Francesca Ragusa

Circulating CXCL10 is increased in non-segmental vitiligo, in presence or absence of autoimmune thyroiditis

Recently the importance of CXCL10 in the pathogenesis of non-segmental vitiligo (NSV) and autoimmune thyroid disorders (AITD) has been shown. No data are present about chemokines CXCL10 (Th1 prototype) and CCL2 (Th2 prototype) circulating levels in NSV patients with/without thyroiditis (AT). Serum CXCL10 and CCL2 have been measured in 50 consecutive NSV patients, in 40 consecutive patients with NSV and AT (NSV+AT), in 50 sex- and age-matched controls without AT (control 1) and in 40 sex- and age-matched patients with AT without NSV (control 2). Serum CXCL10 levels were significantly higher in control 2, than in control 1 (P=0.001; ANOVA). NSV patients have serum CXCL10 levels significantly higher than control 1, or control 2 (P=0.001). NSV+AT patients have serum CXCL10 levels higher than control 1, or 2 (P<0.001), and than NSV (P=0.01). In conclusion, we first demonstrate high serum CXCL10 in NSV patients, overall in presence of AT and hypothyroidism, suggesting the importance of a common Th1 immune response in their immune-pathogenesis. To evaluate if serum CXCL10 might be used as a clinical marker of NSV and/or AT further studies are needed.

Advancements in the treatment of hypothyroidism with L-T4 liquid formulation or soft gel capsule: an update.

ABSTRACT Introduction: The most recent advance concerning levothyroxine (L-T4) therapy is the development of novel oral formulations: the liquid preparation, and the soft gel capsule. Areas covered: This review evaluates the most recent clinical studies about these new formulations. The liquid formulation has been shown to overcome: the food and beverages intereference with L-T4 tablets absorption, caused by food or coffee at breakfast; malabsorption induced by the increased gastric pH, resulting from atrophic gastritis, or due to proton-pump inhibitors; and malabsorption after bariatric surgery. The use of liquid L-T4 has been studied also in pregnancy, newborns and infants, suggesting a better bioequivalence than tablets. Finally, liquid L-T4 is more active than tablets in the control of thyroid-stimulating hormone (TSH) in hypothyroid patients without malabsorption, drug interference, or gastric disorders, leading to a hypothesized higher absorption of liquid L-T4 also in these patients. Few studies have evaluated soft gel L-T4 with promising results in patients with malabsorption related to coffee or gastritis. Expert opinion: Liquid L-T4 (and soft gel capsules) are more active than the tablet L-T4 in the control of TSH in hypothyroid patients with gastric disorders, malabsorption, or drug interference, but also in patients without absorption disorders.

Psoriasis, Psoriatic Arthritis, and Thyroid Autoimmunity

Psoriasis (PsO) is a chronic relapsing/remitting autoimmune skin disease, associated with an increased risk of other autoimmune disorders. Psoriatic arthritis (PsA) is a chronic inflammatory arthritis occurring approximately in 30% of PsO patients. Sporadic cases of association between PsO and autoimmune thyroid disorders (AITDs) have been reported. However, two different recent studies did not find any association between them. In patients with PsO and PsA, an association with AITD has been shown by most of the studies in adults, but not in the juvenile form. In PsA women and men, thyroid autoimmunity [positive antithyroid peroxidase (AbTPO) antibodies, hypoechoic thyroid pattern] and subclinical hypothyroidism were more prevalent than in the general population. An association has been shown also in patients with PsO, arthritis, and inflammatory bowel disease, who have more frequently AITD. A Th1 immune predominance has been shown in early PsO, and PsA, with high serum CXCL10 (Th1 prototype chemokine), overall in the presence of autoimmune thyroiditis. This Th1 immune predominance might be the immunopathogenetic base of the association of these disorders. A raised incidence of new cases of hypothyroidism, thyroid dysfunction, positive AbTPO, and appearance of a hypoechoic thyroid pattern in PsA patients, especially in women, has been shown recently, suggesting to evaluate AbTPO levels, thyroid function, and thyroid ultrasound, especially in PsA women. Thyroid function follow-up and suitable treatments should be performed regularly in PsA female patients at high risk (thyroid-stimulating hormone within the normal range but at the higher limit, positive AbTPO, hypoechoic, and small thyroid).

Autoimmune Thyroid Diseases and Epigenetics

Abstract Genetic mapping has identified several candidate variants in autoimmune conditions; however, thyroid autoimmune diseases cannot be explained by genetic susceptibility alone. In monozygotic twins, the concordance for most autoimmune diseases is only 20%–30%, indicating that epigenetics and environmental factors may also be determinant. Epigenetics refers to inheritable and potentially reversible changes in DNA and chromatin, which regulate gene expression without altering the DNA sequence. Epigenetic regulation includes DNA methylation, histone modification, and noncoding RNA-mediated regulation. Epigenetic mechanisms regulate gene expression levels, and their impairments result in networks of genes that are switched on or off, thus contributing to disease pathogenesis. This chapter describes the contribution of epigenetics to autoimmune thyroid disorders.

Oral L-thyroxine liquid versus tablet in patients submitted to total thyroidectomy for thyroid cancer (without malabsorption): A prospective study: Liquid L-T4 in thyroid cancer patients

No consistent data are present in literature about the effectiveness of Levothyroxine (L‐T4) liquid formulation in patients without malabsorption after thyroidectomy. The aim of this study is to compare the effectiveness of L‐T4 liquid formulation, with L‐T4 tablets, in thyroid cancer patients after thyroidectomy (without malabsorption or drug interference).

Molecular testing in the diagnosis of differentiated thyroid carcinomas

Different genetic mutations and other molecular alterations in papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) can be detected in fine-needle aspiration (FNA) of thyroid nodules, and can be used successfully to ameliorate cancer diagnosis and management of patients with thyroid nodules. The greatest experience has been obtained with the diagnostic use of BRAF mutation that is strongly specific for malignancy when detected using well-validated techniques. The strongest diagnostic result can be obtained testing FNA samples for a panel of mutations that typically involve TERT, BRAF, PAX8/PPARγ, RAS, and RET/PTC. Finding any of these mutations in a thyroid nodule provides strong indication for malignancy and helps to refine clinical management for a significant proportion of patients with indeterminate cytology. The use of molecular markers, as TERT, BRAF, PAX8/PPARγ, RAS, and RET/PTC, may be considered for patients with indeterminate FNA cytology (FNAC) to help guide management. In patients with indeterminate TIR3 FNA, the combination of precise molecular marker expression analysis with molecular mutations evaluations could ameliorate significantly the accuracy of cancer diagnosis. However other prospective studies are needed to identify more accurate molecular markers. Finally, the knowledge of these molecular pathways has permitted the development of new targeted therapies for aggressive TC.

Novel treatment options for anaplastic thyroid cancer

ABSTRACT Introduction: Several genetic alterations have been identified in different molecular pathways ofanaplastic thyroid cancer (ATC) and associated with tumor aggressiveness and progression (BRAF, p53,RAS, EGFR, VEGFR-1, VEGFR-2, etc). New drugs targeting these molecular pathways have beenrecently evaluated in ATC. Areas covered: We review the new targeted therapies of ATC. Interesting results have been reported with molecules targeting different pathways, as: a-BRAF (dabrafenib/trametinib, vemurafenib); b-angiogenesis (sorafenib, combretastatin, vandetanib, sunitinib, lenvatinib, CLM3, etc); c-EGFR (gefitinib); d- PPARγ agonists (rosiglitazone, pioglitazone, efatutazone). In patients with ATC treated with lenvatinib, a median overall survival of 10.6 (3.8–19.8) months was reported. In order to bypass the resistance to the single drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or other targeted drugs is explored. Expert commentary: New, affordable and individual genomic analysis combined with the opportunity to test these new treatments in primary cell cultures from every ATC patient in vitro, may permit the personalization of therapy. Increasing the therapeutic effectiveness and avoiding the use of ineffective drugs. The identification of new treatments is necessary, to extend life duration guaranteing a good quality of life. To bypass the resistance to asingle drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or othertargeted drugs is explored. Moreover, new affordable individual genomic analysis and the opportunity totest these novel treatments in primary cell cultures from every ATC patient in vitro, might permit topersonalize the therapy, increasing the therapeutic effectiveness and avoiding the use of ineffectivedrugs.

Sunitinib in the Treatment of Thyroid Cancer

BACKGROUND Sunitinib (SU11248) is an oral multi-target tyrosine kinase inhibitor (TKI) with low molecular weight, that inhibits platelet-derived growth factor receptors (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), c-KIT, fms-related tyrosine kinase 3 (FLT3) and RET. The concurrent inhibition of these pathways reduces tumor vascularization and causes cancer cell apoptosis, inducing a tumor shrinkage. Sunitinib is approved for the treatment of imatinib-resistant gastrointestinal stromal tumor (GIST), renal carcinoma, and pancreatic neuroendocrine tumors. METHODS We searched the literature on PubMed library. RESULTS In vitro studies showed that sunitinib targeted the cytosolic MEK/ERK and SAPK/JNK pathways in the RET/PTC1 cell inhibiting cell proliferation and causing stimulation of sodium/iodide symporter (NIS) gene expression in RET/PTC1 cells. Furthermore sunitinib is active in vitro and in vivo against anaplastic thyroid cancer (ATC) cells. Most of the clinical studies report that sunitinib is effective as first- and second-line TKI therapy in patients with advanced dedifferentiated thyroid cancer (DeTC), or medullary thyroid cancer (MTC). Sunitinib 37.5 mg/day is well tolerated, and effective. The most common adverse events include: reduction in blood cell counts (in particular leukocytes), hand-foot skin reaction, diarrhea, fatigue, nausea, hypertension, and musculoskeletal pain. CONCLUSION Even if sunitinib is promising in the therapy of differentiated thyroid carcinoma (DTC), until now no phase III studies have been published, and additional prospective researches are necessary in order to evaluate the real efficacy of sunitinib in aggressive thyroid cancer.