Role of the mononuclear cell infiltrate in Graves' orbitopathy (GO): results of a large cohort study.

OBJECTIVE: The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves' orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients. METHODS: We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery. RESULTS: Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI - 0.33 to - 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses. CONCLUSIONS: Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis.

Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

PURPOSE: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse effects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may affect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. METHODS: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. RESULTS: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted significantly associated (14/32, 43.7%) with Hashimoto's thyroiditis, compared to first generation (7/37, 18.9%; p = 0.03). Interestingly, we also found a significant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto's thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p = 0.0001) and hypothyroid (0/43, 0%; p = 0.02) Hashimoto's thyroiditis patients with major molecular response. CONCLUSIONS: Our study confirms and extends our knowledge on the tyrosine kinase inhibitors effects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response.

Features and outcome of differentiated thyroid carcinoma associated with Graves' disease: results of a large, retrospective, multicenter study.

BACKGROUND: Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves' disease (GD) is more aggressive and bound to a less favorable outcome is controversial. OBJECTIVE: Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD-). PATIENTS: Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD-. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. RESULTS: Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD- patients were free of disease. Patients with persistent or recurrent disease (PRD) had "biochemical disease" in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves' orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism. CONCLUSIONS: GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

Primary thyroid leiomyosarcoma: a case report and review of the literature.

Primary thyroid leiomyosarcoma (LMS) is an extremely rare tumor. We report a case of a 47-year-old male with a rapidly growing neck mass and disfagia. Preoperative investigations were diagnostic of anaplastic carcinoma. Total thyroidectomy with partial esophagectomy and dissection of right infrahyoid muscles was performed. Through histolological and immunohistochemical evaluations a primary thyroid high-grade LMS was diagnosed. At 2 months of follow-up a local recurrence was detected and consequently the patient was submitted to chemotherapy with partial response. He is still alive 9 months after surgery. Diagnosis of primary thyroid LMS is difficult due to its similarity to other more common thyroid tumors. To date, there is no standard therapy and prognosis is poor.

High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up.

BACKGROUND: The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains to be elucidated. MATERIALS AND METHODS: A total of 484 HT patients were retrospectively subdivided into two groups: 243 without thyroid nodules, TNs (HTN-) and 241 with TNs (HTN+). Fine-needle aspiration cytology was available in 152 HTN+ patients. This group was compared to a group of 161 patients with nodular goiter (NG) without HT. Finally, 70 HTN+ and 37 NG patients underwent surgery. RESULTS: A very high prevalence of suspicious/malignant cytology (Thy 4-5) at the first diagnosis (38/124; 31%) and during the follow-up (6/28; 22%) was found in HTN+ group. In HTN- group, 22/130 (17%) patients developed TN, but none showed malignant features during the follow-up. HTN+ patients had higher prevalence of Thy 4-5 (44/152 = 28.9%) compared to NG patients (12/161 = 7.4%, p < 0.0001). Increased independent odds ratio (OR) for malignancy was conferred by serum TSH > 1.0 µUI/ml, [OR 1.93, 95% confidence interval (CI) 1.41-2.64, p < 0.0001], male sex (OR 3.44, CI 1.48-8.02, p = 0.004) and HT (OR 3.14; CI 1.08-9.31, p < 0.05). Malignant histology (mostly PTC) was confirmed higher in HTN+ (48/70, 68.6%) compared to NG (15/37, 40.5%; p < 0.05). Higher prevalence of extrathyroidal infiltration (24/48, 50%) and vascular invasion (25/48, 52%) was found in HTN+ vs NG (2/15, 1.3% p < 0.01), (3/16, 1.8% p < 0.05), respectively. CONCLUSIONS: This study confirms higher prevalence of suspicious/malignant cytology and PTC at histology in nodular HT compared to NG, without evidence of malignancy in non-nodular HT patients during the follow-up.

Recommendations for post-surgical thyroid ablation in differentiated thyroid cancer: a 2015 position statement of the Italian Society of Endocrinology.

UNLABELLED: Post-surgical ablation of thyroid remnant with radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is aimed to destroy any thyroid remnant in the thyroid bed (remnant ablation) and any microscopic foci of cancer cells eventually present within the thyroid remnant (adjuvant therapy). The present text is an attempt to offer practice guidelines for the indication of thyroid ablation and the preparation of DTC patients considering the latest achievement in the field and the changing epidemiology of DTC observed in the last 10 years. METHODOLOGY: The executive committee of the Italian Society of Endocrinology appointed a task force of thyroid cancer expert including Nuclear Medicine Physicians and Endocrinologists to provide a consensus on the post-surgical ablation in thyroid cancer patients. The task force had no conflict of interest and had no commercial support. A number of specific topics were selected and the members selected relevant papers by searching in the Pubmed for articles published from 2000 to January 2015. Selected studies were categorized by level of evidence, and the recommendations were graded according to the level of evidence as high (A), moderate (B), or low (C).

Clinical models and biochemical predictors of VTE in lung cancer.

Venous thromboembolism (VTE) is a frequent complication of lung cancer and its treatment, especially in the advanced stages of disease. The risk of a pro-thrombotic state might increase through the activation of hemostasis, occurring both via the induction of a pro-coagulant activity and with platelet involvement, ultimately leading to the development of metastases. Despite the acknowledgement of an increased thrombophilic condition in cancer patients, and the experimental evidence that heparin compounds may have direct anticancer benefits, there is no univocal consent regarding VTE prevention in cancer outpatients receiving therapy. Thus, many authors highlighted the need for the development of stratification techniques to identify at-risk patients who might benefit from thromboprophylaxis. Clinical risk models were developed and validated, in order to assign high-risk patients to a proper thromboprophylaxis regimen that, however, might not be justified in all clusters. Besides, efforts have been devoted to identify candidate biomarkers that may be used in VTE risk assessment, although none has been recognized, so far, as a predictor for VTE in lung cancer patients. In this review, we will summarize the latest information concerning this very controversial topic, with focus on some of the proposed strategies to select the appropriate patients for prophylaxis.

Both thyroid autoimmunity and increased serum TSH are independent risk factors for malignancy in patients with thyroid nodules.

AIM: To assess the relevance of thyroid autoimmunity and TSH as risk factors for malignancy in thyroid nodules (TN). SUBJECTS AND METHODS: Retrospective analysis on 2053 patients with single/prevalent TN submitted to fine needle aspiration cytology (FNAC). Anti-thyroid autoantibodies (ATA) [anti-thyroperoxidase (TPOAb), anti-thyroglobulin (TgAb)] and TSH were measured. Cytology was classified as benign (class II), indeterminate (class III), and suspicious or malignant (class IV). Histology was available in 301 patients. Associations of malignancy with independent variables were determined by multivariate logistic regression analysis. RESULTS: Higher prevalence of class IV (14.2% vs 6.8%: p<0.001) and class III (23.5% vs 17.1%: p<0.001) were found in ATA+ vs ATA- TN. Histology confirmed increased prevalence of cancer in ATA+ (p<0.05) TN and in those with diffuse lymphocytic thyroid infiltration (p<0.05). Interestingly, the prevalence of malignancies observed in operated class III nodules was strikingly lower in ATA+ (1/20, 5%), than in ATA- patients (34/67, 50.7%; p<0.001). Increased independent odds ratio (OR) for malignancy was conferred by any ATA [OR 2.21; 95% confidence interval (CI)=1.49-3.29, p<0.0001]; TPOAb (OR 2.15; CI=1.42-3.25, p<0.0001) and TgAb (OR 1.67; CI=1.05-2.67, p<0.05), by serum TSH>1.0 µUI/ml (OR 1.95; CI=1.01-3.76, p<0.05), and by young age (10-29 yr: OR 2.09; CI=1.02-4.26, p<0.05). A formula was calculated to assess the relative contribution of ATA, TSH, and age to the risk of TN malignancy. CONCLUSIONS: Both thyroid autoimmunity and increased TSH represent independent risk factors for TN malignancy.

Intraoperative parathyroid hormone assay during focused parathyroidectomy for primary hyperparathyroidism: is it really mandatory?

AIM: Intraoperative parathyroid hormone (PTH) assay has become an essential tool in focused parathyroid surgery. The aim of this study was to evaluate the present role of intraoperative PTH monitoring during focused parathyroidectomy for primary hyperparathyroidism in our experience. METHODS: One hundred sixty-one patients were submitted to focused parathyroidectomy with rapid intraoperative Parathyroid hormone assay monitoring. RESULTS: A >50% decrease of PTH occurred in 147 patients (91.3%); in this group persistent hypercalcemia was found in 1; in the remaining 14 (8.7%) values of PTH decreased less than 50% and bilateral neck exploration was performed. An additional pathologic parathyroid was removed in 8 cases, a third in one; in the other five further neck exploration was negative and in four of these persistent postoperative hypercalcemia was demonstrated. In 136 patients >50% decrease of PTH was obtained after 10 minutes, in the other 11 after 20. The overall operative success of the patients was 96.9% with a 5.6% incidence of multiglandular disease. Intraoperative parathormone monitoring changed the operative management in 8.7% of cases. Intraoperative parathormone monitoring was accurate in predicting operative success or failure in 98.7% of patients, with a sensitivity of 99.3%, a specificity of 92.8%, a positive predictive value of 99.3% and a negative predictive value of 92.8%. DISCUSSION AND CONCLUSION: The measurement of intraoperative PTH represents a useful tool to assist the surgeon during parathyroid surgery and its routine use significantly improves cure rates of focused parathyroidectomy. We believe that the use intraoperative PTH is still mandatory in focused parathyroidectomy avoiding relapses and consequent reintervention.

Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia.

BACKGROUND: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open. AIM: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes. METHODS: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters. RESULTS: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%). CONCLUSIONS: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.

Prevalence of Type 1 diabetes autoantibodies (GAD and IA2) in Sardinian children and adolescents with autoimmune thyroiditis.

AIMS: Type 1 diabetes and autoimmune thyroiditis are common autoimmune diseases characterized by the presence of autoantibodies against tissue-specific components. Non-thyroid-specific autoantibodies are frequent in patients with autoimmune thyroiditis. The prevalence of Type 1 diabetes autoantibodies in patients with autoimmune thyroiditis is unknown. METHODS: The prevalence of Type 1 diabetes autoantibodies (GAD and IA2) was analysed in 236 Sardinian children and adolescents with autoimmune thyroiditis. GAD and IA2 antibodies were measured at the time of the diagnosis of autoimmune thyroiditis and re-evaluated after 1 year in the children who were shown to be positive. Autoantibody prevalence was evaluated in 949 healthy age-matched controls. RESULTS: The prevalence of GAD and/or IA2 antibodies was 8% in the children and adolescents with autoimmune thyroiditis and 4.1% in control subjects (P = 0.017). When Type 1 diabetes autoantibodies were separately analysed, the difference remained significant for IA2 (3.39% in autoimmune thyroiditis vs. 1.16% in control subjects, P = 0.012), but not for GAD (5.1% in autoimmune thyroiditis vs. 3.79% in control subjects, P = 0.367). Seven of 10 children with autoimmune thyroiditis and detectable Type 1 diabetes autoantibodies at the diagnosis remained positive after 1 year. In the course of 2 years of follow-up, two patients who were positive for Type 1 diabetes autoantibodies at the time of diagnosis of autoimmune thyroiditis developed diabetes. CONCLUSIONS: This is the first study reporting the prevalence of Type 1 diabetes autoantibodies in a selected cohort of genetically homogeneous children and adolescents with autoimmune thyroiditis. The main finding was that the prevalence of Type 1 diabetes autoantibodies and of newly diagnosed Type 1 diabetes in patients with autoimmune thyroiditis was significantly higher than that observed in the general paediatric population, suggesting that children with autoimmune thyroiditis are at increased risk of developing Type 1 diabetes.

Determinants of homocysteine levels in colorectal and breast cancer patients.

BACKGROUND: Homocysteinemia has been associated with oncogenic risk. This study was designed to investigate the homocysteine (Hcy) genotype/phenotype interactions together with the inflammatory and nutritional status of cancer patients. PATIENTS AND METHODS: The Hcy levels were analyzed in 47 cancer patients in association with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, folate and inflammatory markers. RESULTS: The MTHFR C677T and A1298C genotype distributions did not differ from those predicted by the Hardy-Weinberg distribution. Conversely, the Hcy levels were higher in the cancer patients (p=0.04), who were also characterized by low-grade inflammation. The Hcy levels correlated with the interleukin-6 (IL-6) (p=0.001), tumor necrosis factor-alpha (TNF-alpha) (p=0.042) and folate (p<0.0001) levels of the patients. Multivariate analysis showed that TNF-alpha (p=0.014) and folate (p=0.019) were independent predictors of elevated Hcy levels in the cancer patients. CONCLUSION: The MTHFR polymorphisms do not significantly contribute to tHcy (total Hcy) levels in cancer patients, and cancer-related inflammation may be associated with elevated tHcy levels, possibly involving a TNF-alpha mediated pathway.

Papillary thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases.

OBJECTIVE: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. DESIGN: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c- PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). RESULTS: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. CONCLUSIONS: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Amiodarone-induced thyrotoxicosis. A review.

Amiodarone (AM), a potent class III anti-arrhythmic drug, is an iodine-rich compound with a structural resemblance to thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the commonly employed doses, AM causes iodine overload up to 50-100 times the optimal daily intake, which may be responsible of a spectrum of effects on thyroid function often counterbalancing its heart benefits. Although most patients on chronic AM treatment remain euthyroid, a consistent proportion may develop thyrotoxicosis (AM-induced thyrotoxicosis, AIT) or hypothyroidism. AIT is more prevalent in iodine-deficient areas and is currently subdivided in two different clinico-pathological forms (AIT I and AIT II). AIT I develops in subjects with underlying thyroid disease, and is caused by an exacerbation by iodine load of thyroid autonomous function; AIT II occurs in patients with no underlying thyroid disease and is probably consequent to a drug-induced destructive thyroiditis. Mixed or indeterminate forms of AIT encompassing several features of both AIT I and AIT II may be also observed. The differential diagnosis between AIT I and AIT II (which is important for the choice of the appropriate therapy) is currently made on radioiodine uptake (RAIU), which may be high, normal or low but detectable in AIT I, while is consistently very low or undetectable in AIT II and on colour-flow Doppler sonography (CFDS) showing normal or increased vascularity in AIT I and absent vascularity in AIT II. Quite recently, studies carried out in our Units at the University of Cagliari (Italy) showed that sestaMIBI thyroid scintigraphy may represent the best single test to differentiate AIT I (showing increased MIBI retention) from AIT II (displaying no significant uptake). Treatment of AIT is dependent from its etiology. AIT usually responds to combined thionamides and potassium perchlorate (KClO4) therapy, AIT II generally responds to glucocorticoids, while indeterminate forms may require both therapeutic approaches. In patients with AIT I definitive treatment of hyperthyroidism by administration of (131)I, initially not feasible for the low RAIU and/or the risk of thyrotoxicosis exacerbation, is advised after normalization of iodine overload. To control severe AIT additional treatment with lithium carbonate, the use of short course of iopanoic acid and plasmapheresis have been also proposed. In cases resistant to medical treatment and/or in patients with severe cardiac diseases who cannot interrupt AM or require quick AM reintroduction, total thyroidectomy (possibly carried out by minimally invasive video-assisted technique) may be proposed after rapid correction of thyrotoxicosis with combination of thionamides, KClO4, corticosteroids and a short course of iopanoic acid.

Fifteen-year follow-up of thyroid function in lithium patients.

OBJECTIVE: To study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. METHOD: Patients (no.=150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for thyroid circulating thyroid antibodies, hypothyroidism, hyperthyroidism, and thyroidectomy, during a further period of lithium exposure of up to 15 yr. RESULTS: Annual rates of newly developed circulating thyroid antibodies and hypothyroidism were 1.7 and 1.5%, respectively. Subjects with thyroid antibodies had a higher chance of requiring substitution treatment with levothyroxine for hypothyroidism compared with subjects with no evidence of thyroid antibodies (6.4% annual rate compared to 0.8%; relative risk: 8.4; 95% confidence interval: 2.9-24.0). One case of hyperthyroidism was observed over 976 patient-yr. Three patients underwent thyroidectomy during followup (two for multinodular goiter and one for multicentric papillary carcinoma). CONCLUSIONS: Lithium may be associated with hypothyroidism in particular in the presence of circulating thyroid antibodies. Incidence of thyroid antibodies is comparable with that reported for the general population. Hyperthyroidism and thyroid cancer are rare.

The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies.

OBJECTIVE: Serum thyroglobulin (Tg) is the marker of differentiated thyroid carcinoma (DTC) after total thyroidectomy, but its value is limited by the interference of anti-Tg antibodies (TgAb). Detection of Tg in fine-needle aspiration biopsy (Tg-FNAB) washout fluid is used to identify neck DTC recurrences/metastases, but the interference of serum TgAb in this procedure is unknown. PATIENTS AND METHODS: Seventy-three patients (41 after surgery for thyroid cancer and 32 with thyroid nodules) evaluated for suspicious cervical lymph nodes were retrospectively reviewed. Tg was assayed by immunoradiometric assay or chemiluminescent assay in ultrasound-guided FNAB used for cytology. Serum TgAb were detected by passive agglutination or chemiluminescent assay. On the basis of preliminary data obtained in lymphadenitis, Tg-FNAB more than 36 ng/ml and more than 1.7 ng/ml (in the presence or absence of thyroid gland, respectively) was considered as indicative of metastasis. RESULTS: In 51 TgAb-negative patients, Tg-FNAB was positive in 15 (12 with malignant and three with nondiagnostic cytology), all with histologically confirmed DTC metastases. Of the remaining 36 patients with negative Tg-FNAB, 30 had nonsuspicious and six had suspicious cytology. Histology of the latter showed four undifferentiated thyroid cancer metastases and two lymphadenitis. In 22 TgAb-positive patients, Tg-FNAB was positive in 14 (12 with malignant and two with nondiagnostic cytology), all with histologically confirmed DTC metastases. CONCLUSIONS: Clinical performance of Tg-FNAB appears to be not substantially affected by TgAb, and this procedure remains superior to cytology in the identification of DTC neck metastases. However, cytology should always be performed because, irrespective of TgAb, Tg is undetectable in FNAB from undifferentiated metastases.

Biological effects of a software-controlled voltage pulse generator (PhyBack PBK-2C) on the release of vascular endothelial growth factor (VEGF).

BACKGROUND: Electrical stimulation (ES) may induce vascular permeability and physiological angiogenesis. ES of rat muscles significantly increases the microvessel density and vascular endothelial growth factor (VEGF) protein levels. Thus, a pilot study was designed to analyze the effects of low-voltage electric impulses on VEGF levels in patients with dystrophic ulcers. MATERIALS AND METHODS: Circulating VEGF levels were analyzed in 9 patients undergoing an ES session with low voltage software-controlled impulses applied through topical transducers (1-9 micros width, 1-420-Hz frequency and 30-120 V strength-100 microA max). RESULTS: The session was accompanied by a peak of circulating VEGF (3-10 min from start) in all 9 patients, which was preceded by a rise of TNF-alpha (2-min) and was independently associated with soluble E-selectin levels. Nitric oxide generation was significantly improved on the day after treatment. No hemostatic activation or sustained inflammatory reaction were observed. CONCLUSION: ES may represent a safe method for augmenting VEGF-mediated vascular protection, either directly or by induction of NO.

High prevalence of suspicious cytology in thyroid nodules associated with positive thyroid autoantibodies.

OBJECTIVE: We assessed the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration cytology (FNAC) to avoid the selection bias of surgical series. SUBJECTS AND METHODS: Ultrasound (US)-guided FNACs were obtained from 590 unselected consecutive patients with single thyroid nodules and positive (ATA + , n = 197) or negative (ATA - , n = 393) serum anti-thyroid antibody (ATA). Cytological results were classified in three classes of increased risk of malignancy: low risk or benign (class II); indeterminate risk (class III); and suspect or malignant (class IV). RESULTS: A higher prevalence of class III (28.9% vs 21.4%, P < 0.05) and class IV (18.8% vs 9.2%, P < 0.001) and lower prevalence of class II (52.3% vs 69.5%, P < 0.001) were found in ATA + vs ATA - nodules respectively. By multivariate logistic regression analysis ATA + conferred a significant risk (odds ratio (OR): 2.29 (95% confidence interval (CI): 1.39-3.76)) for class IV cytology independently from age and sex. In 106 patients where thyroidectomy was carried out, thyroid cancer was found in 54/61 (88.5%) patients with class IV nodules (with similar positive predictive value for cancer in ATA + (96.4%) and ATA- (81.8%) nodules), in 6/31 (19.3%) of class III nodules (all ATA - ) and in none of 14 class II nodules. Non-specific cytological atypias from hyperplastic nodules in lymphocytic thyroiditis probably accounted for the different prevalence of cancer in class III ATA + and ATA - nodules. Histologically proven thyroid cancer (mostly papillary) was then observed in a higher proportion (27/197 = 13.7%) of ATA + , when compared with ATA - nodules (33/393 = 8.4%, P = 0.044), but the significance of this finding is limited by the low number of class II nodules operated on. CONCLUSIONS: The presence of ATA + confers an increased risk of suspicious or malignant cytology in unselected thyroid nodules. Since ATA + is not responsible for increased false-positive class IV FNAC, our study provides indirect evidence supporting a significant association between thyroid carcinoma and thyroid autoimmunity, although further studies with a different design are needed for a definitive histological proof.

A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure.

Gain-of-function RET mutations are responsible for multiple endocrine neoplasia syndromes (MEN) 2A and 2B and familial medullary thyroid carcinoma (FMTC), whereas loss-of-function mutations are found in Hirschsprung disease. We report a new RET point mutation [R694Q (CGG-->CAG)], serendipitously found in a 23-yr-old woman with hypothyroidism due to atrophic Hashimoto's thyroiditis and primary ovarian failure, without altered calcitonin secretion. Familial history and clinical and biochemical evaluation of first-degree relatives were negative for FMTC, MEN 2A and 2B, and Hirschsprung disease. Genetic analysis showed that the mutation was inherited from the mother, who was submitted 2 yr before to thyroidectomy for goitrous Hashimoto's thyroiditis. Histological revision and immunohistochemical studies documented normal C cell number and morphology. We cloned the mutation in an expression vector encoding a full-length RET protein. The construct was transiently expressed in 293T cells in parallel with a wild-type RET and a C634R MEN 2A-associated RET mutant. Proteins were harvested from transfected cells, and tyrosine phosphorylation levels were assayed. The mutation did not exert significant potentiating effects on RET kinase. A focus assay was also performed on NIH3T3 fibroblasts; the mutant did not exert significant transforming activity. In conclusion, a new RET mutation was found in two subjects without any evidence of MEN and FMTC. In keeping with clinical data, transfection studies confirmed lack of activating activity. This serendipitous discovery, apparently devoid of oncogenic potential, underscores the problems that may be encountered in genomic studies on RET.