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Blanca Espinet,
Itziar Salaverria,
Sílvia Beà,
Neus Ruiz-Xivillé,
Olga Balagué,
Marta Salido,
Dolors Costa, Joaquim Carreras,
Ana Eugenia Rodríguez-Vicente,
Juan Luís García, [......],
Teresa González,
Francesc Sant,
Ramon Salinas,
María Teresa Ardanaz,
Llorenç Font,
Lourdes Escoda,
Lourdes Florensa,
Sergi Serrano,
Elias Campo,
Francesc Solé
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ABSTRACT: Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31-32, 1p21-22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation-independent prognostic markers indicating poor outcome. © 2010 Wiley-Liss, Inc.
Genes Chromosomes and Cancer 02/2010; 49(5):439 - 451. · 3.31 Impact Factor
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H Liu,
R Brais,
A Lavergne-Slove,
Q Jeng,
K Payne,
H Ye,
Z Liu, J Carreras,
Y Huang,
C M Bacon,
R A Hamoudi,
V Save,
L Venkatraman,
P G Isaacson,
J Woodward,
M-Q Du
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ABSTRACT: An aberrant immunophenotype and monoclonality of intraepithelial lymphocytes (IELs) are frequently found in refractory coeliac disease (RCD). However, the utility of continual monitoring of IEL immunophenotype and clonality in the surveillance of RCD remains to be studied.
The diagnostic and follow-up biopsies from 33 patients with CD, 7 with suspected RCD, 41 with RCD and 20 with enteropathy-associated T cell lymphoma (EATL) (including 11 evolved from RCD) were investigated by CD3epsilon/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged T cell receptor (TCR) genes.
An aberrant immunophenotype (CD3epsilon(+)CD8(-) IELs > or =40%) and monoclonality were detected occasionally in CD biopsies, either transiently in patients with CD not compliant with a gluten-free diet or in those who subsequently developed suspected RCD, RCD or EATL. In contrast, the aberrant immunophenotype and monoclonality were found in 30 of 41 (73%) and 24 of 37 (65%) biopsies, respectively, at the time of RCD diagnosis. Among the patients with RCD who did not show these abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases gained an aberrant immunophenotype and monoclonality, respectively, during follow-up. Irrespective of whether detected in diagnostic or follow-up biopsies, persistence of both abnormalities was characteristic of RCD. Importantly, the presence of concurrent persistent monoclonality and aberrant immunophenotype, especially > or =80% CD3epsilon(+)CD8(-) IELs, was a strong predictor of EATL development in patients with RCD (p=0.001).
Continual monitoring of both immunophenotype and clonality of IELs is more important than snapshot analysis for RCD diagnosis and follow-up, and could provide a useful tool for surveillance of patients at risk of EATL.
Gut 12/2009; 59(4):452-60. · 10.11 Impact Factor
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Jordi Rovira,
Edgar M Arellano, Joaquim Carreras,
Begoña Campos,
Barbara Vodenik,
Elisenda Bañón-Maneus,
María José Ramírez-Bajo,
Daniel Moya-Rull,
Amanda Solé-González,
Astrid Hernández,
Ignacio Revuelta,
Luis F Quintana,
William J Howat,
Josep M Campistol,
Fritz Diekmann
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ABSTRACT: Sirolimus (SRL) is a potent and specific immunosuppressive drug used in organ transplantation, as basic therapy or in combination with calcineurin inhibitors. Although SRL is a nonnephrotoxic drug, many reports have related its use with the development of proteinuria, especially after conversion. Therefore, the aim of this study was to elucidate the interrelation between early and late SRL administration on the development of glomerular hypertrophy and proteinuria in a model of renal mass reduction (RMR).
Rats underwent 2/3 cryoablation of the left kidney and subsequent right nephrectomy (n=42) or sham operations (n=29). Two weeks before (early study) or 12 weeks after (late study) surgery, SRL or vehicle was administered three times weekly. Creatinine clearance and proteinuria were determined throughout the study, and a complete histologic analysis was performed at the end of the study.
Treatment with SRL had no effect on creatinine clearance, independently of the administration time. Four weeks after RMR, a significant increase in proteinuria was observed. Proteinuria was stabilized after early and late SRL administration, whereas vehicle-treated animals showed a further increase in proteinuria. Glomerular hypertrophy was strongly associated with proteinuria, and early SRL introduction prevented glomerular enlargement. The histologic analysis showed less structural damage in the two groups of animals treated with SRL than in the control group.
Although early SRL introduction blocked glomerular hypertrophy, SRL treatment revealed the potential to halt progression of proteinuria and histologic damage at any time of administration in a model of RMR.
Transplantation 10/2009; 88(5):646-52. · 4.00 Impact Factor
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ABSTRACT: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a T-cell malignancy in which ALK expression is a consequence of the t(2;5) or a variant translocation involving Chromosome 2. For the most part, this disease presents in the pediatric population and most, but not all, patients are successfully treated. Although the t(2;5) product nucleophosmin-ALK has been extensively studied for its transforming properties, very little is known regarding cooperative genetic mutations that may contribute to lymphomagenesis and may predict survival outcome, specifically in a purely pediatric population. We set out to determine the frequency and positions of genomic imbalances in this relatively rare disease. We collected biopsy material from 15 UK-resident children with ALK-expressing ALCL. We performed array comparative genomic hybridization at a resolution of 1 MB using DNA isolated from tumor tissue. Some of the more common genomic gains were confirmed by quantitative PCR. Regions of genomic gain were far more common than losses and were most often detected on chromosomes 1-4, 5-12, 14, and 17, with Chromosome 11 being the most frequent site of genomic imbalances. Patients with 14 or fewer imbalances had a lower overall 3-year survival (87.5-40%, P = 0.14) as did patients with gains in the regions of DDB1 or BIRC5. A range of genomic imbalances exist in ALK-expressing ALCL of a pediatric origin, with a greater number associated with poorer overall survival.
Genes Chromosomes and Cancer 09/2009; 48(11):1018-26. · 3.31 Impact Factor
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ABSTRACT: Tumor microenvironment influences the behavior of follicular lymphoma (FL), although the specific cell subsets involved are not well known. The aim of this study was to determine the impact of programmed cell death 1 (PD-1) -positive inhibitory immunoregulatory lymphoid cells in the clinicobiologic features and outcome of patients with FL.
We examined samples from 100 patients (53 men and 47 women; median age, 54 years) at diagnosis, as well as in 32 patients at first relapse, with a recently generated monoclonal antibody against PD-1. The cells were quantified using computerized image analysis. Additional analysis consisted of double immunofluorescence and flow cytometry.
PD-1 expression was alternative to FOXP3 in lymphoid cells from both reactive tonsils and FL. At diagnosis, the median percentage of PD-1-positive cells was 14% (range, 0.1% to 74%). Patients with grade 3 FL, poor performance status, and high serum lactate dehydrogenase showed lower numbers of PD-1-positive cells. After a median follow-up of 6.2 years, patients with PD-1-positive cells <or= 5% (n = 25), 6% to 33% (n = 50), and more than 33% (n = 25) had a 5-year progression-free survival rate of 20%, 46%, and 48% (P = .038) and overall survival (OS) of 50%, 77%, and 95% (P = .004), respectively. PD-1 and FL International Prognostic Index maintained prognostic value for OS in multivariate analysis. Patients with PD-1-positive cells <or= 5% showed a higher risk of histologic transformation. At that time, transformed diffuse large B-cell lymphomas had lower percentage of PD-1-positive cells than FL.
A high content of PD-1-positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.
Journal of Clinical Oncology 02/2009; 27(9):1470-6. · 18.37 Impact Factor
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ABSTRACT: Follicular lymphoma (FL) is a neoplasm derived from follicular germinal center cells. Like the normal components of this lymphoid structure, FL cells interact with various immune cells, such as the follicular helper T cells, suppressor regulatory T cells, dendritic cells, and histiocytes, that define the tumor microenvironment. Gene expression studies have shown that the nature of the tumor microenvironment predicts survival in patients with FL and may influence the response to immunotherapy and risk of transformation. The immune system may either promote or constrain tumor cell development, depending on the relative distribution and activation status of various cell subpopulations. The prognostic value of germline genetic variants of some immune genes suggests that the host genetic background may also influence the biology of FL. Some efforts have been carried out to validate those findings and provide clinical tools that may be used at the time of diagnosis.
Current Hematologic Malignancy Reports 10/2008; 3(4):179-86.
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ABSTRACT: Regulatory T (Treg) cells are altered during HIV replication, but their role in chronic infection is controversial and lacks reproducibility between series. FOXP3 is a specific marker of Treg cells. We study for the first time FOXP3 expression in a unique series of paired samples at different time points of HIV infection. Design: Paired samples from lymphoid tissue and peripheral blood were simultaneously obtained from 27 HIV-infected patients (before and after highly active antiretroviral therapy [HAART]) and 6 controls.
We analyzed FOXP3 expression by TaqMan (Universal PCR Master Mix; Applied Biosystems, Foster City, CA) reverse transcriptase polymerase chain reaction in lymphoid tissue and peripheral blood. Treg cells were assessed in lymphoid tissue by immunohistochemistry/computer image analysis and in peripheral blood by flow cytometry. CD4 cell counts and viral loads were obtained.
HIV-infected patients had a low FOXP3 copy number and Treg cell frequencies in lymphoid tissue but a high number of Treg cells in peripheral blood. Lymphoid tissue FOXP3 expression decreased after HAART, and it correlated to lymphoid tissue viral load. Patients treated with nonnucleoside HAART had the lowest lymphoid tissue FOXP3 expression.
HIV-infected patients had low FOXP3 expression in lymphoid tissue and redistributed Treg to peripheral blood. HAART reduced even more the proportion of lymphoid tissue Treg in association with the immunologic recovery observed after treatment. The type of HAART may have an impact on the distribution of Treg cells.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2008; 46(5):529-37. · 4.43 Impact Factor
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ABSTRACT: Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.
Journal of the American Society of Nephrology 10/2007; 18(10):2653-60. · 9.66 Impact Factor
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ABSTRACT: The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.
Blood 12/2006; 108(9):2957-64. · 9.90 Impact Factor
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Joaquim Carreras,
Neus Villamor,
Lluís Colomo,
Carol Moreno,
Santiago Ramón y Cajal,
Marta Crespo,
Frederic Tort,
Francesc Bosch,
Armando López-Guillermo,
Dolors Colomer,
Emili Montserrat,
Elías Campo
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ABSTRACT: ZAP-70 is a tyrosine kinase that participates in early B-cell differentiation and is a prognostic factor in chronic lymphocytic leukaemia (CLL), where it is associated with an unmutated configuration of the IgV(H) genes. In this study ZAP-70 expression was studied by immunohistochemistry in a spectrum of B-cell lymphoid neoplasms; this staining method was compared with flow cytometry, and the relationship of ZAP-70 expression to mutational status and prognosis was assessed. 242 tissue samples from 225 patients with B-cell lymphoid neoplasms arising at different maturational stages were included. Flow cytometry was performed in all CLL cases (n = 52). IgV(H) mutational status was determined in 25 CLL and 12 mantle cell lymphoma (MCL) patients. ZAP-70 was positive in 34/52 (65%) CLL, 9/31 (31%) Burkitt's lymphoma, 2/7 (29%) lymphoblastic lymphomas, 3/36 (8%) MCL, 1/23 (4%) marginal zone lymphoma, and 1/45 (2%) diffuse large B-cell lymphomas, but in none of the 19 follicular lymphomas or the 14 Hodgkin lymphomas. An identical ZAP-70 pattern was obtained in six patients with simultaneous biopsies from different sites and in 12 patients with sequential biopsies. Immunohistochemistry and flow cytometry gave identical results in 48 the 52 CLLs. All but one ZAP-70-positive CLL had IgV(H) gene in an unmutated configuration, whereas all but one ZAP-70-negative CLL had somatically hypermutated IgV(H). The 12 MCLs analysed were ZAP-70 negative regardless of IgV(H) mutational status (4 mutated, 8 unmutated). ZAP-70 positive CLL was associated with a shorter overall survival (median time 103 months vs. 293 months, p = 0.01) and a shorter time to disease progression (median time 26 months vs. 60 months, p = 0.01). In conclusion, ZAP-70 is expressed in several types of B-cell neoplasm and is easily detected by immunohistochemistry, providing a useful prognostic marker in patients with CLL from whom no other material is available or when other techniques for its assessment cannot be performed.
The Journal of Pathology 04/2005; 205(4):507-13. · 6.32 Impact Factor
