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Nathalie Oliveira Santana, Antonio Marcondes Lerario, Claudia Kliemann Schmerling, Suemi Marui, Venancio Avancini Ferreira Alves, Ana O. Hoff, Peter Kopp, and Debora Lucia Seguro Danilovic

Objective: Genomic alterations in Hürthle cell carcinomas (HCC) include chromosomal losses, mitochondrial DNA mutations, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/β-catenin pathways. This study aimed at characterizing the mutational profile of HCC.

Methods: Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including, among others, the MAPK, PI3K-AKT-mTOR, Wnt/β-catenin, and Notch pathways. HCC was widely invasive in 57.5%, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up, 10% of patients presented with persistent/recurrent disease, but there were no cancer-related deaths.

Results: Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/β-catenin pathway was most frequently affected (30%), followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features.

Conclusions: This series of HCC presents a wide range of mutations in the Wnt/β-catenin, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/β-catenin pathway, particularly mutations in APC and FAT1, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.

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Mario Rotondi, Gloria Groppelli, Laura Croce, Francesco Latrofa, Giuseppe Ancona, Francesca Coperchini, Daniela Pasquali, Carlo Cappelli, Alessandro Fugazza, Valeria Guazzoni, Giorgio Radetti, and Luca Chiovato


The association between chronic autoimmune thyroiditis (CAT) and differentiated thyroid cancer (DTC) remains controversial. The incidence of DTC increases when screening procedures are implemented, as typically occurs in CAT patients being routinely submitted to thyroid ultrasound (US). The aim of this study was to longitudinally evaluate the long-term development of DTC in patients with CAT.

Design and methods:

A retrospective longitudinal cohort study was designed. For the study, 510 patients with chronic autoimmune thyroiditis (CAT) with a 10-year follow-up were enrolled. Patients were divided in two groups according to the presence (CAT+ NOD+; n = 115) or absence (CAT+ NOD−; n = 395) of co-existent nodules at diagnosis. The main outcome measures were appearance of new thyroid-nodules and development of DTC during follow-up.


During a 10-year median follow-up period, new thyroid-nodules were detected in 34/115 (29.5%) patients in the CAT+ NOD+ group and in 41/395 (10.3%) in the CAT+ NOD− group (P < 0.001). Logistic regression analysis showed that thyroid-volume at diagnosis and belonging to the CAT+ NOD+ group significantly predicted the appearance of a new thyroid nodule during follow-up, independently of baseline age and sex. Among the 75 patients experiencing the appearance of a new nodule, 27 (39%) met the criteria for fine-needle-aspiration-cytology (FNAC). A benign cytological diagnosis was rendered in all cases.


In our series of CAT patients, the appearance of new thyroid-nodules was frequent, but none of them were found to be malignant. The presence of CAT appears to be associated with a negligible risk of developing clinically overt DTC.

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Marco Castellana, Giorgio Grani, Maija Radzina, Vito Guerra, Luca Giovanella, Maurilio Deandrea, Rose Ngu, Cosimo Durante, and Pierpaolo Trimboli


Several thyroid imaging reporting and data systems (TIRADS) have been proposed to stratify the malignancy risk of thyroid nodule by ultrasound. The TIRADS by the European Thyroid Association, namely EU-TIRADS, was the last one to be published.


We conducted a meta-analysis to assess the prevalence of malignancy in each EU-TIRADS class and the performance of EU-TIRADS class 5 vs 2, 3 and 4 in detecting malignant lesions.


Four databases were searched until December 2019. Original articles reporting the performance of EU-TIRADS and adopting histology as reference standard were included. The number of malignant nodules in each class and the number of nodules classified as true/false positive/negative were extracted. A random-effects model was used for pooling data.


Seven studies were included, evaluating 5672 thyroid nodules. The prevalence of malignancy in each EU-TIRADS class was 0.5% (95% CI: 0.0–1.3), 5.9% (95% CI: 2.6–9.2), 21.4% (95% CI: 11.1–31.7), and 76.1% (95% CI: 63.7–88.5). Sensitivity, specificity, PPV, NPV, LR+, LR− and DOR of EU-TIRADS class 5 were 83.5% (95% CI: 74.5–89.8), 84.3% (95% CI: 66.2–93.7), 76.1% (95% CI: 63.7–88.5), 85.4% (95% CI: 79.1–91.8), 4.9 (95% CI: 2.9–8.2), 0.2 (95% CI: 0.1–0.3), and 24.5 (95% CI: 11.7–51.0), respectively. A further improved performance was found after excluding two studies because of limited sample size and low prevalence of malignancy in class 5.


A limited number of studies generally conducted using a retrospective design was found. Acknowledging this limitation, the performance of EU-TIRADS in stratifying the risk of thyroid nodules was high. Also, EU-TIRADS class 5 showed moderate evidence of detecting malignant lesions.

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Jacopo Burrello, Alessio Burrello, Jacopo Pieroni, Elisa Sconfienza, Vittorio Forestiero, Martina Amongero, Denis Rossato, Franco Veglio, Tracy A Williams, Silvia Monticone, and Paolo Mulatero

Objective – Adrenal venous sampling (AVS) is the gold standard to discriminate patients with unilateral primary aldosteronism (UPA) from bilateral disease (BPA). AVS is technically-demanding and in cases of unsuccessful cannulation of adrenal veins, the results may not be interpreted. The aim of our study was to develop diagnostic models to distinguish UPA from BPA, in cases of unilateral successful AVS and the presence of contralateral suppression of aldosterone secretion.

Design – Retrospective evaluation of 158 patients referred to a tertiary hypertension unit who underwent AVS. We randomly assigned 110 patients to a training cohort and 48 patients to a validation cohort to develop and test the diagnostic models.

Methods – Supervised machine learning algorithms and regression models were used to develop and validate two prediction models and a 19-point score system to stratify patients according to subtype diagnosis.

Results – Aldosterone levels at screening and after confirmatory testing, lowest potassium, ipsilateral and contralateral imaging findings at CT scanning, and contralateral ratio at AVS, were associated with a diagnosis of UPA and were included in the diagnostic models. Machine learning algorithms correctly classified the majority of patients both at training and validation (accuracy 82.9-95.7%). The score system displayed a sensitivity/specificity of 95.2/96.9%, with an AUC of 0.971. A flow-chart integrating our score correctly managed all patients except 3 (98.1% accuracy), avoiding the potential repetition of 77.2% of AVS.

Conclusions – Our score could be integrated in clinical practice and guide decision-making in patients with unilateral successful AVS and contralateral suppression.

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Anke Tönjes, Annett Hoffmann, Susan Kralisch, Abdul Rashid Qureshi, Nora Klöting, Markus Scholz, Dorit Schleinitz, Anette Bachmann, Jürgen Kratzsch, Marcin Nowicki, Sabine Paeschke, Kerstin Wirkner, Cornelia Enzenbach, Ronny Baber, Joachim Beige, Matthias Anders, Ingolf Bast, Matthias Blüher, Peter Kovacs, Markus Löffler, Ming-Zhi Zhang, Raymond C. Harris, Peter Stenvinkel, Michael Stumvoll, Mathias Fasshauer, and Thomas Ebert


Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far.


In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice.


Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1–3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals.


Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.

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Claire L Wood, Michael Cole, Malcolm Donaldson, David P Dunger, Ruth Wood, Niamh Morrison, John Ns Matthews, Simon Hs Pearce, and Timothy D Cheetham


First line treatment of thyrotoxicosis in young people is thionamide antithyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control.


A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2-16 years with newly diagnosed thyrotoxicosis at 15 UK centres.


Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4y outcome (remission/relapse).


Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60·2% in BR and 63·8% in DT patients; adjusted difference 4·3%, 95% CI (-7·8 to 16·4);p=0.48. Proportions for FT4 were 79·2% in BR and 85·7% in DT patients; adjusted difference 6·8%, (-0·2 to 15·6);p=0·13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y.


This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.

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Colin Patrick Hawkes, Dorothy I Shulman, and Michael A Levine

Introduction: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion.

Methods: In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH) 1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels.

Results: We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4 year-old female whose 24-hour urinary calcium decreased from 7.5 mg/kg to 3.9 mg/kg at one year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-hour urinary calcium decreased from 11.7 mg/kg to 1.7 mg/kg at one year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy.

Conclusions: We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.

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Shirui Wang, Xiang Zhou, and Huijuan Zhu

We appreciate the study by Devuyst et al. on the differential diagnosis of malignant and benign pituitary stalk thickening (PST) based on serum prolactin (PRL) level. We reevaluated the diagnostic performance of PRL to distinct malignant lesions from benign ones in one of largest PST cohorts in China.

According to Devuyst's inclusion criteria, 46 patients (30 benign, 16 malignant) were included in our analysis. There was no difference in PRL between malignant (1.66×ULN, P5-P95 0.40~4.42) and benign group (1.66×ULN, P5-P95 0.40~4.42). The best cut-off (1.03×ULN) resulted in a sensitivity of 87.5% and a specificity of 50.0% (AUC: 0.617). Devuyst suggested 1.27×ULN as a threshold to distinguish malignant and benign etiologies, which yielded a sensitivity of 68.8 and a specificity of 53.3%. Besides, no distinction in PRL level was observed among patients with germinoma, histiocytosis, and hyphphysitis.

Our results suggested that the diagnostic performance of PRL in malignant/benign PST differentiation might be limited. A certain number of patients with benign PST would be misdiagnosed.

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Robin Michelet, Johanna Melin, Zinnia P Parra-Guillen, Uta Neumann, Martin J Whitaker, Viktoria Stachanow, Wilhelm Huisinga, John Porter, Oliver Blankenstein, Richard J Ross, and Charlotte Kloft


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Hanneke M van Santen

Dr Thomas Teinturier et al. describe the influence of growth hormone (GH) therapy on the development of second neoplasms in childhood cancer survivors (CCS)1. The manuscript is an important contribution to literature, as GH deficiency (GHD) is frequently observed in CCS, especially in the childhood brain tumor survivors after exposure to cranial irradiation or in children surviving a tumor in the hypothalamic-pituitary region. In their study, no increased risk was found for recurrence of the original tumor, nor for the development of a second tumor. A slight non significant increased risk is described for the development of meningioma, which may be confounded by previous radiotherapy. These results are reassuring for children who have been diagnosed with GHD after surviving a malignancy and who are treated with GH injections on a daily basis. There are however still some concerns and unanswered questions that need attention in future studies.