Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-gamma and TN Fu is present in serum. In animal models of the disease, IFN-gamma and INF-alpha have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-gamma, and INF-alpha have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL18 binding protein (IL18BP) resulting in an excess of free IL18 Here we studied whether IL-18B P could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18B P treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-gamma and TNF-alpha production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18B P is beneficial in an animal model of HLH and in combination with anti infectious therapy may be a promising strategy to treat HLH patients

Is R-CHOP Therapy a Lymphoma Growth Factor?

International audienceThis article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 x 10(9)/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow

Title page: Increased Mean Corpuscular Haemoglobin Concentration: Artefact or true abnormality? Short running title: Increased MCHC: Artefact or pathology?

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CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

International audienceKey Points Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common. We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine

Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

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Determination of 5-azacitidine in human plasma by LC–MS/MS: application to pharmacokinetics pilot study in MDS/AML patients

International audienceAzacitidine (Vidaza®, AZA) is a mainstay for treating acute myeloid leukemia (AML) in patients unfit for standard induction and other myelodysplastic syndromes (MDS). However, only half of the patients usually respond to this drug and almost all patients will eventually relapse. Predictive markers for response to AZA are yet to be identified. AZA is metabolized in the liver by a single enzyme, cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent great variability in resulting activities in the liver. The quantitative determination of AZA in plasma is challenging due the required sensitivity and because of the instability in the biological matrix upon sampling, possibly resulting in erratic values

Use of platelet-rich plasma in regenerative medicine: technical tools for correct quality control

International audiencebackground/aimsPlatelet-rich plasma (PRP) injections are used in sports medicine and have been the subject of increased clinical interest. However, there have been very few reports of the composition of initial whole blood and the final PRP product. The objective of this study was to provide technical tools to perform a correct characterisation of platelets, leucocytes and red blood cells (RBCs) from whole blood and PRP.MethodsBlood and PRP were obtained from 26 healthy volunteers and prepared according to the varying parameters encountered within PRP process preparation and quantification (harvesting method, anticoagulant used, sampling method, counting method). Concentrations were measured at t=0, t=1, t=6 and t=24 hours.resultsSampling of blood in Eppendorf tubes significantly decreased platelet concentration over time, whereas sampling in Microvette EDTA-coated tube kept platelet concentration stable until 24 hours. A non-significant difference was observed in platelet counts in PRP with impedance (median (IQR): 521.8 G/L (505.3–524.7)) and fluorescence (591.5 G/L (581.5–595.8)) methods. Other studied parameters did not influence platelet concentrations in blood or PRP samples. Leucocytes and RBC counts were similar whatever the anticoagulant, sampling, harvesting and counting methods used for both blood and PRP samples.ConclusionsSystematic sampling of blood and PRP in EDTA-coated tubes for quality control is recommended. The use of a validated counter for PRP sample should also be taken into account

Simultaneous determination of cytosine arabinoside and its metabolite uracil arabinoside in human plasma by LC-MS/MS: Application to pharmacokinetics-pharmacogenetics pilot study in AML patients

International audiencePurine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e., <10 min) and the metabolic instability in biological matrix upon sampling possibly resulting in erratic values. We developed and validated a liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) for the simultaneous determination of Ara-C and Ara-U metabolite in human plasma. After simple and rapid precipitation, analytes were successfully separated and quantitated over a 1-500 ng/ml range for Ara-C and 250-7500 ng/ml range for AraU. The performance and reliability of this method was tested as part of an investigational study in AML patients treated with low dose cytarabine and confirmed marked differences in drug exposure levels and metabolic ratio, depending on the CDA status of the patients. Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in AML patients with respect to their CDA phenotypes

Different sensitivity of CD19-positive bone marrow and lymph node lymphoblasts may cause resistance to blinatumomab in relapsed B-cell acute lymphoblastic leukemia/lymphoma

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