Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Hypothyroidism and metabolic cardiovascular disease.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, representing a major health issue of social and economic relevance. Both hyperthyroidism and hypothyroidism are very common in the adult population, and both disorders may contribute to the onset and progression of CVD. After a brief description of the role of thyroid hormones (THs) on the physiology of the cardiovascular system and the potential mechanism that links THs alterations with changes in cardiac function, blood pressure, endothelial function, and lipid levels, we review updated data about the clinical impact of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) on CV risk, CVD, and mortality. Furthermore, we summarize the current evidence for treating SCH with levothyroxine (L-T4). Several guidelines of distinguished endocrine societies recommend treatment for SCH with TSH higher than 10 mIU/L, where the benefit of L-T4 therapy is more evident for younger people, but still controversial in those aged over 65 years. Based on current knowledge, more research efforts are needed to better address the clinical management of CV risk and CVD in the elderly affected by SCH.

Lactose intolerance and levothyroxine malabsorption: a review of the literature and report of a series of patients treated with liquid L-T4 without lactose.

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 µg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels.

The Clinical Impact of the Pulmonary Embolism Severity Index on the Length of Hospital Stay of Patients with Pulmonary Embolism: A Randomized Controlled Trial.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) is an extensively validated prognostic score, but impact analyses of the PESI on management strategies, outcomes and health care costs are lacking. Our aim was to assess whether the adoption of the PESI for patients admitted to an internal medicine ward has the potential to safely reduce the length of hospital stay (LOS). METHODS: We carried out a multicenter randomized controlled trial, enrolling consecutive adult outpatients diagnosed with acute PE and admitted to an internal medicine ward. Within 48 h after diagnosis, the treating physicians were randomized, for every patient, to calculate and report the PESI in the clinical record form on top of the standard of care (experimental arm) or to continue routine clinical practice (standard of care). The ClinicalTrials.gov identifier is NCT03002467. RESULTS: This study was prematurely stopped due to slow recruitment. A total of 118 patients were enrolled at six internal medicine units from 2016 to 2019. The treating physicians were randomized to the use of the PESI for 59 patients or to the standard of care for 59 patients. No difference in the median LOS was found between the experimental arm (8, IQR 6-12) and the standard-of-care arm (8, IQR 6-12) (p = 0.63). A pre-specified secondary analysis showed that the LOS was significantly shorter among the patients who were treated with DOACs (median of 8 days, IQR 5-11) compared to VKAs or heparin (median of 9 days, IQR 7-12) (p = 0.04). CONCLUSIONS: The formal calculation of the PESI in the patients already admitted to internal medicine units did not impact the length of hospital stay.

Simultaneous Occurrence of Medullary Thyroid Carcinoma and Papillary Thyroid Carcinoma: A Case Series with Literature Review.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. METHODS: This is a retrospective, single-center observational study conducted over 16 years (2001-2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. RESULTS: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. CONCLUSIONS: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin.

Thyroid Autoimmunity and SARS-CoV-2 Infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological culprit of COronaVIrus Disease 19 (COVID-19), can enter the cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which has been found in several tissues including in endocrine organs, such as the ovaries, testes, pancreas, and thyroid. Several thyroid disorders have been associated with SARS-CoV-2 infection [subacute thyroiditis (SAT), thyrotoxicosis, and non-thyroidal illness syndrome (NTIS)] and, in part, they are believed to be secondary to the local virus replication within the gland cells. However, as documented for other viruses, SARS-CoV-2 seems to interfere with several aspects of the immune system, inducing the synthesis of autoantibodies and triggering latent or new onset autoimmune disease (AID), including autoimmune thyroid disease (AITD), such as Hashimoto Thyroiditis (HT) and Graves' disease (GD). Several mechanisms have been hypothesized to explain this induction of autoimmunity by SARS-CoV-2 infection: the immune system hyper-stimulation, the molecular mimicry between the self-antigens of the host and the virus, neutrophils extracellular traps, and finally, the virus induced transcriptional changes in the immune genes; nonetheless, more evidence is needed especially from large, long-term cohort studies involving COVID-19 patients, to establish or reject this pathogenetic relationship.

Thyroid Metastasis from Primary Breast Cancer.

Breast cancer (BC), the most commonly diagnosed malignancy, frequently metastasizes to the bone, lungs, brain and liver at advanced stages, whereas the thyroid gland represents a rare target site for secondary disease. We examined the most recent literature about thyroid metastasis (TM) from BC after we encountered a peculiar case of a 71-year-old woman who developed sudden dysphagia, severe hypothyroidism and hypoparathyroidism due to TM 18 years after the diagnosis of her primary cancer. Based on published data, the prevalence of TM in BC ranges from 3% to 34%, with a median onset time of 48.2 months, although longer time intervals are not infrequent. TM negatively impacts the prognosis of these patients, however thyroid surgery can limit the local disease burden. Therefore, we suggest that clinicians involved in the follow-up care of BC patients should consider a differential diagnosis of secondary thyroid malignancy when incidental lesions are diagnosed during radiological evaluations or local symptoms affect the cervical region, even many years after the diagnosis of the primary cancer.

Chemokines in thyroid autoimmunity.

The chemokine receptor CXCR3 and its chemokines CXCL9, CXCL10, and CXCL11 are involved in the pathogenesis of autoimmune diseases. Th1 lymphocytes are recruited by Th1 chemokines, secreted by damaged cells. In inflamed tissues, the attracted Th1 lymphocytes induce the IFN-gamma and TNF-alpha release, that stimulates the secretion of Th1 chemokines, initiating and reiterating an amplification feedback loop. Autoimmune thyroid disorders (AITD) are the most recurrent autoimmune diseases, including Graves' disease (GD) and autoimmune thyroiditis, clinically defined by thyrotoxicosis and hypothyroidism, respectively. Graves' ophthalmopathy is one of GD extrathyroidal manifestations, occurring in ~30-50% of GD patients. In the early phase of AITD, the Th1 immune response is prevalent, and a following switch to a Th2 immune response has been shown in the late, inactive, phase. The reviewed data underline the importance of chemokines in thyroid autoimmunity and suggest CXCR3-receptor and its chemokines as potential targets of novel drugs for these disorders.

Antineoplastic Activity of Pazopanib in Anaplastic Thyroid Cancer in Primary Culture.

Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.

Teprotumumab for the treatment of thyroid eye disease.

INTRODUCTION: Thyroid eye disease (TED) is an autoimmune disease characterized by inflammation of orbital and extraocular muscles. It induces proptosis and diplopia, leading to a worsening of quality of life (QoL) because of its impact on physical appearance, and visual function. The natural history involves an 'active TED,' which is an autoimmune inflammatory response targeting orbital soft tissues, and 'inactive TED,' where there is tissue expansion remodeling. To date, glucocorticoids represent the main medical therapy, even if often ineffective and associated with side effects. AREAS COVERED: In TED, the autoimmune process leads to production of TSH-R and IGF-1 R autoantibodies. This induces inflammatory changes in the orbital tissue, and activation of fibroblasts with accumulation of glycosaminoglycans, leading to consequent proptosis, and diplopia. In two previous randomized, double-masked, placebo-controlled, parallel-group, multicenter trials, teprotumumab has been shown to be effective in improving proptosis, inflammation, diplopia, and QoL. More recently, it has been shown that teprotumumab is also effective in chronic-inactive TED. Teprotumumab was approved by the FDA on 21 January 2020 for the treatment of TED. EXPERT OPINION: For the above-mentioned reasons teprotumumab represents a potential first line therapy for TED that could replace the use of steroids in the next future.

Graves' Disease Following SARS-CoV-2 Vaccination: A Systematic Review.

(1) Background: Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent a new environmental trigger for AIED, including Graves' disease (GD). (2) Methods: We performed a literature search of MEDLINE/PubMed databases regarding thyroid dysfunction after SARS-CoV-2 vaccination since 1 January 2020 to 31 July 2022, considering only cases of thyrotoxicosis that meet the 2016 American Thyroid Association guidelines criteria for the diagnosis of GD and arising after administration of the anti-SARS-CoV-2 vaccine, regardless of the number of doses. (3) Results: A total of 27 articles were identified, consisting of case reports or case series, of which 24 describe the appearance of 48 new diagnoses of GD and 12 GD recurrences arising after the administration of the anti-SARS-CoV-2 vaccine, and 3 papers that instead report only 3 cases of GD relapse following vaccination. (4) Conclusions: physicians should be aware of the possibility of developing GD and other autoimmune sequelae following SARS-CoV-2 vaccination. Regardless of the underlying pathogenetic mechanisms (autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), cytokines induction, molecular mimicry, and cross-reactivity), an individual predisposition seems to be decisive for their development.

Thyroid autoimmunity and SARS-CoV-2 infection: Report of a large Italian series.

Since the beginning of the pandemic, numerous risk factors have been associated with SARS-CoV-2 infection and COVID-19 outcomes, such as older age, male sex, and the presence of comorbidities, such as hypertension, obesity, and diabetes. Preliminary data also suggest epidemiological association between SARS-CoV-2 infection and systemic autoimmune disease. For this reason, we investigated if patients affected by autoimmune thyroid disorders (AITD) are at risk of developing SARS-CoV-2 infection or COVID-19 disease. From April to September 2020, we have conducted a telephone survey that included 515 consecutive unselected patients with known thyroid disorders, of which 350 were affected by AITD. All 11 definitive diagnosis of COVID-19 (def-sympt-COVID-19) belonged to the AITD group, while the rest 14 cases highly suspected for COVID-19 (suspect-sympt-COVID-19) were equally detected in both group (7 in AITD and 7 in not-AITD). The overall prevalence of symptomatic COVID-19 (def-sympt-COVID-19 + suspect-sympt-COVID-19), recorded in the 350 AITD population was statistically significant higher compared to that reported in the Italian and Tuscan general population at the same time period of the present survey (18/350 = 5.14% vs 516/100000 = 0.51% [p < 0.001; OR = 10.45, 95% CI 6.45-16.92] and vs 394/100000 = 0.39% [p < 0.001; OR = 13.70, 95% CI 8.44-22.25], respectively). Therefore, our results suggest a higher prevalence of SARS-CoV-2 infection and COVID-19 disease in patients with AITD.

Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer.

Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.

Advances in pharmacotherapy for advanced thyroid cancer of follicular origin (PTC, FTC). New approved drugs and future therapies.

INTRODUCTION: The most common altered signaling found in aggressive iodine-refractory thyroid cancers derived from follicular cells (RAI-TC) are RTK, MAPK, PI3K, WNT, BRAF, RAS, RET, and TP53. Tyrosine Kinase Inhibitors (TKI) are multi-kinase inhibitors able to act against different pathways, that elicit an anti-neoplastic activity. AREAS COVERED: The aim of this paper is to review recent novel molecular therapies of RAI-TC. Recently, sorafenib and lenvatinib, have been approved for the treatment of aggressive RAI-TC. Other studies are evaluating vandetanib and selumetinib in RAI-TC. Furthermore, preliminary studies have evaluated dabrafenib, and vemurafenib in BRAF mutated RAI-TC patients to re-induce 131-iodine uptake. The interplay between cells of the immune system and cancer cells can be altered by immune checkpoints inhibitors. The expression of PDL1 in RAI-TC was related to tumor recurrence and poor survival. Several clinical trials are investigating a combination of different therapies, such as lenvatinib and pembrolizumab. EXPERT OPINION: Mechanisms of resistance to TKIs inhibitors can be of intrinsic or acquired origin. An acquired resistance to lenvatinib, or sorafenib can be due to upregulation of FGFR; therefore, anti-FGFR agents are evaluated. A new strategy is to combine TKIs with immunotherapy. Several studies are evaluating lenvatinib and pembrolizumab in RAI-TC patients.

Molecular features of aggressive thyroid cancer.

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAFV600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.

Precision Medicine in Autoimmune Thyroiditis and Hypothyroidism.

Autoimmune thyroid diseases (AITD) are T-cell-mediated organ specific autoimmune disorders, deriving from an altered response of the immune system that leads to the immune attack to the thyroid. Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the two principal AITD clinical presentations. Hypothyroidism and thyrotoxicosis are, respectively, the clinical hallmarks of HT and GD. Patients with autoimmune thyroiditis are treated daily with synthetic L-thyroxine (L-T4) at the dose of 1.5-1.7 µg/kg. Various L-T4 formulations are commercially available (tablet, liquid solution, or soft gel capsule). L-T4 in tablets is generally prescribed to treat hypothyroidism, whereas the liquid formulation, or soft gel capsules, can be administered in hypothyroid patients in case of malabsorption or in patients in therapy with drugs interfering with L-T4 absorption. Furthermore, myoinositol has a crucial role in thyroid autoimmunity and function. Clinical studies reported a significant decline in TSH and antithyroid autoantibodies levels after treatment with myoinositol + selenium in patients with subclinical hypothyroidism and autoimmune thyroiditis. Moreover, thyroidectomy can be rarely recommended in patients with autoimmune thyroiditis, with cosmetic reasons for a goiter, or with important signs or symptoms of local compression, or nodular disease with a "suspicious" cytology for malignancy. Furthermore, a recent randomized trial suggested that total thyroidectomy can improve quality of life and fatigue, while medical therapy did not. In this review, we overview currently available evidence in personalized medicine in patients with autoimmune thyroiditis and hypothyroidism. Further research is needed in larger population to investigate the effect of these new treatments on quality of life.

Precision Medicine in Graves' Disease and Ophthalmopathy.

Graves' disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves' ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

Lenvatinib: an investigational agent for the treatment of differentiated thyroid cancer.

INTRODUCTION: Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain. AREAS COVERED: We provide an overview from the literature of in vitro, in vivo and real-life studies regarding lenvatinib as an investigational agent for the treatment of aggressive TC. EXPERT OPINION: According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.

THERAPY OF ENDOCRINE DISEASE: Endocrine-metabolic effects of treatment with multikinase inhibitors.

Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients' quality of life. The most common adverse events (AEs) include fatigue, hand-foot skin reaction, decreased appetite, nausea, diarrhea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders. Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (~50%), diabetes (~15-40%), and dysthyroidism (~20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity. It is important to evaluate patients, measure glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy. Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3-4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3-6 weeks. Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.