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Primary cutaneous posttransplant lymphoproliferative disorders (PTLDs) after allogeneic hematopoietic stem cell transplant (allo-HSCT) are exceedingly rare, with only 6 published cases, all of them consisting in T-cell neoplasms. In this report, we present for the first time a donor-derived B-cell PTLD consisting in a primary, cutaneous, B-cell, marginal zone, lymphoproliferative disorder (PCMZLPD). The patient, a 37-year-old woman with a history of Hodgkin lymphoma received an allo-HSCT from her healthy, matched, related father, achieving complete host chimerism in the bone marrow and peripheral blood. However, 8 years after the allo-HSCT, she presented asymptomatic skin lesions consisting in oval, well-defined, slightly raised erythematous plaques, located on the arms, trunk, and legs. Skin biopsies of 2 lesions demonstrated a class-switched IgG+, EBV-, PCMZLPD, showing kappa light chain restriction and monoclonal rearrangement of the IgH gene. Microsatellite genotyping and 2-color fluorescence in situ hybridization (X and Y chromosomes) confirmed that the origin of the neoplastic cells was the donor graft. The lesions showed an indolent behavior, good response to topical corticosteroids, and no need for systemic treatment. Our case broadens the spectrum of PTLD, a diverse group of lymphoid and/or plasmacytic proliferations with variable clinical presentations and histopathological features.

Abstract:Fictional works are a medium to not only understand the past but to give voice to the marginalised and lost. For over a century and a half sugar cane was harvested by hand in Australia, first by Melanesian indentured labourers, Asian labourers and then by free, mostly white labour. With the post-World War II economic boom, the sugar industry expanded. Thousands of men signed-on to cut cane, despite its brutality and itinerant lifestyle. For an intense seven months they lived together in barracks and worked in gangs, eyes fixed on the pay packet, cut-out day and the retention money. The powerful sense of mateship that bound the gang often faltered under the heat of a tropical sun, as the cutters battled tangled cane, avaricious farmers, and the intransigent mills’ field arbiters, the cane inspectors. Welsh immigrant author, playwright, and cane cutter John Naish’s sugar country novel, The Cruel Field, authentically exposed the dynamics and workings of the butty gang system in the Australian cane fields in the 1950s and 1960s. In this article, Naish’s novel is used to examine the butty gang in the cane fields, suggesting the potential cogency of seeing labour history through the lens of a fictional work.

The COVID-19 pandemic has highlighted the multifaceted socio-cultural functions of Australian children’s television. As social distancing measures forced school students to study from home, local children’s TV producers and distributors contributed to home-based learning. Yet, in response to the pandemic, the Federal Government has indefinitely suspended Australian children’s television quotas, the regulatory framework that sets minimum hours of local children’s content for commercial television broadcasters. In response to government imposed budgetary restraints, public broadcaster, the ABC, has also made redundances in its children’s content department. Such changes have occurred at a critical juncture in which the sector’s long-standing contributions to the education of Australian children and pedagogy of local teachers, caregivers and parents have been brought to the fore. We argue that this pedagogical function is a core but often overlooked element of the socio-cultural value of the sector that has been highlighted during the pandemic.

ABSTRACTIn the nineteenth century the stereotypical association representing sugarcane growers was a planters’ association, the epitome of which, was the Hawai’ian Sugar Planters’ Association. The Herbert River Farmers’ Association, formed by a group of small farmers in the tropical north of Australia, was the antithesis. This is because they represented two distinct modes of agricultural production, the plantation and the small farm. Both inherited their associative traditions from the British Isles. Much of agricultural association scholarship has had a tendency to focus on associations formed by the elite and studies of regional and local small agricultural associations are scattered and uncoordinated. Drawing upon the Hawai’ian and Australian sugarcane industries this article explores the differing modes of production adopted in each to explain why their agricultural associations took different paths. Hawai’i and north Queensland offer a unique context for a comparative examination of associational behaviour on the colonial periphery.

Acute myeloid leukemias (AMLs) are currently genomically characterized by karyotype, fluorescence in situhybridization (FISH), real-time quantitative PCR, and DNA sequencing. Next-generation sequencing offers the promise of detecting all genomic lesions in a single run. However, technical limitations have hampered the detection of chromosomal rearrangements, so most studies are limited to somatic mutation assessment or require the use of RNA-based strategies. To overcome these limitations, we designed a targeted-DNA capture next-generation sequencing approach associated with easy-to-perform public bioinformatic tools for one-step identification of translocations, inversions, and somatic mutations in AML. Thirty well-characterized newly diagnosed myeloid leukemia patients (27 AML and 3 chronic myeloid leukemia) were tested with the panel. Twenty-three of 24 known rearrangements, as well as one novel fusion gene that could not be detected by karyotype/fluorescence in situhybridization/real-time quantitative PCR, were detected. This strategy also identified all chromosomal breakpoints as potential targets for future high-sensitive minimal residual disease studies. In addition, mutation analysis revealed the presence of missense protein-coding alterations in at least 1 of the 32 genes evaluated in 21 of 30 patients (70%). This strategy may represent a time- and cost-effective diagnostic method for molecular characterization in AML.

The presence of mutations in the TP53gene is a powerful prognostic and predictive marker in chronic lymphocytic leukemia (CLL). Widespread use of NGS has enabled the detection of variants ≤10 % variant allelic frequency (low-VAF variants); however, the overall reliability and reproducibility of NGS techniques to identify such variants have been questioned repeatedly. Individual studies using sensitive, custom NGS-based assays have mostly demonstrated the shortened overall survival (OS) and event-free survival in patients with low-VAF TP53variants treated with chemoimmunotherapy (CIT) regimens with median survival ranging between that of TP53 variants >10 % VAF (high-VAF) and wild-type TP53(wt- TP53).

AbstractIn 2016, The Melbourne Museum staged the world premiere of Jurassic World: The Exhibition, a globally touring exhibition inspired by Universal Pictures’ blockbuster film, Jurassic World (2015), featuring animatronic dinosaurs created by Melbourne’s Creature Technology. The exhibition had the most successful opening month of any exhibition at the Museum to date, selling over 100,000 tickets. Yet Jurassic World also met with controversy for its theme park-esque design and pervasive branding, prioritization of spectacle and attraction over cultural heritage and education, and seamless integration of fact and fiction. In this article, we carry out a close analysis of Jurassic World’s combination of theme park and museum exhibition practices, situating the exhibition as a particularly significant example of the developing trend towards the creation of immersive ‘narrative environments’ in twenty-first century museums, as museums increasingly draw upon the devices of popular entertainment to engage and attract guests. Drawing from Norman Klein’s model of the ‘scripted space’ and Joseph Pine and James Gilmore’s ‘experience economy’, which has its roots in Disney theme parks, our analysis shows how Jurassic World plays with the boundaries of fact and fiction in a way that self-reflexively interrogates the contemporary relationship between popular entertainment and museums.

Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situhybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGHtranslocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGHand six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC,and BRAF. We identified 14 of 17 IGHtranslocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma.

AbstractThe horror genre is in large part defined by a distinctive use of sound, which facilitates the effects by which it is defined. The genre is unique in its creative deployment of sound to activate and intensify dread and shock, and to launch what Peter Hutchings describes as ‘comprehensive assaults upon the senses’. This assaultive use of sound is central to the genre’s characteristic provocation of feelings of entrapment and peril, for, unlike the image, sound resists the viewer’s attempts at momentary escape. The recent supernatural horror film Sinister (Derrickson, 2012) powerfully illustrates the complex associations between sound and image upon which the horror genre relies to conjure its effects. Much of the thematic and aesthetic intensity of Sinister emerges from deeply unsettling interactions between sound and image created by the ambiguous layering of diegetic and non-diegetic sounds. Echoing earlier haunted media films such as The Ring (Verbinski, 2002), Derrickson’s film revolves around Super 8 film reels that house a malevolent supernatural being. This article examines the augmentation of analogue aesthetics in Sinister, and argues that sound is central to the film’s simultaneous evocation and troubling of Super 8’s conventional nostalgic connotations. To achieve this, Derrickson pairs macabre Super 8 imagery with the eerie sounds of hauntology, a form of experimental electronic music that emerged around the turn of the millennium and takes troubled nostalgia as its core theme. The hauntological soundscape of Sinister accompanies the Super 8 footage not only to enhance the sonic textures of technological obsolescence, but to incite conflicted feelings of nostalgia-gone-wrong. As a result, the soundscape of Sinister not only foments the film’s most potent affects, but develops much of its subtext.

B cells have been shown to be refractory to reprogramming and B-cell-derived induced pluripotent stem cells (iPSC) have only been generated from murine B cells engineered to carry doxycycline-inducible Oct4, Sox2, Klf4 and Myc (OSKM) cassette in every tissue and from EBV/SV40LT-immortalized lymphoblastoid cell lines. Here, we show for the first time that freshly isolated non-cultured human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20+ B cells can be reprogrammed to iPSCs carrying complete VDJH immunoglobulin (Ig) gene monoclonal rearrangements using non-integrative tetracistronic, but not monocistronic, OSKM-expressing Sendai Virus. Co-expression of C/EBPa with OSKM facilitates iPSC generation from both CB- and PB-derived B cells. We also demonstrate that myeloid cells are much easier to reprogram than B and T lymphocytes. Differentiation potential back into the cell type of their origin of B-cell-, T-cell-, myeloid- and fibroblast-iPSCs is not skewed, suggesting that their differentiation does not seem influenced by ‘epigenetic memory’. Our data reflect the actual cell-autonomous reprogramming capacity of human primary B cells because biased reprogramming was avoided by using freshly isolated primary cells, not exposed to cytokine cocktails favoring proliferation, differentiation or survival. The ability to reprogram CB/PB-derived primary human B cells offers an unprecedented opportunity for studying developmental B lymphopoiesis and modeling B-cell malignancies.

MYD88L265P mutation has been reported in ∼90 of Waldenström’s Macroglobulinemia (WM) patients and immunoglobulin M (IgM) monoclonal gammopathies of uncertain significance (MGUS), as well as in some cases of lymphoma and chronic lymphocytic leukemia. The present study aimed to develop a real-time allele-specific oligonucleotide PCR (ASO-RQ-PCR) to detect the MYD88L265P mutation. We first evaluated the reproducibility and sensitivity of the technique with a diluting experiment of a previously known positive sample. Then, we evaluated the applicability of the methodology by analyzing 30 selected patients (10 asymptomatic WM, 10 symptomatic WM, and 10 IgM MGUS) as well as 10 healthy donors. The quantitative ASO-PCR assay could detect the MYD88L265P mutation at a dilution of 0.25, showing an inverse correlation between the tumor cell percentage and the cycle threshold (CT) value, thus allowing for tumor burden quantitation. In addition, mutated cases were distinguished from the unmutated by >10 cycles of difference between CTs. To sum up, ASO-RQ-PCR is an inexpensive, robust, and optimized method for the detection of MYD88L265P mutation, which could be considered as a useful molecular tool during the diagnostic work-up of B-cell lymphoproliferative disorders.

Contamos con un buen número de investigaciones que estudian el desarrollo del lenguaje en niños sordos con implantes cocleares educados en contextos orales, pero es reducido el corpus de trabajos que investiga el desarrollo de estos niños cuando están educados en contextos bilingües. El presente estudio tiene como objetivo medir el desarrollo del vocabulario de 14niños sordos con edades cronológicas de 17-62meses y edades auditivas de 6-37meses que aprenden lengua castellana y lengua de signos española. Los niños sordos y sus iguales oyentes comparten aulas en las que están presentes ambas lenguas como herramienta educativa y de aprendizaje. Para medir las 2 lenguas, los niños fueron evaluados utilizando el Inventario de Desarrollo Comunicativo MacArthur-Bates español y un Inventario no estandarizado del vocabulario de lengua de signos española. Los resultados de las evaluaciones indican que todos menos 2 de los niños sordos presentan una producción del lenguaje oral dentro o por encima de los rangos normales en comparación con la edad auditiva o el tiempo transcurrido desde la activación del implante coclear. Al comparar el vocabulario en 2 periodos de tiempo encontramos que la producción en ambas lenguas mejoró significativamente. Los niños usan más lengua de signos que lengua oral en la primera evaluación, pero esta tendencia se invierte en el segundo periodo. Al hallar el vocabulario compuesto o conceptual, obtenemos que los niños tienen un número total de términos léxicos mayor que el que presentan en cada una de las lenguas por separado.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P = .019) and 5-year overall (71% vs 92%, P = .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P= .0008, Pc= .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P< .0005, Pc= .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P= .019) and 5-year overall (71% vs 92%, P= .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D-J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an overrepresentation of IGHV4-34(15.5% overall). Interestingly, all IGHV4-34rearrangements and all unmutated sequences belonged to the nongerminal center B-cell–like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL. The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.

We have evaluated 9 new molecular markers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1gene-expression levels plus FLT3and NPM1mutations) in 121 de novo cytogenetically normal acute myeloblastic leukemias. In the multivariate analysis, high ERGor EVI1and low PRAMEexpressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to 3 score was given by assigning a value of 0 to favorable parameters (low ERG, low EVI1, and high PRAME) and 1 to adverse parameters. This model distinguished 4 subsets of patients with different OS (2-year OS of 79%, 65%, 46%, and 27%; P= .001) and RFS (2-year RFS of 92%, 65%, 49%, and 43%; P= .005). Furthermore, this score identified patients with different OS (P= .001) and RFS (P= .013), even within the FLT3/NPM1intermediate-risk/high-risk subgroups. Here we propose a new molecular score for cytogenetically normal acute myeloblastic leukemias, which could improve patient risk-stratification.

We have evaluated 9 new molecular markers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression levels plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute myeloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAME expressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to 3 score was given by assigning a value of 0 to favorable parameters (low ERG, low EVI1, and high PRAME) and 1 to adverse parameters. This model distinguished 4 subsets of patients with different OS (2-year OS of 79%, 65%, 46%, and 27%; P = .001) and RFS (2-year RFS of 92%, 65%, 49%, and 43%; P = .005). Furthermore, this score identified patients with different OS (P = .001) and RFS (P = .013), even within the FLT3/NPM1 intermediate-risk/high-risk subgroups. Here we propose a new molecular score for cytogenetically normal acute myeloblastic leukemias, which could improve patient risk-stratification.

Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)–αβ+/CD4+/NKa+/CD8−/+dim T-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)–specific TCRVβ+/CD4+/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4+ T-LGL. Peripheral blood samples from patients with monoclonal TCR-αβ+/CD4+ T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the “MQLIPDDYSNTHSTRYVTVK” hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-αβ+/CD4+ T-LGL displayed a strong and characteristic hCMV-specific functional response, reproduced by the hCMV peptide in a subset of HLA-DRB1*0701+ patients bearing TCRVβ13.1+ clonal T cells. Gene expression profile showed that the hCMV-induced response affects genes involved in inflammatory and immune responses, cell cycle progression, resistance to apoptosis, and genetic instability. This is the first study providing evidence for the involvement of hCMV in the ontogeny of CD4+ T-LGL, emerging as a model disorder to determine the potential implications of quite a focused CD4+/cytotoxic immune response.

Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)–αβ+/CD4+/NKa+/CD8−/+dimT-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)–specific TCRVβ+/CD4+/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4+T-LGL. Peripheral blood samples from patients with monoclonal TCR-αβ+/CD4+T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the “MQLIPDDYSNTHSTRYVTVK” hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-αβ+/CD4+T-LGL displayed a strong and characteristic hCMV-specific functional response, reproduced by the hCMV peptide in a subset of HLA-DRB1*0701+patients bearing TCRVβ13.1+clonal T cells. Gene expression profile showed that the hCMV-induced response affects genes involved in inflammatory and immune responses, cell cycle progression, resistance to apoptosis, and genetic instability. This is the first study providing evidence for the involvement of hCMV in the ontogeny of CD4+T-LGL, emerging as a model disorder to determine the potential implications of quite a focused CD4+/cytotoxic immune response.

We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P= 1.07 × 10−6, P= 4.231 × 10−6, P= 6.22 × 10−6, and P= 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (Pcorrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

Detection of recipient versus donor disparities in microsatellite DNA regions (short tandem repeats STR) allows for sensitive and specific monitorization of the degree of hematopoietic chimerism. It is well known that disparities between donor and recipient in various polymorphic systems (mainly human leukocyte antigen HLA) are associated with an increased incidence of graft-versus-host disease (GvHD). However, the possible biological role of STR discrepancies in GvHD development has not yet been well established.

We analyzed patients with hairy cell leukemia (HCL) to achieve a better understanding of the differentiation stage reached by HCL cells and to define the key role of the diversification of cell surface makers, especially CD25 expression.

Despite the key role of memory T‐cells specific for human cytomegalovirus (hCMV) in protecting against hCMV‐reinfection early after immunodeficiency episodes, the precise characterization and definition of the essential components of a protective CD4 T‐cell response still remain to be established.We analyzed by flow cytometry hCMV‐specific immune responses driven by peripheral blood antigen‐presenting cells (APC) and CD4 memory T‐cells at both the cellular and soluble levels, and their cooperation in priming and sustaining the effector function of specific CD8 T cells in adult healthy individuals using a hCMV whole viral lysate stimulatory model.Overall, activated T‐cells showed a heterogeneous phenotype, with a marked predominance of CD45RA−/CCR7+/− memory CD4+ T‐cells. Despite this, cytoplasmic expression of granzyme B was found in both the CD45RA+/effector and CD45RA−/memory T‐cell compartments of the two major CD4+ and CD8+ activated T‐cell subpopulations, further confirming the presence of circulating antigen experienced cytotoxic CD4+ T cells in hCMV‐seropositive individuals. Moreover, we observed that both CD4+ and CD8+ hCMV‐specific T‐cells included relatively restricted numbers of TCR‐Vβ family members. Interestingly, we found a significant association between some HLA Class II and Class I haplotypes and the presence of specifically expanded TCR‐Vβ clones of anti‐hCMV T cells.These results indicate that hCMV‐specific memory T‐cells are phenotypically heterogeneous, their TCR‐Vβ repertoire shaped through the interaction between hCMV epitopes and the HLA haplotype. © 2007 Clinical Cytometry Society.

Monoclonal TCRαβ+/CD4+T-large granular lymphocyte (T-LGL) lymphocytosis is a T-cell disorder with a restricted TCR-Vβ repertoire. In the present study we explored the potential association between the expanded TCR-Vβ families, the CDR3 sequences of the TCR-Vβ gene, and the HLA genotype of patients with monoclonal TCRαβ+/CD4+T-LGL lymphocytosis. For that purpose, 36 patients with monoclonal TCRαβ+/CD4+T-LGL lymphocytosis (15 TCR-Vβ13.1 versus 21 non–TCR-Vβ13.1) were selected. For each patient, both the HLA (class I and II) genotype and the DNA sequences of the VDJ-rearranged TCR-Vβ were analyzed. Our results show a clear association between the TCR-Vβ repertoire and the HLA genotype, all TCR-Vβ13.1+cases being HLA-DRB1*0701 (P= .004). Interestingly, the HLA-DR7/TCR-Vβ13.1–restricted T-cell expansions displayed a highly homogeneous and strikingly similar TCR arising from the use of common TCR-Vβ gene segments, which shared (1) unique CDR3 structural features with a constantly short length, (2) similar combinatorial gene rearrangements with frequent usage of the Jβ1.1 gene, and (3) a homolog consensus protein sequence at recombination junctions. Overall, these findings strongly support the existence of a common antigen-driven origin for monoclonal CD4+T-LGL lymphocytosis, with the identification of the exact peptides presented to the expanded T cells deserving further investigations.

Monoclonal TCRαβ+/CD4+ T-large granular lymphocyte (T-LGL) lymphocytosis is a T-cell disorder with a restricted TCR-Vβ repertoire. In the present study we explored the potential association between the expanded TCR-Vβ families, the CDR3 sequences of the TCR-Vβ gene, and the HLA genotype of patients with monoclonal TCRαβ+/CD4+ T-LGL lymphocytosis. For that purpose, 36 patients with monoclonal TCRαβ+/CD4+ T-LGL lymphocytosis (15 TCR-Vβ13.1 versus 21 non–TCR-Vβ13.1) were selected. For each patient, both the HLA (class I and II) genotype and the DNA sequences of the VDJ-rearranged TCR-Vβ were analyzed. Our results show a clear association between the TCR-Vβ repertoire and the HLA genotype, all TCR-Vβ13.1+ cases being HLA-DRB1*0701 (P = .004). Interestingly, the HLA-DR7/TCR-Vβ13.1–restricted T-cell expansions displayed a highly homogeneous and strikingly similar TCR arising from the use of common TCR-Vβ gene segments, which shared (1) unique CDR3 structural features with a constantly short length, (2) similar combinatorial gene rearrangements with frequent usage of the Jβ1.1 gene, and (3) a homolog consensus protein sequence at recombination junctions. Overall, these findings strongly support the existence of a common antigen-driven origin for monoclonal CD4+ T-LGL lymphocytosis, with the identification of the exact peptides presented to the expanded T cells deserving further investigations.

Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56+, NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56−or expressed very low levels of CD56 (CD56−/+dimNK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56+NK cells, CD56−/+dimNK cells were granzyme B+, CD3−, TCRαβ/γδ−, CD5−, CD28−, CD11a+bright, CD45RA+bright, CD122+, and CD25−and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56−/+dim, they were CD11b−/+dim(heterogeneous), CD7−/+dim(heterogeneous), CD2+(homogeneous), CD11c+bright(homogeneous), and CD38−/+dim(heterogeneous). Moreover, CD56−/+dimNK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56−/+dimNK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56−/+dimshowed a typical Th1 pattern of cytokine production (interferon-γ+, tumor necrosis factor-α+). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56−/+dim/CD11b−/+dimphenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases.

Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally believed to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD cases with 2 or more B-cell clones were studied. Presence of 2 or more B-cell clones was suspected by immunophenotype and confirmed by molecular/genetic techniques in leukemic samples (n = 42) and purified B-cell subpopulations (n = 10). Overall, 4.8% of 477 consecutive B-CLPDs had 2 or more B-cell clones, their incidence being especially higher among hairy cell leukemia (3 of 13), large cell lymphoma (2 of 10), and atypical chronic lymphocytic leukemia (CLL) (4 of 29). In most cases the 2 B-cell subsets displayed either different surface immunoglobulin (sIg) light chain (n = 37 of 53) or different levels of the same sIg (n = 9 of 53), usually associated with other phenotypic differences. Compared with monoclonal cases, B-CLL patients with 2 or more clones had lower white blood cell (WBC) and lymphocyte counts, more frequently displayed splenomegaly, and required early treatment. Among these, the cases in which a CLL clone coexisted with a non-CLL clone were older and more often displayed B symptoms, a monoclonal component, and diffuse infiltration of bone marrow and required early treatment more frequently than cases with monoclonal CLL or 2 CLL clones.

Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally believed to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD cases with 2 or more B-cell clones were studied. Presence of 2 or more B-cell clones was suspected by immunophenotype and confirmed by molecular/genetic techniques in leukemic samples (n = 42) and purified B-cell subpopulations (n = 10). Overall, 4.8% of 477 consecutive B-CLPDs had 2 or more B-cell clones, their incidence being especially higher among hairy cell leukemia (3 of 13), large cell lymphoma (2 of 10), and atypical chronic lymphocytic leukemia (CLL) (4 of 29). In most cases the 2 B-cell subsets displayed either different surface immunoglobulin (sIg) light chain (n = 37 of 53) or different levels of the same sIg (n = 9 of 53), usually associated with other phenotypic differences. Compared with monoclonal cases, B-CLL patients with 2 or more clones had lower white blood cell (WBC) and lymphocyte counts, more frequently displayed splenomegaly, and required early treatment. Among these, the cases in which a CLL clone coexisted with a non-CLL clone were older and more often displayed B symptoms, a monoclonal component, and diffuse infiltration of bone marrow and required early treatment more frequently than cases with monoclonal CLL or 2 CLL clones.

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8+or less frequently natural killer cells; in contrast, monoclonal expansions of CD4+T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4+T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4+T cells of a series of 34 consecutive cases. Like CD8+T-LGL leukemias, CD4+T-LGL leukemia patients have an indolent disease; however, in contrast to CD8+T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4+T-LGLshowed expression of TCRαβ, variable levels of CD8 (CD8−/+dim) and a homogeneous typical cytotoxic (granzyme B+, CD56+, CD57+, CD11b+/−) and activated/memory T cell (CD2+bright, CD7−/+dim, CD11a+bright, CD28−, CD62L−HLA-DR+) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-γ++, tumor necrosis factor-α++, interleukin (IL-2)−/+, IL-4−, IL-10−, IL-13−]. Phenotypic analysis of the TCR-Vβ repertoire revealed large monoclonal TCR-Vβ expansions; only a restricted number of TCR-Vβ families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRαβ+/CD4+/NKa+/CD8−/+dimT-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8+T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder.

At present, a major challenge in the initial diagnosis of leukemia of large granular lymphocytes (LGLs) is to establish the clonal nature of the expanded population. In the present study we have analyzed by flow cytometry immunophenotyping the TCR-Vβ repertoire of 98 consecutive cases of persistent expansions of CD4+or CD8+brightCD3+/TCR-αβ+LGLs and compared the results with those obtained in molecular studies of TCR-β gene rearrangements. Fifty-eight cases were considered to be monoclonal in molecular studies whereas in the remaining 40 cases there was no evidence for monoclonality (11 cases were considered oligoclonal and 29 polyclonal). The TCR-Vβ repertoire was biased to the preferential use of one or more TCR-Vβ families in 96% of cases, a total of 124 TCR-Vβ expansions being diagnosed: one TCR-Vβ expansion in 71 cases and two or more TCR-Vβ expansions in 23 cases. The highest TCR-Vβ expansion observed in each case was higher among monoclonal (74 ± 19%) as compared to nonmonoclonal cases (24 ± 14%) (P= 0.001), as did the fraction of LGLs that exhibited a TCR-Vβ-restricted pattern (86 ± 16% and 42 ± 23%, respectively;P= 0.0001); by contrast, the proportion of cases displaying more than one TCR-Vβ expansion was higher in the latter group: 7%versus48%, respectively (P= 0.001). Results obtained in oligoclonal cases were intermediate between those obtained in polyclonal and monoclonal cases and similar results were observed for CD4+as for CD8+brightT-cell expansions. TCR-Vβ familiesexpressed in CD8+brightT-cell-LGL proliferations showed a pattern of distribution that mimics the frequency at which the individual TCR-Vβ families are represented in normal peripheral blood T cells. Assuming that a given proliferation of LGLs is monoclonal whenever there is an expansion of a given TCR-Vβ family of at least 40% of the total CD4+or CD8+brightT-cell compartment, we were able to predict clonality with a sensitivity of 93% and a specificity of 80%. By increasing the cut-off value to 60%, sensitivity and specificity were of 81% and 100%. In summary, our results suggest that flow cytometry immunophenotypic analysis of the TCR-Vβ repertoire is a powerful screening tool for the assessment of T-cell clonality in persistent expansions of TCR-αβ+LGLs.

Puig: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Ocio:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; Pharmamar: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; BMS: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Mateos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. San-Miguel:Celgene: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; MSD: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Brystol-Myers Squibb: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. García-Sanz:Incyte: Consultancy; Amgen Inc.: Research Funding; Gilead: Research Funding; Spanish Government: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses.

Introduction

INTRODUCTION:Infection complications are important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT), even in HLA-identical sibling donors. Although there are many studies associating single nucleotide polymorphisms (SNPs) and allo-SCT evolution, these are mainly related with graft versus host disease (GVHD) and/or transplant related mortality (TRM), with few focused on post-allo-SCT infections. This multicentric study analyzes the potential implication of SNPs with cytomegalovirus (CMV) reactivation and fungal infection (FI) development in allo-SCT with reduced intensity conditioning (RIC).

We report a patient who developed up to three different lymphomas with the same clonal IGH rearrangement. She was first diagnosed of splenic zone marginal lymphoma and relapsed for the first time with Hodgkin lymphoma histology and later with diffuse large B-cell lymphoma histology. Subsequent biopsies and analysis of clonally rearranged IGH genes helped to elucidate the clonal relationship between the three histologies and to confirm a common origin from the three tissue histologies. An integrated diagnosis should always be performed in order to achieve the most accurate diagnosis and be able to choose the best therapeutic options for our patients.

Mateos: Celgene: Consultancy, Honoraria; Takeda: Consultancy; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Puig:Janssen: Consultancy; The Binding Site: Consultancy.

Background:Waldenström's macroglobulinemia (WM) is a rare immunoproliferative neoplasia with indolent characteristics that shows important variability, involving three different stages of presentation: IgM Monoclonal Gammopathy of Undetermined Significance (IgM-MGUS), asymptomatic WM (AWM), and Symptomatic WM (SWM). Whole-genome sequencing and some specific approaches have identified MYD88L265P (90%) and CXCR4(29%) mutations as the most recurrent somatic mutations in WM. However, other genetic abnormalities under as well as the mechanisms responsible for this clinical heterogeneity still remain to be clarified. Therefore, our aim was to analyze the genomic landscape of WM, distinguishing between the three stages of the disease, by using a targeted next generation sequencing (NGS) strategy.

No relevant conflicts of interest to declare.

Multiple myeloma (MM) pathogenesis has been explained for many years by the cancer biology dogma introduced by Peter Nowell: first, a single plasma cell would be immortalized by an error in the immunoglobulin genes rearrangement process; then, a progressive stepwise acquisition of somatic cell mutations would induce a sequential selection and domination by the fittest clone. In line with this idea of “myeloma stability”, SNP arrays studies in diagnostic-relapse paired samples have revealed the presence of common clonal characteristics. Biologically, the M-protein remains usually constant across MM evolution and further, the variable domain of the rearranged immunoglobulin heavy chain genes (or CDR3 region) has been used as a patient-specific myeloma fingerprint in minimal residual disease (MRD) studies. However, massive genome studies with Next Generation Sequencing (NGS) have challenged this concept, showing a significant intraclonal heterogeneity at diagnosis with the possible presence of several clonal progenitors or tumor-initiating cells.

Acquired potentially N-glycosylation sites are produced by somatic hypermutation (SHM) in the immunoglobulin (Ig) variable region. This phenomenon is produced in ∼9% of normal B-cells and seems to be related to certain B-cell lymphoproliferative disorders (B-LPDs) such as follicular lymphoma (FL, 79%), endemic Burkitt lymphoma (BL, 82%) and diffuse large B-cell lymphoma (DLBCL, 41%). These data suggest that new potential N-glycosylation sites could be related to germinal center B (GCB)-LPDs. By contrast, in other B-LPDs, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), MALT lymphoma, Waldenström macroglobulinemia (WM) or multiple myeloma (MM), these modifications have not been analyzed in deep.To evaluate the acquisition of potential N-glycosylation sites in B-LPDs, including immunohystochemical DLBCL subtypes (GCB and non-GCB) and specific non-GCB-LPDs, such as hairy cell leukemia (HCL), splenic marginal-zone lymphoma (SMZL), CLL, MCL, ocular extranodal marginal zone lymphoma (OAEMZL), MM and WM.A total of 953 sequences (203 from our group and 750 previously published sequences) of B-LPDs were included. Diagnosis distribution was as follows: DLBCL (n=235), MCL (n=235), CLL (n=166), MM (n=96), OAEMZL (n=82), SMZL (n=68), WM (n=38) and HCL (n=33).Acquired N-glycosylation sites were counted according to the sequence Asn-X-Ser/Thr, where X could be any amino acid except Pro. Natural motifs in germline sequences of IGHV1–08, IGHV4–34 e IGHV-5a were not considered. Fisher test was used to perform comparisons between groups. To distinguish DLBCL biological subtypes (GCB and non-GCB DLBCL), Hans' algorithm was used.A total of 83 out of the 235 DLBCL cases acquired at least a new N-glycosylation site, a higher value than in normal B-cells (35% vs. 9%, p<0.0001). Higher incidence of these motifs in the group of GCB as compared to non-GCB DLBCL were observed (52% vs. 20%, p<0.0001). Those cases diagnosed of HCL, CLL, MCL, MM, WM, OAEMZL and SMZL presented a reduced number of new N-glycosylation sites, showing similar values than normal B-cells (range 3–18%, p=ns).We described for the first time the pattern of N-glycosylation in HCL, SMZL, OAEMZL and in the immunohystochemical DLBCL subtypes, where the GCB-DLBCL showed a higher number of new N-glycosylation sites with respect to non-GCB DLBCL and other non-GCB-LPDs. The presence of novel N-glycosylation sites in FL, BL and in GCB-DLBCL strongly suggests that these motifs are characteristic of the germinal center B-LPDs.No relevant conflicts of interest to declare.

The Human Leukocyte Antigen (HLA) system plays an important role in antitumor immune response. In the last years, different genome-wide association studies have suggested that 6p21.3 (which include HLA system), is a risk region for lymphoma susceptibility. It has been also reported that specific alleles could modify the prognosis in patients diagnosed of lymphoma, including diffuse large B cell lymphoma (DLBCL), treated without Rituximab.Our hypothesis is that HLA system could play an essential role in disease control of DLBCL. Here, we have evaluated the effect of HLA Class I (A, B and C) and II (DRB1 and DQB1) alleles in DLBCL incidence and survival.A total of 251 patients diagnosed of DLBCL according to the 2008 WHO classification were analyzed (68% of them received Rituximab-based regimens). Control population consisted in 1940 healthy donor individuals analyzed for HLA-A, B, and DRB1 alleles and 200 for HLA-C and HLA-DQB1.Overall survival (OS) was calculated from diagnosis until death for any cause. Event-free survival (EFS) was calculated from diagnosis until event defined as death for any cause, relapse or progression of the disease.Allele frequencies and Hardy-Weinberg equilibrium were estimated using the Arlequin software package, version 3.5.1.2. Comparison of allele and phenotype frequencies between populations was performed with the two-sided Fisher's exact test or χ2 test using GraphPad Prism 4.0 (GraphPad Software, Inc. San Diego, CA, USA) or SPSS software (SPSS 15.0, Inc. Chicago, IL, USA). P-value was adjusted applying a Bonferroni correction (Pc).The effect of biological and clinical variables on OS and EFS at five years was analyzed by univariate (two-sided log-rank test) and multivariate (Cox multivariate analysis) methods. Differences were considered to be statistically significant when P< 0.05.HLA specificities frequencies in patients and controls (Alcoceba et al, Tissue Antigens 2011) were consistent in all cases with the Hardy-Weinberg equilibrium.Phenotypic frequencies showed significant differences in DLBCL patients compared to control population. DRB1*01 frequency was increased in DLBCL patients (28.9% vs. 19.5%, p=0.0009, Pc=0.0117, OR: 1.68; 95% CI: 1.24–2.26). By contrast, DLBCL patients showed a lower frequency in C*03 allele as compared to the control population (6.4% vs. 18.3, p=0.0005, Pc=0.007, OR: 3.2, 95% CI: 1.62–6.3).As far as the outcome of patients was concerned, the presence of B*18 and/or B*44 was significantly associated with a worse EFS (32% vs. 60%, p<0.001 and 53% vs. 72%, p=0.025, respectively) and OS (41% vs. 78%, p<0.001, and 53% vs. 86%, p=0.006, respectively). These statistical differences were also observed in the group of patients receiving Rituximab-based regimens. The Cox multivariate analysis identified high International Prognostic Index and the presence of any B*18 or B*44 as independent adverse prognostic factors for EFS and OS.Our data revealed that HLA specificities could influence the incidence (DRB1*01 and C*03) and outcome (B*18 and B*44) of DLBCL. These results suggest a role for HLA in the immune-surveillance of DLBCL and, also open possibilities for future investigations to answer how a specific HLA allele could affect in DLBCL.No relevant conflicts of interest to declare.

Abstract 1589