Therapeutic Strategies and Clinical Outcome in Papillary Thyroid Microcarcinoma: A Multicenter Observational Study.

PURPOSE: Papillary thyroid microcarcinoma (MPTC) has an excellent prognosis. We aimed to evaluate the evolution of therapeutic strategies over time and the clinical outcome of MPTC. METHODS: In this retrospective multicenter observational study in a northwest Italian region, patients with intrathyroidal, unifocal tumor ≤1 cm in size, incidentally found at histology or preoperative cytology diagnosis, were included. Exclusion criteria were a previous head-and-neck irradiation and/or node metastases. RESULTS: From 1985 to 2012, 437 patients had an MPTC diagnosis, which was incidental in 85% and preoperative in 15%. Patients with a preoperative diagnosis were younger at the time of diagnosis (47.6 ± 12.7 years, p < 0.01) and had a larger tumor (7.0 ± 2.5 mm, p < 0.0001) than patients with an incidental diagnosis (age 52 ± 13.5 years, size 4.4 ± 2.8 mm), but there were no differences in clinical outcome between both groups. We observed a significant (p < 0.001) reduction in radioiodine remnant ablation during the years. TSH levels were: <0.1 mIU/l in 27.5%, 0.1-0.5 mlU/l in 33.7%, 0.5-2.5 mlU/l in 32.6%, 2.5-4.2 mlU/l in 3.9%, and >4.2 mlU/l in 2.3% of patients. Six patients (1.37%) had nodal recurrence; 5 of them were cured after therapy. MPTC-linked mortality was null. CONCLUSIONS: We confirmed the favorable clinical outcome of MPTC. Despite the reduction in radioiodine ablation, overtreatment of MPTC is still observed.

18F-FDG PET/CT is a prognostic biomarker in patients affected by bone metastases from breast cancer in comparison with 18F-NaF PET/CT.

AIM: To compare 18F-FDG PET/CT and 18F-NaF PET/CT with respect to disease prognostication and outcome in patients affected by bone metastases from breast cancer (BC). PATIENTS, METHODS: We retrospectively investigated 32 women with BC and documented bone metastases. Semi-quantitative parameters were applied to 18F-FDG PET/CT and 18F-Na PET/CT in order to evaluate disease extent and tumour metabolism. We used time-to-event analyses (Kaplan Meier and COX proportional hazard methods) to estimate progression-free (PFS) and overall survival (OS) in order to assess the independent prognostic value of 18F-FDG PET/CT and 18F-Na PET/CT. RESULTS: The sensitivity of 18F-NaF PET/CT (100%) was higher (p < 0.05) than that of 18F-FDG PET/CT (72% and 72%). None of the 18F-FDG PET/CT-negative patients showed disease progression at the end of follow-up. After adjustment for age, Ki-67 levels, presence of visceral metastases, hormone therapy, duration of bone disease and response to first-line therapy, only 18F-FDG SUV mean [HR 15.7, 95% confidence interval (CI) 1.15-214.5] and 18F-FDG whole-body bone metabolic burden (WB-B-MB) (HR 16.9; 95%CI 1.87-152.2) were independently and significantly associated with OS. None of the 18F-NaF PET/CT parameters were associated with OS. None of the conventional clinical prognostic parameters remained significantly associated with OS after the inclusion of PET/CT parameters in the model. CONCLUSION: 18F-FDG PET/CT is independently associated with OS in BC patients with bone metastases and its prognostic impact seems to be higher than conventional clinical and biological prognostic factors. Although 18F-NaF PET/CT has a higher diagnostic sensitivity than 18F-FDG PET/CT, it is not independently associated with OS.

Radioiodine therapy of hyperfunctioning thyroid nodules: usefulness of an implemented dose calculation algorithm allowing reduction of radioiodine amount.

AIM: Radioiodine is a common option for treatment of hyperfunctioning thyroid nodules. Due to the expected selective radioiodine uptake by adenoma, relatively high "fixed" activities are often used. Alternatively, the activity is individually calculated upon the prescription of a fixed value of target absorbed dose. We evaluated the use of an algorithm for personalized radioiodine activity calculation, which allows as a rule the administration of lower radioiodine activities. METHODS: Seventy-five patients with single hyperfunctioning thyroid nodule eligible for 131I treatment were studied. The activities of 131I to be administered were estimated by the method described by Traino et al. and developed for Graves'disease, assuming selective and homogeneous 131I uptake by adenoma. The method takes into account 131I uptake and its effective half-life, target (adenoma) volume and its expected volume reduction during treatment. A comparison with the activities calculated by other dosimetric protocols, and the "fixed" activity method was performed. 131I uptake was measured by external counting, thyroid nodule volume by ultrasonography, thyroid hormones and TSH by ELISA. RESULTS: Remission of hyperthyroidism was observed in all but one patient; volume reduction of adenoma was closely similar to that assumed by our model. Effective half-life was highly variable in different patients, and critically affected dose calculation. The administered activities were clearly lower with respect to "fixed" activities and other protocols' prescription. CONCLUSION: The proposed algorithm proved to be effective also for single hyperfunctioning thyroid nodule treatment and allowed a significant reduction of administered 131I activities, without loss of clinical efficacy.

Could [18]F-fluorodeoxyglucose PET/CT change the therapeutic management of stage IV thyroid cancer with positive (131)I whole body scan?

AIM: Stage-IV differentiated thyroid cancer (DTC) patients may present elevated serum thyroglobulin (Tg) levels associated with positive [(131)I] whole-body-scan (WBS). Nevertheless some patients in whom WBS does not reveal new sites of disease show increased Tg levels. This finding prompts thorough restaging in order to exclude the presence of metastases unable to concentrate iodine. The aim of our study was to evaluate the impact of [(18)F]FDG-PET/CT in both the assessment of overall extent of the disease and the therapeutic management in a group of stage-IV DTC patients. METHODS: On suspicious of non-iodine concentrating additional metastases, 20 stage-IV DTC patients with increasing Tg levels and stable positive post-therapy WBS were enrolled. Conventional imaging (CI) procedures, including neck ultrasonography, bone-scintigraphy and computed tomography (CT) were performed before [(18)F]FDG-PET/CT. RESULTS: [(18)F]FDG-PET/CT was positive in 16 out of 20 patients (80%). In 9 patients (45%) [(18)F]FDG PET/CT detected a larger number of tumour recurrences/metastatic sites than WBS+CI. [(18)F]FDG PET/CT findings prompted modification of the management of 11 patients (55%), in whom surgery or external radiotherapy were eventually considered more appropriate than radioactive iodine therapy. These further therapies improved the quality of life in several patients but did not change their survival rate. CONCLUSION: Our results showed that [18F]FDG-PET/CT can detect new radioiodine-negative metastases in advanced DTC patients with unchanged positive WBS and increasing Tg levels. [(18)F]FDG-PET/CT may constitute a useful tool in the choice of the best therapeutic strategy in such difficult cases.

The need of appropriate brain SPECT templates for SPM comparisons.

AIM: Statistical parametric mapping (SPM) is used worldwide to compare brain perfusion single photon emission computed tomography (SPECT) data. The default template within the SPM package used for SPECT image normalization includes images of a group of healthy subjects studied with [(99m)Tc]HMPAO. Since [(99m)Tc]HMPAO and [(99m)Tc]ECD have shown to distribute differently in SPECT studies, we formulated the hypothesis that comparing set of [(99m)Tc]ECD data normalized by means of a [(99m)Tc]HMPAO template may lead to incorrect results. METHODS: A customized [(99m)Tc]ECD template was built with SPECT and magnetic resonance imaging (MRI) images of 22 neurologically healthy women. Then, two sets of subjects, i.e. a group of patients with very early Alzheimer's disease (eAD) and a matched control group, studied by means of [(99m)Tc]ECD SPECT, were chosen for comparisons. The same statistical approach (t-test between eAD patients and controls and correlation analysis between brain SPECT and a cognitive score) was applied twice, i.e. after normalization with either the default [(99m)Tc]HMPAO template or the customized [(99m)Tc]ECD template. RESULTS: In the comparison between eAD and controls, a cluster of difference in the posterior cingulate gyrus of both hemispheres was only highlighted when using the customized [(99m)Tc]ECD template, but was missed when using the default [(99m)Tc]HMPAO template. In the correlation between brain perfusion and a cognitive score, the significant cluster was more significant and far more extended, also including the right superior temporal gyrus, using the customized [(99m)Tc]ECD template than using the default [(99m)Tc]HMPAO template. CONCLUSION: These data suggest the need of customized, radiopharmaceutical-matched SPECT templates to be used within the SPM package. The present customized [(99m)Tc]ECD template is now freely available on the web.

Pharmacokinetics of radiolabelled Par j 1 administered intranasally to allergic and healthy subjects.

BACKGROUND: Local nasal immunotherapy is accepted as an alternative to the injection route for allergic rhinitis. Despite this, little is known about the kinetics of the allergen after nasal delivery in allergic subjects. OBJECTIVE: We aimed at assessing the biodistribution of 123I-radiolabelled Par j 1 in Parietaria-allergic subjects, in comparison with healthy volunteers. METHODS: Purified Par j 1 was radiolabelled with 123I and sprayed into the nostrils of three control subjects and three Parietaria-allergic volunteers. Dynamic and static scintigraphic images of the head were recorded at serial times and blood samples were obtained to measure the plasma radioactivity, and to assess the presence of circulating radiolabelled species by gel chromatography. RESULTS: In Parietaria-sensitized subjects, the radiolabelled allergen was rapidly cleared from the nasal cavity and transported to pharynx, and little local persistence was seen. This differed from healthy subjects where nasal clearance of the tracer was slower and nasal radioactivity persisted up to 24 h. The increase in plasma radioactivity paralleled swallowing of the allergen in both groups, and plasma chromatographic profile did not differ between allergic and healthy volunteers. CONCLUSIONS: Sensitization to the allergen affects its local biodistribution. Gastrointestinal absorption is relevant also for the intranasal route.

Use of an artificial neural network to predict Graves' disease outcome within 2 years of drug withdrawal.

BACKGROUND: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism, which can relapse in many patients after antithyroid drug treatment withdrawal. Several studies have been performed to predict the clinical course of GD in patients treated with antithyroid drugs, without conclusive results. The aim of this study was to define a set of easily achievable variables able to predict, as early as possible, the clinical outcome of GD after antithyroid therapy. METHODS: We studied 71 patients with GD treated with methimazole for 18 months: 27 of them achieved stable remission for at least 2 years after methimazole therapy withdrawal, whereas 44 patients relapsed. We used for the first time a perceptron-like artificial neural network (ANN) approach to predict remission or relapse after methimazole withdrawal. Twenty-seven variables obtained at diagnosis or during treatment were considered. RESULTS: Among different combinations, we identified an optimal set of seven variables available at the time of diagnosis, whose combination was useful to efficiently predict the outcome of the disease following therapy withdrawal in approximately 80% of cases. This set consists of the following variables: heart rate, presence of thyroid bruits, psycological symptoms requiring psychotropic drugs, serum TGAb and fT4 levels at presentation, thyroid-ultrasonography findings and cigarette smoking. CONCLUSIONS: This study reveals that perceptron-like ANN is potentially a useful approach for GD-management in choosing the most appropriate therapy schedule at the time of diagnosis.

Sensitization to food or inhalant allergens in pediatric patients. Clinical usefulness of first-level panel tests for specific IgE.

First-level in vitro diagnostic tests for specific IgE against common inhalant or food allergens have been used to identify allergic patients. We evaluated the performance of Phadiatop and Fx5 (mixed food allergens) serological tests (Pharmacia Diagnostics AB, Uppsala, Sweden) in different groups of pediatric patients. We studied two groups of pediatric patients: 61 children recruited from an Allergy and Clinical Immunology Unit (Group 1); 136 children from a Pediatric Unit not specifically devoted to allergic diseases (Group 2); the two groups comprised patients with (A) or without (B) clinical suspicion of allergic disease. Sera were collected from routine blood analysis. Frequencies of positivities for Phadiatop and/or Fx5 were very high (68.8%) in Group 1, however, as many as 35.5% of Group 2 children were positive, as well. All the patients of Group 1 with clinical suspicion of allergic disease (1A), confirmed by allergologic diagnostic tests, had a positive first-level test; 42.8% only of the patients in Group 2 with suspicion of allergic disease (2A) had a positive first-level test. None of the Phadiatop/Fx5-negative children of Group 2A had specific-IgE with conventional tests. In 30% of children not suspected for allergic diseases (1B and 2B), positive first-level tests were observed. Such unexpected positivities were confirmed by single specific-IgE assays in 94.7% (for inhalants) or 71% (for foods) of cases. In conclusion, altogether the sensitivity and overall performance of first-level tests in pediatric populations (especially for inhalant allergens) may suggest their use, under appropriate circumstances, both as a first diagnostic approach (to rule out negative patients) and for screening purposes.

Regulation of apoptosis in endocrine autoimmunity: insights from Hashimoto's thyroiditis and Graves' disease.

Dysregulation of apoptosis is associated with the pathogenesis of organ-specific autoimmune diseases, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors such as Fas. A comparative analysis of the expression of Fas and FasL, the antiapoptotic molecule Bcl-2, and apoptosis in both thyrocytes and thyroid-infiltrating lymphocytes (TILs) from patients with either Graves' disease (GD) or Hashimoto's thyroiditis (HT) was performed. GD thyrocytes expressed less Fas than HT thyrocytes, whereas GD TILs had higher levels of Fas and FasL than HT TILs. GD thyrocytes expressed higher levels of Bcl-2 compared with HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. Consistently, thyrocyte apoptosis was marked in HT and poor in GD thyroids, and TIL apoptosis was marked in GD and poor in HT. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl-2 favors apoptosis of infiltrating lymphocytes. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and hypertrophy associated with stimulatory thyroid-stimulating hormone receptor antibodies. In contrast, the regulation of Fas/FasL/Bcl-2 expression in HT can promote thyrocyte apoptosis via homophylic Fas-FasL interactions, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. Fas-mediated apoptosis may be a general mechanism of cell damage in destructive organ-specific autoimmunity.

Different intrathyroid expression of intercellular adhesion molecule-1 (ICAM-1) in Hashimoto's thyroiditis and Graves' disease: analysis at mRNA level and association with B7.1 costimulatory molecule.

Cultured thyroid epithelial cells can be induced to express intercellular adhesion molecule-1 (ICAM-1, or CD54). However, constitutive follicular expression of ICAM-1 has been reported only in thyroid autoimmunity. We evaluated the expression of ICAM-1 mRNA and protein on thyroid tissue from different autoimmune thyroid diseases, and its relationship with other immunologically relevant surface markers, namely costimulatory molecules of B7 family. Thyroid tissue sections were obtained by surgically removed thyroid glands from 6 patients with Hashimoto's thyroiditis (HT), 6 with Graves' disease (GD) and 3 with multinodular nontoxic goiter. We used in situ hybridization to localize ICAM-1 mRNA, and immunohistochemical analysis by alkaline phosphatase anti-alkaline phosphatase (APAAP) method. We showed a clear hybridization pattern, localized in follicular cells, in sections of glands with HT. The hybridization pattern was far less pronounced in GD: no staining was apparent on follicular cells. These results were strictly consistent with those obtained by means of immunohistochemistry. Moreover, double-staining experiments demonstrated colocalization of ICAM-1 and B7.1 molecules in HT, whereas no B7.1 expression was observed in Graves' or in non-autoimmune thyroid diseases. These data agree with the hypothesis of distinct immunoregulatory phenomena and effector mechanisms in the 2 main autoimmune thyroid diseases.

Comparison of ELISA for tissue transglutaminase autoantibodies with antiendomysium antibodies in pediatric and adult patients with celiac disease.

BACKGROUND: Tissue transglutaminase (t-TG) is the main autoantigen recognized by the endomysium antibodies (EMA) observed in patients with celiac disease (CD). The aim of the study was to assess an ELISA method for t-TG antibodies (t-TGA) with respect to EMA IF assay in pediatric and adult patients. METHODS: t-TGA were analyzed by ELISA in 220 sera samples: 82 patients with biopsy-proven untreated CD (23 adults and 59 children), 14 CD children on gluten-free diet, 18 asymptomatic relatives of CD patients, and 106 age-matched control patients with gluten-unrelated gastrointestinal diseases (58 adults and 48 children). Serum IgA EMA were tested on umbilical cord sections in all patients. RESULTS: The great majority (92.7%) of untreated CD patients (both adults and children) were t-TGA positive (values ranging from 20.1 to > 300 AU). None of the child control patients and only two out of 58 (3.4%) of the adults with unrelated gastrointestinal diseases had serum t-TGA positivity; two out of 18 first-degree relatives with biopsy-proved silent CD were t-TGA (as well as EMA) positive. Finally, two out of 14 CD children, assuming a gluten-free diet, had serum t-TGA (as well as EMA). A highly significant correlation (P < 0.001) was observed between t-TGA concentrations and EMA. t-TGA showed a sensitivity of 87% and 95%, a specificity of 97% and 100% for adults and children, respectively. CONCLUSION: The method is highly sensitive and specific in the diagnosis of CD and is promising as a tool for routine diagnostic use and population screening, especially in children.