-
[show abstract]
[hide abstract]
ABSTRACT: Treatment options for patients with newly diagnosed myeloma have evolved significantly over the past 10 years. Although response rates after induction for older or younger patients were limited, with few patients achieving complete remission, more recent combinations have cleared the way for major response and even complete remissions after induction therapy. As a consequence of these changes, patients are now achieving more durable and longer remissions, which have ultimately improved overall survival for patients with myeloma. The age-appropriate use of induction therapy, autologous transplant, and maintenance therapy, all keeping in mind the specific genetic risk group of a given patient, requires a long-term treatment plan for each patient defined early in the treatment course.
Journal of the National Comprehensive Cancer Network: JNCCN 01/2013; 11(1):19-28. · 4.41 Impact Factor
-
Bruno Paiva,
Joaquin Martinez-Lopez,
Maria-Belen Vidriales,
Maria-Victoria Mateos,
Maria-Angeles Montalban,
Elena Fernandez-Redondo,
Lourdes Alonso,
Albert Oriol,
Ana-Isabel Teruel,
Raquel de Paz,
José-Garcia Laraña,
Enrique Bengoechea,
Alejandro Martin,
Joaquin Diaz Mediavilla,
Luis Palomera,
Felipe de Arriba,
Joan Bladé,
Alberto Orfao,
Juan-Jose Lahuerta, Jesus F San Miguel
-
Irena Misiewicz-Krzeminska,
Maria Eugenia Sarasquete,
Dalia Quwaider,
Patryk Krzeminski,
Fany Veronica Ticona,
Teresa Paino,
Manuel Delgado,
Andreia Aires,
Enrique Ocio,
Ramon Garcia-Sanz, Jesus F San Miguel,
Norma C Gutierrez
[show abstract]
[hide abstract]
ABSTRACT: Background. MicroRNAs have been demonstrated to be deregulated in multiple myeloma. We have previously reported the downregulation of miR-214 in myeloma compared to normal plasma cells. Design and Methods. The functional role of miR-214 in myeloma pathogenesis was explored by transfection of multiple myeloma cell lines with synthetic miRNAs followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Results. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this miRNA, gene expression profiling of H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR-214 directly downregulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-UTR. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent upregulation in CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. Conclusions. MiR-214 functions as a tumor suppressor in myeloma by a positive regulation of p53 and inhibition of DNA replication.
Haematologica 10/2012; · 6.42 Impact Factor
-
Jorge Labrador,
Lucia Lopez-Anglada,
Estefania Perez-Lopez,
Francisco S Lozano,
Lucia Lopez-Corral,
Fermin M Sanchez-Guijo,
Lourdes Vazquez,
Jose Angel Perez-Rivera,
Francisco Martin-Herrero,
Mercedes Sanchez-Barba,
Carmen Guerrero,
Maria Consuelo Del Canizo,
Maria Dolores Caballero, Jesus F San Miguel,
Ignacio Alberca,
Jose Ramon Gonzalez-Porras
[show abstract]
[hide abstract]
ABSTRACT: Background. Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two these life-threatening complications in these complex patients are currently not well defined. Design and Methods. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Results. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft versus host disease to be the only independent prognostic risk factor. By contrast, eight factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III - IV graft versus host disease and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (p = 0.856). However, significant clinical bleeding was associated with inferior survival (p < 0.001). Conclusions. In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.
Haematologica 08/2012; · 6.42 Impact Factor
-
Roberto J Pessoa-Magalhaes,
Maria-Belen Vidriales,
Bruno Paiva,
Carlos Fernandez Gimenez,
Ramon Garcia-Sanz,
Maria Victoria Mateos,
Norma Gutierrez,
Quentin Lecrevisse,
Juan F Blanco,
Jose Hernandez, [......],
Monica Roig,
Elaine Sobral da Costa,
Enrique Ocio,
Martin Perez-Andres,
Angelo Maiolino,
Marcio Nucci,
Javier Delarubia,
Juan Jose' Lahuerta, Jesus F San Miguel,
Alberto Orfao
[show abstract]
[hide abstract]
ABSTRACT: Background. Multiple myeloma remains largely incurable. However, a few patients experience ≥10-years relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with complete response, since some revert into an MGUS profile. Design and Methods. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of long-term disease control multiple myeloma (n=28) vs. both newly-diagnosed MGUS (n=23) and symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Results. Similarly to MGUS and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+T-cells and NK-cells. However, bone marrow Tregs were reduced in long-term disease control vs. symptomatic multiple myeloma. Noteworthy, B-cells were depleted in MGUS and symptomatic multiple myeloma, while recovered in long-term disease control patients in both bone marrow and peripheral blood, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B-cells. The number of bone marrow dendritic cells and tissue macrophages significantly differed between long-term disease control and symptomatic multiple myeloma with a recovery trend in the former patient population towards levels similar to those found in healthy adults.Conclusions. In summary, our results indicate that long-term disease control multiple myeloma patients have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting an improved immunesurveillance.Keywords: myeloma, long term follow-up, immunesurveillance, T-cells, Tregs, B-cells.
Haematologica 07/2012; · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile. AREAS COVERED: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed. EXPERT OPINION: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.
Expert Opinion on Investigational Drugs 05/2012; 21(8):1075-87. · 5.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased risk of acute myeloid leukemia/myelodysplastic syndromes following treatment has been reported in multiple myeloma, but whether dysplastic features are already present at diagnosis remains to be investigated. Using multiparameter flow cytometry, we analyzed the distribution and phenotype of bone marrow hematopoietic cells from 47 multiple myeloma patients (15 symptomatic and 32 high-risk smoldering). From the 32 smoldering myeloma patients, 18 were studied at baseline and 22 after nine cycles of lenalidomide/dexamethasone treatment following the QUIREDEX trial (including 8 from baseline). Phenotypic alterations of bone marrow cells of 7 (47%) symptomatic and 6 (33%) smoldering myeloma patients were detected at baseline; there was no difference in the frequency and extent of phenotypic alterations between symptomatic versus smoldering cases. Likewise, no difference was seen between smoldering myeloma patients studied at baseline versus after lenalidomide/dexamethasone treatment. Our results suggest that phenotypic alterations of bone marrow hematopoietic cells are often present in newly diagnosed symptomatic and smoldering multiple myeloma patients. QUIREDEX trial (NCT00480363).
Haematologica 04/2012; 97(10):1608-1611. · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Melphalan-prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant - ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid®), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade®).
Hematology (Amsterdam, Netherlands) 04/2012; 17 Suppl 1:S3-6. · 1.33 Impact Factor
-
Carlos Santamaría,
Sandra Muntión,
Beatriz Rosón,
Belén Blanco,
Olga López-Villar,
Soraya Carrancio,
Fermín M Sánchez-Guijo,
María Díez-Campelo,
Stela Alvarez-Fernández,
María E Sarasquete,
Javier de las Rivas,
Marcos González, Jesús F San Miguel,
María Consuelo Del Cañizo
[show abstract]
[hide abstract]
ABSTRACT: Background Recent findings suggest that a specific deletion of Dicer1 in mesenchymal stromal cell-derived osteoprogenitors triggers several features of myelodysplastic syndrome in a murine model. Our aim was to analyze DICER1 and DROSHA gene and protein expression in mesenchymal stromal cells (the osteoblastic progenitors) obtained from bone marrow of myelodysplastic syndrome patients, in addition to microRNA expression profile and other target genes such as SBDS, a DICER1-related gene that promotes bone marrow dysfunction and myelodysplasia when repressed in a murine model. DESIGN AND METHODS: Mesenchymal stromal cells from 33 bone marrow samples were evaluated. DICER, DROSHA and SBDS gene expression levels were assessed by real-time PCR and protein expression by Western blot. MicroRNA expresion profile was analyzed by commercial low-density arrays and some of these results were confirmed by individual real-time PCR. RESULTS: Mesenchymal stromal cells from myelodysplastic syndrome patients showed lower DICER1 (0.65±0.08 vs. 1.91±0.57; P=0.011) and DROSHA (0.62±0.06 vs. 1.38±0.29; P=0.009) gene expression levels, two relevant endonucleases associated to microRNA biogenesis, in comparison to normal myelodysplastic syndrome. These findings were confirmed at protein levels by Western blot. Strikingly, no differences were observed between paired mononuclear cells from myelodysplastic syndrome and controls. In addition, mesenchymal stromal cells from myelodysplastic syndrome patients showed significant lower SBDS (0.63±0.06 vs. 1.15±0.28; P=0.021) gene expression levels than mesenchymal stromal cells from healthy controls. Furthermore, mesenchymal stromal cells from myelodysplastic syndrome patients showed an underlying microRNA repression compared to healthy controls. Real-time PCR approach confirmed that mir-155, miR-181a and miR-222 were down-expressed in mesenchymal stromal cells from myelodysplastic syndrome patients. Conclusions This is the first description of an impaired microRNA biogenesis in human mesenchymal stromal cells from myelodysplastic syndrome patients, where DICER1 and DROSHA gene and protein downregulation correlated to a gene and microRNA abnormal expression profile, validating the animal model results previously described.
Haematologica 02/2012; 97(8):1218-24. · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P<0.03). When plasma cells from high-risk smoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235).
Haematologica 02/2012; 97(9):1439-43. · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although new therapies have doubled the survival of multiple myeloma patients, this remains an incurable disease. It has been postulated that the so-called myeloma cancer stem cells would be responsible for tumor initiation and relapse but their unequivocal identification remains unclear. Here, we investigated in a panel of myeloma cell lines the presence of CD20(+) cells harboring a stem-cell phenotype. Thus, only a small population of CD20(dim+) cells (0.3%) in the RPMI-8226 cell line was found. CD20(dim+) RPMI-8226 cells expressed the plasma cell markers CD38 and CD138 and were CD19(-)CD27(-). Additionally, CD20(dim+) RPMI-8226 cells did not exhibit stem-cell markers as shown by gene expression profiling and the aldehyde dehydrogenase assay. Furthermore, we demonstrated that CD20(dim+) RPMI-8226 cells are not essential for CB17-SCID mice engraftment and show lower self-renewal potential than the CD20(-) RPMI-8226 cells. These results do not support CD20 expression for the identification of myeloma cancer stem cells.
Haematologica 02/2012; 97(7):1110-4. · 6.42 Impact Factor
-
Antonio Palumbo,
Sara Bringhen,
Heinz Ludwig,
Meletios A Dimopoulos,
Joan Bladé,
Maria V Mateos,
Laura Rosiñol,
Mario Boccadoro,
Michele Cavo,
Henk Lokhorst, [......],
Roman Hàjek,
Hans E Johnsen,
Fernando Leal Da Costa,
Orhan Sezer,
Andrew Spencer,
Meral Beksac,
Gareth Morgan,
Hermann Einsele, Jesus F San Miguel,
Pieter Sonneveld
[show abstract]
[hide abstract]
ABSTRACT: Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.
Blood 08/2011; 118(17):4519-29. · 9.90 Impact Factor
-
Simona Lapusan,
Maria B Vidriales,
Xavier Thomas,
Stephane de Botton,
Anne Vekhoff,
Ruoping Tang,
Charles Dumontet,
Rodica Morariu-Zamfir,
John M Lambert,
Marie-Laure Ozoux,
Philippe Poncelet, Jesus F San Miguel,
Ollivier Legrand,
Daniel J DeAngelo,
Francis J Giles,
Jean-Pierre Marie
[show abstract]
[hide abstract]
ABSTRACT: The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumab-ozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicity was mainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1-D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m(2) × 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates.
Investigational New Drugs 04/2011; 30(3):1121-31. · 3.36 Impact Factor
-
Bruno Paiva,
Joaquin Martinez-Lopez,
Maria-Belen Vidriales,
Maria-Victoria Mateos,
Maria-Angeles Montalban,
Elena Fernandez-Redondo,
Lourdes Alonso,
Albert Oriol,
Ana-Isabel Teruel,
Raquel de Paz,
José-Garcia Laraña,
Enrique Bengoechea,
Alejandro Martin,
Joaquin Diaz Mediavilla,
Luis Palomera,
Felipe de Arriba,
Joan Bladé,
Alberto Orfao,
Juan-Jose Lahuerta, Jesus F San Miguel
[show abstract]
[hide abstract]
ABSTRACT: To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple myeloma (MM) treated with novel agents.
From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study.
Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction.
Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
Journal of Clinical Oncology 03/2011; 29(12):1627-33. · 18.37 Impact Factor
-
Rebeca Lorenzo Pérez,
Jose A Pérez-Simón,
Teresa Caballero-Velazquez,
Teresa Flores,
Soraya Carrancio,
Carmen Herrero,
Belén Blanco,
Silvia Gutierrez-Cosio,
Cristina Cañete-Campos,
Fernando Cruz González, Jesus F San-Miguel,
Emiliano Hernández-Galilea,
Ignacio Sánchez-Abarca
[show abstract]
[hide abstract]
ABSTRACT: Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality among patients undergoing allogeneic hematopoietic stem cell transplantation. Although animal models have been clearly established for the study of skin, liver, and gut, currently there is no equivalent experiemental model for analyzing ocular involvement, which is rather common, especially among patients diagnosed with chronic GVHD. In the current study we have developed a murine model of ocular GVHD and, for the first time, we describe the histopathologic features involving cornea and limbus, which could play a role in the physiopathology of the disease at the ocular level. Our results represent a major finding that allows us to define a model for evaluating new therapeutic strategies for treating ocular GVHD prior to their use in clinical setting.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2011; 17(2):270-3. · 3.15 Impact Factor
-
Enrique Colado,
Teresa Paíno,
Patricia Maiso,
Enrique M Ocio,
Xi Chen,
Stela Alvarez-Fernández,
Norma C Gutiérrez,
Jesús Martín-Sánchez,
Juan Flores-Montero,
Laura San Segundo,
Mercedes Garayoa,
Diego Fernández-Lázaro,
Maria-Belen Vidriales,
Carlos M Galmarini,
Pablo Avilés,
Carmen Cuevas,
Atanasio Pandiella, Jesús F San-Miguel
[show abstract]
[hide abstract]
ABSTRACT: Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin.
The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid.
Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX).
The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials.
Haematologica 02/2011; 96(5):687-95. · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to determine how mesenchymal stem cells (MSC) could improve bone marrow (BM) stroma function after damage, both in vitro and in vivo. Human MSC from 20 healthy donors were isolated and expanded. Mobilized selected CD34(+) progenitor cells were obtained from 20 HSCT donors. For in vitro study, long-term bone marrow cultures (LTBMC) were performed using a etoposide damaged stromal model to test MSC effect in stromal confluence, capability of MSC to lodge in stromal layer as well as some molecules (SDF1, osteopontin,) involved in hematopoietic niche maintenance were analyzed. For the in vivo model, 64 NOD/SCID recipients were transplanted with CD34+ cells administered either by intravenous (i.v.) or intrabone (i.b.) route, with or without BM derived MSC. MSC lodgement within the BM niche was assessed by FISH analysis and the expression of SDF1 and osteopontin by immunohistochemistry. In vivo study showed that when the stromal damage was severe, TP-MSC could lodge in the etoposide-treated BM stroma, as shown by FISH analysis. Osteopontin and SDF1 were differently expressed in damaged stroma and their expression restored after TP-MSC addition. Human in vivo MSC lodgement was observed within BM niche by FISH, but MSC only were detected and not in the contralateral femurs. Human MSC were located around blood vessels in the subendoestal region of femurs and expressed SDF1 and osteopontin. In summary, our data show that MSC can restore BM stromal function and also engraft when a higher stromal damage was done. Interestingly, MSC were detected locally where they were administered but not in the contralateral femur.
PLoS ONE 01/2011; 6(10):e26241. · 4.09 Impact Factor
-
Juan F Blanco,
Ignacio F Graciani,
Fermin M Sanchez-Guijo,
Sandra Muntión,
Pilar Hernandez-Campo,
Carlos Santamaria,
Soraya Carrancio,
Maria-Victoria Barbado,
Graciela Cruz,
Silvia Gutierrez-Cosío,
Carmen Herrero, Jesus F San Miguel,
Jesus G Briñon,
Maria-Consuelo del Cañizo
[show abstract]
[hide abstract]
ABSTRACT: To identify mesenchymal stromal cells (MSC) from degenerate human nucleus pulposus (NP) and compare them with bone marrow (BM) MSC.
To test whether MSC obtained from NP and BM from the same subjects share similar biologic characteristics.
Recent studies have proposed biologic strategies for the treatment of intervertebral disc degeneration, including cell therapy. Bone marrow (BM) MSC could be an attractive approach to restore disc function, and there is evidence that NP may contain MSC-like cells.
Tissue samples were obtained from degenerate lumbar NP and from iliac crest of the same 16 patients with degenerative disc diseases, undergoing discectomy and fusion procedures. MSC isolated from both sources were compared regarding their expansion time, immunophenotype, differentiation ability, and molecular analysis.
In all cases, MSC from NP were isolated and expanded. They fulfil nearly all morphological, inmunophenotypical, and differentiation criteria described by the International Society of Cell Therapy for MSC, with the exception that NP-MSC are not able to differentiate into adipocytes. Slight differences were observed with BM-MSC from the same subjects.
The NP contains mesenchymal stem cells. These cells were quite similar to mesenchymal stem cells from BM, with the exception of their adipogenic differentiation ability. These findings suggest that we may treat intervertebral disc degeneration by cell therapy (MSC from BM) and by stimulating endogenous MSC from NP.
Spine 12/2010; 35(26):2259-65. · 2.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Encouraging progress has been made in the treatment of patients with relapsed/refractory multiple myeloma (MM). The rapidly evolving understanding of key pathways responsible for tumor growth and survival has led to the development of novel agents (including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and other targeted agents) with the potential to provide significant improvements in response and survival, and influence treatment guidelines. This review summarizes recent advances in understanding of the biology of relapsed/refractory MM and clinical trials with novel targeted agents that are currently under investigation for patients with this disease.
European Journal Of Haematology 10/2010; 86(1):1-15. · 2.61 Impact Factor
-
James R Berenson,
Kenneth C Anderson,
Robert A Audell,
Ralph V Boccia,
Morton Coleman,
Meletios A Dimopoulos,
Matthew T Drake,
Rafael Fonseca,
Jean-Luc Harousseau,
Douglas Joshua, [......],
Ruben Niesvizky,
Antonio Palumbo,
G David Roodman, Jesus F San-Miguel,
Seema Singhal,
Donna M Weber,
Maurizio Zangari,
Eric Wirtschafter,
Ori Yellin,
Robert A Kyle
[show abstract]
[hide abstract]
ABSTRACT: On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated.
British Journal of Haematology 07/2010; 150(1):28-38. · 4.94 Impact Factor
