Do PFCAs drive the establishment of thyroid cancer microenvironment? Effects of C6O4, PFOA and PFHxA exposure in two models of human thyroid cells in primary culture.

BACKGROUND: Exposure to environmental pollutants is suspected to be one of the potential causes accounting for the increase in thyroid cancer (TC) incidence worldwide. Among the ubiquitous pollutants, per-polyfluoroalkyl substances (PFASs), were demonstrated to exert thyroid disrupting effects. Perfluoroalkyl carboxylates (PFCAs) represent a subgroup of PFAS and include perfluoro carboxylic acids (PFOA and PFHxA) and perfluoropolyether carboxylic acid (C6O4). The potential relationship between exposure to PFCAs and TC was not yet fully elucidated. This in vitro study investigated whether certain PFCAs (C6O4, PFOA, and PFHxA) can influence the composition of TC microenvironment. METHODS: Two models of normal thyroid cells in primary cultures: Adherent (A-NHT) and Spheroids (S-NHT) were employed. A-NHT and S-NHT were exposed to C6O4, PFOA or PFHxA (0; 0.01; 0.1, 1; 10; 100; 1000 ng/mL) to assess viability (WST-1 and AV/PI assay), evaluate spherification index (SI) and volume specifically in S-NHT. CXCL8 and CCL2 (mRNA and protein), and EMT-related genes were assessed in both models after exposure to PFCAs. RESULTS: PFHxA reduced the viability of both A-NHT and S-NHT. None of the PFCAs interfered with the volume or spherification process in S-NHT. CXCL8 and CCL2 mRNA and protein levels were differently up-regulated by each PFCAs, being PFOA and PFHxA the stronger inducers. Moreover, among the tested PFCAs, PFHxA induced a more consistent increase in the mRNA levels of EMT-related genes. CONCLUSIONS: This is the first evaluation of the effects of exposure to PFCAs on factors potentially involved in establishing the TC microenvironment. PFHxA modulated the TC microenvironment at three levels: cell viability, pro-tumorigenic chemokines, and EMT-genes. The results provide further evidence of the pro-tumorigenic effect of PFOA. On the other hand, a marginal effect was observed for C6O4 on pro-tumorigenic chemokines.

Per-polyfluoroalkyl substances (PFAS) as thyroid disruptors: is there evidence for multi-transgenerational effects?

INTRODUCTION: The environmental spread of pollutants has led to a persistent exposure of living beings to multiple chemicals, by now become ubiquitous in the surrounding environment. Environmental exposure to these substances has been reported to cause multi- and/or transgenerational health effects. Per- and Polyfluorinated Substances (PFAS) raise great concern, given their known effects both as endocrine disruptors and potential carcinogens. The multi/trans-generational effects of different endocrine disruptors have been investigated by several studies, and harmful effects observed also for PFAS. AREAS COVERED: This review examines the current data on the multi-trans-generational effects of PFAS, with a focus on their impact on the thyroid axis. The aim is to determine if there is evidence of potential multi-trans-generational effects of PFAS on the thyroid and/or if more research is needed. EXPERT OPINION: PFAS exposure impacts thyroid homeostasis and can cross the placental barrier. In addition PFAS have shown multi-transgenerational effects in laboratory experiences and animal models, but thyroid disruptive effects of PFAS were also investigated only in a small number of these studies. Efforts are needed to study the adverse effects of PFAS, as not all PFAS are regulated and removal strategies are still being developed.

The interplay between subclinical hypothyroidism and poor sleep quality: A systematic review.

BACKGROUND: The relationship between subclinical hypothyroidism (SHYPO) and sleep disturbances is still poorly investigated. This systematic review aims to critically appraise the existing literature to provide more insights in understanding whether SHYPO favors sleep disturbances or it is the sleep disturbance per se that affects the hypothalamus-pituitary-thyroid axis regulation. METHODS: Original studies on sleep quality and duration in patients with SHYPO were searched in the PubMed/MEDLINE, Embase, Web of Science and Scopus databases. Two reviewers independently screened articles for inclusion, extracted data, and assessed the quality of included studies. RESULTS: Eight studies, including 2916 patients with SHYPO and 18,574 healthy controls, were retrieved. An overall agreement (7 out of 8 studies), about a positive correlation between decreased sleep quality and/or duration and SHYPO was observed. Five studies investigated sleep quality through self-reported surveys; only two studies explored both subjective and objective assessment of sleep quality with actigraphy (n = 1) or polysomnography (n = 1); finally, one study assessed subjective evaluation of sleep quality through a single question regarding the number of sleeping hours. A high level of heterogeneity among studies was manifest due to differences in population source, sleep measure assessment and criteria for diagnosing SHYPO. DISCUSSION: Overall, the existing literature data suggest a link between SHYPO and sleep disturbances, but further studies on larger populations of patients with homogeneous study designs and outcomes are warranted.

The American Thyroid Association risk classification of papillary thyroid cancer according to presurgery cytology.

OBJECTIVE: To compare the American Thyroid Association (ATA) risk staging of histologically proven papillary thyroid cancer (PTC) in patients who received a presurgery cytologic result of either indeterminate thyroid nodules (ITNs, Bethesda III/IV) or suspicious for malignancy/malignant (TIR 4/5, Bethesda V/VI). METHODS: Clinical, ultrasonographic, cytological data from patients with histologically diagnosed PTC were retrospectively collected. RESULTS: Patients were stratified according to the preoperative fine-needle aspiration cytology into 2 groups: 51 ITNs (TIR3A/3B) and 118 suspicious/malignant (TIR 4/5). Male/female ratio, age, and presurgery TSH level were similar between the 2 groups. At ultrasound, TIR 4/5 nodules were significantly more frequently hypoechoic (P = .037), with irregular margins (P = .041), and with microcalcifications (P = .020) and were more frequently classified as high-risk according to the European Thyroid Imaging and Reporting Data System (EU-TIRADS; P = .021). At histology, the follicular PTC subtype was significantly more prevalent among ITNs while classical PTC subtype was more frequent in TIR 4/5 group (P = .002). In TIR 4/5 group, a higher rate of focal vascular invasion (P < .001) and neck lymph node metastasis (P = .028) was observed. Intermediate-risk category according to ATA was significantly more frequent in TIR 4/5 group while low-risk category was more frequently found among ITNs (P = .021), with a higher number of patients receiving radioiodine in TIR 4/5 group (P = .002). At multivariate logistic regression, having a TIR 4/5 cytology was associated with a significant risk of having a higher ATA risk classification as compared to ITN (OR 4.6 [95% CI 1.523-14.007], P = .007), independently from presurgery findings (nodule size at ultrasound, sex, age, and EU-TIRADS score). CONCLUSIONS: Papillary thyroid cancers recorded among ITNs are likely less aggressive and are generally assessed as at lower risk according to ATA classification.

Relationship between maternal obesity and first-trimester TSH in women with negative anti-TPO antibodies.

Objective: Obesity is associated with increased thyroid-stimulating hormone (TSH) in non-pregnant subjects, but this phenomenon has not been fully characterized during pregnancy. Our aim was to evaluate the impact of BMI on first-trimester TSH in a wide cohort of pregnant women with negative anti-thyroperoxidase antibodies (AbTPO) and its implications on uterine artery pulsatility index (UtA-PI), a marker of early placentation. Methods: The study included 2268 AbTPO-negative pregnant women at their first antenatal visit. Anamnestic data, BMI, TSH, anti-nuclear antibody (ANA) and extractable nuclear antigen (ENA) positivity and mean UtA-PI were collected. Results: A total of 1693 women had normal weight, 435 were overweight and 140 were obese. Maternal age, ANA/ENA positivity, history of autoimmune diseases and familiar history of thyroid diseases were similar in the three groups. TSH was significantly higher in obese women (1.8 (IQR: 1.4-2.4) mU/L) when compared to normal weight (1.6 (IQR: 1.2-2.2) mU/L) and overweight (median: 1.6 (IQR: 1.2-2.2) mU/L) ones (P < 0.001). BMI was significantly related with the risk of having a TSH level ≥4 mU/L at logistic regression, independently from non-thyroid autoimmunity, smoking or familiar predisposition for thyroid diseases (OR: 1.125, 95% CI: 1.080-1.172, P < 0.001). A restricted cubic splines regression showed a non-linear relationship between BMI and TSH. Women with a TSH ≥4 mU/L had a higher UtA-PI, independently from BMI. Conclusion: Overweight/obesity is significantly related with TSH serum levels in AbTPO-negative pregnant women, independently from the other risk factors for hypothyroidism during pregnancy. The increase of TSH levels could be clinically relevant, as suggested by its association with abnormal UtA-PI, a surrogate marker of abnormal placentation.

Canagliflozin reduces thyroid cancer cells migration in vitro by inhibiting CXCL8 and CCL2: An additional anti-tumor effect of the drug.

PURPOSE: Canagliflozin exert anti-cancer effects in several types of cancer including thyroid cancer (TC). However, whether it could modulate chemokines secreted in TC microenvironment is still unknown. The aim of the present study is to evaluate whether Canagliflozin could inhibit pro-tumorigenic chemokines CXCL8 and CCL2 and/or the TC cell migration induced by them. EXPERIMENTAL DESIGN: TC cell lines, TPC-1 and 8505C, HUVEC and normal thyroid cells NHT were treated with increasing concentrations of Canagliflozin. Viability was assessed by WST-1 and colony formation/proliferation by cristal violet. Chemokines were measured in cell supernatants by ELISA. mRNAs were evaluated by RT-PCR. TC migration (trans-well) and HUVEC proliferation (cristal violet) were assessed by treating cells with Canagliflozin alone or in combination with CXCL8 or CCL2. RESULTS: Canagliflozin reduced TC, HUVEC and NHT cells viability. The ability to form colonies of TC and the HUVEC proliferation (basal and CXCL8 or CCL2-induced) was also inhibited. mRNA and the secretion of CXCL8 was reduced in all cell types. The secretion of CCL2 was reduced by Canagliflozin in all cell types whereas its mRNA levels were reduced only in TPC-1. IL-6 was reduced in all cell types, while CXCL10 increased. More interestingly the CXCL8 and CCL2-induced TC cell migration as well as HUVEC proliferation was inhibited by Canagliflozin in both cell types. CONCLUSION: Canagliflozin exerts anti-cancer effects not only by reducing TC viability or colonies formation, but also by modulating two pro-tumorigenic chemokines resulting in reduced TC cells migration. These results expand the spectrum of canagliflozin-promoted anti-cancer effects.

Drug repositioning in thyroid cancer treatment: the intriguing case of anti-diabetic drugs.

Cancer represents the main cause of death worldwide. Thyroid cancer (TC) shows an overall good rate of survival, however there is a percentage of patients that do not respond or are refractory to common therapies. Thus new therapeutics strategies are required. In the past decade, drug repositioning become very important in the field of cancer therapy. This approach shows several advantages including the saving of: i) time, ii) costs, iii) de novo studies regarding the safety (just characterized) of a drug. Regarding TC, few studies considered the potential repositioning of drugs. On the other hand, certain anti-diabetic drugs, were the focus of interesting studies on TC therapy, in view of the fact that they exhibited potential anti-tumor effects. Among these anti-diabetic compounds, not all were judjed as appropriate for repositioning, in view of well documented side effects. However, just to give few examples biguanides, DPP-4-inhibitors and Thiazolidinediones were found to exert strong anti-cancer effects in TC. Indeed, their effects spaced from induction of citotoxicity and inhibition of metastatic spread, to induction of de-differentiation of TC cells and modulation of TC microenvironment. Thus, the multifacial anti-cancer effect of these compounds would make the basis also for combinatory strategies. The present review is aimed at discuss data from studies regarding the anti-cancer effects of several anti-diabetic drugs recently showed in TC in view of their potential repositioning. Specific examples of anti-diabetic repositionable drugs for TC treatment will also be provided.

A comparative cross-sectional study on sleep quality in patients with a history of differentiated thyroid carcinoma and its correlation with quality of life.

PURPOSE: To evaluate sleep quality in differentiated thyroid carcinoma (DTC) patients and correlate sleep disturbances with quality of life (QoL). METHODS: 119 DTC patients were enrolled (DTC group). The Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) inventories were administered. The Thyroid-specific Patient-Reported Outcome (ThyPRO) questionnaire, the Billewicz scale (BS) and an ad-hoc visual analogic scale (VAS) were used to measure QoL and subjective therapy-related complaints. The same examinations were conducted in 53 subjects (control group) who had undergone surgery for benign thyroid pathology. RESULTS: L-T4 dosages and TSH levels differed between the groups. BS and VAS scores were comparable. PSQI documented a similar percentage of poor sleepers in the DTC (74%) and control (62%) groups. ISI showed no difference in subjects without clinically significant insomnia: DTC (43%) and controls (48%). ThyPRO showed significantly worse scores in DTC than control subjects. In DTC patients, PSQI (P = 0.002) and ISI (P = 0.04) correlated significantly with age. In control subjects, TSH displayed a significant positive association with PSQI (P = 0.02) and ISI (P < 0.05). The ThyPRO general score correlated significantly with PSQI in DTC patients. In both groups, ISI correlated significantly with several ThyPRO scales and the ThyPRO general score. "Anxiety" and "emotional susceptibility" were the scales most significantly related with PSQI and ISI. CONCLUSION: In disease-free DTC patients and subjects who undergo thyroid surgery for benign pathology, abnormal sleep components and insomnia are similar. The ThyPRO questionnaire closely reflects sleep disturbances in all subjects. Recognising and treating sleep disturbances might improve QoL.

A Comparison of Two Hybrid Closed-Loop Systems in Italian Children and Adults With Type 1 Diabetes.

Tandem Control-IQ and Minimed 780G represent the most Advanced Hybrid Closed Loop (AHCL) systems currently available in pediatric and adult subjects with Type 1 Diabetes (T1D). We retrospectively compared clinical and continuous glucose monitoring data from 51 patients who upgraded to Minimed 780G system and have completed 1-month observation period with data from 39 patients who upgraded to Tandem Control-IQ. Inverse probability weighting was used to minimize the basal characteristics imbalances. Both AHCL systems showed a significant improvement in glycemic parameters. Minimed 780G group achieved higher TIR increase (p= 0.004) and greater reduction of blood glucose average (p= 0.001). Tandem Control-IQ system significantly reduced the occurrence of TBR (p= 0.010) and the Coefficient of Variation of glucose levels (p= 0.005). The use of ACHL systems led to a significant improvement of glycemic control substantially reaching the International recommended glycemic targets. Minimed 780G appears to be more effective in managing hyperglycemia, while Tandem Control-IQ seems to be more effective in reducing time in hypoglycemia.

Cross-sectional and prospective study on anti-Müllerian hormone changes in a cohort of pre-menopausal women with a history of differentiated thyroid cancer.

BACKGROUND: Anti-Müllerian hormone (AMH) decreases acutely after post-surgical radioactive iodine (RAI) ablation in females with differentiated thyroid cancer (DTC). AIM: We performed a cross-sectional and prospective study on AMH levels in pre-menopausal females with a history of DTC. METHODS: Fifty-nine females after surgery and RAI (group 1) and 30 females after surgery alone (group 2) were studied. The control group consisted of 141 healthy women (group 3). The prospective study was performed in 43 and 14 females from groups 1 and 2, respectively. RESULTS: On first evaluation, AMH levels were similar in groups 1 and 2, but lower than in group 3. In all groups, AMH was negatively related with chronological age and FSH levels. When subjects were stratified according to age, AMH levels were not different between groups. When AMH was evaluated up to 2 years after the baseline evaluation, no changes emerged in either group of women with DTC. In the prospective study, the incidence of abnormal menstrual cycles and the onset of menopause were observed in similar percentages of women with a history of RAI-treated DTC and of those treated with surgery alone. CONCLUSIONS: AMH can be considered a reliable index of ovarian reserve in women with DTC. Chronological age is the main factor influencing AMH levels in both DTC patients and controls. After age-related stratification, AMH levels are similar in women with DTC treated with RAI and those treated with surgery alone.

Case report: lenvatinib in neoadjuvant setting in a patient affected by invasive poorly differentiated thyroid carcinoma.

We report a case of an elderly woman presenting with a huge cervical mass invading the tracheal lumen. Diagnosed as invasive poorly differentiated thyroid cancer, after an endotracheal biopsy, stenting and radiotherapy, it was judged eligible for total thyroidectomy, but surgery was delayed due to pulmonary thromboembolism. The patient was therefore treated with lenvatinib with a neoadjuvant intent until hemodynamic stability was obtained. Thyroidectomy and radioiodine therapy were then performed and the postdose scan revealed an area of modest uptake in the anterior part of the neck. The patient is now in a good clinical status and she continues her follow-up program without any adjuvant therapy.

Risk factors for the development of micro-vascular complications of type 2 diabetes in a single-centre cohort of patients.

AIMS: In type 2 diabetes, we aimed at clarifying the role of glycated haemoglobin variability and other risk factors in the development of the main micro-vascular complications: peripheral neuropathy, nephropathy and retinopathy. METHODS: In a single-centre cohort of 900 patients, glycated haemoglobin variability was evaluated as intra-individual standard deviation, adjusted standard deviation and coefficient of variation of serially measured glycated haemoglobin in the 2-year period before a randomly selected index visit. We devised four models considering different aspects of glycated haemoglobin evolution. Multivariate stepwise logistic regression analysis was performed including the following covariates at the index visit: age, disease duration, body mass index, total cholesterol, high-density lipoprotein cholesterol, triglycerides, sex, smoking habit, hypertension, dyslipidemia, treatment with anti-diabetic drugs, occurrence of macro-vascular events and the presence of another micro-vascular complication. RESULTS: Males with high mean glycated haemoglobin, long duration of diabetes, presence of macro-vascular events and retinopathy emerged at higher risk for peripheral neuropathy. Development of nephropathy was independently associated with higher glycated haemoglobin variability, older age, male sex, current smoking status, presence of retinopathy, of peripheral neuropathy and of hypertension. Higher mean glycated haemoglobin, younger age, longer duration of diabetes, reduced estimated glomerular filtration rate and the presence of peripheral neuropathy were significantly associated with increased incidence of retinopathy. CONCLUSION: Glycated haemoglobin variability was associated with increased incidence of nephropathy, while mean glycated haemoglobin emerged as independent risk factor for the development of retinopathy and peripheral neuropathy. The presence of macro-vascular events was positively correlated with peripheral neuropathy. Finally, the occurrence of another micro-vascular complication was found to be a stronger risk factor for developing another micro-vascular complication than the mean or variability of glycated haemoglobin.

A dashboard-based system for supporting diabetes care.

Objective: To describe the development, as part of the European Union MOSAIC (Models and Simulation Techniques for Discovering Diabetes Influence Factors) project, of a dashboard-based system for the management of type 2 diabetes and assess its impact on clinical practice. Methods: The MOSAIC dashboard system is based on predictive modeling, longitudinal data analytics, and the reuse and integration of data from hospitals and public health repositories. Data are merged into an i2b2 data warehouse, which feeds a set of advanced temporal analytic models, including temporal abstractions, care-flow mining, drug exposure pattern detection, and risk-prediction models for type 2 diabetes complications. The dashboard has 2 components, designed for (1) clinical decision support during follow-up consultations and (2) outcome assessment on populations of interest. To assess the impact of the clinical decision support component, a pre-post study was conducted considering visit duration, number of screening examinations, and lifestyle interventions. A pilot sample of 700 Italian patients was investigated. Judgments on the outcome assessment component were obtained via focus groups with clinicians and health care managers. Results: The use of the decision support component in clinical activities produced a reduction in visit duration (P ≪ .01) and an increase in the number of screening exams for complications (P < .01). We also observed a relevant, although nonstatistically significant, increase in the proportion of patients receiving lifestyle interventions (from 69% to 77%). Regarding the outcome assessment component, focus groups highlighted the system's capability of identifying and understanding the characteristics of patient subgroups treated at the center. Conclusion: Our study demonstrates that decision support tools based on the integration of multiple-source data and visual and predictive analytics do improve the management of a chronic disease such as type 2 diabetes by enacting a successful implementation of the learning health care system cycle.

Machine Learning Methods to Predict Diabetes Complications.

One of the areas where Artificial Intelligence is having more impact is machine learning, which develops algorithms able to learn patterns and decision rules from data. Machine learning algorithms have been embedded into data mining pipelines, which can combine them with classical statistical strategies, to extract knowledge from data. Within the EU-funded MOSAIC project, a data mining pipeline has been used to derive a set of predictive models of type 2 diabetes mellitus (T2DM) complications based on electronic health record data of nearly one thousand patients. Such pipeline comprises clinical center profiling, predictive model targeting, predictive model construction and model validation. After having dealt with missing data by means of random forest (RF) and having applied suitable strategies to handle class imbalance, we have used Logistic Regression with stepwise feature selection to predict the onset of retinopathy, neuropathy, or nephropathy, at different time scenarios, at 3, 5, and 7 years from the first visit at the Hospital Center for Diabetes (not from the diagnosis). Considered variables are gender, age, time from diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), hypertension, and smoking habit. Final models, tailored in accordance with the complications, provided an accuracy up to 0.838. Different variables were selected for each complication and time scenario, leading to specialized models easy to translate to the clinical practice.

Hierarchical Bayesian Logistic Regression to forecast metabolic control in type 2 DM patients.

In this work we present our efforts in building a model able to forecast patients' changes in clinical conditions when repeated measurements are available. In this case the available risk calculators are typically not applicable. We propose a Hierarchical Bayesian Logistic Regression model, which allows taking into account individual and population variability in model parameters estimate. The model is used to predict metabolic control and its variation in type 2 diabetes mellitus. In particular we have analyzed a population of more than 1000 Italian type 2 diabetic patients, collected within the European project Mosaic. The results obtained in terms of Matthews Correlation Coefficient are significantly better than the ones gathered with standard logistic regression model, based on data pooling.