19 research outputs found
Clinical management of paragangliomas
Diabetes mellitus: pathophysiological changes and therap
Detection and treatment of pheochromocytomas and paragangliomas: current standing of MIBG scintigraphy and future role of PET imaging.
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69796timmers.pdf (publisher's version ) (Open Access)Pheochromocytomas are rare tumors arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. These tumors are characterized by synthesis, storage, metabolism and secretion of catecholamines. Similar to the sympathetic nervous system, pheochromocytomas express cellular norepinephrine transporters (NET) through which catecholamines can enter pheochromocytoma cells to be stored in vesicles. Metaiodobenzylguanidine (MIBG) resemblance to norepinephrine and its good affinity and uptake by NET resulted in its use in pheochromocytoma diagnosis from 1981. Both [(123)I]MIBG and [(131)I]MIBG (lower sensitivity) scintigraphy are used for localization of these tumors. Recent discoveries of different hereditary syndromes associated with pheochromocytomas led to the identification of several and new distinct genotype-phenotype associations. Importantly, with this distinction of clinical phenotypes, MIBG was found to have a different performance in subsets of pheochromocytoma patients. Reduced sensitivity of MIBG scintigraphy in some familial paraganglioma syndromes, malignant disease and extra-adrenal paragangliomas has been found. Therefore, newer compounds, especially for positron emission tomography (PET), such as [(11)C]hydroxyephedrine ([(11)C]HED), [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG), [(18)F]fluoro-dihydroxyphenylalanine ([(18)F] FDOPA) and [(18)F]fluorodopamine ([(18)F]FDA) have emerged and were found to be superior to MIBG in the localization of certain types of pheochromocytoma and paragangliomas. Finally, using [(131)I]MIBG represents an important treatment option in patients with malignant pheochromocytoma, but the development of newer treatment modalities is expected. In this review, we provide the reader with an overview of the current standing of [(123)I]- and [(131)I]MIBG in diagnosis and treatment of pheochromocytoma amongst the newer PET imaging agents
Identification of proteins in activated human neutrophils susceptible to tyrosyl radical attack. A proteomic study using a tyrosylating fluorophore
New imaging approaches to phaeochromocytomas and paragangliomas.
Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often multiple in various locations throughout the body. Furthermore, tumours are often malignant and perhaps more aggressive if associated with SDHB gene mutations. Some paragangliomas are clinically silent and may present only with dopamine hypersecretion. In the current era where CT and MRI are more commonly used, tumours are more often found as incidentalomas and MRI may be less specific for phaeochromocytoma and paraganglioma than previously thought. Because of unique tumour characteristics (e.g. the presence of cell membrane and intracellular vesicular norepinephrine transporters) these tumours were 'born' to be imaged by means of specific functional imaging approaches. Moreover, additional recent discoveries related to apoptosis, hypoxia, acidosis, anaerobic glycolysis and angiogenesis, often disturbed in tumour cells, open new options and challenges to specifically image phaeochromocytomas and paragangliomas and possibly link those results to their pathophysiology, genotypic alterations and metastatic potential. Functional imaging, especially represented by positron emission tomography (PET), offers an excellent approach by which tumour-specific processes can be detected, evaluated and seen in the context of tumour-specific behaviour and its genetic signature. In this review, we address the recent developments in new functional imaging modalities for phaeochromocytoma and paraganglioma and provide the reader with suggested imaging approaches in various phaeochromocytomas and paragangliomas of sympathetic origin. Current imaging algorithms of head and neck parasympathetic paragangliomas are not discussed. Finally, this review outlines some future perspectives of functional imaging of these tumours.Diabetes mellitus: pathophysiological changes and therap
Urinary 5-HIAA excretion is not increased in patients with head and neck paragangliomas.
Item does not contain fulltextBackground: Case reports have documented carcinoid-like features in head and neck paragangliomas (HNPGLs), which, in addition to catecholamine storing granules, may also contain granules with serotonin. Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA). Aim: To assess the urinary excretion rates of 5-HIAA and catecholamines in HNPGL patients.Methods: In 114 consecutive HNPGL patients, normetanephrine, metanephrine, norepinephrine, epinephrine, VMA, dopamine, 3-methoxytyramine and 5-HIAA excretion rates were measured in two 24-hour urinary samples. Increased excretion rates were defined as an increase of the average hormone excretion rate of 2 urine samples above the reference range. In all patients with catecholamine excess, intrathoracic and abdominal paragangliomas were excluded by 123I-MIBG scintigraphy, MRI and/or CT. Genetic screening for mutations in genes of the succinate dehydrogenase (SDH) family was performed. Results: Mean urinary 5-HIAA excretion rate was 14+/-9 mumol/24 hours (reference range 10-44 mumol/24 hours). Urinary 5-HIAA excretion was slightly increased in only 1 patient (48 mumol/24 hours). None of the 50 patients (44%) with increased urinary excretion rates of catecholamines and/or their metabolites had elevated 5-HIAA excretion.Conclusion: Urinary 5-HIAA excretion is within the normal reference range in almost all HNPGL patients. Therefore, this parameter has no clinical relevance in the routine clinical assessment of HNPGL patients
Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion
Heterogeneity assessment of antibody-derived therapeutics at the intact and middle-up level by low-flow sheathless capillary electrophoresis-mass spectrometry
Antibody-based pharmaceuticals often encompass a complex structural heterogeneity requiring enhanced analytical methods for reliable characterization of variants and degradation products. We have explored the capabilities of low-flow sheathless capillary electrophoresis-mass spectrometry (CE-MS) for the high-resolution and sensitive profiling of antibody therapeutics. Near-zero electroosmotic flow was achieved by employing a novel neutral capillary coating that also prevents protein adsorption. CE-MS analysis of intact model proteins using an acidic background electrolyte demonstrated satisfactory performance, with overall migration-time RSDs below 2.2% from three different capillaries tested. For system evaluation, three nanobody preparations, including mono- and bivalent forms, and three monoclonal antibodies (mAbs) were analyzed. Intact nanobodies were resolved from their degradation products, which could be assigned to deamidated, cleaved, and truncated forms at the C-terminal tag. Excellent resolution of isomeric deamidated products was obtained. The mAbs were analyzed intact and after digestion by the endoproteinase IdeS (middle-up approach). CE-MS of intact mAbs provided resolution of clipped species (e.g. light chain and light chain-heavy chain fragments) from the native protein. Moreover, glycoforms containing sialic acids were resolved from their non-sialylated counterparts. For IdeS-digested, F (ab)(2) and Fc/2 portions where efficiently resolved for the three mAbs. Whereas the migration time of the Fc/2 fragments was fairly similar, the migration time of the F (ab)(2) part was strongly varied among the mAbs. For all mAbs, separation of Fc/2 charge variants - including sialylated glycoforms and other post-translational modifications, such as loss of C-terminal lysine or asparagine deamidation - was achieved. This allowed a detailed and reliable assessment of the Fc/2 heterogeneity (18-33 proteoforms) of the three analyzed mAbs. (C) 2018 The Authors. Published by Elsevier B.V.Proteomic
Expression clustering reveals detailed co-expression patterns of functionally related protein during B cell differentiation. A proteomics study using a combination of 1D gel electrophoresis, LC-MS/MS and SILAC
Relational Vs. absolute representation in categorization. American Journal of Psychology. 125, 4, 481- 497.
Objectives: Many reports demonstrate improvements in cardiovascular risk factors during GH replacement (rhGH) in adult GH deficiency (GHD). However, it remains to be determined to what extent these changes translate into a reduction of increased cardiovascular morbidity and mortality. The aim of this study was to evaluate the effects of long-term rhGH replacement on the prevalence of the metabolic syndrome (MS). Design, settings, main outcome measures: The MS was scored by the National Cholesterol Education Program-Adult Treatment Panel III definition in 50 consecutive GHD patients (45 9 years of age), before and after 2 and 5 years of rhGH replacement, and the data of untreated patients were compared with the general population using data from a Dutch population-based study (n = 1062, 44 +/- 8 years of age). Results: Hypertriglyceridaemia (46.0 vs 18.5%, P <0.0001), hypertension (66.0 vs 35.5%, P <0.0001) and abdominal obesity (38.0 vs 23.4%, P=0.0178) were more prevalent in untreated patients when compared with controls, resulting in a higher prevalence of the MS in patients (38.0 vs 15.7%, P <0.0001). During rhGH replacement at a mean dose of 0.5 +/- 0.2 mg/day resulting in IGF-I concentrations in the normal age-adjusted reference range, mean high-density lipoprotein cholesterol level increased compared with baseline (P <0.001). However, the prevalence of (components of) the MS did not change after 2 or 5 years of treatment with rhGH. Conclusion: In this study, the prevalence of the MS in patients with GHD is increased compared with healthy controls, irrespective of rhGH replacement
Pheochromocytomas and extra-adrenal paragangliomas detected by screening in patients with SDHD-associated head-and-neck paragangliomas
Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas for which screening has been advised. To assess clinical, biochemical, and radiological outcomes of screening in a large single-center cohort of SDHD-positive patients with HNP and to address the necessity for repetitive follow-up, we evaluated 93 patients with SDHD-associated HNP (p.Asp92Tyr, p.Leu139Pro). Screening consisted of measurement of 24 h urinary excretion of catecholamines and/or their metabolites in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients, in whom urinary excretion was above the reference limit, imaging studies with (123)I-MIBG (metaiodobenzylguanidine) scintigraphy and magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate blockade. Median follow-up was 4.5 years (range 0.5-19.5 years). Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients. Paragangliomas that do not secrete catecholamines might be more prevalent than previously reported. Future studies will have to establish whether routine imaging studies should be included in the screening of SDHD mutation carriers, irrespective of biochemical screening