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Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the 'Dutch Approach' initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-tomedium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences. [ABSTRACT FROM AUTHOR]

Background: The joint Union International Contre le Cancer and American Jo int Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomizati on of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of o ur study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-sp ecific survival (DSS). Methods: We retrospectively studied two cohorts of adult DTC patients f rom The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC ) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV. Results: We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. How ever, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small. Conclusions: The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although thes e two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable. [ABSTRACT FROM AUTHOR]

Objective: Congenital hypothyroidism (CH) is defined as thyroid hormone de ficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pitu itary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxin e-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serv es as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C. Design and methods: In the present study, we evaluated 11 years of Dutch CH NBS us ing a database of referred cases by assessing the contribution of each criterion in the unique s tepwise T4-TSH-TBG NBS algorithm. Results: Between 2007 and the end of 2017, 1 963 465 newborns were scre ened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C ca ses by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T 4-TSH-TBG NBS algorithm was 21.0%. Conclusion: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS a lgorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the N etherlands, at the cost of a lower PPV compared to TSHbased NBS strategies. [ABSTRACT FROM AUTHOR]

Objective: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodinerefractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. Methods: From three Dutch centres Electronic Health Records (EHRs) of p atients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in o ther studies. Results: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade =3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). Conclusions: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life populati on and the SELECT study population regarding patient characteristics should be taken into account. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of somatostatin analogs (SSAs) on mortalit y in relation to disease control of acromegaly after pituitary surgery. Design: A retrospective study in two large tertiary referral centers i n The Netherlands. Methods: Overall, 319 patients with acromegaly in whom pituitary surger y was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatme nt with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and wit hout SSA at any moment postoperatively and at last visit. Results: In total, 27 deaths were observed. In univariate analysis, det erminants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions: Postoperative use of SSA is not associated with increased mort ality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease contr ol, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality. [ABSTRACT FROM AUTHOR]

Objective: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. Design: Retrospective multicenter study in eight University Medical Centers in The Netherlands. Methods: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. Results: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. Conclusions: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The Dutch National Registry of GH Treatment in Adults was established in 1998 as an initiative of the Ministry of Health. The main goals were to gain more insight into long-term efficacy, safety, and costs of GH therapy (GHT) in adult GH-deficient (GHD) patients in The Netherlands. METHODS: Baseline patient characteristics and diagnostic test procedures were evaluated. RESULTS: Until January 2009 in roughly 10 years, 2891 patients (1475 men and 1416 women, mean age 43.5±16.5 years) were registered. GHD was of childhood-onset (CO) in over 20% of the patients and of isolated in 11%. The most common causes of GHD were pituitary tumors and/or their treatment, craniopharyngiomas, and idiopathic GHD. In 85% of the patients, a GH stimulation test was performed, in the majority an insulin tolerance test (ITT) (49%) or a combined GHRH–arginine test (25%). In 12% of the patients, IGF1 levels were ≤–2 S.D. combined with two or more additional pituitary hormone deficits, and in 2%, it concerned patients with CO-GHD continuing GHT in adulthood. Over the years, the test of first choice shifted from ITT toward GHRH–arginine test. CONCLUSION: Nearly, 2900 patients were included in the nationwide surveillance database of the Dutch National Registry of GH Treatment in Adults until January 2009. Baseline patient characteristics are comparable to that reported previously. In 85% of these patients, the diagnosis of GHD was established by provocative testing, particularly an ITT or a combined GHRH–arginine test, with an evident increase in the percentage of GHRH–arginine tests being performed in the last years. [ABSTRACT FROM AUTHOR]