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M Lafeber, A M E Stades, G D Valk, M J Cramer, F Teding van Berkhout and P M J Zelissen

Background

Cabergoline, a dopamine agonist used to treat hyperprolactinemia, is associated with an increased risk of fibrotic adverse reactions, e.g. cardiac valvular fibrosis, pleuropulmonary, and retroperitoneal fibrosis.

Objective

This study evaluated the prevalence and risk of fibrotic adverse reactions during cabergoline therapy in hyperprolactinemic and acromegalic patients.

Design

A cross-sectional study was conducted in a University Hospital.

Patients

A total of 119 patients with hyperprolactinemia and acromegaly who were on cabergoline therapy participated in the study.

Methods

All patients were requested to undergo a cardiac assessment, pulmonary function test, chest X-ray, and blood tests as recommended by the European Medicine Agency. Matched controls were recruited to compare the prevalence of valvular regurgitation. Cardiac valvular fibrosis was evaluated by assessing valvular regurgitation and the mitral valve tenting area (MVTa). The risk of pleuropulmonary fibrosis was assessed by a pulmonary function test, a chest X-ray, and if indicated, by additional imaging studies.

Results

The prevalence of clinically relevant valvular regurgitation was not significantly different between cases (11.3%) and controls (6.1%; P=0.16). The mean MVTa was 1.27±0.17 and 1.24±0.21 cm2 respectively (P=0.54). Both valvular regurgitation and the MVTa were not related to the cumulative dose of cabergoline. A significantly decreased pulmonary function required additional imaging in seven patients. In one patient, possible early interstitial fibrotic changes were seen. Lung function impairment was not related to the cumulative cabergoline dose.

Conclusion

Cabergoline, typically dosed for the long-term treatment of hyperprolactinemia or acromegaly, appears not to be associated with an increased risk of fibrotic adverse events.

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J A A Meijer, L E H Bakker, G D Valk, W W de Herder, J H W de Wilt, R T Netea-Maier, N Schaper, E Fliers, P Lips, J T Plukker, T P Links and J A Smit

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.

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E B Conemans, L Lodewijk, C B Moelans, G J A Offerhaus, C R C Pieterman, F H Morsink, O M Dekkers, W W de Herder, A R Hermus, A N van der Horst-Schrivers, M L Drent, P H Bisschop, B Havekes, L A A Brosens, K M A Dreijerink, I H M Borel Rinkes, H Th M Timmers, G D Valk and M R Vriens

Objective

Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.

Design and methods

Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.

Results

We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.

Conclusion

Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.