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1.
Blood Cancer J ; 14(1): 74, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684670

ABSTRACT

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.


Subject(s)
Biomarkers, Tumor , Disease Progression , Drug Resistance, Neoplasm , Mutation , Smoldering Multiple Myeloma , Humans , Male , Drug Resistance, Neoplasm/genetics , Female , Smoldering Multiple Myeloma/genetics , Biomarkers, Tumor/genetics , Middle Aged , Aged , High-Throughput Nucleotide Sequencing , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
2.
Leukemia ; 32(4): 971-978, 2018 04.
Article in English | MEDLINE | ID: mdl-29099494

ABSTRACT

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.


Subject(s)
Antigens, CD/metabolism , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplasm, Residual/metabolism , Neoplasm, Residual/pathology , Prognosis
3.
Ann Hematol ; 96(10): 1699-1705, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28770277

ABSTRACT

Chromosome 1q gains and 13q deletions are common cytogenetic aberrations in multiple myeloma (MM) that confer a poor prognosis. There are several techniques for the targeted study of these alterations, but interphase fluorescence in situ hybridization (FISH) is the current gold standard. The aim of the present study was to validate quantitative PCR (qPCR) as an alternative to FISH studies in CD138+-enriched plasma cells (PCs) from MM patients at diagnosis. We analyzed 1q gains and 13q deletions by qPCR in 57 and 60 MM patients, respectively. qPCR applicability was 84 and 88% for 1q and 13q, respectively. The qPCR and FISH methods had a sensitivity and specificity of 88 and 71% for 1q gains, and 79 and 100% for 13q deletions. A second qPCR assay for each region was carried out to confirm the previous results. Paired qPCR (two assays) and FISH results were available from 53 MM patients: 26 for 1q amplification and 27 for 13q deletion. qPCR assays gave concordant results (qPCR-consistent) in 20 of the 26 (77%) 1q gains and 25 of the 27 (93%) 13q deletions. Considering only the consistent data, the overall concordance among qPCR and FISH was 85 and 100% for 1q gains and 13q deletions, respectively. Our results show a substantial agreement between qPCR and the gold standard FISH technique, indicating the potential of qPCR as an alternative approach, particularly when the starting material is too scarce or cells are too damaged to obtain accurate results from FISH studies.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Chromosomes, Human, Pair 1/genetics , Multiple Myeloma/genetics , Real-Time Polymerase Chain Reaction , Female , Humans , In Situ Hybridization, Fluorescence , Male , Multiple Myeloma/pathology
4.
Blood Cancer J ; 7(8): e591, 2017 08 25.
Article in English | MEDLINE | ID: mdl-28841204

ABSTRACT

Transformation of Waldenström's macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM.


Subject(s)
Biomarkers, Tumor/genetics , CD79 Antigens/genetics , Cell Transformation, Neoplastic/genetics , Exome , Lymphoma, Large B-Cell, Diffuse/genetics , Mutation , Neoplasm Proteins/genetics , Waldenstrom Macroglobulinemia/genetics , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
6.
Leukemia ; 31(2): 382-392, 2017 02.
Article in English | MEDLINE | ID: mdl-27479184

ABSTRACT

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.


Subject(s)
Multiple Myeloma/diagnosis , Multiple Myeloma/metabolism , Plasma Cells/metabolism , Plasma Cells/pathology , Adult , Antigens, CD/metabolism , Biomarkers , Bone Marrow/metabolism , Bone Marrow/pathology , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Case-Control Studies , Cell Cycle , DNA Methylation , Female , Gene Expression Profiling , Genetic Heterogeneity , High-Throughput Nucleotide Sequencing , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/mortality , Mutation , Neoplasm Grading , Phenotype , Prognosis , Single-Cell Analysis , Young Adult
7.
Leukemia ; 30(10): 2026-2031, 2016 10.
Article in English | MEDLINE | ID: mdl-27133826

ABSTRACT

The diagnosis of smoldering multiple myeloma (SMM) includes patients with a heterogeneous risk of progression to active multiple myeloma (MM): some patients will never progress, whereas others will have a high risk of progression within the first 2 years. Therefore, it is important to improve risk assessment at diagnosis. We conducted a retrospective study in a large cohort of SMM patients, in order to investigate the role of Bence Jones (BJ) proteinuria at diagnosis in the progression to active MM. We found that SMM patients presenting with BJ proteinuria had a significantly shorter median time to progression (TTP) to MM compared with patients without BJ proteinuria (22 vs 88 months, respectively; hazard ratio=2.3, 95% confidence interval=1.4-3.9, P=0.002). We also identified risk subgroups based on the amount of BJ proteinuria: ⩾500 mg/24 h, <500 mg/24 h and without it, with a significantly different median TTP (13, 37 and 88 months, P<0.001). Thus, BJ proteinuria at diagnosis is an independent variable of progression to MM that identifies a subgroup of high-risk SMM patients (51% risk of progression at 2 years) and ⩾500 mg of BJ proteinuria may allow, if validated in another series, to reclassify these patients to MM requiring therapy before the end-organ damage development.


Subject(s)
Bence Jones Protein/urine , Multiple Myeloma/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/urine , Disease Progression , Female , Humans , Male , Middle Aged , Multiple Myeloma/urine , Proteinuria , Retrospective Studies , Risk Assessment , Time Factors
8.
Leukemia ; 30(4): 861-72, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26658839

ABSTRACT

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) cells must attach to the bone marrow (BM) microvasculature before lodging in the BM microenvironment. Using intravital microscopy (IVM) of the BM calvariae we demonstrate that the α4ß1 integrin is required for MM and CLL cell firm arrest onto the BM microvasculature, while endothelial P-selectin and E-selectin mediate cell rolling. Talin, kindlin-3 and ICAP-1 are ß1-integrin-binding partners that regulate ß1-mediated cell adhesion. We show that talin and kindlin-3 cooperatively stimulate high affinity and strength of α4ß1-dependent MM and CLL cell attachment, whereas ICAP-1 negatively regulates this adhesion. A functional connection between talin/kindlin-3 and Rac1 was found to be required for MM cell attachment mediated by α4ß1. Importantly, IVM analyses with talin- and kindlin-3-silenced MM cells indicate that these proteins are needed for cell arrest on the BM microvasculature. Instead, MM cell arrest is repressed by ICAP-1. Moreover, MM cells silenced for talin and kindlin-3, and cultured on α4ß1 ligands showed higher susceptibility to bortezomib-mediated cell apoptosis. Our results highlight the requirement of α4ß1 and selectins for the in vivo attachment of MM and CLL cells to the BM microvasculature, and indicate that talin, kindlin-3 and ICAP-1 differentially control physiological adhesion by regulating α4ß1 activity.


Subject(s)
Bone Marrow/pathology , Cell Adhesion , Endothelium, Vascular/pathology , Integrin alpha4beta1/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Multiple Myeloma/pathology , Adaptor Proteins, Signal Transducing , Animals , Apoptosis , Blotting, Western , Bone Marrow/metabolism , Cell Movement , Cell Proliferation , Cytoplasm/metabolism , E-Selectin/genetics , E-Selectin/metabolism , Endothelium, Vascular/metabolism , Flow Cytometry , Humans , Integrin alpha4beta1/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Intravital Microscopy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Microvessels , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , P-Selectin/genetics , P-Selectin/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Talin/genetics , Talin/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
10.
Leukemia ; 29(3): 705-14, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25102946

ABSTRACT

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.


Subject(s)
Antineoplastic Agents/pharmacology , Dexamethasone/pharmacology , Gene Expression Regulation, Neoplastic , Plasmacytoma/drug therapy , Thalidomide/analogs & derivatives , Adaptor Proteins, Signal Transducing , Animals , Apoptosis/drug effects , Benzimidazoles/pharmacology , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Drug Therapy, Combination , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Ikaros Transcription Factor/genetics , Ikaros Transcription Factor/metabolism , Lenalidomide , Mice , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasm Transplantation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Plasmacytoma/genetics , Plasmacytoma/metabolism , Plasmacytoma/pathology , Signal Transduction , Thalidomide/pharmacology , Trans-Activators/genetics , Trans-Activators/metabolism
11.
Leukemia ; 29(5): 1186-94, 2015 May.
Article in English | MEDLINE | ID: mdl-25388955

ABSTRACT

Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.


Subject(s)
Multiple Myeloma/genetics , Cell Separation , Coculture Techniques , Disease Progression , Drug Resistance, Neoplasm , Flow Cytometry , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Multiple Myeloma/classification , Phenotype , Plasma Cells/cytology , Principal Component Analysis , Prognosis , Stromal Cells/cytology
12.
Leukemia ; 27(10): 2056-61, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23743858

ABSTRACT

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.


Subject(s)
Algorithms , Flow Cytometry , Immunophenotyping , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Multiple Myeloma/diagnosis , Paraproteinemias/diagnosis , Plasma Cells/pathology , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Case-Control Studies , Combined Modality Therapy , Disease Progression , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Male , Middle Aged , Monoclonal Gammopathy of Undetermined Significance/immunology , Monoclonal Gammopathy of Undetermined Significance/therapy , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Paraproteinemias/immunology , Paraproteinemias/therapy , Prognosis , Remission Induction , Transplantation, Autologous
13.
Leukemia ; 27(8): 1722-8, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23446312

ABSTRACT

We evaluated the MYD88 L265P mutation in Waldenström's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity ∼10(-3)). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P=0.022), more lymphocytosis (24 vs 5%, P=0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P=0.002), atypical immunophenotype (CD23-CD27+ +FMC7+ +), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P=0.012) and less IGHV3-23 gene selection (9 vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival.


Subject(s)
Mutation , Myeloid Differentiation Factor 88/genetics , Waldenstrom Macroglobulinemia/genetics , Aged , Aged, 80 and over , Biomarkers/metabolism , Disease Progression , Humans , Immunoglobulin M/metabolism , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/metabolism , Middle Aged , Myeloid Differentiation Factor 88/metabolism , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/metabolism , Waldenstrom Macroglobulinemia/mortality
14.
Leukemia ; 27(3): 610-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22936014

ABSTRACT

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.


Subject(s)
Biomarkers, Tumor/genetics , CpG Islands/genetics , DNA Methylation , Gene Expression Profiling , Genome, Human , Myelodysplastic Syndromes/genetics , Case-Control Studies , DEAD-box RNA Helicases/genetics , DNA, Neoplasm/genetics , Epigenesis, Genetic , Gene Expression Regulation, Leukemic , Humans , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Prognosis , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Receptors, Interleukin/genetics , Ribonuclease III/genetics , Risk Factors , Tumor Cells, Cultured
15.
Oper Dent ; 38(1): 57-62, 2013.
Article in English | MEDLINE | ID: mdl-22770430

ABSTRACT

OBJECTIVES: People increasingly desire tooth whitening. Considering the wide range of whitening products on the market, this study evaluated the efficacy of whitening toothpastes and mouth rinses compared with the 10% carbamide peroxide (CP) whitening gel. METHODS: We obtained 120 cylindrical specimens from bovine teeth, which were darkened for 24 hours in a coffee solution. The color measurement was performed by a spectrophotometer using the CIE L*a*b* system, and specimens were divided into six groups according to the use of the following agents: group 1, conventional fluoridated toothpaste; group 2, Close Up White Now; group 3, Listerine Whitening; group 4, Colgate Plax Whitening; group 5, experimental mouth rinse with Plasdone; and group 6, 10% CP Whiteness Perfect. After the simulation of 12 weeks of treatment for groups 1 to 5 and 14 days of treatment for group 6, the specimens were subjected to a new color reading. RESULTS: Data were subjected to one-way analysis of variance (α=0.05), which showed significant differences among groups after 12 weeks for ΔE (p=0.001). Results of the Tukey test revealed that groups 3, 4, and 6 presented significantly higher color alteration than groups 1, 2, and 5. CONCLUSIONS: The whitening toothpaste Close Up White Now and the experimental mouth rinse with Plasdone showed similar color alteration as conventional toothpaste after a 12-week treatment simulation. These groups presented significantly lower color alteration compared with whitening mouth rinses Listerine and Colgate Plax Whitening, which showed similar results to those observed after 14 days of bleaching with 10% CP treatment.


Subject(s)
Mouthwashes/therapeutic use , Tooth Bleaching Agents/therapeutic use , Tooth Bleaching/methods , Toothpastes/therapeutic use , Animals , Carbamide Peroxide , Cariostatic Agents/therapeutic use , Cattle , Coffee , Color , Dental Enamel/drug effects , Dental Enamel/pathology , Detergents/therapeutic use , Diphosphates/therapeutic use , Fluorides/therapeutic use , Hydrogen Peroxide/therapeutic use , Materials Testing , Peroxides/therapeutic use , Povidone/therapeutic use , Sodium Dodecyl Sulfate/therapeutic use , Spectrophotometry/instrumentation , Time Factors , Tooth Discoloration/drug therapy , Tooth Discoloration/pathology , Urea/analogs & derivatives , Urea/therapeutic use
16.
Int J Hematol ; 96(3): 383-5, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22767142

ABSTRACT

All-trans retinoic acid (ATRA) induces complete remission in 64-100 % of patients with acute promyelocytic leukemia (APL), and is considered to be a safe agent. Pseudotumor cerebri is a neurological side effect of ATRA reported in pediatric patients, and which is characterized by raised cerebrospinal fluid pressure in the absence of any intracranial pathology or secondary causes of intracranial hypertension. Involvement of cranial nerves other than II and VI is very uncommon in idiopathic intracranial hypertension (IIH); peripheral facial nerve palsy is exceptional and has rarely been described in the context of treatment with ATRA. We describe the case of a 15-year-old female patient with APL who developed an IIH and involvement of cranial nerves (bilateral papilledema, left facial and right sixth nerves) after receiving induction therapy including ATRA. Viral infections and other causes of secondary cranial nerve lesions were excluded. Symptoms completely subsided with the temporary withdrawal of ATRA and did not recur after reintroducing the drug. To date, the patient has managed to receive the treatment as per protocol. In conclusion, we report an atypical presentation of IIH that merits consideration, especially with respect to young patients with APL receiving ATRA; our most important observation is that the drug could be safely reintroduced once the symptoms had resolved.


Subject(s)
Antineoplastic Agents/adverse effects , Cranial Nerve Diseases/chemically induced , Intracranial Hypertension/chemically induced , Leukemia, Promyelocytic, Acute/complications , Tretinoin/adverse effects , Adolescent , Antineoplastic Agents/therapeutic use , Cranial Nerve Diseases/diagnosis , Cranial Nerve Diseases/drug therapy , Female , Humans , Intracranial Hypertension/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Remission Induction , Treatment Outcome , Tretinoin/therapeutic use
17.
Leukemia ; 26(12): 2521-9, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22565645

ABSTRACT

Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P=0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P=0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.


Subject(s)
Chromosomes, Human/genetics , Gene Dosage , Genomics , Loss of Heterozygosity , Multiple Myeloma/genetics , Paraproteinemias/genetics , Polymorphism, Single Nucleotide/genetics , Chromosome Aberrations , Chromosome Mapping , Cytogenetic Analysis , Humans , Multiple Myeloma/pathology , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , Paraproteinemias/pathology , Prognosis
18.
Leukemia ; 26(8): 1862-9, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22333880

ABSTRACT

The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.


Subject(s)
Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Plasma Cells/metabolism , Tetraspanin 28/genetics , Aged , Aged, 80 and over , Gene Expression Regulation, Neoplastic , Humans , Immunophenotyping , Middle Aged , Multiple Myeloma/mortality , Prognosis , Survival Analysis , Tetraspanin 28/metabolism
19.
Ann Oncol ; 23(8): 2138-2146, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22228453

ABSTRACT

BACKGROUND: The presence of genetic changes is a hallmark of chronic lymphocytic leukemia (CLL). The most common cytogenetic abnormalities with independent prognostic significance in CLL are 13q14, ATM and TP53 deletions and trisomy 12. However, CLL displays a great genetic and biological heterogeneity. The aim of this study was to analyze the genomic imbalances in CLL cytogenetic subsets from both genomic and gene expression perspectives to identify new recurrent alterations. PATIENTS AND METHODS: The genomic imbalances and expression levels of 67 patients were analyzed. The novel recurrent abnormalities detected with bacterial artificial chromosome array were confirmed by FISH and oligonucleotide microarrays. In all cases, gene expression profiling was assessed. RESULTS: Copy number alterations were identified in 75% of cases. Overall, the results confirmed FISH studies for the regions frequently involved in CLL and also defined a new recurrent gain on chromosome 20q13.12, in 19% (13/67) of the CLL patients. Oligonucleotide expression correlated with the regions of loss or gain of genomic material, suggesting that the changes in gene expression are related to alterations in copy number. CONCLUSION: Our study demonstrates the presence of a recurrent gain in 20q13.12 associated with overexpression of the genes located in this region, in CLL cytogenetic subgroups.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 20 , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Comparative Genomic Hybridization , Gene Dosage , Gene Expression Profiling , Genomic Instability , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/blood
20.
Leukemia ; 25(4): 697-706, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21252988

ABSTRACT

Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM.


Subject(s)
Bone Marrow Cells/cytology , Hematopoietic Stem Cells/cytology , Multiple Myeloma/pathology , Paraproteinemias/pathology , Plasma Cells/cytology , Adult , Aged , Aged, 80 and over , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , Bone Marrow Cells/metabolism , Case-Control Studies , Cell Movement , Cells, Cultured , Clone Cells , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Hematopoietic Stem Cells/metabolism , Humans , Immunophenotyping , Male , Middle Aged , Multiple Myeloma/metabolism , Paraproteinemias/metabolism , Plasma Cells/metabolism , Prospective Studies
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