Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Hypothyroidism and Somatization: Results from E-Mode Patient Self-Assessment of Thyroid Therapy, a Cross-Sectional, International Online Patient Survey.

Background: Between 10% and 15% of hypothyroid patients experience persistent symptoms despite achieving biochemical euthyroidism. Unexplained persistent symptoms can be a sign of somatization. This is associated with distress and high health care resource use and can be classified as somatic symptom disorder (SSD). Prevalence rates for SSD differ depending on classification criteria and how they are ascertained, varying between 4% and 25%. As this has not been studied in hypothyroid patients before, the aim of this study was to document somatization in people with hypothyroidism and to explore associations with other patient characteristics and outcomes. Methods: Online, multinational cross-sectional survey of individuals with self-reported, treated hypothyroidism, which included the validated Patient Health Questionnaire-15 (PHQ-15) for assessment of somatization. Chi-squared tests with the Bonferroni correction were used to explore outcomes for respondents with a PHQ-15 score ≥10 (probable somatic symptom disorder [pSSD]) versus a PHQ-15 score <10 (absence of SSD). Results: A total of 3915 responses were received, 3516 of which contained the valid PHQ-15 data (89.8%). The median score was 11.3 (range 0-30 [confidence interval 10.9-11.3]). The prevalence of pSSD was 58.6%. Associations were found between pSSD and young age (p < 0.001), women (p < 0.001), not working (p < 0.001), having below average household income (p < 0.001), being treated with levothyroxine (LT4) (rather than combination of LT4 and L-triiodothyronine [LT3], LT3 alone, or desiccated thyroid extract) (p < 0.001), expression of the view that the thyroid medication taken did not control the symptoms of hypothyroidism well (p < 0.001), and with number of comorbidities (p < 0.001). pSSD was associated with respondent attribution of most PHQ-15 symptoms to the hypothyroidism or its treatment (p < 0.001), dissatisfaction with care and treatment of hypothyroidism (p < 0.001), a negative impact of hypothyroidism on daily living (p < 0.001), and with anxiety and low mood/depression (p < 0.001). Conclusions: This study demonstrates a high prevalence of pSSD among people with hypothyroidism and associations between pSSD and negative patient outcomes, including a tendency to attribute persistent symptoms to hypothyroidism or its treatment. SSD may be an important determinant of dissatisfaction with treatment and care among some hypothyroid patients.

An innovative synthetic support for immunocytochemical assessment of cytologically indeterminate (Bethesda III) thyroid nodules.

Background: Fine needle aspiration (FNA) is the procedure of choice in the evaluation of thyroid nodules. Nodules with indeterminate cytological categories, Bethesda III and IV, pose challenges in clinical practice and are frequently submitted to diagnostic surgery. CytoFoam Core (CFCS) uses an absorbent foam device inserted into the needle hub to collect the cytological sample aspirated during FNA. Specimen is formalin-fixed and paraffin-embedded. Aim of the study: Assessing diagnostic efficacy of CFCS, compared to traditional cytology, in re-evaluating thyroid nodules classified as Bethesda III, using post-surgical histology as reference standard. Method: Retrospective study on 89 patients with a first indeterminate cytological report who were referred to the Department of Endocrinology of Regina Apostolorum Hospital (Albano L. Rome, Italy) for a second FNA. FNA was performed after at least one month under ultrasound guidance with a 23G needle according to the established procedure. During the second procedure, both traditional cytological (TC) smears and a single-pass CFCS specimen were obtained for each patient. On CFCS samples immunocytochemical staining for Galectin-3, HBME-1, and CK-19 was also performed. 51 patients eventually underwent surgery, and their histological diagnoses were compared to the TC and CFCS reports. Four parameters were evaluated: inadequacy rate, rate of persistent indeterminate (Bethesda III and IV) reports, rate of malignancy in persistently indeterminate nodules, and rate of cancer in lesions cytologically classified as malignant. Results: Non-diagnostic samples were 6 (11.8%) in TC vs 3 (5.9%) in CFCS (p=0.4). Persistent indeterminate samples were 31 (60.8%) in TC vs 19 (37.2%) in CFCS (p=0.01). Rate of malignancy in persistently indeterminate nodules was 8/19 (42.1%) in CFCS vs 9/31 (29%) in TC group (p=0.3). Nine/51 (17.6%) samples were classified as benign by TC vs 21/51 (41.2%) samples by CFCS (p<0.01). All nodules resulted benign at post-surgical evaluation. Five/51 (9.8%) samples were classified as suspicious for malignancy/malignant in TC group against 8/51 (15.7%) samples in CFCS (p=0.5). Post-surgical evaluation confirmed malignancy in all these cases. Conclusion: CFCS demonstrated greater diagnostic accuracy than TC in repeat FNA assessment of cytologically indeterminate nodules. CFCS increased the conclusive diagnosis rate and decreased the number of cytologically indeterminate cases.

The Impact of Hypothyroidism on Satisfaction with Care and Treatment and Everyday Living: Results from E-Mode Patient Self-Assessment of Thyroid Therapy, a Cross-Sectional, International Online Patient Survey.

Background: Hypothyroid patients often report dissatisfaction and poor quality of life. This survey explored the impact of hypothyroidism on patient satisfaction, everyday living, experiences with health care professionals, and influence of demographic and socioeconomic factors. Methods: Cross-sectional questionnaire survey targeting an international population of hypothyroid patients. Multilevel regression modeling was used for analyses. Results: The total number of responses was 3915 from 68 countries. Satisfaction with care and treatment was not associated with type of treatment for hypothyroidism. Having no confidence and trust in health care professionals was strongly associated with dissatisfaction (p < 0.001). Controlling for all other variables, significant differences were found among satisfaction rates between countries. A weak inverse relationship was found between satisfaction with care and treatment and impact on everyday living (p < 0.001). Respondents taking levothyroxine (LT4) alone were more likely to report a positive impact on everyday living (pooled odds ratio 2.376 [confidence interval: 0.941-5.997]) than respondents taking liothyronine-containing treatments. Conclusions: Low levels of satisfaction with care and treatment for hypothyroidism were strongly associated with lack of confidence and trust and negative experiences with health care professionals. Differences in responses between countries were noted, implying the potential influence of national health care systems, socioeconomic and cultural factors. Contrary to widespread anecdotes in social media, this large-scale survey shows no association between type of treatment for hypothyroidism and patient satisfaction, as well as better outcomes on everyday living associated with LT4, compared with liothyronine-containing treatments.

An International Survey on Utilization of Five Thyroid Nodule Risk Stratification Systems: A Needs Assessment with Future Implications.

Background: Multiple ultrasound-based risk stratification systems (RSSs) for thyroid nodules are used worldwide. Variations in structure, performance, and recommendations are confusing for physicians and patients and complicate management decisions. The goal of this study was to determine the factors that are associated with choice of RSS and barriers to RSS use. These results are intended to inform development of a universal international thyroid ultrasound RSS. Methods: An online survey with questions about usage of RSSs, ultrasound practice and volumes, training, specialty, practice type, and geographic region was made available to members of five professional societies via email. Subgroup analysis was performed to identify the factors that governed use of one or more of five leading RSSs: American Association of Clinical Endocrinology (AACE), American College of Endocrinology (ACE), and Associazione Medici Endocrinologi (AME) Medical Guidelines, American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS), American Thyroid Association (ATA) guidelines, European Thyroid Association TIRADS (EU-TIRADS), and Korean Society of Thyroid Radiology/Korean Thyroid Association TIRADS (K-TIRADS). Results: There were 875 respondents from 52 countries (response rate not estimated due to overlapping society membership). More than 7 specialties were represented, with most (538; 61.5%) in endocrinology. The choice of RSS was strongly associated with medical specialty and geographic region. Of 692 respondents who indicated that their practice used an RSS, 213 (30.8%) used more than one. The specialties that were more likely to use multiple RSSs were surgery and others (40%), followed by endocrinology (33.0%), and radiology or nuclear medicine (17%) (p < 0.001). Of 271 (31.0%) respondents who indicated that they do not personally use an RSS, the majority (168; 62%) preferred to describe the specific sonographic characteristics/features that they believe are most relevant in a nodule. Conclusions: Almost one third of respondents indicated use of more than one RSS in their practice, potentially leading to confusion, and a similar proportion reported not using an RSS for various reasons. A unified international system that addresses their concerns and simplifies risk classification of thyroid nodules may benefit practitioners and patients. This is particularly important as newer thyroid nodule management options gain acceptance.

Morphological and Molecular Assessment in Thyroid Cytology Using Cell-Capturing Scaffolds.

The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation.

Inter- and Intraobserver Agreement in the Assessment of Thyroid Nodule Ultrasound Features and Classification Systems: A Blinded Multicenter Study.

Background: Single-center trials demonstrated moderate-substantial level of interobserver agreement in the evaluation of ultrasound (US) features of thyroid nodules. Multicenter studies on US agreement, however, are scanty, and data on intraobserver agreement are poor. Aim of the study was to assess inter- and intraobserver agreement between different thyroid centers and different specialists. Methods: A blinded analysis of 100 electronically recorded thyroid nodule US images was conducted in three large-volume thyroid centers by seven radiologists and endocrinologists. The evaluation was repeated after randomization 4 months later. The following US characteristics were evaluated: composition, echogenicity, margins, intranodular echogenic spots, vascularity, and shape. Thyroid nodules were also classified according to AACE/ACE/AME, EU-TIRADS, ATA, and ACR-TIRADS US classifications. Intra- and interobserver agreement was calculated using cross-tabulation expressed as mean Cohen's Kappa. Results: Interobserver agreement for US features: K-coefficient was 0.53 for composition, 0.47 for echogenicity, 0.46 for intranodular vascularity, and 0.33 for margins of the nodules. For echogenic foci, the K-coefficient was 0.47 for microcalcifications, 0.38 for macrocalcifications, 0.11 for the subcategory comet-tail artifacts, and 0.42 for shape. Operators resulted uncertain on hyperechoic foci definition in 16% of cases and described them as "hyperechoic foci of uncertain significance." Interobserver Cohen-K for US classification systems was 0.44 for AACE, 0.42 for ACR-TIRADS, 0.39 EU-TIRADS, and 0.34 for ATA. Intraobserver agreement: the K-coefficient for nodule US features was 0.62 for intranodular vascularity, 0.58 for composition, 0.60 for echogenicity, 0.54 for macrocalcifications, 0.55 for microcalcifications, 0.47 for comet tails, 0.39 for margins, and 0.35 for shape. Intraobserver Cohen-K for US classification systems was 0.54 for AACE, 0.49 for ACR-TIRADS, 0.38 for ATA, and 0.33 for EU-TIRADS. Conclusions: Intraobserver reproducibility for thyroid nodule US reporting and US classification systems appears fairly adequate, while the interobserver agreement between different centers is lower than that assessed in single-center trials. Reporting and rating ability of thyroid US examiners still appear not consistent. An unified lexicon of thyroid US features, a simplified method of classification, and a dedicated training in the description of thyroid US findings may increase the observers' agreement and the predictive value of US classification systems in real world practice.

Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms.

Well-established criteria for evaluating the response to treatment and the appropriate followup of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

State-of-the-Art Review on Diabetes Care in Italy.

BACKGROUND: Diabetes is a significant health problem in Italy as in other western countries. OBJECTIVE: To review available epidemiological data and the legislative framework for diabetes care in Italy. METHODS: Review of Italian Health Ministry's official documents and analysis of epidemiological data published by Italian Scientific Societies. FINDINGS: Diabetes affects more than 5% of the Italian population. The expenditures for the care of people with diabetes are about €10 billion ($US 11 billion) a year and are increasing over time. Italian law regulates the clinical care of people with diabetes and creates a clinical framework involving medical organizations, prevention programs, personnel training, and legal protection. The National Health Program is structured in essential levels of assistance that can be defined differently in the various regions. In 2013, the "National Diabetes Plan," defining priority areas for intervention, was approved and represents the main regulatory tool for the management of diabetes within the Italian National Health Service. In Italy, the status of diabetes care is being monitored using the data from 2 permanent observatories: the ARNO Observatory Diabetes and the Associazione Medici Diabetologi Annals. CONCLUSIONS: A comprehensive approach to diabetes is offered to all citizens, consonant with the constitutionally guaranteed right to health. However, this important effort translates into a relevant financial burden for the National Health Service.

The advent of ultrasound-guided ablation techniques in nodular thyroid disease: towards a patient-tailored approach.

Surgery is the long-established therapeutic option for benign thyroid nodules, which steadily grow and become symptomatic. The cost of thyroid surgery, the risk of temporary or permanent complications, and the effect on quality of life, however, remain relevant concerns. Therefore, various minimally invasive treatments, directed towards office-based management of symptomatic nodules, without requiring general anaesthesia, and with negligible damage to the skin and cervical tissues, have been proposed during the past two decades. Today, ultrasound-guided percutaneous ethanol injection and thermal ablation with laser or radiofrequency have been thoroughly evaluated, and are accessible procedures in specialized centres. In clinical practice, relapsing thyroid cysts are effectively managed with percutaneous ethanol injection treatment, which should be considered therapy of choice. In solid non-functioning thyroid nodules that grow or become symptomatic, trained operators may safely induce, with a single session of laser ablation treatment or radiofrequency ablation, a 50% volume decrease and, in parallel, improve local symptoms. In contrast, hyperfunctioning nodules remain best treated with radioactive iodine, which results in a better control of hyperthyroidism, also in the long-term, and fewer side-effects. Currently, minimally invasive treatment is also investigated for achieving local control of small size neck recurrences of papillary thyroid carcinoma in patients who are poor candidates for repeat cervical lymph node dissection. This particular use should still be considered experimental.

Thyroid nodule guidelines: agreement, disagreement and need for future research.

This article reviews agreement, disagreement and need for future research of the thyroid nodule guidelines published by the British Thyroid Association, National Cancer Institute, American Thyroid Association and the joint, transatlantic effort of three large societies, the American Society of Clinical Endocrinologists, Associazione Medici Endocrinologi and the European Thyroid Association, published in 2010. Consensus exists for most topics in the various guidelines. A few areas of disagreement, such as the use of scintigraphy, are mostly due to differences in disease prevalence in different countries. Most of the discordance, for example, on the use of calcitonin screening or fine-needle aspiration cytology classification, could probably be resolved by further expert discussions, as the basis is the same published evidence. Importantly, owing to a current lack of evidence in many areas, clinically very relevant areas of uncertainty need to be addressed by further research. This situation applies, for instance, to better definition of ultrasound malignancy criteria and the evaluation of emerging new diagnostic and therapeutic techniques, including molecular markers. For clinicians who advise individual patients, these areas of uncertainty can currently only be resolved by sound management on the basis of clinical judgment, experience and patient preference.

Thyroid nodules: clinical importance, assessment, and treatment.

In the general population, thyroid nodules are found in 5% by palpation and in 50% by ultrasonography (US). Initial evaluation of nodules should include serum thyroid-stimulating hormone measurement, fine-needle aspiration (FNA) biopsy, and US. Thyroid micronodules are being detected with increasing frequency and are currently evaluated by US-FNA. Routine measurement of serum calcitonin and thyroglobulin and FNA rebiopsy are not recommended. Cytologically benign thyroid nodules should be followed rather than treated. Novel treatment options including iodine 131, percutaneous ethanol injection, and percutaneous laser thermal ablation have specific indications, advantages, and adverse effects.

Percutaneous ethanol injection treatment in benign thyroid lesions: role and efficacy.

GOAL: To establish the role of percutaneous ethanol injection (PEI) treatment in benign thyroid lesions by evaluating: (1) the long-term efficacy and side effects of the treatment, (2) the factors predictive of efficacy of PEI, and (3) the cost effectiveness of the procedure. MATERIALS AND METHODS: Fifty-eight recurrent cystic nodules, 95 autonomously functioning nodules (AFTN), and 17 hyperfunctioning nodules causing thyrotoxicosis (toxic nodules) were treated by PEI from 1990 to 1996 in our center. Ultrasound (US) and color flow doppler (CFD) examinations were carried out before and after each treatment. In patients with AFTN, serum thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) levels were tested before and after PEI. All patients were independently reexamined by two external reviewers after a minimum follow-up of 5 years (median, 6.9 years). RESULTS: The median number of treatments was 2.0 (range, 1.0-4.0) for cystic nodules, 4 (range, 2.0-6.0) for AFTN, and 5 (range, 3.0-7.0) for toxic nodules. At the 5-year evaluation cystic nodules showed a volume reduction greater than 75% versus baseline in 86.2% of cases and an improvement of local symptoms in 91.4% of cases. AFTN presented serum TSH within normal limits in 60.0% of patients. Toxic nodules showed a detectable serum TSH and normal FT3 and FT4 values in 35.3% of cases. Two cases of transient dysphonia were observed. In cystic lesions no significant correlation was found between the baseline and the final volume (r2 = 0.17) and no significant predictor of treatment efficacy was found. However, unilocularity was associated with a lower number of treatments than multilocularity (median, 2.0 vs. 3.0). Independent predictors of clinical efficacy in both AFTN and toxic nodules were a baseline volume less than 5.0 mL and a fluid component greater than 30% (odds ratio [OR] = 6.1 and 3.3, respectively). CONCLUSIONS: Most recurrent cystic lesions of the thyroid can be cured by PEI, which should become the first line of treatment. The majority of AFTN and toxic nodules with volume less than 5.0 mL presented a marked volume decrease and normal serum TSH levels when treated by PEI, which seems a valid alternative to clinical follow-up alone in patients refusing 131I. PEI is not indicated in large or toxic nodules, for which 131I is the treatment of choice.

Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features.

The aim of the study was to correlate the sonographic [ultrasound (US)] and color-Doppler (CFD) findings with the results of US-guided fine needle aspiration biopsy (FNA) and of pathologic staging of resected carcinomas to establish: 1) the relative importance of US features as risk factors of malignancy; and 2) a cost-effective management of nonpalpable thyroid nodules. Four hundred ninety-four consecutive patients with nonpalpable thyroid nodules (8-15 mm) were evaluated by US, CFD, and US-FNA. Ninety-two patients with inadequate cytology were excluded from the study. All patients with suspicious or malignant cytology underwent surgery, whereas subjects with benign cytology had clinical and US control 6 months later. Thyroid malignancies were observed in 18 of 195 (9.2%) solitary thyroid nodules and in 13 of 207 (6.3%) multinodular goiters. Cancer prevalence was similar in nodules greater or smaller than 10 mm (9.1 vs. 7.0%). Extracapsular growth (pT(4)) was present in 35.5%, and nodal involvement in 19.4% of neoplastic lesions, with no significant differences between tumors greater or smaller than 10 mm. At US cancers presented a solid hypoechoic appearance in 87% of cases, irregular or blurred margins in 77.4%, an intranodular vascular pattern in 74.2%, and microcalcifications in 29.0%. Irregular margins (RR 16.83), intranodular vascular spots (RR 14.29), and microcalcifications (RR 4.97) were independent risk factors of malignancy. FNA performed on hypoechoic nodules with at least one risk factor was able to identify 87% of the cancers at the expence of cytological evaluation of 38.4% of nonpalpable lesions. The majority of nonpalpable thyroid tumors can be identified by cytological evaluation of lesions presenting hypoechoic appearance in conjunction with one independent risk factor. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-FNA should be performed on all 8-15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without risk factors should be followed by means of clinical and US evaluation.