Accuracy and prognostic impact of FDG PET/CT and biopsy in bone marrow assessment of follicular lymphoma at diagnosis: A Nation-Wide cohort study.

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

MicroRNAs as New Regulators of Neutrophil Extracellular Trap Formation.

Neutrophil extracellular traps (NETs) are formed after neutrophils expelled their chromatin content in order to primarily capture and eliminate pathogens. However, given their characteristics due in part to DNA and different granular proteins, NETs may induce a procoagulant response linking inflammation and thrombosis. Unraveling NET formation molecular mechanisms as well as the intracellular elements that regulate them is relevant not only for basic knowledge but also to design diagnostic and therapeutic tools that may prevent their deleterious effects observed in several inflammatory pathologies (e.g., cardiovascular and autoimmune diseases, cancer). Among the potential elements involved in NET formation, several studies have investigated the role of microRNAs (miRNAs) as important regulators of this process. miRNAs are small non-coding RNAs that have been involved in the control of almost all physiological processes in animals and plants and that are associated with the development of several pathologies. In this review, we give an overview of the actual knowledge on NETs and their implication in pathology with a special focus in cardiovascular diseases. We also give a brief overview on miRNA biology to later focus on the different miRNAs implicated in NET formation and the perspectives opened by the presented data.

miR-146a in Cardiovascular Diseases and Sepsis: An Additional Burden in the Inflammatory Balance?

The new concept of thrombosis associated with an inflammatory process is called thromboinflammation. Indeed, both thrombosis and inflammation interplay one with the other in a feed forward manner amplifying the whole process. This pathological reaction in response to a wide variety of sterile or non-sterile stimuli eventually causes acute organ damage. In this context, neutrophils, mainly involved in eliminating pathogens as an early barrier to infection, form neutrophil extracellular traps (NETs) that are antimicrobial structures responsible of deleterious side effects such as thrombotic complications. Although NETosis mechanisms are being unraveled, there are still many regulatory elements that have to be discovered. Micro-ribonucleic acids (miRNAs) are important modulators of gene expression implicated in human pathophysiology almost two decades ago. Among the different miRNAs implicated in inflammation, miR-146a is of special interest because: (1) it regulates among others, Toll-like receptors/nuclear factor-κB axis which is of paramount importance in inflammatory processes, (2) it regulates the formation of NETs by modifying their aging phenotype, and (3) it has expression levels that may decrease among individuals up to 50%, controlled in part by the presence of several polymorphisms. In this article, we will review the main characteristics of miR-146a biology. In addition, we will detail how miR-146a is implicated in the development of two paradigmatic diseases in which thrombosis and inflammation interact, cardiovascular diseases and sepsis, and their association with the presence of miR-146a polymorphisms and the use of miR-146a as a marker of cardiovascular diseases and sepsis.

Pilot Study on the Role of Circulating miRNAs for the Improvement of the Predictive Ability of the 2MACE Score in Patients with Atrial Fibrillation.

Background. Atrial fibrillation (AF) increases the risk for stroke but also for non-stroke major adverse cardiovascular events (MACE). The 2MACE score was recently proposed to predict these events. Since the interest of microRNAs (miRNAs) in cardiovascular diseases is increasing, we aimed to investigate whether miRNA levels may improve the predictive performance of the 2MACE score. Methods. We included consecutive AF patients stable on vitamin K antagonist therapy. Blood samples were drawn at baseline and plasma expression of miRNAs was assessed. During a median of 7.6 (interquartile range (IQR) 5.4-8.0) years, the occurrence of any MACE (nonfatal myocardial infarction/cardiac revascularization and cardiovascular death) was recorded. Results. We conducted a miRNA expression analysis in plasma from 19 patients with and without cardiovascular events. The miRNAs selected (miR-22-3p, miR-107, and miR-146a-5p) were later measured in 166 patients (47% male, median age 77 (IQR 70-81) years) and all were associated with a higher risk of MACE. The addition of miR-107 and miR-146a-5p to the 2MACE score significantly increased the predictive performance (c-indexes: 0.759 vs. 0.694, p = 0.004), and the model with three miRNAs also improved the predictive performance compared to the original score (c-indexes: 0.762 vs. 0.694, p = 0.012). 2MACE models with the addition of miRNAs presented higher net benefit and potential clinical usefulness. Conclusions. Higher miR-22-3p andmiR-107 and lower miR-146a-5p levels were associated with a higher risk of MACE. The addition of these miRNAs to the 2MACE score significantly increased the predictive performance for MACE, which may aid to some extent in the decision-making process about risk stratification in AF.

Severe liver toxicity in a chronic myeloid leukemia patient probably induced by a drug interaction between imatinib and sertraline.

Our objective is to describe a chronic myeloid leukemia patient with a severe liver toxicity likely due to a drug-drug interaction between imatinib and sertraline. The patient started treatment with sertraline three months after starting imatinib. From the beginning of sertraline treatment, the patient developed vomiting, and five weeks later she developed a severe hepatic failure and was admitted to the hospital. The Naranjo nomogram showed a probable correlation between this adverse effect and the interaction between imatinib and sertraline. This interaction is extremely rare and the mechanism of action is not clear; it could be a mix of pharmacokinetic and pharmacodynamic processes. To our knowledge, this is the first case in medical literature of a severe liver toxicity due to an interaction between imatinib and sertraline. This interaction is also not described in the main secondary data sources, such as Lexicomp® and Micromedex®. However, due to the severity of this event, the hepatic function should be carefully monitored in patients treated with imatinib and sertraline.