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There is much evidence linking oxidative stress to thyroid cancer, and stem cells are thought to play a key role in the tumor-initiating mechanism. Their vulnerability to oxidative stress is unexplored. This study aimed to comparatively evaluate the antioxidant capacity of stem/precursor thyroid cells and mature thyrocytes. Human stem/precursor cells and mature thyrocytes were exposed to increasing concentrations of menadione, an oxidative-stress-producing agent, and reactive oxygen species (ROS) production and cell viability were measured. The expression of antioxidant and detoxification genes was measured via qPCR as well as the total antioxidant capacity and the content of glutathione. Menadione elevated ROS generation in stem/precursor thyroid cells more than in mature thyrocytes. The ROS increase was inversely correlated ( p = 0.005) with cell viability, an effect that was partially prevented by the antioxidant curcumin. Most thyroid antioxidant defense genes, notably those encoding for the glutathione-generating system and phase I detoxification enzymes, were significantly less expressed in stem/precursor thyroid cells. As a result, the glutathione level and the total antioxidant capacity in stem/precursor thyroid cells were significantly decreased. This reduced antioxidant defense may have clinical implications, making stem/precursor thyroid cells critical targets for environmental conditions that are not detrimental for differentiated thyrocytes.

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2-3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage.

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the "normal" range.

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gianì, Masto, Trovato, Franco, Pandini and Vigneri.)

Background: Maternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy., Methods: Placental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either ≥90 mg/dl or <90 mg/dl, regardless of the diagnosis., Results: In T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p<0.0001) in the placenta of patients with peripartum glucose >90 mg/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg/dl (p=0.046)., Conclusions: To the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tumminia, Scalisi, Milluzzo, Ettore, Vigneri and Sciacca.)

Objective: Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases (AIDs). Although most of T1D patients are sporadic cases (S-T1D), 10% to 15% have a familial form (F-T1D) involving 2 or more first-degree relatives. This study evaluated the effect of T1D family aggregation and age onset on AIDs occurrence., Methods: In this observational, cross-sectional, case-control, single center study, we enrolled 115 F-T1D and 115 S-T1D patients matched for gender, age, T1D age onset, and duration. With respect to T1D age onset (before or after 18 years), both groups were further subdivided into young- or adult-onset F-T1D and young- or adult-onset S-T1D. The presence of organ-specific antibodies and/or overt AIDs was evaluated., Results: The F-T1D group had a higher percentage of AIDs (29.8% vs 18.4%, P = .04) and a significant earlier onset of AIDs at Cox regression analysis (P = .04) than the S-T1D group. Based on multivariate analysis, the adult-onset F-T1D subgroup had the highest prevalence of both additional organ-specific antibodies (60.5%) and overt AIDs (34.9%), whereas the adult S-T1D subgroup was the least frequently involved (29.1% and 12.7%, respectively). In F-T1D patients, offsprings develop T1D and AIDs earlier than their parents do., Conclusions: In T1D patients, familial aggregation and adult-onset of T1D increase the risk for coexistent AIDs. These clinical predictors could guide clinicians to address T1D patients for the screening of T1D-related AIDs., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

In addition to being a major metabolic hormone, insulin is also a growth factor with a mitogenic effect on all cells, more marked in malignant cells that often overexpress the insulin receptor. In patients with metabolic diseases characterized by hyperinsulinemia (obesity, type 2 diabetes, and metabolic syndrome), the incidence of several types of cancer is increased, as is cancer-related mortality. Because of the worldwide growing prevalence of metabolic diseases and the diffuse use of insulin and its analogs for treating diabetes, the relationship between insulin and cancer has become a clinically relevant issue. Clinical studies have not clarified the degree to which hyperinsulinemia can influence cancer occurrence and prognosis. To better understand this issue, an improved scientific approach is required, with more careful consideration of the mechanisms related to hyperinsulinemia and carcinogenesis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Obesity represents a major risk factor for metabolic disorders, but some individuals, "metabolically healthy" (MHO), show less clinical evidence of these complications, in contrast to "metabolically unhealthy" (MUO) individuals. The aim of this cross-sectional study is to assess the prevalence of the MHO phenotype in a cohort of 246 overweight/obese Italian children and adolescents, and to evaluate their characteristics and the role of insulin resistance. Homeostasis model assessment-insulin resistance (HOMA-IR), insulin sensitivity index (ISI), insulinogenic index (IGI) and disposition index (DI) were all calculated from the Oral Glucose Tolerance Test (OGTT). MHO was defined by either: (1) HOMA-IR < 2.5 (MHO-IRes), or (2) absence of the criteria for metabolic syndrome (MHO-MetS). The MHO prevalence, according to MHO-MetS or MHO-IRes criteria, was 37.4% and 15.8%, respectively. ISI was the strongest predictor of the MHO phenotype, independently associated with both MHO-IRes and MHO-MetS. The MHO-MetS group was further subdivided into insulin sensitive or insulin resistant on the basis of HOMA-IR (either < or ≥ 2.5). Insulin sensitive MHO-MetS patients had a better metabolic profile compared to both insulin resistant MHO-MetS and MUO-MetS individuals. These data underscore the relevance of insulin sensitivity to identifying, among young individuals with overweight/obesity, the ones who have a more favorable metabolic phenotype.

Background: A course of anti-thyroid drugs (ATD) is the most common first line treatment for Graves' hyperthyroidism. However, hyperthyroidism relapse is frequent (30-70%). Due to the autoimmune nature of Graves' disease, the immunosuppressive treatment used for active Graves' orbitopathy (GO) may reduce the relapses after ATD discontinuation. Objective: To evaluate the recurrence rate in Graves' patients who, in addition to standard ATD, were treated or not treated with parenteral methylprednisolone (MPDS) for GO. Methods: Single-center retrospective study in a continuous series of 162 newly diagnosed Graves' patients, with or without GO, all gone into remission and followed-up until hyperthyroidism recurrence or at least 4 years after ATD discontinuation. Patients with moderate-severe active GO underwent middle dose MPDS treatment according to the EuGoGo guidelines. Cox proportional-hazard model was used to comparatively evaluate the risk of recurrence and the predictive factors in patients treated or not treated with MPDS pulse therapy. Results: MPDS treatment was the most significant factor that independently correlated with a reduced risk of hyperthyroidism relapse (HR = 0.53, 95% C.I. = 0.31-0.89). FT3 and female sex were also independent protective factors, while age almost reached the significance level, p = 0.062. The efficacy of MPDS was very high in patients aged <40 years (42.1% decrease in relapses, p < 0.01) but it was not significant in older patients. Discussion: Our study found that after ATD discontinuation the frequency of Graves' hyperthyroidism relapse was reduced in patients treated with MPDS pulse therapy for GO. This effect was more marked in young patients., (Copyright © 2020 Le Moli, Malandrino, Russo, Lo Giudice, Frasca, Belfiore and Vigneri.)

Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause-effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.

Background: The concentration of trace elements and metals in the thyroid is the result of exposure, uptake, retention, and clearance. The specificity and selectivity of thyroid capacity to concentrate these elements relative to other tissues are not known. To obtain this information, we measured the tissue concentration of 26 elements in the thyroid, muscle, and fat of euthyroid human subjects and also in normal rats. Methods: At programmed surgery, small (<1 g) tissue fragments were collected in 77 euthyroid subjects. Macroscopically normal thyroid tissue, sternothyroid muscle, and neck subcutaneous fat samples were excised, and thyroid tissue was confirmed to be morphologically normal through microscopy. Tissue specimens (thyroid, hindlimb muscle, and abdominal fat) were also obtained from normal rats. Measurements of trace elements were performed on tissues using inductively coupled plasma mass spectrometry (DRC-ICP-MS). Results: Only 19 of the 26 investigated elements were measurable as 7 elements were below the limit of detection. The ranking concentration in human thyroid tissue, not considering iodide, indicated that Zn, Br, Cu, Cr, Se, and Mn represented over 95% of the measured elements. A similar ranking was observed in the rat thyroid. A comparison with other tissues indicated that in addition to I, also Br, Mn, Se, and Sn were significantly more concentrated in the thyroid, and this was also the case for the recognized carcinogens As, Cd, and Hg. As and Hg, but not Cd (which was not detectable in any of the rat tissues), were also more concentrated in the rat thyroid. Since human thyroid specimens were also obtained from residents of a volcanic area, where environmental pollution may cause human biocontamination, we compared the trace element concentration in specimens from the volcanic area with controls. Many trace elements were slightly, but not significantly, increased in the volcanic area specimens. Conclusions: In the normal human thyroid, many trace elements, including Br, Mn, Se, and Sn, and the recognized carcinogens, As, Cd, and Hg, are significantly more concentrated than in muscle and fat of the same individual. Similar data were observed in rats. The reason for the differential element accumulation in the thyroid is unclear; a better understanding may be useful to further clarify thyroid biology.

Background: Childhood obesity is encouraged by low physical activity (PA), time spent using screens (screen time, ST), and by sugar-sweetened beverage consumption (SSBc). It is also influenced by unfavorable parents' characteristics, such as a high body mass index (BMI) and low education level (EL). Our aim was to evaluate the overall and specific influence of these factors on childhood adiposity., Material and Methods: Anthropometric parameters including BMI z-score, waist circumference (WC), waist to height ratio (WtHR), and fat mass were measured in a cohort of 1702 schoolchildren (6.0-14.5 years, mean 10.7 ± 1.8) and questionnaires concerning children's PA, ST, and SSBc, and parent's BMI and EL were administered to parents., Results: Overweight/obesity prevalence was higher (P < .0001) in males (57%) than in females (43%). Less physically active children (28.9%) had a higher prevalence of overweight/obesity and higher BMI z-score, WC, WtHR, and fat mass relative to more physically active children (P < .05). PA was negatively associated with the BMI z-score (r = 0.18, P < .0001) and fat mass percentage (r = 0.18, P < .0001). Children with more ST had higher WC and WtHR than non-ST viewers (P < .05) but not BMI. Moreover, SSBc did not influence the anthropometric parameters. At multivariate analysis, male gender, less PA, and parental risk factors (parent's overweight/obesity and low/medium EL) were independently associated with overweight and obesity among childhood with a progressively increasing odds ratio (1.65, 1.40, and 1.80, respectively)., Conclusions: Male gender, behavioral risk factors (particularly low PA), and parent's characteristics are important correlates of obesity in children., (© 2019 John Wiley & Sons, Ltd.)

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

The short-term adverse effects of anticancer drugs (AD) in patients with type 2 diabetes (T2D) are poorly studied and their management still represents an important challenge for clinicians. We carried out a retrospective single-center study in 168 patients with T2D and cancer, evaluating both the short-term effects of first-line AD on glycemic control and chronic diabetes complications. Average glycated hemoglobin significantly increased after AD compared to values before treatment (7.5 vs. 7.1%, p < 0.005). In 46.4% of patients, diabetes therapy had to be potentiated, in most cases (82.1%) by shifting to insulin. The use of alkylating agents and high-dose glucocorticoids predicted the need to potentiate diabetes therapy. After AD transaminase values significantly increased, whereas the estimated glomerular filtration rate decreased (in 12.5% <60 mL/min). Kinase inhibitors significantly increased the risk of microalbuminuria onset or progression. The present study provides a real-life information on the effects of different AD on the management of patients with T2D affected by several types of cancer.

Context: Differentiated thyroid cancer (DTC) has an excellent prognosis, but up to 20% of patients with DTC have disease events after initial treatment, indistinctly defined as persistent/recurrent disease., Objective: To evaluate the prevalence and outcome of "recurrent" disease (relapse after being 12 months disease-free) compared with "persistent" disease (present ab initio since diagnosis)., Design: Retrospective analysis of persistent/recurrent disease in patients with DTC (1990 to 2016) with 6.5 years of mean follow-up., Setting: Tertiary referral center for thyroid cancer., Patients: In total, 4292 patients all underwent surgery ± 131I treatment of DTC., Main Outcome Measures: DTC cure of disease persistence or recurrence., Results: A total of 639 of 4292 (14.9%) patients had disease events after initial treatment, most (498/639, 78%) with persistent disease and 141 (22%) with recurrent disease. Relative to patients with recurrent disease, patients with persistent disease were significantly older (mean age 46.9 vs 45.7 years) and with a lower female to male ratio (1.9/1 vs 4.8/1). Moreover, in this group, structured disease was more frequent (65.7% vs 41.1%), and more important, distant metastases were significantly more frequent (38.4% vs 17.0%). At multivariate analysis, male sex (OR = 1.7), age (OR = 1.02), follicular histotype (OR = 1.5), T status (T3; OR = 3), and N status (N1b; OR = 7.7) were independently associated with persistent disease. Only the N status was associated with recurrent disease (N1b; OR = 2.5)., Conclusions: In patients with DTC not cured after initial treatment, persistent disease is more common and has a worse outcome than recurrent disease. Postoperative status evaluated during first-year follow-up may have important clinical implications for planning tailored treatment strategies and long-term follow-up procedures.

Objective: Muscle cramps occur in >50% of diabetic patients and reduce the quality of life. No effective treatment is available. We evaluated the clinical effectiveness of botulinum toxin A (BTX-A) injections for treating cramps in diabetic patients with neuropathy., Methods: This single-center, double-blind, placebo-controlled perspective study investigated the efficacy and safety of BTX-A intramuscular injection for treating calf or foot cramps refractory to common pharmacological drugs. Fifty diabetic patients with peripheral neuropathy and cramps were randomly assigned to 2 matched groups. BTX-A (100 or 30 units) or saline was injected on each side into the gastrocnemius or the small flexor foot muscles. Changes in pain intensity (primary outcome) and cramp frequency were evaluated over the course of 20 weeks after BTX-A administration. Cramp interference in daily life and the electrophysiological cramp threshold frequency were also measured. The treatment was repeated 5 months after first injection in 19 responders., Results: All outcome measures improved significantly after BTX-A compared with placebo. The changes with respect to baseline were already significant after 1 week and persisted up to week 14. Only 5 of 25 (20%) patients were nonresponders (<50% decrease of the primary outcome). The responses to a second BTX-A injection provided results similar to the first administration. Mild pain at the injection site (4/25 cases) was the only adverse event, and it disappeared within 2 to 3 days., Interpretation: Local BTX-A infiltration is an efficacious and safe procedure for obtaining a sustained amelioration of muscle cramps associated with diabetic neuropathy. Ann Neurol 2018;84:682-690., (© 2018 American Neurological Association.)

Purpose: Papillary thyroid cancer (PTC) has good prognosis with a very low chance of mortality. The prognostic role of metastatic lymph node location was judged controversial and more recently (TNM VIII ed.) was considered to have no impact on the prognosis of older patients. The aim of the study was to evaluate the role of metastasized node location on PTC-related mortality., Methods: PTC-related mortality was analysed in a consecutive retrospective series of 1653 PTC patients followed at our Thyroid Clinic (mean follow-up 5.9 years)., Results: Sixteen out of 1653 patients (0.96%) died because of PTC. Average age was 68 years at presentation and 74.7 at death. F/M ratio was 1:1. The death rate increased in relation to the lymph node status: 0.2% in N0, 0.3% in N1a and 3.0% in N1b., Conclusions: The presence of lymph node metastases in the N1b compartment should be considered as a risk factor for distant metastatic spread and for cancer-related death and included in post-surgery evaluation.

Objective: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC)., Study Design: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification)., Results: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%)., Conclusions: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification., (© 2018 Wiley Periodicals, Inc.)

Purpose: Recent evidence indicates that people with normal glucose tolerance (NGT) but 1-h post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk category with deeper metabolic impairment. The aim of this study was to identify, among women with gestational diabetes (GDM), which alterations at OGTT during pregnancy are more frequently associated with 1-h OGTT ≥ 155 mg/dl at post-partum examination., Methods: Among 297 women affected by GDM, we retrospectively evaluated 244 resulted NGT after delivery. Based on post-partum glucose levels at 1-h OGTT, these people were divided into 188 cases (77.0%) with 1-h OGTT < 155 mg/dl (L-NGT) and 56 (23.0%) with 1-h OGTT ≥ 155 mg/dl (H-NGT)., Results: Abnormal glucose levels at 1-h OGTT during pregnancy (≥ 180 mg/dl) were more frequent in H-NGT than in L-NGT (39.3 vs. 24.6%, odds ratio 3.7 [95% CI 1.4-9.6]; p = 0.016). Moreover, H-NGT showed more frequently the simultaneous alteration of all three OGTT plasma glucose values during pregnancy (10.7 vs. 2.1%, odds ratio 4.5 [95% CI 1.5-20.3]; p = 0.038) and less frequently the alteration of fasting plasma glucose alone (14.3 vs. 30.8%, odds ratio 0.4 [95% CI 0.1-0.7]; p = 0.028)., Conclusions: Abnormal 1-h OGTT during pregnancy predicts an increased risk for post-partum 1-h OGTT ≥ 155 mg/dl in women with previous GDM. Even if NGT after delivery, these women may require a closer long-term post-partum follow-up, being at higher risk to develop future glucose intolerance.

Aims: Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial., Data Synthesis: In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long-acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long-acting analog class characteristic or a specific effect of a single agent is not clear., Conclusions: In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Diabetes and cancer are common, chronic, and potentially fatal diseases that frequently co-exist. Observational studies have reported an increased risk of cancer in patients with diabetes. Furthermore, many patients with cancer already have diabetes, or develop hyperglycaemia as a consequence of the tumor or of cancer therapies, and coexisting diabetes confers a greater risk of mortality for many malignancies. Managing oncologic patients with diabetes is often complicated, since the co-existence of diabetes and cancer poses several complex clinical questions: what level of glycaemic control to achieve, which therapy to use, how to deal with glucocorticoid therapies and artificial nutrition, how diabetes complications can affect cancer management, which drug-drug interactions should be taken into account, or even how to manage diabetes at the end of life. In the clinical setting, both at hospital and at home, there are little agreed, evidence-based guidelines on the best management and criteria upon which clinical decisions should be based. A practical solution lies in the implementation of care networks based on communication and ongoing collaboration between Oncologists, Endocrinologists, and the nursing staff, with the patient at the centre of the care process. This manuscript aims to review the current evidence on the effect of cancer therapies on glucose metabolism and to address some of the more common challenges of diabetes treatment in patients with cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In the last two decades thyroid cancer incidence has increased worldwide more than any other cancer. Overdiagnosis of subclinical microcarcinomas has certainly contributed to this increase but many evidences indicate that a true increase, possibly due to environmental factors, has also occurred. Thyroid cancer incidence is markedly increased in volcanic areas. Thus, the volcanic environment is a good model to investigate the possible factors favoring thyroid cancer. In the volcanic area of Mt. Etna in Sicily, as well as in other volcanic areas, a non-anthropogenic pollution with heavy metals has been documented, a consequence of gas, ash and lava emission. Soil, water and atmosphere contamination, via the food chain, biocontaminate the residents as documented by high levels in the urines and the scalp hair compared to individuals living in adjacent non-volcanic areas. Trace amounts of metals are essential nutrients but, at higher concentrations, can be toxic for living cells. Metals can behave both as endocrine disruptors, perturbing the hormonal system, and as carcinogens, promoting malignant transformation. Similarly to other carcinogens, the transforming effect of heavy metals is higher in developing organisms as the fetus (contaminated via the mother) and individuals in early childhood. In the last decades environment metal pollution has greatly increased in industrialized countries. Although still within the "normal" limits for each single metal the hormesis effect (heavy metal activity at very low concentration because of biphasic, non linear cell response) and the possible potentiation effect resulting from the mixture of different metals acting synergistically can explain cell damage at very low concentrations. The effect of metals on the human thyroid is poorly studied: for some heavy metals no data are available. The scarce studies that have been performed mainly focus on metal effect as thyroid endocrine disruptors. The metal concentration in tissues has been rarely measured in the thyroid. Heavy metal accumulation and metabolism in the thyroid or the carcinogenic activity of different doses and different speciation of metals has not been investigated. These studies are now warranted to better understand thyroid biology and heavy metal role in human thyroid carcinogenesis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Papillary thyroid carcinoma (PTC), the most common thyroid cancer histotype, has a good prognosis even when spread to the neck lymph node (LN). The prognostic role of LN metastases' location is still controversial. The aim of the present study was to evaluate the clinical relevance of the number and location of LN metastases at presentation in PTCs., Methods: This retrospective study included a consecutive series of 1653 PTC patients followed for a mean period of 5.9 years in a referral thyroid cancer clinic. All patients have undergone thyroidectomy with the dissection of at least six LNs. According to the LN status, patients were subdivided into 569 N0 (34.4%), 644 N1a (39.0%, central compartment) and 440 N1b (26.6%, latero-cervical compartment)., Results: Age at diagnosis was significantly lower in N1b (39.8, IQR 30.7-51.6) and N1a (40.1, IQR 31.3-50.1) than in N0 (44.7, IQR 36.6-55.0 yrs). The male gender was more prevalent in N1b than in N1a and N0 (F/M = 1.9/1, 4.0/1 and 5.5/1, respectively). Persistent/recurrent disease at last control was significantly more frequent in N1b (29.8%) than in N1a (14.3%), and in N1a than in N0 (4.2%) (p < 0.01 for all). Also, distant metastases were significantly (p < 0.001) more frequent in N1b (14.1%) than in N1a (4.3%) and N0 (1.6%). LN metastases' number (>5) was a significant risk factor for persistent/recurrent disease only for N1a patients., Conclusions: These data indicate that persistent/recurrent disease and distant metastases are significantly more frequent in patients with latero-cervical LN (N1b) metastases and that the LN location should be used for a better postsurgical risk stratification.