Biomedical subjects

Emili Montserrat

Publications and source records attributed to Emili Montserrat.

At least 55 records · Page 3Linked to original sources

PubMed2004

Detection of Aspergillus galactomannan by enzyme immunoabsorbent assay in recipients of allogeneic hematopoietic stem cell transplantation: a prospective study.

BACKGROUND: Invasive aspergillosis (IA) has become the leading infectious cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This is partially because of the lack of a sensitive, specific, and noninvasive diagnostic test. New diagnostic tests for IA, such as the detection of Aspergillus galactomannan antigen (AGA) by sandwich enzyme-linked immunoabsorbent assay (ELISA), have recently been described. This study validates the usefulness of this diagnostic tool in the allo-HSCT setting. METHODS: From January 1999 to January 2001, all consecutive adult patients undergoing allo-HSCT were prospectively studied with a galactomannan antigenemia assay (ELISA test) twice weekly from admission until death or discharge, and weekly afterward if the patient received immunosuppressive therapy. Proven, probable, and possible IA were defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: During the 2 years of study, 74 patients underwent an allo-HSCT. A total of 832 serum samples were collected. According to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, it was ascertained that 66 patients did not fulfill any criteria of IA, 2 patients were classified with possible IA, 5 patients were classified with probable IA, and 1 patient was classified with proven IA. Fourteen samples were positive for AGA, all from patients with IA. The sensitivity and specificity of the test were 75% and 100%, respectively. The positive predictive and negative predictive values were 100% and 97%, respectively. CONCLUSIONS: In this study, AGA detection was clearly related to IA. Although the ELISA test did not have any role in the anticipation of the diagnosis, it clarifies the diagnosis of IA in allo-HSCT.

Aspergillosis↗

PubMed2004

Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature.

BACKGROUND: Acute myeloid leukemia (AML) after solid organ transplantation is rare, with only six AML cases after liver transplantation (LT) being reported. METHODS: Characteristics of three AML cases observed among 799 recipients of LT in the authors' institution and estimation of the standardized incidence ratio (SIR) are presented. RESULTS: Three AML cases were diagnosed (French-American-British classification subtypes M0, M3, and M1) at 38 days, 2 years, and 3.5 years after LT, respectively. The immunosuppressive regimen consisted of cyclosporine A and prednisone. The recipient's origin of blasts could be demonstrated in two cases. All patients achieved complete remission after standard treatment. Nonetheless, disease relapsed in two patients at 2 and 6 months, whereas the patient with acute promyelocytic leukemia remains disease-free 4 years after diagnosis. As compared with the general population, the observed incidence of AML in the authors' series of LT results in a significantly higher SIR of 11.41 (P=0.0023). CONCLUSIONS: The higher SIR found in the authors' series suggests an increased risk of AML in patients undergoing LT.

Adult↗

PubMed2004

Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation.

The t(8;16)(p11;p13) fuses the MOZ (MYST3) gene at 8p11 with CBP (CREBBP) at 16p13 and is associated with an infrequent but well-defined type of acute myeloid leukemia (AML) that has unique morphocytochemical findings (monocytoid blast morphology with erythrophagocytosis and simultaneously positive for myeloperoxidase and nonspecific esterases). RT-PCR amplification of MOZ/CBP (MYST3/CREBBP) chimera has proved difficult, with four different transcripts found in four reported cases. We studied 7 AML-t(8;16) patients, 5 with cytogenetically demonstrated t(8;16) and 2 with similar morphocytochemical and immunophenotypical characteristics. Clinically, 3 cases presented as therapy-related leukemia. Extramedullar involvement was observed at presentation in 2 patients and coagulopathy in 4. The clinicobiological findings confirmed the distinctiveness of this entity. Of note is the erythrophagocytosis in 5 of 7 cases and the immunological negativity for CD34 and CD117 and positivity for CD56. Using a new RT-PCR strategy, we were able to amplify a specific band of 212 bp in six cases in which sequence analysis confirmed the presence of the previously described MOZ/CBP fusion transcript type I. This is the largest molecularly studied AML-t(8;16) series, which demonstrates that MOZ/CBP breakpoints are usually clustered in intron 16 of MOZ and intron 2 of CBP. The newly designed single-round PCR provides a simple tool for the molecular confirmation of MOZ/CBP rearrangement.

Acute Disease↗

PubMed2004

Role of auto- and allotransplantation in B-cell chronic lymphocytic leukemia.

Although important progress has been made in its management, B-cell chronic lymphocytic leukemia (CLL) remains incurable with standard therapies. Hematopoietic stem-cell transplants (HSCT) are frequently being offered to individuals with CLL, the hope being that, as in other hematologic malignancies, they can prolong survival in or even cure some patients. This article analyzes which patients with CLL are appropriate candidates for HSCT, current transplant procedures, results with autologous and allogeneic HSCT, and future trends in transplantation in this form of leukemia.

Humans↗

PubMed2004

Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival.

Survivin is a member of the inhibitor of apoptosis protein family that is expressed in G2/M phase. Survivin is overexpressed and associated with parameters of poor prognosis in different human tumors. The role of survivin in the pathogenesis of mantle cell lymphoma (MCL) was examined in a series of typical and blastoid tumors. Survivin was detected as a nuclear pattern in a variable number of tumor cells. Mitotic figures were always positive with a strong delineation of the chromosomes. Western blot analysis confirmed the presence of survivin only in nuclear fractions. Protein expression detected by immunohistochemistry correlated with mRNA levels analyzed by quantitative real-time reverse transcription-polymerase chain reaction (P < 0.0001). Survivin expression levels were higher in blastoid MCL variants (P < 0.0001) and were associated with the proliferative activity (P = 0.001), but not with the ploidy status of the tumors. The number of apoptotic cells was independent of survivin or Ki-67 expression. Overall survival was significantly shorter in patients with high survivin expression. However, in a multivariate analysis, proliferative index was a better predictor of survival than survivin score. These findings indicate that survivin is commonly expressed in MCL with a nuclear and mitotic pattern. The expression levels are strongly associated with the proliferative activity of the tumors and the survival of the patients, suggesting a potential role in cell cycle regulation and tumor progression.

Apoptosis↗

PubMed2004

Treatment options in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult hematological malignancy in the Western world and predominantly affects the elderly. The disease encompasses a wide spectrum of clinical symptoms, which translate into variable prognosis and survival. The stratification of patients based on their clinical risk profile has been aided by the recognition of novel prognostic markers, for example, VH mutations and ZAP-70 expression, and this process is fundamental to assigning the most appropriate treatment strategy on an individual basis. Although CLL remains incurable with standard treatments, important progress in treatment has been made. The discovery of purine analogs such as fludarabine has led to significant improvements in remission rates and freedom from progression but, unfortunately, no significant prolongation in survival. With the success of newer therapeutic approaches, such as the monoclonal antibodies and stem cell transplantation, the focus of current therapy is on using these approaches in combination with fludarabine to produce high rates of molecular complete response, to eradicate minimal residual disease, and to lengthen survival. This paper provides an overview of CLL and discusses how recent therapeutic developments have changed the management of this form of leukemia.

Antineoplastic Agents↗

PubMed2004

Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis.

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare. We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells. The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.

Aged↗

PubMed2004

Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease > or =50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow-up of 12.5 months (range: 4-21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0.002) and higher Hb at start treatment of (P = 0.01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.

Aged↗

PubMed2004

Cytotoxic effects of B lymphocytes mediated by reactive oxygen species.

Reactive oxygen species (ROS) are produced in all mammalian cells as a result of norman cellular metabolism and due to the activation of oxidant-producing enzymes in response to exogenous stimuli. The balance between ROS production and antioxidant defenses determines the degree of oxidative stress. Generation of ROS has been associated with cell signaling, stress responses, cell proliferation, aging and cancer development. The ability of ROS to induce cellular damage and to cause cell death opens the possibility to exploit this property in the treatment of cancer through a fee radical-mediated mechanism.

2-Methoxyestradiol↗

PubMed2004

Familial lymphoid neoplasms in patients with mantle cell lymphoma.

BACKGROUND AND OBJECTIVES: Familial aggregation has been recognized in patients with several lymphoid neoplasms, but the genetic basis for this familial clustering is not known. Germ-line mutations in the ataxia-telangiectasia mutated (ATM) and CHK2 genes have been detected in patients with mantle cell lymphoma (MCL), suggesting a potential role of these genes in genetic predisposition to these tumors. However, no familial association has been previously recognized in MCL. DESIGN AND METHODS: To determine the possible existence of familial lymphoid neoplasms in MCL, we searched clinical records of MCL patients and identified three families in which a MCL, an acute B-cell lymphoblastic leukemia, and a lymphoplasmacytic lymphoma occurred in a first-degree relative of a MCL patient. RESULTS: The neoplasms in two daughters appeared at an earlier age and were more aggressive than that in the respective parent, suggesting that the phenomenon of anticipation may characterize familial lymphomas associated with MCL. No mutations were detected in the ATM, CHK2, CHK1, and p53 genes. INTERPRETATION AND CONCLUSIONS: Our findings suggest that inactivation of the investigated DNA damage response genes do not account for familial disease aggregation in MCL patients, although such aggregation may occur and seems to be associated with the phenomenon of anticipation.

Adult↗

PubMed2004

Feasibility and results of autologous stem cell transplantation in de novo acute myeloid leukemia in patients over 60 years old. Results of the CETLAM AML-99 protocol.

BACKGROUND AND OBJECTIVES: The benefits of high-dose cytarabine, anthracyclines and hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia (AML) are greater in younger rather than in older patients. We assessed the proportion of patients over 60 years with de novo AML who qualified for intensive therapy and determined the feasibility and results of autologous stem cell transplantation (ASCT) in first complete remission (CR). DESIGN AND METHODS: Induction therapy included idarubicin, cytarabine and etoposide. Patients who achieved CR received one cycle of mitoxantrone and cytarabine and ASCT as consolidation therapies. RESULTS: Over a 4-year period, 258 patients were registered of whom 135 (52%) were enrolled for intensive treatment. The CR rate was 61%, advanced age (p=0.033) and unfavorable cytogenetics (p=0.015) emerged as independent negative prognostic factors for CR. The 2-year overall survival (OS) was 23 % (CI 14%-30%) and was poorer in patients with unfavorable cytogenetics (p=0.035), age over 70 years (p=0.019) or leukocytosis (p=0.006). Only 27% of the potential candidates underwent ASCT. The probability of 2-year leukemia-free survival after consolidation was 39% (CI 6%-71%) for these patients and 22% (CI 6% - 39%) for candidate patients not undergoing ASCT (p=0.07). INTERPRETATION AND CONCLUSIONS: Over 25% of the patients 60 to 70 years with de novo AML benefit from standard intensive treatment. In these patients, ASCT has a tolerable toxicity and may have a positive impact on leukemia-free survival.

Acute Disease↗

PubMed2004

Extramedullary multiple myeloma escapes the effect of thalidomide.

BACKGROUND AND OBJECTIVES: Thalidomide is an antiangiogenic drug that produces a response rate ranging from 32 to 64% in patients with refractory/relapsed multiple myeloma (MM). However, the efficacy of thalidomide in patients with soft-tissue plasmacytomas is controversial. The aim of this study was to assess the response rate to thalidomide in patients with advanced MM and to correlate the response rate with the presence of extramedullary involvement. DESIGN AND METHODS: Thirty-eight patients with refractory/relapsed MM were treated with thalidomide. Eleven patients had extramedullary involvement when therapy was initiated. The response rate was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation. RESULTS: Sixteen of the 38 patients (42%) responded to thalidomide. The response rate was significantly higher in patients without extramedullary involvement (59% vs 0%, p=0.0006). Although four of the 11 patients with extramedullary involvement had a serological response, a progression of the soft-tissue masses was observed in all of them. INTERPRETATION AND CONCLUSIONS: Thalidomide is effective in patients with advanced MM. However, extramedullary disease does not respond to thalidomide, as delivered in this series. The mechanisms to explain different response to therapy depending on tumor homing warrant further investigation.

Adult↗

PubMed2004

Treatment of primary acute myeloid leukemia: results of a prospective multicenter trial including high-dose cytarabine or stem cell transplantation as post-remission strategy.

BACKGROUND AND OBJECTIVES: To evaluate a regimen of induction and consolidation chemotherapy, followed by a post-remission therapy which depended on age and cytogenetics, in patients with primary acute myeloid leukemia. DESIGN AND METHODS: Two hundred patients up to 60 years old received idarubicin, standard dose cytarabine and etoposide as induction chemotherapy and one consolidation course including intermediate dose cytarabine and mitoxantrone. Subsequently, patients with favorable cytogenetics, [i.e., t(8;21), inv(16)] were scheduled to receive 2 courses of high-dose cytarabine. The remainder were scheduled for allogeneic stem cell transplantation (SCT), if 50 years old or lacking a donor. RESULTS: In patients with favorable cytogenetics the 4-year probabilities of survival and leukemia-free survival (LFS) were 62+/-9% and 41+/-10%, respectively. The results were better in patients with t(8;21). LFS at 4 years in patients 50 years old assigned to auto-SCT had a 4-year LFS of 17+/-9%. Adverse cytogenetics and white blood cell count >or= 20 yen 109/L at diagnosis were associated with lower probability of survival and leukemia-free survival. INTERPRETATION AND CONCLUSIONS: We confirmed that high-dose cytarabine seems a good option for patients with t(8;21). Autologous and allogeneic SCT led to similar leukemia-free survival in patients <or= 50 years of age. In older patients, the results of auto-SCT were poor. Finally, cytogenetics and white cell count at diagnosis, together with new prognostic markers, should be considered in the design of future risk-adapted trials.

Adolescent↗

PubMed2004

Frequent polymorphic changes but not mutations of TRAIL receptors DR4 and DR5 in mantle cell lymphoma and other B-cell lymphoid neoplasms.

BACKGROUND AND OBJECTIVES: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 have been mapped to chromosome 8p21-22, a region frequently deleted in different lymphoid neoplasms. DESIGN AND METHODS: To investigate the potential alterations of these genes in lymphoid neoplasms, we examined the presence of gene mutations in exons 3, 4, and 9 in 69 cases with mantle cell lymphoma (MCL), 16 with chronic lymphocytic leukemia (CLL), 12 with follicular lymphomas (FL) and 17 with large B-cell-lymphomas (DLBCL), as well as in 4 lymphoid cell lines carrying the t(11;14) translocation, and 91 healthy blood donors. RESULTS: Three CLL and three MCL cases had 8p deletions. Two nucleotide changes in or near the intron 3 splice consensus sequence and a silent change were found. These rare changes were also present in the germ-line of the patients. The DR4 death domain A1322G polymorphism was significantly more frequent in MCL [odds ratio (OR) = 5.9; 95% confidence interval (CI), 1.92-18.1] and CLL (OR = 4.5; CI, 1.18-17) patients than in a sex and age-adjusted healthy population. In contrast, the DR4 exon 4 C626G polymorphism was associated with a significant overall decreased risk for MCL (OR = 0.3; CI, 0.12-0.8). No mutations or cancer-associated polymorphic changes were found in DR5 domains. INTERPRETATION AND CONCLUSIONS: These findings indicate that mutations of DR4 and DR5 are uncommon in lymphoid neoplasms but DR4 polymorphic alleles may contribute to the pathogenesis of these malignancies.

Alleles↗

PubMed2003

Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

Adult↗

PubMed2003

ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia.

BACKGROUND: The mutational status of immunoglobulin heavy-chain variable-region (IgVH) genes in the leukemic cells of chronic lymphocytic leukemia (CLL) is an important prognostic factor in the disease. We investigated whether the expression of ZAP-70 by CLL cells correlated with the IgVH mutational status, disease progression, and survival. METHODS: The expression of ZAP-70 was analyzed in T-cell and B-cell lines and in peripheral-blood samples from 56 patients with CLL with the use of flow cytometry, Western blotting, and immunohistochemistry. The results were correlated with the IgVH mutational status and clinical outcome. RESULTS: ZAP-70 was detected by flow-cytometric analysis in cells of T-cell lineage and in leukemic cells from 32 of 56 patients with CLL. In all patients in whom at least 20 percent of the leukemic cells were positive for ZAP-70, IgVH was unmutated, whereas IgVH mutations were found in 21 of 24 patients in whom less than 20 percent of the leukemic cells were positive for ZAP-70 (P<0.001). Concordant results were obtained when ZAP-70 expression was assessed by immunohistochemistry or Western blotting. The level of ZAP-70 expression did not change over time (median, 37 months) in sequential samples from 30 patients with CLL. Patients with Binet stage A CLL who had at least 20 percent ZAP-70-positive leukemic cells had more rapid progression and poorer survival than those with less than 20 percent ZAP-70-positive cells. CONCLUSIONS: Among patients with CLL, expression of ZAP-70, as detected by flow-cytometric analysis, correlated with IgVH mutational status, disease progression, and survival.

ADP-ribosyl Cyclase↗

PubMed2003

Mechanism of action and resistance to monoclonal antibody therapy.

Monoclonal antibodies (MoAbs) are increasingly used in the treatment of patients with hematological malignancies and autoimmune diseases. The most commonly employed humanized and chimeric MoAbs are rituximab, alemtuzumab (Campath-1H, Ilex Pharmaceuticals, San Antonio, TX), and gemtuzumab-ozogamicin (Mylotarg, Wyeth-Ayerst Laboratories, St Davids, PA). The mechanism of action of these antibodies, and host and cellular factors influencing the response, are not completely known. Induction of apoptosis, antibody-dependent cell cytotoxicity (ADCC), and complement-mediated cell death (CDC) is the proposed mechanism of action of these antibodies. We review the current understanding of the mechanism of action of and resistance to these MoAbs.

Alemtuzumab↗

PubMed2003

High levels of chromosomal imbalances in typical and small-cell variants of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare postthymic T-cell disorder that may show different morphologic variants and a very aggressive clinical behavior. On occasion, patients may present with an indolent clinical course and long survival. The disease is genetically characterized by the presence of complex karyotypes with recurrent alterations involving chromosomes 8, 14, and 11. The possible relationship between genetic alterations and morphologic variants and the clinical course of the disease, however, is not well known. Comparative genomic hybridization (CGH) was used to detect chromosomal imbalances in eight patients diagnosed with T-PLL, including three cases of small-cell variant with an indolent clinical evolution. Abnormal profiles were detected in all cases. The chromosomal regions most often over-represented were 8q (75%), 5p (62%), and 14q (37%), as well as 6p and 21 (both 25%). The chromosomal regions most often underrepresented were 8p and 11q (75%), 13q (37%), and 6q, 7q, 16q, 17p, and 17q (25%). The number of chromosomal imbalances in the three small-cell variants was relatively similar to that of cases with typical morphology. Only gains of 6p and losses of 7q present in three and two cases, respectively, with typical morphology were not detected in any small-cell variant. CGH analysis revealed alterations in 15 chromosomal regions not detected by conventional cytogenetics. These results indicate that T-PLL carry a high number of chromosomal alterations that are not related to the morphologic variants or the clinical behavior of the disease.

Adult↗