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Ramón García-Sanz

Publications and source records attributed to Ramón García-Sanz.

18 recordsLinked to original sources
PubMed2006

Functional class switch recombination may occur 'in vivo' in Waldenström macroglobulinaemia.

Waldenström macroglobulinaemia (WM) malignant cells have been considered incapable of undergoing class switch recombination (CSR). However, we report a WM patient who developed an IgG M-component 4 years after diagnosis. When the second monoclonal component appeared, reverse transcription-polymerase chain reaction showed the presence of pre (Cmu) and postswitch (Cgamma) clonotypic isotypes; sequencing of these isotypes demonstrated that both corresponded to the single clone amplified at diagnosis, including the same complementarity-determining region 3 and somatic mutation pattern. This proves that WM cells can undergo a functional in vivo CSR.

Complementarity Determining Regions↗
PubMed2006

The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma.

p14/p16 and p15 gene expression was assessed by quantitative polymerase chain reaction in purified plasma cells (PC) from 52 patients with symptomatic multiple myeloma (MM) and seven with smoldering MM in order to clarify the impact of these genes on the proliferative activity of tumor cells and patients' outcome. p15 expression was lower in symptomatic MM than in smoldering SMM (-1.80 vs.1.51,p=0.026); similar results were observed for p14/p16. MM patients whose PC displayed high p15 and/or p14/p16 expression had a lower percentage of S-phase PC than the remaining cases (1.79%+/-1.35 vs. 3.04%+/-1.42, p=0.028), favorable prognostic factors and longer survival (100% vs. 49%at 2.5 years; p=0.007).

Cell Proliferation↗
PubMed2006

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.

Standard first-line treatment for elderly multiple myeloma (MM) patients ineligible for stem cell transplantation is melphalan plus prednisone (MP). However, complete responses (CRs) are rare. Bortezomib is active in patients with relapsed MM, including elderly patients. This phase 1/2 trial in 60 untreated MM patients aged at least 65 years (half older than 75 years) was designed to determine dosing, safety, and efficacy of bortezomib plus MP (VMP). VMP response rate was 89%, including 32% immunofixation-negative CRs, of whom half of the IF- CR patients analyzed achieved immunophenotypic remission (no detectable plasma cells at 10(-4) to 10(-5) sensitivity). VMP appeared to overcome the poor prognosis conferred by retinoblastoma gene deletion and IgH translocations. Results compare favorably with our historical control data for MP--notably, response rate (89% versus 42%), event-free survival at 16 months (83% versus 51%), and survival at 16 months (90% versus 62%). Side effects were predictable and manageable; principal toxicities were hematologic, gastrointestinal, and peripheral neuropathy and were more evident during early cycles and in patients aged 75 years or more. In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features.

Aged↗
PubMed2006

Risk of recurrent venous thrombosis in patients with G20210A mutation in the prothrombin gene or factor V Leiden mutation.

The impact of the G20210A prothrombin mutation, factor V Leiden and 677T mutation of methylene tetrahydrofalate reductase (MTHFR) in recurrent deep venous thrombosis (DVT) is not so clear. We have prospectively monitored 259 patients following a first episode of DVT in order to determine which factors influence the development of a recurrent event. Several clinical and biological factors together with the genetic polymorphisms of factor V Leiden, G20210A prothrombin and 677T MTHFR were assessed. During a median follow-up of 786 patient-years, 27 patients (14%) developed one objective episode of recurrent venous thrombosis. The carriers of a double defect, homozygous or double heterozygous for factor V Leiden and G20210A, had an increased risk after a first episode of DVT, while patients who were isolated heterozygous for factor V Leiden or G20210 had a risk of recurrent DVT similar to patients who had neither mutation (annual incidence of 12.1, 3.1, 2.9 and 2.8%). The 677T MTHFR mutation alone or combined with hyperhomocysteinemia was not associated with an increased risk of recurrent events. The development of proximal DVT (P=0.01) and the presence of a double defect (P=0.01) were the only two risk factors independently associated with a high recurrence ratio in the multivariate analysis. Thus, the annual incidence of DVT recurrence in patients without any of these two risk factors was only 0.6% (95% confidence interval, 0.2-0.9). We have identified a group of patients with DVT but at very low risk of re-thrombosis in whom an extended secondary thromboprophylaxis should be carefully considered.

Adolescent↗
PubMed2006

Thalidomide in multiple myeloma.

Multiple myeloma is an incurable bone marrow cancer, the treatment of which is notoriously difficult. Only modest advances have been achieved using complex polychemotherapeutic regimens, transplant strategies and supportive therapy. In 1999, when new drugs for myeloma were urgently needed, thalidomide was introduced and opened up a completely new line of therapy for the disease. Although the mechanism of action is not yet completely understood, thalidomide has demonstrated efficacy in patients with refractory, relapsed myeloma, even in late-stage cases. This article reviews the current knowledge of thalidomide in myeloma treatment, focusing especially on the possible mechanisms of action, clinical results and adverse events of this drug.

Humans↗
PubMed2005

Prognostic features of multiple myeloma.

The outcome of myeloma patients is highly heterogeneous, with survival ranging from a few months to more than 10 years. Accordingly, investigation of prognostic factors may contribute to identification of risk categories and to provision of more accurate information about individual disease outcome. For many years prognostic factors have relied on clinical parameters such as age, hemoglobin level and renal function. Subsequently, biological parameters such as the proliferative activity of plasma cells and beta2-microglobulin have been added to the prognostic arsenal. More recently, cytogenetic and molecular markers with significant influence on disease outcome have been identified. Here we will review the most relevant prognostic factors reported in the literature in patients treated with both conventional chemotherapy and high-dose therapy followed by autologous stem-cell support, as well as in asymptomatic MM and MGUS patients.

Hematopoietic Stem Cell Transplantation↗
PubMed2005

Analysis of methylation pattern in multiple myeloma.

DNA methylation is involved in malignancy and is seen, in progression, in more than 80% of all solid tumours. Methylation is one of the main physiological processes to induce silencing of gene expression. Much work has focused on the suppressor gene p16, which acts as a negative cell cycle regulator, while its inhibition (via methylation) will have a positive effect on the cell cycle advance. The methylation status of the p16 gene was analysed in a group of 159 patients. Methylation of the p16 gene was seen in 41/98 (42%) patients with multiple myeloma and 4/5 (80%) patients with primary plasma cell leukaemias. This data favours the importance of p16 methylation on cell cycle regulation in multiple myeloma. In a proposed mechanism, methylated CpG islands attract a protein, MeCP2, which recruits a transcriptional inhibitory complex that includes histone deacetylases. The deacetylated lysine tails of the histones closely interact with DNA, resulting in a transcriptionally repressed chromatin with inhibited gene transcription, providing potential synergy between demethylating drugs and histone deacetylase inhibitors. Based on the knowledge of epigenetic mechanisms, the potential application of demethylating agents should be further investigated. Multiple myeloma remains an incurable disease, so new treatment strategies are needed to improve the outcome of patients.

Animals↗
PubMed2005

Molecular characteristics and gene segment usage in IGH gene rearrangements in multiple myeloma.

BACKGROUND AND OBJECTIVES: Analysis of IgH rearrangements in B-cell malignancies has provided clinical researchers with a wide range of information during the last few years. However, only a few studies have contributed to the characterization of these features in multiple myeloma (MM), and they have been focused on the analysis of the expressed IgH allele only. Comparison between the expressed and the non-functional IgH alleles allows further characterizion of the selection processes to which pre-myeloma cells are submitted. DESIGN AND METHODS: We analyzed a cohort of 84 untreated MM patients in order to characterize their functional VDJH and non-functional DJH rearrangements. The pattern of mutations and gene segment usage for both types of rearrangements was analyzed by polymerase chain reaction and sequencing. RESULTS: VH3 and VH1 family members were over- and under-represented, respectively. VH3-30 and VH3-15 segments were the most frequently used, whereas VH4-34 was found only in non-functional or heavily mutated VDJH rearrangements. DH2 and DH3 family members were over-represented in both VDJH and DJH repertoires, while the DH1 family was under-represented only in the productive VDJH rearrangements. Finally, DH3-22 and DH2-21 gene segments were found to be over-represented in the functional repertoire while segments commonly used by less mature B-cell malignancies, such as DH6-19 or DH3-3, were under-represented. INTERPRETATION AND CONCLUSIONS: Data reported here help to identify the clonogenic MM cell as a post-germinal center B cell that has undergone selection processes during the germinal center reaction.

Antibody Diversity↗
PubMed2005

Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry.

BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) studies are useful in multiple myeloma (MM). However, the definition of the best technique and clinical utility are still unresolved issues. The aim of this study was to analyze and compare the clinical utility of MRD studies in MM with two different techniques: allelic-specific oligonucleotide real-time quantitative PCR (ASO-RQ-PCR), and flow cytometry (FCM). DESIGN AND METHODS: Bone marrow samples from 32 MM patients who had achieved complete response after transplantation were evaluated by ASO-RQ-PCR, using TaqMan technology, and multiparametric FCM. RESULTS: ASO-RQ-PCR was only applicable in 75% of patients for a variety of technical reasons, while FCM was applicable in up to 90%. Therefore, simultaneous PCR/FCM analysis was possible in only 24 patients. The number of residual tumor cells identified by both techniques was very similar (mean=0.29%, range=0.001-1.61%, correlation coefficient=0.861). However, RQ-PCR was able to detect residual myelomatous cells in 17 patients while FCM only did so in 11; thus, 6 cases were FCM negative but PCR positive, all of them displaying a very low number of clonal cells (median=0.014%, range=0.001-0.11). Using an MRD threshold of 0.01% (10(-4)) two risk groups with significantly different progression-free survival could be identified by either PCR (34 vs. 15m, p=0.04) or FCM (27 vs. 10m, p=0.05). INTERPRETATION AND CONCLUSIONS: Although MRD evaluation by ASO-RQ-PCR is slightly more sensitive and specific than FCM, it is applicable in a lower proportion of MM patients and is more time-consuming, while both techniques provide similar prognostic information.

Aged↗
PubMed2004

Influence of biologic markers on the outcome of Hodgkin's lymphoma: a study by the Spanish Hodgkin's Lymphoma Study Group.

PURPOSE: Current therapies fail to cure a significant proportion of patients with Hodgkin's lymphoma (HL). Predictive systems for stratification of the disease and selection of treatment based on sets of clinical variables, such as the international prognostic score (IPS), are of relatively small practical value. The predictive use of biologic parameters has so far provided limited and inconsistent results. Here we explore the influence of a set of molecular markers on the outcome of HL. PATIENTS AND METHODS: Forty molecular markers involved in B-cell differentiation and activation, signal transduction, cell cycle, and apoptosis control were analyzed in 259 classic HL patient cases by using tissue microarrays. Univariate analysis was performed to evaluate the influence of markers on favorable outcome (complete remission of > 12 months). Significant variables were included in a multivariate logistic regression analysis, and the probability of favorable outcome was estimated. RESULTS: Univariate analysis revealed four molecular markers that predicted outcome, and the multivariate analysis showed p53, Bcl-X(L), and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) to have independent significance. The combination of these factors determined two groups of patients (group I, zero to one factor; group II, two to three factors) with a probability of a favorable outcome of.948 and.687, respectively. A multivariate Cox's model shows that these biologic risk groups have special predictive power in low-IPS patients. CONCLUSION: The data from this exploratory study suggest that the accumulation of molecular events seems to influence the outcome of HL, particularly in the low-IPS group.

Adolescent↗
PubMed2004

FLT3-activating mutations are associated with poor prognostic features in AML at diagnosis but they are not an independent prognostic factor.

FLT3: gene alterations (internal tandem duplications - ITDs - and D835 mutations) are thought to be associated with poor-risk acute myeloid leukemia (AML). However, not all studies confirm this association, so it is still a matter of debate. Moreover, their association with other molecular abnormalities is less studied. We have investigated the presence of FLT3-ITD and D835 mutations in AML patients and their correlation with clinical and biological disease characteristics. The presence of ITD was analyzed in diagnostic samples of 176 AML patients and the D835 mutation in 135 of these patients. In all these patients, the presence of four well-known molecular abnormalities were also simultaneously characterized: PML/RARalpha, AML1/ETO, CBFbeta/MYH11 and MLL rearrangements. In all, 41 (23%) patients harbored FLT3 mutations, with 34 (19.3%) of them positive for the ITD, and seven (5%) positive for the D835 mutation. Of the acute promyelocytic leukemia (APL) patients, 16 (27%) showed FLT3 mutations, more frequently in M3 hypogranular cases (62% versus 17%, P=0.001) and cases with the short (bcr3) PML-RARalpha isoform (69%, P=0.002). In contrast, FLT3 was never altered in patients with inv(16), t(8;21) or 11q23 abnormalities. FLT3 mutations were significantly associated with some negative prognostic features at diagnosis (leukocytosis, high blast-cell percentage, and elevated LDH values), but they were not associated with different disease-free or overall survival. Therefore, we confirm a high frequency of FLT3 mutations in APL and in adult AML without recurrent cytogenetic translocations. In addition, they were not found as independent prognostic factors although associated with several adverse features at diagnosis.

Acute Disease↗
PubMed2004

Bone remodelation markers are useful in the management of monoclonal gammopathies.

The evaluation of bone disease in multiple myeloma (MM) by conventional radiology has low reproducibility. In the last decade, several serum and urine biochemical parameters, for evaluation of bone turnover, have become available. The present study was designed to explore the value of six bone remodelation markers. It was studied in a series of 176 newly diagnosed patients with monoclonal gammopathies (107 MM and 69 monoclonal gammopathies of unknown significance (MGUS)). As control groups we used 25 patients with benign osteoporosis (BO) and 32 healthy individuals (HI). The bone markers analyzed included: bone resorption markers (BRM) (total pyridinoline, total deoxypyridinoline, free deoxypyridinoline and C-terminal telopeptide of collagen I) and bone formation markers (BFM) (bone alkaline phosphatase (bAP) and osteocalcin (OC)). Serum or urinary levels of BRM were significantly higher in MM patients than in MGUS patients, BO patients or HI (P < 0.001, respectively). BRM were higher in MM patients with lytic lesions. However, only C-terminal telopeptide discriminated MM patients without bone lesions from MGUS patients. BFM did not show significant differences in the aforementioned comparisons, although a trend toward higher values of OC and lower values of bAP in patients with early bone affectation was observed. Ratios BRM/BFM that contained bAP exhibited differences that were most significant between the MM group and other entities, as well as between the different MM subgroups. In fact, the ratios BRM/bAP provided discrimination between the MM subgroup without lyses and MGUS group (P < 0.01). BRM and BFM, especially the ratios, are useful in the evaluation of bone lesions in patients with monoclonal gammopathies.

Adult↗
PubMed2003

Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value.

Investigation of minimal residual disease (MRD) in acute leukemias by immunophenotyping and/or molecular techniques is proving to be increasingly valuable for disease monitoring. In acute lymphoblastic leukemia (ALL), most MRD studies have focused on children, whereas in contrast, information on the value of MRD on adult ALL is scanty, and almost exclusively restricted to polymerase chain reaction (PCR) studies. Early response to therapy is one of the most important prognostic factors in acute leukemia, which prompted us to investigate whether or not early immunophenotypic assessment of MRD could also be a valuable tool for predicting relapse in adult patients with ALL. For that purpose we have analyzed the level of MRD during the initial phase of treatment (induction phase) by multiparameter flow cytometry in a series of 102 adolescent (older than 14 years) and adult patients with ALL. Immunophenotypic evaluation of the bone marrow (BM) at day +35 showed that patients with low MRD levels (< 0.05% leukemia-associated phenotype [LAP+] cells) had a significantly longer relapse-free survival (RFS) than patients with high MRD levels, and this prognostic influence was retained when only those patients in morphologic complete remission (mCR) at day +35 were considered (median RFS: 42 months vs 16 months; P =.001). Moreover, immunophenotyping helped to identify a small subset of patients (n = 12) with negative or low MRD levels (< 0.03% LAP+ cells) by day +14, with an excellent prognosis (projected RFS of 90% at 5 years). The contrary is true of patients who achieved late mCR (after day +35), since immunophenotypic investigation of MRD showed that, in spite of the mCR, none of the cases with more than 0.1% LAP+ cells would be relapse-free after 2 years. Multivariate analysis showed that the immunologic evaluation of MRD at day +35 was the most relevant independent prognostic parameter for adult patients with ALL, and together with age, white blood cell (WBC) count at diagnosis, and presence of the Philadelphia (Ph) chromosome, represented the most informative combination of variables for predicting relapse-free survival.

Adolescent↗
PubMed2003

Myeloma: update on supportive care strategies.

Despite substantial innovations in the treatment of multiple myeloma (MM), it remains an incurable disease. In addition, it is debatable whether the progress in survival is attributable simply to the therapy used to destroy the tumor clone or if it is also because of therapy designed to ameliorate disease complications. Supportive therapy has evolved greatly alongside general supportive measures used in hematologic malignancies (such as new antibiotics, antifungal agents, and growth factors) in addition to better indications in complementary treatments such as radiotherapy, dialysis, and surgery. However, in MM, several specific adjuvant therapies have also been introduced (eg, bisphosphonates and erythroid-stimulating factors), which have conferred a key role to supportive therapy in the general treatment of patients with MM.

Antineoplastic Agents↗
PubMed2002

The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma.

INTRODUCTION: Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic effect upon its association with other drugs with proven efficacy in MM. MATERIAL AND METHODS: The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). RESULTS: Adverse effects were moderate (grade or=2 were noted. Other side effects included grade 50% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). CONCLUSION: This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.

Aged↗
PubMed2002

Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti-tumour effect.

Twelve patients with smouldering or indolent multiple myeloma (MM) received 12 courses of intravenous pamidronate as a single agent to evaluate both the antitumour and bone metabolism effects. One patient achieved minor response, eight had stable disease, and three - all indolent MM - showed disease progression. Serum interleukin 6 (IL-6), IL-1beta and Oncostatin-M remained stable throughout the study, while tumour necrosis factor-alpha increased. Bone density significantly increased after four and 12 courses compared with baseline. Markers for bone resorption and bone formation decreased with treatment. These results suggest that pamidronate treatment reduces bone turnover in smouldering or indolent MM, but has no significant antitumour effect.

Aged↗
PubMed2002

Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival.

In order to gain further insights into the role of the p16 gene in cell cycle regulation and the prognostic implications of its inactivation, we investigated the methylation status of the p16 gene in 98 untreated patients using a polymerase chain reaction assay based on the inability of some restriction enzymes to digest methylated sequences. Forty-one patients showed a p16 methylated gene (42%). The percentage of S-phase plasma cells (PC) in these patients was almost three times higher than in those with an unmethylated p16 gene (4.16% +/- 3.37%vs 1.5% +/- 1.41%, P < 0.001). The presence of p16 methylation also correlated with both elevated beta2-microglobulin serum levels and high C-reactive protein values. Patients with a p16 methylated gene had shorter overall and progression-free survival than those patients without p16 methylation. However, this feature did not retain independent prognostic influence on multivariate analysis, probably due to its association with the S-phase PC, which had more potent statistical significance in the Cox model. These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.

Adult↗