Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy.

BACKGROUND: Whether serum TSH undergoes seasonal fluctuations in euthyroid and hypothyroid residents of temperate climates is controversial. METHODS: Monthly TSH and thyroid hormone levels were cross-sectionally analysed in a large cohort of euthyroid subjects (n=11 806) and L-thyroxine (L-T4)-treated athyreotic patients (n=3 934). Moreover, in a small group (n=119) of athyreotic patients treated with an unchanged dosage of L-T4 monotherapy, hormones were measured both in the coldest and in the hottest seasons of the same year (longitudinal study). RESULTS: No seasonal hormone change was observed in the euthyroid subjects except for a small FT3 increase in winter (+2.9%, P<.001). In contrast, the L-T4-treated athyreotic patients had significantly higher serum TSH values in the cold season when the FT4 values were significantly lower. The differences were more notable in the longitudinal series (TSH, 0.80 vs. 0.20 mU/L and FT4, 16.3 vs. 17.8 pmol/L in December-March vs. June-September, respectively). In these patients also serum FT3 values significantly decreased in winter (in the longitudinal series, 3.80 in winter vs 4.07 pmol/L in summer). Regression analysis showed that in athyreotic subjects, a greater FT4 change is required to obtain a TSH change similar to that of euthyroid controls and that this effect is more pronounced in the summer. CONCLUSION: Athyreotic patients undergoing L-T4 monotherapy have abnormal seasonal variations in TSH. These changes are secondary to the FT4 and FT3 serum decreases in winter, which occur in spite of the constant treatment. The underlying mechanisms are unclear, but in some cases, these changes may be clinically relevant.

Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism.

INTRODUCTION: Mitotane, a steroidogenesis inhibitor with adrenolytic properties used to treat adrenocortical cancer (ACC), can affect thyroid function. A reduction of FT4 levels with normal FT3 and TSH has been described in these patients. Using an in vitro murine model, the secretory capacity of thyrotrophic cells has been shown to be inhibited by mitotane. OBJECTIVE: To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC. PATIENTS AND METHODS: In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 µg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10). RESULTS: Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal. CONCLUSIONS: Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes observed in hypothyroid conditions. This finding thus confirms in vitro studies and may have a therapeutic implication for treatment with thyroid hormones, as suggested by current guidelines for this specific condition.

A novel RET gene mutation in a patient with apparently sporadic pheochromocytoma.

Pheochromocytoma (Pheo) is a chromaffin tumor arising from the adrenal medulla. The recent discovery of new germline mutations in RET, SDHA, SDHB, SDHC, SDHD, VHL, NF1, TMEM127, MAX genes, increased the rate of genetic disease from 10% to 28% in patients with apparently sporadic tumor. RET germline mutations cause multiple endocrine neoplasia type 2 syndrome (MEN 2A) characterized by complete penetrance of medullary thyroid cancer (MTC), and lower prevalence of Pheo and hyperparathyroidism. We describe the genetic etiology of an apparently sporadic case of monolateral Pheo in a 42-year-old male patient. A new (not previously reported) MEN 2A-associated germline RET mutation located in exon 11 (Glu632Gly, caused by an A>G point mutation at position 1895 of the RET cDNA) was found in the patient but not in his living first-degree relatives. This observation increases the number of possible germline RET mutations. Genotype-phenotype correlation of this new genetic alteration is unknown, but this rare mutation is probably associated with a low risk for MTC (usually the first tumor diagnosed in MEN 2A syndrome) and with the development of Pheo before the onset of MTC. Since we expect MTC to occur in our patient, strict follow-up is mandatory. Our findings emphasize the relevance of genetic testing in patients with Pheo, especially when the clinical presentation (family history, young age at diagnosis, multiple locations, malignant lesions, and bilateralism) is suggestive.

Efficacy of real-time continuous glucose monitoring on glycaemic control and glucose variability in type 1 diabetic patients treated with either insulin pumps or multiple insulin injection therapy: a randomized controlled crossover trial.

BACKGROUND: The aim of this study was to determine the efficacy of real-time continuous glucose monitoring in T1D patients treated with insulin pump therapy or multiple daily insulin therapy. METHODS: Twenty adult patients (ten insulin pump therapy and ten multiple daily insulin) with poor glycaemic control (HbA1c > 8.0%) were randomized into two groups for 6 months: the continuous glucose monitoring arm (using real-time continuous glucose monitoring) and the SMBG arm. After 2 months of wash-out, the participants crossed over. The primary outcome was HbA1c reduction. The secondary outcomes were hypoglycaemia and hyperglycaemia risk assessment (area under the curve < 70 mg/dL/day and AUC > 200 mg/dL/day, respectively) and glucose variability. RESULTS: Fourteen patients (eight multiple daily insulin, six insulin pump therapy) used continuous glucose monitoring appropriately (at least 40% of the time). In these patients, the improvement in glycaemic control was more evident during the real-time continuous glucose monitoring period (7.76% ± 0.4 vs 8.54% ± 0.4, p < 0.05) than during the self-monitoring of blood glucose period (8.42% ± 0.4 vs 8.56% ± 0.5, p = 0.2). Better results with continuous glucose monitoring were observed in patients using multiple daily insulin with greater improvement in both glycaemic control (7.71% ± 0.2 vs 8.58% ± 0.2, p < 0.05) and glucose variability and with a marked reduction in the risk of both hypoglycaemia and hyperglycaemia. CONCLUSIONS: Appropriate use of real-time continuous glucose monitoring improved glycometabolic control in T1D patients. The effects of continuous glucose monitoring were more evident in patients under multiple daily insulin treatment, compared with insulin pump therapy. Glucose variability, in addition to glycaemic control, was improved in compliant diabetic patients.

Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression.

Hyperinsulinemia is a likely cause of the increased cancer incidence and mortality in diabetic patients, but its role is difficult to define in vivo. Previous in vitro studies testing the mitogenic potential of insulin and its analogs provided incomplete and sometimes contradictory results. To better evaluate cancer cell responsiveness to insulin, to its analogs and to IGF-I, we measured under identical experimental conditions cell proliferation, invasiveness, and foci formation in six cancer cell lines with different insulin receptor family expression levels. The cancer cells studied have a different expression of insulin receptor (IR), its isoforms (IR-A and IR-B), and of the IGF-I receptor. The data indicate that insulin stimulates proliferation in all cancer cell lines, invasiveness in some, and foci formation in none. Cancer cell responses to insulin (and IGF-I) are not related to receptor expression levels; moreover, hormone-stimulated proliferation and invasiveness are not correlated. IGF-I is a more potent stimulator than insulin in most but not all cancer cell lines. Insulin analogs including M1 and M2 Glargine metabolites stimulate cancer cells similar to insulin. However, exceptions occur for specific analogs in particular cancer cells. In conclusion, in vitro insulin is an effective growth factor for all cancer cells but the biological response to insulin cannot be predicted on the basis of receptor expression levels. In the clinical setting, these observations should be taken in account when deciding treatment for diabetic patients who are at risk of undiscovered cancer or survivors of oncological diseases.

17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells.

Prostate carcinomas frequently express estrogen receptors (ER), irrespective of androgen receptor (AR) expression; however, the role of ERs and estrogens in prostate cancer is controversial. We found that 17beta-estradiol (E(2)) is able to markedly up-regulate insulin-like growth factor (IGF)-I receptor (IGF-IR) mRNA and protein expression in both AR-positive (LNCaP cells) and AR-negative (PC-3 cells) prostate cancer cells. This effect occurs not only via ERalpha but also via ERbeta stimulation and is specific for IGF-IR because it does not involve the cognate insulin receptor. IGF-IR up-regulation is associated with increased IGF-IR phosphorylation and with increased mitogenic and motogenic activities in response to IGF-I. IGF-IR up-regulation by E(2) does not require ER binding to DNA and is poorly sensitive to antiestrogen blockade, whereas it is associated with the activation of cytosolic kinase cascades involving Src, extracellular signal-regulated kinase (ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. In conclusion, our data indicate that estrogens may contribute to IGF system deregulation in prostate cancer through the activation of a nongenotropic pathway. Estrogens may have a role, therefore, in tumor progression to androgen independence. Inhibition of the IGF-IR or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in prostate cancer.

Cardiovascular Effects of Pioglitazone or Sulfonylureas According to Pretreatment Risk: Moving Toward Personalized Care.

CONTEXT: Hypoglycemic drugs with proven cardiovascular (CV) benefits are recommended for patients with type 2 diabetes and CV disease. Whether the beneficial effects extend to those at lower risk remains unclear. AIM: We investigated the long-term CV effects of pioglitazone or sulfonylureas (SUs) across the spectrum of pretreatment CV risk. METHODS: Among 2820 participants of the TOSCA.IT trial, four subgroups with different risk of outcome-a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, urgent coronary revascularization-were identified by the RECursive Partitioning and AMalgamation (RECPAM) method. Within each group, the effect of SUs or pioglitazone on the outcome was evaluated. RESULTS: Sex was the first splitting variable, followed by urinary albumin-to-creatinine ratio (UACR) (>9 mg/g or ≤9 mg/g) and body mass index (BMI) (>28.7 or ≤28.7 kg/m2). Female patients had the lowest risk (reference); male patients with UACR >9 mg/g and BMI >28.7 kg/m2 had the highest risk [hazard ratio (HR), 5.58; 95% CI, 3.32 to 9.69]. Patients in this group present a cluster of conditions suggestive of marked insulin resistance (higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower high-density lipoprotein cholesterol) than the other groups. Treatment with pioglitazone in this group was associated with a significantly lower occurrence of the outcome than SUs (HR, 0.48; 95% CI, 0.25 to 0.76). No significant difference between study treatments was observed in the other RECPAM classes. CONCLUSIONS: It is possible to identify patients with type 2 diabetes early in the stage of their disease and who are largely free from evident CV disease in whom add-on pioglitazone to metformin confers CV protection as compared with SUs.

The role of insulin receptors and IGF-I receptors in cancer and other diseases.

There is evidence, both in vitro and in vivo, that receptor tyrosine kinases play a key role in the formation and progression of human cancer. In particular, the insulin-like growth factor receptor (IGF-IR), a tyrosine kinase receptor for IGF-I and IGF-II, has been well documented in cell culture, animal studies, and humans to play a role in malignant transformation, progression, protection from apoptosis, and metastasis. In addition, the hormone insulin (which is very closely related to the IGFs) and its tyrosine kinase receptor (the IR, which is very closely related to the IGR-IR) have been documented both in vitro and in vivo to play a key role in cancer biology. Indeed, several epidemiological studies have shown that insulin resistance status, characterized by hyperinsulinaemia, is associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. IR is over-expressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially over-expressed in cancer. IR-A is the IR foetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. In addition, the IR contributes to formation of hybrid receptors with the IGF-IR (HR). By binding to hybrid receptors, insulin may stimulate specific IGF-IR signalling pathways. Over-expression of IR-A is, therefore, a major mechanism of IGF system over-activation in cancer. In this respect, IR-A isoform and hybrid receptors should be regarded as potential molecular targets, in addition to IGF-IR, for novel anti-cancer therapy. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinaemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmacological approaches to avoid an increased risk for cancer. Moreover, native insulin and insulin analogue administration should be carefully evaluated in terms of the possible increase in cancer risk.

Impact of a Mediterranean Dietary Pattern and Its Components on Cardiovascular Risk Factors, Glucose Control, and Body Weight in People with Type 2 Diabetes: A Real-Life Study.

This study evaluates the relation of a Mediterranean dietary pattern and its individual components with the cardiovascular risk factors profile, plasma glucose and body mass index (BMI) in people with type 2 diabetes. We studied 2568 participants at 57 diabetes clinics. Diet was assessed with the EPIC (European Prospective Investigation into Cancer and Nutrition) questionnaire, adherence to the Mediterranean diet was evaluated with the relative Mediterranean diet score (rMED). A high compared to a low score was associated with a better quality of diet and a greater adherence to the nutritional recommendations for diabetes. However, even in the group achieving a high score, only a small proportion of participants met the recommendations for fiber and saturated fat (respectively 17% and 30%). Nonetheless, a high score was associated with lower values of plasma lipids, blood pressure, glycated hemoglobin, and BMI. The relationship of the single food items components of the rMED score with the achievement of treatment targets for plasma lipids, blood pressure, glucose, and BMI were also explored. The study findings support the Mediterranean dietary model as a suitable model for type 2 diabetes and the concept that the beneficial health effects of the Mediterranean diet lie primarily in its synergy among various nutrients and foods rather than on any individual component.

Effects of either LT4 monotherapy or LT4/LT3 combined therapy in patients totally thyroidectomized for thyroid cancer.

After total thyroidectomy all thyroid cancer patients require lifelong treatment with thyroid hormones; the treatment of choice is synthetic levothyroxine (LT4). The question of whether these patients might benefit from the combined LT4 and liothyronine (LT3) treatment has been addressed with conflicting conclusions. The aim of the present study was to compare the effects of combined low LT4/LT3 molar ratio therapy versus LT4 monotherapy on various target organs and tissues in patients thyroidectomized for thyroid cancer. Urine collection (24 hour), a fasting blood sample for laboratory examinations, thyroid function clinical score, and cardiovascular, neurological, and neuropsychological evaluations were obtained. Clinical parameters and peripheral markers of thyroid function were measured during the two different treatment regimens in 20 patients. Mean serum aspartate aminotransferase, alanine aminotransferase, sex hormone binding globulin, and osteocalcin values were significantly higher during the combined treatment. No significant differences in the clinical score, the systolic and diastolic performance, and the neurological and neuropsychological evaluations were observed between the two treatment regimens. Moreover, no alteration due to subclinical hyperthyroidism or to the fluctuations in serum T3 concentrations during the combined therapy was observed. In conclusion, we found no evidence that combined therapy with a low LT4/LT3 molar ratio resulted in improved well-being and cognitive function or in increased thyroid hormone action on peripheral tissues in respect to LT4 monotherapy. Until future large, blind, randomized, and controlled trials prove otherwise, LT4 should remain the standard treatment for thyroid cancer patients.

Botulinum toxin treatment for oropharyngeal dysphagia associated with diabetic neuropathy.

OBJECTIVE: No specific treatment for oropharyngeal dysphagia related to diabetic neuropathy has been described to date. Chemical myotomy of the cricopharyngeus (CP) muscle by botulinum neurotoxin type A (BoNT/A) has been effective in reducing or abolishing dysphagia associated with upper esophageal sphincter (UES) hyperactivity of different etiologies. In the present study, we evaluated the efficacy of BoNT/A injections into the CP muscle in diabetic patients with severe oropharyngeal dysphagia associated with diabetic autonomic and/or somatic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Twelve type 2 diabetic patients with severe dysphagia for both solid and liquid foods associated with autonomic and/or peripheral somatic neuropathy were investigated. Swallowing function was evaluated by clinical examination, videofluoroscopy, and simultaneous needle electromyography (EMG) of the CP and pharyngeal inferior constrictor (IC) muscles. Clinical evaluation using a four-level dysphagia severity score was performed every other day for the 1st week and thereafter every other week until week 24. Videofluoroscopy and EMG follow-up were carried out at week 1, 4, 12, 16, 18, and 24 after BoNT/A injection. BoNT/A was injected percutaneously into the CP muscle under EMG control. RESULTS: BoNT/A induced the complete recovery of dysphagia in 10 patients and had a significant (P = 0.0001, ANOVA) improvement in 2 patients within 4 +/- 1.1 days (range 3-7). Clinical improvement was confirmed by videofluoroscopy and EMG. CONCLUSIONS: Our findings suggest a potential benefit from BoNT/A treatment in dysphagia associated with diabetic neuropathy. Randomized controlled trials are needed to confirm this observation.

Thyroid Cancer in the Pediatric Age in Sicily: Influence of the Volcanic Environment.

BACKGROUND/AIM: Pediatric thyroid cancer (TC) is rare but its incidence is increasing. We analyzed incidence and characteristics of pediatric TC in Sicily and comparatively evaluated data from the volcanic and non-volcanic areas. MATERIALS AND METHODS: All incident pediatric (0-19 years) TCs in Sicily between 2002-2009 were analyzed for the area of residence and compared to data for adults. RESULTS: A total of 54 differentiated TCs (DTC) and nine medullary TCs were diagnosed in Sicily in children between 2002-2009. DTC age standardized rate for the world population (ASRw) was 0.8/105 in females and 0.2/105 in males, with a higher incidence in the volcanic area (ASRw=1.4/105 in females, 0.5/105 in males) vs. the rest of Sicily (ASRw=0.6/105 in females, 0.1/105 in males). Pediatric TCs were larger in size and more frequently with extrathyroid extension and lymph-node involvement in comparison to TCs in adults. CONCLUSION: In the volcanic environment of Sicily, TC incidence is markedly increased in children, suggesting a short-term effect of unidentified carcinogens of volcanic origin.

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.

BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Polyphenol intake and cardiovascular risk factors in a population with type 2 diabetes: The TOSCA.IT study.

BACKGROUND: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes. AIM: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes. METHODS: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet. RESULTS: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m2, HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population. CONCLUSIONS: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes. CLINICAL TRIAL: http://www.clinicaltrials.gov; Study ID number: NCT00700856.

Outcome of the Diffuse Sclerosing Variant of Papillary Thyroid Cancer: A Meta-Analysis.

INTRODUCTION: The diffuse sclerosing variant (DSV) of papillary thyroid cancer (PTC) is considered an aggressive histotype associated with poor prognosis. However, the available data for both the outcome and best management of this disease are inconsistent. METHODS: This study reviewed the current literature by searching PubMed up to November 30, 2015, using the search terms "diffuse sclerosing variant" and "papillary thyroid cancer (or carcinoma)" and selecting only studies evaluating recurrent/persistent disease and cancer-related mortality in both DSV and classic PTC (cPTC). The association with some features of aggressiveness at diagnosis, the risk of recurrence or persistence, and the risk of cancer-related death were reported as odds ratio (OR) with confidence intervals (CI). Meta-regression analysis was used to assess the effect of covariates across the studies. RESULTS: Ten studies met the eligibility criteria and contributed 585 DSV and 64,611 cPTC patients. Relative to patients with cPTC, patients with DSV exhibited a higher risk of extrathyroidal extension and lymph node and distant metastases. The risk of persistent/recurrent disease was three times higher in patients with DSV than it was in cPTC patients (OR = 3.19 [CI 1.86-5.49]). This risk was not different when only studies where post-surgical (131)I was routinely administered were considered (OR = 2.07 [CI 0.88-4.90]). The risk of cancer-related mortality was not different between DSV and cPTC (OR = 1.34 [CI 0.76-2.38]). CONCLUSIONS: This meta-analysis confirms the aggressive biological behavior of DSV thyroid cancer. When preoperatively suspected, total thyroidectomy with lymph node excision followed by radioiodine therapy should be the correct management for DSV.

Increased thyroid cancer incidence in a basaltic volcanic area is associated with non-anthropogenic pollution and biocontamination.

The increased thyroid cancer incidence in volcanic areas suggests an environmental effect of volcanic-originated carcinogens. To address this problem, we evaluated environmental pollution and biocontamination in a volcanic area of Sicily with increased thyroid cancer incidence. Thyroid cancer epidemiology was obtained from the Sicilian Regional Registry for Thyroid Cancer. Twenty-seven trace elements were measured by quadrupole mass spectrometry in the drinking water and lichens (to characterize environmental pollution) and in the urine of residents (to identify biocontamination) in the Mt. Etna volcanic area and in adjacent control areas. Thyroid cancer incidence was 18.5 and 9.6/10(5) inhabitants in the volcanic and the control areas, respectively. The increase was exclusively due to the papillary histotype. Compared with control areas, in the volcanic area many trace elements were increased in both drinking water and lichens, indicating both water and atmospheric pollution. Differences were greater for water. Additionally, in the urine of the residents of the volcanic area, the average levels of many trace elements were significantly increased, with values higher two-fold or more than in residents of the control area: cadmium (×2.1), mercury (×2.6), manganese (×3.0), palladium (×9.0), thallium (×2.0), uranium (×2.0), vanadium (×8.0), and tungsten (×2.4). Urine concentrations were significantly correlated with values in water but not in lichens. Our findings reveal a complex non-anthropogenic biocontamination with many trace elements in residents of an active volcanic area where thyroid cancer incidence is increased. The possible carcinogenic effect of these chemicals on the thyroid and other tissues cannot be excluded and should be investigated.

Metastatic malignant struma ovarii with coexistence of Hashimoto's thyroiditis.

UNLABELLED: Struma ovarii is a rare ovarian teratoma characterized by the presence of thyroid tissue as the major component. Malignant transformation of the thyroidal component (malignant struma ovarii) has been reported in approximately 5% of struma ovarii. The management and follow-up of this unusual disease remain controversial. We report the case of a woman with a history of autoimmune thyroiditis and a previous resection of a benign struma ovarii that underwent hystero-annexiectomy for malignant struma ovarii with multiple papillary thyroid cancer foci and peritoneal involvement. Total thyroidectomy and subsequent radioiodine treatment lead to complete disease remission after 104 months of follow-up. The diagnosis and natural progression of malignant struma ovarii are difficult to discern, and relapses can occur several years after diagnosis. A multidisciplinary approach is mandatory; after surgical excision of malignant struma, thyroidectomy in combination with (131)I therapy should be considered after risk stratification in accordance with a standard approach in differentiated thyroid cancer patients. LEARNING POINTS: Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined.Predominant sites of metastasis are adjacent pelvic structures.Thyroidectomy and (131)I therapy should be considered after risk stratification in accordance with standard approaches in DTC patients.

Integrated insulin pump therapy with continuous glucose monitoring for improved adherence: technology update.

Insulin pump therapy combined with real-time continuous glucose monitoring, known as sensor-augmented pump (SAP) therapy, has been shown to improve metabolic control and to reduce the rate of hypoglycemia in adults with type 1 diabetes compared to multiple daily injections or standard continuous subcutaneous insulin infusion. Glycemic variability is also reduced in patients on SAP therapy. This approach allows patients to monitor their glucose levels being informed of glycemic concentration and trend. Trained diabetic patients, therefore, can appropriately modify insulin infusion and/or carbohydrate intake in order to prevent hypo- or hyperglycemia. For these reasons, SAP therapy is now considered the gold standard for type 1 diabetes treatment. To be clinically effective, however, devices and techniques using advanced technology should not only have the potential to theoretically ameliorate metabolic control, but also be well accepted by patients in terms of satisfaction and health-related quality of life, because these factors will improve treatment adherence and consequently overall outcome. SAP therapy is generally well tolerated by patients; however, many clinical trials have identified significant noncompliance in the use of this device, most notably in the pediatric and adolescent populations. In this review we aim to analyze the main reasons for good or poor adherence to SAP therapy and to provide useful tips in order to fully benefit from this kind of novel therapeutic approach.

Several Site-specific Cancers are Increased in the Volcanic Area in Sicily.

BACKGROUND: Worldwide, thyroid cancer incidence is increased in many volcanic areas. Whether the incidence of other types of cancers are also increased is not known. MATERIALS AND METHODS: We analyzed cancer registries covering 82% of the population of Sicily to compare the incidence of 34 site-specific types of cancer in area around the volcano Mt. Etna (where thyroid cancer is very high) with adjacent non-volcanic areas. Differences in crude incidence rate ratios (IRR) between the two areas were calculated. RESULTS: Considering 72,197 incident cases, thyroid cancer (IRR=1.68 in females and 1.40 in males) and lymphatic leukemia (IRR: females=1.48, males=1.39) were significantly increased in the volcanic area in both men and women. Hodgkin's lymphoma, stomach and breast cancer in women and prostate cancer in men were also significantly increased in the volcanic area. CONCLUSION: Several, but not all types of cancers are significantly increased in the volcanic area of Sicily, indicating that an active volcanic environment may be a risk factor for cancer other than thyroid cancer.

Familial Non-Medullary Thyroid Cancer Represents an Independent Risk Factor for Increased Cancer Aggressiveness: A Retrospective Analysis of 74 Families.

OBJECTIVES: To assess whether familial non-medullary thyroid cancer (FNMTC) represents an independent risk factor for increased aggressiveness of the tumor, as concern as the clinical presentation and the long-term follow-up in respect of sporadic differentiated thyroid cancer (SDTC). DESIGN: Retrospective study; 1976-2014. PATIENTS AND METHODS: Seventy-four FNMTC families (151 affected individuals): family relationship and number of affected family members were evaluated. Clinical and histopathological features and outcome were compared to that of 643 SDTC patients followed in the same period according to the same institutional protocols. Median follow-up was 57.7 months (range 12-136) in FNMTC and 59.7 (range 15-94.6) in SDTC patients. RESULTS: Three cases occurred in 3 families and 2 cases in the other 71. F:M was 3.7:1 in FNMTC and 4.3:1 in SDTC (NS). The family relationship was siblings in 62.2%. Mean age at diagnosis was lower in FNMTC than in SDTC (p < 0.005). Papillary/follicular histotype distribution was similar (86%). Papillary tumors were more frequently multifocal in FNMTC (p = 0.004) and with lymph-node metastases (p = 0.016). Disease-free survival (DFS) was shorter in FNMTC vs. SDTC (p < 0.0001) with 74.8 vs. 90.8% patients free of disease at the last control (p < 0.005). Three patients died in FNMTC group vs. 1 in SDTC (p = 0.02). CONCLUSION: Familial non-medullary thyroid cancer displays distinct characteristics as earlier age of onset and increased aggressiveness at diagnosis and a higher rate of persistent/recurrent disease and mortality with a shorter DFS in respect with SDTC. FNMTC patients, therefore, should be followed accurately. As the specific gene (or genes) responsible for susceptibility for FNMTC has not yet been identified, a low frequency periodic screening of relatives DTC patients may be useful to identify FNMTC patients at early stage of disease.