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Free access

Cardiac dysfunction is reversed upon successful treatment of Cushing's syndrome

Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W A Smit, Jeroen J Bax, and Richard A Feelders

Objective

In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function.

Methods

In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured.

Results

At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (−16.5±3.5 vs −19.7±3.4%, P=0.013) and longitudinal (−15.9±1.9 vs −20.1±2.3%, P<0.001) directions and decreased SRIVRT (0.3±0.15 vs 0.4±0.2/ s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized.

Conclusion

CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess.

Free access

Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours

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.

Free access

Limited predictive value of an acute test with subcutaneous octreotide for long-term IGF-I normalization with Sandostatin LAR in acromegaly

Wouter W de Herder, H Rob Taal, Piet Uitterlinden, Richard A Feelders, Joop A M J L Janssen, and Aart-Jan van der Lely

Objectives: To study whether the growth hormone (GH) response after the subcutaneous administration 50 μg of octreotide (acute octreotide test) has any predictive value for long-term IGF-I normalization with Sandostatin LAR.

Design: Twenty four therapy-naive patients with active acromegaly were studied.

Results: >75% GH decrease in the acute octreotide test predicted long-term IGF-I normalization with Sandostatin LAR in 8/11 (73%) of patients. 3/13 (23%) patients with <75% GH decrease in the acute octreotide test were long-term biochemically controlled with Sandostatin LAR. Using the >75% GH reduction criterion, the sensitivity and specificity of this test for predicting long-term normalization of serum IGF-I with Sandostatin LAR treatment were 73% and 77%, respectively (positive and negative predictive values: 73% and 77%, respectively). 6/8 (75%) patients with GH suppression to levels <1.1 μg/l and 9/16 (56%) patients with GH suppression to levels <2 μg/l in the acute octreotide test showed normalization of serum IGF-I with long-term Sandostatin LAR treatment. The sensitivity and specificity of GH suppression <1.1 μg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 55% and 85%, respectively (positive and negative predictive values: 75% and 69%, respectively). The sensitivity and specificity of GH suppression <2 μg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 82% and 46%, respectively (positive and negative predictive values: 56% and 75%, respectively).

Conclusion: The acute octreotide is not recommended for clinical decision making with regard to long-term treatment using the long-acting somatostatin analog Sandostatin LAR in acromegaly.

Free access

Increased myocardial fibrosis and left ventricular dysfunction in Cushing's syndrome

Kai Hang Yiu, Nina Ajmone Marsan, Victoria Delgado, Nienke R Biermasz, Eduard R Holman, Johannes W A Smit, Richard A Feelders, Jeroen J Bax, and Alberto M Pereira

Objective

Active Cushing's syndrome (CS) is associated with cardiomyopathy, characterized by myocardial structural, and ultrastructural abnormalities. The extent of myocardial fibrosis in patients with CS has not been previously evaluated. Therefore, the objective of this study was to assess myocardial fibrosis in CS patients, its relationship with left ventricular (LV) hypertrophy and function, and its reversibility after surgical treatment.

Design and methods

Fifteen consecutive CS patients (41±12 years) were studied together with 30 hypertensive (HT) patients (matched for LV hypertrophy) and 30 healthy subjects. Echocardiography was performed in all patients including i) LV systolic function assessment by conventional measures and by speckle tracking-derived global longitudinal strain, ii) LV diastolic function assessment using E/E′, and iii) myocardial fibrosis assessment using calibrated integrated backscatter (IBS). Echocardiography was repeated after normalization of cortisol secretion (14±3 months).

Results

CS patients showed the highest value of calibrated IBS (−15.1±2.5 dB) compared with HT patients (−20.0±2.6 dB, P<0.01) and controls (−23.8±2.4 dB, P<0.01), indicating increased myocardial fibrosis independent of LV hypertrophy. Moreover, calibrated IBS in CS patients was significantly related to both diastolic function (E/E′, r=0.79, P<0.01) and systolic function (global longitudinal strain, r=0.60, P=0.02). After successful surgical treatment, calibrated IBS normalized (−21.0±3.8 vs −15.1±2.5 dB, P<0.01), suggestive of regression of myocardial fibrosis.

Conclusions

Patients with CS have increased myocardial fibrosis, which is related to LV systolic and diastolic dysfunction. Successful treatment of CS normalizes the extent of myocardial fibrosis. Therefore, myocardial fibrosis appears to be an important factor in the development and potential regression of CS cardiomyopathy.

Free access

Serum inhibin pro-αC is a tumor marker for adrenocortical carcinomas

Johannes Hofland, Richard A Feelders, Ronald van der Wal, Michiel N Kerstens, Harm R Haak, Wouter W de Herder, and Frank H de Jong

Objective

The insufficient diagnostic accuracy for differentiation between benign and malignant adrenocortical disease and lack of sensitive markers reflecting tumor load emphasize the need for novel biomarkers for diagnosis and follow-up of adrenocortical carcinoma (ACC).

Design

Since the inhibin α-subunit is expressed within the adrenal cortex, the role of serum inhibin pro-αC as a tumor marker for ACC was studied in patients.

Methods

Regulation of adrenal pro-αC secretion was investigated by adrenocortical function tests. Serum inhibin pro-αC levels were measured in controls (n=181) and patients with adrenocortical hyperplasia (n=45), adrenocortical adenoma (ADA, n=32), ACC (n=32), or non-cortical tumors (n=12). Steroid hormone, ACTH, and inhibin A and B levels were also estimated in patient subsets.

Results

Serum inhibin pro-αC levels increased by 16% after stimulation with ACTH (P=0.043). ACC patients had higher serum inhibin pro-αC levels than controls (medians 733 vs 307 ng/l, P<0.0001) and patients with adrenocortical hyperplasia, ADA, or non-adrenocortical adrenal tumors (148, 208, and 131 ng/l, respectively, P=0.0003). Inhibin pro-αC measurement in ACC patients had a sensitivity of 59% and specificity of 84% for differentiation from ADA patients. Receiver operating characteristic analysis displayed areas under the curve of 0.87 for ACC vs controls and 0.81 for ACC vs ADA (P<0.0001). Surgery or mitotane therapy was followed by a decrease of inhibin pro-αC levels in 10/10 ACC patients tested during follow-up (P=0.0065).

Conclusions

Inhibin pro-αC is produced by the adrenal gland. Differentiation between ADA and ACC by serum inhibin pro-αC is limited, but its levels may constitute a novel tumor marker for ACC.

Restricted access

Prognostic value of dysnatremia for survival in neuroendocrine neoplasm patients

Julie Refardt, Tessa Brabander, Noémie S Minczeles, Richard A Feelders, Wouter W de Herder, and Johannes Hofland

Objective

Hyponatremia and hypernatremia are common electrolyte abnormalities in patients with malignancy and have been independently associated with worse survival outcomes. To date, there are no data on the impact of dysnatremia on survival outcomes in patients with neuroendocrine neoplasms (NENs).

Design

This study involves retrospective cohort analysis from a tertiary care center of NEN patients treated with peptide receptor radionuclide therapy (PRRT) with a cumulative activity of at least 3.7 GBq 177Lu-DOTATATE between the years 2000 and 2015.

Methods

Comparison of overall survival of patients with the occurrence of hyponatremia (serum sodium < 135 mmol/L) or hypernatremia (serum sodium > 145 mmol/L) before starting or during PRRT was perfomed.

Results

A total of 649 patients were included. Hyponatremia occurred in 57 patients during the observation period and was associated with a shorter median overall survival (95% CI) of 25 months (14–36) compared to 55 months (48–61) of the 512 normonatremic patients (P < 0.001), adjusted hazard ratio (HR): 1.48 (95% CI: 1.04–2.12). Overall survival time was reduced regardless of whether hyponatremia was present at baseline or during PRRT. In contrast, hypernatremia occurred in 80 patients and was associated with a longer median overall survival (95% CI) of 94 months (47–140) compared with the 512 normonatremic patients (P = 0.018), adjusted HR: 0.61 (95% CI: 0.40–0.92). This association was driven by the patients with hypernatremia during PRRT. No association between dysnatremia and progression-free survival after PRRT was observed.

Conclusions

The occurrence of hypo- or hypernatremia in PRRT-treated NET patients is associated with opposing outcomes with regard to overall survival. Sodium levels might have a prognostic role in these patients.

Free access

Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing's syndrome

Johannes Hofland, Wouter W de Herder, Lieke Derks, Leo J Hofland, Peter M van Koetsveld, Ronald R de Krijger, Francien H van Nederveen, Anelia Horvath, Constantine A Stratakis, Frank H de Jong, and Richard A Feelders

Context

Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.

Objective

Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.

Materials and methods

A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.

Results

Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.

Conclusion

PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.

Open access

Diagnostic imaging of dopamine receptors in pituitary adenomas

Wouter W de Herder, Ambroos E M Reijs, Richard A Feelders, Maarten O van Aken, Eric P Krenning, Aart-Jan van der Lely, and Dik J Kwekkeboom

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using 123I-S-(−)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (123I-IBZM) and 123I-epidepride. 123I-epidepride is generally superior to 123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, 123I-IBZM and 123I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with 11C-N-raclopride and 11C-N-methylspiperone.

Free access

Scalp hair cortisol for diagnosis of Cushing’s syndrome

Vincent L Wester, Martin Reincke, Jan W Koper, Erica L T van den Akker, Laura Manenschijn, Christina M Berr, Julia Fazel, Yolanda B de Rijke, Richard A Feelders, and Elisabeth F C van Rossum

Objective

Current first-line screening tests for Cushing’s syndrome (CS) only measure time-point or short-term cortisol. Hair cortisol content (HCC) offers a non-invasive way to measure long-term cortisol exposure over several months of time. We aimed to evaluate HCC as a screening tool for CS.

Design

Case-control study in two academic referral centers for CS.

Methods

Between 2009 and 2016, we collected scalp hair from patients suspected of CS and healthy controls. HCC was measured using ELISA. HCC was available in 43 confirmed CS patients, 35 patients in whom the diagnosis CS was rejected during diagnostic work-up and follow-up (patient controls), and 174 healthy controls. Additionally, we created HCC timelines in two patients with ectopic CS.

Results

CS patients had higher HCC than patient controls and healthy controls (geometric mean 106.9 vs 12.7 and 8.4 pg/mg respectively, P < 0.001). At a cut-off of 31.1 pg/mg, HCC could differentiate between CS patients and healthy controls with a sensitivity of 93% and a specificity of 90%. With patient controls as a reference, specificity remained the same (91%). Within CS patients, HCC correlated significantly with urinary free cortisol (r = 0.691, P < 0.001). In two ectopic CS patients, HCC timelines indicated that cortisol was increased 3 and 6 months before CS became clinically apparent.

Conclusions

Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset.

Free access

Dopamine agonist therapy of clinically non-functioning pituitary macroadenomas. Is there a role for 123I-epidepride dopamine D2 receptor imaging?

Wouter W de Herder, Ambroos E M Reijs, Richard A Feelders, Maarten O van Aken, Eric P Krenning, Hervé L J Tanghe, Aart-Jan van der Lely, and Dik J Kwekkeboom

Objective: Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivo imaging of D2 receptors using 123I-epidepride and the radiological response of NFPA to DA in 18 patients.

Methods: Patients were treated with either cabergoline (1–2 mg/week) or quinagolide (150–300 μg/day) for a mean period of 89.7 months (range, 34–187 months).

Results: Pituitary uptake of 123I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage.

Conclusion: In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.