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Purpose There is currently no consensus on which protective strategy is most effective to prevent I-131 uptake in the thyroid during medical interventions in children. We aimed to collect the best available evidence to determine which pharmacological intervention is most effective in protecting the thyroid gland from damage by radioactive iodine (RAI). Methods Literature searches were performed using PubMed, Embase, OLDMEDLINE, and the Cochrane Central Register of Controlled Trials. Only original studies were included (1950–2022). Studies comparing pharmacological prevention of the thyroid against RAI uptake or occurrence of hypothyroidism, thyroid nodule or thyroid cancer were included. Included studies were graded according to the Grading of Recommendations Assessment, Development and Evaluation considerations. Pharmacological interventions were compared for effectiveness on reduction of thyroidal intake or relevant clinical thyroidal outcomes. Results Forty studies were included. Quality of included studies was low and many different outcome variables were used, making meta-analysis impossible. In 81% of studies, the pharmacological intervention could not prevent RAI uptake or thyroid damage. The administration of potassium iodide (KI) 1 h before exposure to RAI seemed most effective to reduce thyroidal uptake, however, hypothyroidism was reported in up to 64% as well as several cases of thyroid carcinoma. The combination of KI, thyroxine and thiamazole reduced RAI uptake and occurrence of hypothyroidism; yet, after follow-up of 9 years, still 50% of patients developed hypothyroidism. KI with potassium perchlorate showed hypothyroidism to occur in up to 12% of patients after short follow-up time. Conclusions The lack of well-designed studies impairs making strong recommendations on the optimal way to prevent thyroid damage when using radioactive coupled ligands for medical interventions. To improve the protection of the thyroid against radiation damage by I-131, well-designed randomized clinical trials with sufficient follow-up time, comparing new protective strategies’ effects on valid and well-defined thyroid outcomes are needed.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Thyroid dysfunction is known to occur following radiotherapy or chemotherapy for childhood cancer. Thyroid dysfunction during treatment for childhood cancer has, however, not been studied extensively, although thyroid hormones are of utmost importance during childhood. This information is needed to develop adequate screening protocols and may be of special importance with upcoming drugs, such as checkpoint inhibitors, which are highly associated with thyroid dysfunction in adults. In this systematic review we have evaluated the occurrence and risk factors for thyroid dysfunction in children during treatment with systemic antineoplastic drugs, up to three months after the end of therapy. Two review authors independently performed the study selection, data extraction and risk of bias assessment of included studies. After an extensive search (January 2021), in total six heterogeneous articles were included, reporting on 91 childhood cancer patients with a thyroid function test during treatment with systemic antineoplastic therapy for childhood cancer. All studies had risk of bias issues. Primary hypothyroidism was found in 18% of children treated with high dose interferon-α (HDI-α) and in 0–10% after tyrosine kinase inhibitors (TKIs). Transient euthyroid sick syndrome (ESS) was common (in 42–100%) during treatment with systematic multi-agent chemotherapy. Only one study addressed possible risk factors, showing different types of treatment to increase the risk. However, the exact prevalence, risk factors and clinical consequences of thyroid dysfunction remain unclear. Prospective high-quality studies including large study samples are needed to longitudinally assess the prevalence, risk factors and possible consequences of thyroid dysfunction during childhood cancer treatment.

ObjectiveHypothalamic syndrome (HS) in childhood is a rare condition. Its epidemiology is not well known because incidence and prevalence are related to very rare underlying diseases. In addition, different criteria for the syndrome are used across studies. Recognizing the HS may be difficult, due to its rareness and variety of symptoms. Having diagnostic criteria for signs and symptoms of hypothalamic dysfunction may aid in early recognition and diagnosis, in the reporting and understanding of its etiology, in predicting its course and its management. We aimed to define diagnostic criteria for hypothalamic dysfunction and a score for the presence of HS in childhood.MethodsDiagnostic criteria for hypothalamic dysfunction were developed and subdivided into hyperphagia, hypophagia, body mass index, behavioral problems, sleep disorders, temperature regulation disorders, pituitary dysfunction, radiological hypothalamic assessment, and presence/suspicion of a hypothalamic genetic syndrome. Subsequently, the scoring system was tested in a retrospective cohort of 120 patients at risk for hypothalamic dysfunction.ResultsA score for presence of HS was developed. Using this new hypothalamic score, in total 52.5% were scored as having HS. Of these patients, 76.7% were diagnosed with pituitary dysfunction, 32.5% with hyperphagia, 40% with sleep disorders, and 14.2% with temperature dysregulation. For several criteria, clinical data was missing in more than 50% of cases.ConclusionsThe here proposed diagnostic criteria for hypothalamic dysfunction and score for presence of HS may be used for care purposes and to aid in early recognition. Also it will be useful for research or registration purposes.

Contains fulltext : 291510.pdf (Publisher’s version ) (Open Access) BACKGROUND: Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study). PROCEDURE: From the multi-center DCCSS LATER cohort of 6165 five-year survivors diagnosed during 1963-2001, we invited 4735 eligible survivors in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific subprojects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, clinical tests, questionnaires). Furthermore, blood/saliva samples were taken for deoxyribonucleic acid (DNA) extraction. RESULTS: In total, 2519 (53.2%) survivors participated in the LATER 2 study. When comparing participants with nonparticipants, we observed that males, CNS survivors, and those treated with surgery only were less likely to participate. Of the participating survivors, 49.3% were female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8-54.7 years) and median attained age was 34.4 years (range 15.4-66.6 years). CONCLUSIONS: The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and physical and psychosocial health outcomes and factors for early recognition of those health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors.

Endocrine Connections 11(12), e220092 (2022). doi:10.1530/EC-22-0092, Published by BioScientifica, Bristol

At present, no European recommendations for the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC) exist. Differences in clinical, molecular, and pathological characteristics between pediatric and adult DTC emphasize the need for specific recommendations for the pediatric population. An expert panel was instituted by the executive committee of the European Thyroid Association including an international community of experts from a variety of disciplines including pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology. The 2015 American Thyroid Association Pediatric Guideline was used as framework for the present guideline. Areas of discordance were identified, and clinical questions were formulated. The expert panel members discussed the evidence and formulated recommendations based on the latest evidence and expert opinion. Children with a thyroid nodule or DTC require expert care in an experienced center. The present guideline provides guidance for healthcare professionals to make well-considered decisions together with patients and parents regarding diagnosis, treatment, and follow-up of pediatric thyroid nodules and DTC.

Childhood cancer survivors are at risk for developing endocrine disorders, including deficits in growth hormone, thyroid hormone and sex hormones. The influence these hormones have on cell growth and metabolism has raised concerns regarding the safety of their use as treatments in survivors of childhood cancer and brain tumors. This article offers a summary of current knowledge, controversies and areas for future research pertaining to this area.

Background Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e’ mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8–60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2–48.8). Between the first and second evaluation, the e’ mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e’ mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e’ mean (β coefficient: −0.169, 95% CI: −0.292; −0.047, P = 0.008 and β coefficient: −0.177, 95% CI: −0.240; −0.113, P < 0.001, respectively). Conclusions and relevance In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Error in Figure In the original article [1], there was a mistake in Figure 1 as published. In this figure, two years are missing (2000 and 2001). The AAPC values as previously published are correct. The corrected Figure 1 appears below. In addition, in the original article, there was a mistake in Figure 2A–C as published. In these figures, two years are missing (2000 and 2001). The AAPC values were correct and do not require adjustment. The corrected Figure 2A–C appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated. (figure presented).

Background Metaiodobenzylguanidine (MIBG) labeled with radioisotopes can be used for diagnostics 123I−) and treatment (131I−) in patients with neuroblastic tumors. Thyroid dysfunction has been reported in 52% of neuroblastoma (NBL) survivors after 131I-MIBG, despite thyroid protection. Diagnostic 123I-MIBG is not considered to be hazardous for thyroid function; however, this has never been investigated. Therefore, the aim of this study was to evaluate the prevalence of thyroid dysfunction in survivors of a neuroblastic tumor who received diagnostic 123I-MIBG only. Methods Thyroid function and uptake of 123I− in the thyroid gland after 123I-MIBG administrations were evaluated in 48 neuroblastic tumor survivors who had not been treated with 131I-MIBG. All patients had received thyroid prophylaxis consisting of potassium iodide or a combination of potassium iodide, thiamazole and thyroxine during exposure to 123I-MIBG. Results After a median follow-up of 6.6 years, thyroid function was normal in 46 of 48 survivors (95.8%). Two survivors [prevalence 4.2% (95% CI 1.2–14.0)] had mild thyroid dysfunction. In 29.2% of the patients and 11.1% of images 123I− uptake was visible in the thyroid. In 1 patient with thyroid dysfunction, weak uptake of 123I− was seen on 1 of 10 images. Conclusions The prevalence of thyroid dysfunction does not seem to be increased in patients with neuroblastic tumors who received 123I-MIBG combined with thyroid protection. Randomized controlled trials are required to investigate whether administration of 123I-MIBG without thyroid protection is harmful to the thyroid gland.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Gonadal dysfunction and infertility after cancer treatment are major concerns for childhood cancer survivors and their parents. Uncertainty about fertility or being diagnosed with infertility has a negative impact on quality of survival. In this article, determinants of gonadal damage are reviewed and consequences for fertility and pregnancies are discussed. Recommendations for screening and treatment of gonadal function are provided. These should enable timely treatment of gonadal insufficiency aiming to improve linear growth, pubertal development, and sexual functioning. Options for fertility preservation are discussed.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Metaiodobenzylguanidine (MIBG) labeled with radioisotopes can be used for diagnosticsThyroid function and uptake ofAfter a median follow-up of 6.6 years, thyroid function was normal in 46 of 48 survivors (95.8%). Two survivors [prevalence 4.2% (95% CI 1.2-14.0)] had mild thyroid dysfunction. In 29.2% of the patients and 11.1% of imagesThe prevalence of thyroid dysfunction does not seem to be increased in patients with neuroblastic tumors who received

Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling. However, these are mostly ineffective and no medications that are specifically approved for the treatment of HS are available. Specific challenges in HS are because the syndrome represents an adverse effect of different diseases, and that diagnostic criteria, aetiology, pathogenesis and management of HS are not completely defined.

Background Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms. Objective In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone. Main outcome measures The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured. Results In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient. Conclusions Dexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.

Contains fulltext : 225882.pdf (Publisher’s version ) (Closed access) Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged

Purposes Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer.

Objective To evaluate the usefulness of [18F]fluorodeoxyglucose (FDG) positron emissive tomography (PET)/CT in patients with low detectable thyroglobulin levels suspicious for persistent or recurrent differentiated thyroid cancer (DTC). Methods A retrospective case series study evaluating FDG PET/CT in patients with detectable thyroglobulin (Tg) levels (≥0.20 and Results Twenty-seven patients underwent FDG PET/CT. Median Tg level at FDG PET/CT was 2.00 ng/mL (range 0.30–9.00). FDG PET/CT was positive in 14 patients (51.9%): lesions suspicious for lymph node metastases were depicted in 12 patients, and lung metastases in 2. DTC was confirmed in 13/14 FDG PET/CT-positive patients. In 9/13 patients with a negative FDG PET/CT, DTC was confirmed ≤3 months after FDG PET/CT. The sensitivity, PPV, specificity and NPV were 59.1, 92.9, 80.0 and 30.8%, respectively. Conclusions This case series shows that FDG PET/CT might be useful to detect persistent or recurrent DTC in patients with low detectable Tg. However, when FDG PET/CT is negative, this does not rule out DTC and further investigations are necessary.

Background: Thyroid hormone anomalies during childhood might affect neurological development, school performance and quality of life, as well as daily energy, growth, body mass index and bone development. Thyroid dysfunction (hypo- or hyperthyroidism) may occur during childhood cancer treatment, although its prevalence is unknown. The thyroid profile may also change as a form of adaptation during illness, which is called euthyroid sick syndrome (ESS). In children with central hypothyroidism, a decline in FT4 of >20% has been shown to be clinically relevant. We aimed to quantify the percentage, severity and risk factors of a changing thyroid profile in the first three months of childhood cancer treatment. Methods: In 284 children with newly diagnosed cancer, a prospective evaluation of the thyroid profile was performed at diagnosis and three months after starting treatment. Results: Subclinical hypothyroidism was found in 8.2% and 2.9% of children and subclinical hyperthyroidism in 3.6% and in 0.7% of children at diagnosis and after three months, respectively. ESS was present in 1.5% of children after three months. In 28% of children, FT4 concentration decreased by ≥20%. Conclusions: Children with cancer are at low risk of developing hypo- or hyperthyroidism in the first three months after starting treatment but may develop a significant decline in FT4 concentrations. Future studies are needed to investigate the clinical consequences thereof.

Significance The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. This study describes an organoid-based model system to study mouse and human thyroid biology. Moreover, the study explores the potential of human organoids for modeling autoimmune disease, the anti-TSH receptor (TSHR) antibody-driven Graves’ hyperthyroidism., The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of three-dimensional (3D) organoids from adult thyroid tissue representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCOs) harbor the complete machinery of hormone production as visualized by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarized epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single-cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs. We show clinically relevant responses (increased proliferation and hormone secretion) of human TFCOs toward a panel of Graves’ disease patient sera, demonstrating that organoids can model human autoimmune disease.

Simple Summary Thyroid cancer is a rare disease in childhood; however, its incidence is rising. Thyroid cancer consists of three main types: Papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and medullary thyroid cancer (MTC). The aim of our retrospective study was to investigate the incidence and survival trends of these three thyroid cancer types in Dutch children, adolescents, and young adults over a 30-year life span. In total, 839 patients aged 0–24 years had been diagnosed with thyroid cancer between 1990 and 2019. The incidence of PTC increased significantly over time, the incidence of FTC showed a stable trend, while the incidence of MTC decreased significantly. Overall, the 10-year survival rates over the last decades were high (>95%) for PTC, FTC, and MTC in young individuals. Abstract Thyroid cancer is the most common endocrine malignancy in children. A rising incidence has been reported worldwide. Possible explanations include the increased use of enhanced imaging (leading to incidentalomas) and an increased prevalence of risk factors. We aimed to evaluate the incidence and survival trends of thyroid cancer in Dutch children, adolescents, and young adults (0–24 years) between 1990 and 2019. The age-standardized incidence rates of differentiated thyroid cancer (DTC, including papillary and follicular thyroid cancer (PTC and FTC, respectively)) and medullary thyroid cancer (MTC), the average annual percentage changes (AAPC) in incidence rates, and 10-year overall survival (OS) were calculated based on data obtained from the nationwide cancer registry (Netherlands Cancer Registry). A total of 839 patients aged 0–24 years had been diagnosed with thyroid carcinoma (PTC: 594 (71%), FTC: 128 (15%), MTC: 114 (14%)) between 1990 and 2019. The incidence of PTC increased significantly over time (AAPC +3.6%; 95%CI +2.3 to +4.8), the incidence rate of FTC showed a stable trend ((AAPC −1.1%; 95%CI −3.4 to +1.1), while the incidence of MTC decreased significantly (AAPC: −4.4% (95%CI −7.3 to −1.5). The 10-year OS was 99.5% (1990–1999) and 98.6% (2000–2009) in patients with DTC and 92.4% (1990–1999) and 96.0% (2000–2009) in patients with MTC. In this nationwide study, a rising incidence of PTC and decreasing incidence of MTC were observed. For both groups, in spite of the high proportion of patients with lymph node involvement at diagnosis for DTC and the limited treatment options for MTC, 10-year OS was high.

Objective Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. Design It is a retrospective case series. Methods Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. Results Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. Conclusions This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.

Background Prevalent vitamin D deficiency (VDD) and low bone mineral density (BMD) have led to vitamin D supplementation for children with cancer, regardless vitamin D status. However, it remains unsettled whether this enhances bone strength. We sought to address this issue by carrying out a systematic review of the literature. Methods We conducted a literature search using PubMed, Embase, and Cochrane databases. Studies including children up to 5 years after cancer therapy were assessed for the association between 25‐hydroxyvitamin D (25OHD) levels and BMD Z‐scores or fractures, and the effect of vitamin D supplementation on BMD or fractures. Evidence quality was assessed using the GRADE methodology. Results Nineteen studies (16 observational and 3 interventional, mainly involving children with hematologic malignancies) were included. One study which analyzed 25OHD as a threshold variable (≤10 ng/ml) found a significant association between 25OHD levels and BMD Z‐scores, while 25OHD as a continuous variable was not significantly associated with BMD Z‐scores in 14 observational studies. We found neither a significant association between lower 25OHD levels and fractures (2 studies), nor between vitamin D (and calcium) supplementation and BMD or fracture frequency (3 studies) (very low quality evidence). Conclusion There is a lack of evidence for an effect of vitamin D (and calcium) supplementation on BMD or fractures in children with cancer. Further research is needed; until then, we recommend dietary vitamin D/calcium intake in keeping with standard national guidelines, and periodic 25OHD monitoring to detect levels, The relationship between 25OHD levels and BMD or fractures has been inadequately studied, and there is lack of evidence for an effect of universal vitamin D supplementation on BMD or fractures in children with cancer. Further research is needed; we provide recommendations to ensure 25OHD levels adequate for bone health in this population based on the current very low quality evidence and expert opinion. ​

PURPOSE Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS. METHODS Prevalence of and risk factors for significant weight gain (body mass index [BMI] change ≥ +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors. RESULTS Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS. CONCLUSION Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance.

Background Potential late effects of treatment for childhood cancer include adiposity, insulin resistance, dyslipidemia, and hypertension. These risk factors cluster together as metabolic syndrome and increase the risk for development of diabetes mellitus and cardio- and cerebrovascular disease. Knowledge on risk factors, timely diagnosis, and preventive strategies is of importance to prevent cardio- and cerebrovascular complications and improve quality of life. Currently, no national cohort studies on the prevalence and determinants of metabolic syndrome in childhood cancer survivors, including biomarkers and genetic predisposition, are available. Objective The objectives of the Dutch LATER METS study are to assess 1) the prevalence and risk factors of metabolic syndrome and its separate components, and 2) the potential diagnostic and predictive value of additional biomarkers for surveillance of metabolic syndrome in the national cohort of adult long-term survivors of childhood cancer. Methods This is a cross-sectional study based on recruitment of all survivors treated in the Netherlands between 1963 and 2002. Metabolic syndrome will be classified according to the definitions of the third Adult Treatment Panel Report of the National Cholesterol Education Program as well as the Joint Interim Statement and compared to reference data. Dual-energy x-ray absorptiometry scans were performed to assess body composition in more detail. The effect of patient characteristics, previous treatment, and genetic variation on the risk of metabolic syndrome will be assessed. The diagnostic and predictive value of novel biomarkers will be tested. Results Patient accrual started in 2016 and lasted until April 2020. A total of 2380 survivors from 7 pediatric oncology hospitals have participated. From July 2020, biomarker testing, single nucleotide polymorphism analysis, and data analysis will be performed. Conclusions The Dutch LATER METS study will provide knowledge on clinical and genetic determinants of metabolic syndrome and the diagnostic value of biomarkers in childhood cancer survivors. The results of this study will be used to optimize surveillance guidelines for metabolic syndrome in survivors based on enhanced risk stratification and screening strategies. This will improve diagnosis of metabolic syndrome and prevent complications. International Registered Report Identifier (IRRID) DERR1-10.2196/21256

Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.

Childhood cancer survivors (CCS) are at increased risk of developing thyroid disorders during follow-up. Radiation therapy to a field that includes the thyroid gland and 131I-meta-iodobenzylguanidine (131I-MIBG) treatment are the main risk factors for thyroid sequelae, which include decreased thyroid function, hyperthyroidism, thyroid nodules, and differentiated thyroid cancer, specifically papillary thyroid carcinoma. In addition, treatment with anti-neoplastic drugs or immunotherapy may result in thyroid dysfunction. Central hypothyroidism may be seen in CCS after cranial radiotherapy, after immunotherapy, or secondary to a brain tumor that involves the hypothalamic-pituitary region and will be discussed elsewhere in this series. In this chapter, the prevalence, risk factors, surveillance, and management of primary hypothyroidism, hyperthyroidism, thyroid nodules, and differentiated thyroid carcinoma in CCS are discussed.

Contains fulltext : 245660.pdf (Publisher’s version ) (Closed access) Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [β-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Childhood cancer survivors (CCS) are at increased risk of developing thyroid disorders during follow-up. Radiation therapy to a field that includes the thyroid gland and 131I-meta-iodobenzylguanidine (131I-MIBG) treatment are the main risk factors for thyroid sequelae, which include decreased thyroid function, hyperthyroidism, thyroid nodules, and differentiated thyroid cancer, specifically papillary thyroid carcinoma. In addition, treatment with anti-neoplastic drugs or immunotherapy may result in thyroid dysfunction. Central hypothyroidism may be seen in CCS after cranial radiotherapy, after immunotherapy, or secondary to a brain tumor that involves the hypothalamic-pituitary region and will be discussed elsewhere in this series. In this chapter, the prevalence, risk factors, surveillance, and management of primary hypothyroidism, hyperthyroidism, thyroid nodules, and differentiated thyroid carcinoma in CCS are discussed.

Endocrine late effects, including reproductive disorders and secondary thyroid cancer, have been reported in up to 50 %childhood cancer survivors (CCS) more than 5 years after treatment. Most endocrine disorders are amenable to treatment; awareness of symptoms is therefore of great importance. Recognition of these symptoms may be delayed however because many are nonspecific. Timely treatment of endocrine disorders improves quality of life in CCS and prevents possible consequences, such as short stature, bone and cardiovascular disorders, and depression. At-risk CCS must therefore be regularly and systematically monitored. This article provides a summary of the most commonly reported endocrine late effects in CCS.

Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.

From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed.All studies included childhood cancer survivors, diagnosed at age21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios.Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P.0001) and age15 years at radiation therapy (RR = 1.3, P = .005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males14 years of age, increasing to 29% for females15 years of age.A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses.