Clinical and molecular impact of concurrent thyroid autoimmune disease and thyroid cancer: From the bench to bedside.

The recent incorporation of immune checkpoint inhibitors targeting the PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways into the therapeutic armamentarium of cancer has increased the need to understand the correlation between the immune system, autoimmunity, and malignant neoplasms. Both autoimmune thyroid diseases and thyroid cancer are common clinical conditions. The molecular pathology of autoimmune thyroid diseases is characterized by the important impact of the PD-1/PD-L1 axis, an important inhibitory pathway involved in the regulation of T-cell responses. Insufficient inhibitory pathways may prone the thyroid tissue to a self-destructive immune response that leads to hypothyroidism. On the other hand, the PD-1/PD-L1 axis and other co-inhibitory pathways are the cornerstones of the immune escape mechanisms in thyroid cancer, which is a mechanism through which the immune response fails to recognize and eradicate thyroid tumor cells. This common mechanism raises the idea that thyroid autoimmunity and thyroid cancer may be opposite sides of the same coin, meaning that both conditions share similar molecular signatures. When associated with thyroid autoimmunity, thyroid cancer may have a less aggressive presentation, even though the molecular explanation of this clinical consequence is unclear. More studies are warranted to elucidate the molecular link between thyroid autoimmune disease and thyroid cancer. The prognostic impact that thyroid autoimmune disease, especially chronic lymphocytic thyroiditis, may exert on thyroid cancer raises important insights that can help physicians to better individualize the management of patients with thyroid cancer.

Blended intensive programme's implementation in dental education: post-pandemic evolution of learning.

Blended Intensive Programmes (BIP's) represent a valuable tool for gathering knowledge and summarising the latest trends in medicine and dentistry. Blended education has been found, even before the COVID-19 pandemic, to increase the level of education and stimulate effective learning for postgraduate healthcare professionals. Interprofessional education is critical for preparing students to enter the health workforce, where teamwork and collaboration are important competencies. This article outlines the key points of the Blended Intensive Programme's implementation in dental education organised by Wroclaw Medical University in Poland. BIP involved professors from 12 universities or research institutions from Europe and South America and 28 participants from 8 countries. The course was taught remotely and in person. In addition, it included a visit to the university and practical classes with artificial simulation and practice in dentistry. A structured questionnaire enabled measuring the evaluation of students' perception of the COVID-19 education before and after the pandemic. The European Region Action Scheme for the Mobility of University Students (ERASMUS) was fundamental to carrying out the BIP with the participation of several countries, allowing the exchange of knowledge, assessing the impact of the pandemic on dental universities, and strengthening international collaborations and the future project of research, education and clinical assistance. We conclude that hybrid teaching programmes broaden the learning spectrum in dental studies by allowing transnational and interdisciplinary approaches that make students aware of the importance of their work within the framework of the general health approach, as this differs from country to country.

The immune landscape of the microenvironment of thyroid cancer is closely related to differentiation status.

We have read with great interest the article entitled "Identification of an immune-related signature indicating the dedifferentiation of thyroid cells" by Wang et al. Their data reinforce our own previous results, here compiled. Anaplastic thyroid carcinoma had higher stromal scores, immune scores and enrichment of most immune cells than the control groups, suggesting that the immune microenvironment may correlate with differentiation status in thyroid cancer. We previously demonstrated that the differentiation status expressed by the pattern of protein expression may be related to the profile of immune cell infiltration of differentiated thyroid carcinoma. Wang et al. also explored the differences between the high-risk and low-risk score groups of samples. Among the distinct signaling pathways enriched in the high-risk score group, the epithelial to mesenchymal transition, TNFα signaling, and some common immune-related signaling pathways, including the IL-6/JAK/STAT3 pathway, interferon alpha response, interferon gamma response and inflammatory response were observed with high normalized enrichment score. We also investigated the IL-6 protein immune-histochemical expression in a retrospective study of 114 patients with papillary thyroid carcinoma and 39 patients with follicular thyroid carcinoma. We also obtained samples of 14 normal thyroid tissues from autopsies, 50 goiters and 43 follicular adenoma. We found IL-6 more frequently positive among malignant tumors than non-malignant samples. We demonstrated that IL-6 positivity was associated with infiltration of CD3 + cells, CD16 + cells and CD68 + macrophages. In addition, IL-6 expression was associated with infiltration of activated lymphocytes such as Granzyme B + cells and CD69 + cells. IL-6 positivity was not associated with infiltration of CD4+, CD8+, CD20+, FOXP3+, CD25 + cells but IL-6 was associated with tumor expression of PD-L1, FOXP3, IL-17, COX2, IL-1ß, IL-10, CD134, IL-23. In summary, Wang et al. beautiful data reinforce the seminal idea that the immune landscape is closely related to the differentiation status of the tumor. This concept may help select individuals who deserve more careful attention, an essential point in the management of patients with mostly indolent tumors such as those of the thyroid. In fact, our results, here compiled, were obtained with immune-histochemistry, a routine laboratory technique that offers the possibility of simpler and practical execution.

Clinical utility of the imunohistochemical co-expression of p53 and MDM2 in thyroid follicular lesions.

In order to investigate the possible correlation between p53 and MDM2 co-expression with clinicopathological features of differentiated thyroid cancer (DTC) and its use as diagnostic and/or prognostic markers, we used immunohistochemistry to evaluate 317 thyroid samples including 208 DTC and 94 benign nodules, in addition to 15 normal tissues. MDM2 and p53 expression were highly associated (r = 0.7161; p < 0.0001). The co-expression of p53-MDM2 was observed more frequently in malignant lesions (p < 0.0001) and helped characterize follicular patterned lesions distinguishing FVPTC from FA (p < 0.0001) and FVPTC from FTC (p < 0.0001). In addition, p53-MDM2 co-expression was associated with characteristics of less aggressiveness. It was more frequent in patients ≤45 years old (p = 0.0035), with unique tumors (p = 0.0095), tumors <2 cm (p < 0.0001), tumors without extrathyroid invasion (p = 0.0425), without metastasis at evolution (p = 0.0179), and in patients evolving free of disease after treatment (p = 0.0485). We suggest that p53-MDM2 co-expression profile analysis might help establishing diagnostic and determining prognostic of DTC patients.

Expression of the NEK family in normal and cancer tissue: an immunohistochemical study.

BACKGROUND: The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy. METHODS: The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue. RESULTS: We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer. CONCLUSION: Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis. TRIAL REGISTRATION: This study was retrospectively registered.  www.accamargo.org.br/cientistas-pesquisadores/comite-de-etica-em-pequisa-cep.

Thyroid autoimmune diseases and thyroid tumors: Would EBV infection be the link?

The role of EBV in thyroid cancer development and the patient's outcome is still unclear. Using nested-PCR, Moghoofei et al. reported a high incidence of a virus in thyroid tumor samples, different from our results, obtained by quantitative real-time PCR and confirmed by in situ hybridization. Because lymphocytes are the main reservoir of the virus and tumor-infiltrating lymphocytes are commonly observed in thyroid cancer, it is important to distinguish follicular cells infection from lymphoid tissue infection. The association between autoimmune diseases and thyroid cancer raises the importance of continuing to investigate the role of ubiquitous pathogens in thyroid tumorigenesis.

Interleukin 10 expression is related to aggressiveness and poor prognosis of patients with thyroid cancer.

Most patients with thyroid cancer will evolve very well with current therapies. However, 10-30% of these patients will present recurrent disease and some of them will eventually die. IL-10 is an anti-inflammatory and immunosuppressive cytokine that can contribute to the immune escape of neoplastic cells. We aimed to investigate IL-10 as a molecular marker to improve the clinical management of patients with thyroid cancer. We retrospectively studied 162 patients with follicular cell-derived thyroid cancer who attended to our institution, including 63 classic papillary thyroid carcinomas, 46 follicular variant of papillary thyroid carcinomas, 11 poorly differentiated thyroid carcinomas and 42 follicular thyroid carcinomas. Patients were treated according to current guidelines and followed-up for 1-150 months. Additionally, we studied 96 samples of non-malignant tissues. We investigated the expression of IL-10 in tumor cells by semiquantitative and quantitative methods. Malignant tissues presented higher positivity (0.773 ± 0.140) than non-malignant samples (0.623 ± 0.190; p < 0.001). Tumors with extrathyroidal invasion at diagnosis presented higher levels of positivity for IL-10 (0.802 ± 0.125) than tumors without extrathyroidal invasion (0.731 ± 0.147; p = 0.004). We observed a positive correlation between tumor size and IL-10 positivity (correlation coefficient = 0.407; p < 0.001). Patients with IL-10 positivity above the median presented lower relapse-free survival rate compared to those patients whose tumors presented IL-10 positivity below the median. We suggest that a simple IL-10 IHC analysis could help selecting patients who would benefit from a more intensive approach.

CD8+ tumour-infiltrating lymphocytes and COX2 expression may predict relapse in differentiated thyroid cancer.

BACKGROUND/OBJECTIVE: There is an increasing rate of papillary thyroid carcinomas that may never progress to cause symptoms or death. Predicting outcome and determining tumour aggressiveness could help diminish the number of patients submitted to aggressive treatments. We aimed to evaluate whether markers of the immune system response and of tumour-associated inflammation could predict outcome of differentiated thyroid cancer (DTC) patients. DESIGN: Retrospective cohort study. PATIENTS: We studied 399 consecutive patients, including 325 papillary and 74 follicular thyroid carcinomas. MEASUREMENTS: Immune cell markers were evaluated using immunohistochemistry, including tumour-associated macrophages (CD68) and subsets of tumour-infiltrating lymphocytes (TIL), such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69 and CD25. We also investigated the expression of cyclooxygenase 2 (COX2) in tumour cells and the presence of concurrent lymphocytic infiltration characterizing chronic thyroiditis. RESULTS: Concurrent lymphocytic infiltration characterizing chronic thyroiditis was observed in 29% of the cases. Among all the immunological parameters evaluated, only the enrichment of CD8+ lymphocytes (P = 0·001) and expression of COX2 (P =0·01) were associated with recurrence. A multivariate model analysis identified CD8+ TIL/COX2 as independent risk factor for recurrence. A multivariate analysis using Cox's proportional-hazards model adjusted for the presence of concurrent chronic thyroiditis demonstrated that the presence of concurrent chronic thyroiditis had no effect on prognostic prediction mediated by CD8+ TIL and COX2. CONCLUSION: In conclusion, we suggest the use of a relatively simple pathology tool to help select cases that may benefit of a more aggressive approach sparing the majority of patients from unnecessary procedures.

Both gender and concurrent chronic lymphocytic thyroiditis may influence the nuclear texture of papillary thyroid carcinomas cells.

A disparity in gender incidence has been reported in both papillary thyroid carcinoma (PTC) and chronic lymphocytic thyroiditis (CLT) diseases frequently associated and whose incidence has been increasing in parallel. We aimed to analyze differences in morphometric variables between male and female PTC patients and their relationship with the presence of concurrent CLT. The nuclear texture features of 100 hematoxylin-eosin stained nuclei from 100 consecutive classic PTC patients enrolled in our service were compared with their clinical and pathological features, including the presence of CLT. All patients were submitted to a standard management protocol and followed-up for 13-248 months (Mo = 117 months). Chromatin in women tended to present a denser and more homogeneous structure, in a less mottled pattern, with higher values of energy (p = 0.008) and diagonal moment (p = 0.032) than men. Concurrent CLT was more prevalent in women (41.42%) than in men (13.33%, p = 0.04) and was associated with higher cluster prominence values (p = 0.027), a parameter that indicates a predominance of high nuclear contrasted heterochromatin. A multivariate logistic regression analysis showed that higher cluster prominence was independently correlated with chromatin in patients who presented CLT but did not demonstrate any association between concurrent CLT and gender. We were unable to demonstrate any association between gender and any characteristic of tumor aggressiveness or patients outcome. Our results suggest that chromatin texture of hematoxylin-eosin stained nuclei in paraffin sections of PTC cells is related to both gender and concurrent CLT.

Immunotherapy for patients with thyroid cancer: a comprehensive appraisal.

Thyroid cancer is the most common endocrine malignancy. It presents a significant challenge despite advances in treatment. Immunotherapy, which harnesses the body's immune system to fight cancer, has emerged as a potential solution. The immune system's interaction with cancer cells follows a complex process involving immune surveillance, equilibrium, and escape. On the other hand, cancer cells develop mechanisms, such as loss of antigenicity and immunogenicity, as well as creating an immunosuppressed tumor microenvironment, to evade immune response. Immunotherapy modalities, including immune checkpoint inhibitors like anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1/programmed cell death protein-ligand 1 (PD-1/PD-L1), have shown promising results in various cancers. In the context of thyroid cancer, immunotherapy, particularly PD-1/PD-L1 blockade, has been explored in patients with follicular cell-derived thyroid carcinomas and medullary thyroid carcinomas (MTCs). Clinical trials using PD-1/PD-L1 inhibitors, such as pembrolizumab and nivolumab, have been conducted for these cases, with varying degrees of success. Although preclinical studies have suggested the potential benefit of immunotherapy modalities for patients with follicular cell-derived thyroid carcinoma, to date, clinical studies have failed to demonstrate clear clinical benefits in patients with advanced thyroid cancer. Additionally, other approaches like dendritic cell vaccination and radioimmunotherapy have been explored mainly for MTC, showing potential but requiring further investigation. While immunotherapy holds promise, especially in combination with other treatments, further research, and high-quality clinical trials are necessary to establish its effectiveness in treating advanced thyroid cancers.

Impact of a simple informative leaflet on Brazilian doctors' attitudes towards active surveillance of thyroid microcarcinomas.

Introduction: Active surveillance (AS) is increasingly recognized as an appropriate strategy for selected patients with papillary thyroid microcarcinomas (PTMC). However, some factors, including physician-related ones, hinder its widespread adoption. Methods: To explore the prevailing barriers and the impact of information on attitudes towards AS implementation, we developed a questionnaire that was completed before and after reading a simple information leaflet by 317 doctors working in different work environments. This leaflet provides information about the overdiagnosis of PTMC, the concept of AS, results of early studies, and main advantages and disadvantages of AS. Results: We observed a greater resistance to AS among male physicians who were more likely to maintain the initial recommendation for surgery or referral to a head and neck surgeon than female physicians (77 % vs. 46 %, p = 0.01), regardless of their medical specialty. Fear of disease progression and of the patient losing follow-up were the main concerns. Reading the educational material significantly increased the number of physicians who endorsed AS as an initial approach to PTMC without risk factors from 14 % to 34 % (p < 0,001). This change in attitude was even more significant when doctors were confronted with a case of PTMC in an elderly patient. Gender, medical specialty, age range and academic environment were the factors that were determinants on the influence of the informative leaflet on the decision-making. The leaflet also increased the number of doctors who considered themselves capable of dealing with this patient profile; however, 17 % declared that the place where they worked would not be able to meet the need for periodic assessments and necessary examinations. This was particularly true for the 20 % of the professionals working in rural areas. Conclusion: A simple educational leaflet with basic information presented via social media increased the number of Brazilian physicians who endorsed AS for PTMC management and proved to be a facilitating tool for understanding and accepting it. Our results suggest that this method can be easily extended to larger population.

The diagnostic and prognostic role of miR-146b-5p in differentiated thyroid carcinomas.

Introduction: Samples classified as indeterminate correspond to 10-20% of cytologies obtained by fine needle biopsy of thyroid nodules, preventing an adequate distinction between benign and malignant lesions and leading to diagnostic thyroidectomies that often prove unnecessary, as most cases are benign. Furthermore, although the vast majority of patients with differentiated thyroid cancer (DTC) have such a good prognosis that active surveillance is permitted as an initial therapeutic option, relapses are not rare, and a non-negligible number of patients experience poor outcomes. MicroRNAs (miR) emerge as potential biomarkers capable of helping to define more precise management of patients in all these situations. Methods: Aiming to investigate the clinical utility of miR-146b-5p in the diagnostic of thyroid nodules and evaluating its prognostic potential in a realworld setting, we studied 89 thyroid nodule samples, correlating miR-146b-5p expression with clinical tools such as the 8th edition from the American Joint Committee on Cancer (AJCC/UICC) and the American Thyroid Association Guideline Stratification Systems for the rate of recurrence (RR). Results: miR-146b-5p expression levels distinguished benign from malignant thyroid FNA samples (p< 0.0001). For indeterminate nodules, overexpression of miR-146b-5p with a cut-off of 0.497 was able to diagnose malignancy with a 90% accuracy; specificity=87.5%; sensitivity=100%. An increased expression of miR-146b-5p was associated with greater RR (p=0.015). A cut-off of 2.21 identified cases with more vascular involvement (p=0.013) and a cut-off of 2.420 was associated with a more advanced TNM stage (p-value=0.047). Discussion: We demonstrated that miR-146b5p expression in FNA samples is able to differentiate benign from malignant indeterminate nodules and is associated with an increased risk of recurrence and mortality, suggesting that this single miRNA may be a useful diagnostic and prognostic marker in the personalized management of DTC patients.

Potential new cancer biomarkers revealed by quantum chemistry associated with bioinformatics in the study of selectin polymorphisms.

Understanding the complex mechanisms involved in diseases caused by or related to important genetic variants has led to the development of clinically useful biomarkers. However, the increasing number of described variants makes it difficult to identify variants worthy of investigation, and poses challenges to their validation. We combined publicly available datasets and open source robust bioinformatics tools with molecular quantum chemistry methods to investigate the involvement of selectins, important molecules in the cell adhesion process that play a fundamental role in the cancer metastasis process. We applied this strategy to investigate single nucleotide variants (SNPs) in the intronic and UTR regions and missense SNPs with amino acid changes in the SELL, SELP, SELE, and SELPLG genes. We then focused on thyroid cancer, seeking these SNPs potential to identify biomarkers for susceptibility, diagnosis, prognosis, and therapeutic targets. We demonstrated that SELL gene polymorphisms rs2229569, rs1131498, rs4987360, rs4987301 and rs2205849; SELE gene polymorphisms rs1534904 and rs5368; rs3917777, rs2205894 and rs2205893 of SELP gene; and rs7138370, rs7300972 and rs2228315 variants of SELPLG gene may produce important alterations in the DNA structure and consequent changes in the morphology and function of the corresponding proteins. In conclusion, we developed a strategy that may save valuable time and resources in future investigations, as we were able to provide a solid foundation for the selection of selectin gene variants that may become important biomarkers and deserve further investigation in cancer patients. Large-scale clinical studies in different ethnic populations and laboratory experiments are needed to validate our results.

P53 and expression of immunological markers may identify early stage thyroid tumors.

BACKGROUND: Besides its major role in cell proliferation, DNA repair, and apoptosis, functional p53 protein is involved in the induction of antitumor cytotoxic-T-cell activity against carcinoma cells. We aimed to investigate p53 and immune cell markers utility as diagnostic and prognostic markers of differentiated thyroid cancer (DTC). METHODS: ACIS-III system was used to evaluate p53 and immune cell markers including tumor-associated macrophages (TAM); CD68 and tumor-infiltrating lymphocytes (TIL) subsets such as CD3, CD4, CD8, and CD20 in 206 thyroid carcinomas, 105 benign nodules, and 18 normal tissues. Also, TP53 was sequenced in 78 out of 164 patients with papillary thyroid carcinoma. RESULTS: P53 expression was observed more frequently in malignant than in benign lesions (P < 0.0001) and helped discriminate follicular patterned lesions. In addition, p53 was more frequent in smaller (P = 0.0015), unique tumors (P = 0.0286), with thyroiditis (P = 0.0486) and without metastasis at diagnosis (P = 0.0201). TAM was more frequent in P53 negative tumors (P = 0.002). Infiltration of CD8+ TIL was found in 61.7% of P53 positive and 25.6% of P53 negative DTC (P < 0.001). CONCLUSIONS: We suggest that p53 and CD8+ TIL immune profile analysis might be useful in DTC.

NR3C1 rs6198 Variant May Be Involved in the Relationship of Graves' Disease with Stressful Events.

Although stressful events are known to trigger Graves' disease (GD), the mechanisms involved in this process are not well understood. The NR3C1 gene, encoding for the glucocorticoid receptor (GR), presents single nucleotide polymorphisms (SNPs) that are associated with stress-related diseases. To investigate the relationship between NR3C1 SNPs, GD susceptibility, and clinical features, we studied 792 individuals, including 384 patients, among which 209 presented with Graves' orbitopathy (GO), and 408 paired healthy controls. Stressful life events were evaluated in a subset of 59 patients and 66 controls using the IES-R self-report questionnaire. SNPs rs104893913, rs104893909, and rs104893911 appeared at low frequencies and presented similar profiles in patients and controls. However, variant forms of rs6198 were rarer in GD patients, suggesting a protective effect. Stressful events were more common in patients than controls, and were reported to have clearly occurred immediately before the onset of GD symptoms in 23 cases. However, no association was found between these events and rs6198 genotypes or GD/GO characteristics. We suggest that the NR3C1 rs6198 polymorphism may be an important protective factor against GD, but its relationship with stressful events needs further investigation.

Investigation of the clinical utility of adhesion molecules in the management of thyroid nodules.

To better understand the relationship among cell adhesion molecules (CAM) and investigate the clinical diagnostic and prognostic application of ICAM-1 (ICAM1), LFA-1 (ITGAL), and L-selectin (SELL) proteins and mRNA corresponding expression in thyroid cancer. Gene expression was evaluated by RT-qPCR, and protein expression was evaluated by immunohistochemistry. We evaluated 275 patients (218 women, 57 men, 48.4 ± 14.5 years old), including 102 benign and 173 malignant nodules. The 143 papillary thyroid carcinoma (PTC) and 30 follicular thyroid carcinoma (FTC) patients were managed according to current guidelines and followed-up for 78.7 ± 54.2 months. Malignant and benign nodules differed concerning mRNA (p = 0.0027) and protein (p = 0.0020 for nuclear) expression of L-selectin and ICAM-1 (mRNA: p = 0.0001 and protein: p = 0.0014) and protein expression of LFA-1 (p = 0.0168), but not mRNA expression of LFA-1 (p = 0.2131). SELL expression was more intense in malignant tumors (p = 0.0027). ICAM1 (p = 0.0064) and ITGAL (p = 0.0244) mRNA expression was higher in tumors with lymphocyte infiltrate. ICAM-1 expression correlated with younger age at diagnosis (p = 0.0312) and smaller tumor size (p = 0.0443). Also, LFA-1 expression correlated with higher age at diagnosis (p = 0.0376) and was more intense at stage III and IV (p = 0.0077). In general, the protein expression of the 3 CAM decreased as the process of cellular dedifferentiation occurred. We suggest that the SELL and ICAM1 genes and L-selectin and LFA-1 protein expression may help confirm malignancy and assist in the histological characterization of follicular patterned lesions, but we were unable to correlate these CAMs with patient outcomes.

Obesity and excess protein and carbohydrate consumption are risk factors for thyroid cancer.

Conflicting data concerning the association between obesity and differentiated thyroid cancer (DTC) may be attributed to the lack of records showing dietary intake and inadequate evaluation of nutrient composition. We evaluated 115 DTC patients carefully paired with 103 healthy control individuals by using a structured questionnaire, including a 24-h recordatory during 3 days, to investigate calorie intake and macronutrient (proteins, carbohydrates, and lipids) composition of the diet. We observed that excess weight (body mass index > 25 kg/m(2)) increased individual susceptibility to DTC [odds ratio (OR) = 3.787; 95% confidence interval (CI) = 1.115-6.814; P < 0.0001). This augmented risk was evident in women (OR = 1.925; 95% CI = 1.110-3.338; P = 0.0259) but not in men (P = 0.3498). Excess calorie intake was more frequent in patients with DTC than in controls (OR = 5.890; 95% CI = 3.124-11.103; P < 0.0001), and both excess protein (OR = 4.601; 95% CI = 1.634-12.954; P = 0.0039) and carbohydrate (OR = 4.905; 95% CI = 2.593-9.278; P < 0.0001) consumption were associated with an increased risk of DTC, contrarily to lipid/fiber intake and physical activity (P = 0.894 and 0.5932, respectively). In conclusion, our data indicate that overweight and risk of DTC are associated with higher protein and carbohydrate consumption than the rates recommended by the World Health Organization. The nutritional orientation should be part of preventive strategy targets designed to combat the increasing incidence of both obesity and DTC.

Translating the immune microenvironment of thyroid cancer into clinical practice.

Thyroid cancer is an excellent model for studying tumor immune microenvironment, as it often shows local signs of an immune response. The tumor immune microenvironment of thyroid cancer is the heterogeneous histological space in which tumor cells coexist with host cells. The final composition of this cellular aggregate is associated with the clinical aggressiveness characteristics of the neoplasm. High-performance multiplex technologies suggest that specific genetic signatures of the tumor immune microenvironment may provide data for the delineation of a robust prognostic model. Several proposals integrate clinic, pathologic and immunological information in an attempt to translate the knowledge gained from molecular science into a more personalized approach for the treatment strategy of patients with thyroid cancer. In addition, the tumor immune microenvironment displays multiple molecular connections between cells, revealing complex crosstalk. This interesting network generates several molecular nodes that can be used as targets for immunotherapy. In this scenario, immunotherapy emerges as a promising weapon, mainly for patients with advanced thyroid cancer, both medullary and follicular cell-derived. In fact, although most patients with thyroid cancer have an excellent prognosis with current therapies, around 30% of cases evolve in an unfavorable way, leading to the urgent need to improve immunotherapy for high-risk patients. Preclinical and early clinical investigations are providing optimistic prospects, but more studies are needed to make immunotherapy a more viable and efficient tool for years to come.