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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

Objective:

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.

Results:

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.

Conclusions:

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

Objective:

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.

Design:

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.

Methods:

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.

Results:

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.

Conclusions:

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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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

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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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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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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.

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Robin P. Peeters and Juan P. Brito

There is controversy on the treatment of subclinical hypothyroidism (SCH). While a number of guidelines from professional societies recommend treatment of SCH based on TSH levels, age, and presence of comorbidities, a recent guideline issued a recommendation against thyroid hormone treatment in adults with SCH. In this debate article, we explore this controversy by presenting two points of view about SCH and its treatment. Treatment of patients who are pregnant or trying to become pregnant will not be discussed.

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Ola Nilsson

Short stature is one of the most common causes for referrals to pediatric endocrinologists. However, in a majority of the children, no underlying cause can be identified and the child instead receives the unhelpful diagnosis of idiopathic short stature (ISS), often after extensive work-up and testing. Recent advances in genetic methodology have allowed for the identification of a number of different monogenic conditions within the large cohort of ISS children. Isolated short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800) due to heterozygous aggrecan gene mutations exemplifies how this progress is changing the way we assess, counsel and treat children with non-endocrine growth disorders.

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Mischa de Ridder, Els Nieveen van Dijkum, Anton Engelsman, Ellen Kapiteijn, Heinz-Josef Klümpen, and Coen R N Rasch

Objective

To perform a nationwide population based study in ATC on incidence, treatment and survival.

Design

Retrospective cohort study.

Methods

All patients with primary ATC between 1989 and 2016 were identified in the Netherlands Cancer Registry (NCR). Of all these patients excerpts from the pathology reports from PALGA: Dutch Pathology registry were linked to the data of the NCR. Standardized incidences were calculated, survival was estimated using Kaplan–Meier method and univariable statistically significant factors were included in a multivariable regression model.

Results

In total, 812 patients were included. Mean standardized incidence rates were 0.18/100 000 (range 0.11–0.27/100 000) with a significant trend over the years with an estimated annual percentage change of 1.3% per year (95% CI 0.4–2.1%). Median overall survival was 2.2 months, and estimated 1-year survival was 12%. Patients without distant metastases at diagnosis had an estimated 1-year survival of 21.6%. Prognostic factors for prolonged survival were double or triple therapy, age below 65 years, M0-status and absence of bilateral lymph node metastases.

Conclusions

ATC is rare, but often lethal, form of thyroid cancer, with a median survival of 2 months and 1-year survival of approximately 10%. The incidence is slightly rising in the Netherlands over the past 3 decades. There appears to be a subgroup of patients that survive longer, mainly those with relatively limited disease who underwent double or triple therapy. Further research is needed to define these patients more distinctively.

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Rougin Khalil, Leen Antonio, Michaël R Laurent, Karel David, Na Ri Kim, Pieter Evenepoel, Anton Eisenhauer, Alexander Heuser, Etienne Cavalier, Sundeep Khosla, Frank Claessens, Dirk Vanderschueren, and Brigitte Decallonne

Objective

Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover.

Design

Prospective cohort study.

Methods

Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied.

Results

Of 26 screened patients, 17 were included. The median age was 44 (range 20–75) years. The median time interval between baseline and first follow-up was 13 (6–27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4–12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01–0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7–35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered.

Conclusions

In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.