Sara Watutantrige‐Fernando

Istituto Oncologico Veneto

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Caterina Mian

University of Padua

Susi Barollo

University of Padua

Loris Bertazza

University of Padua

Gianmaria Pennelli

University of Padua

Simona Censi

University of Padua

Federica Vianello

Istituto Oncologico Veneto

Francesca Galuppini

University of Padua

Elisabetta Cavedon

Istituto Oncologico Veneto

Jacopo Manso

University of Padua

Davide Nacamulli

University of Padua

Cooperative Institutions

University of Padua

Istituti di Ricovero e Cura a Carattere Scientifico

Azienda Ospedaliera di Padova

Istituto Oncologico Veneto

Sapienza University of Rome

University of Milan

Policlinico Umberto I

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Endocrinology Research Center

University of Verona

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Differentiated Thyroid Carcinoma in Pediatric Age: Genetic and Clinical Scenario

Frontiers in Endocrinology (2019)

Francesca Galuppini Federica Vianello Simona Censi Susi Barollo Loris Bertazza

Introduction: Follicular-derived differentiated thyroid carcinoma (DTC) is the most common endocrine and epithelial malignancy in children. The differences in the clinical and pathological features of pediatric vs. adult DTC could relate to a different genetic profile. Few studies are currently available in this issue, however, and most of them involved a limited number of patients and focused mainly on radiation-exposed populations. Materials and Methods: We considered 59 pediatric patients who underwent surgery for DTC between 2000 and 2017. RET/PTC rearrangement was investigated with fluorescent in situ hybridization and real-time polymerase chain reaction. Sequencing was used to analyze mutations in the BRAF, NRAS, PTEN, PIK3CA genes, and the TERT promoter. The pediatric patients' clinical and molecular features were compared with those of 178 adult patients. Results: In our pediatric sample, male gender and age <15 years coincided with more extensive disease and more frequent lymph node and distant metastases. Compared with adults, the pediatric patients were more likely to have lymph node and distant metastasis, and to need second treatments (p < 0.01). In all, 44% of the pediatric patients were found to carry molecular alterations. RET/PTC rearrangement was confirmed as the most frequent genetic alteration in childhood DTC (24.6%) and correlated with aggressive features. BRAFV600E was only identified in 16% of the pediatric DTCs, while NRASQ61R, NRASQ61K, and TERTC250T mutations were very rare. Conclusions: Pediatric DTC is more aggressive at diagnosis and more likely to recur than its adult counterpart. Unlike the adult disease, point mutations have no key genetic role.

10.3389/fendo.2019.00552

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von Hippel–Lindau disease integrated care pathway: Centralizing, expanding specialists' theatre, and measuring improvement

Cancer (2022)

Mario Gardi Umberto Basso Alfonso Massimiliano Ferrara Stefania Zovato Alberto Feletti

Stefania Zovato reports personal fees from GlaxoSmithKline, Eisai, and Eli Lilly and Company outside the submitted work. The remaining authors made no disclosures.

Von Hippel–Lindau disease

10.1002/cncr.34460

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Citations (1)

Deregulated expression of VHL mRNA variants in papillary thyroid cancer

Molecular and Cellular Endocrinology (2017)

Enke Baldini Chiara Tuccilli Yannick Arlot‐Bonnemains Frank Chesnel Salvatore Sorrenti

10.1016/j.mce.2017.01.019

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Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14)

Frontiers in Oncology (2021)

Marco Maruzzo Elena Verzoni Maria Giuseppa Vitale Michele Dionese Sebastiano Buti

Background Thyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet. Materials and Methods We recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS. Results We analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p<0.001); median OS in the three groups were 36.5, 48.6, and 70.5 months respectively (p =0.006). The low fT3/fT4 ratio maintained its prognostic role at the multivariate analysis independently from IMDC and other well-established prognostic factors. The development of iatrogenic hypothyroidism was not associated with a better outcome. Conclusion We found that baseline thyroid hormone impairment, represented by a low fT3/fT4 ratio, is a strong prognostic factor in patients treated for mRCC in first line setting and is independent of other parameters currently used in clinical practice.

Value (mathematics)

10.3389/fonc.2021.787835

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AHR Over-Expression in Papillary Thyroid Carcinoma: Clinical and Molecular Assessments in a Series of Italian Acromegalic Patients with a Long-Term Follow-Up

PLoS ONE (2014)

Caterina Mian Filippo Ceccato Susi Barollo Sara Watutantrige‐Fernando Nora Albiger

Aim Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3–7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.

Thyroid Nodules

10.1371/journal.pone.0101560

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Iodine Status in the Elderly: Association with Milk Intake and Other Dietary Habits

Journal of Nutritional Health & Food Science (2016)

Sara Watutantrige‐Fernando

Background: Iodine deficiency is still an issue with important consequences, not only in younger people, but also in the elderly.We proposed to assess iodine status in elderly females, to analyze their eating habits and to compare results with our previous findings on female from childhood to fertile age. Materials and Methods:This observational study that involved 189 menopausal women (51-86 years old) undergoing endocrinological evaluation at our center in the Veneto region, a northeast Italian area.We measured Urinary Iodine Concentration (UIC) from spot urine samples and participants were asked to fill in a food frequency questionnaire; we also collected data on bone metabolism from the hospital laboratory database network system. Results:The median UIC of the sample as a whole was 30 μg/l, corresponding to a moderate iodine deficiency.Among these subjects 47.7% were daily milk consumers: such women had a higher UIC than the occasional milk consumers (43 vs 30 μg/l, P= 0.0041).Regarding other dietary habits, a great proportion of women resulted undernourished; moreover the declining trend in milk consumption with increasing age is similar to the age-related decline in UIC and 24h-Urinary Calcium (U-Ca).Conclusions: women of menopausal age in our series were lacking in iodine because of reduced milk intake, in the contest of a major condition of global undernourishment.We confirm that milk is per se an important source of iodine if consumed in appropriate quantities.

Association (psychology)

10.15226/jnhfs.2017.00189

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Citations (7)

Prognostic significance of TERT promoter and BRAF mutations in cytologically suspicious or malignant thyroid nodules: a monocentric case series at a tertiary-level endocrinology unit

Endocrine Abstracts (2019)

Simona Censi Susi Barollo Elisabetta Grespan Sara Watutantrige‐Fernando Elisabetta Cavedon

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Thyroid Nodules

10.1530/endoabs.63.gp83

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<p>Programmed cell death 4 (PDCD4) as a novel prognostic marker for papillary thyroid carcinoma</p>

Cancer Management and Research (2019)

Francesca Galuppini Matteo Fassan Loris Bertazza Susi Barollo Luciano Cascione

Background: The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose: The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods: We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15–98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results: We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion: These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone. Keywords: papillary thyroid cancer, PDCD4, BRAF , outcome

10.2147/cmar.s194344

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The Effects of Iodine Supplementation in Pregnancy on Iodine Status, Thyroglobulin Levels and Thyroid Function Parameters: Results from a Randomized Controlled Clinical Trial in a Mild-to-Moderate Iodine Deficiency Area

Nutrients (2019)

Simona Censi Sara Watutantrige‐Fernando Giulia Groccia Jacopo Manso Mario Plebani

Background: Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated. Methods: A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants’ urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns’ urinary iodine concentrations were evaluated in 16 cases. Results: Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat ≥ 150 ug/g, and in the Iodine group at T2 (p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study (p = 0.03, r = −0.1268). A lower TSH level was found in the Iodine group at T3 (p = 0.001). TV increased by +Δ7.43% in the Iodine group, and by +Δ11.17% in the Placebo group. No differences were found between the newborns’ TSH levels on screening the two groups. Conclusion: Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function.

Thyroglobulin

Thyroid-stimulating hormone

10.3390/nu11112639

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Citations (37)

BRAF in primary and recurrent papillary thyroid cancers: the relationship with 131I and 2-[18F]fluoro-2-deoxy-d-glucose uptake ability

European Journal of Endocrinology (2010)

Susi Barollo Gianmaria Pennelli Federica Vianello Sara Watutantrige‐Fernando Isabella Negro

BRAF V600E is a potential marker of poor prognosis in papillary thyroid cancers (PTC). In a previous report, we showed that recurrent PTC with no radioiodine ((131)I) uptake are frequently associated with BRAF mutations, a low expression of thyroid-related genes and a high expression of glucose type-1 transporter gene.The aim of the present study was to assess BRAF status in a large series of recurrent PTC patients, considering paired primary and recurrent cancers. The BRAF genotype was correlated with the ability to concentrate (131)I and/or 2-[(18)F]fluoro-2-deoxi-d-glucose ((18)F-FDG) in the recurrent cancers, serum markers of recurrence, and patient outcome.We studied 50 PTC patients with recurrent cervical disease submitted to a re-intervention, followed up in median for 9 years. BRAF analysis was conducted by direct sequencing and mutant allele-specific PCR amplification. In 18 cases, molecular analysis was also assessed in the primary cancer. Out of 50 patients, 30 underwent (18)F-FDG-positron emission tomography-computed tomography.BRAF V600E-positive recurrent patients were found (131)I-negative in 94% of cases (P<0.001); 73% of the cancers carrying BRAF V600E were both (131)I-negative and (18)F-FDG positive. In paired primary and recurrent PTC, BRAF V600E was observed in 79% of the primary cancers and 84% of their recurrences. Three patients with (131)I-negative and BRAF V600E-positive recurrent cancers deceased during follow-up.BRAF mutations are more common in thyroid recurrences with no (131)I uptake than in (131)I-positive cases. They are correlated with the ability to concentrate (18)F-FDG, and they can appear, albeit rarely, as a de novo event in the course of PTC recurrences.

Primary (astronomy)

10.1530/eje-10-0290

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Citations (60)