148 results on '"Santiago Montes-Moreno"'
Search Results
2. Supplementary Table 1 from Prevalence and Clinical Implications of Epstein–Barr Virus Infection in De Novo Diffuse Large B-Cell Lymphoma in Western Countries
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Ken H. Young, L. Jeffrey Medeiros, Miguel A. Piris, Jane N. Winter, Roberto N. Miranda, Carlo E. Bueso-Ramos, Michael B. Møller, John P. Farnen, Andrés J.M. Ferreri, Maurilio Ponzoni, Weiyun Ai, Jooryung Huh, J. Han van Krieken, William W. L. Choi, Eric D. Hsi, Kristy L. Richards, Jiayu Chen, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Karen Dybaer, Santiago Montes-Moreno, Ganiraju C. Manyam, Alexander Tzankov, Carlo Visco, Zijun Y. Xu-Monette, Ling Li, and Chi Young Ok
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PDF file - 57KB, Supplemental Table 1. Genes differently expressed in EBV+ DLBCL vs. EBV-negative DLBCL. A. Genes upregulated in EBV+ DLBCL; B. Genes downregulated in EBV+ DLBCL
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- 2023
3. Supplementary Figure 1 from Prevalence and Clinical Implications of Epstein–Barr Virus Infection in De Novo Diffuse Large B-Cell Lymphoma in Western Countries
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Ken H. Young, L. Jeffrey Medeiros, Miguel A. Piris, Jane N. Winter, Roberto N. Miranda, Carlo E. Bueso-Ramos, Michael B. Møller, John P. Farnen, Andrés J.M. Ferreri, Maurilio Ponzoni, Weiyun Ai, Jooryung Huh, J. Han van Krieken, William W. L. Choi, Eric D. Hsi, Kristy L. Richards, Jiayu Chen, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Karen Dybaer, Santiago Montes-Moreno, Ganiraju C. Manyam, Alexander Tzankov, Carlo Visco, Zijun Y. Xu-Monette, Ling Li, and Chi Young Ok
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PDF file - 3781KB, Supplemental Figure 1. Morphologic subtypes of EBV+ DLBCL. A, E, I, and M. The monomorphic subtype is composed of monotonous sheets of large transformed B-cells. B, F, J and N. The polymorphic subtype, canonical large B-cell neoplasm variant contains high density of large neoplastic cells and scattered cells with HRS-like features. C, G, K and O. The polymorphic subtype, Hodgkin-like variant shows lower density of neoplastic cells with HRS-like features. D, H, L and P. The polymorphic subtype, lymphoproliferative disorder-like variant has low density of neoplastic cells without Hodgkin lymphoma-like features. By immunohistochemistry, the monomorphic variant had a GCB phenotype, but all 3 polymorphic variants showed non-GCB phenotype.
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- 2023
4. Data from Prevalence and Clinical Implications of Epstein–Barr Virus Infection in De Novo Diffuse Large B-Cell Lymphoma in Western Countries
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Ken H. Young, L. Jeffrey Medeiros, Miguel A. Piris, Jane N. Winter, Roberto N. Miranda, Carlo E. Bueso-Ramos, Michael B. Møller, John P. Farnen, Andrés J.M. Ferreri, Maurilio Ponzoni, Weiyun Ai, Jooryung Huh, J. Han van Krieken, William W. L. Choi, Eric D. Hsi, Kristy L. Richards, Jiayu Chen, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Karen Dybaer, Santiago Montes-Moreno, Ganiraju C. Manyam, Alexander Tzankov, Carlo Visco, Zijun Y. Xu-Monette, Ling Li, and Chi Young Ok
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Purpose: Epstein–Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries.Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).Results: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative (EBV−) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV+ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV− DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV+ DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.Conclusions: The clinical characteristics of patients with EBV+ versus EBV− DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338–49. ©2014 AACR.
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- 2023
5. Supplmentary Documents including Methods, Tables, and Legends for Supplementary Figures, and Supplementary Figure S1-S5 from Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma
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Ken H. Young, Yong Li, L. Jeffrey Medeiros, Jane N. Winter, Miguel A. Piris, Roberto N. Miranda, Sa A. Wang, Michael B. Møller, Ben M. Parsons, Andrés J.M. Ferreri, Maurilio Ponzoni, Jooryung Huh, J. Han van Krieken, William W.L. Choi, Eric D. Hsi, Kristy L. Richards, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Santiago Montes-Moreno, Han Liang, Li Zhang, Jun Li, Karen Dybkær, Carlo Visco, Dehui Zou, Xiao-xiao Wang, Yi Xia, Ling Li, Alexander Tzankov, Ganiraju C. Manyam, Qipan Deng, and Zijun Y. Xu-Monette
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The supplementary documents include: (1) Supplementary methods for detection of MYC mutations and rearrangements, assessment of Myc expression, and functional studies. (2) Supplementary Tables S1-S8. Supplementary Table S1. Numbers of MYC mutation present in the coding sequence and the untranslated regions. Supplementary Table S2. Clinical and molecular characteristics of the DLBCL cohort with wild-type or mutated Myc or N11S single nucleotide polymorphism. Supplementary Table S3. List of Myc mutations and corresponding patient survival. Supplementary Table S4. Multivariate survival analysis. Supplementary Table S5. Molecular characteristics of patients with wild-type or mutated MYC untranslated regions. Supplementary Table S6. List of MYC 3Ã,'UTR mutations and corresponding patient survival. Supplementary Table S7. Gene profiling comparisons between wild-type and mutated MYC. Supplementary Table S8. Brief summary of major findings by this study. (3) Legends for Supplementary Figures S1-S5. Supplementary Figure S1. Survival analysis for MYC mutations in DLBCL respective to GCB/ABC subtypes, homo/heterozygosity, and MYC translocations. Supplementary Figure S2. Comparison of Myc levels and gene expression profiles between DLBCL groups. Supplementary Figure S3. Differential expression of genes between the WT-Myc and MUT-Myc groups. Supplementary Figure S4. Comparison of gene expression between the WT-Myc and MUT-Myc groups. Supplementary Figure S5. Differential expression of proteins between the WT-Myc and MUT-Myc groups.
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- 2023
6. Data from Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma
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Ken H. Young, L. Jeffrey Medeiros, Jane N. Winter, Miguel A. Piris, Michael B. Møller, John P. Farnen, Francesco Bertoni, Andrés J.M. Ferreri, Maurilio Ponzoni, Xiaoying Zhao, Jooryung Huh, J. Han van Krieken, William W.L. Choi, Eric D. Hsi, Kristy L. Richards, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Karen Dybkær, Santiago Montes-Moreno, Carlo Visco, Ling Li, Ganiraju C. Manyam, Alexandar Tzankov, Zijun Y. Xu-Monette, Jiayu Chen, and Chi Young Ok
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Purpose: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.Experimental Design: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.Results: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell–like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK–STAT pathway to be enriched in pSTAT3+ DLBCL.Conclusions: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK–STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113–23. ©2014 AACR.
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- 2023
7. Data from Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma
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Ken H. Young, Yong Li, L. Jeffrey Medeiros, Jane N. Winter, Miguel A. Piris, Roberto N. Miranda, Sa A. Wang, Michael B. Møller, Ben M. Parsons, Andrés J.M. Ferreri, Maurilio Ponzoni, Jooryung Huh, J. Han van Krieken, William W.L. Choi, Eric D. Hsi, Kristy L. Richards, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Santiago Montes-Moreno, Han Liang, Li Zhang, Jun Li, Karen Dybkær, Carlo Visco, Dehui Zou, Xiao-xiao Wang, Yi Xia, Ling Li, Alexander Tzankov, Ganiraju C. Manyam, Qipan Deng, and Zijun Y. Xu-Monette
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Purpose: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.Experimental Design: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP–treated patients.Results: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3′ untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.Conclusions: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593–605. ©2016 AACR.
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- 2023
8. Supplement Figures 1 - 5 and Tables 1 - 6 from Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma
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Ken H. Young, L. Jeffrey Medeiros, Jane N. Winter, Miguel A. Piris, Michael B. Møller, John P. Farnen, Francesco Bertoni, Andrés J.M. Ferreri, Maurilio Ponzoni, Xiaoying Zhao, Jooryung Huh, J. Han van Krieken, William W.L. Choi, Eric D. Hsi, Kristy L. Richards, Govind Bhagat, Youli Zu, Attilio Orazi, April Chiu, Karen Dybkær, Santiago Montes-Moreno, Carlo Visco, Ling Li, Ganiraju C. Manyam, Alexandar Tzankov, Zijun Y. Xu-Monette, Jiayu Chen, and Chi Young Ok
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Supplementary Figure 1. Morphology and immunophenotype of pSTAT3+ DLBCL. Supplementary Figure 2. Relationship between STAT3 mRNA and pSTAT3 expression and survival analysis based on STAT3 mRNA level. Supplementary Figure 3. Survival analyses based on pSTAT3 expression in DLBCL with MYC/BCL2 double expression and DLBCL without MYC/BCL2 double expression after COO stratification. Supplementary Figure 4. Overall survival (OS) and progression-free survival (PFS) in all DLBCL cases, DLBCL with germinal center B-cell-like phenotype (GCB) and DLBCL with activated B-cell-like phenotype (ABC). Supplementary Figure 5. Survival analyses in 3 and 4 groups based on pSTAT3 expression in lymphoma cells. Supplementary Table 1. Number of cases based on pSTAT3 expression, MYC/BCL2 double expression and COO classification Supplementary Table 2. The numbers and percentages of pSTAT3 positive DLBCL with each cutoff Supplementary Table 3. Clinical characteristics and cell-of-origin differentiation with 30% cutoff for pSTAT3 expression Supplementary Table 4. Distribution of cell-of-origin classification based on 4 groups of pSTAT3 expression in lymphoma cells. Supplementary Table 5. Distribution of cell-of-origin classification based on 3 groups of pSTAT3 expression in lymphoma cells. Supplementary Table 6. Bivariate analyses of pSTAT3 with each variable and pSTAT3.
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- 2023
9. Data from NIK Controls Classical and Alternative NF-κB Activation and Is Necessary for the Survival of Human T-cell Lymphoma Cells
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Miguel A. Piris, Purificación Domínguez Franjo, Federico García Bragado, Javier Menarguez Palanca, Teresa Flores, Rafael Ramos-Asensio, Juan Carlos Solera-Arroyo, Francisca Iniesta-Martínez, Socorro M. Rodríguez-Pinilla, Jose Rodriguez, Pablo L. Ortiz-Romero, Lydia Sánchez-Verde, Raquel Pajares, Esperanza Martín-Sánchez, Santiago Montes-Moreno, Margarita Sánchez-Beato, and Lina Odqvist
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Purpose: Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB–inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas.Experimental Design: We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability.Results: We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors.Conclusions: The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies. Clin Cancer Res; 19(9); 2319–30. ©2013 AACR.
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- 2023
10. Supplementary Methods, Tables 1 - 6, Figures 1 - 6 from NIK Controls Classical and Alternative NF-κB Activation and Is Necessary for the Survival of Human T-cell Lymphoma Cells
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Miguel A. Piris, Purificación Domínguez Franjo, Federico García Bragado, Javier Menarguez Palanca, Teresa Flores, Rafael Ramos-Asensio, Juan Carlos Solera-Arroyo, Francisca Iniesta-Martínez, Socorro M. Rodríguez-Pinilla, Jose Rodriguez, Pablo L. Ortiz-Romero, Lydia Sánchez-Verde, Raquel Pajares, Esperanza Martín-Sánchez, Santiago Montes-Moreno, Margarita Sánchez-Beato, and Lina Odqvist
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PDF file - 1756K, Supplementary Materials and Methods; Table S1: Antibodies and conditions for immunohistochemistry; Table S2: Multivariate Cox analysis; Table S3: Immunohistochemical staining of NF-κB in T cell lymphoma cell lines; Table S4: Pathways positively correlated with NIK expression in PTCL; Table S5: Gene Sets enriched in control cells after NIK knockdown in MyLa and SR-786 cells; Table S6: Genes with altered expression after NIK knockdown; Figure S1: Overall survival in PTCL-NOS and AITL; Figure S2: p100 and p105 levels after NIK knockdown; Figure S3: Cell cycle alterations induced by NIK knockdown; Figure S4: Knockdown of IKKα and IKKβ in SR-786; Figure S5: Efficiencies of NIK knockdown; Figure S6: IL6 and IL21 levels in PTCL cell lines.
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- 2023
11. Kikuchi–Fujimoto disease type lymph node reaction with increased plasmacytoid dendritic cells may appear as a side effect following COVID-19 vaccination: Report of a case and literature review
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Germán Moreno de Juan, Amaia Pérez Del Barrio, Eduardo Germán Herrera Romero, Mario González Ruiz, and Santiago Montes Moreno
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Pathology and Forensic Medicine - Published
- 2023
12. BCL2 translocation in high grade B cell lymphoma (NOS, DH/TH) is associated with reduced progression free survival
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Jorge Gayoso Cruz, Reyes Arranz, Alejandro Martín, Mariana Bastos, Oscar Blanco, Pau Abrisqueta, Gustavo Tapia, Sonia González de Villambrosia, Grupo Español de linfomas y trasplante, Andres Lopez, Ana García-Noblejas, Magdalena Adrados, Javier Menarguez Palanca, Josep Castellví, Sara Alvarez Alonso, Santiago Montes-Moreno, and José-Tomás Navarro
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Cancer Research ,medicine.medical_specialty ,business.industry ,High grade B-cell lymphoma ,Chromosomal translocation ,Hematology ,First line treatment ,Oncology ,hemic and lymphatic diseases ,Molecular genetics ,Cancer research ,Medicine ,Progression-free survival ,Stage (cooking) ,Who classification ,business ,Survival analysis - Abstract
High Grade B Cell Lymphoma, NOS, and High Grade B Cell Lymphoma with Dual Hit or Triple Hit have been recently recategorized in the 2016 revision of the WHO classification of lymphoid neoplasms. In this study we have characterized the genetic, histopathological, and clinical features of a series of this type of lymphoid neoplasia (17 HGBCL NOS and 53 HGBCL DH/TH).HGBCL NOS showed better response to first line treatment than HGBCL with DH/TH but no significant differences in PFS or OS were found between the two categories. Survival analysis in the whole cohort of cases found that only the presence of BCL2 translocation was significantly associated with PFS. Other clinical features such as IPI, LDH or stage were equivalent in both categories. Furthermore, both high grade and DLBCL morphological patterns showed equivalent PFS and OS in this set of High grade BCL NOS/DH/TH.Key pointsBCL2 translocation in High Grade B Cell Lymphoma NOS and High Grade B Cell Lymphoma with DH/TH is associated with reduced progression free survival.Both high grade and DLBCL morphological patterns showed equivalent outcome regarding PFS and OS in HGBCL.
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- 2021
13. Idiopathic Multicentric Castleman Disease Interactive Disease Awareness and Educational Tool for Pathologists
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Elena Sabattini, Jadee Neff, Daisy Alapat, Thomas Tousseyn, Grzegorz Rymkiewicz, Henrique Moura de Paula, Kateřina Kamarádová, Santiago Montes Moreno, and Stephen Lade
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
14. From Castleman disease histopathological features to idiopathic multicentric Castleman disease: a multiparametric approach to exclude potential iMCD histopathological mimickers
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Laura Rodriguez Merino, Aitana Avendaño Pomares, Jose Revert Arce, and Santiago Montes-Moreno
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General Medicine ,Pathology and Forensic Medicine - Abstract
AimsInternational consensus diagnostic criteria for idiopathic multicentric Castleman disease (iMCD) includes lymph node Castleman disease (CD) histopathological features as major criteria. Our aim was to apply those criteria in a series of 42 cases with CD to find differences among unicentric CD, iMCD, HHV-8+multicentric CD (HHV-8+MCD) and POEMS/plasma cell neoplasia (PCN)-associated CD.MethodsAvailable clinical and laboratory criteria were collected. Histopathological features (germinal centre hyperplasia/regression, plasmacytosis, hypervascularity and follicular dendritic cell (FDC) prominence) were graded and immunohistochemistry with antibodies against CD20, CD3, CD138, HHV-8, Ig isotype (IgG, IgG4, IgA, IgM, IgD), kappa, lambda was performed in all cases.ResultsFourteen cases had hyaline-vascular type unicentric CD, 15 were HHV-8+MCD, 7 cases PCN/POEMS-associated CD and 5 cases were iMCD. One case was consistent with systemic lupus erythematosus (SLE) lymphadenopathy. Differences in grading of the CD-associated histopathological features showed that FDC proliferation was prominent in unicentric CD, hypervascularity was increased in HHV-8 positive MCD and germinal centre hyperplasia was restricted to iMCD cases and SLE. Monotypic plasma cells were readily identifiable in the lymph node biopsies in 43% of PCN/POEMS-associated CD. All three cases had lambda light chain restriction with IgA (two cases) and IgG (one case) isotypes.ConclusionsHHV-8+ MCD and PCN/POEMS-related CD are the major mimickers of iMCD in lymph node biopsies. Grading of the five histopathological features for CD might be useful to, in conjunction with complete ancillary testing, suggest for specific disease entities.
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- 2023
15. CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma
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Giovanna Roncador, Joan Puñet-Ortiz, Lorena Maestre, Luis Gerardo Rodríguez-Lobato, Scherezade Jiménez, Ana Isabel Reyes-García, Álvaro García-González, Juan F. García, Miguel Ángel Piris, Santiago Montes-Moreno, Manuel Rodríguez-Justo, Mari-Pau Mena, Carlos Fernández de Larrea, and Pablo Engel
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Limfomes ,B cells ,Cancer Research ,Leukemia ,Cèl·lules B ,Biochemical markers ,Mieloma múltiple ,Leucèmia ,Limfòcits ,Oncology ,Multiple myeloma ,hemic and lymphatic diseases ,Marcadors bioquímics ,Lymphomas ,Lymphocytes ,leukemia ,lymphoma ,myeloma ,CD229 ,Ly9 ,soluble receptor - Abstract
CD229 is a cell-surface molecule predominantly expressed on lymphocytes. Its expression in B-cell malignancies is poorly known. We tested the presence of this immunoreceptor on a large number of malignancies and normal tissue using a new monoclonal antibody and tissue microarrays. Our data show that CD229 expression is restricted to hematopoietic cells. It was strongly expressed in myeloma and marginal-zone lymphomas. Because of the high expression on multiple myeloma cells, we also analyze the presence of soluble CD229 in the sera of these patients. We showed that serum levels of soluble CD229 in myeloma patients, at the time of diagnosis, could be useful as a prognostic biomarker. Altogether, our results indicate that CD229 represents not only a useful disease biomarker but also an attractive therapeutic target. CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a regulator of the development of marginal-zone B cells and other innate-like T and B lymphocytes. The expression on leukemias and lymphomas remains poorly understood due to the lack of CD229 monoclonal antibodies (mAb) for immunohistochemistry application (IHC). In this study, we used a new mAb against the cytoplasmic region of CD229 to study the expression of CD229 on normal tissues and B-cell malignancies, including multiple myeloma (MM), using tissue microarrays. We showed CD229 to be restricted to hematopoietic cells. It was strongly expressed in all cases of MM and in most marginal-zone lymphomas (MZL). Moderate CD229 expression was also found in chronic lymphocyte leukemia (CLL), follicular (FL), classic mantle-cell (MCL) and diffuse large B-cell lymphoma. Given the high expression on myeloma cells, we also analyzed for the presence of soluble CD229 in the sera of these patients. Serum levels of soluble CD229 (sCD229) at the time of diagnosis in MM patients could be useful as a prognostic biomarker. In conclusion, our results indicate that CD229 represents not only a useful biomarker but also an attractive therapeutic target.
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- 2022
16. An integrated prognostic model for diffuse large B-cell lymphoma treated with immunochemotherapy
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Marta Rodríguez, Ruth Alonso‐Alonso, Ismael Fernández‐Miranda, Rufino Mondéjar, Laura Cereceda, Álvaro Tráscasa, Anabel Antonio‐Da Conceiçao, Jennifer Borregón, Lucía Gato, Laura Tomás‐Roca, Carmen Bárcena, Begoña Iglesias, Fina Climent, Eva González‐Barca, Francisca Inmaculada Camacho, Émpar Mayordomo, Gabriel Olmedilla, Pilar Gómez‐Prieto, Yolanda Castro, Juana Serrano‐López, Joaquín Sánchez‐García, Santiago Montes‐Moreno, Mónica García‐Cosío, Paloma Martín‐Acosta, Juan F. García, María Planelles, Cristina Quero, Mariano Provencio, Ignacio Mahíllo‐Fernández, Socorro M. Rodríguez‐Pinilla, Enrico Derenzini, Stefano Pileri, Margarita Sánchez‐Beato, Raúl Córdoba, Miguel A. Piris, and Universidad de Cantabria
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DLBCL ,Gene expression ,Diffuse large B-cell lymphoma ,General Medicine ,Immunochemotherapy ,Prognosis - Abstract
Diffuse large B-cell lymphoma (DLBCL), the most frequent non-Hodgkin's lymphoma subtype, is characterized by strong biological, morphological, and clinical heterogeneity, but patients are treated with immunochemotherapy in a relatively homogeneous way. Here, we have used a customized NanoString platform to analyze a series of 197 homogeneously treated DLBCL cases. The platform includes the most relevant genes or signatures known to be useful for predicting response to R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) in DLBCL cases. We generated a risk score that combines the International Prognostic Index with cell of origin and double expression of MYC/BCL2, and stratified the series into three groups, yielding hazard ratios from 0.15 to 5.49 for overall survival, and from 0.17 to 5.04 for progression-free survival. Group differences were highly significant (p < 0.0001), and the scoring system was applicable to younger patients (
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- 2022
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17. Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma
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Ainara Pereña Gonzalez, Sanam Loghavi, Joseph D. Khoury, Emanuele d' Ámore, Nerea Martinez Magunacelaya, Sergi Beltran, Sonia González de Villambrosia, Raul Tonda, Julia Garcia-Reyero, Santiago Montes-Moreno, Carlo Visco, Angela Gomez Mediavilla, and Marta Gut
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STAT3 Transcription Factor ,Epstein-Barr Virus Infections ,Carcinogenesis ,Population ,Aggressive Non-Hodgkin's Lymphoma ,Gene mutation ,Biology ,Translocation, Genetic ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,PRDM1 ,Tumor Microenvironment ,medicine ,Humans ,B-cell lymphoma ,education ,EP300 ,education.field_of_study ,Point mutation ,Targeted NGS ,Hematology ,CD79B ,medicine.disease ,Immune microenvironment ,Oncogene activation ,030220 oncology & carcinogenesis ,Cancer research ,Plasmablastic lymphoma ,030215 immunology - Abstract
The mutational profile of plasmablastic lymphoma has not been described. We performed a targeted, exonic next-generation sequencing analysis of 30 plasmablastic lymphoma cases with a Bcell lymphoma-dedicated panel and fluorescence in situ hybridization for the detection of MYC rearrangements. Complete phenotyping of the neoplastic and microenvironmental cell populations was also performed. We identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and three cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in Epstein-Barr virus (EBV)-positive disease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed consistent MYC expression, which was higher in cases with MYC rearrangements, together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironmental cell populations were heterogeneous and unrelated to EBV, with enrichment of tumor-associated macrophages (TAM) and PD1-positive T cells. PD-L1 was expressed in all cases in the TAM population but only in the neoplastic cells in five cases (4 of 14 EBV-positive cases). HLA expression was absent in the majority of cases of plasmablastic lymphoma. In summary, the mutational profile of plasmablastic lymphoma is heterogeneous and related to EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV-positive disease. An enrichment in TAM and PD1 reactive T lymphocytes is found in the microenvironment of plasmablastic lymphoma and a fraction of the neoplastic cells express PD-L1.
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- 2020
18. Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis
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Maurilio Ponzoni, German Ott, John R. Goodlad, Judith A. Ferry, Alexandra Traverse-Glehen, Ilske Oschlies, Maria Calaminici, Rebecca L. King, Snjezana Dotlic, and Santiago Montes-Moreno
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Lymphoma ,Breast Implants ,Immune Privilege ,Biology ,Education ,Pathology and Forensic Medicine ,Central Nervous System Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Testicular Neoplasms ,Immune privilege ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,B-cell lymphoma ,Molecular Biology ,Anaplastic large-cell lymphoma ,B cell ,Cell Biology ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Testicular Lymphoma ,030220 oncology & carcinogenesis ,Lymphoma, Large-Cell, Anaplastic ,Female ,Lymphoma, Large B-Cell, Diffuse ,Hematopathology ,Diffuse large B-cell lymphoma ,Signal Transduction - Abstract
Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.
- Published
- 2019
19. Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas
- Author
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Snjezana Dotlic, Ilske Oschlies, Judith A. Ferry, Alexandra Traverse-Glehen, German Ott, Rebecca L. King, Santiago Montes-Moreno, Maria Calaminici, Maurilio Ponzoni, and John R. Goodlad
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Follicular lymphoma ,Lymphoproliferative disorders ,Lymphoma, T-Cell ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,T-cell lymphoma ,Oncogene Fusion ,B-cell lymphoma ,Molecular Biology ,B cell ,Gastrointestinal tract ,business.industry ,MALT lymphoma ,Lymphoma, B-Cell, Marginal Zone ,Cell Biology ,General Medicine ,medicine.disease ,Lymphoproliferative Disorders ,Gastrointestinal Tract ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mantle cell lymphoma ,business - Abstract
This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as STAT3-JAK2 fusion. In addition, novel clonal markers of disease, such as AXL and JAK3 somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with IRF4 translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e., CCND3-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.
- Published
- 2019
20. Systemic Mastocytosis with Associated Hematological Neoplasms. Diagnostic features and unique response pattern to tyrosine kinase inhibitors and allo-bone marrow transplantation therapy
- Author
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Santiago Montes Moreno, Andrés Insunza Gaminde, Sonia González de Villambrosia, and Irene Hernández Alconchel
- Subjects
Bone marrow transplantation ,medicine.diagnostic_test ,business.industry ,Mast cell ,medicine.disease ,Pathology and Forensic Medicine ,medicine.anatomical_structure ,Biopsy ,Cancer research ,Medicine ,Hematological neoplasm ,Bone marrow ,Systemic mastocytosis ,Stem cell ,business ,Tyrosine kinase - Abstract
Systemic Mastocytosis is a clonal proliferation of mast cells; in a significant fraction of cases it is associated with another concurrent hematological neoplasm. Molecular analysis of KIT mutations and other associated genetic alterations suggest a common origin in the stem cell compartment. Mast cell infiltration patterns in bone marrow biopsy may be subtle in cases associated with t (8;21) AML. Here we report three cases of clonally related SM-AHN, two cases with SM-CMML and one case with SM- t (8;21) AML. We describe in detail the bone marrow infiltration pattern at diagnosis and during the course of treatment with allogeneic stem cell transplant and novel TK inhibitors, showing the unique dynamics of mast cell clearance after therapy.
- Published
- 2021
21. UPDATED RESULTS OF A PHASE 2 STUDY FROM GELTAMO INVESTIGATING THE COMBINATION OF IBRUTINIB WITH R‐GEMOX IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA
- Author
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R. Andreu, B. Rey Búa, Eva Giné, J. J. Sánchez Blanco, F. de la Cruz, A. Martín García-Sancho, I. Zeberio Etxetxipia, Án. Ramírez‐Páyer, MJ Peñarrubia, Arantxa Gutiérrez, C. Grande, Santiago Montes-Moreno, Miguel Ángel Ramírez, Pau Abrisqueta, M. D. Caballero Barrigón, Ana Jiménez-Ubieto, Maria Cruz Viguria, A. De la Fuente, and M. José Terol
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Hematology ,General Medicine ,GemOx ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,Medicine ,Refractory Diffuse Large B-Cell Lymphoma ,In patient ,business - Published
- 2021
22. ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer
- Author
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Javier Freire, Carlos Revilla, Pablo Isidro, Ignacio Varela, Rosa M. Blanco, Paola Scaffidi, Laura González-Silva, Javier Gómez-Román, Thaidy Moreno, Berta Casar, Antonio Agraz-Doblas, Laura Cereceda, Eduardo Salido, Cristina Morales Torres, Isabel Betancor-Fernández, Piero Crespo, Beatriz Monterde, Laura Quevedo, Aurora Astudillo, Santiago Montes-Moreno, Universidad de Cantabria, Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, European Research Council, Ministerio de Educación y Formación Profesional (España), Centro de Investigación Biomédica en Red Cáncer (España), Asociación Española Contra el Cáncer, Fundación Francisco Cobos, Cancer Research UK, Medical Research Council (UK), Principado de Asturias, Instituto de Salud Carlos III, Obra Social Cajastur, and Wellcome Trust
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Cell ,Nude ,Mice ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Aetiology ,Lung ,Cancer ,Tumor ,Lung Cancer ,High-Throughput Nucleotide Sequencing ,Chromatin ,SWI/SNF ,Survival Rate ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Tumor suppressor gene ,DNA repair ,Clinical Sciences ,Oncology and Carcinogenesis ,Mice, Nude ,Chromatin remodelling ,Biology ,Next-generation sequencing technologies ,Chromatin remodeling ,Article ,Target validation ,Cell Line ,03 medical and health sciences ,Rare Diseases ,ARID2 ,Cell Line, Tumor ,medicine ,Genetics ,Animals ,Humans ,Oncology & Carcinogenesis ,Lung cancer ,Molecular Biology ,medicine.disease ,030104 developmental biology ,Tumor progression ,A549 Cells ,Cancer research ,Non-small-cell lung cancer ,Transcription Factors - Abstract
The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically., IV is supported by SAF2012-31627 and SAF2016-76758-R grants from the Spanish Ministerio de Economía y Competitividad (MINECO), by a Fundación Ramón Areces grant and by ERC2014-StG637904 grant from the European Research Council. IV has been awardee of the Programa Ramón y Cajal (MINECO, Spain). TM has been awardee of the Ayudas para la contratación de investigadores predoctorales (MINECO, Spain). BM is awardee of the Ayudas para la formación de profesorado universitario (FPU, Ministerio de Educación y Formación Profesional, Spain). PC laboratory is supported by grant SAF-2015-63638R (MINECO/FEDER, UE); by Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113. BC has been supported by a Retos Jóvenes Investigadores grant SAF-2015-73364-JIN (AEI/FEDER, UE) and a grant from Fundación Francisco Cobos. PS is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152) and the UK Medical Research Council (FC001152). HUCA/IUOPA is jointly financed by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III, and Fundación Bancaria Cajastur. This research was funded in part by the Wellcome Trust [FC001152].
- Published
- 2021
23. Pathological fracture from clinically occult breast cancer
- Author
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Marta Fernández-Ayala, Ismael Abascal Carrera, Elena Casuso Sáenz, Santiago Montes-Moreno, Miguel F Carrascosa, Marta Cano Hoz, and José Manuel López-Vega
- Subjects
medicine.medical_specialty ,business.industry ,MEDLINE ,Breast Neoplasms ,medicine.disease ,Prognosis ,Occult ,Breast cancer ,Text mining ,Fractures, Spontaneous ,Oncology ,medicine ,Humans ,Female ,Radiology ,business ,Pathological ,Aged - Published
- 2021
24. ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer
- Author
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Paola Scaffidi, Santiago Montes-Moreno, Pablo Isidro, Antonio Agraz-Doblas, Ignacio Varela, Berta Casar, Laura Cereceda, Isabel Betancor-Fernández, Beatriz Monterde, Eduardo Salido, Laura González-Silva, Thaidy Moreno, Javier Gómez-Román, Aurora Astudillo, Javier Freire, Carlos Revilla, Cristina Morales Torres, Laura Quevedo, and Piero Crespo
- Subjects
0303 health sciences ,Tumor suppressor gene ,business.industry ,DNA repair ,Poly ADP ribose polymerase ,Cancer ,medicine.disease ,Chromatin remodeling ,3. Good health ,Chromatin ,03 medical and health sciences ,0302 clinical medicine ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Lung cancer ,030304 developmental biology - Abstract
The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. Last decade’s research has evidenced a clear role of chromatin structure in cancer development and several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown.In this study, we have performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure, as well as functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development.We have identified ARID2 production loss in 20% of lung cancer patients. Additionally, we have shown that ARID2-deficiency provokes profound chromatin structural changes, alters the transcriptional programme and impairs DNA repair which bolster the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we have demonstrated that ARID2 deficiency significantly affects the sensitivity of the cells to PARP inhibition.All these results support that ARID2 is a bona-fide tumor suppressor gene in lung cancer that might be exploited therapeutically.
- Published
- 2020
25. High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations
- Author
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Scherezade Jiménez, Miguel A. Piris, Patricia González-García, Alberto J. Arribas, Santiago Montes-Moreno, Lorena Maestre, Eduardo Caleiras, Giovanna Roncador, Alison H. Banham, Álvaro García-González, Juan Fernando García-García, Ana Isabel Reyes-García, European Commission, Comunidad de Madrid (España), Instituto de Salud Carlos III - ISCIII, Comunidad de Madrid, and Instituto de Salud Carlos III
- Subjects
0301 basic medicine ,Male ,B Cells ,Physiology ,Chronic lymphocytic leukemia ,Protein Expression ,Follicular lymphoma ,Gene Expression ,Hematologic Cancers and Related Disorders ,White Blood Cells ,Antibodies, Monoclonal, Murine-Derived ,Mice ,fluids and secretions ,0302 clinical medicine ,Animal Cells ,immune system diseases ,Antibody Specificity ,T-Lymphocyte Subsets ,Immune Physiology ,hemic and lymphatic diseases ,Medicine and Health Sciences ,Lymph node ,Staining ,Multidisciplinary ,T Cells ,High Mobility Group Proteins ,Cell Staining ,Hematology ,Marginal zone ,Thymocyte ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Lymphomas ,Female ,Cellular Types ,Anatomy ,Research Article ,Lymphoma, B-Cell ,Lymphoid Tissue ,Immune Cells ,Science ,T cell ,Immunology ,B-Lymphocyte Subsets ,Biology ,Research and Analysis Methods ,Lymphoma, T-Cell ,Lymphatic System ,03 medical and health sciences ,Cell Line, Tumor ,Gene Expression and Vector Techniques ,medicine ,Animals ,Humans ,RNA, Messenger ,Rats, Wistar ,Antibody-Producing Cells ,Molecular Biology Techniques ,Immunohistochemistry Techniques ,Molecular Biology ,Molecular Biology Assays and Analysis Techniques ,Blood Cells ,Biology and Life Sciences ,Cancers and Neoplasms ,Cell Biology ,medicine.disease ,Lymphoma ,Rats ,Histochemistry and Cytochemistry Techniques ,Mice, Inbred C57BL ,030104 developmental biology ,Specimen Preparation and Treatment ,Immunologic Techniques ,Cancer research ,bacteria ,Lymph Nodes ,Spleen - Abstract
Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype. This work was supported by grants from the Plan Nacional de I+D+I, co-financed by the ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER), CIBERONC -CB16/12/00291 (MAP), and Programs of R&D activities among research groups of the Community of Madrid in Biomedicine (B2017/BMD-3778) (MAP, GR, JFGG). All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí
- Published
- 2020
26. Diagnostic value of bone marrow core biopsy patterns in lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia and description of its mutational profiles by targeted NGS
- Author
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Sergi Beltran, Marta Gut, Raul Tonda, Ainara Pereña Gonzalez, Andrés Insunza, Angela Gomez Mediavilla, Marcela Urquieta Lam, Santiago Montes-Moreno, Sonia González de Villambrosia, Julia Garcia-Reyero, and Nerea Martinez Magunacelaya
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Lymphoma ,Biopsy ,Monoclonal Gammopathy of Undetermined Significance ,Pathology and Forensic Medicine ,Lymphoplasmacytic Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Gammopathy ,medicine ,Humans ,Alleles ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Molecular pathology ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Immunohistochemistry ,Histopathology ,Female ,Bone marrow ,Waldenstrom Macroglobulinemia ,business - Abstract
AimsThe aim of this study was to describe the characteristics of the bone marrow infiltration found in a series of clinically defined lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia (WM) and IgM-monoclonal gammopathy of undetermined significance (MGUS) and to perform a targeted next-generation sequencing (NGS) for the identification of additional somatic mutations to MYD88p.L265P in LPL/WM.MethodsWe have reviewed a series of 35 bone marrow biopsies from 28 patients with a clinical diagnosis of LPL/WM (24 cases) or MGUS (4 cases). Bone marrow infiltration characteristics by morphology, immunohistochemistry, flow cytometry (FCM), allele-specific real-time PCR for the detection of MYD88p.L265P mutation, targeted exonic amplicon-based NGS of 35 lymphoma-related genes and direct sequencing were analysed.ResultsOur findings show that bone marrow trephine biopsy evaluation is superior to FCM in the identification of significant lymphoid infiltrates. A combined paratrabecular and interstitial infiltration pattern is the most common feature in LPL/WM while a patchy interstitial pattern characterises IgM-MGUS cases. MYD88p.L265P mutation was found by allele-specific-PCR in 92% of the LPL cases (22 out of 24) and 25% of IgM-MGUS cases (1 out of 4 cases). In addition to MYD88p.L265P somatic mutations in CXCR4, KMT2D, PRDM1/Blimp1, MYC and ID3 were found by NGS and direct sequencing in 4 cases.ConclusionsIn conclusion, bone marrow core biopsy evaluation is critical in the identification of unequivocal bone marrow infiltration by LPL/WM. In addition to MYD88p.L265P, somatic mutations in CXCR4, KMT2D, PRDM1/Blimp1, MYC and ID3 can appear in a fraction of LPL/WM.
- Published
- 2019
27. Richter transformation driven by Epstein-Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia
- Author
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Felipe Prosper, Ana Balanzategui, María José Larrayoz, Miguel A. Piris, Jose A. Martinez-Climent, Shuhua Yi, Sebastian Böttcher, Ken H. Young, María José Calasanz, Victor Segura, Antonio Martinez, Blanca Gonzalez-Farre, Marta Larrayoz, Cristina Jimenez, Davide Rossi, Jesús F. San Miguel, Jesús M. Hernández-Rivas, Julie Morscio, María José García-Barchino, Mingzhi Zhang, María Eugenia Sarasquete, Thomas Tousseyn, Marcos González, Alberto Orfao, Zijun Y. Xu-Monette, Santiago Montes-Moreno, Noemi Puig-Moron, Jon Celay, Miguel Alcoceba, Idoia Rodriguez, Xavier Sagaert, Bruno Paiva, Eloy F. Robles, Carlos Panizo, Gianluca Gaidano, Jianyong Li, Ricardo García-Muñoz, Sergio Roa, Vicente Fresquet, and M. Rabasa
- Subjects
0301 basic medicine ,Ganciclovir ,Lymphocytosis ,medicine.medical_treatment ,medicine.disease_cause ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,neoplasms ,business.industry ,Immunosuppression ,medicine.disease ,Epstein–Barr virus ,Fludarabine ,Lymphoma ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Monoclonal ,Cancer research ,medicine.symptom ,business ,medicine.drug - Abstract
The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2-/- IL2γc-/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2018
28. Castleman Disease and Rosai-Dorfman Disease
- Author
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Santiago Montes-Moreno, Miguel A. Piris, Elena Aguirregoicoa, and Catuxa Celeiro-Muñoz
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Follicular dendritic cells ,business.industry ,Castleman Disease ,Castleman disease ,Russell bodies ,Plasma cell ,medicine.disease ,Pathology and Forensic Medicine ,Emperipolesis ,03 medical and health sciences ,Histiocytosis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Humans ,Histiocytosis, Sinus ,business ,Histiocyte ,Rosai–Dorfman disease - Abstract
This chapter describes the main features of two different diseases, Castleman Disease (CD) and Rosai-Dorfman Disease (RDD). Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder that encompasses at least three distinct entities with some common overlapping morphological features: Hyaline Vascular CD (HVCD), Unicentric Plasma Cell CD and Multicentric CD. The most important feature of HVCD is the presence of abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, this outlining HVCD as a disorder of follicular dendritic cells. Unicentric and multicentric CD are, in contrast, lymphoproliferative lesions. Proinflammatory hypercytokinemia is an essential feature of multicentric CD, distinguished by a florid clinical presentation. Rosai-Dorfmann Disease is a histiocytic proliferative disorder diagnosed by the presence of tissue infiltration by S100-positive CD1a-negative histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis. Initially considered to be an inflammatory/reactive condition, molecular studies suggest that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process.
- Published
- 2018
29. Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1
- Author
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Laura Cereceda-Company, Santiago Montes-Moreno, Ana Batlle, Carmen Almaraz, Miguel A. Piris, Nerea Martínez-Magunacelaya, Sonia González de Villambrosia, Tomás Zecchini-Barrese, Tamara Ranchal, Jose Bernardo Revert-Arce, Emma Linares, and María Rodríguez-Pinilla
- Subjects
Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,HIV Infections ,Chromosomal translocation ,Biology ,medicine.disease_cause ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,PRDM1 ,medicine ,Humans ,Neoplasm ,B-cell lymphoma ,Aged ,Aged, 80 and over ,Age Factors ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,Phenotype ,Lymphoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,Plasmablastic Lymphoma ,Cancer research ,Female ,Positive Regulatory Domain I-Binding Factor 1 ,Carcinogenesis ,Plasmablastic lymphoma - Abstract
Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (~60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PRDM1-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimp1α protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1α owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.
- Published
- 2017
30. Angioimmunoblastic T-cell lymphoma with a clonal plasma cell proliferation that underwent immunoglobulin isotype switch in the skin, coinciding with cutaneous disease progression
- Author
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Ana E. Suárez, Carlos Santonja, P. De Pablo, Miguel A. Piris, María-Jesús Artiga, Luis Requena, Socorro María Rodríguez-Pinilla, and Santiago Montes-Moreno
- Subjects
Pathology ,medicine.medical_specialty ,Angioimmunoblastic T-cell lymphoma ,Histology ,CD30 ,medicine.diagnostic_test ,business.industry ,Lymph node biopsy ,Dermatology ,Plasma cell ,medicine.disease ,BCL6 ,Peripheral T-cell lymphoma ,Pathology and Forensic Medicine ,Lymphoma ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,T-cell lymphoma ,business - Abstract
Plasma cell proliferations in specific cutaneous lesions of angioimmunoblastic T-cell lymphoma(AITL) are very uncommon. Here, we report a case of clonal plasma cell proliferation in skin with heavy-chain-immunoglobulin-isotype-switch after cutaneous disease progression. Histopathologically, initial plaque lesions were suggestive of marginal-zone B-cell-lymphoma. Nevertheless, this 77-year-old lady was diagnosed with AITL after the progression of skin lesions from plaques to nodular tumors. A lymph node biopsy confirmed the diagnosis. Both cutaneous specimens showed a polymorphic cellular infiltrate with atypical T-cell-lymphocytes arranged in a pseudonodular pattern that expressed CD3, PD1 and BCL6, with patchy expression of CD30. Interestingly, a slight IgG-Lambda plasma cell component was seen at the periphery of the infiltrate in the first specimen which increased in number in the later nodular lesion, showing not only Lambda light chain restriction and IgG but also IgG4. PCR studies for IgH and TCR genes showed an IgH clonal peak on both skin lesions but not on lymph node biopsy. On the contrary, the same clonal TCR peak was found in the three specimens. Neoplastic follicular helper T-cells within cutaneous-specific microenvironment could be responsible for the modulation of the immunoglobulin isotype class switch change. Further studies are needed to support this hypothesis.
- Published
- 2016
31. The clinico-pathological spectrum of primary cutaneous lymphoma other than mycosis fungoides/Sezary syndrome
- Author
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Judith A. Ferry, Alexandra Traverse-Glehen, Maria Calaminici, Rebecca L. King, Santiago Montes-Moreno, German Ott, John R. Goodlad, Maurilio Ponzoni, Snjezana Dotlic, and Ilske Oschlies
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Lymphoma, B-Cell ,Skin Neoplasms ,T cell ,Lymphoproliferative disorders ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Molecular Biology ,B cell ,Mycosis fungoides ,Leukemia ,business.industry ,Cell Biology ,General Medicine ,medicine.disease ,Dermatology ,Lymphoproliferative Disorders ,Lymphoma, T-Cell, Cutaneous ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Clinico pathological ,business ,Hematopathology ,CD8 ,Rare disease - Abstract
The major aim of Session 1 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop was to collect examples of cutaneous lymphomas, excluding mycosis fungoides/Sezary syndrome, as defined in the current WHO classification of tumours of the haemetopoietic and lymphoid tissues. Overall 42 cases were submitted. These were considered in four main categories: primary cutaneous B cell lymphomas (12 cases), primary cutaneous T cell lymphomas/lymphoproliferations with CD8+/cytotoxic phenotype (12 cases), primary cutaneous CD30-positive lymphoproliferative disorders (15 cases) and primary cutaneous T cell lymphomas/leukaemias with CD4+ phenotype (4 cases). Using these cases as examples, we were able to present the full spectrum of cutaneous lymphoproliferations (excluding mycosis fungoides/Sezary syndrome), including examples of rare, provisional and new entities as listed in the 2017 update of the WHO classification. The findings are summarized in this report with emphasis on differential diagnostic considerations and the importance of clinico-pathological correlation for final subtyping. In presenting these findings we hope to raise awareness of this enigmatic group of neoplasms and to further our understanding of these rare disease entities.
- Published
- 2019
32. Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma
- Author
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Paloma Martín, Mariano Provencio, Manuela Mollejo, David Pérez-Callejo, Lucia Pedrosa, José Gómez-Codina, Juan F. García, Javier Menárguez, Carmen Bárcena, Luis de la Cruz-Merino, Antonio Rueda, Sagrario Gómez, Margarita Sánchez-Beato, Ana Royuela, Francisca I. Camacho, Cristina Quero, Consuelo Parejo, Alberto J. Arribas, Delvys Rodriguez-Abreu, Julia González-Rincón, Luciano Cascione, Ivo Kwee, Francesco Bertoni, Marta Llanos, Silvia Monsalvo, Carmen Bellas, Santiago Montes-Moreno, Socorro María Rodríguez-Pinilla, Miriam Mendez, and Miguel A. Piris
- Subjects
Male ,B Cells ,Cell Lines ,Biopsy ,Follicular lymphoma ,medicine.disease_cause ,Hematologic Cancers and Related Disorders ,White Blood Cells ,Animal Cells ,Medicine and Health Sciences ,Copy-number variation ,Frameshift Mutation ,Lymphoma, Follicular ,B-Lymphocytes ,Mutation ,Multidisciplinary ,Massive parallel sequencing ,Cell Differentiation ,Hematology ,Genomics ,Diffuse large B-cell lymphoma ,Middle Aged ,Copy Number Variation ,Neoplasm Proteins ,Cell Transformation, Neoplastic ,Oncology ,Medicine ,Lymphomas ,Female ,Biological Cultures ,Lymphoma, Large B-Cell, Diffuse ,Cellular Types ,Raji Cells ,Research Article ,Adult ,Follicular Lymphoma ,Immune Cells ,Science ,Immunology ,Surgical and Invasive Medical Procedures ,Biology ,Research and Analysis Methods ,Genome Complexity ,Genetics ,medicine ,Humans ,Antibody-Producing Cells ,Aged ,Blood Cells ,Biology and Life Sciences ,Cancers and Neoplasms ,Computational Biology ,Cell Biology ,medicine.disease ,GNA13 ,Lymphoma ,Transformation (genetics) ,Cancer research ,Follow-Up Studies - Abstract
Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.
- Published
- 2019
33. DUSP22-rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers
- Author
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Socorro María Rodríguez-Pinilla, Arantza Onaindia, Sonia González de Villambrosia, Santiago Montes-Moreno, Lucía Prieto-Torres, Carmen González-Vela, Miguel A. Piris, UAM. Departamento de Anatomía Patológica, and Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
- Subjects
Medicina ,JAK-STAT signaling pathway ,STAT Transcription Factors ,Hematology ,Gene rearrangement ,Biology ,medicine.disease ,Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,Adult genetics ,medicine ,Cancer research ,Cytotoxic T cell ,Neoplasm ,Christian ministry ,Online Only Articles ,Biomarkers ,030215 immunology ,Lynphoma - Abstract
This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Economy and Competence (MINECO, RTICC ISCIII and CIBERONC) (SAF2013-47416- R, RD06/0020/0107-RD012/0036/0060 and Plan Nacional I+D+I: PI16/01294 and PIE15/0081), AECC and the Madrid Autonomous Community.
- Published
- 2019
34. Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group
- Author
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Jorge Gayoso, Javier López-Jiménez, José Rifón, Miguel Canales, Luis Palomera, Mercedes Colorado, Alba Redondo, María Suárez-Lledó, Reyes Arranz, Aurelio López, Raquel Del Campo, Dolores Caballero, Ana P Gonzalez-Rodriguez, Jose Luis Bello, David Valcárcel, María José Ramírez, Armando López-Guillermo, Isidro Jarque, Andrés Sánchez, Alejandro Martín, Javier Briones, Nerea Castro, María José Terol, María José Rodríguez, and Santiago Montes-Moreno
- Subjects
Adult ,Male ,Bendamustine ,Melphalan ,medicine.medical_specialty ,Transplantation Conditioning ,Lymphoma ,BEAM ,Aggressive lymphoma ,autologous stem-cell transplantation ,Gastroenterology ,Disease-Free Survival ,aggressive lymphomas ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Bendamustine Hydrochloride ,Humans ,bendamustine ,Autografts ,Etoposide ,Aged ,Podophyllotoxin ,Peripheral Blood Stem Cell Transplantation ,Carmustine ,business.industry ,Cytarabine ,clinical trial ,Hematology ,Middle Aged ,Survival Rate ,Transplantation ,Regimen ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Abstract
We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 x 10(9)/l and >20 x 10(9)/l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
- Published
- 2018
35. Epstein-Barr virus-associated diffuse large B-cell lymphoma: diagnosis, difficulties and therapeutic options
- Author
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Santiago Montes-Moreno, Ana Battle-Lopez, Sonia González de Villambrosia, Miguel A. Piris, Maria-Luisa Cagigal, Eulogio Conde, and J. Núñez
- Subjects
Male ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,CD30 ,Ki-1 Antigen ,CHOP ,medicine.disease_cause ,Antiviral Agents ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Epstein–Barr virus infection ,B-Lymphocytes ,business.industry ,Prognosis ,medicine.disease ,Epstein–Barr virus ,Lymphoma ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Immunology ,Cancer research ,Female ,Rituximab ,Immunotherapy ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Epstein Barr Virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) most frequently affects elderly patients, without previous immunosuppression, with frequent extra-nodal involvement and whose disease runs an aggressive clinical course with high International Prognostic Index (IPI) scores. Various EBV-related transforming mechanisms, much favored by immunosenescence, have been described, including activation of the NFKB transcriptional program. Elderly patients show poor survival after treatment with conventional CHOP regimens, even after addition of Rituximab. Younger patients, however, have a better outcome with a similar prognosis to EBV-negative DLBCL cases. New therapeutic strategies, including treatments targeting EBV, new drugs directed against specific pathways constitutively activated in these lymphomas, and new specific conjugate antibodies against molecules usually expressed in the tumor cells, such as CD30, are described.
- Published
- 2016
36. CD30 Expression by B and T Cells
- Author
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Socorro María Rodríguez-Pinilla, Antoni Tardio, César Ortega, Lucía González, Arantza Onaindia, Santiago Montes-Moreno, Nerea Martinez, Jose B. Revert, Sonia García, Carmen González-Vela, Carmen Almaraz, Francisca I. Camacho, Laura Cereceda, and Miguel A. Piris
- Subjects
0301 basic medicine ,Angioimmunoblastic T-cell lymphoma ,CD30 ,Biopsy ,T-Lymphocytes ,T cell ,Ki-1 Antigen ,Peripheral T-cell lymphoma not otherwise specified ,Lymphoma, T-Cell ,Immunophenotyping ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,RNA, Messenger ,B-Lymphocytes ,integumentary system ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Gene Expression Profiling ,Lymphoma, T-Cell, Peripheral ,medicine.disease ,Immunohistochemistry ,Lymphoma ,Gene expression profiling ,Reverse transcription polymerase chain reaction ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Immunoblastic Lymphadenopathy ,030220 oncology & carcinogenesis ,Cancer research ,Surgery ,Anatomy ,business - Abstract
CD30 expression in peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL) is currently of great interest because therapy targeting CD30 is of clinical benefit, but the clinical and therapeutic relevance of CD30 expression in these neoplasms still remains uncertain. The aim of this study was to better quantify CD30 expression in AITL and PTCL-not otherwise specified (NOS). The secondary objective was to determine whether CD30 cells exhibit a B-cell or a T-cell phenotype. Gene expression profiling was studied in a series of 37 PTCL cases demonstrating a continuous spectrum of TNFRSF8 expression. This prompted us to study CD30 immunohistochemical (IHC) expression and mRNA levels by reverse transcription polymerase chain reaction (RT-PCR) in a different series of 51 cases (43 AITLs and 8 PTCL-NOSs) in routine samples. Double stainings with PAX5/CD30, CD3/CD30, and LEF1/CD30 were performed to study the phenotype of CD30 cells. Most (90%) of the cases showed some level of CD30 expression by IHC (1% to 95%); these levels were high (>50% of tumoral cells) in 14% of cases. CD30 expression was not detected in 10% of the cases. Quantitative RT-PCR results largely confirmed these findings, demonstrating a moderately strong correlation between global CD30 IHC and mRNA levels (r=0.65, P=1.75e-7). Forty-four of the positive cases (98%) contained CD30-positive B cells (PAX5), whereas atypical CD30-positive T cells were detected in 42 cases (93%). In conclusion, our data show that most AITL and PTCL-NOS cases express CD30, exhibiting very variable levels of CD30 expression that may be measured by IHC or RT-PCR techniques.
- Published
- 2016
37. Correction to: Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas
- Author
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Maria Calaminici, Alexandra Traverse-Glehen, Snjezana Dotlic, Rebecca L. King, Santiago Montes-Moreno, German Ott, Ilske Oschlies, Judith A. Ferry, John R. Goodlad, and Maurilio Ponzoni
- Subjects
Gastrointestinal tract ,medicine.medical_specialty ,business.industry ,Disease spectrum ,medicine ,Lymphoproliferative disorders ,Cell Biology ,General Medicine ,medicine.disease ,business ,Molecular Biology ,Dermatology ,Pathology and Forensic Medicine - Published
- 2020
38. Spontaneously Ruptured Spleen Samples in Patients With Infectious Mononucleosis: Analysis of Histology and Lymphoid Subpopulations
- Author
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Marcos M, Siliézar, Catuxa Celerio, Muñoz, Jon Danel, Solano-Iturri, Laura, Ortega-Comunian, Manuela, Mollejo, Santiago, Montes-Moreno, and Miguel A, Piris
- Subjects
Adult ,Male ,Adolescent ,Lymphoma ,Rupture, Spontaneous ,Splenic Rupture ,Immunohistochemistry ,Diagnosis, Differential ,Young Adult ,Splenectomy ,Humans ,Female ,Infectious Mononucleosis ,Lymphocytes ,Biomarkers ,Follow-Up Studies - Abstract
Spontaneous rupture of the spleen is occasionally seen as the presenting event in infectious mononucleosis (IM). Diagnosis of these cases can be very challenging.We describe the morphologic and immunohistochemical findings in a series of seven splenectomy specimens removed after spontaneous rupture in patients with IM. Most cases were submitted for a second opinion since the histology of the cases suggested malignant lymphoma.All the cases showed similar findings, with red pulp expansion occupied by activated T and B cells, including scattered large lymphocytes with both T- and B-cell markers, together with a polymorphic background rich in cytotoxic T cells. Clonality analysis revealed T-cell receptor clonal patterns in four of the six cases evaluated.IM should be considered a possible diagnosis in any case of splenic rupture whose histology suggests possible aggressive lymphoma.
- Published
- 2018
39. Clonal Evolution in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System
- Author
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Nuria Teran-Villagra, Nerea Martinez Magunacelaya, Sonia González de Villambrosia, Ana Batlle, Ainara Azueta, Jose Revert Arce, Santiago Montes-Moreno, Ainara Gonzalez Pereña, Julia Garcia-Reyero, and Sara Marcos Gonzalez
- Subjects
0301 basic medicine ,Male ,Histology ,Somatic cell ,B-cell receptor ,Receptors, Antigen, B-Cell ,Biology ,Somatic evolution in cancer ,Pathology and Forensic Medicine ,Central Nervous System Neoplasms ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Testicular Neoplasms ,hemic and lymphatic diseases ,Adrenal Glands ,medicine ,Humans ,NF-kappa B ,High-Throughput Nucleotide Sequencing ,CD79B ,Middle Aged ,medicine.disease ,Phenotype ,Temporal Lobe ,Lymphoma ,Medical Laboratory Technology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Myeloid Differentiation Factor 88 ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,Diffuse large B-cell lymphoma ,CD79 Antigens - Abstract
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is an aggressive subtype of DLBCL with characteristic clinicopathologic features. Relapse outside the CNS involving extranodal locations has been found in a fraction of cases (16%). Here we describe a case of DLBCL arising in the CNS that relapsed 18 months after the initial diagnosis in the testis and bilateral adrenal glands. Both tumors showed equivalent morphology, phenotype, cytogenetic features, and clonal relationship. Somatic mutation analysis by next generation sequencing demonstrated MYD88L265P mutation in both tumors and de novo CD79B Y196S mutation exclusive to the relapse. The pattern of mutations suggest that the 2 tumors might have evolved from a common progenitor clone with MYD88L265P being the founder mutation. A meta-analysis of the literature shows a significantly high frequency of concurrent MYD88L265P and CD79B ITAM mutations in primary CNS lymphoma and testicular DLBCL, underscoring the role of B cell receptor and nuclear factor kB activation by somatic mutations in these lymphomas that colonize immune-privileged sites. In summary, here we illustrate that targeted next generation sequencing for the detection of hot spot somatic mutations in relapsed DLBCL is useful to confirm ABC phenotype and discovers relevant information that might influence therapeutic decision.
- Published
- 2018
40. Richter transformation driven by Epstein-Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia
- Author
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Maria J, García-Barchino, Maria E, Sarasquete, Carlos, Panizo, Julie, Morscio, Antonio, Martinez, Miguel, Alcoceba, Vicente, Fresquet, Blanca, Gonzalez-Farre, Bruno, Paiva, Ken H, Young, Eloy F, Robles, Sergio, Roa, Jon, Celay, Marta, Larrayoz, Davide, Rossi, Gianluca, Gaidano, Santiago, Montes-Moreno, Miguel A, Piris, Ana, Balanzategui, Cristina, Jimenez, Idoia, Rodriguez, Maria J, Calasanz, Maria J, Larrayoz, Victor, Segura, Ricardo, Garcia-Muñoz, Maria P, Rabasa, Shuhua, Yi, Jianyong, Li, Mingzhi, Zhang, Zijun Y, Xu-Monette, Noemi, Puig-Moron, Alberto, Orfao, Sebastian, Böttcher, Jesus M, Hernandez-Rivas, Jesus San, Miguel, Felipe, Prosper, Thomas, Tousseyn, Xavier, Sagaert, Marcos, Gonzalez, and Jose A, Martinez-Climent
- Subjects
Adult ,Male ,B-Lymphocytes ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Cell Transformation, Neoplastic ,Humans ,Female ,Lymphoma, Large B-Cell, Diffuse ,Middle Aged ,Leukemia, Lymphocytic, Chronic, B-Cell ,Immunosuppressive Agents ,Aged - Abstract
The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV
- Published
- 2018
41. In situ neoplasia in lymph node pathology
- Author
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Naoki Oishi, Andrew L. Feldman, and Santiago Montes-Moreno
- Subjects
In situ ,Pathology ,medicine.medical_specialty ,Cell of origin ,Cell ,Follicular lymphoma ,Lymphoma, Mantle-Cell ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Humans ,Histopathology ,Mantle cell lymphoma ,Lymph Nodes ,Compartment (pharmacokinetics) ,Lymph node ,Lymphoma, Follicular ,030215 immunology - Abstract
In situ neoplasia represents the earliest form of malignant progression and is characterized by localization limited to the compartment corresponding to the cell of origin. Like other cancers, lymphoid neoplasms are considered to develop by multistep pathogenetic mechanisms. However, because of the circulating nature of lymphocytes, in situ lymphoid neoplasia may be difficult to identify histopathologically, and the compartment to which it is restricted may be physiological rather than strictly anatomical. The 2016 WHO classification of lymphoid neoplasms recognizes two in situ entities: in situ follicular neoplasia (ISFN) and in situ mantle cell neoplasia (ISMCN). This review summarizes the clinical features, histopathology, genetics, and differential diagnoses of these two entities, including distinction from both their overly malignant counterparts and a variety of reactive processes.
- Published
- 2017
42. Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions
- Author
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Jooryung Huh, Ling Li, Ganiraju C. Manyam, Ken H. Young, Santiago Montes-Moreno, Andrés J M Ferreri, Huilan Rao, William W.L. Choi, Carlo Visco, Mark J. Routbort, Govind Bhagat, Michael Boe Møller, Jane N. Winter, Zijun Y. Xu-Monette, April Chiu, Maurilio Ponzoni, Ben M. Parsons, Kristy L. Richards, Sa A. Wang, Youli Zu, Karen Dybkær, L. Jeffrey Medeiros, Eric D Hsi, J. Han van Krieken, Li Zhang, Attilio Orazi, Chi Young Ok, Alexandar Tzankov, Miguel A. Piris, Ok, Chi Young, Xu-Monette, Zijun Y, Li, Ling, Manyam, Ganiraju C, Montes-Moreno, Santiago, Tzankov, Alexandar, Visco, Carlo, Dybkær, Karen, Routbort, Mark J, Zhang, Li, Chiu, April, Orazi, Attilio, Zu, Youli, Bhagat, Govind, Richards, Kristy L, Hsi, Eric D, Choi, William W L, van Krieken, J Han, Huh, Jooryung, Ponzoni, Maurilio, Ferreri, Andrés J M, Parsons, Ben M, Rao, Huilan, Møller, Michael B, Winter, Jane N, Piris, Miguel A, Wang, Sa A, Medeiros, L Jeffrey, and Young, Ken H
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,P50 ,Lymphoma ,CD30 ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Kaplan-Meier Estimate ,Biology ,Fluorescence ,Disease-Free Survival ,Pathology and Forensic Medicine ,NF-kappa B p52 Subunit ,immune system diseases ,hemic and lymphatic diseases ,parasitic diseases ,Gene expression ,Large B-Cell ,medicine ,Humans ,neoplasms ,In Situ Hybridization ,In Situ Hybridization, Fluorescence ,Aged ,Proportional Hazards Models ,RELB ,NF-kappa B ,Germinal center ,Middle Aged ,medicine.disease ,Diffuse ,Immunohistochemistry ,Gene expression profiling ,Proto-Oncogene Proteins c-bcl-2 ,Tissue Array Analysis ,CD30 Ligand ,Female ,Lymphoma, Large B-Cell, Diffuse ,Signal Transduction ,Transcriptome ,Germinal center B-cell like diffuse large B-cell lymphoma - Abstract
Contains fulltext : 155215.pdf (Publisher’s version ) (Closed access) Nuclear factor-kappaB (NF-kappaB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-kappaB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-kappaB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-kappaB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P=0.0170), singular expression of the remaining NF-kappaB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P=0.0307 and P=0.0247). When cases were stratified into GCB- and ABC-DLBCL, p52 or p52/RELB dimer expression status was associated with better OS and PFS (P=0.0134 and P=0.0124) only within the GCB subtype. However, multivariate analysis did not show p52 expression to be an independent prognostic factor. Beneficial effect of p52 in GCB-DLBC appears to be its positive correlation with CD30 and negative correlation with BCL2 expression. Gene expression profiling (GEP) showed that p52(+) GCB-DLBCL was distinct from p52(-) GCB-DLBCL. Collectively, our data suggest that DLBCL patients with p52 expression might not benefit from therapy targeting the NF-kappaB pathway.
- Published
- 2015
43. Primary cutaneous anaplastic large cell lymphomas with 6p25.3 rearrangement exhibit particular histological features
- Author
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Miguel A. Piris, Santiago Montes-Moreno, Glenda M Bermúdez, Antonio M Rodríguez, Sonia González de Villambrosia, Arantza Onaindia, Carmen González-Vela, Victor Alegre, Socorro María Rodríguez-Pinilla, and Ana Batlle
- Subjects
CD20 ,Pathology ,medicine.medical_specialty ,Histology ,CD30 ,Lymphoproliferative disorders ,Primary cutaneous anaplastic large cell lymphoma ,General Medicine ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Immunophenotyping ,hemic and lymphatic diseases ,Pagetoid ,medicine ,biology.protein ,Immunohistochemistry ,Lymphomatoid papulosis - Abstract
Aims CD30-positive primary cutaneous lymphoproliferative disorders include several entities with differing clinical presentation but overlapping histological features, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (C-ALCL). DUSP22–IRF4 locus translocation is present in 20–57% of C-ALCLs, and has also been described in a series of 11 lymphomatoid papulosis patients, where it was associated with a particular biphasic histological pattern, including pagetoid reticulosis-type epidermal infiltration. We aimed to study whether the presence of this translocation may define distinctive histological features in C-ALCL. Methods and results We collected three cases of C-ALCL with histological features similar to those described in the new variant of lymphomatoid papulosis with 6p25.3 rearrangement. We studied their histological features and immunophenotype, using a panel of antibodies against CD30, TCR-βF1, TCR-γ, CD4, CD8, CD20, Ki-67 and ALK. FISH analyses were performed using an IRF4–DUSP22 break-apart probe for the study of the 6p25.3 rearrangement. FISH results were positive in the three cases, which all showed distinctive histological and immunohistochemical features: a diffuse dermal infiltrate of atypical medium-to-large cells, and marked epidermotrophism with small, atypical intra-epidermal lymphocytes. Conclusions Our findings suggest that the presence of 6p25.3 rearrangement might be related to this particular biphasic pattern.
- Published
- 2015
44. CD20-negative diffuse large B-cell lymphomas: biology and emerging therapeutic options
- Author
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Santiago Montes-Moreno, Jorge J. Castillo, Francisco J. Hernandez-Ilizaliturri, and Julio C. Chavez
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Anaplastic Lymphoma ,Lymphoproliferative disorders ,Antineoplastic Agents ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,B cell ,CD20 ,B-Lymphocytes ,biology ,business.industry ,Castleman Disease ,Herpesviridae Infections ,Hematology ,Antigens, CD20 ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,Herpesvirus 8, Human ,biology.protein ,Lymphoma, Large B-Cell, Diffuse ,Primary effusion lymphoma ,Multicentric Castleman Disease ,business ,Plasmablastic lymphoma - Abstract
CD20-negative diffuse large B-cell lymphoma (DLBCL) is a rare and heterogeneous group of lymphoproliferative disorders. Known variants of CD20-negative DLBCL include plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus 8-associated multicentric Castleman disease and anaplastic lymphoma kinase-positive DLBCL. Given the lack of CD20 expression, atypical cellular morphology and aggressive clinical behavior characterized by chemotherapy resistance and inferior survival rates, CD20-negative DLBCL represents a challenge from the diagnostic and therapeutic perspectives. The goals of the present review are to summarize the current knowledge on the biology of the distinct variants of CD20-negative DLBCL, provide future therapeutic directions based on the limited preclinical and clinical data available, and increase awareness concerning these rare malignancies among pathologists and clinicians.
- Published
- 2015
45. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group
- Author
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Lucía Ferrando-Lamana, Andres Lopez, Santiago Montes-Moreno, Miguel A. Piris, Luis A. Lopez, José A. García-Marco, Ana Batlle, Noelia Purroy, Laura Gallur, Josep Castellví, Juan M. Sancho, Juan Bergua, Fernando Carnicero, Julio Prieto, and Sonia González de Villambrosia
- Subjects
Adult ,Male ,Vincristine ,medicine.medical_specialty ,Follicular lymphoma ,Gastroenterology ,Antibodies, Monoclonal, Murine-Derived ,Young Adult ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,EPOCH (chemotherapy) ,B-cell lymphoma ,Cyclophosphamide ,Aged ,Etoposide ,Neoplasm Staging ,business.industry ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,BCL6 ,Lymphoma ,Surgery ,Treatment Outcome ,Doxorubicin ,Prednisone ,Female ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Grading ,business ,medicine.drug - Abstract
This prospective multi-institutional phase II study was designed to assess the efficacy and safety of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphomas. Eighty-one patients diagnosed with diffuse large B-cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age-adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21-77). Sixty-five patients (80·2%) achieved complete response. After a median follow-up time of 64 months, 10-year event-free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10-year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B-cell tumours and germinal centre B-cell without BCL2 rearranged tumours. Results achieved with DA-EPOCH-R showed a good long-term outcome and a tolerable toxicity profile in high-risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high-risk DLBCL patients.
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- 2014
46. Childhood florid follicular hyperplasia with immunoglobulin light-chain restriction in the gastrointestinal tract
- Author
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Juan Luis Afonso-Martin, Ana Batlle, Francisco Mazorra, Santiago Montes-Moreno, Sonia González de Villambrosia, Miguel A. Piris, Thomas M. Grogan, Rafael Ramos, Azahara Martinez-Lopez, and Universidad de Cantabria
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Histology ,Lymphoproliferative disorders ,Rectum ,Appendix ,Biology ,Immunoglobulin light chain ,Pathology and Forensic Medicine ,medicine ,Humans ,Overdiagnosis ,Child ,music ,In Situ Hybridization, Fluorescence ,B cell ,Gastrointestinal tract ,Hyperplasia ,music.instrument ,General Medicine ,medicine.disease ,Immunohistochemistry ,Follicular hyperplasia ,Lymphoproliferative Disorders ,medicine.anatomical_structure ,Child, Preschool ,Immunology ,biology.protein ,Female ,Immunoglobulin Light Chains ,Antibody ,Multiplex Polymerase Chain Reaction - Abstract
Aims Immunoglobulin light-chain expression is used routinely as an indirect marker of clonality for recognizing B cell lymphoproliferative disorders. Methods and results Here we describe four floral follicular hyperplasia cases in the gastrointestinal tract (appendix and rectum) of children (4 to 6 years). Immunohistochemical studies revealed lambda light-chain restriction that was associated with polyclonal IgH pattern. Clinical features and follow-up of the patients did not reveal any other systemic symptoms, laboratory abnormalities or organ alterations. Conclusions Recognition of this phenomenon is useful in the diagnosis of nodular lymphoid hyperplasia of the gastrointestinal tract, for avoiding overdiagnosis of lymphoid malignancies, and raises concerns that the identification of light-chain restriction is not necessarily a marker of monoclonality.
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- 2014
47. Evaluación sistemática de la biopsia de médula ósea en casos de sospecha de mielofibrosis primaria. Propuesta de informe diagnóstico estandarizado. Consenso de expertos de las SEAP/SEHH
- Author
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Máximo Fraga, Carlos Besses, Santiago Montes-Moreno, Reyes Calzada, Javier Menárguez, Juan F. García, María Rozman, Agustín Acevedo, José María Raya, Antonio Ferrández, Mar Garcia, and Empar Mayordomo-Aranda
- Subjects
Gynecology ,medicine.medical_specialty ,Homogeneous ,business.industry ,medicine ,In patient ,medicine.disease ,business ,Myeloproliferative neoplasm ,Pathology and Forensic Medicine ,Surgery - Abstract
A consensus based on Delphi methodology was developed to produce a guide for the evaluation and reporting of bone marrow biopsies in patients with a clinical suspicion of myeloproliferative neoplasm with fibrosis. Ten expert haematopathologists formulated a questionnaire including: clinical and laboratory data required before regarding a biopsy suspicious for primary myelofibrosis (PMF), descriptive aspects to be reported and the main histopathological differential diagnoses to be considered. It was circulated among 37 hematopathologists and consensus was defined when more than 70% of the experts "strongly agreed" or "agreed" after two rounds. The recommendations gave rise to a proposal for a standardized diagnostic report form to aid in the diagnostic workup and homogeneous reporting of cases with a clinical suspicion of PMF.
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- 2014
48. Risk adapted high-dose and dose-dense therapies modulate the impact of biological classification in diffuse large B-cell lymphoma prognosis
- Author
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Dolores Caballero, Antonio Rueda, Emilia Pardal, Sonia González de Villambrosia, Eva González-Barca, Carlos Grande, Francisco Ramon Garcia Arroyo, David Aguiar, Eulogio Conde, Marta Llanos, Laura Cereceda, Beatriz Sanchez-Espiridion, Noelia Purroy, Andrés Insunza, José Gómez Codina, Miguel Cruz, Santiago Montes-Moreno, Ana Batlle, Francisco Mazorra, Andres Lopez, Alejandro Martín, Cristina Quero, Mariano Provencio, and Miguel A. Piris
- Subjects
Male ,Oncology ,Limfomes ,Pathology ,Stem cells ,Disease ,Diagnòstic ,Prednisone ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Quimioteràpia ,Diagnosis ,Young adult ,Aged, 80 and over ,high-dose ,Hematology ,Middle Aged ,Prognosis ,Vincristine ,Female ,Risk Adjustment ,Lymphomas ,Lymphoma, Large B-Cell, Diffuse ,Cèl·lules mare ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,Cèl·lules B ,diffuse large B-cell lymphoma ,Young Adult ,biological classification ,Internal medicine ,medicine ,Humans ,Chemotherapy ,Doxorubicin ,Online Only Articles ,dose-dense therapies ,Aged ,B cells ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,Lymphoma ,business ,Diffuse large B-cell lymphoma ,Follow-Up Studies ,Stem Cell Transplantation - Abstract
Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease entity. Young patients with high-intermediate and high aa-IPI score seem to be good candidates to receive alternative treatments to standard RCHOP-21 including EPOCH-R,2 R-ACVBP+HDT-ASCT3 and upfront autologous stem cell transplantation. Other risk factors can be used to identify patients for the use of more doseintense regimens including bulky disease, interim PET positivity and, importantly, molecular profiles.
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- 2014
49. Prevalence and clinical implications of cyclin D1 expression in diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: A report from the International DLBCL Rituximab-CHOP Consortium Program
- Author
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Eric D. Hsi, Santiago Montes-Moreno, L. Jeffrey Medeiros, J. Han van Krieken, Alexandar Tzankov, Govind Bhagat, Kristy L. Richards, Youli Zu, Miguel A. Piris, Carlo Visco, John P. Farnen, Chi Young Ok, Michael Boe Møller, Ken H. Young, Jane N. Winter, Karen Dybkær, Dennis P. O'Malley, Zijun Y. Xu-Monette, Maurilio Ponzoni, and Attilio Orazi
- Subjects
Cancer Research ,Vincristine ,business.industry ,Germinal center ,medicine.disease ,BCL6 ,Lymphoma ,Cyclin D1 ,Oncology ,Cyclin D2 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Cancer research ,CD5 ,business ,neoplasms ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
BACKGROUND Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression. METHODS The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene (CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression. RESULTS In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 (BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog (MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase (MDM2), MDM4, and tumor protein 53 (TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL. CONCLUSIONS Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL. Cancer 2014;120:1818–1829. © 2014 American Cancer Society.
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- 2014
50. B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies
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Santiago Montes-Moreno, Nerea Martinez, Margarita Sánchez-Beato, Ana Batlle-López, Miguel A. Piris, Cristina Perez, José P. Vaqué, and Universidad de Cantabria
- Subjects
Chromosome Aberrations ,Regulation of gene expression ,Lymphoma, B-Cell ,Molecular pathogenesis ,Hematology ,Computational biology ,Biology ,medicine.disease ,Bioinformatics ,Lymphoma ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Mirna expression ,microRNA ,medicine ,Humans ,RNA, Neoplasm ,Personalized therapy ,B-cell lymphoma ,Review Articles ,Human cancer - Abstract
B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities.
- Published
- 2014
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