Jacques W M Lenders

Technische Universität Dresden, Dresden, Saxony, Germany

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Publications (294)1467.56 Total impact

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    ABSTRACT: After the first cases of primary aldosteronism were described and characterized by Conn, a substantial body of experimental and clinical evidence about the long-term effects of excess aldosterone on the cardiovascular system was gathered over the last 5 decades. The prevalence of primary aldosteronism varies considerably between different studies among hypertensive patients, depending on patient selection, the used diagnostic methods, and the severity of hypertension. Prevalence rates vary from 4.6 to 16.6% in those studies in which confirmatory tests to diagnose primary aldosteronism were used. There is also growing evidence indicating that prolonged exposure to elevated aldosterone concentrations is associated with target organ damage in the heart, kidney, and arterial wall, and high cardiovascular risk in patients with primary aldosteronism. Therefore, the aim of treatment should not be confined to BP normalization and hypokalemia correction, but rather should focus on restoring the deleterious effects of excess aldosterone on the cardiovascular system. Current evidence convincingly demonstrates that both surgical and medical treatment strategies beneficially affect cardiovascular outcomes and mortality in the long term. Further studies can be expected to provide better insight into the relationship between cardiovascular risk and complications and the genetic background of primary aldosteronism.
    Hormone and Metabolic Research 11/2015; DOI:10.1055/s-0035-1565124 · 2.12 Impact Factor
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    ABSTRACT: Adrenal steroid hormones, which regulate a plethora of physiological functions, are produced via tightly controlled pathways. Investigations of these pathways, based on experimental data, can be facilitated by computational modeling for calculations of metabolic rate alterations. We therefore used a model system, based on mass balance and mass reaction equations, to kinetically evaluate adrenal steroidogenesis in human adrenal cortex-derived NCI H295R cells. For this purpose a panel of 10 steroids was measured by liquid chromatographic-tandem mass spectrometry. Time-dependent changes in cell incubate concentrations of steroids - including cortisol, aldosterone, dehydroepiandrosterone and their precursors - were measured after incubation with angiotensin II, forskolin and abiraterone. Model parameters were estimated based on experimental data using weighted least square fitting. Time-dependent angiotensin II- and forskolin-induced changes were observed for incubate concentrations of precursor steroids with peaks that preceded maximal increases in aldosterone and cortisol. Inhibition of 17-alpha-hydroxylase/17,20-lyase with abiraterone resulted in increases in upstream precursor steroids and decreases in downstream products. Derived model parameters, including rate constants of enzymatic processes, appropriately quantified observed and expected changes in metabolic pathways at multiple conversion steps. Our data demonstrate limitations of single time point measurements and the importance of assessing pathway dynamics in studies of adrenal cortical cell line steroidogenesis. Our analysis provides a framework for evaluation of steroidogenesis in adrenal cortical cell culture systems and demonstrates that computational modeling-derived estimates of kinetic parameters are an effective tool for describing perturbations in associated metabolic pathways.
    The Journal of steroid biochemistry and molecular biology 10/2015; 155(Pt A). DOI:10.1016/j.jsbmb.2015.09.038 · 3.63 Impact Factor
  • Jaap Deinum · Niels P Riksen · Jacques W M Lenders ·
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    ABSTRACT: Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 07/2015; 154. DOI:10.1016/j.pharmthera.2015.07.006 · 9.72 Impact Factor
  • Theo Thien · Eveline B M Keltjens · Jacques W M Lenders · Jaap Deinum ·
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    ABSTRACT: To establish whether the results of blood pressure (BP) measurements are affected by wearing clothing underneath the BP cuff during measurement. Normotensive and hypertensive patients (n=133; 65 men) of an outpatient clinic participated in this study. BP was measured according to a rigorous protocol with a validated oscillometric device under three conditions: with one layer of own clothing (OC) underneath the cuff, with one layer of standardized clothing (SC) underneath the cuff, and with the cuff on a bare arm (BA), in a randomized order. Patients were seated on a chair with their right arm on the table and their feet flat on the floor during BP measurement. The mean BP values (±SEM) measured during BA, OC, and SC were, respectively, 132.8±1.3, 132.3±1.4, and 133.2±1.4 mmHg for systolic blood pressure (SBP), 78.3±0.9, 78.3±0.9, and 78.5±0.9 mmHg for diastolic blood pressure (DBP), and 90.3±1.0, 90.0±1.0, and 91.5±1.0 mmHg for mean arterial blood pressure (MAP). The differences in SBP, DBP, and MAP between BA, OC, and SC measurements were not statistically significant, but there was considerable intraindividual variation in SBP deviations of more than 5 mmHg between BA versus OC and SC. There was no significant order effect of the three conditions. The absence of differences between BA, OC, and SC was not determined by age, sex, BMI, and arm circumference. We could not find differences in MAP, SBP, and DBP between the bare and clothed arms, but intraindividual variation of SBP between the three conditions is not negligible. Despite this caveat, these data suggest that in an outpatient clinic, BP can be measured reliably with one layer of clothing underneath the cuff. This is timesaving and more comfortable for patients.
    Blood pressure monitoring 07/2015; 20(6). DOI:10.1097/MBP.0000000000000142 · 1.53 Impact Factor

  • 06/2015; DOI:10.4158/EP15723.CR
  • Article: PP.32.13
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    ABSTRACT: Objective: Adrenal venous sampling (AVS) is the preferred method to distinguish excess unilateral from bilateral aldosterone secretion in patients with primary aldosteronism. Although it is invasive and expensive conventional CT adrenal imaging is considered to be inferior to AVS. To examine whether 128-slice dual-source CT using strict standardized radiological diagnostic criteria may approach the diagnostic performance of AVS. Design and method: From May 2012 to August 2014 we performed both AVS and 128-slice dual-source CT in 50 consecutive patients with PA. AVS was pursued after correction of hypokalemia and adjustment of antihypertensive therapy, under continuous ACTH infusion. Blood samples were taken from both adrenal veins (AV) and the lower caval vein (LCV). Selective cannulation was defined as an AV/LCV ratio for cortisol of >=3. Lateralization was defined as a dominant/non-dominant ratio for aldosterone-to-cortisol of >=4. In addition suppression of the contralateral side was required. Computer tomography imaging was performed using 128-slice dual-source CT with a 1mm-thickness slice. As a diagnostic criterion of adrenal nodule on CT-scan a focal change > 7 mm was used. A diffuse thickening of adrenal limbs > 5 mm was thought to fit with adrenal hyperplasia. A unilateral change (adenoma/hyperplasia) was defined as a change within one single adrenal gland with normal contralateral gland. Bilateral abnormalities included bilateral adenomas and/or bilateral adrenal hyperplasia. Results: The cannulation failed in 2 (4%) subjects. No complications were observed during and after procedures. Twentythree patients (48%) demonstrated unilateral aldosterone production (14 left-sided, 9 right-sided), and 25 (48%) patients were characterized by bilateral aldosterone production. In 43,8% of the patients there was disagreement between results of AVS vs CT. In 11 subjects (22.9%) a unilateral change was found on CT-scan, while there was no lateralization on AVS. In 7 patients (14,6%) CT-scan revealed bilateral abnormalities or symmetrical normal adrenal glands whereas in AVS unilateral aldosterone secretion was observed. In 2 cases there was complete discordance between the affected sides as diagnosed by CT and AVS. Conclusions: Despite adopting strict radiological criteria to differentiate uni- from bilateral disease, the diagnostic performance of 128-slice dual-source CT-scan is inferior to that of AVS. Copyright
    Journal of Hypertension 06/2015; 33:e423-e424. DOI:10.1097/01.hjh.0000468707.42826.7b · 4.72 Impact Factor
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    ABSTRACT: (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy plays an important role in the diagnostic evaluation of patients with pheochromocytoma and paraganglioma (PPGL). MIBG targets cell membrane and vesicular catecholamine transporters of chromaffin cells and facilitates localization of the primary tumor and metastatic lesions. Its specificity for the diagnosis of adrenomedullary chromaffin cell tumors can be jeopardized by physiological uptake by the normal adrenal medulla. The aim of this study was to distinguish between PPGLs and normal adrenal glands by evaluating semi-quantitative (123)I-MIBG uptake and to examine genotype-specific differences in correlation with expression of catecholamine transporter systems. Sixty-two PPGLs collected from 57 patients with hereditary mutations in SDHA (n = 1), SDHB (n = 2), SDHD (n = 4), VHL (n = 2), RET (n = 12), NF1 (n = 2), MAX (n = 1) and with sporadic PPGLs (n = 33) were investigated. Pre-operative planar and single-photon emission computed tomographic (SPECT) images were semi-quantitatively analyzed using uptake measurements. Tumor-to-liver (T/L) and normal-adrenal-to-liver (NA/L) ratios were calculated and correlated with clinical characteristics including genotype, tumor size and plasma metanephrines concentrations. The expression of norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT-1) was evaluated immunohistochemically in paraffin-embedded tumor tissues. Mean T/L ratios of PPGL lesions were significantly higher than NA/L ratios (p<0.001). Cut-off values to distinguish between physiological and pathological adrenal uptake were established at 0.7 (100% sensitivity, 10.3% specificity) and 4.3 (100% specificity, 66.1% sensitivity). No statistically significant differences in (123)I-MIBG uptake were found across PPGLs of different genotypes. Mean NET expression in hereditary cluster 2 (RET, NF1, MAX) and apparently sporadic tumors was significantly higher than for hereditary cluster 1 (SDHx, VHL) PPGLs (P = 0.011 and P = 0.006, respectively). Mean VMAT-1 expression in hereditary cluster 1 PPGLs was significantly higher than for cluster 2 tumors (P = 0.010). (123)I-MIBG uptake significantly correlated with maximum tumor diameter (P = 0.002). MIBG uptake, however, did not correlate with either NET or VMAT-1 expression. Liver normalized semi-quantitative (123)I-MIBG uptake may be helpful to distinguish between pheochromocytoma and physiological adrenal uptake. Genotype-specific differences in expression of NET and VMAT-1 do not translate into differences in (123)I-MIBG uptake. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 04/2015; 56(6). DOI:10.2967/jnumed.115.154815 · 6.16 Impact Factor

  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547715 · 1.56 Impact Factor

  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547722 · 1.56 Impact Factor
  • J Lenders ·
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    ABSTRACT: The possibility that a patient with newly diagnosed hypertension has an underlying cause that is directly.sponsible for the increased blood pressure deserves more attention from clinicians than is currently the case. This limited attention and consideration is responsible for delaying and yen missing the diagnosis and proper treatment of secondary hypertension. The reasons are manifold, varying from minimal knowledge of diagnostic tests to easy and low threshold in rescription of antihypertensive drugs. In addition there is the misconception that the prevalence of secondary hypertension; so low that it hardly needs any consideration. However, some forms of secondary hypertension are much more revalent than previously thought and this applies in particular endocrine hypertension. In addition, in recent years there re emerging new scientific developments in the field of endocrine hypertension, varying from pathogenesis, genetics, and therapeutics. It is therefore quite remarkable that endocrinologists seem to have hardly any interest in endocrine hypertension, unless there is a clear cut case such as a patient with an already diagnosed pheochromocytoma. They leave the analysis of hypertension to other specialists who have hardly any expertise a for instance the analysis of patients suspected to have primary or pseudo-aldosteronism. The contribution of endocrinology is however essential, not only for detecting more patients with concealed endocrine hypertension but also for optimizing he understanding of the pathogenesis and treatment of high blood pressure in the larger group of patients with primary hypertension.
    Choroid Plexus - Pineal Gland Correlations Medical Anthropology - Computed Tomography Studies Intracranial Physiological Calcification 01/2015; 11(1):1-6. DOI:10.4183/aeb.2015.1 · 0.27 Impact Factor
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    ABSTRACT: Objective: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations. Design and methods: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42+/-16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production. Results: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours. Conclusion: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.
    European Journal of Endocrinology 11/2014; 172(2). DOI:10.1530/EJE-14-0756 · 4.07 Impact Factor
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    ABSTRACT: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct sub-cluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2014; 135(9). DOI:10.1002/ijc.28868 · 5.09 Impact Factor
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    ABSTRACT: Background Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC–MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling. Methods A novel LC–MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18-hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC–MS/MS were compared with those measured by immunoassay. Results Reproducibility of measurements with coefficients of variation ≤10% as well as analytical sensitivity sufficient to measure low pV levels particularly of aldosterone demonstrate the utility of the assay for profiling adrenal steroids in primary aldosteronism. Method comparisons indicated assay and concentration dependent differences of cortisol and aldosterone concentrations measured by immunoassay and LC–MS/MS. Median AV/pV ratios of 11-deoxycortisol (53.0), 17-hydroxyprogesterone (33.4), pregnenolone (62.4), androstenedione (40.6) and dehydroepiandrosterone (33.3) were 2.9- to, 5.4-fold larger than those for cortisol (11.6), with additionally generally larger increases than for cortisol with than without cosyntropin stimulation. Conclusion Our LC–MS/MS assay, in addition to improvements over existing immunoassay measurements of aldosterone and cortisol, offers profiling of 13 other adrenal steroids, providing a potentially useful method for the clinical work-up of patients with primary aldosteronism. In particular, the larger AV/pV ratios of several steroids compared to cortisol suggest more sensitive alternatives to the latter for assessing positioning of AV sampling catheters.
    The Journal of Steroid Biochemistry and Molecular Biology 10/2014; 145. DOI:10.1016/j.jsbmb.2014.10.006 · 3.63 Impact Factor
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    ABSTRACT: Objective: Diagnosis of pheochromocytoma during pregnancy can be difficult and the tumor carries an unfavorable prognosis if not diagnosed and treated in a timely manner.Methods: To present a case, of Takotsubo-like cardiomyopathy, characterized by transient left ventricular apical ballooning due to pheochromocytoma following delivery.Results: A few hours after Caesarean section a 32-year-old Caucasian woman presented with pulmonary edema followed by cardiac arrest, with echocardiographic and ventriculographic evidence of reversible acute myocardial failure characteristic of Takotsubo-like cardiomyopathy. A previously unrecognized adrenal pheochromocytoma was found during further clinical work-up. Left ventricle function normalized after surgical removal of the tumor carried out after implementing alpha-adrenoreceptor blockade. Hemorrhagic necrosis of the pheochromocytoma was seen on histopathology, which might have triggered the sequence of events leading to the development of Takotsubo-like cardiomyopathy and hemodynamic collapse.Conclusion: To the best of our knowledge we describe here the first reported case of Takotsubo-like cardiomyopathy related to pheochromocytoma following the delivery. This emphasizes the increased cardiovascular risk if pheochromocytoma is not diagnosed and treated in a timely manner especially during pregnancy.
    Endocrine Practice 08/2014; 1(-1):1-16. DOI:10.4158/EP13498.CR · 2.81 Impact Factor
  • B.J. Kramers · C. Kramers · J.W.M. Lenders · J. Deinum ·

    Clinical Therapeutics 08/2014; 36(8):e12. DOI:10.1016/j.clinthera.2014.05.059 · 2.73 Impact Factor
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    ABSTRACT: Context: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. Objective: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. Design, Setting and Patients: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. Main outcome measure: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. Results: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. Conclusions: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.
    Journal of Clinical Endocrinology &amp Metabolism 07/2014; 99(10):jc20142151. DOI:10.1210/jc.2014-2151 · 6.21 Impact Factor
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    ABSTRACT: Unlabelled: Pheochromocytomas and paragangliomas (PPGLs) can be localized by (18)F-FDG PET. The uptake is particularly high in tumors with an underlying succinate dehydrogenase (SDH) mutation. SDHx-related PPGLs are characterized by compromised oxidative phosphorylation and a pseudohypoxic response, which mediates an increase in aerobic glycolysis, also known as the Warburg effect. The aim of this study was to explore the hypothesis that increased uptake of (18)F-FDG in SDHx-related PPGLs is reflective of increased glycolytic activity and is correlated with expression of different proteins involved in glucose uptake and metabolism through the glycolytic pathway. Methods: Twenty-seven PPGLs collected from patients with hereditary mutations in SDHB (n = 2), SDHD (n = 3), RET (n = 5), neurofibromatosis 1 (n = 1), and myc-associated factor X (n = 1) and sporadic patients (n = 15) were investigated. Preoperative (18)F-FDG PET/CT studies were analyzed; mean and maximum standardized uptake values (SUVs) in manually drawn regions of interest were calculated. The expression of proteins involved in glucose uptake (glucose transporters types 1 and 3 [GLUT-1 and -3, respectively]), phosphorylation (hexokinases 1, 2, and 3 [HK-1, -2, and -3, respectively]), glycolysis (monocarboxylate transporter type 4 [MCT-4]), and angiogenesis (vascular endothelial growth factor [VEGF], CD34) were examined in paraffin-embedded tumor tissues using immunohistochemical staining with peroxidase-catalyzed polymerization of diaminobenzidine as a read-out. The expression was correlated with corresponding SUVs. Results: Both maximum and mean SUVs for SDHx-related tumors were significantly higher than those for sporadic and other hereditary tumors (P < 0.01). The expression of HK-2 and HK-3 was significantly higher in SDHx-related PPGLs than in sporadic PPGLs (P = 0.022 and 0.025, respectively). The expression of HK-2 and VEGF was significantly higher in SDHx-related PPGLs than in other hereditary PPGLs (P = 0.039 and 0.008, respectively). No statistical differences in the expression were observed for GLUT-1, GLUT-3, and MCT-4. The percentage anti-CD 34 staining and mean vessel perimeter were significantly higher in SDHx-related PPGLs than in sporadic tumors (P = 0.050 and 0.010, respectively). Mean SUVs significantly correlated with the expression of HK-2 (P = 0.027), HK-3 (P = 0.013), VEGF (P = 0.049), and MCT-4 (P = 0.020). Conclusion: The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased (18)F-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters.
    Journal of Nuclear Medicine 06/2014; 55(8). DOI:10.2967/jnumed.114.137034 · 6.16 Impact Factor
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    ABSTRACT: Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(6):1915-1942. DOI:10.1210/jc.2014-1498 · 6.21 Impact Factor
  • A van Berkel · K Pacak · J W M Lenders ·
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    ABSTRACT: Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging since anatomical imaging modalities can either fail to locate the tumor or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease by using the whole body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumor visualization during the past decade. (123) I-meta-iodobenzylguanidine scintigraphy is the most widely used functional imaging modality and its sensitivity to identify chromaffin cell tumors varies from 85-88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70-100% and 84-100%, respectively. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 05/2014; 81(3). DOI:10.1111/cen.12482 · 3.46 Impact Factor
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    ABSTRACT: Context: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia. Objective: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs. Design and Methods: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi. Results: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes. Conclusions: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; 99(7):jc20134255. DOI:10.1210/jc.2013-4255 · 6.21 Impact Factor

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7k Citations
1,467.56 Total Impact Points


  • 2010-2015
    • Technische Universität Dresden
      • • Faculty of Medicine Carl Gustav Carus
      • • Institute of Chemistry and Laboratory Medicine
      Dresden, Saxony, Germany
  • 1986-2015
    • Radboud University Nijmegen
      • Department of General Internal Medicine
      Nymegen, Gelderland, Netherlands
  • 1984-2013
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2009-2012
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2003-2008
    • Maastricht University
      • Department of Internal Medicine
      Maestricht, Limburg, Netherlands
  • 1992-2008
    • National Institutes of Health
      • Branch of Behavioral Neuroscience
      베서스다, Maryland, United States
  • 2007
    • University of Groningen
      • Department of General Practice
      Groningen, Groningen, Netherlands
  • 2002-2005
    • University of Florence
      Florens, Tuscany, Italy
  • 1996
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands