Evaluating local thyroid cytopathology practices by molecular quality metrics: A multi-institutional study on 4651 FNAs with a focus on the role of the interventional cytopathologist.

Background: The diagnostic accuracy of thyroid fine-needle aspiration (FNA) can be highly influenced by the technical skills of the operator performing the procedure and by interobserver variability in microscopic interpretation. This is particularly true for the indeterminate categories. Recently, molecular testing has been proposed as an ancillary tool for monitoring the performance of different thyroid cytopathology practices.

D898_E901 Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms.

Purpose: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case.

Materials And Methods: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells.

Type 2 deiodinase is expressed in anaplastic thyroid carcinoma and its inhibition causes cell senescence.

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial-mesenchymal transition.

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage.

The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability.

Deiodinases in thyroid tumorigenesis.

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells.

Divergent Thyroid Hormone Levels in Plasma and Left Ventricle of the Heart in Compensated and Decompensated Cardiac Hypertrophy Induced by Chronic Adrenergic Stimulation in Mice.

Chronic hemodynamic overload of the heart induces ventricular hypertrophy that may be either compensatory or progress to decompensation and heart failure. The gradual impairment of ventricular function is, at least in part, the result of a reduction of cardiac thyroid-hormone (TH) action. Here, we examined the proposed roles of increased cardiac expression of the TH-inactivating enzyme deiodinase type 3 (D3) and reduced plasma TH levels in diminishing cardiac TH levels.

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy.

Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices.

Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors.

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity.

Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.

The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal.

Predictive molecular pathology in metastatic thyroid cancer: the role of fusions.

Background: Rearranged during transfection () gene fusions are detected in 10-20% of thyroid cancer patients. Recently, fusion-positive metastatic thyroid cancers have attracted much attention owing to the FDA approval of two highly selective anti-RET tyrosine kinase inhibitors, namely, selpercatinib, and pralsetinib.

Areas Covered: This review summarizes the available evidence on the biological and predictive role of gene fusions in thyroid carcinoma patients and the latest screening assays currently used to detect these genomic alterations in histological and cytological specimens.

Impact of a cardio-oncology unit on prevention of cardiovascular events in cancer patients.

Aims: As the world population grows older, the co-existence of cancer and cardiovascular comorbidities becomes more common, complicating management of these patients. Here, we describe the impact of a large Cardio-Oncology unit in Southern Italy, characterizing different types of patients and discussing challenges in therapeutic management of cardiovascular complications.

Methods And Results: We enrolled 231 consecutive patients referred to our Cardio-Oncology unit from January 2015 to February 2020.

The relevance of T in the management of hypothyroidism.

Levothyroxine monotherapy has been the standard of care for treatment of hypothyroidism for more than 40 years. However, patients treated with levothyroxine have relatively lower serum tri-iodothyronine (T) concentrations than the general population, and symptoms of hypothyroidism persist for some patients despite normalisation of thyroid-stimulating hormone (TSH) concentrations. The understanding that maintenance of normal T concentrations is the priority for the thyroid axis has redirected the clinical focus to serum T concentrations in patients with hypothyroidism.

Inactivation of Type 3 Deiodinase Results in Life-long Changes in the Brown Adipose Tissue Transcriptome in the Male Mouse.

Adaptive thermogenesis in small mammals and infants takes place in brown adipose tissue (BAT). Heat is produced via uncoupling protein 1 (UCP1)-mediated uncoupling between oxidation of energy substrates and adenosine 5'-triphosphate synthesis. Thyroid hormone (TH) signaling plays a role in this process.

Do policies affect management? Evidence from a survey of clinicians of the Italian National Health Service.

Since the early 1990s, New Public Management ideas have deeply influenced reforms and their implementation in the Italian NHS. We compare doctors' perceptions about management systems in two Italian regions which differ in the dominant values of the regional political environment. In total 220 doctors, orthopaedists and cardiologists, working in public hospitals in Lombardy and Emilia-Romagna, were surveyed.

Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid Cancer: A Case Report.

Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy.

Thyroid Hormone Action in Muscle Atrophy.

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin-proteasome.

Imaging medullary thyroid cancer patients with detectable serum markers: state of the art and future perspectives.

Purpose: Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C-cells and represents <5% of all thyroid cancers. Serum Calcitonin (CTn) is considered the most sensitive marker of persistent or recurrent disease and is measured in association to CEA. According to the American Thyroid Association (ATA) guidelines, following initial surgery when CTn level remains below 150 pg/mL, follow-up may rely on repeated serum marker determinations and on neck ultrasonography (US).

Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.

Background: Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves' disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3'-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease.

Methods: To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used.

Advances in Functional Imaging of Differentiated Thyroid Cancer.

The present review provides a description of recent advances in the field of functional imaging that takes advantage of the functional characteristics of thyroid neoplastic cells (such as radioiodine uptake and FDG uptake) and theragnostic approach of differentiated thyroid cancer (DTC). Physical and biological characteristics of available radiopharmaceuticals and their use with state-of-the-art technologies for diagnosis, treatment, and follow-up of DTC patients are depicted. Radioactive iodine is used mostly with a therapeutic intent, while PET/CT with F-FDG emerges as a useful tool in the diagnostic management and complements the use of radioactive iodine.

Long-Term Prognostic Value of the Response to Therapy Assessed by Laboratory and Imaging Findings in Patients with Differentiated Thyroid Cancer.

This study assessed the long-term predictive value of the response to therapy, evaluated by serum thyroglobulin (Tg) determination and neck ultrasound, and estimated the potential additional impact of diagnostic whole-body scan (WBS) in patients with differentiated thyroid cancer (DTC) treated with surgery and radioactive iodine (RAI) therapy. We retrospectively evaluated 606 DTC patients treated with surgery and RAI. Response to I therapy at 12 months was assessed by serum Tg measurement, neck ultrasound, and diagnostic WBS.

Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas.

Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer.

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results.

Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options.

Moving towards a local testing solution for undetermined thyroid fine-needle aspirates: validation of a novel custom DNA-based NGS panel.

Aims: In thyroid cytopathology, the undetermined diagnostic categories still pose diagnostic challenges. Although next-generation sequencing (NGS) is a promising technique for the molecular testing of thyroid fine-needle aspiration (FNA) specimens, access to such technology can be difficult because of its prohibitive cost and lack of reimbursement in countries with universal health coverage. To overcome these issues, we developed and validated a novel custom NGS panel, specifically designed to target 264 clinically relevant mutations involved in thyroid tumourigenesis.

The importance of the RET gene in thyroid cancer and therapeutic implications.

Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma.