Antonio Polini

Is Elastography Actually Useful in the Presurgical Selection of Thyroid Nodules with Indeterminate Cytology

BACKGROUND Although fine-needle aspiration cytology remains the mainstay of the preoperative workup of thyroid nodules, those with follicular proliferation still represent a diagnostic challenge. Real-time elastography (RTE) estimates the stiffness/elasticity of lesions and is regarded as a promising technique for the presurgical selection of thyroid nodules (including those with indeterminate cytology). AIM Our aim was to verify the potential role of RTE in the presurgical diagnosis of cancer in a large cohort of consecutive patients with follicular thyroid nodules. PATIENTS AND METHODS One hundred two patients were submitted to conventional ultrasonography and RTE evaluation before being operated on for thyroid nodule with indeterminate cytology (54% single nodules). Tissue stiffness on RTE was scored from 1 (greatest elasticity) to 4 (no elasticity). RESULTS At conventional ultrasonography examination, the nodules (median diameter 2.2 cm) were solid (cystic areas < 10%); microcalcifications were detected in 56% of them and a hypoechoic pattern in 64%. Elasticity was high in eight cases only (score 1-2) although low in 94 (score 3-4). Cancer was diagnosed in 36 nodules (35%), being associated with microcalcifications (P < 0.0001) and inversely related to nodule diameter (P < 0.01). Malignancy was detected in 50% of the nodules with RTE score 1-2 and in 34% of those with score 3-4. Therefore, either the positive (34%) or the negative predictive value (50%) was clinically negligible. CONCLUSIONS The current study does not confirm the recently reported usefulness of RTE in presurgical selection of nodules with indeterminate cytology and suggest the need for quantitative analytical assessment of nodule stiffness to improve RTE efficacy.

Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in late-onset Alzheimer's disease patients and healthy controls.

AIMS We screened 378 late-onset Alzheimers disease (LOAD) patients and 308 matched controls for the presence of the common MTHFR 677C>T, MTRR 66A>G, MTR 2756 A>G, and TYMS 28 bp repeat polymorphisms, searching for association with disease risk and age at onset. Moreover, we searched for correlation between each of the studied polymorphisms and available data on plasma homocysteine (Hcy), serum folate, and vitamin B12 values. RESULTS We observed a significant increased frequency of the MTHFR 677T allele (0.48 vs. 0.42; p=0.019) and of MTHFR 677CT (OR=1.46; 95%CI=1.03-2.06) and TT genotypes (OR=1.62; 95%CI=1.05-2.49) in LOAD subjects with respect to controls. We also observed a significant increased frequency of the MTRR 66G allele (0.49 vs. 0.43; p=0.044) and of the MTRR 66GG genotype (OR=1.57; 95%CI=1.01-2.46) in the LOAD group. Significantly increased mean plasma Hcy levels (22.7±1.7 vs 14.5±1.7 μmol/L; p=0.037) and decreased serum folate values (5.7±0.5 vs. 7.8±0.8 ng/mL; p=0.005) were observed in LOAD subjects with respect to controls, whilst the difference in serum vitamin B12 values did not reach statistical significance. Several interactions between the studied polymorphisms and biochemical biomarkers were observed. None of the studied polymorphisms was associated with disease age at onset. INNOVATION The present study suggests that the MTRR 66G allele might contribute to LOAD risk and confirms an increased frequency of the MTHFR 677T allele in LOAD. CONCLUSION Overall, present results support a contribution for one-carbon metabolism to LOAD pathogenesis.

Inducible Nitric Oxide Synthase Is Involved in Endothelial Dysfunction of Mesenteric Small Arteries from Hypothyroid Rats

The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T(4) replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T(4) replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability.

Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study.

BACKGROUND Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated thyrotropin (TSH, <10 mIU/L). In this study, we assessed the possible influence of gender and age on this relationship. METHODS The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 women, 434 men, mean age 47.5±14.1 and 46.9±14.0 years, respectively) and on whom studies of thyroid status and lipoprotein profile were conducted after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. RESULTS There were 628 patients receiving L-thyroxine who had a diagnosis of hypothyroidism: 200 were hyperthyroid, and 120 were still hypothyroid. Overall, 648 patients were hypothyroid, and 290 were hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e., TSH frequency distribution) was observed. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/high-density lipoprotein cholesterol (HDLc) ratio (p<0.03) were elevated not only in unselected women with TSH values in the 4th TSH group (>10 mIU/L) but also in those of the 3rd group (3.6-10.0 mIU/L) who were older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 vs. euthyroid women). Among unselected men, only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group who were older than 65 years had significantly higher TC, LDLc, and LDL/HDLc values as well (p=0.03, p=0.02 and p=0.01, respectively vs. euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, free thyroxine (FT4), and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) when looking at TC and LDLc; whereas BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) when looking at triglyceride variation. CONCLUSIONS This study confirms a gender differentiation in the relationship between hypothyroidism and the lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/L).

1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters

INTRODUCTION The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively. AIM The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features. PATIENTS AND METHODS P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 +/- 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter. RESULTS The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). CONCLUSIONS Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.

Soluble Human Leukocyte Antigen-G and Its Insertion/Deletion Polymorphism in Papillary Thyroid Carcinoma: Novel Potential Biomarkers of Disease?

INTRODUCTION Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers. AIMS Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimotos thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness. METHODS Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines. RESULTS Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 ± 3.3 ng/ml; P = 0.002) and HT patients (49.1 ± 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 ± 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without. CONCLUSIONS Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression.

Cardiovascular Risk and Quality of Life in Elderly People with Mild Thyroid Hormone Deficiency

Subclinical hypothyroidism (sHT) is a common condition in the general population, the prevalence increases with age, especially in women. An association between sHT and increased coronary heart disease (CHD) and heart failure (HF) risk and mortality has been described. However, this association is far to be established in older people (>65 years), especially in the oldest old (>85 years). Individuals with sHT may experience symptoms that resemble those observed in the overt form of the disease, leading to an impaired quality of life (QoL). Although very old people are frequently frail and potentially more susceptible to the effects of a disease, few studies were designed to assess the effect of sHT on QoL in this subset of population. Interestingly, the serum TSH concentration curve of general population has a skewed distribution with a “tail” toward higher values, which is amplified with aging. Thus, the diagnosis of sHT and the interpretation of its potential effects on CV function and QoL in older people may be a challenge for the clinician. Giving these premises, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) since 1980 regarding hypothyroidism, sHT, elderly, cardiovascular risk, CHD or HF events and mortality, health-related QoL, and LT4 therapy. Consistent results among large prospective cohort studies suggest an age-independent relationship between sHT and HF progression, while an impact of sHT on CHD events and mortality is essentially reported in young adults (aged below 65–70 years) with long-lasting disease. Scanty data are available on QoL of older people with sHT (>65 years) and, generally, no significant alterations are described.

Fasting hyperglycaemia and in-hospital mortality in elderly population

Background:  Admission hyperglycaemia has shown to be a marker of poor clinical outcome. The prevalence of admission hyperglycaemia and its relationship with in‐hospital mortality in elderly population has not been clearly defined. We assessed the prevalence and prognostic significance of admission fasting hyperglycaemia in aged patients.

Off-Label Use of Sunitinib in Patients with Advanced, Epithelial Thyroid Cancer: A Retrospective Analysis

Tyrosine kinase receptors play an important role in tumor angiogenesis and, their implication in epithelial thyroid tumor growth has been highlighted. Sunitinib is a novel tyrosine kinase inhibitor, approved in 2006 by Food and Drug Administration for the treatment of advanced renal cell and gastrointestinal stromal tumors. Preliminary promising results have been also obtained in patients with RAI-resistant thyroid neoplasia. In the current study, our experience on 9 patients with advanced thyroid epithelial cancer is analyzed and discussed in relation to the new patents in this field. According to RECIST criteria, partial response was obtained in 5/9 (55.5%) patients at 3 months and in 6/9 (66.6%) at 6 months. Median treatment follow-up was 13.0 months and median overall survival and progression-free survival were 20 [95% confidence interval (CI) 9.3 - 30.6] and 21 months (95% CI 6.9 - 35.1), respectively. One case of severe thoracic hemorrhage was observed, the most common adverse events being represented by fatigue, (44.4% ), skin rash (33.3% ), headache (33.3% ), and one case each of hypertension, macrocytosis and acute pneumonia. These results confirm sunitinib as a potential useful tool for the treatment of advanced thyroid cancers and may open the way for new patents of molecules with more specific target selectivity.

Cognitive Function and Quality of Life in Mild Thyroid Hormone Deficiency

Subclinical hypothyroidism (sHT) is very common in general population, especially in women and older people. sHT individuals may experience symptoms that resemble those observed in overt hypothyroidism, resulting in impaired quality of life (QOL). Asymptomatic patients may suffer a reduction in perceived health status due to the awareness of disease. Cognitive function represents one of the most important domains of the QOL questionnaires. Given the intrinsic relationship between cognitive status and QOL it is worth to address these topics together, in a systematic review of the literature. Thus, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) sine 1980 regarding hypothyroidism, sHT, elderly, L-thyroxine (LT4) therapy, QOL, cognition, brain. We supplemented the search with records from personal files, textbooks, and relevant articles. The possible link, at molecular level, between cognition and thyroid failure was also assessed. Conflicting results on the association between sHT and cognitive and health related QOL impairment are still present, although the most recent, naturalistic studies did not find any significant relationship. Interestingly, a reduction in health related QOL is frequently reported in patients with thyroid autoimmune diseases regardless of thyroid dysfunction. We also report most significant patents on the topic.