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Wouter W de Herder

For patients with neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas (GEP) (GEP-NETs), excellent care should ideally be provided by a multidisciplinary team of skilled health care professionals. In these patients, a combination of nuclear medicine imaging and conventional radiological imaging techniques is usually mandatory for primary tumour visualisation, tumour staging and evaluation of treatment. In specific cases, as in patients with occult insulinomas, sampling procedures can provide a clue as to where to localise the insulin-hypersecreting pancreatic NETs. Recent developments in these fields have led to an increase in the detection rate of primary GEP-NETs and their metastatic deposits. Radiopharmaceuticals targeted at specific tumour cell properties and processes can be used to provide sensitive and specific whole-body imaging. Functional imaging also allows for patient selection for receptor-based therapies and prediction of the efficacy of such therapies. Positron emission tomography/computed tomography (CT) and single-photon emission CT/CT are used to map functional images with anatomical localisations. As a result, tumour imaging and tumour follow-up strategies can be optimised for every individual GEP-NET patient. In some cases, functional imaging might give indications with regard to future tumour behaviour and prognosis.

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Marloes Louwerens, Wouter W de Herder, Pieter TE Postema, Hervé LJ Tanghe and Steven WJ Lamberts

Louwerens M, de Herder WW, Postema PTE, Tanghe HLJ, Lamberts SWJ. Pituitary insufficiency and regression of acromegaly caused by pituitary apoplexy following cerebral angiography. Eur J Endocrinol 1996;134:737–40. ISSN 0804–4643

Pituitary apoplexy as a complication of cerebral angiography has been described in only a few case reports. Some studies have reported the clinical resolution of active acromegaly after pituitary apoplexy. We present a patient with active acromegaly due to a growth hormone (GH)-secreting pituitary macroadenoma, who developed anterior and posterior pituitary insufficiency following cerebral angiography. Furthermore, a significant reduction in tumour size was accompanied by normalization of mean 24 h in GH insulin-like growth factor I (IGF-I) and IGF binding protein 3 levels.

WW de Herder, Department of Internal Medicine III and Clinical Endocrinology, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

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R A Alwani, L W Schmit Jongbloed, F H de Jong, A J van der Lely, W W de Herder and R A Feelders

Objective

To evaluate the diagnostic performance of four different tests in order to differentiate between Cushing's disease (CD) and pseudo-Cushing's syndrome (PCS).

Methods

In this prospective study, a total of 73 patients with clinical features of hypercortisolism and insufficient suppression of serum cortisol after 1 mg overnight dexamethasone and/or an elevated excretion of cortisol in 24-h urine samples were included. The circadian rhythm of serum cortisol levels as well as midnight serum cortisol (MserC) levels were assessed in all 73 patients. Late-night salivary cortisol (LNSC) concentrations were obtained in 44 patients. The dexamethasone–CRH (Dex–CRH) test was performed in 54 patients.

Results

Fifty-three patients were diagnosed with CD and subsequently treated. Twenty patients were classified as having PSC. Serum cortisol circadian rhythm: the diurnal rhythmicity of cortisol secretion was retained in PCS. A cortisol midnight:morning ratio of >0.67 is highly suggestive of CD (positive predictive value (PPV) 100% and negative predictive value (NPV) 73%). MserC concentration >243 nmol/l has a PPV of 98% in predicting true CD (NPV 95%). LNSC level >9.3 nmol/l predicted CD in 94% of patients (NPV 100%). Dex–CRH test: after 2 days of dexamethasone suppression, a CRH-stimulated cortisol level >87 nmol/l (T=15 min) resulted in a PPV of 100% and an NPV of 90%.

Conclusion

The Dex–CRH test as well as a single measurement of cortisol in serum or saliva at late (mid-) night demonstrated high diagnostic accuracy in differentiating PCS from true CD.

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K Kamp, R A Alwani, E Korpershoek, G J H Franssen, W W de Herder and R A Feelders

Objective

Several series report on the relative contribution of ectopic ACTH syndrome (EAS) in the spectrum of Cushing's syndrome. However, prevalence of EAS in patients with thoracic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is currently unknown.

Design

We assessed, in a tertiary referral center, the prevalence of EAS in a large cohort of thoracic and GEP-NET patients including clinical, biochemical, and radiological features; management; and treatment outcome.

Methods

In total, 918 patients with thoracic or GEP-NETs were studied (1993–2012). Multiple endocrine neoplasia type 1 and small cell lung carcinoma patients were excluded. Differentiation between synchronous, metachronous, and cyclic occurrence of EAS was made.

Results

Out of the 918 patients with thoracic and GEP-NETs (469 males and 449 females; median age 58.7 years (range: 17.3–87.3)), 29 patients (3.2%) had EAS (ten males and 19 females; median age 48.1 years (range: 24.7–77.9)). EAS occurred synchronously in 23 patients (79%), metachronously in four patients (14%), and cyclical in two patients (7%) respectively. NETs causing EAS included lung/bronchus (n=9), pancreatic (n=9), and thymic (n=4). In four patients, the cause of EAS was unknown (n=4). Median overall survival (OS) of non-EAS thoracic and GEP-NET patients was 61.2 months (range: 0.6–249.4). Median OS of EAS patients was 41.4 months (range: 2.2–250.9). After comparison, only the first 5-year survival was significantly shorter (P=0.013) in EAS patients.

Conclusion

Prevalence of EAS in this large cohort of patients with thoracic and GEP-NETs was 3.2%. EAS was mostly caused by thoracic and pancreatic NETs. First 5-year survival of EAS patients was shorter compared with non-EAS patients.

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J Feenstra, M O van Aken, W W de Herder, R A Feelders and A J van der Lely

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.

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Wouter W de Herder, Piet Uitterlinden, Aart-Jan van der Lely, Leo J Hofland and Steven WJ Lamberts

de Herder WW, Uitterlinden P, van der Lely A-J, Hofland LJ. Lamberts SWJ. Octreotide, but not bromocriptine, increases circulating insulin-like growth factor binding protein 1 levels in acromegaly. Eur J Endocrinol 1995;133:195–9. ISSN 0804–4643

Twenty-three patients with active acromegaly underwent serum sampling for growth hormone (GH), insulin and insulin-like growth factor binding protein 1 (IGFBP-1) after placebo or single doses of octreotide or bromocriptine. Integrated 24-h serum GH levels decreased by 90% after octreotide and 49% after bromocriptine. A statistically significant correlation between the course of GH levels after octreotide and bromocriptine was observed (p < 0.001). Octreotide, but not bromocriptine, induced a significant increase in integrated 24-h serum IGFBP-1 levels to 37.4 times the baseline values. Bromocriptine caused a non-significant increase in integrated 24-h serum IGFBP-1 levels, which argues against a direct regulatory effect of GH on IGFBP-1 production in acromegaly. In conclusion, octreotide induces in acromegaly the production of IGFBP-1, which occurs independently of the number of somatostatin receptors on the GH-secreting pituitary adenoma. The supposed inhibitory effect of IGFBP-1 on the biological effect of IGF-I might result in an additional clinical benefit in acromegalic patients as compared to treatment directed at the pituitary level.

WW de Herder, Department of Internal Medicine III and Clinical Endocrinology, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

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Wouter T Zandee, Kimberly Kamp, Roxanne C S van Adrichem, Richard A Feelders and Wouter W de Herder

Objective

To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers.

Design and methods

Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2–10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan−Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses.

Results

A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09–2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01–1.08), grade 3 disease (HR 5.09, 95% CI: 2.20–11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34–4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56–8.34) remained as the predictors.

Conclusion

Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.

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Frank RE Nobels, Wouter W de Herder, Dik J Kwekkeboom, Willy Coopmans, Andries Mulder, Roger Bouillon and Steven WJ Lamberts

Nobels FRE, de Herder WW, Kwekkeboom DJ, Coopmans W, Mulder A, Bouillon R, Lamberts SWJ. Serum chromogranin A in the differential diagnosis of Cushing's syndrome. Eur J Endocrinol 1994:131:589–93. ISSN 0804–4643

We evaluated whether measuring serum levels of chromogranin A, a marker of neuroendocrine tumours, could be useful in the differential diagnosis between pituitary, adrenal and ectopic causes of Cushing's syndrome. Thirty patients with Cushing's syndrome were studied. The localization of the tumours responsible was pituitary in 15, adrenal in 5 and ectopic in 10 patients. Serum concentrations of chromogranin A were measured in all patients. Petrosal sinus sampling for chromogranin A was performed in the cases with pituitary-dependent Cushing's syndrome. Immunohistochemical staining for chromogranin A was carried out on part of the tumour specimens. Slightly elevated serum levels of chromogranin A (range 223–262 μg/1) were detected in inferior petrosal sinus and peripheral venous samples from three patients with pituitary-dependent Cushing's syndrome. Serum chromogranin A showed no significant pituitary to peripheral gradient in these patients. Chromogranin A levels were not elevated in cases of adrenal Cushing's syndrome. Markedly elevated concentrations (range 270–13900 μg/1) were shown in seven of 10 patients with neuroendocrine tumours with ectopic adrenocorticotrophin (ACTH) and/or corticotrophin-releasing hormone (CRH) production. Widespread metastasis was present in all these cases. Subjects with "occult" carcinoid tumours, with limited spread, had normal chromogranin A levels Immunohistochemical staining for chromogranin A was positive in three out of five pituitary adenomas and in all neuroendocrine tumours with ectopic ACTH and/or CRH production, while it was negative in all adrenocortical tumour specimens. It is concluded that elevated serum levels of chromogranin A can serve as markers of neuroendocrine tumours with ectopic ACTH and/or CRH production. The circulating levels are dependent mainly on the size of the tumours. Serum chromogranin A is not useful in the diagnosis of so-called occult Cushing's syndrome, caused by ectopic ACTH and/or CRH secretion by small neuroendocrine tumours.

F Nobels, Department of Endocrinology, Onze Lieve Vrouw Hospital, 164 Moorselbaan, 9300 Aalst, Belgium

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Wouter A van der Zwan, Lisa Bodei, Jan Mueller-Brand, Wouter W de Herder, Larry K Kvols and Dik J Kwekkeboom

Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15–35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, ‘targeted’ therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to ‘standard’ treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

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C E Andreescu, R A Alwani, J Hofland, L H J Looijenga, W W de Herder, L J Hofland and R A Feelders

Cushing syndrome (CS) during pregnancy is a rare condition with only a few cases reported in the literature. Misdiagnosis of CS is common because of overlapping features like fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy. Changes in maternal hormones and their binding proteins complicate assessment of glucocorticoid hormone levels during gestation. CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion by a pituitary adenoma. Furthermore, aberrant expression of luteinizing hormone (LH) receptors in the adrenal cortex has been suggested to be involved in the pathogenesis of adrenal CS during pregnancy. We report three pregnant women with ACTH-independent Cushing’s syndrome and an adrenal tumor. After uncomplicated delivery, patient 1 underwent in vivo testing for aberrant hormone receptor expression by the adenoma. Cortisol responses were found after administration of luteinizing hormone-releasing hormone (LHRH), human chorionic gonadotropin (hCG), glucagon, vasopressin and a standard mixed meal. All patients were treated with laparoscopic adrenalectomy. Adrenal tumor tissue of two patients showed positive immunohistochemical staining of LH receptors. Considering the cortisol responses to LHRH and hCG, and the development of CS during pregnancy in these patients, it is likely that ACTH-independent hypercortisolism was induced by the pregnancy-associated rise in hCG levels that activated aberrantly expressed LH receptors in the adrenal adenoma. Remarkably, adrenal adenomas may simultaneously express multiple aberrant receptors and individual ligands may play a role in the regulation of cortisol production in CS during pregnancy.