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T Vanbrabant, M Fassnacht, G Assie and O M Dekkers

Objective

Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis. Many publications in ACC report on risk factors for a poor outcome; one risk factor studied is hormonal hypersecretion (cortisol, sex-hormones, steroid precursors or aldosterone). The aim of this systematic review was to study the association between hormonal secretion and recurrence or mortality in ACC.

Design

Systematic review and meta-analysis. We searched PubMed, EMBASE and The Cochrane library (January 2018) for cohort studies examining the association between hormonal secretion on overall or recurrence-free survival in ACC.

Methods

A random-effects model meta-analysis was performed to obtain a weighted relative risk comparing cortisol-secreting and/or androgen-secreting ACCs to non-secreting tumours regarding overall and recurrence-free survival. Risk of bias assessment was performed for all studies included.

Results

Nineteen publications were included representing a total of 3814 patients. Most studies were generally considered low/intermediate risk of bias. Meta-analysis showed higher mortality risk for cortisol-secreting ACCs, weighted relative risk 1.71 (95% CI: 1.18–2.47) combining studies that adjusted for tumour stage; also a higher recurrence risk was found for cortisol producing ACCs, relative risk 1.43 (95% CI: 1.18–1.73). Androgen secretion was not clearly associated with survival (RR: 0.82, 95% CI: 0.60–1.12).

Conclusion

This systematic review and meta-analysis show that cortisol-secreting ACCs are associated with a worse overall survival; future research is needed to establish whether this association points to negative effects of cortisol action, whether it signifies a more aggressive ACC subtype or whether cortisol is merely a prognostic marker.

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O M Dekkers, J M Timmermans, J W A Smit, J A Romijn and A M Pereira

Objectives

To compare the cortisol response of the 1 μg and the 250 μg ACTH test in a large study of patients with suspected adrenal insufficiency.

Design

Retrospective cohort study.

Methods

Single center study assessing patients tested for primary or secondary adrenal insufficiency between January 2004 and December 2007, who had both ACTH tests (1 μg and 250 μg; n=207) within a time interval of 6 weeks. Test results were compared with a Bland–Altman plot and McNemar's test.

Results

The mean difference between the cortisol responses in the two ACTH tests was 26 nmol/l (95% confidence interval (CI) 13, 40), showing a marginally higher response for the 250 μg test. The diagnostic performances of the two tests were similar (P=0.49) using a cut-off value for cortisol of 550 nmol/l. A normal cortisol response to the 1 μg ACTH test could be accompanied by an abnormal response to the 250 μg ACTH test, and vice versa.

Conclusion

This study shows that the 1 μg and the 250 μg ACTH tests have comparable cortisol responses in patients with suspected adrenal insufficiency. However, in individual patients, the difference in cortisol response to the two tests can be substantial, and the response in the 250 μg test is not invariably higher than the response in a 1 μg test.

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O M Dekkers, V Ehrenstein, M Bengtsen, D Kormendine Farkas, A M Pereira, H T Sørensen and J O L Jørgensen

Objective

To enhance the precision of the risk estimate for breast cancer in hyperprolactinemia patients by collecting more data and pooling our results with available data from former studies in a meta-analysis.

Design

Population-based cohort study and meta-analysis of the literature.

Methods

Using nationwide registries, we identified all patients with a first-time diagnosis of hyperprolactinemia during 1994–2012 including those with a new breast cancer diagnoses after the start of follow-up. We calculated standardised incidence ratios (SIRs) as a measure of relative risk (RR) using national cancer incidence rates. We performed a meta-analysis, combining data from our study with data in the existing literature.

Results

We identified 2457 patients with hyperprolactinemia and 20 breast cancer cases during 19 411 person-years of follow-up, yielding a SIR of 0.99 (95% CI 0.60–1.52). Data from two additional cohort studies were retrieved and analyzed. When the three risk estimates were pooled, the combined RR was 1.04 (95% CI 0.75–1.43).

Conclusions

We found no increased risk of breast cancer among patients with hyperprolactinemia.

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Femke M van Haalen, Leonie H A Broersen, Jens O Jorgensen, Alberto M Pereira and Olaf M Dekkers

The aim of this systematic review and meta-analysis was to investigate whether mortality is increased in patients biochemically cured after initial treatment for Cushing's disease. This is a systematic review and meta-analysis of follow-up studies in patients cured from Cushing's disease after initial treatment was performed. Eight electronic databases were searched from 1975 to March 2014 to identify potentially relevant articles. Original articles reporting the standardized mortality ratio (SMR) for patients cured of Cushing's disease were eligible for inclusion. SMRs were pooled in a random effects model. I 2 statistics was used for quantification of heterogeneity. Eight cohort studies with a total of 766 patients were included. Out of eight studies, seven showed an SMR above 1.0 for cured patients. The pooled SMR was 2.5 (95% CI 1.4–4.2). The I 2 statistics showed evidence for statistical heterogeneity (78%, Q-statistics P<0.001), which was largely explained by two outliers. This meta-analysis reveals that mortality remains increased in patients with Cushing's disease even after initial biochemical cure remission, suggesting that cure does not directly reverse the metabolic consequences of long-term overexposure to cortisol. Other conditions such as hypopituitarism, including persistent adrenocortical insufficiency after surgery, may also contribute to the increased mortality risk.

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A de Rooij, J P Vandenbroucke, J W A Smit, M P M Stokkel and O M Dekkers

Background

Despite the long experience with radioiodine for hyperthyroidism, controversy remains regarding the optimal method to determine the activity that is required to achieve long-term euthyroidism.

Objectives

To compare the effect of estimated versus calculated activity of radioiodine in hyperthyroidism.

Design

Systematic review and meta-analysis.

Methods

We searched the databases Medline, EMBASE, Web of Science, and Cochrane Library for randomized and nonrandomized studies, comparing the effect of activity estimation methods with dosimetry for hyperthyroidism. The main outcome measure was the frequency of treatment success, defined as persistent euthyroidism after radioiodine treatment at the end of follow-up in the dose estimated and calculated dosimetry group. Furthermore, we assessed the cure rates of hyperthyroidism.

Results

Three randomized and five nonrandomized studies, comparing the effect of estimated versus calculated activity of radioiodine on clinical outcomes for the treatment of hyperthyroidism, were included. The weighted mean relative frequency of successful treatment outcome (euthyroidism) was 1.03 (95% confidence interval (CI) 0.91–1.16) for estimated versus calculated activity; the weighted mean relative frequency of cure of hyperthyroidism (eu- or hypothyroidism) was 1.03 (95% CI 0.96–1.10). Subgroup analysis showed a relative frequency of euthyroidism of 1.03 (95% CI 0.84–1.26) for Graves' disease and of 1.05 (95% CI 0.91–1.19) for toxic multinodular goiter.

Conclusion

The two main methods used to determine the activity in the treatment of hyperthyroidism with radioiodine, estimated and calculated, resulted in an equally successful treatment outcome. However, the heterogeneity of the included studies is a strong limitation that prevents a definitive conclusion from this meta-analysis.

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O M Dekkers, N R Biermasz, J W A Smit, L E Groot, F Roelfsema, J A Romijn and A M Pereira

Objective: Quality of life (QoL) has become increasingly important in the evaluation of treatment of pituitary and hormonal diseases. A reduced QoL has been reported in childhood-onset craniopharyngioma; however, reports of QoL in adult craniopharyngioma patients are scarce. In the present study, we assessed QoL in adult patients successfully treated for craniopharyngioma in our centre.

Design: This was a case-control study.

Methods: In this study, we assessed QoL in 29 adult patients in remission during long-term follow-up after treatment for craniopharyngioma. Four validated health-related questionnaires (HADS, MFI-20, NHP and SF-36) were used, covering multiple aspects of physical, psychological and social functioning. Patient outcomes were compared to controls (n = 142) and to age-adjusted reference values derived from literature.

Results: General fatigue, physical fatigue, energy, physical condition and physical mobility were significantly impaired, compared with controls. The main independent predictors for decreased QoL were visual field defects (depression, total HADS score, activity, motivation and energy), female gender (depression, motivation and pain), repeat surgery (role limitations due to emotional problems) and radiotherapy (mental fatigue) (the last two predictors to a lesser extent).

Conclusion: Adult patients treated for craniopharyngioma show persistent impairment in QoL, especially in the physical subscales.

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O M Dekkers, S Hammer, R J W de Keizer, F Roelfsema, P J Schutte, J W A Smit, J A Romijn and A M Pereira

Objective: The natural history of non-functioning pituitary macroadenomas (NFMA) has not been completely elucidated. Therefore, we evaluated pituitary function, visual fields, and tumor size during long-term follow-up of non-operated patients with NFMA.

Design: Follow-up study.

Patients: Twenty-eight patients (age 55 ± 3 years) with NFMA, not operated after initial diagnosis, were included.

Results: Initial presentation was pituitary insufficiency in 44%, visual field defects in 14%, apoplexy in 14%, and chronic headache in 7% of the patients. The duration of follow-up was 85 ± 13 months. Radiological evidence of tumor growth was observed in 14 out of 28 patients (50%) after duration of follow-up of 118 ± 24 months. Six patients (21%) were operated, because tumor growth was accompanied by visual field defects. Visual impairments improved in all the cases after transsphenoidal surgery. Spontaneous reduction in tumor volume was observed in eight patients (29%). No independent predictors for increase or decrease in tumor volume could be found by regression analysis.

Conclusion: Observation alone is a safe alternative for transsphenoidal surgery in selected NFMA patients, without the risk of irreversibly compromising visual function.

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A A van der Klaauw, J A Romijn, N R Biermasz, J W A Smit, J van Doorn, O M Dekkers, F Roelfsema and A M Pereira

Context: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement.

Patients and methods: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued.

Results: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 ± 0.5 mmol/l at baseline vs 1.7 ± 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 ± 0.7 mmol/l to 5.0 ± 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged.

Conclusion: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.

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E N Klein Hesselink, D Steenvoorden, E Kapiteijn, E P Corssmit, A N A van der Horst-Schrivers, J D Lefrandt, T P Links and O M Dekkers

Context

Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.

Methods

All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand–foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.

Results

In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33–64)%, and was 17 (95% CI 12–24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14–77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34–46)% and 27 (95% CI 22–32)% respectively. Clinical benefit was found in 53 (95% CI 48–59)% of DTC patients on sorafenib, and in 84 (95% CI 79–88)% and 55 (95% CI 49–61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.

Conclusion

The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

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Jakob Dal, Ulla Feldt-Rasmussen, Marianne Andersen, Lars Ø Kristensen, Peter Laurberg, Lars Pedersen, Olaf M Dekkers, Henrik Toft Sørensen and Jens Otto L Jørgensen

Design

Valid data on acromegaly incidence, complications and mortality are scarce. The Danish Health Care System enables nationwide studies with complete follow-up and linkage among health-related databases to assess acromegaly incidence, prevalence, complications and mortality in a population-based cohort study.

Method

All incident cases of acromegaly in Denmark (1991–2010) were identified from health registries and validated by chart review. We estimated the annual incidence rate of acromegaly per 106 person-years (py) with 95% confidence intervals (95% CIs). For every patient, 10 persons were sampled from the general population as a comparison cohort. Cox regression and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used.

Results

Mean age at diagnosis (48.7 years (CI: 95%: 47.2–50.1)) and annual incidence rate (3.8 cases/106 persons (95% CI: 3.6–4.1)) among the 405 cases remained stable. The prevalence in 2010 was 85 cases/106 persons. The patients were at increased risk of diabetes mellitus (HR: 4.0 (95% CI: 2.7–5.8)), heart failure (HR: 2.5 (95% CI: 1.4–4.5)), venous thromboembolism (HR: 2.3 (95% CI: 1.1–5.0)), sleep apnoea (HR: 11.7 (95% CI: 7.0–19.4)) and arthropathy (HR: 2.1 (95% CI: 1.6–2.6)). The complication risk was also increased before the diagnosis of acromegaly. Overall mortality risk was elevated (HR: 1.3 (95% CI: 1.0–1.7)) but uninfluenced by treatment modality.

Conclusion

(i) The incidence rate and age at diagnosis of acromegaly have been stable over decades, and the prevalence is higher than previously reported. (ii) The risk of complications is very high even before the diagnosis. (iii) Mortality risk remains elevated but uninfluenced by mode of treatment.