PERsistent Sitagliptin treatment & Outcomes (PERS&O 2.0) study, long-term results: a real-world observation on DPP4-inhibitor effectiveness.

INTRODUCTION: Sitagliptin is a dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes (T2D). Limited real-world data on its effectiveness and safety are available from an Italian population. RESEARCH DESIGN AND METHODS: We evaluated long-term clinical data from the single-arm PERsistent Sitagliptin Treatment & Outcomes (PERS&O) study, which collected information on 440 patients with TD2 (275 men, 165 women; mean age 64.1 years; disease median duration: 12 years) treated with sitagliptin 'add-on'. For each patient, we estimated the 10-year cardiovascular (CV) risk using the UK Prospective Diabetes Study (UKPDS) Risk Engine (RE). Drug survival was evaluated using Kaplan-Meier survival curves; repeated measures mixed effects models were used to evaluate the evolution of glycated hemoglobin (HbA1c) and CV risk during sitagliptin treatment. RESULTS: At baseline, most patients were overweight or obese (median body mass index (BMI) (kg/m2) 30.2); median HbA1c was 8.4%; median fasting plasma glucose: 172 mg/dL; median UKPDS RE score: 24.8%, being higher in men (median 30.2%) than in women (median 17.0%) as expected. Median follow-up from starting sitagliptin treatment was 5.6 years. From Kaplan-Meier curves, the estimated median drug survival was 32.8 months when considering discontinuation for any cause and 58.4 months when considering discontinuation for loss of efficacy. A significant improvement in HbA1c was evident during treatment with sitagliptin (p<0.01): the reduction was rapid (median HbA1c after 4-6 months: 7.5%) and continued at longer follow-up. When comparing patients treated with sitagliptin versus those stopping sitagliptin and switching to another antihyperglycemic drug, we detected a significant difference in the evolution of HbA1c in favor of patients who continued sitagliptin treatment. The UKPDS RE score at 10 years and the BMI significantly improved during treatment with sitagliptin (p<0.001). Adverse events were relatively uncommon. CONCLUSION: Patients with T2D treated with sitagliptin achieved an improvement in metabolic control and a reduction in CV risk and did not experience relevant adverse events.

GENDER INFLUENCES THE CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF GRAVES DISEASE.

OBJECTIVE: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD. METHODS: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated. RESULTS: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset. CONCLUSION: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD. ABBREVIATIONS: ATD = antithyroid drug FT3 = free triiodothyronine FT4 = free thyroxine GD = Graves disease GO = Graves orbitopathy RAI = radioiodine TRAb = thyroid-stimulating hormone-receptor antibody TSH = thyroid-stimulating hormone.

Anti-Mullerian hormone as a predictor of ovarian reserve in ART protocols: the hidden role of thyroid autoimmunity.

BACKGROUND: Protocols of controlled ovarian hyper-stimulation (COH) require, as a crucial step, the identification of reliable predictors of ovarian reserve. Anti-Mullerian hormone (AMH) is one of the most reliable predictors of ovarian reserve but other factors including autoimmune thyroid diseases (ATD) have been associated with reduced fertility and poor COH outcome. Aim of the present study was to evaluate the relationship between ATD and AMH, and their role on the outcome of COH. METHODS: The study group included 288 sub-fertile euthyroid women aged less than 40 years attending a single center for Reproductive Medicine. Among them, 55 were ATD-positive and 233 ATD-negative. The serum levels of AMH, FSH, LH, estradiol (E2), and TSH were measured before COH. The ratio between serum E2 concentration on the day of oocytes pick-up and the total dose of administered recombinant FSH (r-FSH) (E2/r-FSH ratio) was calculated. RESULTS: The serum levels of AMH were significantly related to E2/r-FSH ratio, total dose of r-FSH and number of M II oocytes, both in ATD-positive and ATD-negative women. Within the low stratum of AMH levels, the presence of ATD did not further affect the outcome of COH. When the serum levels of AMH were in the high stratum, the presence of ATD significantly affected the E2/rFSH ratio, the total dose of r-FSH and the number of M II oocytes. CONCLUSIONS: The probability of a poor response to COH is high, and independent from ATD, in women with low AMH serum levels. In women with a good ovarian reserve, as assessed by high AMH serum levels, the presence of ATD impairs the outcome of COH.

Maximal stiffness evaluation by real-time ultrasound elastography, an improved tool for the differential diagnosis of thyroid nodules.

OBJECTIVE: The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size. METHODS: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1, <1 cm; G2, 1-2 cm; G3, >3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. RESULTS: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P<.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P<.0001, respectively) and in the G1 and G2 subgroups. CONCLUSION: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.

ER-alpha and ER-beta expression in differentiated thyroid cancer: relation with tumor phenotype across the TNM staging and peri-tumor inflammation.

Thyroid cancer may express estrogen receptors (ERs) and various grades of peri-tumor inflammation. The aim of the study was to evaluate the expression of ERs in relation to the TNM stage and peri-tumor inflammatory infiltrate in differentiated thyroid cancers. 127 patients (109 females, 18 males) with differentiated thyroid cancer (T1 = 91, T2 = 18, T3 = 11, T4 = 7) were evaluated. In tumors and in the correspondent extra-tumor parenchyma, ERs expression was evaluated by immunohistochemistry. In 114 tumors and correspondent peri-tumor tissues, the presence of inflammatory infiltration was also recorded. ER-alpha expression was higher in clinical than in incidental tumors of the T1 subgroup (p = 0.037), and was associated with capsular invasion in T2 tumors (p < 0.0001). ER-beta expression was negatively associated with vascular invasion in T1 (p = 0.005) and T2 tumors (p = 0.015). No significant relationship between ERs expression and tumor phenotype emerged in T3 and T4 subgroups. Tumors without inflammatory cell infiltrate showed a higher expression of both ER-alpha (p = 0.035) and ER-beta (p = 0.026) than the ones with inflammatory infiltrate. The relationship between tumor phenotype and ERs expression did not vary in the presence or absence of peri-tumor inflammatory infiltration. ER-alpha positivity and ER-beta negativity are associated with a more aggressive phenotype in both T1 and T2 thyroid cancers, suggesting that tumor biology may be more relevant than tumor size for cancer risk assessment. Inflammatory status is also associated with ERs expression, but not with tumor growth or phenotype.

Comparison of elastographic strain index and thyroid fine-needle aspiration cytology in 631 thyroid nodules.

CONTEXT: Ultrasound (US) elastography (USE) was recently been reported as a sensitive, noninvasive tool for identifying thyroid cancer. However, the accuracy of this technique is hampered by the intra- and interoperator variability, some US features of the nodule, and the coexistence of autoimmune thyroid disease (ATD). OBJECTIVES: The purpose of this article was to assess the accuracy of USE findings in the differential diagnosis of thyroid nodules compared with other US features to evaluate its feasibility in the presence of ATDs and identify the strain index (SI) cutoff with the highest diagnostic performance. DESIGN: We evaluated 528 consecutive patients for a total of 661 thyroid nodules. All nodules underwent fine-needle aspiration cytology (FNAC) and USE evaluation. The SI was calculated as a ratio of the nodule strain divided by the strain of the softest part of the surrounding normal tissue. RESULTS: The median SI value was significantly higher in THY4 and THY5 than in THY2 nodules in ATD-positive, ATD-negative, and ATD-unknown patients. The cutoff of SI for malignancy was estimated to be 2.905 by receiver operating characteristic curve analysis in a screening set (379 FNAC results), and then tested in a replication set (252 FNAC results). In all cases, a SI value of ≥ 2.905 conferred to the nodule a significantly greater probability of being malignant. This SI cutoff had the greatest area under the curve, sensitivity, and negative predictive value, compared with the conventional US features of malignancy. CONCLUSION: The elastographic SI has a high sensitivity, specificity, and negative predictive value for the diagnosis of thyroid malignancy both in the presence and in the absence of ATD. If our data on USE are also confirmed in THY3 nodules, FNAC could be avoided in a number of thyroid nodules with certain features.

Impaired outcome of controlled ovarian hyperstimulation in women with thyroid autoimmune disease.

BACKGROUND: Controlled ovarian hyperstimulation (COH) is a crucial step of assisted reproductive technology (ART). Thyroid dysfunction and autoimmune thyroid disease (ATD) may negatively affect the outcome of ART, but the underlying mechanisms are still poorly understood. Our aim was to evaluate the respective role of ATD and thyroid function, as assessed by serum thyrotropin (TSH), on the early outcome of COH. METHODS: In total, 262 (202 ATD-negative and 60 ATD-positive) euthyroid subfertile women underwent ART. Before COH, serum follicle-stimulating hormone (FSH), luteinizing hormone, and estradiol (E2) were measured at cycle day 3, and progesterone at cycle day 21. At oocyte pickup and at embryo transfer, we evaluated the performance of recombinant FSH (r-FSH), as assessed by serum E2 concentration/total administered r-FSH units (E2/r-FSH) ratio and by oocyte quality. RESULTS: At both oocyte pickup and embryo transfer, the performance of r-FSH was significantly poorer in ATD-positive than in ATD-negative women. In the ATD-positive group, women with a TSH <2.5 mIU/L displayed a higher serum E2 concentration at oocyte pickup, a higher E2/r-FSH ratio, and a greater number of mature metaphase II oocytes than women with a TSH >2.5 mIU/L. When ATD-positive women were divided into quartiles according to their serum TSH level, both the ovarian response to r-FSH and the number of mature metaphase II oocytes significantly increased from the lowest to the highest quartiles of serum TSH concentration. CONCLUSIONS: ATD has a negative effect on the early outcome of COH, but this negative influence may be avoided with adequate levothyroxine therapy aimed at keeping TSH <2.5 mU/L. Thyroid antibodies and serum TSH should be checked in any woman undergoing ART.