Publications (311) View all
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Article: Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability.
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ABSTRACT: Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated.The Journal of Immunology 05/2013; · 5.79 Impact Factor -
Article: Biological and clinical relevance of miRNA expression signatures in primary plasma cell leukemia.
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ABSTRACT: PURPOSE: Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasia. To date, no information on miRNA expression in pPCL has been reported. This study was aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness. Experimental design: Global miRNA expression profiles were analyzed in highly-purified malignant plasma cells from 18 pPCL untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma (MM) patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles in pPCL and MM samples. RESULTS: We identified a series of deregulated miRNAs in pPCL (42 up- and 41 down-regulated) in comparison with MM. Some of them, based on their reported functions and putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL. As regards to chromosomal aberrations, the expression of some miRNAs mapped to hot-spot altered regions was associated with DNA copy number of the corresponding loci. Finally, four miRNA (miR-497, miR-106b, miR-181a* and miR-181b) were identified having expression levels correlated with treatment response, and four (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. CONCLUSIONS: Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.Clinical Cancer Research 04/2013; · 7.74 Impact Factor -
Article: Transcriptional characterization of a prospective series of primary plasma cell leukemia revealed signatures associated with tumor progression and poorer outcome.
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ABSTRACT: PURPOSE: Plasma cell leukemia (PCL) is a rare form of plasma cells dyscrasia that presents either as a progression of previously diagnosed multiple myeloma (MM), namely secondary PCL, or as initial manifestation of disease, namely primary PCL (pPCL). Although presenting signs and symptoms include those seen in MM, pPCL is characterized by several aspects that define more aggressive course. Herein, we have investigated the transcriptome of pPCLs and correlated differential expression profiles with outcome, to provide insights into the biology of the disease. Experimental design: The expression profiles of 21 newly-diagnosed pPCLs included in a multicenter prospective clinical trial were generated using high-density microarray, then evaluated in comparison with a representative series of multiple myeloma (MM) patients and in association with clinical outcome. RESULTS: All but one of the pPCLs had one of the main IGH translocations, whose associated transcriptional signatures resembled those observed in MM. A 503-gene signature distinguished pPCL from MM, from which emerged 26 genes whose expression trend was associated with progressive stages of plasma cells dyscrasia in a large dataset from multiple institutions, including samples from normal donors throughout PCL. Finally, three genes were identified having expression levels correlated with response to the first-line treatment with lenalidomide/dexamethasone, whereas a 27-gene signature was associated with overall survival independently of molecular alterations, hematological parameters and renal function. CONCLUSIONS: Overall, our data contribute to a fine dissection of pPCL and may provide novel insights into the molecular definition of patients with poorer prognosis.Clinical Cancer Research 04/2013; · 7.74 Impact Factor -
Article: Addressing the questions of tomorrow: melphalan and new combinations as conditioning regimens before autologous hematopoietic progenitor cell transplantation in multiple myeloma.
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ABSTRACT: Introduction: The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure. Areas covered: We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens. Expert opinion: For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.Expert Opinion on Investigational Drugs 04/2013; · 5.27 Impact Factor -
Article: Total body computed tomography scan in the initial work-up of binet stage a chronic lymphocytic leukemia patients: Results of the prospective, multicenter o-cll1-gisl study.
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ABSTRACT: Total body computed tomography (TB-CT) scan is not mandatory in the diagnostic/staging algorithm of chronic lymphocytic leukemia (CLL). The aim of this study was to determine the value and prognostic significance of TB-CT scan in early stage CLL patients. Baseline TB-CT scan was performed in 240 Binet stage A CLL patients (179 Rai low- and 61 Rai intermediate-risk) included in a prospective multicenter observational study (clinicaltrial.gov ID:NCT00917549). The cohort included 69 clinical monoclonal B lymphocytosis (cMBLs). Patients were re-staged considering only radiological data. Following TB-CT scans, 20% of cases re-classified as radiologic Binet (r-Binet) stage B. r-Binet B patients showed a higher incidence of unfavorable cytogenetic abnormalities (P=.027), as well as a shorter PFS (P=.001). At multivariate analysis, r-Binet stage [HR=2.48; P=.004] and IGHV mutational status [HR=3.01; P=.002] retained an independent predictive value for PFS. Among 179 Rai low-risk cases, 100 were re-defined as r-Rai intermediate-risk based upon TB-CT scan data, showing a higher rate of cases with higher ZAP-70 (P=.033) and CD38 expression (P=.029) and β2-microglobulin levels (P<.0001), as well as a shorter PFS than those with r-Rai low-risk (P=.008). r-Rai stage [HR=2.78; P=.046] and IGHV mutational status [HR=4.25; P=.009] retained a significant predictive value for PFS at multivariate analysis. 42% of cMBL patients were re-classified as r-small lymphocytic lymphomas (r-SLLs) by TB-CT scan. TB-CT scan appears to provide relevant information in early stage CLL related to the potential and the timing of patients to progress towards the more advanced disease stages.American Journal of Hematology 04/2013; · 4.67 Impact Factor
