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Open access

Ichelle M.a.a. van Roessel, Boudewijn Bakker, Hanneke M van Santen, and Wassim Chemaitilly

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 manuscript offers a summary of current knowledge, controversies and areas for future research pertaining to this area.

Open access

Alexander Heinzel, Dirk Müller, Hanneke M van Santen, Sarah C Clement, Arthur B Schneider, and Frederik A Verburg

Background

Childhood cancer survivors (CCS) who received radiation therapy exposing the thyroid gland are at increased risk of developing differentiated thyroid cancer (DTC). Therefore, the International Guideline Harmonization Group (IGHG) on late effects of childhood cancer therefore recommends surveillance. It is unclear whether surveillance reduces mortality.

Aim

The aim of this study was to compare four strategies for DTC surveillance in CCS with the aim of reducing mortality: Strategy-1, no surveillance; Strategy-2, ultrasound alone; Strategy-3, ultrasound followed by fine-needle biopsy (FNB); Strategy-4, palpation followed by ultrasound and FNB.

Materials and methods

A decision tree was formulated with 10-year thyroid cancer-specific survival as the endpoint, based on data extracted from literature.

Results

It was calculated that 12.6% of CCS will develop DTC. Using Strategy-1, all CCS with DTC would erroneously not be operated upon, but no CCS would have unnecessary surgery. With Strategy-2, all CCS with and 55.6% of CCS without DTC would be operated. Using Strategy-3, 11.1% of CCS with DTC would be correctly operated upon, 11.2% without DTC would be operated upon and 1.5% with DTC would not be operated upon. With Strategy-4, these percentages would be 6.8, 3.9 and 5.8%, respectively. Median 10-year survival rates would be equal across strategies (0.997).

Conclusion

Different surveillance strategies for DTC in CCS all result in the same high DTC survival. Therefore, the indication for surveillance may lie in a reduction of surgery-related morbidity rather than DTC-related mortality. In accordance with the IGHG guidelines, the precise strategy should be decided upon in a process of shared decision-making.

Open access

Anne-Sophie C A M Koning, Philippe C Habets, Marit Bogaards, Jan Kroon, Hanneke M van Santen, Judith M de Bont, and Onno C Meijer

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.

Open access

Laura van Iersel, Sarah C Clement, Antoinette Y N Schouten-van Meeteren, Annemieke M Boot, Hedi L Claahsen-van der Grinten, Bernd Granzen, K Sen Han, Geert O Janssens, Erna M Michiels, A S Paul van Trotsenburg, W Peter Vandertop, Dannis G van Vuurden, Hubert N Caron, Leontien C M Kremer, and Hanneke M van Santen

Objective

The incidence of cranial radiotherapy (cRT)–induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS.

Design

Nationwide, 10-year retrospective study of irradiated CBTS.

Methods

TSHD was defined as ‘diagnosed’ when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as ‘presumed’ when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test).

Results

Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9–9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P < 0.01) to diagnosis of TSHD and 12.4% (P= 0.02) in GH-deficient CBTS without diagnosed TSHD.

Conclusions

FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.