Diffuse large B-cell lymphoma Li, Shaoying; Young, Ken H.; Medeiros, L. Jeffrey
Pathology,
January 2018, 2018-Jan, 2018-01-00, 20180101, Letnik:
50, Številka:
1
Journal Article
Recenzirano
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, representing approximately 30–40% of all cases in different geographic regions. Patients most often ...present with a rapidly growing tumour mass in single or multiple, nodal or extranodal sites. The most common type of DLBCL, designated as not otherwise specified, represents 80–85% of all cases and is the focus of this review. There are also rare types of lymphoma composed of large B-cells, in aggregate about 15–20% of all neoplasms that are sufficiently distinctive to recognise separately. DLBCL not otherwise specified (referred to henceforth as DLBCL) is a heterogeneous entity in terms of clinical presentation, genetic findings, response to therapy, and prognosis. A major advance was the application of gene expression profiling (GEP) to the study of DLBCL which further clarified this heterogeneity and provided a rationale for subdividing cases into groups. The most popular system divides cases of DLBCL according to cell-of-origin into germinal centre B-cell like (GCB) and activated B-cell like (ABC) subtypes, with about 10–15% of cases being unclassifiable. Patients with the GCB subtype usually have better prognosis than patients with the ABC subtype. Although cell-of-origin is useful for predicting outcome, the GCB and ABC subtypes remain heterogeneous, with better and worse prognostic subsets within each group. Next generation sequencing (NGS) analysis of DLBCL has facilitated global identification of numerous and diverse genetic abnormalities in these neoplasms and has shown that GCB and ABC tumours have different mutation profiles. Although the therapy of patients with DLBCL is an active area of research, the current 5-year overall survival rate is 60–70% using standard-of-care frontline therapy. A precision medicine approach for the design of new therapies based on molecular findings in DLBCL is likely the best path forward. As pathologists, our role has expanded beyond diagnosis. We must perform a complete work-up of DLBCL cases. In addition to our traditional role in establishing the diagnosis, we need to analyse markers that provide information regarding prognosis and potential therapeutic targets. We also must ensure that adequate tissue is triaged for molecular studies which are essential for designing therapy regimens, particularly in the setting of disease relapse.
In this work, the hydrogen’s ionization energy was used to constrain the free parameter
b
of three Born–Infeld-like electrodynamics namely Born–Infeld itself, Logarithmic electrodynamics and ...Exponential electrodynamics. An analytical methodology capable of calculating the hydrogen ground state energy level correction for a generic nonlinear electrodynamics was developed. Using the experimental uncertainty in the ground state energy of the hydrogen atom, the bound
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×
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, where
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=
2
,
4
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and
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for the Born–Infeld, Logarithmic and Exponential electrodynamics respectively, was established. In the particular case of Born–Infeld electrodynamics, the constraint found for
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was compared with other constraints present in the literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of ...SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.
8p11 myeloproliferative syndrome: a review Jackson, Courtney C., MD; Medeiros, L. Jeffrey, MD; Miranda, Roberto N., MD
Human pathology,
04/2010, Letnik:
41, Številka:
4
Journal Article
Recenzirano
Summary The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 tyrosine kinase gene on chromosome ...8p11-12. By our count, 65 cases are currently reported in the literature. This neoplasm affects patients of all ages, with a slight male predominance. Patients often present with peripheral blood eosinophilia without basophilia. Bone marrow examination commonly is hypercellular, with or without eosinophilia, which usually leads to the initial diagnosis of a myeloproliferative neoplasm. Many patients also present with or develop lymphadenopathy. Lymph node biopsy in these patients has commonly shown lymphoblastic leukemia/lymphoma, most often reported as being of T-cell lineage, but bilineal myeloid/T-cell lymphomas and less often a myeloid sarcoma are also reported. The natural history of this neoplasm is to evolve into acute leukemia, usually of myeloid or mixed lineage, and less frequently of T- or B-lymphoid lineage. The prognosis is poor despite aggressive chemotherapy, with a few patients achieving long clinical remission after stem cell transplantation. At the molecular level, all cases carry a chromosomal abnormality involving the fibroblast growth factor receptor 1 ( FGFR1 ) gene at chromosome 8p11, where 10 translocations and 1 insertion have been identified. These abnormalities disrupt the FGFR1 and various partner genes, and result in the creation of novel fusion genes and chimeric proteins. The latter include the N-terminal portion of the partner genes and the C-terminal portion of FGFR1. The most common partner is ZNF198 on chromosome 13q12. In the current World Health Organization classification, the 8p11 myeloproliferative syndrome is designated as “myeloid and lymphoid neoplasms with FGFR1 abnormalities.”
Routine molecular testing in acute myeloid leukemia involves screening several genes of therapeutic and prognostic significance for mutations. A comprehensive analysis using single-gene assays ...requires large amounts of DNA, is cumbersome and timely consolidation of results for clinical reporting is challenging. High throughput, next-generation sequencing platforms widely used in research have not been tested vigorously for clinical application. Here we describe the clinical application of MiSeq, a next-generation sequencing platform to screen mutational hotspots in 54 cancer-related genes including genes relevant in acute myeloid leukemia (NRAS, KRAS, FLT3, NPM1, DNMT3A, IDH1/2, JAK2, KIT and EZH2). We sequenced 63 samples from patients with acute myeloid leukemia/myelodysplastic syndrome using MiSeq and compared the results with those obtained using another next-generation sequencing platform, Ion-Torrent Personal Genome Machine and other conventional testing platforms. MiSeq detected a total of 100 single nucleotide variants and 23 NPM1 insertions that were confirmed by Ion Torrent or conventional platforms, indicating complete concordance. FLT3-internal tandem duplications (n=10) were not detected; however, re-analysis of the MiSeq output by Pindel, an indel detection algorithm, did detect them. Dilution studies of cancer cell-line DNA showed that the quantitative accuracy of mutation detection was up to an allelic frequency of 1.5% with a high level of inter- and intra-run assay reproducibility, suggesting potential utility for monitoring response to therapy, clonal heterogeneity and evolution. Examples demonstrating the advantages of MiSeq over conventional platforms for disease monitoring are provided. Easy work-flow, high throughput multiplexing capability, 4-day turnaround time and simultaneous assessment of routinely tested and emerging markers make MiSeq highly applicable for clinical molecular testing in acute myeloid leukemia.
Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might ...identify biomarkers that predict the efficacy of immunotherapy with anti–programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell–derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1+ B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.
•BCR-mediated NFATc1 activation stimulates the immunosuppressive IL-10/STAT3/PD-L1 signaling pathway in DLBCL cells.•Small molecule inhibitors of BTK block BCR-mediated NFATc1 activation and, thereby, downregulate IL-10/STAT3/PD-L1 signaling in DLBCL cells.
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Diffuse large B-cell lymphoma variants: an update Sukswai, Narittee; Lyapichev, Kirill; Khoury, Joseph D. ...
Pathology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, representing approximately one-third of all cases worldwide. In the World Health Organization (WHO) classification of ...lymphomas, most cases of DLBCL are designated as not otherwise specified (NOS). About 20% of cases, however, are designated as specific variants of DLBCL. These variants, 13 in total, are specified on the basis of distinctive morphological or immunophenotypic findings or distinctive biological or clinical issues associated with their diagnoses. In this review we discuss the following variants: T-cell/histiocyte-rich large B-cell lymphoma; ALK-positive large B-cell lymphoma; plasmablastic lymphoma; intravascular large B-cell lymphoma; large B-cell lymphoma with IRF4 rearrangement; primary mediastinal large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, leg type; primary diffuse large B-cell lymphoma of the central nervous system; diffuse large B-cell lymphoma associated with chronic inflammation; lymphomatoid granulomatosis; primary effusion lymphoma; and HHV8-positive diffuse large B-cell lymphoma, NOS. Two additional variants recognised in the WHO classification, EBV-positive diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer are discussed elsewhere in another review within this issue of Pathology. Although not recognised as a specific variant in the current WHO classification, primary testicular diffuse large B-cell lymphoma also has unique biological features and requires some modification of the standard treatment approach for patients with DLBCL. Therefore, we suggest that primary testicular diffuse large B-cell lymphoma also should be recognised as a specific variant of DLBCL in a future version of the WHO classification.
Pure erythroid leukemia Wang, Wei; Wang, Sa A.; Medeiros, L. Jeffrey ...
American journal of hematology,
March 2017, 2017-03-00, 20170301, Letnik:
92, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous ...2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area.
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