scholarly journals The molecular hallmarks of primary and secondary vitreoretinal lymphoma

2021 ◽  
Author(s):  
Irina Bonzheim ◽  
Philip Sander ◽  
Julia Salmeron-Villalobos ◽  
Daniela Süsskind ◽  
Peter Szurman ◽  
...  
Keyword(s):  
B Cell ◽  
Mutational Analysis ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Profile ◽  
Vitreous Fluid ◽  
Cell Free Dna ◽  
Free Dna ◽  
Vitreoretinal Lymphoma ◽  
Negative Controls

Vitreoretinal lymphoma (VRL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) considered a variant of primary central nervous system lymphoma (PCNSL). Diagnosis of VRL requires examination of vitreous fluid, but cytologic differentiation from uveitis remains difficult. Due to its rarity and difficulty in obtaining diagnostic material, little is known about the genetic profile of VRL. The aim of our study was to investigate the mutational profile of a large series of primary and secondary VRL. Targeted next generation sequencing using a custom panel containing the most frequent mutations in PCNSL was performed on 34 vitrectomy samples of 31 patients with VRL and negative controls with uveitis. In a subset of cases, genome-wide copy number alterations (CNA) were assessed using the Oncoscan platform. Mutations in MYD88 (74%), PIM1 (71%), CD79B (55%), IGLL5 (52%), TBL1XR1 (48%), ETV6 (45%) and 9p21/CDKN2A deletions (85%) were the most common alterations, with similar frequencies in primary (15), synchronous (3) or secondary (13) VRL. This mutational spectrum is similar to MYD88mut/CD79Bmut (MCD or cluster 5) DLBCL with activation of Toll-like and B-cell receptor pathways and CDKN2A loss, confirming their close relationship. Oncoscan analysis demonstrated a high number of CNAs (mean 18.6/case). Negative controls lacked mutations or CNAs. Using cell free DNA of vitreous fluid supernatant, mutations present in cellular DNA were reliably detected in all examined cases. Mutational analysis is a highly sensitive and specific tool for the diagnosis of VRL and can also be applied successfully to cell free DNA derived from the vitreous.

Cell-free DNA as a biomarker in diffuse large B-cell lymphoma: A systematic review

2019 ◽  
Vol 139 ◽  
pp. 7-15 ◽  
Author(s):  
Javier Arzuaga-Mendez ◽  
Endika Prieto-Fernández ◽  
Elixabet Lopez-Lopez ◽  
Idoia Martin-Guerrero ◽  
Juan Carlos García-Ruiz ◽  
...  
Keyword(s):  
Systematic Review ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Free Dna ◽  
Free Dna ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals 5-Hydroxymethylcytosines of Circulating Cell-Free DNA and Prognosis in Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2985-2985
Author(s):  
Brian C.-H. Chiu ◽  
Zhou Zhang ◽  
Qiancheng You ◽  
Elizabeth Stepniak ◽  
Paige Bracci ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Cell Free Dna ◽  
Free Dna ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Circulating Cell Free Dna

Abstract Background: Elevated levels of circulating cell-free DNA (cfDNA) have been associated with poor prognosis and relapse in patients with diffuse large B-cell lymphoma (DLBCL). However, the tumor-specific molecular targets in cfDNA that have prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosine (5hmC), a mark of active demethylation and gene activation, in cfDNA from plasma and prognosis in DLBCL. Methods: We used the 5hmC-Seal, a highly sensitive chemical labeling technique integrated with next-generation sequencing (NGS), to profile 5hmC in plasma cfDNA samples from Caucasian patients at the University of Chicago who were newly diagnosed with DLBCL (n=43) or follicular lymphoma (FL, n=28), the two most common histological subtypes of non-Hodgkin lymphoma (NHL), in 2011-13. Baseline clinical, laboratory, and vital status data were abstracted from medical records. Patients were followed through December 31, 2017 and those who relapsed after completion of treatment, lost to follow-up, or died were censored. We profiled 5hmC with 1-2 ng of cfDNA extracted from ~2 ml of plasma for library construction and the NGS. We obtained ~25 million reads per sample, providing a depth of coverage ~600X in terms of gene bodies. We normalized read counts and identified differential 5hmC markers using DESeq2. Cox proportional hazards model were used to estimate the association between 5hmC markers and overall survival. Results: We found that in cfDNA from DLBCL patients, 5hmC markers were enriched within gene bodies and depleted in CpG islands. The cfDNA-based 5hmC profiles at diagnosis differed between DLBCL and FL, and in DLBCL, the 5hmC profiles differed between Ann Arbor stage (stage 1/2 vs stage 3/4), lactate dehydrogenase (LDH) level (normal vs elevated), and cell-of-origin (germinal center B-like and activated B-cell-like DLBCL). In addition, genome-wide 5hmC distribution patterns in cfDNA samples are highly correlated with those found in cfDNA-paired tumor tissues, supporting the tumor relevance of cfDNA in a patient. Next, we evaluated the prognostic significance of cfDNA-based 5hmC in DLBCL using a two-step approach. In the discovery phase (7 DLBCL patients with relapse and 12 age- and sex-matched patients without relapse within two years following treatment), a substantial number of 5hmC markers were associated with relapse (449 gene bodies at 5% false discovery rate [FDR]). These relapse-associated 5hmC signatures showed high sensitivity, specificity, and overall accuracy (area under curve [AUC]=0.91) in predicting relapse in the independent validation set (relapse=5, no relapse=13). Finally, we identified a panel of 128 5hmC markers (fold change >20% and p-value <0.05) that were associated with 4-year overall survival. Conclusion: These findings suggest that 5hmC signatures in cfDNA at the time of DLBCL diagnosis correlate with standard clinical prognostic indices and hold promise as non-invasive markers for prognosis and survival. Disclosures Smith: BMS: Consultancy; Portola: Honoraria.

scholarly journals Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire

2020 ◽  
Vol 4 (7) ◽  
pp. 1357-1366
Author(s):  
Nabila Belhouachi ◽  
Aliki Xochelli ◽  
Myriam Boudjoghra ◽  
Claude Lesty ◽  
Nathalie Cassoux ◽  
...  
Keyword(s):  
B Cell ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Heavy Chains ◽  
Vitreoretinal Lymphoma ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p ◽  
Antigen Selection

Abstract Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.

Gene Expression Profiling of Primary Vitreoretinal Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1239-1239
Author(s):  
Ayako Arai ◽  
Hiroshi Takase ◽  
Kouhei Yamamoto ◽  
Hiroki Akiyama ◽  
Manabu Mochizuki ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Vitreous Fluid ◽  
Primary Vitreoretinal Lymphoma ◽  
Vitreoretinal Lymphoma ◽  
Profiling Analysis

Abstract Background: Primary vitreoretinal lymphoma (PVRL) is a rare form of non-Hodgkin lymphoma, whose original lesions are limited in the intraocular tissues: the vitreous and the retina. Although its morphological and genetic findings show that most cases are diffuse large B-cell lymphoma (DLBCL), the characteristics of the tumor cells of PVRL, including their origin, have not been defined to date. DLBCL is subdivided into 3 groups: activated B-cell (ABC) type, germinal center B-cell (GCB) type, and primary mediastinal B-cell lymphoma on the basis of genes expressed in differentiation or biologic response of B-cell. In order to determine the origin of the tumor cells of PVRL, we performed gene expression profiling analysis. Methods: PVRL was diagnosed using the following criteria: (1) typical eye involvement: a cloudy vitreous body and/or subretinal proliferative lesions, (2) presence of lymphoma cells in the vitreous fluid, and (3) clonality of the infiltrating lymphoma cells in the vitreous fluid using either PCR analysis of IgH gene rearrangements, or flow cytometry analysis. Patients who had (1) accompanied by either (2) or (3) were diagnosed with VRL. VRL confined to the eyes at diagnosis was defined as PVRL. We used the samples from nodal DLBCL whose types were pathologically determined according to Hans classifier (Blood, 103, p 275, 2004) as control. RNA was extracted from the vitreous fluid and the lymph nodes from PVRL and nodal DLBCL patients, respectively. Since the extracted RNA from PVRL was very small in amount, all RNA samples were amplified with WTA reaction. Then, one-color microarray-based gene expression analysis was performed using SurePrint G3 Human GE Microarray 8x60K v2 (Agilent Technology). Data were extracted and the agglomerative hierarchical clustering was performed on the basis of the genes discriminating GCB/ABC signatures that were published initially by Alizadeh et al. (Nature, 403, p503, 2000). Gene ontology (GO) analysis was performed using DAVID data base. We calculated Z-scores and ratios (non-log scaled fold-change) from the normalized signal intensities of each probe for comparison between 2 groups. Results: We performed gene expression profiling analysis for 7 samples from PVRL patients. We also examined 6 samples from nodal DLBCL patients as control; 4 samples were ABC type, and 2 samples were GCB type. Six of 7 PRVL showed different gene expression profiling from ABC type nodal DLBCL. They were close to that of GCB type. Genes regulating cell adhesion were enriched by GO analysis for genes whose expression was different between PRVL and GCB. Next we examined the relation between the gene expression and the outcomes of PVRL. Four GCB-like PRVL samples were obtained from the patients treated with the same strategy: intravitreal administration of methotrexate (MTX) followed by systemic high dose MTX. Among them, 2 patients revealed early relapse in the CNS a year after the treatment whereas the others did not. We compared the gene expression between them. Three genes, SLC35F1, ADAM19, and SMC1A related to neurological disorders, cell migration, and cell division, respectively, were significantly upegulated in the PRVL with early relapse. Conclusion: The majority of PVRL in the present study were different from ABC type and close to GCB type DLBCL. Further studies are required to confirm that and to determine the genes predicting the outcome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Remote immune processes revealed by immune-derived circulating cell-free DNA

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ilana Fox-Fisher ◽  
Sheina Piyanzin ◽  
Bracha Lea Ochana ◽  
Agnes Klochendler ◽  
Judith Magenheim ◽  
...  
Keyword(s):  
Blood Cell ◽  
B Cell ◽  
Immune Cell ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Cell Free Dna ◽  
Cell Counts ◽  
Free Dna ◽  
Blood Cell Counts ◽  
Circulating Cell Free Dna

Blood cell counts often fail to report on immune processes occurring in remote tissues. Here we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N=242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N=92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with Eosinophilic Esophagitis (N=21) and B-cell lymphoma (N=27) showed selective elevation of eosinophil and B-cell cfDNA respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.

scholarly journals Circulating Cell-Free DNA (ccfDNA) Isolation from Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Comparative Analysis of Commercial Kits

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4931-4931
Author(s):  
Karolliny Silva de Oliveira ◽  
Hebert Fabricio Culler ◽  
Débora Levy ◽  
José Roberto Assis Filho ◽  
Daniel Silva Nogueira ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Genetic Material ◽  
B Cell Lymphoma ◽  
Cell Free Dna ◽  
Free Dna ◽  
Large B Cell Lymphoma ◽  
Commercial Kits ◽  
Large B Cell ◽  
Circulating Cell Free Dna

Abstract Introduction: Isolation of circulating cell-free DNA (ccfDNA) and circulating tumor DNA (ctDNA) are useful methodologies for studies of neoplastic genetic material and can provide information about cancer heterogeneity, prognosis and minimal residual disease (MRD) [1,2]. Therefore, the recovery of ccfDNA in sufficient quantity and adequate purity is crucial to provide accurate and reproducible results. In this study, we investigate the efficiency of four different commercial kits to recover short fragments of DNA compatible with the ccfDNA. Methods: Ten mL of total peripheral blood from seven patients with Diffuse Large B-Cell Lymphoma (DLBCL) were collected in EDTA and were immediately processed. Plasma was obtained by centrifugation at 1.900 x g for 10 min at 4 ºC, followed by other centrifugation at 20.000 x g for 10 min at 4 ºC to remove cellular debris. Aliquots of 1.0 mL of plasma were stored at -80 ºC until ccfDNA extraction. The ccfDNA extraction was performed using the same samples by the following kits: QIAamp MinElute ccfDNA kit (CFDNA - Qiagen, Hilden, Germany), QIAamp DNA Mini Kit (QBLOOD - Qiagen, Hilden, Germany), Illustra Blood GenomicPrep Mini Spin Kit (GE - GE Healthcare Bio-Sciences Corp, UK) and ccfDNA isolation kit Quick-ccfDNA Serum & Plasma Kit (ZYMO - Zymo Research, Irvine, USA) [Table 1] according to the manufacturer's recommendations. The ccfDNA obtained was eluted in 30 µL of elution buffer for the subsequent experiments. The measurement of the ccfDNA obtained for each kit was performed in a Qubit 2.0 fluorometer using Qubit dsDNA HS assay kit (Thermo Fischer Scientific, Waltham, USA). The analysis of integrity, purity and the size of the fragments of DNA were performed in the Agilent 2100 Bioanalyzer (Agilent Technologies, Germany) equipment using the High Sensitivity DNA kit (Agilent Technologies, Germany). Results: The results obtained for each commercial kit in the Qubit-analysis were: CFDNA (0.27 ng/uL), QBLOOD (0.26 ng/uL), ZYMO (0.03 ng/uL) and GE (0.02 ng/uL) [Figure 1]. The Bionalyzer eletrophoresis showed that CFDNA kit was able to recover two different fragments sizes of ccfDNA one of 360-380 bp (0.114 ng/uL) and other of 160-180 bp (1.808 ng/uL). The DNA recovered with QBLOOD revealed sizes of 360-380 bp (0.031 ng/uL) and 160-180 bp (0.079 ng/uL). Both kits, GE and ZYMO were not able to isolate fragments of DNA smaller than 10.380 pb . Conclusion: We demonstrated that QIAamp MinElute ccfDNA kit (CFDNA) was capable to recovery high quantity of small fragments of DNA compatible with ccfDNA. This result supports the use of protocols based in magnetic beads in experiments working with ccfDNA. Additionally, we highlight the importance to verify the quality and not only the quantity of the DNA extracted to confirm the presence of ccfDNA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Remote immune processes revealed by immune-derived circulating cell-free DNA

2021 ◽  
Author(s):  
Ilana Fox-Fisher ◽  
Sheina Piyanzin ◽  
Agnes Klochendler ◽  
Bracha Lea Ochana ◽  
Judith Magenheim ◽  
...  
Keyword(s):  
Blood Cell ◽  
B Cell ◽  
Immune Cell ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Cell Free Dna ◽  
Cell Counts ◽  
Free Dna ◽  
Blood Cell Counts ◽  
Circulating Cell Free Dna

Blood cell counts often fail to report on immune processes occurring in remote tissues. Here we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N=242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N=92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with Eosinophilic Esophagitis (N=21) and B-cell lymphoma (N=27) showed selective elevation of eosinophil and B-cell cfDNA respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.

scholarly journals Assessment of Cell-Free DNA (cfDNA) in 221 Patients with Lymphoproliferative Malignancies at Diagnosis and during Follow-up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 492-492 ◽  
Author(s):  
Marcio M Andrade-Campos ◽  
Antonio Salar ◽  
Blanca Sanchez-Gonzalez ◽  
Concepción Fernández-Rodríguez ◽  
Eva Gimeno ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Plasma Samples ◽  
Cell Free Dna ◽  
Free Dna ◽  
The Mean ◽  
Post Therapy

Background:The isolation of cell-free DNA (cfDNA) evolved the concept of liquid biopsy. Several works have analyzed the presence of cfDNA in lymphomas, especially in diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), however there is limited information regarding the detection of cfDNA in other types of lymphomas or the role of cfDNA detection to monitor disease outcome. Objectives:1.- To analyze the presence of cfDNA at diagnosis of patients with lymphoproliferative malignancies. 2.- To evaluate the change in concentration of cfDNA ([cfDNA]) after treatment in DLBCL patients. Material and Methods:A retrospective study in a single center was performed including 221 adult patients since January 2015 to February 2019 with: DLBCL, HL, marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL) and peripheral T-cell lymphomas (TCL). All patients had plasma samples collected at diagnosis that were stored in the institutional biobank (MarBiobank). The cfDNA were obtained from 1 mL of -80°C frozen stored plasma using the MagMax Cell Free DNA isolation kit (Thermo Fisher Scientific). The cfDNA quantification was performed using the Qubit system with the dsDNA high sensitivitykit (Thermo Fisher) and is expressed as ng/mL of plasma. In addition, patients with DLBCL who were treated with rituximab-CHOP/CHOP-like regimens were evaluated for [cfDNA] analysis, pre and post-treatment, and results were compared with PET-CT scan findings. Results: Stored plasma samples at diagnosis were available in 221 patients: DLBCL 82, HL 22, CLL/LPL 13, FL 36, MZL 37, MCL: 11, TCL 10 and others 10 (B-cell lymphoma unclassified, hairy cell leukemia, Burkitt lymphoma). Successful identification of cfDNA was obtained in 95.9% (212/221) of samples. DLBCL patients showed higher [cfDNA] globally and, DLBCL, HL and FL patients showed a higher concentration than MZL who exhibited the lower concentration of all groups (p=0.009; p=0.013 and p=0.002); see table 1. 50 DLBCL patients with a median follow-up since diagnosis of 25.5 (5-51) months were analyzed. Median age was 67 (19-79) years, males 56% (28). IPI distribution: low-risk 28% (14), low-intermediate 26% (13), high-intermediate 24% (12) and high risk 22% (11) cases. Detection of cfDNA was successful in 100% at diagnosis and in 98% (49) cases post-therapy. The mean [cfDNA] at diagnosis was 2.21 (standard deviation- SD: 1.60) ng/mL with a correlation with LDH concentration (p&lt;0.001) and with high-risk IPI category (p=0.02). The mean [cfDNA] in the post-therapy sample was 4.39 (SD 16.46) ng/mL. After therapy 86% (43) of patients achieved at least PR (41 complete response), and the mean [cfDNA] for these patients was 1.58 (SD 1.96); patients who showed no response or progressive disease after therapy exhibited higher [cfDNA] 21.25 ng/mL (SD 41.91)(p&lt;0.001). In order to evaluate the clinical relevance of the changes of [cfDNA] after treatment, we considered a variation of +/-25% of [cfDNA at diagnosis] regarding [cfDNA after therapy] to classify the results. Therefore, 13 patients had an increase of [cfDNA after therapy], 6 patients had no change, and 31 patients had a decrease. Patients with a decrease in [cfDNA] at the end of therapy were less likely to relapse (p&lt;0.01) During follow-up, two patients relapsed after 24 and 8 months. The patient who relapsed after 24 months showed an increase in [cfDNA], from 0.966 ng/mL to 20.80ng/mL three months before the histological confirmation of relapse. Conclusions:Isolation of cfDNA was feasible in &gt;95% of lymphoma patients independently of histology or disease stage. Patients with DLBCL exhibited the higher cfDNA concentration which were also correlated with LDH concentrations and high-risk IPI. Kinetics of [cfDNA] is related to response to therapy in DLBCL and also might detect relapse. Even though additional studies are necessary, monitoring of cfDNA may help in management of patients with DLBCL. Disclosures Salar: Roche: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy. Sanchez-Gonzalez:Takeda: Consultancy, Speakers Bureau; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Gimeno:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Bellosillo:Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

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