BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

The t(14;19)(q32;q13) often juxtaposes BCL3 with IGH resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3-rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in CLL but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter 4 tumors transformed to a large B-cell lymphoma. We designed a novel FISH assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively

BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively

Epstein–Barr Virus-Associated T- and NK-Cell Lymphoproliferative Diseases: A Review of Clinical and Pathological Features

Epstein–Barr virus (EBV) is a ubiquitous virus detected in up to 95% of the general population. Most people are asymptomatic, while some may develop a wide range of EBV-associated lymphoproliferative disorders (LPD). Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV. The 2017 World Health Organization (WHO) classification recognizes the following entities characterized by different outcomes: chronic active EBV infection of T- or NK-cell types (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, EBV-positive aggressive NK-cell leukemia, extra nodal NK/T-cell lymphoma nasal type, and the new provisional entity known as primary EBV-positive nodal T/NK-cell lymphoma. In addition, EBV associated-hemophagocytic lymphohistiocytosis is part of EBV-positive T/NK LPD, but has not been included in the WHO classification due to its reactive nature. Despite novel insights from high-throughput molecular studies, EBV-positive NK/T-cell LPD diagnoses remain challenging, especially because of their rarity and overlap. Until now, an accurate EBV-positive NK/T LPD diagnosis has been based on its clinical presentation and course correlated with its histological features. This review aims to summarize clinical, pathological and molecular features of EBV-positive T/NK LPD subtypes and to provide an overview of new understandings regarding these rare disorders

Current and Future Tools for Diagnosis of Kaposi’s Sarcoma

International audienceKaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized (AIDS-related, iatrogenic, endemic or classic KS). Although clinical examination is sufficient to diagnose cutaneous lesions of KS, additional explorations are necessary in order to detect lesions involving other organs. New histological markers have been developed in recent years concerning the detection of HHV-8 latent or lytic proteins in the lesions, helping to confirm the diagnosis when it is clinically doubtful. More recently, the evaluation of the local immune response has also been shown to provide some guidance in choosing the appropriate therapeutic option when necessary. We also review the indication and the results of conventional radiological imaging and of non-invasive imaging tools such as 18F-fluoro-deoxy-glucose positron emission tomography, thermography and laser Doppler imaging for the diagnosis of KS and for the follow-up of therapeutic response in patients requiring systemic treatment

Phenotypic and Histological Distribution Analysis Identify Mast Cell Heterogeneity in Non-Small Cell Lung Cancer

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). However, MCs have been only barely characterized in studies focusing on global immune infiltrate phenotyping. Consequently, their role in cancer is still poorly understood. Furthermore, their prognosis value is confusing since MCs have been associated with good and bad (or both) prognosis depending on the cancer type. In this pilot study performed on a surgical cohort of 48 patients with Non-Small Cell Lung Cancer (NSCLC), we characterized MC population within the TME and in matching non-lesional lung areas, by multicolor flow cytometry and confocal microscopy. Our results showed that tumor-associated MCs (TAMCs) harbor a distinct phenotype as compared with MCs present in non-lesional counterpart of the lung. Moreover, we found two TAMCs subsets based on the expression of CD103 (also named alphaE integrin). CD103+ TAMCs appeared more mature, more prone to interact with CD4+ T cells, and located closer to cancer cells than their CD103− counterpart. In spite of these characteristics, we did not observe a prognosis advantage of a high frequency of CD103+ TAMCs, while a high frequency of total TAMC correlated with better overall survival and progression free survival. Together, this study reveals that TAMCs constitute a heterogeneous population and indicates that MC subsets should be considered for patients’ stratification and management in future research

Histological Subtypes Drive Distinct Prognostic Immune Signatures in Classical Hodgkin Lymphoma

International audienceSimple Summary Classical Hodgkin lymphoma (cHL) is a highly curable disease, with about 80% of patients cured using standard first-line chemotherapy. However, outcomes for relapsed/refractory patients remain unfavorable and there is a critical lack of predictive biomarkers for early identification of these patients who may benefit from new therapeutic strategies. Here we evaluated the dynamic expression of 586 immune-related genes in a cohort of 42 cHL patients using NanoString technology. We identified a 19-gene immune signature predictive of relapse at the time of diagnosis, which was found to be strongly dependent on histological subtype. Moreover, comparative analyses between paired diagnostic/relapsed biopsies of nodular sclerosis cHL showed 118 differentially expressed genes, highlighting an immune contexture shift at relapse not found in mixed-cellularity cases. Overall, these results strongly suggest that the predictive value of immune signature in cHL is influenced by histological subtype, a criterion that should be considered when assessing new immunotherapy strategies. Despite the success of standard front-line chemotherapy, 20% of classical Hodgkin lymphoma (cHL) patients still relapse or have refractory disease (r/r), and a subset of them die due to disease progression. There is a critical lack of predictive factors for early identification of those r/r patients who may benefit from new therapeutic strategies. This study aimed to evaluate the dynamic expression of 586 immune-related genes in a cohort of 42 cHL patients including 30 r/r cHL after first-line chemotherapy. Gene expression profiling (GEP) using NanoString technology identified a 19-gene immune signature at diagnosis predictive of cHL relapse, but dependent on histological subtypes. Genes related to tumor survival were found upregulated while genes related to B-lineage were downregulated at diagnosis in r/r nodular sclerosis cHL. In contrast to the mixed-cellularity subtype, comparative GEP analyses between paired diagnosis/relapse biopsies of nodular sclerosis cHL showed 118 differentially expressed genes, supporting an immune contexture switch at relapse with upregulation of immunosuppressive cytokines, such as LGALS1 and TGFB1, and downregulation of the T-cell co-stimulatory receptor ICOS. These results indicate that the predictive value of immune signature in cHL is strongly influenced by histological subtype which should be considered when assessing new immunotherapy target strategies

Designing and demonstrating a Master student project to explore carbon dioxide capture technology

International audienceThe rise in carbon dioxide (CO2) concentration in the Earth's atmosphere, and the associated strengthening of the greenhouse effect, requires the development of low carbon technologies. New carbon capture processes are being developed to remove CO2 that would otherwise. be emitted from industrial processes and fossil fuel power stations. Given the increasing importance of this technology, we report on a new educational project, which is aimed to instill greater awareness of the role of CO2 in climate change while stimulating student interest in science, technology, engineering, and the environment. The project was carried out by master students, that is, Cool(L)Cap team, who contributed to the design and manufacture of a pilot plant that demonstrates the basic operation of an amine scrubbing plant. The main goal of. the project was to develop educational material and presentations for a range of audiences, from primary school to university students and academics. In this article, we present the project team's approach to design, commission, and deliver the pilot plant and educational material as well as the feedback received from 267 students from a primary school and a university. We provide additional information to enable other educators to recreate our pilot plant design

Using a contextualized sensemaking model for interaction design: A case study of tumor contouring

Sensemaking theories help designers understand the cognitive processes of a user when he/she performs a complicated task. This paper introduces a two-step approach of incorporating sensemaking support within the design of health information systems by: (1) modeling the sensemaking process of physicians while performing a task, and (2) identifying software interaction design requirements that support sensemaking based on this model. The two-step approach is presented based on a case study of the tumor contouring clinical task for radiotherapy planning. In the first step of the approach, a contextualized sensemaking model was developed to describe the sensemaking process based on the goal, the workflow and the context of the task. In the second step, based on a research software prototype, an experiment was conducted where three contouring tasks were performed by eight physicians respectively. Four types of navigation interactions and five types of interaction sequence patterns were identified by analyzing<br/>the gathered interaction log data from those twenty-four cases. Further in-depth study on each of the navigation interactions and interaction sequence patterns in relation to the contextualized sensemaking model revealed five main areas for design improvements to increase sensemaking support. Outcomes of the case study indicate that the proposed two-step approach was beneficial for gaining a deeper understanding of the sensemaking process during the task, as well as for identifying design requirements for<br/>better sensemaking support