Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P ‫؍‬ .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD ؊ immunofixation-negative (IFx ؊ ) patients and MRD ؊ IFx ؉ patients had significantly longer PFS than MRD ؉ IFx ؊ patients. Multivariate analysis identified MRD status by MFC at day 100 after ASCT as the most important independent prognostic factor for PFS (HR ‫؍‬ 3.64, P ‫؍‬ . IntroductionIn most hematologic malignancies, response to front-line therapy is a good predictor of prognosis, with the longest survival seen in patients achieving an optimal response. This paradigm is represented by chronic myeloid leukemia (CML), in which hematologic, cytogenetic, and molecular remissions define progressively better response to therapy. In consequence, investigations to define these levels of remission are mandatory in routine clinical practice for treatment stratification and assessment of prognosis. 1 The situation is similar for other malignancies such as acute promyelocytic leukemia (APL) or acute lymphoblastic leukemia (ALL). 2,3 For this reason, there are continuous efforts to improve the sensitivity of the methods used to assess response to therapy, mainly through the introduction and refinement of both molecular and immunophenotyping approaches, as well as imaging techniques.Multiple myeloma (MM) should be no exception to this paradigm. For many years, the major goal of MM therapy was to achieve partial response (PR) or disease stabilization. 4,5 With the introduction of high-dose therapy plus autologous stem cell transplantation (HDT/ASCT), the new goal became the achievement of complete response (CR), defined as absence of M-protein by immunofixation (IFx) and less than 5% plasma cells (PCs) in bone marrow (BM). 6,7 More recently, the International Myeloma Working Group proposed a new response category of "stringent CR," which requires normalization of the free light chain ratio and the absence of residual clonal cells in the BM by immunohistochemistry or immunofluorescence. 8 As noted previously, the assessment of minimal residual disease (MRD), residual tumor cells persisting after therapy, is part of the standard of care in many hematologic malignancies, whereas in MM this is still considered investigational. Thus, MRD studies in MM have involved mainly small series of patients or have...

The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A 2 (sPLA 2 -V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (

Background and Purpose-Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. Methods-We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. Results-We found the ability to activate protein C decreased by half (Pϭ0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5Ϯ19.9 and 72.1Ϯ18.8 arbitrary intensity units, meanϮstandard deviation; Pϭ0.028). No differences were detected in endothelial protein C receptor expression. Conclusions-Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke. (Stroke. 2011;42:2622-2624.)Key Words: anticoagulation Ⅲ embolic stroke Ⅲ embolism Ⅲ endothelium Ⅲ protein C anticoagulant system Ⅲ thrombomodulin A trial fibrillation is the most commonly sustained cardiac arrhythmia and the most important risk factor for cardioembolic stroke. 1 The left atrium, particularly the left atrial appendage (LAA), is the most frequent location of the embolic thrombi even when the right atrium undergoes the same pathological process. 2 The blood stasis at the LAA and the right atrial appendage (RAA) is similar, 3 so this cannot explain the higher propensity of thrombi to be formed in the LAA. In the search for additional factors to explain the difference between the 2 atria in thrombogenicity, study of their endothelial phenotypes deserves consideration. Attention recently has focused on the functional consequences of endothelial heterogeneity among different vascular beds. 4 Endothelium has been classically considered a thromboresistent surface because of the presence of receptors involved in several antithrombotic pathways. Among these, thrombomodulin and the endothelial protein C/activated protein C receptor (EPCR) play a crucial role in the protein C anticoagulant pathway. 5 EPCR expression is high in large arteries and veins but is virtually absent in capillaries. 6 Thrombomodulin expression is particularly high in the pulmonary endothelium and is low in the brain endothelium. 7 Differences also have been reported within 1 vessel: in veins, both EPCR and thrombomodulin are expressed more in the valvular sinus endothelium as opposed to the vein lumenal endothelium. 8 The association between protein C deficiency and thrombosis is well-documented. 9 For this reason, we propose the hypothesis that the left atrium has a lower ability to activate protein C than the right one. Mate...