Early Massive Fibrosis of a Single Extraocular Muscle Causing Severe Unilateral Euthyroid Graves' Ophthalmopathy in a Patient with Hypercholesterolemia Who Smokes.

Background: Graves' ophthalmopathy (GO) is an autoimmune manifestation of orbit affecting approximately 25% of patients with Graves' disease (GD). Autoreactive T cells involved in thyroid autoimmunity can recognize the thyroid-stimulating receptor (TSHr) expressed in orbital tissues of GO patients. Clinical manifestations of GO are rather different depending on the presence of some risk factors, such as smoking, hyperthyroidism duration, age, biological activity of anti-TSHr antibodies (TSH-R-Ab) and metabolic diseases. Case Presentation: Here, we present a rare case of euthyroid single muscular GO in a 50-year-old patient who was a smoker and had dyslipidemia for several years. The patient experienced a very rapid and severe depression of ocular motility of the right eye that caused uncorrectable and constant diplopia, severely affecting his quality of life. He was euthyroid, and TSH-R-Ab plasmatic levels were only slightly elevated. Intravenous corticosteroid pulse therapy was partially effective, and two rounds of wall orbital surgical decompression were necessary. Massive mono-muscular fibrosis was evidenced by biopsy of the right inferior rectus muscle. Conclusion: Severe unilateral, mono-muscular GO in a euthyroid Graves' patient was found to be sustained by rapid and massive fibrosis of the inferior rectus muscle of the right orbit. Clarification of the pathogenetic mechanisms of these GO clinical forms requires further studies.

Obesity and Monitoring Iodine Nutritional Status in Schoolchildren: is Body Mass Index a Factor to Consider?

Background: The frequency of overweight (OW) and obese (OB) children has increased worldwide, particularly in economically developed countries. No studies have been conducted to verify whether the increasing frequency of OW and obesity in schoolchildren may affect the evaluation of iodine nutritional status in populations. The aim of this study was to verify whether urinary iodine concentration (UIC), thyroid volume (TV), and thyroid hypoechoic pattern may be affected by body mass index (BMI) in schoolchildren. Methods: The children included in this study (aged 11-13 years) were a part of the schoolchildren recruited in the second nationwide survey (period 2015-2019) conducted in Italy to monitor by law (Atto di Intesa Stato-Regioni February 26, 2009) the nationwide iodine prophylaxis program. Specifically, 1281 schoolchildren residing in iodine-sufficient areas (IS group) and 384 children residing in a still mildly iodine-deficient area (ID group) were recruited between January and March 2015 in the first-degree secondary state schools. In all the children, spot UIC was measured, thyroid ultrasound was performed to evaluate TV, and hypoechogenicity was assessed to indirectly evaluate iodine-associated thyroid autoimmunity. Results: The frequency of OW, OB, and adequate weight (AW) children was similar in the IS and ID groups at any age. After adjusting for sex and age, the regression analysis showed lower UIC values in OB children than in AW children of the IS group (beta coefficient = -34.09 [95% confidence interval -65.3 to -2.8]), whereas no significant differences were observed in the ID group. In both the IS and ID groups, the distribution of TV in AW children was significantly shifted toward lower values in comparison to the distribution of OB children (p < 0.001 in the IS group; p = 0.012 in the ID group). Furthermore, the frequency of thyroid hypoechogenicity was higher in the ID group than in the IS group (10.9% vs. 6.6%, p = 0.005); however, in both groups, it was significantly lower in AW children than in OB children (p < 0.01). Conclusions: This study for the first time demonstrates that BMI may be a confounding factor in monitoring iodine nutritional status in schoolchildren. Since in Italy as in other Western countries the number of OW and OB children is high, BMI is a factor to consider in monitoring salt iodization programs worldwide.

Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves' Ophthalmopathy to Parenteral Corticosteroids.

Background: High dose intravenous glucocorticoid (ivGC) therapy is the first line treatment in moderate to severe Graves' ophthalmopathy (GO) and is associated with a clinical response rate ranging from 50% to 80%. Recently, a positive correlation between total cholesterol and low-density lipoproteins cholesterol (LDLc) with GO presentation and activity has been described. Objective: We aimed at evaluating whether, in patients with moderate to severe active GO treated with ivGC therapy, cholesterol, and LDLc could represent valuable predictive factors of medium-term GO outcome. Methods: This single center retrospective study was conducted in a consecutive series of 87 patients undergone ivGC therapy because affected by moderate to severe active GO. Clinical outcome of GO was evaluated at week 6 (W6) and 12 (W12) in respect to baseline conditions (week 0) by the seven points CAS according to EUGOGO recommendations. Univariate analysis and binary logistic regression were performed for the outcome variable W12CAS. Results: In patients with active GO, an early positive clinical response to ivGC therapy (as evaluated by CAS at 6W) was a strong determinant (OR=13) of the clinical outcome at week 12. Moreover, high levels of LDLc at baseline were positively associated with a reduction in the likelihood of being classified as improved at 12W. Patients with LDLc >193.6 mg/dl were very likely to respond negatively to ivGC therapy independently from the response at 6W. Based on these results, we propose a predictive decision-making model to be tested in future prospective studies. Discussion: We found that, in patients with active GO, both an early clinical response to ivGC therapy and baseline LDLc levels are significant determinants of GO outcome (W12CAS). These data support the need of a cholesterol-lowering treatment before addressing these patients to ivGC therapy.

Thyroidectomy as Treatment of Choice for Differentiated Thyroid Cancer.

BACKGROUND: Despite a large amount of data, the optimal surgical management of differentiated thyroid cancer remains controversial. Current guidelines recommend total thyroidectomy if primary thyroid cancer is >4 cm, while for tumors that are between 1 and 4 cm in size, either a bilateral or a unilateral thyroidectomy may be appropriate as surgical treatment. In general, total thyroidectomy would seem to be preferable because subtotal resection can be correlated with a higher risk of local recurrences and cervical lymph node metastases; on the other hand, total thyroidectomy is associated with more complications. METHODS: This is a retrospective study conducted on 359 patients with differentiated thyroid cancer, subjected to total thyroidectomy. Our aim was to correlate clinical and pathological features (extrathyroid tumor growth, bilaterality, nodal and distant metastasis) with patient (gender and age) and tumor (size and histotype) characteristics. Moreover, we recorded postoperative complications, including hypoparathyroidism and laryngeal nerve damage. RESULTS: In our study, we found a high occurrence of pathological features indicating cancer aggressiveness (bilaterality, nodal metastases, and extrathyroid invasion). On the other hand, total thyroidectomy was associated with relatively low postsurgical complication rates. CONCLUSIONS: Our data support the view that total thyroidectomy remains the first choice for the routine treatment of differentiated thyroid cancer.

Differentiated thyroid cancer in children: Heterogeneity of predictive risk factors.

OBJECTIVE: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC). STUDY DESIGN: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification). RESULTS: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%). CONCLUSIONS: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification.

Outcome of the Diffuse Sclerosing Variant of Papillary Thyroid Cancer: A Meta-Analysis.

INTRODUCTION: The diffuse sclerosing variant (DSV) of papillary thyroid cancer (PTC) is considered an aggressive histotype associated with poor prognosis. However, the available data for both the outcome and best management of this disease are inconsistent. METHODS: This study reviewed the current literature by searching PubMed up to November 30, 2015, using the search terms "diffuse sclerosing variant" and "papillary thyroid cancer (or carcinoma)" and selecting only studies evaluating recurrent/persistent disease and cancer-related mortality in both DSV and classic PTC (cPTC). The association with some features of aggressiveness at diagnosis, the risk of recurrence or persistence, and the risk of cancer-related death were reported as odds ratio (OR) with confidence intervals (CI). Meta-regression analysis was used to assess the effect of covariates across the studies. RESULTS: Ten studies met the eligibility criteria and contributed 585 DSV and 64,611 cPTC patients. Relative to patients with cPTC, patients with DSV exhibited a higher risk of extrathyroidal extension and lymph node and distant metastases. The risk of persistent/recurrent disease was three times higher in patients with DSV than it was in cPTC patients (OR = 3.19 [CI 1.86-5.49]). This risk was not different when only studies where post-surgical (131)I was routinely administered were considered (OR = 2.07 [CI 0.88-4.90]). The risk of cancer-related mortality was not different between DSV and cPTC (OR = 1.34 [CI 0.76-2.38]). CONCLUSIONS: This meta-analysis confirms the aggressive biological behavior of DSV thyroid cancer. When preoperatively suspected, total thyroidectomy with lymph node excision followed by radioiodine therapy should be the correct management for DSV.

Increased thyroid cancer incidence in a basaltic volcanic area is associated with non-anthropogenic pollution and biocontamination.

The increased thyroid cancer incidence in volcanic areas suggests an environmental effect of volcanic-originated carcinogens. To address this problem, we evaluated environmental pollution and biocontamination in a volcanic area of Sicily with increased thyroid cancer incidence. Thyroid cancer epidemiology was obtained from the Sicilian Regional Registry for Thyroid Cancer. Twenty-seven trace elements were measured by quadrupole mass spectrometry in the drinking water and lichens (to characterize environmental pollution) and in the urine of residents (to identify biocontamination) in the Mt. Etna volcanic area and in adjacent control areas. Thyroid cancer incidence was 18.5 and 9.6/10(5) inhabitants in the volcanic and the control areas, respectively. The increase was exclusively due to the papillary histotype. Compared with control areas, in the volcanic area many trace elements were increased in both drinking water and lichens, indicating both water and atmospheric pollution. Differences were greater for water. Additionally, in the urine of the residents of the volcanic area, the average levels of many trace elements were significantly increased, with values higher two-fold or more than in residents of the control area: cadmium (×2.1), mercury (×2.6), manganese (×3.0), palladium (×9.0), thallium (×2.0), uranium (×2.0), vanadium (×8.0), and tungsten (×2.4). Urine concentrations were significantly correlated with values in water but not in lichens. Our findings reveal a complex non-anthropogenic biocontamination with many trace elements in residents of an active volcanic area where thyroid cancer incidence is increased. The possible carcinogenic effect of these chemicals on the thyroid and other tissues cannot be excluded and should be investigated.

Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors.

Background. In the last decades, thyroid cancer incidence has continuously and sharply increased all over the world. This review analyzes the possible reasons of this increase. Summary. Many experts believe that the increased incidence of thyroid cancer is apparent, because of the increased detection of small cancers in the preclinical stage. However, a true increase is also possible, as suggested by the observation that large tumors have also increased and gender differences and birth cohort effects are present. Moreover, thyroid cancer mortality, in spite of earlier diagnosis and better treatment, has not decreased but is rather increasing. Therefore, some environmental carcinogens in the industrialized lifestyle may have specifically affected the thyroid. Among potential carcinogens, the increased exposure to medical radiations is the most likely risk factor. Other factors specific for the thyroid like increased iodine intake and increased prevalence of chronic autoimmune thyroiditis cannot be excluded, while other factors like the increasing prevalence of obesity are not specific for the thyroid. Conclusions. The increased incidence of thyroid cancer is most likely due to a combination of an apparent increase due to more sensitive diagnostic procedures and of a true increase, a possible consequence of increased population exposure to radiation and to other still unrecognized carcinogens.

Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway.

CONTEXT: Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas. OBJECTIVE: We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors. DESIGN: We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines. RESULTS: We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRAS(G12A/Q61R) mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors. CONCLUSIONS: These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.

Papillary thyroid microcarcinomas: a comparative study of the characteristics and risk factors at presentation in two cancer registries.

CONTEXT: Papillary thyroid microcarcinoma (PTMC) is an indolent neoplasia, often asymptomatic and discovered incidentally. Some PTMCs, however, exhibit a more aggressive behavior, frequently recur, and can even cause cancer-related death. OBJECTIVE: The aim of this study was to evaluate the prevalence of PTMCs and the associated risk factors at presentation in 2 thyroid cancer registries from areas with different genetic and environmental characteristics. DESIGN AND PATIENTS: We conducted a retrospective, observational study of all incident cases of PTMCs recorded over a 5-year period in the Sicilian Regional Registry for Thyroid Cancer (SRRTC) and in the Surveillance Epidemiology and End Results (SEER) US registry. SETTING: The study took place at an academic hospital. RESULTS: The incidence of PTMCs was much higher in Sicily (1777 PTMC diagnosed in 2002-2006; age-standardized incidence rate for the world population [ASRw] = 5.8 per 100 000) than in the United States (14 423 PTMC in the period 2004-2008; ASRw = 2.9 per 100 000). Within the SRRTC, a significantly higher incidence was observed in the volcanic area (ASRw = 10.4 vs 4.6 in the rest of Sicily). In Sicily, the female to male ratio was higher, and PTMC patients were younger. In both registries, a significant inverse correlation was observed between age and tumor size. Young patients (≤45 y) exhibited a higher frequency of nodal metastases. CONCLUSIONS: PTMC incidence is twice as high in Sicily compared with the United States, and within Sicily, the incidence is twice as high in the volcanic area. In young patients, PTMCs are larger at presentation and exhibit more risk factors. In both registries, more than 35% of PTMCs exhibited 2 or more risk factors, suggesting that they may require surgery and follow-up similar to that of larger carcinomas.

Thyroid cancer in thyroglossal duct cysts requires a specific approach due to its unpredictable extension.

CONTEXT: Differentiated thyroid cancer (DTC) in thyroglossal duct cysts is uncommon. The requirement of total thyroidectomy and lymph node dissection is still controversial. SETTING: The study was performed in a referral thyroid cancer center at an academic hospital. PATIENTS: We conducted a single center retrospective study of a consecutive series of 26 patients with DTC in thyroglossal duct cyst, all having undergone cyst resection and total thyroidectomy. MAIN OUTCOME MEASURES: Diagnostic modalities, surgical treatment, histopathological features, and clinical outcome were included in the study. RESULTS: Thyroglossal duct cyst cancer histotype was papillary in 23 of 26 patients (88.5%) and follicular-Hurthle in 3 of 26 cases (11.5%). A concomitant papillary DTC in the thyroid gland was found in 16 of 26 cases (61.5%), and it was multifocal in 8 of 16 cases (50%). At presentation, the patients with cancer in both the thyroglossal duct cyst and the thyroid were older than the patients who only had cancer in the thyroglossal duct cyst (44.9 ± 7.6 vs 32.0 ± 12.7; P = .006). Lymph node dissection, performed in 17 of 26 patients (65.4%), indicated that the central compartment was involved in 6 patients (35.3%, all having cancer also in the thyroid), the laterocervical compartments in 10 patients (58.8%), and the submental in 4 (23.5%). Six patients (23.1%) had persistent disease at 6-year median follow-up. CONCLUSIONS: DTC in thyroglossal duct cysts occurs at a younger age and with more aggressive features at presentation. Concomitant cancer in the thyroid and lymph node metastases is present in most cases. Lymph node compartment involvement is different from that of cancers in the thyroid gland. Therefore, surgical treatment should include both thyroglossal duct cyst resection and total thyroidectomy, with individualized surgical nodal dissection. Subsequent management should follow current DTC guidelines.

Update on thyroid cancer treatment.

Surgery and radioiodine therapy are usually effective for most patients with differentiated thyroid cancer. However, poorly differentiated and anaplastic thyroid carcinomas represent a challenge to physicians on the basis of the current cancer treatment modalities. These cancer subtypes are often lethal and refractory to radioiodine therapy as well as most of the common chemotherapy drugs. Several kinase inhibitors are promising targeted therapies for these malignancies; however, clinical trials involving these drugs have provided controversial results and their clinical use is still under debate. Advanced medullary thyroid carcinomas may also be refractory to conventional therapies and novel kinase inhibitors may also be useful to control tumor progression in certain patients. Novel evidence is emerging that thyroid cancer is a stem cell disease, thereby implying that the driving force of thyroid cancers is a subset of undifferentiated cells (thyroid cancer stem cells) with unlimited growth potential and resistance to conventional therapeutic regimens. Thyroid cancer stem cells have been proposed as responsible for tumor invasiveness, metastasis, relapse and differentiation. Therefore, drugs that selectively target these cells could serve as a cornerstone in the treatment of poorly differentiated thyroid cancer.

Graves' orbitopathy: extraocular muscle/total orbit area ratio is positively related to the Clinical Activity Score.

BACKGROUND AND OBJECTIVE: Both extraocular muscle (EOM) and orbital fat are involved in Graves' orbitopathy (GO) but their enlargement might occur with a different temporal pattern. Two GO subtypes have been described, one with predominant EOM enlargement and the other with prevalent fat tissue involvement. We longitudinally investigated the EOM in patients with GO and their relationship with clinical activity. PATIENTS AND METHODS: By using commercial software with a segmentation technique, we calculated from computed tomography (CT) scan EOM coronal area (CA) and total orbit coronal area (TOA) in 23 control subjects and in 32 patients with GO. The latter were studied both at presentation and 18 months later. Superior, lateral, inferior, and medial EOM areas and TOA were selected by 3 different contiguous CT slices: A, B, and C, chosen at globe pole tangent and 2 and 4 mm backward. The Clinical Activity Score (CAS) was also measured. RESULTS: Orbital EOM CA/TOA ratio (OM/TOA ratio) after 18 months decreased in most patients with GO, indicating that EOM area decrement contributed significantly to OM/TOA ratio reduction. Clinical Activity Score decrease was significantly correlated to the OM/TOA ratio decrease. CONCLUSIONS: An easy method to measure CA of EOM and orbit allowed us to observe that in most patients with GO the OM/TOA ratio decreases with time, suggesting that macroscopic EOM involvement occurs initially and resolves as the other clinical signs and symptoms of the disease resolve, as indicated by the significant OM/TOA ratio correlation with CAS.

Severe Graves' ophthalmopathy after percutaneous ethanol injection in a nontoxic thyroid nodule.

BACKGROUND: Percutaneous ethanol injection (PEI) is used to treat cystic or mixed benign thyroid nodules. This treatment can result in rare complications, and three cases of Graves' disease (GD) without Graves' ophthalmopathy (GO) have been reported after PEI treatment of toxic thyroid adenomas. Here we present a 55-year-old male patient who developed GD and severe GO after PEI treatment of a mixed cystic-solid, nontoxic thyroid nodule. PATIENT FINDINGS: Six months after PEI, the nodule volume had decreased from 8.9 to 3.0 mL, but we observed severe hyperthyroidism with elevated serum free triiodothyronine, free thyroxine, and thyrotropin receptor antibody levels. We also observed ophthalmopathy with symmetrical orbit and soft tissue involvement (grade b/c) and a clinical activity score of 4/7. The diagnosis of GO was confirmed by bilateral corneal damage, increased intraocular pressure on upgaze, and inconstant diplopia. A computed tomography scan showed that the inferior, medial, and superior extraocular muscles were bilaterally enlarged, the perineural space at the orbital cone was slightly reduced and the ophthalmic vein was congested. SUMMARY: A cause-effect relationship between PEI and GD/GO was likely in this patient because of the temporal sequence. Although the mechanism was unknown, we speculated that the thyroid tissue damage caused by PEI released a large amount of antigenic materials from follicular thyroid cells, including thyrotropin receptor protein, which triggered the autoimmune inflammatory response against the thyroid itself and the orbital soft tissues. The patient did not have any risk factors for either GD or GO. CONCLUSIONS: This observation raises the concern, therefore, that unpredictable and severe complications, such as GD and GO, may occur in a few patients treated with PEI.

Risk-adapted management of differentiated thyroid cancer assessed by a sensitive measurement of basal serum thyroglobulin.

CONTEXT: Treatment and follow-up of patients thyroidectomized for differentiated thyroid carcinoma (DTC) mainly depends on the identification of the patient's risk of recurrence. Thyroglobulin (Tg) is the most important marker of persistent/recurrent disease. The recent introduction of a new, more sensitive Tg measurement allows for the early detection of the disease by measuring the basal (under L-T(4) therapy) serum Tg level without TSH stimulation. OBJECTIVE: The goal of this study is to identify the basal serum Tg threshold value that indicates recurrent disease by using a second-generation Tg assay. DESIGN AND PATIENTS: A continuous series of 425 DTC patients, all thyroidectomized and treated with (131)I after surgery and having basal Tg of no more than 1.0 ng/ml, negative anti-Tg antibodies, and a recombinant human TSH-stimulated Tg measurement was retrospectively analyzed. SETTING: The study took place at an academic hospital. RESULTS: The most accurate basal Tg value for predicting the presence of recurrent/residual disease was more than 0.15 ng/ml (sensitivity 87%, specificity 91%, negative predictive value 98.6%, and positive predictive value 47.8%). When the basal Tg level was no more than 0.15 ng/ml, the risk of disease presence was very low, even in patients classified at an intermediate or high risk. In contrast, when the basal Tg level was more than 0.15 ng/ml, the percentage of recurrent disease was relatively high (12.5% or one in eight cases) in low-risk patients. CONCLUSIONS: Basal Tg, measured using a second-generation Tg assay allows for the identification of DTC patients who are likely to remain disease free with great accuracy. This simple measurement, therefore, may be sufficient to assess the risk-adapted management of DTC patients.

A diffuse sclerosing variant of papillary thyroid carcinoma: clinical and pathologic features and outcomes of 34 consecutive cases.

BACKGROUND: The diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is a relatively rare variant of papillary thyroid cancer. Large studies of patients with DSPC have been infrequently performed, and controversy still exists concerning some DSPC features and outcomes. The aim of the present study was to retrospectively evaluate the clinicopathologic features and outcomes in a series of 34 consecutive patients with DSPC and to compare them with a larger group of 245 consecutive patients with the classic variant of papillary thyroid carcinoma (cPTC) that were evaluated in the same period. PATIENTS AND METHODS: Clinical and histological features (sex, age, tumor size,multifocality, bilaterality, extra thyroid extension, and local and distant metastases) were recorded in all patients, as well as any persistent or recurrent disease and the patients' disease status at last observation. Patients with cPTC were classified as either low (122) or high risk (123). DSPC and high-risk patients were all treated with the same protocol, including ¹³¹I treatment. All patients were included in a Cox regression model analysis to investigate the effect of each variable on the hazard ratio. RESULTS: As expected, multifocality, bilaterality, and extra thyroid extension were more frequently noted at presentation, and the pT1 category of TNM classification was less frequently noted in DSPC and high-risk patients with cPTC compared with low-risk patients with cPTC. No significant difference was found between patients with DSPC and those with high-risk cPTC, except that extra thyroid extension was found more frequently in the patients with DSPC. Using multivariate analysis, diffuse sclerosing variant was an independent variable for predicting a high risk of persistent and recurrent disease during initial follow-up. However, at a later time, and after further treatment, the disease status was not different between patients with DSPC and those with high-risk cPTC, and only the presence of distant metastases affected the final outcome. CONCLUSIONS: DSPC is a thyroid papillary carcinoma variant characterized by high aggressiveness. In patients with DSPC, the outcome is worse than in patients with low-risk cPTC; and, at presentation, characteristics are somewhat worse than for patients with high-risk cPTC.At medium term, the outcome is similar to that observed in patients with high-risk cPTC, provided aggressive treatment is used (additional surgical intervention, when required, and/or ¹³¹I radiotherapy).

Effects of either LT4 monotherapy or LT4/LT3 combined therapy in patients totally thyroidectomized for thyroid cancer.

After total thyroidectomy all thyroid cancer patients require lifelong treatment with thyroid hormones; the treatment of choice is synthetic levothyroxine (LT4). The question of whether these patients might benefit from the combined LT4 and liothyronine (LT3) treatment has been addressed with conflicting conclusions. The aim of the present study was to compare the effects of combined low LT4/LT3 molar ratio therapy versus LT4 monotherapy on various target organs and tissues in patients thyroidectomized for thyroid cancer. Urine collection (24 hour), a fasting blood sample for laboratory examinations, thyroid function clinical score, and cardiovascular, neurological, and neuropsychological evaluations were obtained. Clinical parameters and peripheral markers of thyroid function were measured during the two different treatment regimens in 20 patients. Mean serum aspartate aminotransferase, alanine aminotransferase, sex hormone binding globulin, and osteocalcin values were significantly higher during the combined treatment. No significant differences in the clinical score, the systolic and diastolic performance, and the neurological and neuropsychological evaluations were observed between the two treatment regimens. Moreover, no alteration due to subclinical hyperthyroidism or to the fluctuations in serum T3 concentrations during the combined therapy was observed. In conclusion, we found no evidence that combined therapy with a low LT4/LT3 molar ratio resulted in improved well-being and cognitive function or in increased thyroid hormone action on peripheral tissues in respect to LT4 monotherapy. Until future large, blind, randomized, and controlled trials prove otherwise, LT4 should remain the standard treatment for thyroid cancer patients.

Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases.

To investigate predictors of relapse in small (

Left ventricular function in acute hypothyroidism: a Doppler echocardiography study.

BACKGROUND: Acute changes in cardiac parameters may occur after L-thyroxine withdrawal in patients totally thyroidectomized for thyroid cancer. The literature data regarding cardiac function in acute hypothyroidism are limited and discordant. METHODS: In order to evaluate the effects of acute hypothyroidism on cardiac function, 20 athyreotic patients (3 males, 17 females, mean age 46.4 +/- 8.6 years, range 18-58 years) underwent Doppler echocardiography during L-thyroxine therapy (euthyroid phase) and 5 weeks after hormone therapy withdrawal (hypothyroid phase). RESULTS: Significant changes in the left ventricular mass (83 +/- 12 vs 93 +/- 17 g/m2, p = 0.004) and end-diastolic volume (56 +/- 9 vs 50 +/- 9 ml/m2, p = 0.01) were found. Among systolic function parameters, the pre-ejection period/left ventricular ejection time (PEP/LVET) ratio (0.33 +/- 0.07 vs 0.40 +/- 0.08, p = 0.0002), aortic peak flow velocity corrected for heart rate (3.9 +/- 0.7 vs 3.5 +/- 0.5 cm/s, p = 0.02) and mean aortic acceleration corrected for heart rate (45 +/- 15 vs 38 +/- 9 cm/s2, p = 0.007) showed significant variations, whereas the left ventricular fractional shortening (39 +/- 5 vs 40 +/- 6%, p = NS) and ejection fraction (69 +/- 6 vs 68 +/- 7%, p = NS) did not change. Among diastolic function parameters, only the E-wave velocity decreased (73 +/- 17 vs 65 +/- 12 cm/s, p = 0.01); no significant modification was found in the A-wave velocity (62 +/- 19 vs 58 +/- 14 cm/s, p = NS), E/A ratio (1.2 +/- 0.5 vs 1.1 +/- 0.3, p = NS), isovolumic relaxation time (93 +/- 16 vs 95 +/- 37 ms, p = NS) and E-wave deceleration time (233 +/- 48 vs 235 +/- 45 ms, p = NS). The pattern of left ventricular filling remained unchanged, except in 2 patients. The Suga-Sagawa's index, a known parameter of myocardial contractility, was unchanged (5.6 +/- 2 vs 6.1 +/- 2 mmHg/ml, p = NS). The systemic vascular resistance increased (1511 +/- 599 vs 2216 +/- 408 dynes-s-cm(-5), p = 0.002), while the stroke index (39 +/- 8 vs 33 +/- 7 ml/m2, p = 0.001) and cardiac index (2.74 +/- 0.6 vs 2.07 +/- 0.5 l/min/m2, p = 0.0001) significantly decreased. CONCLUSIONS: Acute hypothyroidism was associated with left ventricular systolic dysfunction, probably due to pre- and afterload alterations rather than to an impaired myocardial contractility. The diastolic function was not significantly modified. An increase in cardiac mass was also found, possibly a consequence of early interstitial myxedema. Unlike the PEP/LVET ratio, both the fractional shortening and ejection fraction may be unreliable indicators of left ventricular systolic dysfunction in patients with acute hypothyroidism.