Serum Soluble TACI, a BLyS Receptor, Is a Powerful Prognostic Marker of Outcome in Chronic Lymphocytic Leukemia

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells' surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients' outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS ( = −0.000021), b2-microglobulin ( = 0.005), anemia ( = −0.03), thrombocytopenia ( = 0.04), Binet stage ( = 0.02), and free light chains ratio ( = 0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT ( = 0.0003 and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival ( = 0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS

Investigation of the probable clinical, biological and prognostic significance of the presence of intact monoclonal immunoglobulin in plasma cell dyscracias and in B-lymphoproliferative disorders

The immunoglobulins are produced by terminally differentiated BLymphocytes and participate in the primary and secondary immune response.Plasma cell dyscrasias and B-Lymphoproliferative disorders are maindiseases where a monoclonal immunoglobulin may be found. In many ofthese entities we find reduced levels of polyclonal antibodies.In the present thesis we studied patients with Multiple Myeloma at diagnosisand during follow up, others with Waldenström’s Macroglobulinemia atdiagnosis, as well as patients with Chronic Lymphocytic Leukemia andMarginal Zone Lymphoma. The aim was to investigate the impact of theproduced immunoglobulins in the pathogenesis and clinical behavior of theaforementioned diseases. The levels of the Igs were measured with classicalnephelometry as well as with the new HevyliteTM method, that determines themonoclonal Ig (HLC) and the polyclonal Ig of the same class and allows thecalculation of the ratio of monoclonal/polyclonal of the same class (HLCR).In all the diseases studied we found that HLC and the ratio HLCR werecorrelated with disease parameters and in some of them they also provide prognostic information.Furthermore we studied the cytokines soluble-Syndecan-1, BLys and TGF-β1in relation to the above mentioned diseases and to the production ofimmunoglobulins. We found them to correlate with disease parametersreflecting tumour burden and with the production of monoclonal andpolyclonal Igs.Our results are highly suggestive that these cytokines and the determinationof immunoglobulins with these new methods provide useful information forclinical, biological and prognostic purposes.Οι ανοσοσφαιρίνες παράγονται από τελικά διαφοροποιημένα Β Λεμφοκύτταρακαι συμμετέχουν στην πρωτογενή και δευτερογενή ανοσολογική απάντηση. ΟιΠλασματοκυτταρικές δυσκρασίες και τα Β-Λεμφοϋπερλαστικά νοσήματααποτελούν πρότυπα νοσήματα, όπου έχουμε παραγωγή μονοκλωνικώνανοσοσφαιρινών, ενώ σε πολλά από αυτά ανευρίσκονται μειωμένα επίπεδαπολυκλωνικών αντισωμάτων.Μελετήθηκαν ασθενείς με Πολλαπλούν Μυέλωμα στη διάγνωση και τηνπορεία, με Μακροσφαιριναιμία του Waldenström στη διάγνωση, με ΧρόνιαΛεμφογενή Λευχαιμία και με Λέμφωμα Οριακής Ζώνης επίσης στη διάγνωση.Σκοπός ήταν να διερευνηθεί αν οι παραγόμενες ανοσοσφαιρινώναντικατοπτρίζουν στοιχεία της παθογένειας και της κλινικής συμπεριφοράςτων νοσημάτων αυτών. Ο προσδιορισμός των Igs πραγματοποιήθηκε μεκλασσική νεφελομετρία καθώς και με τις νέες μεθόδους HevyliteTM.Βρέθηκε σε όλα τα νοσήματα συσχέτιση των HLC και του λόγου HLCR μεπαράγοντες νόσου, ενώ σε πολλά από αυτά φαίνεται να έχουν και προγνωστική αξία.Παράλληλα μελετήθηκαν οι κυτταροκίνες διαλυτός-Syndecan-1, BLys καιTGF-β1 σε σχέση με το ρόλο τους στα παραπάνω νοσήματα και τηνπαραγωγή των ανοσοσφαιρινών. Βρήκαμε ότι όλοι οι παραπάνω βιολογικοίπαράγοντες σχετίστηκαν σε διαφορετικά νοσήματα με διαφορετικούςπαράγοντες νόσου και με την παραγωγή τόσο των μονοκλωνικών όσο καιτων πολυκλωνικών Igs.Προτείνεται ο προσδιορισμός των ανοσοσφαιρινών με νέες μεθόδους, καθώςπροσφέρουν χρήσιμες πληροφορίες ως προς την συμπεριφορά τωννοσημάτων αυτών

Genetic and molecular mechanisms in multiple myeloma: a route to better understand disease pathogenesis and heterogeneity.

Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm presenting with a wide range of clinical manifestations. In spite of the availability of very performing treatment modalities, survival is highly varying, ranging from a few months to several years. Underlying genetic and microenvironmental mechanisms are thought to be responsible for clinical heterogeneity. Disease etiology is unknown but progresses in the understanding of its pathogenesis have shown that MM precursor cell transformation into a malignant one occurs in a multistep process. Possibly during class switch recombination a primary genetic event takes place. With the occurrence of additional events and the support of bone marrow microenvironmental cells, neoplastic plasma cells actively proliferate and disease behavior may change. Recurrent translocations involving the IgH locus (11q13, 4p16, 16q23, 21q12, and 6p21), deletions of chromosome 13, trisomies of chromosomes 3, 5, 9, 11, 15, 19, and 21, and dysregulated expression of cyclin D genes, are considered initiating or primary events. Alterations related to further disease transformation and adverse prognosis are deletion of 17p13, c-myc translocations, and gains of chromosome 1q21. In relation to the underlying genetic defects, disease subgroups are recognized. Accordingly treatment effectiveness may differ among groups. Intense research is ongoing in this field

Ratio of involved/uninvolved immunoglobulin quantification by Hevylite™ assay: clinical and prognostic impact in multiple myeloma

<p>Abstract</p> <p>Background</p> <p>HevyLite™ is a new, recently developed method that facilitates separate quantification of the kappa- and lambda-bounded amounts of a given immunoglobulin (Ig). Using this method, we measured intact immunoglobulin (heavy/light chain; HLC) IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda individually, as well as their deriving ratios (HLCR) in a series of IgG or IgA multiple myeloma (MM) patients, to investigate and assess the contribution of these tests to disease evaluation.</p> <p>Patients and methods</p> <p>HevyLite™ assays were used in sera from 130 healthy individuals (HI) and 103 MM patients, at time of diagnosis. In patients, the level of paraprotein was IgG in 78 (52 IgG-kappa, 26 IgG-lambda) and IgΑ in 25 (13 IgΑ-kappa, 12 IgΑ-lambda). Durie-Salmon and International Staging System stages were evenly distributed. Symptomatic patients (n = 77) received treatment while asymptomatic ones (n = 26) were followed. Patients' median follow-up was at 32.6 months. HLCR was calculated with the involved Ig (either G or A) as numerator.</p> <p>Results</p> <p>In HI, median IgG-kappa was 6.85, IgG-lambda 3.81, IgA-kappa 1.19 and IgA-lambda 0.98 g/L. The corresponding median involving HLC values in MM patients were 25.8, 23.45, 28.9 and 36.4 g/L. HLC-IgG related to anemia, high serum free light chain ratio and extensive bone marrow infiltration, while high HLCR correlated with the same plus increased β2-microglobulin. In addition, increased HLCR and the presence of immunoparesis correlated with time to treatment. Patients with high HLCR had a significantly shorter survival (<it>p </it>= 0.022); HLCR retained its prognostic value in multivariate analysis.</p> <p>Conclusions</p> <p>HLC and HLCR quantify the precise amount of the involved immunoglobulin more accurately than other methods; moreover, they carry prognostic information regarding survival in MM patients.</p

High frequency of chronic lymphocytic leukemia-like low-count monoclonal B-cell lymphocytosis in Japanese descendants living in Brazil

FAPESP (proc 2010/17668-6) and CAPES (scholarship MFF) from Brazil; RD12/0036/0048, CB16/12/00400 (CIBERONC), PI12/00905-FEDER and PI17/00399-FEDER, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, (Madrid, Spain and FONDOS FEDER).Peer reviewe