Publications by authors named "Federica Vianello"

42 Publications

Prevalence of SARS-CoV-2-IgG Antibodies in Children with CKD or Immunosuppression.

Clin J Am Soc Nephrol 2021 Jun 7. Epub 2021 Jun 7.

G Montini, Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano, Italy

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http://dx.doi.org/10.2215/CJN.00330121DOI Listing
June 2021

The role of the size in thyroid cancer risk stratification.

Sci Rep 2021 Mar 31;11(1):7303. Epub 2021 Mar 31.

Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.

Only a minority of cases of differentiated thyroid carcinoma (DTC) have a poor clinical outcome. Clinical outcomes and molecular aspects were assessed in: 144 DTC ≤ 40 mm without distant metastases (group 1); 50 DTC > 40 mm without distant metastases (group 2); and 46 DTC with distant metastases (group 3). Group 3 had a worse outcome than the other two groups: during the follow-up, patients more frequently had persistent disease, died, or underwent further treatment. The outcomes did not differ between groups 1 and 2. Group 3 had a higher prevalence of TERT promoter mutations than group 2 (32.6% vs 14%). Group 1 had a higher frequency of BRAF mutations than groups 2 or 3 (61.1% vs 16.0% and 26.1%, respectively), while RAS mutations were more common in group 2 than in groups 1 and 3 (16.0% vs 2.1% and 6.5%, respectively). Groups 1 and 2 shared the same outcome, but were genetically distinct. Only lymph node involvement, distant metastases, older age and (among the molecular markers) TERT promoter mutations were independent predictors of a worse outcome. Metastatic DTC had the worst outcome, while the outcome was identical for large and small non-metastatic DTC, although they showed different molecular patterns. TERT promoter mutations emerged as an independent factor pointing to a poor prognosis.
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http://dx.doi.org/10.1038/s41598-021-86611-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012699PMC
March 2021

Adjuvant radiotherapy and radioiodine treatment for locally advanced differentiated thyroid cancer: systematic review and meta-analysis.

Tumori 2021 Mar 16:300891621996817. Epub 2021 Mar 16.

Radiation Oncology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, Italy.

Background: Treatment for locally advanced differentiated thyroid cancer is surgery followed by radioiodine while the role of adjuvant external beam radiotherapy (EBRT) is debated.

Methods: The panel of the Italian Association of Radiotherapy and Clinical Oncology developed a clinical recommendation on the addition of EBRT to radioiodine after surgery for locally advanced differentiated thyroid cancer by using the Grades of Recommendation, Assessment, Development, and Evaluation methodology and the Evidence to Decision framework. A systematic review with meta-analysis about this topic was conducted with a focus on outcome of benefits and toxicity.

Results: Locoregional control was improved by EBRT while no considerable toxicity impact was reported.

Conclusion: The panel judged uncertain the benefit/harms balance; final recommendation was conditional both for EBRT + radioiodine and radioiodine alone in the adjuvant setting.
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http://dx.doi.org/10.1177/0300891621996817DOI Listing
March 2021

Prognostic significance of the sum of the diameters of single foci in multifocal papillary thyroid cancer: the concept of new-old tumor burden.

Ther Adv Endocrinol Metab 2020 12;11:2042018820964326. Epub 2020 Oct 12.

Department of Medicine (DIMED), Endocrinology Unit, Padua University, Padua, Italy.

Aim: The prognostic value of multifocality (Mu) in papillary thyroid cancer (PTC) remains controversial. The present study aimed to investigate this issue and test the possible prognostic significance of the sum of the diameters of single foci (SDSF), the total number of foci (TNF), and primary tumor size (PTS) in multifocal PTC.

Methods: We retrospectively analyzed a single-center consecutive series of 370 PTCs. For multifocal cases we analyzed bilaterality occurrence, SDSF, TNF, and PTS.

Results: Mu was observed in 41.1% PTCs, and bilaterality in 30%. Mu was associated with an advanced T-category. In bilateral multifocal PTC, the PTS was larger, and microPTC was less frequent, while T-categories were higher. Mu and bilaterality had no impact on prognosis. At univariate analysis, PTS, SDSF, vascular invasion, lymph node metastases, distant metastases, T-categories, Initial Risk Stratification System score, second treatment and TERT promoter mutation correlated with persistence/recurrence or death in the multifocal PTC group. On multivariate Cox proportional hazards regression analyses, SDSF again independently predicted persistence/recurrence or death in multifocal PTCs. We found that a cut-off for SDSF less than 40 mm was able to identify multifocal PTC patients with a very low risk of persistence/recurrence (negative predictive value 96.9%). Disease-free survival was significantly shorter in patients with multifocal PTCs and SDSF ⩾40 mm.

Conclusions: Mu and bilaterality were not prognostically significant. SDSF emerged as a new independent prognostic factor for persistence/recurrence of multifocal PTC. SDSF might better represent the tumor burden in multifocal PTC, with SDSF < 40 mm identifying multifocal PTC patients with a good prognosis.
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http://dx.doi.org/10.1177/2042018820964326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557686PMC
October 2020

Prevalence, diagnosis, and management of secondary pseudohypoaldosteronism.

Pediatr Nephrol 2020 04 20;35(4):713-714. Epub 2019 Dec 20.

Pediatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1007/s00467-019-04419-zDOI Listing
April 2020

BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma.

Eur J Cancer 2020 01 29;124:161-169. Epub 2019 Nov 29.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management.

Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months).

Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC.

Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.
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http://dx.doi.org/10.1016/j.ejca.2019.10.017DOI Listing
January 2020

Programmed cell death 4 (PDCD4) as a novel prognostic marker for papillary thyroid carcinoma.

Cancer Manag Res 2019 20;11:7845-7855. Epub 2019 Aug 20.

Pathology Unit, Department of Medicine (DIMED), University of Padova, Padova 35121, Italy.

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.
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http://dx.doi.org/10.2147/CMAR.S194344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708393PMC
August 2019

Differentiated Thyroid Carcinoma in Pediatric Age: Genetic and Clinical Scenario.

Front Endocrinol (Lausanne) 2019 7;10:552. Epub 2019 Aug 7.

Endocrinology Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy.

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. We considered 59 pediatric patients who underwent surgery for DTC between 2000 and 2017. rearrangement was investigated with fluorescent hybridization and real-time polymerase chain reaction. Sequencing was used to analyze mutations in the genes, and the promoter. The pediatric patients' clinical and molecular features were compared with those of 178 adult patients. 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 ( < 0.01). In all, 44% of the pediatric patients were found to carry molecular alterations. rearrangement was confirmed as the most frequent genetic alteration in childhood DTC (24.6%) and correlated with aggressive features. was only identified in 16% of the pediatric DTCs, while NRASQ61R, NRASQ61K, and TERTC250T mutations were very rare. 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.
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http://dx.doi.org/10.3389/fendo.2019.00552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698790PMC
August 2019

Prognostic significance of TERT promoter and BRAF mutations in TIR-4 and TIR-5 thyroid cytology.

Eur J Endocrinol 2019 Jul;181(1):1-11

Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy.

Objective: Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases.

Methods: TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7-293 months) was available for 384/423 patients with malignant nodes.

Results: TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06-539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48-463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201).

Conclusions: TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up.
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http://dx.doi.org/10.1530/EJE-19-0073DOI Listing
July 2019

BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer.

J Clin Oncol 2018 09 2;36(27):2787-2795. Epub 2018 Aug 2.

Fei Wang, Shihua Zhao, and Yangang Wang, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Fei Wang, Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto Auxologico Italiano, Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Institute Oncology Center, Gliwice, Poland; Alfred K. Lam, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols" and Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
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http://dx.doi.org/10.1200/JCO.2018.78.5097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145834PMC
September 2018

Bioimpedance Spectroscopy Imprecisely Assesses Lean Body Mass in Pediatric Dialysis Patients.

J Pediatr Gastroenterol Nutr 2018 Oct;67(4):533-537

Department of Pediatric Nephrology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.

Objectives: Alterations in body compositions are strongly associated with poor outcomes in end-stage renal disease patients. Hence, assessment of lean body mass is crucial for clinically monitoring these patients. The use of multifrequency bioimpedance spectroscopy measurements has also been advocated, but their usefulness in children is questioned. We investigated whether their application is appropriate for lean body mass measurement in pediatric patients receiving chronic dialysis.

Methods: Lean body mass estimates as assessed by multifrequency bioimpedance spectroscopy and by deuterium dilution were obtained for 15 patients (mean age 10.9 ± 3.6 years).

Results: Lean body mass (mean ± standard deviation) determined by bioimpedance was 24.2 ± 10.7 and 24.4 ± 10.3 kg by deuterium technique. Bland-Altman analysis showed a mean (±standard deviation) difference between the 2 methods of -0.25 ± 2.30 kg with 95% limits of agreement of -4.80 to 4.25 kg. In a multiple linear regression model, the hydration status was associated with measurement bias after adjusting for age, sex, weight, and body surface area.

Conclusions: Our results show a high level of agreement between measurements by bioimpedance and deuterium technique, but the limits of agreement were wide. These findings do not support the use of bioimpedance to individually assess lean body mass in pediatric dialysis patients with and without overhydration.
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http://dx.doi.org/10.1097/MPG.0000000000002063DOI Listing
October 2018

Efficacy of educational intervention to improve awareness of the importance of iodine, use of iodized salt, and dietary iodine intake in northeastern Italian schoolchildren.

Nutrition 2018 09 23;53:134-139. Epub 2018 Mar 23.

Endocrinology Unit, Department of Medicine, University of Padua, via Ospedale Civile 105, 35128, Padua, Italy. Electronic address:

Objective: An educational program was conducted among school-aged children to improve their knowledge about iodine prophylaxis, their iodine status, and their dietary habits.

Methods: At the baseline (T0) and after 6 mo (T1), participants (970 at T0 and 949 at T1) answered questionnaires testing their knowledge about iodine prophylaxis and their eating habits. Urine samples were collected from a randomly selected subgroup of participants (313 at T0 and 312 at T1).

Results: From T0 to T1 there was a significant improvement in respondents' knowledge about iodine prophylaxis (from 44% to 70%), iodized salt consumption (from 78% to 84%), and median urine iodine concentrations (from 70 µg/L to 91 µg/L). Milk and iodized salt intakes were associated with a better iodine status per se, and more so when used simultaneously. Girls drank milk less often than boys did (daily in 52% and 59% of cases, respectively). Children of foreign origin ate sodium-rich food more often than Italians did.

Conclusion: Educational intervention improved the children's knowledge about iodine prophylaxis and use of iodized salt. Consuming salt in addition to milk improves iodine status. Children of foreign origin have different eating habits.
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http://dx.doi.org/10.1016/j.nut.2018.02.010DOI Listing
September 2018

EF24 (a Curcumin Analog) and ZSTK474 Emphasize the Effect of Cabozantinib in Medullary Thyroid Cancer.

Endocrinology 2018 06;159(6):2348-2360

Endocrinology Unit, Department of Medicine, Padua University Hospital, Padova, Italy.

XL184 is a small-molecule kinase inhibitor recently included in first-line systemic therapy for patients with advanced, progressive medullary thyroid cancer (MTC). EF24 is a curcumin analog with a high bioavailability, and ZSTK474 is an inhibitor of the phosphatidylinositol 3-kinase signaling pathway. We investigated the effect of these compounds, alone and in combination, in two rearranged during transfection (RET)-mutated TT and MZ-CRC-1 MTC cell lines and in six mostly RET wild-type human MTC primary cultures. Low IC50 values demonstrated the efficacy of the drugs, whereas the combination index revealed an important synergistic effect of combinations of XL184 + ZSTK474 and XL184 + EF24. Cell-cycle changes and the induction of apoptosis or necrosis were modulated by single compounds or combinations thereof. Both XL184 and EF24, alone or combined, were effective in reducing calcitonin secretion. Western blot and in-cell Western analysis showed that the compounds prompted a decrease in general reactivity to phosphorylated antibodies. Our data confirm XL184 alone as the reference drug for RET-mutated MTC, but we also demonstrated that EF24 alone is effective in inhibiting MTC cell viability. We tested the combinations XL184 + ZSTK474 and XL184 + EF24 too, finding that they act synergistically, irrespective of RET mutation status.
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http://dx.doi.org/10.1210/en.2018-00124DOI Listing
June 2018

A new standardized data collection system for interdisciplinary thyroid cancer management: Thyroid COBRA.

Eur J Intern Med 2018 07 21;53:73-78. Epub 2018 Feb 21.

Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

The big data approach offers a powerful alternative to Evidence-based medicine. This approach could guide cancer management thanks to machine learning application to large-scale data. Aim of the Thyroid CoBRA (Consortium for Brachytherapy Data Analysis) project is to develop a standardized web data collection system, focused on thyroid cancer. The Metabolic Radiotherapy Working Group of Italian Association of Radiation Oncology (AIRO) endorsed the implementation of a consortium directed to thyroid cancer management and data collection. The agreement conditions, the ontology of the collected data and the related software services were defined by a multicentre ad hoc working-group (WG). Six Italian cancer centres were firstly started the project, defined and signed the Thyroid COBRA consortium agreement. Three data set tiers were identified: Registry, Procedures and Research. The COBRA-Storage System (C-SS) appeared to be not time-consuming and to be privacy respecting, as data can be extracted directly from the single centre's storage platforms through a secured connection that ensures reliable encryption of sensible data. Automatic data archiving could be directly performed from Image Hospital Storage System or the Radiotherapy Treatment Planning Systems. The C-SS architecture will allow "Cloud storage way" or "distributed learning" approaches for predictive model definition and further clinical decision support tools development. The development of the Thyroid COBRA data Storage System C-SS through a multicentre consortium approach appeared to be a feasible tool in the setup of complex and privacy saving data sharing system oriented to the management of thyroid cancer and in the near future every cancer type.
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http://dx.doi.org/10.1016/j.ejim.2018.02.012DOI Listing
July 2018

Predictive value of EEG for febrile seizure recurrence.

Brain Dev 2018 Apr 23;40(4):311-315. Epub 2017 Dec 23.

Department of Pediatric Emergency, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Clinica De Marchi, Milan, Italy.

Objective: To define the role of the EEG in predicting recurrence of febrile seizures (FS) in children after a first FS.

Methods: Children with a first simple or complex FS who underwent EEG at our hospital were retrospectively enrolled. EEG recordings were classified in three groups: normal, abnormal (slow activity or epileptiform discharges), and pseudo-petit mal discharge (PPMD) pattern. Children were followed-up for at least three years.

Results: A total of 126 patients met the entry criteria, and 113 of them completed the follow-up. Risk of FS recurrence decreased linearly with increasing age (-2% per month). The risk was higher among patients with PPMD pattern (absolute risk 86%, adjusted relative risk 2.00) and abnormal EEG (epileptiform discharges: absolute risk 71%, adjusted relative risk 2.00; slow activity: absolute risk 56%, adjusted relative risk 1.44), compared with those with normal EEG (absolute risk 41%).

Conclusions: PPMD and abnormal EEG should be considered as an independent risk factor for FS recurrence.
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http://dx.doi.org/10.1016/j.braindev.2017.12.004DOI Listing
April 2018

Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer.

J Clin Oncol 2018 02 14;36(5):438-445. Epub 2017 Dec 14.

Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; Alfred K. Lam, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, The University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh School of Medicine, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Ciberonc, Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
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http://dx.doi.org/10.1200/JCO.2017.74.5497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807010PMC
February 2018

The Hobnail Variant of Papillary Thyroid Carcinoma: Clinical/Molecular Characteristics of a Large Monocentric Series and Comparison with Conventional Histotypes.

Thyroid 2018 01 2;28(1):96-103. Epub 2018 Jan 2.

1 Endocrinology Unit, Department of Medicine, University of Padua , Padua, Italy .

Background: The hobnail variant of papillary thyroid carcinoma (HPTC) has an aggressive behavior. The aims of this prospective study were to define the clinical/molecular characteristics of HPTC, and to compare them to those of conventional papillary thyroid carcinoma (PTC).

Methods: From 2010 to 2016, 25 cases of HPTC, characterized clinically and molecularly (BRAF, RAS, TERT promoter, and TP53 mutations), were compared to a series of 165 consecutive cases of PTC. All patients underwent total thyroidectomy and received radioactive iodine treatment. Follow-up was available for 19 HPTC patients.

Results: Among the HPTC patients, 64% had a hobnail component ≥30%, and 64% had multifocal disease. The mean tumor size was 30 mm; 96% of tumors were angio-invasive; 68% were N1, and 12% were M1; 58% harbored the BRAF mutation, 12% had a mutation in the TERT promoter, 17% had a TP53 mutation, and not had a RAS mutation. At a mean follow-up of 39 months, 32% of patients had biochemical and/or structural disease. Tumor size was the only significant difference between patients with persistent disease and those with an excellent response (40 mm and 24 mm, respectively; p = 0.02). Compared to the PTC control group, the HPTC patients had larger tumors (30 mm vs. 16 mm; p < 0.001), more frequent lymph node involvement (68% vs. 38%; p = 0.01), and remote disease (16% vs. 3%; p < 0.0001), a similar prevalence of the BRAF mutation (58% vs. 59%), a higher prevalence of TP53 mutations (17% vs. 1%; p < 0.05), and a worse outcome (structural/biochemical disease: 32% vs. 9%; p < 0.0001).

Conclusions: HPTC is an aggressive variant, characterized by large tumor size, lymph node involvement, a tendency to metastasize, and a worse outcome.
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http://dx.doi.org/10.1089/thy.2017.0248DOI Listing
January 2018

BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment.

J Natl Cancer Inst 2018 04;110(4):362-370

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.

Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.

Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.

Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
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http://dx.doi.org/10.1093/jnci/djx227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658860PMC
April 2018

Frequency and Significance of Promoter, and Mutations in Cytologically Indeterminate Thyroid Nodules: A Monocentric Case Series at a Tertiary-Level Endocrinology Unit.

Front Endocrinol (Lausanne) 2017 16;8:273. Epub 2017 Oct 16.

Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy.

Purpose: The management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of promoter, and gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.

Methods: -,-, promoter and gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.

Results: 69/199 (35%) were malignant on histopathological review. mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. mutations were detected in 15/199 (8%), and a K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.

Conclusion: The residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy.
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http://dx.doi.org/10.3389/fendo.2017.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650698PMC
October 2017

MiR-375 and YAP1 expression profiling in medullary thyroid carcinoma and their correlation with clinical-pathological features and outcome.

Virchows Arch 2017 Nov 31;471(5):651-658. Epub 2017 Aug 31.

Department of Medicine (DIMED), Surgical Pathology Unit, University of Padova, Via Gabelli 61, 35121, Padova, Italy.

Medullary thyroid cancer (MTC) is a tumor marked by an indolent growth for which few prognostic factors and therapeutic strategies are actually available. Different studies have recently appraised well-differentiated thyroid cancers are characterized by a dysregulation in different microRNA sets; however, only few of them investigated the role of miRNA expression in MTCs. In this study, we have assessed the miR-375 expression in a series of 130 MTCs (104 are sporadic and 26 familial) with a median follow-up of 39 months (range 1-138) and then we have correlated our results with the clinical-pathological features and the patients' outcome.Moreover, we have appraised YAP1 (Yes-associated protein 1) immunohistochemical expression in the same MTC series and in 5 C-cells hyperplasia (CCH) samples as well. We observed a significant upregulation of miR-375 in all MTCs, when compared to the normal thyroid tissues. Besides, miR-375 expression was found to be closely linked to neoplastic size, a chance of thyroid capsule infiltration, the risk of lymph node metastasis, and the staging of the tumor. At the end of follow-up, only 10% (13/130) showed a tumor progression and a higher miR-375 expression was found to be closely linked to a worst patient' outcome. On the contrary, YAP1 immunohistochemical expression was sharply downregulated in tumors, whereas it was weakly expressed in CCHs. Our results suggest miR-375 plays a central role in MTC progression and, therefore, we seek following the idea that miR-375 pathway may be an effective target in novel MTC therapeutic strategies.
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http://dx.doi.org/10.1007/s00428-017-2227-7DOI Listing
November 2017

Ictal and interictal electroencephalogram of benign infantile seizures associated with mild gastroenteritis.

Minerva Pediatr 2017 10;69(5):456-457

Department of Pediatric Emergency, IRCCS Ca' Granda Foundation, "Maggiore-Policlinico" Hospital, Milan, Italy.

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http://dx.doi.org/10.23736/S0026-4946.16.04533-3DOI Listing
October 2017

Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma.

Int J Endocrinol 2017 6;2017:4915736. Epub 2017 Jun 6.

Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection () and rat sarcoma () mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. (10/107 cases, 9%) and (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis ( = 0.03, = -0.3); advanced stage ( = 0.001); persistent disease ( = 0.001); progressive disease ( = 0.002); and disease-related death ( = 0.0001). We found a significant positive correlation between miR-224 expression and somatic mutations ( = 0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test = 0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in -mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients.
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http://dx.doi.org/10.1155/2017/4915736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476902PMC
June 2017

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer.

J Clin Endocrinol Metab 2017 09;102(9):3241-3250

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.

Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC.

Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation.

Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database.

Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.
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http://dx.doi.org/10.1210/jc.2017-00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587077PMC
September 2017

Bioimpedance and Fluid Status in Children and Adolescents Treated With Dialysis.

Am J Kidney Dis 2017 Mar 13;69(3):428-435. Epub 2017 Jan 13.

Pediatric Nephrology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.

Background: Assessment of hydration status in patients with chronic kidney failure treated by dialysis is crucial for clinical management decisions. Dilution techniques are considered the gold standard for measurement of body fluid volumes, but they are unfit for day-to-day care. Multifrequency bioimpedance has been shown to be of help in clinical practice in adults and its use in children and adolescents has been advocated. We investigated whether application of multifrequency bioimpedance is appropriate for total-body water (TBW) and extracellular water (ECW) measurement in children and adolescents on dialysis therapy.

Study Design: A study of diagnostic test accuracy.

Setting & Participants: 16 young dialysis patients (before a hemodialysis session or after peritoneal dialysis treatment) from the Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, and the Emma Children's Hospital-Academic Medical Center, Amsterdam, the Netherlands.

Index Test: TBW and ECW volumes assessed by multifrequency bioimpedance.

Reference Tests: TBW and ECW volumes measured by deuterium and bromide dilution, respectively.

Results: Mean TBW volumes determined by multifrequency bioimpedance and deuterium dilution were 19.2±8.7 (SD) and 19.3±8.3L, respectively; Bland-Altman analysis showed a mean bias between the 2 methods of -0.09 (95% limits of agreement, -2.1 to 1.9) L. Mean ECW volumes were 8.9±4.0 and 8.3±3.3L measured by multifrequency bioimpedance and bromide dilution, respectively; mean bias between the 2 ECW measurements was +0.6 (95% limits of agreement, -2.3 to 3.5).

Limitations: Participants ingested the deuterated water at home without direct supervision by investigators, small number of patients, repeated measurements in individual patients were not performed.

Conclusions: Multifrequency bioimpedance measurements were unbiased but imprecise in comparison to dilution techniques. We conclude that multifrequency bioimpedance measurements cannot precisely estimate TBW and ECW in children receiving dialysis.
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http://dx.doi.org/10.1053/j.ajkd.2016.10.023DOI Listing
March 2017

External beam radiotherapy in thyroid carcinoma: clinical review and recommendations of the AIRO "Radioterapia Metabolica" Group.

Tumori 2017 Mar 1;103(2):114-123. Epub 2016 Sep 1.

 Radiation Oncology Department, Gemelli-ART, Università Cattolica del Sacro Cuore, Rome - Italy.

The therapeutic approach to thyroid carcinoma usually involves surgery as initial treatment. The use of external beam radiotherapy (EBRT) is limited to high-risk patients and depends on clinical stage and histologic type. Different behavior patterns and degrees of aggressiveness of thyroid carcinomas require different management for differentiated, medullary, and anaplastic carcinoma. However, the role of EBRT is an issue of debate. Most clinical studies are retrospective and based on single-institution experiences. In this article, we review the main literature and give recommendations for the use of EBRT in thyroid carcinoma on behalf of the "Radioterapia Metabolica" Group of the Italian Radiation Oncology Association.
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http://dx.doi.org/10.5301/tj.5000532DOI Listing
March 2017

New program for identification of child maltreatment in emergency department: preliminary data.

Ital J Pediatr 2016 Jul 13;42(1):66. Epub 2016 Jul 13.

Pediatric Emergency Department, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Early detection of child maltreatment in pediatric emergency department is one of the most important challenges for the Italian and European medical care system. Several interventions have been proposed, but results are often unquantifiable or inadequate to face this problem. We promoted an educational program and built up an interdisciplinary team to improve the identification and management of maltreated children. Aim of this study is to report preliminary results of these interventions. Meetings structured with lecture-based teaching and case-based lessons were focused on identification and management of maltreatment cases. An interdisciplinary team with forensic physicians, dermatologists, orthopedics, radiologists, gynecologists, oculists, psychologists and psychiatrics, was created to manage children with suspected diagnosis of maltreatment. We analysed the characteristics of subjects diagnosed after these interventions and their number was compared with the one in the two previous years. An increased rate of diagnoses of 16.9 % was found. Results of the reported program are encouraging, but many efforts are still mandatory to improve the child maltreatment identification in emergency departments.
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http://dx.doi.org/10.1186/s13052-016-0275-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944310PMC
July 2016

Treatment of Severe Hypervolemic Hyponatremia in a Child With Pneumonia.

Pediatr Emerg Care 2016 Jun;32(6):390-1

From the Departments of *Pediatric Emergency, †Pathophysiology and Transplantation, and ‡Pediatric Surgery, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

A 21-month-old boy came to our attention because of pneumonia. His weight increased before presentation, and his blood test results showed hyponatremia (116 mEq/L), low plasma osmolarity (241 mOsm/L), and high urine osmolarity (435 mOsm/L). He was treated with 0.9% sodium chloride solution and intravenous furosemide, and sodium levels rose up to 135 mEq/L in 36 hours. No standard treatment is available for severe hyponatremia in children. The use of vaptans in pediatric patients is described in literature, but it lacks evidence about safety and effectiveness. We suggest that furosemide administration plus salt replacement is effective in restoring normal values of plasma sodium concentration in severe euvolemic and hypervolemic hyponatremia.
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http://dx.doi.org/10.1097/PEC.0000000000000823DOI Listing
June 2016

BRAF analysis before surgery for papillary thyroid carcinoma: correlation with clinicopathological features and prognosis in a single-institution prospective experience.

Clin Chem Lab Med 2016 Sep;54(9):1531-9

Background: Risk stratification in patients with papillary thyroid carcinoma (PTC) currently relies on postoperative parameters. Testing for BRAF mutations preoperatively may serve as a novel tool for identifying PTC patients at risk of persistence/recurrence after surgery.

Methods: The study involved 185 consecutive patients with a histological diagnosis of PTC and BRAF analysis performed on thyroid fine-needle aspiration biopsy (FNAB). We assessed BRAF status in FNAB specimens obtained before thyroidectomy for PTC, and examined its association with the clinicopathological characteristics identified postoperatively, and with outcome after a mean 55±15 months of follow-up.

Results: One hundred and fifteen of 185 (62%) PTCs carried a BRAF mutation. Univariate analysis showed that BRAF status correlated with the histological variant of PTC, cancer size, and stage at diagnosis, but not with gender, age, multifocality, or lymph node involvement. BRAF-mutated cases had a higher prevalence of persistent/recurrent disease by the end of the follow-up (11% vs. 8%), but this difference was not statistically significant. The Kaplan-Meier curve shows that among the patients with persistent/recurrent disease, BRAF-mutated patients needed a second treatment earlier than patients with BRAF wild-type, although the difference did not completely reach the statistical significance.

Conclusions: Our study confirmed that preoperatively-identified BRAF mutation are associated with certain pathological features of PTC that correlate with prognosis. We speculate that it has a role in identifying PTCs that would generally be considered low-risk but that may reveal an aggressive behavior during their follow-up.
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http://dx.doi.org/10.1515/cclm-2015-0218DOI Listing
September 2016

Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants.

J Clin Endocrinol Metab 2016 Jan 3;101(1):264-74. Epub 2015 Nov 3.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine (X.Shi., R.L., X.Shen., D.T., M.X.), Johns Hopkins University School of Medicine, Baltimore, MD 21287; Department of Surgery, Division of Pathology (F.B., R.G.), 56126 Pisa, Italy; The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism (H.G., Z.S., W.T.), The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Endocrine Surgery (T.J.M.), University Medical Center, Johannes Gutenberg University Mainz, 55101 Mainz, Germany; Human Cancer Genomic Research (K.A.K.), Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Kingdom of Saudi Arabia; Fondazione Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Policlinico, Milan, and Department of Pathophysiology and Transplantation (L.E., C.C.), University of Milan, 20122 Milan Italy; Endocrine Oncology Branch, Center for Cancer Research (E.K.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (A.C., B.J.), 44-101 Gliwice, Poland; Department of Molecular Endocrinology (B.B., V.S.), Institute of Endocrinology, Prague 11694, Czech Republic; Institute of Molecular Pathology and Immunology (Manuel Sobrinho-Simões, M.S.S.; Paula Soares, P.So.), University of Porto (Ipatimup) and Medical Faculty of the University of Porto, 4200-319 Porto, Portugal; College of Medicine (Y.K.S., T.Y.K.), University of Ulsan College of Medicine, Seoul, South Korea; Department of Pathology (S.C.; S.L.A.), University Health Network, Toronto, ON M5G 2C4 Canada; Endocrine Unit, Department of Clinical and Experimental Medicine (D.V., R.E.), World Health Organization, Collaborating Center for the Study and Treatment of Thyroid Diseases and Other Endocrine and Meta

Context: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support.

Objective: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC).

Methods: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo).

Results: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old.

Conclusion: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.
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http://dx.doi.org/10.1210/jc.2015-2917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701842PMC
January 2016

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC.

Oncotarget 2015 Oct;6(31):32104-14

Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice.
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http://dx.doi.org/10.18632/oncotarget.5194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741662PMC
October 2015