Wnt/B-catenin activation and TP53 mutations associate with distinct immune profiles in advanced thyroid cancer.

CONTEXT: Anaplastic thyroid carcinomas (ATCs) and poorly differentiated thyroid carcinomas (PDTCs) exhibit distinct immune-related gene expression profiles. Most ATCs are characterized by active immune interactions (hot or altered immunosuppressed immunophenotypes), while PDTCs are largely immunologically inert (cold immunophenotypes). OBJECTIVE: This study aimed to elucidate the mechanisms driving these divergent immunological fates, focusing on the Wnt/ß-catenin pathway and TP53 mutations. RESULTS: Our data reveal that ATCs frequently harbor TP53 mutations (83.3%), which correlate with a hot immunophenotype, characterized by high expression of ß-catenin-regulated cytokine CCL4 and recruitment of CD103+ dendritic cells. Conversely, PDTCs, with a lower incidence of TP53 mutations (12.5%), often exhibit a cold immunophenotype. In cold cancers and PDTCs, ß-catenin is overexpressed suggesting that Wnt/ß-catenin pathway activation drives immune exclusion through CCL4 downregulation.Further analysis indicated that loss of p53 function is inversely correlated with ß-catenin expression. P53-mutated cancers showed significantly higher expression of CCL4 and densities of CD103+ dendritic cells compared to their p53-wild-type counterparts. Additionally, p53-mutated ATCs expressed a higher number of immune-related genes, supporting the role of p53 loss in activating immune responses in cancer. CONCLUSION: Our study indicates a potential correlation between the activation of the Wnt/ß-catenin pathway and the development of cold thyroid cancers, which may be mediated by the suppression of CCL4 expression. Concurrently, mutations in the p53 gene appear to be linked with the occurrence of hot thyroid cancers. While these associations are compelling, they are based on observational data. Experimental research is necessary to determine the causal relationships underlying these findings.

Data-Driven Thyroglobulin Cutoffs for Low- and Intermediate-Risk Thyroid Cancer Follow-Up: ITCO Real-World Analysis.

CONTEXT: The utility of thyroglobulin (Tg) in the follow-up of differentiated thyroid cancer (DTC) patients has been well-documented. Although third-generation immunoassays have improved accuracy, limitations persist (interfering anti-Tg antibodies and measurement variability). Evolving treatment strategies require a reevaluation of Tg thresholds for optimal patient management. OBJECTIVE: To assess the performance of serum Tg testing in two populations: patients receiving total thyroidectomy and radioiodine remnant ablation (RRA), or treated with thyroidectomy alone. DESIGN: Prospective observational study. Setting. Centers contributing to the Italian Thyroid Cancer Observatory (ITCO) database. PATIENTS: We included 540 patients with 5 years of follow-up and negative anti-Tg antibodies. INTERVENTIONS: Serum Tg levels assessed at 1-year follow-up visit. MAIN OUTCOME MEASURE: Detection of structural disease within 5 years of follow-up. RESULTS: After excluding 26 patients with structural disease detected at any time point, the median Tg did not differ between patients treated with or without radioiodine. Data-driven Tg thresholds were established based on the 97th percentile of Tg levels in disease-free individuals: 1.97 ng/mL for patients undergoing thyroidectomy alone (lower than proposed by the MSKCC protocol and ESMO Guidelines, yet demonstrating good predictive ability, with a negative predictive value (NPV) of 98%) and 0.84 ng/mL for patients receiving post-surgical RRA. High sensitivity and NPV supported the potential of these thresholds in excluding structural disease. CONCLUSIONS: This real-world study provides evidence for the continued reliability of 1-year serum Tg levels. The data-driven Tg thresholds proposed offer valuable insights for clinical decision-making in patients undergoing total thyroidectomy with or without RRA.

GranoScan: an AI-powered mobile app for in-field identification of biotic threats of wheat.

Capitalizing on the widespread adoption of smartphones among farmers and the application of artificial intelligence in computer vision, a variety of mobile applications have recently emerged in the agricultural domain. This paper introduces GranoScan, a freely available mobile app accessible on major online platforms, specifically designed for the real-time detection and identification of over 80 threats affecting wheat in the Mediterranean region. Developed through a co-design methodology involving direct collaboration with Italian farmers, this participatory approach resulted in an app featuring: (i) a graphical interface optimized for diverse in-field lighting conditions, (ii) a user-friendly interface allowing swift selection from a predefined menu, (iii) operability even in low or no connectivity, (iv) a straightforward operational guide, and (v) the ability to specify an area of interest in the photo for targeted threat identification. Underpinning GranoScan is a deep learning architecture named efficient minimal adaptive ensembling that was used to obtain accurate and robust artificial intelligence models. The method is based on an ensembling strategy that uses as core models two instances of the EfficientNet-b0 architecture, selected through the weighted F1-score. In this phase a very good precision is reached with peaks of 100% for pests, as well as in leaf damage and root disease tasks, and in some classes of spike and stem disease tasks. For weeds in the post-germination phase, the precision values range between 80% and 100%, while 100% is reached in all the classes for pre-flowering weeds, except one. Regarding recognition accuracy towards end-users in-field photos, GranoScan achieved good performances, with a mean accuracy of 77% and 95% for leaf diseases and for spike, stem and root diseases, respectively. Pests gained an accuracy of up to 94%, while for weeds the app shows a great ability (100% accuracy) in recognizing whether the target weed is a dicot or monocot and 60% accuracy for distinguishing species in both the post-germination and pre-flowering stage. Our precision and accuracy results conform to or outperform those of other studies deploying artificial intelligence models on mobile devices, confirming that GranoScan is a valuable tool also in challenging outdoor conditions.

Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019).

CONTEXT: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking. OBJECTIVE: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program. METHODS: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism. RESULTS: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 µg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%. CONCLUSION: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy.

A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

A Data-Driven Approach to Refine Predictions of Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study.

CONTEXT: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features. OBJECTIVE: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors. METHODS: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction. RESULTS: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis. CONCLUSION: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

Improving plant disease classification by adaptive minimal ensembling.

A novel method for improving plant disease classification, a challenging and time-consuming process, is proposed. First, using as baseline EfficientNet, a recent and advanced family of architectures having an excellent accuracy/complexity trade-off, we have introduced, devised, and applied refined techniques based on transfer learning, regularization, stratification, weighted metrics, and advanced optimizers in order to achieve improved performance. Then, we go further by introducing adaptive minimal ensembling, which is a unique input to the knowledge base of the proposed solution. This represents a leap forward since it allows improving the accuracy with limited complexity using only two EfficientNet-b0 weak models, performing ensembling on feature vectors by a trainable layer instead of classic aggregation on outputs. To the best of our knowledge, such an approach to ensembling has never been used before in literature. Our method was tested on PlantVillage, a public reference dataset used for benchmarking models' performances for crop disease diagnostic, considering both its original and augmented versions. We noticeably improved the state of the art by achieving 100% accuracy in both the original and augmented datasets. Results were obtained using PyTorch to train, test, and validate the models; reproducibility is granted by providing exhaustive details, including hyperparameters used in the experimentation. A Web interface is also made publicly available to test the proposed methods.

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4).

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p = 0.65), tumor size >2 cm (OR 1.45, p = 0.34), aggressive PTC histology (OR 0.55, p = 0.15), and age at diagnosis (OR 0.90, p = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (p = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Event, currere, and the ignorant schoolmaster.

The Covid-19 pandemic has transformed the higher education systems in ways that make visible problems that already existed but that previously were not fully noticed. The pandemic can be understood as an event that inspired social and subjective reflection aimed at a redefinition of the university curriculum. The closure of universities, which began as a preventive measure, has forced professors to reorganize their work through virtual methods and environments. The teaching methods required during the pandemic have eliminated professors' centrality at the university. However, the change from a face-to-face model to a virtual one is not the core problem; rather, the problem is how professors and students can turn the new forms for their relationship into opportunities for emancipation.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

THERAPY OF ENDOCRINE DISEASE Immunotherapy of advanced thyroid cancer: from bench to bedside.

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition.

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis.

Immune Landscape of Thyroid Cancers: New Insights.

Immune system plays a key role in cancer prevention as well as in its initiation and progression. During multistep development of tumors, cells must acquire the capability to evade immune destruction. Both in vitro and in vivo studies showed that thyroid tumor cells can avoid immune response by promoting an immunosuppressive microenvironment. The recruitment of immunosuppressive cells such as TAMs (tumor-associated macrophages), TAMCs (tumor-associated mast cells), MDSC (myeloid-derived suppressor cells), TANs (tumor-associated neutrophils) and Tregs (regulatory T cells) and/or the expression of negative immune checkpoints, like PD-L1 (programmed death-ligand 1), CTLA-4 (cytotoxic T-lymphocyte associated protein 4), and/or immunosuppressive enzymes, as IDO1 (indoleamine 2,3-dioxygenase 1), are just some of the mechanisms that thyroid cancer cells exploit to escape immune destruction. Some authors systematically characterized immune cell populations and soluble mediators (chemokines, cytokines, and angiogenic factors) that constitute thyroid cancer microenvironment. Their purpose was to verify immune system involvement in cancer growth and progression, highlighting the differences in immune infiltrate among tumor histotypes. More recently, some authors have provided a more comprehensive view of the relationships between tumor and immune system involved in thyroid carcinogenesis. The Cancer Genome Atlas (TCGA) delivered a large amount of data that allowed to combine information on the inflammatory microenvironment with gene expression data, genetic and clinical-pathological characteristics, and differentiation degree of papillary thyroid carcinoma (PTC). Moreover, using a new sensitive and highly multiplex analysis, the NanoString Technology, it was possible to divide thyroid tumors in two main clusters based on expression of immune-related genes. Starting from these results, the authors performed an immune phenotype analysis that allowed to classify thyroid cancers in hot, cold, or intermediate depending on immune infiltration patterns of the tumor microenvironment. The aim of this review is to provide a comprehensive and updated view of the knowledge on immune landscape of thyroid tumors. Understanding interactions between tumor and microenvironment is crucial to effectively direct immunotherapeutic approaches in the treatment of thyroid cancer, particularly for those not responsive to conventional therapies.

Immune Profiling of Thyroid Carcinomas Suggests the Existence of Two Major Phenotypes: An ATC-Like and a PDTC-Like.

OBJECTIVES: The understanding of the mechanisms underlying thyroid cancer immune escape can lead to the identification of new molecular targets and/or efficacy biomarkers. For this purpose, we performed immune expression profiling in thyroid cancers to obtain a comprehensive view on immune mechanisms activated during cancer progression. METHODS: The study was conducted retrospectively in 25 papillary thyroid carcinomas (PTCs), 14 poorly differentiated thyroid carcinomas (PDTC), 13 anaplastic thyroid carcinomas (ATCs), and 7 normal thyroid (NT) tissue samples. Gene expression profiling was obtained on RNA samples using the Nanostring platform and its nCounter PanCancer Immune Profiling Panel. RESULTS: Gene expression comparison of ATC, PTC, and PDTC vs NT showed high number of regulated genes in cancer samples. In detail, immune-related gene sets were significantly upregulated (ATC > PTC > > PDTC). Most ATC and approximately half of PTC showed a microenvironment infiltrated by macrophages and T-cells with CD8+ effector phenotype, part of which appeared to be functionally exhausted. Conversely, most PDTC, as NT samples, as the remaining part of PTC, displayed a poor or absent infiltration by immune cells. Interestingly, an upregulation of inhibitory immune checkpoint mediators, including PDL1, PDL2, PD1, LAG-3, TIM-3, PVR, and TIGIT, could be detected in ATC and PTC. CONCLUSIONS: These data indicated the existence of two major immune phenotypes in thyroid carcinoma: an ATC-like one, including hot and altered-immunosuppressed tumors and a PDTC-like one, including altered-excluded and cold tumors. Confirmation of the findings in locally advanced or metastatic cancer tissues is expected to have important immunotherapeutic implications.

Are Evidence-Based Guidelines Reflected in Clinical Practice? An Analysis of Prospectively Collected Data of the Italian Thyroid Cancer Observatory.

OBJECTIVES: The goal of evidence-based practice guidelines is to optimize the management of emerging diseases, such as differentiated thyroid cancer (DTC). The aim of this study was to assess therapeutic approaches for DTC in Italy and to see how closely these practices conformed to those recommended in the 2009 American Thyroid Association (ATA) guidelines. METHODS: The Italian Thyroid Cancer Observatory was established to collect data prospectively on thyroid cancers consecutively diagnosed in participating centers (uniformly distributed across the nation). Data on the initial treatment of all pathologically confirmed DTC cases present in the database from January 1, 2013 (database creation) to January 31, 2016, were analyzed. RESULTS: A total of 1748 patients (77.2% females; median age 48.1 years [range 10-85 years]) were enrolled in the study. Most (n = 1640; 93.8%) were papillary carcinomas (including 84 poorly differentiated/aggressive variants); 6.2% (n = 108) were follicular and Hürthle cell carcinomas. The median tumor diameter was 11 mm (range 1-93 mm). Tumors were multifocal in 613 (35%) and presented extrathyroidal extension in 492 (28%) cases. Initial treatments included total thyroidectomy (involving one or two procedures; n = 726; 98.8%) and lobectomy (n = 22; 1.2%). A quarter of the patients who underwent total thyroidectomy had unifocal, intrathyroidal tumors ≤1 cm (n = 408; 23.6%). Neck dissection was performed in 40.4% of the patients (29.5% had central compartment dissection). Radioiodine remnant ablation (RRA) was performed in 1057 (61.2%) of the 1726 patients who underwent total thyroidectomy: 460 (41.2%) of the 983 classified by 2009 ATA guideline criteria as low-risk, 570 (87.1%) of the 655 as intermediate-risk, and 82 (93.1%) of the 88 as high-risk patients (p < 0.001). RRA was performed in 44% of the cases involving multifocal DTCs measuring ≤1 cm. CONCLUSIONS: The treatment approaches for DTCs used in Italy display areas of inconsistency with those recommended by the 2009 ATA guidelines. Italian practices were characterized by underuse of thyroid lobectomy in intrathyroidal, unifocal DTCs ≤1 cm. The use of RRA was generally consistent with risk-stratified recommendations. However, its frequent use in small DTCs (≤1 cm) that are multifocal persists, despite the lack of evidence of benefit. These data provide a baseline for future assessments of the impact of international guidelines on DTC management in Italy. These findings also illustrate that the dissemination and implementation of guideline recommendations, and the change in practice patterns, require ongoing education and time.

Qualidade microbiológica de queijos minas frescal e ricota comercializados na região metropolitana de Campinas-SP / Microbiological quality of fresh cheese commercialized in the metropolitan region of Campinas-SP

Os queijos minas frescal e ricota são alimentos derivados do leite, muito nutritivos e muito consumidos pela população em geral. Por ser um veículo frequente de patógenos, a contaminação microbiológica dos queijos gera um grande risco de surtos de doenças de origem alimentar aos consumidores. O objetivo do trabalho foi verificar a qualidade microbiológica de queijos minas frescal e ricota comercializados na região metropolitana de Campinas/SP. Foram analisadas 20 amostras (5 queijo minas frescal caseiro, 5 queijo minas frescal industrializados, 5 queijo frescal ultrafiltrados e 5 ricotas) para quantificação de coliformes a 35ºC e 45ºC, E. coli, aeróbios mesófilos totais, bolores e leveduras, estafilococos, Salmonella sp e Listeria monocytogenes. As amostras apresentaram contagens de coliformes 35ºC (13 amostras ­ até >1,1x10³NMP/ mL), coliformes a 45ºC (5 amostras ­ até >1,1x10³NMP/mL), E. coli (12 amostras ­ até >1,1x10³ UFC/g), aeróbios mesófilos totais (13 amostras acima de 106 UFC/g), bolores e leveduras (7 amostras acima de 106 UFC/g) e Staphylococcus aureus (10 amostras acima de 5x10² UFC/g). Em nenhuma das amostras foi detectada Salmonella sp. e L. monocytogenes. 11 amostras estiveram em desacordo com a legislação RDC nº 12/2001 por causa da alta contagem de S. aureus e coliformes a 45ºC. O processo de ultrafiltração do queijo reduziu a contagem microbiológica para todas as amostras exceto uma, mostrando que mesmo após o processo é preciso ter boas práticas para evitar a recontaminação. A alta contagem de micro-organismos indica falhas na higiene durante as etapas de fabricação, manipulação e transporte do produto. Assim boas práticas de fabricação devem ser aplicadas aos queijos minas frescal caseiros e industriais, para se adequar a legislação e não oferecer riscos à saúde pública.

Signal Transducer and Activator of Transcription 1 Plays a Pivotal Role in RET/PTC3 Oncogene-induced Expression of Indoleamine 2,3-Dioxygenase 1.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors.

Qualidade microbiológica de saladas in natura servidas em restaurantes e fast foods na cidade de Campinas e região / Microbiological quality of salads in natura served in restaurants and fast foods in the city of Campinas and region

O consumo de saladas tem aumentado significantemente em todo o mundo, por causa do aumento da população, pela mudança nos hábitos alimentares e a preocupação do consumidor em relação à saúde. As hortaliças consumidas como salada são ricas em sais minerais e vitaminas, por isso podem estar contaminadas com micro-organismos patógenos e estão frequentemente relacionadas a doenças de origem alimentar em todo mundo. A legislação brasileira em vigor estabelece limites microbiológicos, para hortaliças in natura, de coliformes a 45ºC e Salmonella. O objetivo deste trabalho foi analisar a qualidade microbiológica de diferentes saladas servidas em restaurantes e fast foods da cidade de Campinas-SP e região. Foram avaliadas 24 amostras de saladas: 3 de alface, 3 de tomate, 3 de agrião, 3 de cenoura, 3 de beterraba (1 crua e 2 cozidas), 3 de pepino e 6 de salada mista de diferentes restaurantes e fast foods no período de maio a junho de 2013. As amostras foram submetidas às análises microbiológicas de Salmonella, coliformes a 35 e 45ºC, E. coli, aeróbios mesófilos totais e fungos filamentosos e leveduras. Nenhuma amostra estava contaminada com Salmonella, porém foi verificada a presença de outros micro-organismos: Citrobacter sp, Klebsiella pneumoniae, Enterobacter sp e Pseudomonas sp. Coliformes a 45ºC estavam presentes em 13 amostras (54,16%) e apresentaram valores acima do permitido pela legislação (10² UFC/g), consideradas impróprias para o consumo. Em relação aos coliformes a 35ºC, 18 amostras (75%) apresentaram contagens acima de 1,1x103UFC/g, e mesmo não sendo uma análise contemplada pela legislação, sua presença indica condições de higiene insatisfatórias. A presença de E. coli foi observada em 14 amostras (58,33%), e destas, 2 (14,28%) com contagens acima de 1,2x102NMP/g, representando risco à saúde dos consumidores. Contagem total de aeróbios mesófilos e fungos filamentosos e leveduras foram observadas em todas as amostras variando entre 103 a 106UFC/g o que mostra que o processo de higienização desses vegetais foi deficiente e até mesmo houve excesso de manipulação durante o preparo. Para diminuir a quantidade de micro-organismos presentes nas saladas, boas práticas de manipulação devem ser adotadas nos restaurantes e fast foods e assim evitar possíveis surtos alimentares.

Consumption of salads has increased significantly worldwide, because of increasing population, the change in eating habits and consumer concern about health. The vegetables consumed as salad are rich in minerals and vitamins, so it may be contaminated with pathogens microorganisms and are often related to foodborne diseases worldwide. The Brazilian legislation, RDC 12/2001 establishes microbiological limits for fresh vegetables for coliforms at 45°C and Salmonella. The aim of this study was to analyze the microbiological quality of different salads served in restaurants and fast foods in Campinas-SP city and region. 24 salad samples were evaluated: 3 lettuce, 3 tomatoes, 3 watercress, 3 carrots, 3 beet (1 raw and 2 cooked), 3 cucumber and 6 mixed salad of different restaurants and fast foods in the period of May to June 2013. The samples were submitted to microbiological analysis of Salmonella, coliforms at 35 and 45°C, E. coli, aerobic mesophilic and filamentous fungi and yeast. No sample was contaminated with Salmonella, but it was verified the presence of other microorganisms: Citrobacter sp, Klebsiella pneumoniae, Enterobacter sp and Pseudomonas sp. Coliforms at 45°C were present in 13 samples (54.16%) and showed higher values than those permitted by law (10² CFU/g), deemed unfit for consumption. Regarding coliforms at 35°C, 18 samples (75%) presented counts above 1,1x103 UFC/0g, and although this analysis is not contemplated by the legislation, their presence indicates unsatisfactory hygiene conditions. The presence of E. coli was found in 14 samples (58.33%), and of these, two (14.28%) with counts above 1,2x102 NMP/g, representing a risk to consumer health. Total count of mesophilic aerobic and filamentous fungi and yeasts were observed in all samples ranging from 103 to 106 UFC/g shows that the process of cleaning was poor and there was even excessive handling during preparation. To decrease the amount of microorganisms present in salads, good handling practices should be adopted in restaurants and fast foods and thus avoid possible food outbreaks.

Acute liver damage following intravenous glucocorticoid treatment for Graves' ophthalmopathy.

PURPOSE: Over the last years, there have been several reports on the occurrence of acute liver damage (ALD) in patients affected with Graves' ophthalmopathy (GO) receiving intravenous glucocorticoids (ivGCs). This article is aimed at reviewing the literature on this specific topic and reporting two new cases of ALD occurring in GO patients while on ivGCs. METHODS: The terms "glucocorticoid therapy" and "Graves' Ophthalmopathy"/"Graves' Orbitopathy"/"Thyroid eye disease" were used both separately and in conjunction with the terms "liver disease," "liver damage," "hepatotoxicity," "liver failure," to search MEDLINE for articles published since the first report of ALD in 2000 and up to 2015. RESULTS: ALD [defined as an increase in alanine aminotransferase (ALT) >300 U/L] during or after completion of ivGCs has been so far reported in 17 fully documented cases. Overall, one-half of those patients were diagnosed as having autoimmune hepatitis (AIH) and in the vast majority of the remaining cases a diagnosis of methylprednisolone(MP)-induced hepatotoxicity was suspected. The clinical course of liver injury varied from asymptomatic hypertransaminasemia in the vast majority of patients to fatal hepatic failure in four patients receiving higher (>8 g) cumulative doses of MP. CONCLUSIONS: The overall risk of ALD is relatively low (~1 %), and seems higher using a single dose >0.5 g and a cumulative dose >8.5 g MP. Whenever ivGC treatment is required, serum liver enzymes, viral hepatitis markers, and autoantibodies related to AIH should be obtained prior to ivGC administration. Liver function should be monitored during ivGC and up to 6 months after the end of treatment. Prolonging observation after 6 months is likely unnecessary, since all cases of ALD so far reported always occurred well within this term.