CLM3 e Carcinoma Anaplastico della Tiroide

Il carcinoma anaplastico della tiroide (ATC) è una delle forme tumorali più aggressive e letali, che quasi inevitabilmente in tempi brevi conduce alla morte i pazienti affetti. Nonostante siano state testate varie modalità di trattamento, tra cui la combinazione dell’intervento chirurgico con la radioterapia e/o la chemioterapia, la prognosi di questi pazienti non risulta sostanzialmente modificata. Sono state, quindi, proposte nuove strategie di trattamento, tra cui l’utilizzo di nuovi agenti farmacologici, in particolare le molecole inibitrici delle tirosin-chinasi (TKI). I TKI risultano avere un ruolo importante nel trattamento dell’oncogenesi e dell’angiogenesi patologica, in quanto determinano l’inibizione della trasmissione del segnale mitogeno attraverso il fattore di crescita vascolare endoteliale (VEGFR) e il recettore del fattore di crescita epidermico (EGFR), impedendo la fosforilazione dei residui di tirosina associati al recettore. Con questa tesi è stata studiata l’attività antineoplastica e antiangiogenica di un composto pirazolopirimidinico (CLM3) con la capacità di inibire multiple vie di trasduzione del segnale (includendo la tirosin-chinasi RET, EGFR e VEGF) in colture cellulari primarie di ATC, nella linea cellulare umana 8305C (carcinoma indifferenziato della tiroide) e in una linea cellulare di ATC (AF), ottenuta spontaneamente in coltura. CLM3 è stato testato sulle cellule primarie di ATC alle concentrazioni di 5, 10, 30, e 50 μM; nelle cellule 8305C e nella linea AF sono state utilizzate le concentrazioni 1, 5, 10, 30, 50, or 100 μM. CLM3 è stato, inoltre, testato in vivo nei topi CD nu/nu con la linea AF. CLM3 ha inibito significativamente la proliferazione cellulare nelle linee 8305C e AF, inducendo anche l’apoptosi. Si è osservata una significativa riduzione della proliferazione anche nelle cellule ATC (p < 0.01). CLM3 aumentava la percentuale di apoptosi nelle cellule di ATC in maniera dose dipendente (p < 0.001), inibiva la migrazione (p < 0.01) e l’invasione (p < 0.001). La linea cellulare AF è stata iniettata a livello sottocutaneo in topi CD nu/nu e ha portato allo sviluppo di una massa tumorale identificabile nei successivi 15 giorni. CLM3 (50 mg/Kg/die) ha inibito significativamente la crescita tumorale partendo dal sedicesimo giorno dopo l’inizio del trattamento. CLM3 riduceva significativamente l’espressione di VEGF-A e la densità microvascolare del tessuto tumorale AF. CLM3 inibiva, inoltre, la fosforilazione di EGFR, AKT ed ERK1/2 e deregolava la ciclina D1 nelle 8305C e nella linea AF. In conclusione, l’attività antitumorale e antiangiogenica di CLM3, composto pirazolopirimidinico, risulta essere interessante e molto promettente nel trattamento dell’ATC, aprendo la strada alla futura valutazione clinica

Reversible normalisation of serum TSH levels in patients with autoimmune atrophic gastritis who received L-T4 in tablet form after switching to an oral liquid formulation: A case series

Background: L-thyroxine (L-T4) malabsorption is a potential concern in patients with autoimmune atrophic gastritis. Methods: We evaluated five patients with autoimmune gastritis, who showed high serum thyrotropin (TSH) levels (in the hypothyroid range) while in therapy with L-T4 in tablet. All patients were switched to receive an oral L-T4 liquid formulation maintaining the same dosage. Results: In all patients who received L-T4 in tablet form after switching to an oral liquid formulation with the same L-T4 dosage, TSH circulating levels were normalized. In four patients who were switched back again to receive L-T4 in tablets, maintaining the dosage, TSH levels worsened again reaching levels in the hypothyroid range. Conclusions: The fact that the change from tablets to liquid oral formulation normalised serum TSH levels, and that switching back to tablets caused thyrotropin levels to worsen, leads us to believe that absorption of L-T4 is greater with oral liquid formulations in these patients. These results suggest that the L-T4 oral liquid formulation could circumvent the pH alteration resulting from atrophic gastritis

New Targeted Molecular Therapies for Dedifferentiated Thyroid Cancer

Dedifferentiated thyroid cancer (DeTC) derived from follicular epithelium is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. In cases, RET/PTC rearrangements are found in 30%–40%, RAS mutations in about 10%, and BRAF mutations in around 40%–50%, with no overlap between these mutations results in papillary thyroid cancer, while a higher prevalence of BRAF mutations (up to 70%) has been observed in DeTC. The identification of these activating mutations in DeTC makes this malignancy an excellent model to examine the effect of tyrosine kinase inhibitors (TKIs). Clinical trials with several TKIs targeting RET, and to a lesser extent BRAF, and other TKRs have shown positive results, with about one-third of DeTC showing a reduction in tumor size up to 50%, with the longest treatment duration of approximately three-four years. Angiogenesis inhibitors have also shown promising activity in DeTC. Progress is being made toward effective targeted DeTC therapy. The possibility of testing the sensitivity of primary DeTC cells from each subject to different TKIs could increase the effectiveness of the treatment

The association of other autoimmune diseases in patients with Graves’ disease (with or without ophthalmopathy): Review of the literature and report of a large series

Graves’ disease (GD) and autoimmune thyroiditis (AT) are the two main clinical presentations of AITD, and their clinical hallmarks are thyrotoxicosis and hypothyroidism, respectively. GD, and AT, can be associated with other organ specific, or systemic autoimmune diseases in the same patient. However discordant results have been reported in the literature about the possible associations. Here, we review the association of GD and other autoimmune syndromes. Furthermore, we report the results of our prospective study that investigated the prevalence of other autoimmune disorders in 3209 GD patients (984 with Graves’ ophthalmopathy), with respect to 1069 healthy controls, or 1069 patients with AT, or 1069 with multinodular goiter (matched by age, gender, coming from the same area, with a similar iodine intake). On the whole, 16.7% of GD patients had another associated autoimmune disease; and the most frequently observed were: vitiligo (2.6%), chronic autoimmune gastritis (2.4%), rheumatoid arthritis (1.9%), polymyalgia rheumatica (1.3%), multiple sclerosis (0.3%), celiac disease (1.1%), diabetes (type 1) (0.9%), systemic lupus erythematosus and sarcoidosis (&lt;0.1%), Sjogren disease (0.8%). Moreover, 1.5% patients with GD had three associated autoimmune disorders. Interestingly, patients with Graves’ ophthalmopathy (GO) had another autoimmmune disorder more frequently (18.9%), with respect to GD patients without GO (15.6%). However the pattern of the associated autoimmune disorders in GD was not significantly different from that observed in AT patients. In conclusion, we suggest GD patients who are still sick, or who develop new unspecific symptoms (even if during an appropriate treatment of hyperthyroidism) should be appropriately screened for the presence of other autoimmune disorders

Serum TSH Levels Normalisation in Patients Affected by Autoimmune Atrophic Gastritis, After the Switch From Oral L-T4 in Tablet Form to L-T4 in Liquid Formulation

Abstract Patients affected by autoimmune atrophic gastritis could have some issues in L-thyroxine (L-T4) absorption, due to drug malabsorption, induced by the increased gastric pH. Different factors influence L-T4 absorption, such as dietary habits, interference with other drugs, absorption kinetics, age of the patient, adherence to therapy, and others. We enrolled 36 patients affected by autoimmune atrophic gastritis with high serum thyrotropin (TSH) levels under therapy with L-T4 in the tablet formulation. L-T4 tablets were changed to an oral liquid L-T4 preparation, maintaining the same dose. The switch from L-T4 in tablet formulation to the liquid one, at the same L-T4 dosage, led to the normalisation/reduction of circulating TSH levels. Then 14 patients, who were switched back again to receive L-T4 in tablets (with the same dose), had a worsening of TSH values, falling in the hypothyroid range. In conclusion, our findings led to hypothesize that the pH alteration issue caused by autoimmune atrophic gastritis could be overcome by the oral L-T4 liquid formulation administration

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

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

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&lt;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

The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients

We have evaluated prospectively the prevalence of other autoimmune disorders in outpatient clinic in 3069 consecutive patients with diagnosed chronic autoimmune thyroiditis (AT), with respect to two age- and sex-matched control groups: a) a control group of 1023 subjects, extracted from a random sample of the general population without thyroid disorders; b) 1023 patients with non-toxic multinodular goiter extracted from the same random sample of the general population, with similar iodine intake. The results of our study demonstrate a significant increase of the prevalence of autoimmune disorders in AT patients (with respect to both controls), for the following diseases: chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymialgia rheumatica (Polym), celiac disease, diabetes, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, alopecia, psoriathic arthritis, systemic sclerosis, and HCV-related cryoglobulinemia. While the statistical analysis reached near the significance for Addison's disease and ulcerative colitis. Interestingly, the association of three autoimmune disorders was observed almost exclusively in AT patients, and the most frequent associations were AT+CAG+Vit and AT+CAG+Polym. We suggest that patients with AT who remain unwell, or who develop new not specific symptoms (despite adequate treatment) should be screened for other autoimmune disorders, avoiding the delay in the diagnosis of these disorders

New Targeted Therapies for Thyroid Cancer

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases [vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR)] involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies (sorafenib, sunitinib, axitinib, imanitib, vandetanib, pazopanib, gefitinib) in stabilizing the course of the disease. Until now, however, no consensus guidelines have been established for patient selection and more data on toxicities and side effects are needed to be collected

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

Objective: 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). Methods: One hundred five patients were recruited; 52 patients were treated with liquid L-T4 formulation, while 53 with L-T4 tablets, at the same dosage (1.5 mcg/kg/day). Patients started to assume the drug the day after surgery, 30 min before breakfast. In both groups circulating levels of thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were dosed at week 6 (first control), and then at week 12 (second control). Results: We obtained significantly lower TSH values in the liquid L-T4 group patients, compared to the tablet L-T4 group, at the first control (P &lt; .05), and at the second control (P &lt; .01), while FT4 and FT3 levels were not significantly different. Hypothyroid range (TSH &gt; 3.6 mcU/mL) was significantly more prevalent in the patients treated with L-T4 tablet. Conclusions: A better control of TSH was observed in thyroidectomized patients (without malabsorption, gastric disorders, or drug interference) with liquid L-T4 regimen. Level of Evidence: 2c-Outcomes Research