC rearrangement and BRAF(V600E) mutation are the two prevalent molecular alterations associated with papillary thyroid carcinoma (PTC), and their identification is increasingly being used as an adjunct to cytology in diagnosing PTC. However, there are caveats associated with the use of the molecular approach in fine-needle aspiration (FNA), particularly for RET/PTC, that should be taken into consideration. It has been claimed that a clonal or sporadic presence of this abnormality in follicular cells can distinguish between malignant and benign nodules. Nevertheless, the most commonly used PCR-based techniques lack the capacity to quantify the number of abnormal cells. Because fluorescence in situ hybridization (FISH) is the most sensitive method for detecting gene rearrangement in a single cell, we compared results from FISH and conventional RT-PCR obtained in FNA of a large cohort of consecutive patients with suspicious nodules and investigated the feasibility of setting a FISH-FNA threshold capable of distinguishing non-clonal from clonal molecular events. For this purpose, a home brew break-apart probe, able to recognize the physical breakage of RET, was designed. While a ≥3% FISH signal for broken RET was sufficient to distinguish nodules with abnormal follicular cells, only samples with a ≥6.8% break-apart FISH signal also exhibited positive RT-PCR results. On histological analysis, all nodules meeting the ≥6.8% threshold proved to be malignant. These data corroborate the power of FISH when compared with RT-PCR in quantifying the presence of RET/PTC in FNA and validate the RT-PCR efficiency in detecting clonal RET/PTC alterations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-13-0157DOI Listing
August 2013

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

PLoS Genet 2013 7;9(2):e1003266. Epub 2013 Feb 7.

Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1003266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567175PMC
June 2013