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Al Assaf C.,Catholic University of Leuven | Van Obbergh F.,Catholic University of Leuven | Billiet J.,Laboratory of Hematology | Lierman E.,Catholic University of Leuven | And 10 more authors.
Haematologica | Year: 2015

The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival. © 2015 Ferrata Stor ti Foundation.


Verroken A.,Saint Luc University Hospital | Bauraing C.,Mont Godinne University Hospital | Deplano A.,Erasme University Hospital | Bogaerts P.,Mont Godinne University Hospital | And 3 more authors.
Clinical Microbiology and Infection | Year: 2014

During an 8-month period, 24 Corynebacterium striatum isolates recovered from lower respiratory tract specimens of 10 hospitalized patients were characterized. The organisms were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and by 16S rRNA gene sequencing. The cluster of C. striatum exclusively affected patients who had been admitted to an intensive care unit and/or subsequently transferred to one medium-size respiratory care unit. Prolonged duration of hospitalization, advanced stage of chronic obstructive pulmonary disease, recent administration of antibiotics and exposure to an invasive diagnostic procedure were the most commonly found risk factors in these patients. Seven patients were colonized and three infected. All strains displayed a similar broad spectrum resistance to antimicrobial agents, remaining susceptible to vancomycin only. Typing analysis by MALDI-TOF MS and by semi-automated repetitive sequence-based PCR (DiversiLab typing) showed that all outbreak-associated C. striatum isolates clustered together in one single type while they differed markedly from epidemiologically unrelated C. striatum isolates. Pulsed-field gel electrophoresis (PFGE) profiles revealed three distinct PFGE types among the C. striatum isolates associated with the outbreak while all external strains except one belonged to a distinct type. We conclude that C. striatum is an opportunistic nosocomial pathogen in long-term hospitalized patients and can be at the origin of major outbreaks. The routine use of MALDI-TOF MS greatly facilitated the recognition/identification of this organism in clinical samples and this technique could also offer the potential to be used as an easy and rapid epidemiological typing tool for outbreak investigation. © 2013 European Society of Clinical Microbiology and Infectious Diseases.


PubMed | UZ Leuven, Mont Godinne University Hospital, Maria Sklodowska Curie Memorial Cancer Center and Institute, AZ St Jan AV and 2 more.
Type: Journal Article | Journal: Genes, chromosomes & cancer | Year: 2016

The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3JAK2-5PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. 2016 Wiley Periodicals, Inc.


Hasdenteufel F.,Allergy Therapeutics | Luyasu S.,Mont Godinne University Hospital | Hougardy N.,Clinic of South Luxembourg | Fisher M.,University of Sydney | And 3 more authors.
Current Clinical Pharmacology | Year: 2012

Structure-activity relationships (SARs) refer to the relation between chemical structure and pharmacologic activity for a series of compounds. Since the pioneering work of Crum-Brown and Fraser in 1868, they have been increasingly used in the pharmaceutical, chemical and cosmetic industries, especially for drug and chemical design purposes. Structure-activity relationships may be based on various techniques, ranging from considerations of similarity or diversity of molecules to mathematical relationships linking chemical structures to measured activities, the latter being referred to as quantitative SAR or QSAR. This review aims at briefly reviewing the history of SARs and highlighting their interest in delayed and immediate drug allergy using selected examples from the literature. Studies of SAR are commonly conducted in the area of contact dermatitis, a delayed hypersensitivity reaction, to determine the allergenic potential of a given compound without animal testing. In immediate, immunoglobulin E-mediated drug hypersensitivity, this kind of approach remains rather confidential. It has been mainly applied to neuromuscular blocking drugs (muscle relaxants) and betalactam antibiotics (penicillins, cephalosporins). This review shows that SARs can prove useful to (i) predict the allergenic potential of a chemical or a drug, (ii) help identify putative antigenic determinants for each patient or small group of patients sharing the same cross-reactivity pattern, and (iii) predict the likelihood of adverse reactions to related molecules and select safe alternatives. © 2012 Bentham Science Publishers.


Ghardi M.,Belgian Nuclear Research Center | Moreels M.,Belgian Nuclear Research Center | Chatelain B.,Mont Godinne University Hospital | Chatelain C.,Mont Godinne University Hospital | Baatout S.,Belgian Nuclear Research Center
International Journal of Molecular Medicine | Year: 2012

In case of accidental radiation exposure or a nuclear incident, physical dosimetry is not always complete. Therefore, it is important to develop tools that allow dose estimates and determination that are based on biological markers of radiation exposure. Exposure to ionizing radiation triggers a large-scale activation of specific DNA signaling and repair mechanisms. This includes the phosphorylation of γH2AX in the vicinity of a double-strand break (DSB). A DNA DSB is a cytotoxic form of DNA damage, and if not correctly repaired can initiate genomic instability, chromosome aberrations, mutations or apoptosis. Measurements of DNA DSBs and their subsequent repair after in vitro irradiation has been suggested to be of potential use to monitor cellular responses. The bone marrow and the blood are known to be the most radiosensitive tissues of the human body and can therefore be of particular importance to find radiation-induced biological markers. In the present study, changes in H2AX phosphorylation and apoptosis of irradiated human peripheral blood mononuclear cells (PBMCs) were analyzed. Freshly isolated PBMCs from healthy donors were irradiated with X-rays (0.1, 0.25, 0.5, 1, 2 and 4 Gy). The phosphorylation of γH2AX was measured at different time points (0, 0.25, 1, 2, 4, 6 and 24 h) after irradiation. We detected a linear dose-dependency of γH2AX phosphorylation measured by γH2AX foci scoring using immunofluorescence microscopy as well as by γH2AX fluorescence detection using flow cytometry. Apoptosis was detected by measuring DNA fragmentation at different time points (0, 24, 48, 72, 96 h) after X-irradiation using DNA ladder gel electrophoresis. The apoptotic DNA fragmentation increased in a dose-dependent manner. In conclusion, DNA DSBs and subsequent apoptotic DNA fragmentation monitoring have potential as biomarkers for assessing human exposure in radiation biodosimetry.


Luyasu S.,Mont Godinne University Hospital | Wamelink M.M.C.,VU University Amsterdam | Galanti L.,Mont Godinne University Hospital | Dive A.,Mont Godinne University Hospital
Acta Clinica Belgica | Year: 2014

High anion gap metabolic acidosis due to pyroglutamic acid (5-oxoproline) is a rare complication of acetaminophen treatment (which depletes glutathione stores) and is often associated with clinically moderate to severe encephalopathy. Acquired 5-oxoprolinase deficiency (penicillins) or the presence of other risk factors of glutathione depletion such as malnutrition or sepsis seems to be necessary for symptoms development. We report the case of a 55-year-old women who developed a symptomatic overproduction of 5-oxoproline during flucloxacillin treatment for severe sepsis while receiving acetaminophen for fever control. Hemodialysis accelerated the clearance of the accumulated organic acid, and was followed by a sustained clinical improvement. © Acta Clinica Belgica 2014.


Verroken A.,Mont Godinne University Hospital | Janssens M.,Catholic University of Leuven | Berhin C.,Mont Godinne University Hospital | Bogaerts P.,Mont Godinne University Hospital | And 3 more authors.
Journal of Clinical Microbiology | Year: 2010

The identification of Nocardia species, usually based on biochemical tests together with phenotypic in vitro susceptibility and resistance patterns, is a difficult and lengthy process owing to the slow growth and limited reactivity of these bacteria. In this study, a panel of 153 clinical and reference strains of Nocardia spp., altogether representing 19 different species, were characterized by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). As reference methods for species identification, full-length 16S rRNA gene sequencing and phenotypical biochemical and enzymatic tests were used. In a first step, a complementary homemade reference database was established by the analysis of 110 Nocardia isolates (pretreated with 30 min of boiling and extraction) in the MALDI BioTyper software according to the manufacturer's recommendations for microflex measurement (Bruker Daltonik GmbH, Leipzig, Germany), generating a dendrogram with species-specific cluster patterns. In a second step, the MALDI BioTyper database and the generated database were challenged with 43 blind-coded clinical isolates of Nocardia spp. Following addition of the homemade database in the BioTyper software, MALDI-TOF MS provided reliable identification to the species level for five species of which more than a single isolate was analyzed. Correct identification was achieved for 38 of the 43 isolates (88%), including 34 strains identified to the species level and 4 strains identified to the genus level according to the manufacturer's log score specifications. These data suggest that MALDI-TOF MS has potential for use as a rapid (<1 h) and reliable method for the identification of Nocardia species without any substantial costs for consumables. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Krug B.,Mont Godinne University Hospital | Crott R.,Catholic University of Leuven | de Canniere L.,Mont Godinne University Hospital | D'Hondt L.,Mont Godinne University Hospital | Vander Borght T.,Mont Godinne University Hospital
Colorectal Disease | Year: 2013

Aim: Treatment of locally advanced rectal cancer (LARC) includes preoperative radiation therapy with or without chemotherapy followed by radical surgery, but the clinical outcome is uncertain. A systemic review was carried out to determine the predictive value of 18F-fluoro-2-deoxyglucose positron emission tomography (18FDG-PET) for assessing disease-free (DFS) and overall survival (OS) in LARC. Method: A literature search (PubMed/MEDLINE, EMBASE, Cochrane) up to January 2012 to identify full papers with sequential 18FDG-PET and survival data, using indexing terms and free text words. The inclusion criteria were: a study of at least 10 patients, having sequential 18FDG-PET imaging before and after adjuvant chemoradiation and a minimal follow-up of 24 months. Studies were selected by two of the authors. A meta-analysis was performed for DFS and OS using the hazard ratio (HR) as the primary outcome. Results: Five eligible studies were identified including 330 patients (mean age 63 years, 64% men), in which PET-CT or PET imaging was used. The American Joint Committee on Cancer stage distribution was as follows: Stage I, 2%; Stage II, 44%; Stage III, 52%; Stage IV, 1%. The pooled HRs for complete metabolic response versus partial or no response were 0.39 (95% CI 0.18-0.86; P = 0.02) for OS and 0.70 (95% CI 0.16-3.14; P = 0.64) for DFS. The lack of significance for DFS might be explained by different follow-up characteristics. There was also clinical heterogeneity among the different studies. Conclusion: This systematic review indicates that complete metabolic response on sequential 18FDG-PET data after preoperative chemoradiation of LARC is predictive of OS, but not of DFS. © 2013 The Association of Coloproctology of Great Britain and Ireland.


Laloux P.,Mont Godinne University Hospital | Lemonnier F.,Mont Godinne University Hospital | Jamart J.,Catholic University of Leuven
Acta Neurologica Belgica | Year: 2010

The profile of recurrent ischemic strokes has not been much investigated. The aim of this study was to evaluate how the therapeutic strategies recommended for secondary prevention after an ischemic stroke are implemented in the real world of clinical practice. All patients admitted for a recurrent ischemic stroke or TIA were prospectively registered. The etiology was determined according to the TOAST classification. The risk factors and cardiovascular treatment at the time of the recurrence were recorded. A total of 168 patients were evaluated. Most of the patients (61%) recurred after 1 year. The recurrent stroke was not associated with a particular etiological subtype. The most frequent risk factor was hypertension (79%), followed by hypercholesterolemia (43%), smoking (25%), and diabetes (22%). Most of the patients had more than 1 risk factor (84%). Hypertension was not satisfactorily controlled in 38% of patients, hypercholesterolemia in 42%, and diabetes in 59%. A significant minority of patients (15%) were not taking any antithrombotic agent despite a history of stroke or TIA. Only 34% of the cases with a known atrial fibrillation were on anticoagulant therapy and the International Normalized Ratio was <2.0 in 71% of them. In conclusion, stroke prevention needs to be improved by better implementation of therapeutic strategies in clinical practice. The patients should also be better informed about target values as well as the importance of physical activity and smoking cessation.


Muschart X.,Mont Godinne University Hospital | Blommaert D.,Mont Godinne University Hospital
Acta Cardiologica | Year: 2013

Alcohol is the most widely tolerated and consumed drug worldwide. Alcohol consumption is associated with both good and bad cardiovascular effects. The link between drinking alcohol and heart disease, or arrhythmia, in healthy individuals or with existing heart disease has been well demonstrated. We report the case of a patient with no evidence of heart disease who presented with sustained ventricular tachycardia and syncope after acute alcohol consumption. Alcohol is an uncommon and little-known cause of sustained ventricular tachycardia.

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