Immunotherapy in aggressive B-cell lymphomas

The idea that the immune system could be co-opted to treat cancer is not new; it has existed for centuries. However, what is new is the advancement of our understanding of how the immune system is regulated and how a tumor evolves to evade an immune response. This knowledge, combined with modern technologies to manipulate the immune system, both pharmacologically and genetically, has led to the realization of immuno-oncology as a new frontier in cancer therapeutics. This review will focus on pharmacologic immunotherapies in aggressive B cell lymphomas: checkpoint inhibition and bispecific antibodies. The success of checkpoint inhibitors in this heterogenous collection of diseases has largely been limited to those that genetic aberrations involving genes for checkpoint ligands, whereas bispecific antibodies appear to be more broadly efficacious but responses are short-lived. Investigation into the tumor microenvironment for each of the aggressive B cell lymphoma histologies, and interrogation of mechanisms of resistance as well as predictors of response to these immunotherapy approaches, will undoubtedly identify rational combinations as well as new therapeutic targets such that outcomes can be improved across these diseases.     

Clinicopathologic features of adult EBV-associated B-cell lymphoproliferative disease

In the present study, 21 cases of adult/late-onset EBV-associated lymphoproliferative disease (AELPD) with an uncertain malignant potential were investigated with regard to their histomorphology, immunophenotype, clonal rearrangement of the heavy chain (IgH) and T-cell receptor (TCR) genes and clinical course.The cases were histomorphologically reevaluated and assigned to one of three morphological groups: mononucleosis-like, Hodgkin-like, or polymorphous. In addition, cases with or without detectable necrosis were investigated for differences in clinical outcome.Overall survival was highest in the group with Hodgkin-like morphology (4/4 patients), followed by patients with mononucleosis-like phenotype (4/5 patients surviving). Cases with polymorphous morphology showed the poorest survival rates with 7/12 patients dead of disease (58%). 4/6 patients with histologically detectable necrosis died (66%), but only 4/15 patients without necrosis (27%). 11/21 cases with AELPD showed clonal rearrangement for IgH (n?=?4), TCR (n?=?5) or IgH?+?TCR (n?=?2). 5/11 patients with clonal rearrangement died (45%), and this percentage was similar in all of the three subgroups.In conclusion, the present study shows that polymorphous morphology and detection of necrosis in AELPD are frequently linked to a fatal clinical course, whereas Hodgkin-like morphology seems to be associated with a more favourable prognosis. Clonal rearrangement of IgH or TCR is frequent in AELPD, but prognosis is unpredictable from this feature.     

Identification of potential drugs for diffuse large b-cell lymphoma based on bioinformatics and Connectivity Map database

Diffuse large B-cell lymphoma (DLBCL) is the most main subtype in non-Hodgkin lymphoma. After chemotherapy, about 30% of patients with DLBCL develop resistance and relapse. This study was to identify potential therapeutic drugs for DLBCL using the bioinformatics method. The differentially expressed genes (DEGs) between DLBCL and non-cancer samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. The R software package (SubpathwayMiner) was used to perform pathway analysis on DEGs affected by drugs found in the Connectivity Map (CMap) database. Protein–protein interaction (PPI) networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes online database and Cytoscape software. In order to identify potential novel drugs for DLBCL, the DLBCL-related pathways and drug-affected pathways were integrated. The results showed that 1927 DEGs were identified from TCGA and GEO. We found 54 significant pathways of DLBCL using KEGG pathway analysis. By integrating pathways, we identified five overlapping pathways and 47 drugs that affected these pathways. The PPI network analysis results showed that the CDK2 is closely associated with three overlapping pathways (cell cycle, p53 signaling pathway, and small cell lung cancer). The further literature verification results showed that etoposide, rinotecan, methotrexate, resveratrol, and irinotecan have been used as classic clinical drugs for DLBCL. Anisomycin, naproxen, gossypol, vorinostat, emetine, mycophenolic acid and daunorubicin also act on DLBCL. It was found through bioinformatics analysis that paclitaxel in the drug-pathway network can be used as a potential novel drug for DLBCL.     

Genomic Analysis Reveals Distinct Subtypes in Two Rare Cases of Primary Ovarian Lymphoma

Primary (localized) non-Hodgkin lymphoma (NHL) of the ovary is extremely rare; only a few cases have been reported in the literature. We report two cases of primary ovarian lymphoma (POL), one involving bilateral ovaries in a 15-year-old girl and other involving one ovary in a 5-year-old girl. This report describes detailed clinical, histopathological, and imaging findings, along with the review of literature of primary diffuse large B-cell lymphoma (DLBCL) arising from an ovary. In addition, we describe findings of targeted capture panel sequencing on both tumors and identify the major genetic mutations that are recurrently mutated in pan-cancers. Compared to the genomic mutation features of major subtypes of DLBCL, we distinguish that each POL belongs to distinctive subtypes, GCB (germinal center B-cell subtype) DLBCL and ABC (activated B-cell subtype) DLBCL, respectively. The findings from the genomic analysis may help to understand the pathogenesis of POL and to guide potential targeted therapy in the future.     

Modulación del cambio de isotipo de las inmunoglobulinas por señales del sistema inmunitario innato

Mature B cells emerge from the bone marrow and continue to diversify their immunoglobulin genes through 2 antigen-dependent processes known as somatic hypermutation and class switch recombination. These processes require AID, a DNA-editing enzyme. Although both processes predominantly occur in germinal center B cells engaged in a T cell-dependent (TD) antibody response against protein antigens recent, evidence shows that B cells receive additional help from invariant natural killer T cells, dendritic cells, and various granulocytes, including neutrophils, eosinophils, and basophils. These innate immune cells enhance TD antibody responses by delivering B-cell helper signals whether in germinal centers, postgerminal lymphoid centers, or the bone marrow. In addition to enhancing and complementing the B-cell helper activity of canonical T cells, invariant natural killer T cells, dendritic cells, and granulocytes can deliver T cell-independent B-cell helper signals at the mucosal interface and in the marginal zone of the spleen to initiate rapid innate-like antibody responses. In this review, we discuss recent advances in the role of innate cells in B-cell helper signals and in antibody diversification and production.     

A case of refractory polyarteritis nodosa successfully treated with rituximab

A 59-year-old man who presented with continuous fever, livedo reticularis, and left leg ischemia with multiple tibial artery stenosis and renal artery aneurysm, as demonstrated by arteriography, was diagnosed with polyarteritis nodosa (PAN) 6 years ago. Although he frequently relapsed in spite of intensive immunosuppressive therapies, the disease activity of PAN was controlled with repeated rituximab (RTX) therapies and steroid doses were tapered safely. Peripheral CD19⁺ B-cells disappeared soon after the 1st administration of RTX. Although CD19⁺ B-cells remained absent, 3.1% of CD3⁺CD20⁺ T-cells were observed in the peripheral blood prior to the 2nd administration of RTX. Recent studies have suggested the pathogenic role of CD3⁺CD20⁺ T-cells in autoimmune diseases in the context of RTX therapy; therefore, their roles in the pathogenesis of PAN also need to be considered.     

原发纵隔大B细胞淋巴瘤的研究进展

原发纵隔大B细胞淋巴瘤（PMBCL）是一种原发于纵隔的侵袭性大B细胞淋巴瘤，由于其独特的临床和组织学特征，世界卫生组织淋巴肿瘤分类将PMBCL重新分类为一个单独的实体。PMBCL的诊断主要依赖于病理学特征、影像学检查和临床特征等。当前针对PMBCL的治疗方案有很多种，最常用的是R-CHOP和R-EPOCH方案等。放疗对部分患者有益，但也可以导致远期毒性。新药的研发也在不断进行，包括嵌合抗原受体T细胞疗法、抗程序性死亡受体1药物等，治疗后疗效判断和指导下一步的治疗策略主要依赖PET-CT。     

Identification of protective B-cell epitopes of Atroxlysin-I: A metalloproteinase from Bothrops atrox snake venom

Atroxlysin-I (Atr-I) is a hemorrhagic snake venom metalloproteinase (SVMP) from Bothrops atrox venom, the snake responsible for the majority of bites in the north region of South America. SVMPs like Atr-I produce toxic effects in victims including hemorrhage, inflammation, necrosis and blood coagulation deficiency. Mapping of B-cell epitopes in SVMPs might result in the identification of non-toxic molecules capable of inducing neutralizing antibodies and improving the anti-venom therapy. Here, using the SPOT-synthesis technique we identified two epitopes located in the N-ter region of Atr-I (AtrEp1—²²YNGNSDKIRRRIHQM³⁶; and AtrEp2—⁵⁵GVEIWSNKDLINVQ⁶⁸). Based on the sequence of AtrEp1 and AtrEp2 a third peptide named Atr-I biepitope (AtrBiEp) was designed and synthesized (²³NGNSDKIRRRIH³⁴GG⁵⁵GVEIWSNKDLINVQ⁶⁸). AtrBiEp was used to immunize BALB/c mice. Anti-AtrBiEp serum cross-reacted against Atr-I in western blot and was able to fully neutralize the hemorrhagic activity of Atr-I. Our results provide a rational basis for the identification of neutralizing epitopes on Atr-I snake venom toxin and show that the use of synthetic peptides could improve the generation of immuno-therapeutics.