Papillary thyroid carcinoma: ≤ 10 mm does not always mean pN0. A multicentric real-world study.

The incidence of papillary thyroid carcinoma (PTC) is increasing and PTC ≤ 10 mm (PTMC) accounts for most new diagnoses. PTMCs are not always low risk, as detection of lymph nodes metastasis (LNM) may occur. The purpose of the study was to analyze the clinical pattern, frequency, and independent risk factors of patients with PTMC and LNM. From January 2022 to June 2023, PTCs managed at CTO Hospital, Rome; Policlinico Vanvitelli, Naples; and Garibaldi Nesima Hospital, Catania were included. PTC management followed the same diagnostic-therapeutic procedures according to the ATA guidelines. Variables such as age, sex, maximum diameter, histologic evidence of LNM (HELNM +), Hashimoto's thyroiditis (HT), multifocality, capsule invasion, and histological subtype were considered. PTCs were divided according to HELNM and size. Two hundred ninety-eight PTCs were included. PTMCs were 136 (45.6%) and LNM occurred in 27.2% of them. In the HELNM + group, analysis of PTMC vs 'MacroPTC' (PTC > 10 mm) did not show any statistical difference. Multivariate regression revealed that young age (OR 0.93; CI 95% 0.90-0.96; p < 0.01) and male sex (male OR 3.44; CI 95% 1.16-10.20; p = 0.03) were the only independent risk factors for HELNM + in PTMC. The risk of LNM in PTMC is not negligible; therefore, a careful evaluation by an expert thyroidologist is mandatory for patients with small thyroid nodule, especially in younger and male patients before excluding surgery. In the future, new tools are needed to detect early PTMC with LNM before surgery.

Lymph Node Ratio as a Predictive Factor of Persistent/Recurrent Disease in Patients With Medullary Thyroid Cancer: A Single-Center Retrospective Study.

OBJECTIVE: Thyroidectomy with neck lymph node dissection is curative for most patients with medullary thyroid cancer (MTC). Lymph node ratio (LNR, ie, the ratio between the metastatic and the removed lymph nodes) is a reliable parameter with which to estimate both disease extent and quality of neck dissection. The aim of this study was to investigate the prognostic role of LNR to predict persistent/recurrent disease in patients with MTC. METHODS: A single-center, retrospective study of a consecutive cohort of 95 patients with MTC treated with total thyroidectomy and neck dissection. Receiver operating characteristics curve analysis was performed to identify the LNR cut-off. RESULTS: LNR was positively associated with tumor size, preoperative and postoperative calcitonin values, postsurgery carcinoembryonic antigen values, persistent/recurrent disease, and the occurrence of distant metastases during follow-up. At multivariate analysis, persistent/recurrent disease was independently associated with the LNR value and was accurately predicted by a cut-off value of 0.12 (area under the curve = 0.85). Indeed, patients with LNR ≥0.12 had a higher probability of developing persistent/recurrent disease (79.3% vs 10.6%, odds ratio = 32.3, 95% CI = 9.8-106.4; P < .001) and distant metastasis (34.5% vs 3.0%, odds ratio = 16.8, 95% CI = 3.4-83.6; P < .001) than patients with LNR <0.12. The median time to progression was 15 months in patients with LNR ≥0.12 whereas it was not reached in patients with LNR <0.12 (hazard ratio: 7.18, 95% CI = 3.01-17.11, P < .001). CONCLUSIONS: LNR is a reliable prognostic factor to predict the risk of recurrence, persistence, and distant metastases in patients with MTC.

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.

Levothyroxine therapy, calculated deiodinases activity and basal metabolic rate in obese or nonobese patients after total thyroidectomy for differentiated thyroid cancer, results of a retrospective observational study.

INTRODUCTION: Therapy for hypothyroid obese patients is still under definition since the thyrotropin-stimulating hormone (TSH) level is a less reliable marker of euthyroidism than nonobese patients. Indeed, TSH levels positively correlate with body mass index (BMI), and this increase may be a compensatory mechanism aimed at increasing energy expenditure in obese people. In contrast, the correlation of BMI with thyroid hormone levels is not completely clear, and conflicting results have been obtained by several studies. The L-T4 replacement dose is more variable in obese hypothyroid patients than in nonobese patients, and a recent study indicated that the L-T4 replacement dose is related to lean body mass in obese thyroidectomized patients. We aimed to study the correlations of L-T4-administered dose, thyroid hormone levels and TSH secretion with basal metabolic rate (BMR) and total calculated deiodinase activity (GD) in obese and nonobese athyreotic patients. We also looked for individualized L-T4 replacement dose set points to be used in clinical practice. METHODS: We studied retrospectively 160 athyreotic patients, 120 nonobese and 40 obese. GD was calculated by SPINA Thyr 4.2, the responsiveness of the hypothalamic/pituitary thyrotrope by Jostel's thyrotropin (TSH) index and BMR by the Mifflin-St. Jeor formula, the interplay of GD and BMR with L-T4, thyroid hormones and TSH index (TSHI) was also evaluated. RESULTS: In our study, the L-T4 dose was an independent predictor of GD, and approximately 30% of athyreotic patients under L-T4 therapy had a reduced GD; FT4 levels were higher and negatively modulated by BMR in obese athyreotic patients respect to nonobese, in these patients a T4 to T3 shunt, in terms of TSHI suppression is observed suggesting a defective hypothalamic pituitary T4 to T3 conversion and a resistance to L-T4 replacement therapy. CONCLUSIONS: L-t4 dose is the most important predictor of GD, BMR modulates T4 levels in obese athyreotic patients that are resistant to L-T4 replacement therapy.

IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance?

Insulin-like growth factor 2 (IGF2) is upregulated in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. However, our understanding of its physiological and pathological role is lagging behind what we know about IGF1. Dysregulation of the expression and function of IGF2 receptors, insulin receptor isoform A (IR-A), insulin growth factor receptor 1 (IGF1R), and their downstream signaling effectors drive cancer initiation and progression. The involvement of IGF2 in carcinogenesis depends on its ability to link high energy intake, increase cell proliferation, and suppress apoptosis to cancer risk, and this is likely the key mechanism bridging insulin resistance to cancer. New aspects are emerging regarding the role of IGF2 in promoting cancer metastasis by promoting evasion from immune destruction. This review provides a perspective on IGF2 and an update on recent research findings. Specifically, we focus on studies providing compelling evidence that IGF2 is not only a major factor in primary tumor development, but it also plays a crucial role in cancer spread, immune evasion, and resistance to therapies. Further studies are needed in order to find new therapeutic approaches to target IGF2 action.

Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management.

Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves' ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.

Early detection of suspicious lymph nodes in differentiated thyroid cancer.

BACKGROUND: Early identification of cervical lymph node (LN) metastases cervical lymph node metastases (CLNM) is crucial in the management of differentiated thyroid cancer differentiated thyroid cancer (DTC) as it influences the indication and the extent of surgery with an impact on the recurrence risk and overall survival. The present review focused on novel sensitive and specific diagnostic techniques, by searching through online databases like MEDLINE and Scopus up to February 2022. AREAS COVERED: The techniques identified included contrast-enhanced ultrasound (CEUS), dosage of fragment 21-1 of cytokeratin 19 (CYFRA 21-1) in lymph node fine needle aspiration washout, sentinel LN biopsy (SNB), and artificial intelligence (AI) - deep learning applied to ultrasonography and computed tomography. These methods displayed widely varying sensitivity and specificity results, ranging from approximately 60-100%. This variability is mainly due to the operator's experience because of the great complexity of execution of these new techniques, which require a long-learning curve. EXPERT OPINION: Despite the appearance of many candidate methods to improve the detection of metastatic lymph nodes, none seem to be clearly superior to the tools currently used in clinical practice and FNA-Tg measurement remains the more accurate tool to detect neck recurrences and CLNM from DTC.

Orbital metastasis from thyroid cancer: a case report and review of the literature.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far. CASE DESCRIPTION: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration. CONCLUSIONS: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Recent insights into the pathogenesis of autoimmune hypophysitis.

INTRODUCTION: Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents, its pathogenesis is far to be fully understood. The present review is focused on recent evidence concerning the pathogenesis of autoimmune hypophysitis by searching through online databases like MEDLINE and Scopus up to May 2021. AREAS COVERED: Hypophysitis frequently develops in the context of a strong autoimmune background, including a wide spectrum of subtypes ranging from the commonest form of lymphocytic hypophysitis to the newly described and less common IgG4-, anti-PIT-1, and ICI-induced forms. A peculiar combination of genetic predisposition, pituitary damage and immunological setting represents the pathogenetic basis of autoimmune hypophysitis, which is characterized by diffuse infiltration of the gland by lymphocytes and variable degrees of fibrosis followed by pituitary cell destruction. Anti-pituitary antibodies (APA) have been described in sera from patients suffering from autoimmune hypophysitis, though their pathophysiological significance remains largely unknown and their diagnostic value limited. EXPERT OPINION: In recent years hypophysitis has gained interest due to the increased number of new diagnoses and the recognition of novel subtypes. Further studies could lead to improvements in biochemical/immunological diagnosis and targeted treatments.

Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.

BACKGROUND: Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome. CASE PRESENTATION: A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of 99mTc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of 99mTc-pertechnatate and the presence of a "cool" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion. CONCLUSION: We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.

Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression.

Previous reports indicate that selenium supplementation may be useful to reduce cell oxidative stress. In particular, selenium may decrease the level of thyroid autoantibodies in patients with Hashimoto's thyroiditis (HT). Recent studies also indicate that myo-inositol may have beneficial effects on thyroid function in patients with HT. Hence, the aim of the present study is to evaluate whether myo-inositol may enhance the protective effect of selenium on HT progression to hypothyroidism. The study was designed as observational and retrospective. Thyroid hormones were evaluated in patients with HT who were either euthyroid or subclinically hypothyroid. These patients were subdivided into three groups: untreated, treated with selenomethionine alone (Se-meth: 83 µg/day) and treated with Se-meth plus myo-inositol (Se-meth + Myo-I: 83 µg/day + 600 mg/day). Outcome evaluation was performed at baseline and after 6 and 12 months of treatment. High-resolution ultrasound of the thyroid gland was performed to evaluate changes in thyroid echoic pattern during the study. Compared to baseline, levels of thyroid-stimulating hormone (TSH) increased significantly in untreated patients but decreased by 31% and 38%, respectively, in those treated with Se-meth and Se-meth + Myo-I. Moreover, in the latter group the TSH reduction was observed earlier than in the Se-meth-treated group. Densitometric analysis of thyroid ultrasonography showed an echoic pattern improvement in both treated groups compared to untreated patients, although this difference was not statistically significant. Thus, Se-meth treatment is effective in patients with HT and its effect may be improved in combination with Myo-I through earlier achievement of TSH levels closer to physiological concentrations.

Corticosteroid Pulse Therapy for Graves' Ophthalmopathy Reduces the Relapse Rate of Graves' Hyperthyroidism.

Background: A course of anti-thyroid drugs (ATD) is the most common first line treatment for Graves' hyperthyroidism. However, hyperthyroidism relapse is frequent (30-70%). Due to the autoimmune nature of Graves' disease, the immunosuppressive treatment used for active Graves' orbitopathy (GO) may reduce the relapses after ATD discontinuation. Objective: To evaluate the recurrence rate in Graves' patients who, in addition to standard ATD, were treated or not treated with parenteral methylprednisolone (MPDS) for GO. Methods: Single-center retrospective study in a continuous series of 162 newly diagnosed Graves' patients, with or without GO, all gone into remission and followed-up until hyperthyroidism recurrence or at least 4 years after ATD discontinuation. Patients with moderate-severe active GO underwent middle dose MPDS treatment according to the EuGoGo guidelines. Cox proportional-hazard model was used to comparatively evaluate the risk of recurrence and the predictive factors in patients treated or not treated with MPDS pulse therapy. Results: MPDS treatment was the most significant factor that independently correlated with a reduced risk of hyperthyroidism relapse (HR = 0.53, 95% C.I. = 0.31-0.89). FT3 and female sex were also independent protective factors, while age almost reached the significance level, p = 0.062. The efficacy of MPDS was very high in patients aged <40 years (42.1% decrease in relapses, p < 0.01) but it was not significant in older patients. Discussion: Our study found that after ATD discontinuation the frequency of Graves' hyperthyroidism relapse was reduced in patients treated with MPDS pulse therapy for GO. This effect was more marked in young patients.

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.

Efficacy of Botulinum Toxin A for Treating Cramps in Diabetic Neuropathy.

OBJECTIVE: Muscle cramps occur in >50% of diabetic patients and reduce the quality of life. No effective treatment is available. We evaluated the clinical effectiveness of botulinum toxin A (BTX-A) injections for treating cramps in diabetic patients with neuropathy. METHODS: This single-center, double-blind, placebo-controlled perspective study investigated the efficacy and safety of BTX-A intramuscular injection for treating calf or foot cramps refractory to common pharmacological drugs. Fifty diabetic patients with peripheral neuropathy and cramps were randomly assigned to 2 matched groups. BTX-A (100 or 30 units) or saline was injected on each side into the gastrocnemius or the small flexor foot muscles. Changes in pain intensity (primary outcome) and cramp frequency were evaluated over the course of 20 weeks after BTX-A administration. Cramp interference in daily life and the electrophysiological cramp threshold frequency were also measured. The treatment was repeated 5 months after first injection in 19 responders. RESULTS: All outcome measures improved significantly after BTX-A compared with placebo. The changes with respect to baseline were already significant after 1 week and persisted up to week 14. Only 5 of 25 (20%) patients were nonresponders (<50% decrease of the primary outcome). The responses to a second BTX-A injection provided results similar to the first administration. Mild pain at the injection site (4/25 cases) was the only adverse event, and it disappeared within 2 to 3 days. INTERPRETATION: Local BTX-A infiltration is an efficacious and safe procedure for obtaining a sustained amelioration of muscle cramps associated with diabetic neuropathy. Ann Neurol 2018;84:682-690.

Integrated insulin pump therapy with continuous glucose monitoring for improved adherence: technology update.

Insulin pump therapy combined with real-time continuous glucose monitoring, known as sensor-augmented pump (SAP) therapy, has been shown to improve metabolic control and to reduce the rate of hypoglycemia in adults with type 1 diabetes compared to multiple daily injections or standard continuous subcutaneous insulin infusion. Glycemic variability is also reduced in patients on SAP therapy. This approach allows patients to monitor their glucose levels being informed of glycemic concentration and trend. Trained diabetic patients, therefore, can appropriately modify insulin infusion and/or carbohydrate intake in order to prevent hypo- or hyperglycemia. For these reasons, SAP therapy is now considered the gold standard for type 1 diabetes treatment. To be clinically effective, however, devices and techniques using advanced technology should not only have the potential to theoretically ameliorate metabolic control, but also be well accepted by patients in terms of satisfaction and health-related quality of life, because these factors will improve treatment adherence and consequently overall outcome. SAP therapy is generally well tolerated by patients; however, many clinical trials have identified significant noncompliance in the use of this device, most notably in the pediatric and adolescent populations. In this review we aim to analyze the main reasons for good or poor adherence to SAP therapy and to provide useful tips in order to fully benefit from this kind of novel therapeutic approach.

Insulin analogs and cancer.

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time-course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart, and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the extracellular-signaling-regulated kinase (ERK) rather than the protein kinase B (PKB/AKT) intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.

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.

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.

Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients.

CONTEXT: Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients. OBJECTIVE: To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. DESIGN: Retrospective study. SETTING: Academic hospital. PATIENTS: 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls. MEASUREMENTS: TSH, FT4 and FT3 concentrations by immunoassays. RESULTS: FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients. CONCLUSIONS: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid 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).