Novel Molecular Insights into the Combination Treatment of Acromegaly

In chapter 2 of this thesis we have confirmed that LA-SSA in combination with PEGV as a treatment modality for acromegaly still appears to be highly effective, after almost a decade of experience in the Rotterdam cohort (n=112). Normalization of IGF-I levels occurred in 97% of the patients, provided that the required PEGV dose was used. The median PEGV dose to achieve this efficacy rate was 80 mg/week [interquartile range: 60 – 120 mg]. Side effects such as lipohypertrophy (2.8%) and elevated transaminases of more than three times the upper limit of normal (13.5%) were mild and transient (n=141). Tumor size control and even tumor shrinkage is observed in a vast majority of patients. Pituitary tumor size increase was observed in one patient. Normalization of IGF-I levels in acromegaly patients is associated with the expression of SSTR2 on somatotroph adenomas. In the Rotterdam cohort (n=39), the SSTR2 expression was lower in patients pre-treated with LA-SSA and PEGV compared to drug-naive acromegaly patients after transsphenoidal surgery, which is described in chapter 3. Moreover, a higher required PEGV dose in combination with LA-SSA was needed in patients with a lower SSTR2 expression on drug-naive somatotroph adenomas to achieve normalized IGF-I levels. (Partial) resistance for LA-SSA alone could be one of the reasons why these patients with a lower SSTR2 expression necessitate LA-SSA in combination with PEGV. Chapter 4 and 5 focus on the common growth hormone polymorphism lacking exon 3, which is associated with disease severity and has been reported to be more responsive to PEGV treatment in acromegaly patients. Clinical data from the Rotterdam cohort (n=112) does not support a role for GHR genotype in treatment response or PEGV dosing nor PEGV serum levels in patients treated with LA-SSA in combination with PEGV. A meta-analysis obtained from four separate study cohorts including the Rotterdam cohort (n=324), confirmed that the presence of the d3- GHR in acromegaly patients has no impact on clinical practice. The polymorphism was not of added value for either the determination of the required PEGV dose or the prediction of PEGV responsiveness. Finally, the last study of this thesis did identify predictors for PEGV dosing. IGF-I levels, weight, height and age are associated with the required PEGV dose in order to normalize IGF-I levels in addition to LASSA. The IGF-I normalization dosage during PEGV monotherapy is only associated with patients weight. A multivariate prediction model which can be used as a clinical guidance tool for PEGV dosing in addition to LASSA can be found in chapter 6

Novel Molecular Insights into the Combination Treatment of Acromegaly

In chapter 2 of this thesis we have confirmed that LA-SSA in combination with PEGV as a treatment modality for acromegaly still appears to be highly effective, after almost a decade of experience in the Rotterdam cohort (n=112). Normalization of IGF-I levels occurred in 97% of the patients, provided that the required PEGV dose was used. The median PEGV dose to achieve this efficacy rate was 80 mg/week [interquartile range: 60 – 120 mg]. Side effects such as lipohypertrophy (2.8%) and elevated transaminases of more than three times the upper limit of normal (13.5%) were mild and transient (n=141). Tumor size control and even tumor shrinkage is observed in a vast majority of patients. Pituitary tumor size increase was observed in one patient. Normalization of IGF-I levels in acromegaly patients is associated with the expression of SSTR2 on somatotroph adenomas. In the Rotterdam cohort (n=39), the SSTR2 expression was lower in patients pre-treated with LA-SSA and PEGV compared to drug-naive acromegaly patients after transsphenoidal surgery, which is described in chapter 3. Moreover, a higher required PEGV dose in combination with LA-SSA was needed in patients with a lower SSTR2 expression on drug-naive somatotroph adenomas to achieve normalized IGF-I levels. (Partial) resistance for LA-SSA alone could be one of the reasons why these patients with a lower SSTR2 expression necessitate LA-SSA in combination with PEGV. Chapter 4 and 5 focus on the common growth hormone polymorphism lacking exon 3, which is associated with disease severity and has been reported to be more responsive to PEGV treatment in acromegaly patients. Clinical data from the Rotterdam cohort (n=112) does not support a role for GHR genotype in treatment response or PEGV dosing nor PEGV serum levels in patients treated with LA-SSA in combination with PEGV. A meta-analysis obtained from four separate study cohorts including the Rotterdam cohort (n=324), confirmed that the presence of the d3- GHR in acromegaly patients has no impact on clinical practice. The polymorphism was not of added value for either the determination of the required PEGV dose or the prediction of PEGV responsiveness. Finally, the last study of this thesis did identify predictors for PEGV dosing. IGF-I levels, weight, height and age are associated with the required PEGV dose in order to normalize IGF-I levels in addition to LASSA. The IGF-I normalization dosage during PEGV monotherapy is only associated with patients weight. A multivariate prediction model which can be used as a clinical guidance tool for PEGV dosing in addition to LASSA can be found in chapter 6

Combined treatment of somatostatin analogues with pegvisomant in acromegaly

Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV

Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant

Background: Growth hormone secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also down regulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve IGF-I normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenomas tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pre-treatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated to the required PEGV dose to achieve IGF-I normalization during post-surgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression is lower in patients pre-treated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Accuracy Assessment of the ESA CCI 20M Land Cover Map: Kenya, Gabon, Ivory Coast and South Africa

This working paper presents the overall and spatial accuracy assessment of the European Space Agency (ESA) 20 m prototype land cover map for Africa for four countries: Kenya, Gabon, Ivory Coast and South Africa. This accuracy assessment was undertaken as part of the ESA-funded CrowdVal project. The results varied from 44% (for South Africa) to 91% (for Gabon). In the case of Kenya (56% overall accuracy) and South Africa, these values are largely caused by the confusion between grassland and shrubland. However, if a weighted confusion matrix is used, which diminishes the importance of the confusion between grassland and shrubs, the overall accuracy for Kenya increases to 79% and for South Africa, 75%. The overall accuracy for Ivory Coast (47%) is a result of a highly fragmented land cover, which makes it a difficult country to map with remote sensing. The exception was Gabon with a high overall accuracy of 91%, but this can be explained by the high amount of tree cover across the country, which is a relatively easy class to map

A new chemical library of food compounds and food-derived metabolites developed in FOODBALL

International audienceFOODBALL (Food Biomarkers Alliance) is a large collaborative project (22 partners from 11 countries) funded by the JPI HDHL (2015-2017) which includes a systematic exploration and validation of nutritional biomarkers to obtain a good coverage of the food intake in different population groups within Europe. One of the aims of FOODBALL is to develop new online resources to facilitate identification of nutritional biomarkers using metabolomics. A major limitation in metabolomics is the lack of commercial standards to validate putative identifications. The FOODBALL chemical library will facilitate the sharing of not easily accessible standards for diet-derived compounds. It will be a virtual library, with compounds stored in the laboratory where they have been isolated. Version 1.0 will be an online catalog of pure compounds and reference materials (food extracts, biofluids from animals fed pure compounds, incubation media from in vitro systems to produce metabolites…) made available by FOODBALL partners and associated collaborators. The catalog will contain the list of available compounds with associated data including elemental formula, monoisotopic mass, solubility, origin, purity, available quantity, storage conditions, stability, links to existing databases, type of spectral data available and contact details of the laboratory offering to share the standard. The catalog will be queryable by compound name and chemical structure. In the final version, which should be available at the end of 2016, spectral data (GC-MS, LC-MS, NMR, UV, IR) collected in standardized formats will be made queryable online. Anyone interested in one compound in the catalog will directly contact the provider. A bilateral negotiation will define the terms of collaboration. A financial compensation in addition to the shipping fees is possible if agreed. Contributors and users will have to respect a charter of good practices. For example the provider will have to indicate on a packing slip the minimum information regarding the appearance of the product, quantity, recommended storage conditions, stability and safety information if available. The acquirer will bear all shipping costs, and will have to share the spectral analyses he has acquired on his own analytical platform. This will continuously enrich the content of the chemical library. The library will allow to post a demand for a non-available compound, to stimulate its synthesis or isolation. The greatest need is for human metabolites of food-derived compounds

Heterologous expression of a basic elicitin from Phytophthora cryptogea in Phytophthora infestans increases its ability to cause leaf necrosis in tobacco

International audienc

The Effect of the Exon-3-Deleted GH-Receptor in Pegvisomant-Treated Acromegaly : A Systematic Review and Meta-Analysis

Background: The common exon 3 deletion polymorphism of the growth hormone receptor (d3-GHR) is associated with disease severity in acromegaly patients. The GHR antagonist pegvisomant (PEGV) is highly effective in treating severe acromegaly. Response to PEGV treatment seems to be influenced by d3-GHR and appears to be more responsive to PEGV, although available results remain conflicting. Objective: To assess the influence of d3-GHR on the responsiveness of acromegaly patients to PEGV by compiling the evidence derived from the largest available studies. Design: A systematic review of the literature identified three published studies and one conference abstract. Acromegaly patients (n = 324, 49.7% d3-GHR carriers) were treated with either PEGV monotherapy or PEGV combined with long-acting somatostatin analogues (LA-SSA) and/or cabergoline. A meta-analysis of raw data from these studies was performed. Results: No significant effect of the d3-GHR was observed while bringing IGF-I levels below the upper limit of normal with PEGV, which was defined as the lowest IGF-I level during PEGV-treatment (mean difference: -2.3%; 95% CI: -6.5 to 1.8%, p = 0.270). The PEGV dose required to achieve the lowest IGF-I levels was also not significantly influenced by individuals carrying d3-GHR (mean difference: 4.1 mg weekly; 95% CI: -5.1 to 13.2, p = 0.385). For both outcomes, separate analysis of PEGV monotherapy and combination treatment gave similar results. Conclusion: Our findings suggest that the d3-GHR polymorphism has no effect on biochemical disease control in acromegaly, as it is not of added value for either the prediction of PEGV responsiveness or the determination of the required PEGV dose

FoodComEx: une chimiothèque internationale pour les composés dérivés de l’alimentation

National audienceLe manque de standards commerciaux pour de nombreux composés dérivés de l’alimentation, en particulier les métabolites retrouvés dans le sang et les tissus chez l’homme après consommation des aliments constitue une limitation importante en nutrition. Par exemple l’identification de centaines de métabolites détectés dans les profils métabolomiques reste difficile sans standard, d’autre part les études mécanistiques sur modèles cellulaires se font encore trop souvent avec des composés qui ne sont pas ceux retrouvés au niveau physiologique. FoodComEx (Food Compound Exchange, http://foodcomex.org/) est une nouvelle chimiothèque initiée dans le cadre du projet européen FoodBAll pour faciliter l’accès à des molécules dérivées de l’alimentation qui sont aujourd’hui peu ou pas disponibles. Dans le cadre de projets divers, beaucoup de composés ont été produits à petite échelle dans des laboratoires académiques, par synthèse chimique ou enzymatique, par purification à partir de matrices biologiques ou encore par incubation avec des microorganismes. Des collections entières de composés précieux dorment dans des laboratoires du monde entier. L’objectif de FoodComEx est de mettre à disposition ces composés pour une large communauté d’utilisateurs. FoodComEx sera un catalogue interrogeable en ligne des composés disponibles, indiquant les coordonnées du laboratoire offrant de partager chaque composé. Tout utilisateur intéressé contactera directement le laboratoire producteur et les termes de la collaboration seront décidés par les deux partenaires, dans le cadre de la charte des bonnes pratiques de FoodComEx. Des données physico-chimiques, spectrales ainsi que des informations décrivant l’origine du composé, sa stabilité, sa pureté, etc seront disponibles dans la fiche de chaque composé. Les données analytiques seront enrichies continuellement par les utilisateurs. FoodComEx est une initiative récente qui bénéficie déjà du soutien de réseaux tels que la société allemande des food chemists et l’action COST POSITIVe. Tout laboratoire souhaitant partager des composés dérivés de l’alimentation est évidemment le bienvenu pour enrichir la collection de FoodComEx et permettre de nouvelles collaborations. Financement : Projet FoodBall JPI HDHL