306 results on '"Lymphoma, B-Cell blood"'
Search Results
2. Inflammatory and subtype-dependent serum protein signatures predict survival beyond the ctDNA in aggressive B cell lymphomas.
- Author
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Arffman M, Meriranta L, Autio M, Holte H, Jørgensen J, Brown P, Jyrkkiö S, Jerkeman M, Drott K, Fluge Ø, Björkholm M, Karjalainen-Lindsberg ML, Beiske K, Pedersen MØ, Leivonen SK, and Leppä S
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Blood Proteins genetics, Blood Proteins analysis, Inflammation blood, Inflammation genetics, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Lymphoma, B-Cell mortality, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Prognosis, Tumor Microenvironment immunology, Tumor Microenvironment genetics, Circulating Tumor DNA blood, Circulating Tumor DNA genetics
- Abstract
Background: Biological heterogeneity of large B cell lymphomas (LBCLs) is poorly captured by current prognostic tools, hampering optimal treatment decisions., Methods: We dissected the levels of 1,463 serum proteins in a uniformly treated trial cohort of 109 patients with high-risk primary LBCL (ClinicalTrials.gov: NCT01325194) and correlated the profiles with molecular data from tumor tissue and circulating tumor DNA (ctDNA) together with clinical data., Findings: We discovered clinically and biologically relevant associations beyond established clinical estimates and ctDNA. We identified an inflamed serum protein profile, which reflected host response to lymphoma, associated with inflamed and exhausted tumor microenvironment features and high ctDNA burden, and translated to poor outcome. We composed an inflammation score based on the identified inflammatory proteins and used the score to predict survival in an independent LBCL trial cohort (ClinicalTrials.gov: NCT03293173). Furthermore, joint analyses with ctDNA uncovered multiple serum proteins that correlate with tumor burden. We found that SERPINA9, TACI, and TARC complement minimally invasive subtype profiling and that TACI and TARC can be used to evaluate treatment response in a subtype-dependent manner in the liquid biopsy., Conclusions: Altogether, we discovered distinct serum protein landscapes that dissect the heterogeneity of LBCLs and provide agile, minimally invasive tools for precision oncology., Funding: This research was funded by grants from the Research Council of Finland, Finnish Cancer Organizations, Sigrid Juselius Foundation, University of Helsinki, iCAN Digital Precision Cancer Medicine Flagship, Orion Research Foundation sr, and Helsinki University Hospital., Competing Interests: Declaration of interests H.H. (all outside of the submitted work): Genmab: honoraria, safety committee; Gilead: honoraria, advisory board; Incyte: honoraria, advisory board; Nordic Nanovector: honoraria, safety committee; Novartis: honoraria, advisory board; Takeda: honoraria, advisory board. J.J. (all outside of the submitted work): BMS: consultancy; Gilead: consultancy; Incyte: consultancy; Novartis: consultancy; Orion Pharma: consultancy; Roche: consultancy. M.B. (all outside of the submitted work): Astra Zeneca: consultancy; BMS/Celgene: consultancy; Incyte: consultancy; Janssen: consultancy; Mundipharma: consultancy; Nanexa: consultancy; Pfizer: consultancy; Roche: consultancy; Schain Research: consultancy; WntResearch: consultancy. M.J. (all outside of the submitted work): Abbvie: honoraria, research funding; Astra Zeneca: honoraria, research funding; BMS: honoraria, research funding; Genmab: honoraria; Incyte: honoraria; Janssen: honoraria, research funding; Kite/Gilead: consultancy, honoraria, research funding; Novartis: honoraria; Orion: honoraria; Roche: honoraria, research funding. S.L. (all outside of the submitted work): Genmab: consultancy, research funding; Gilead: consultancy; Incyte: consultancy; Nordic Nanovector: research funding; Novartis: consultancy, honoraria, research funding; Roche: consultancy, research funding; Merck: consultancy; Bayer: research funding; Celgene: consultancy, research funding; Orion: consultancy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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3. CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells.
- Author
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Storci G, De Felice F, Ricci F, Santi S, Messelodi D, Bertuccio SN, Laprovitera N, Dicataldo M, Rossini L, De Matteis S, Casadei B, Vaglio F, Ursi M, Barbato F, Roberto M, Guarino M, Asioli GM, Arpinati M, Cortelli P, Maffini E, Tomassini E, Tassoni M, Cavallo C, Iannotta F, Naddeo M, Tazzari PL, Dan E, Pellegrini C, Guadagnuolo S, Carella M, Sinigaglia B, Pirazzini C, Severi C, Garagnani P, Kwiatkowska KM, Ferracin M, Zinzani PL, Bonafè M, and Bonifazi F
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Aged, Receptors, Chimeric Antigen immunology, Prospective Studies, Extracellular Vesicles immunology, Extracellular Vesicles metabolism, Immunotherapy, Adoptive, Antigens, CD19 immunology, Lymphoma, B-Cell immunology, Lymphoma, B-Cell therapy, Lymphoma, B-Cell blood
- Abstract
BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).
- Published
- 2024
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4. Hematological ratios and indices in canine large B-cell lymphoma.
- Author
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Gavazza A, Cremonini V, Miglio A, Starita C, Rossi G, and Antognoni MT
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- Dogs, Animals, Retrospective Studies, Case-Control Studies, Male, Female, Blood Cell Count veterinary, Lymphoma, Large B-Cell, Diffuse veterinary, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, B-Cell veterinary, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Prognosis, Dog Diseases blood, Dog Diseases diagnosis
- Abstract
Background: Canine lymphoma is the most common hematopoietic cancer in dogs. Numerous studies have evaluated the prognostic value of hematological abnormalities and ratios in both humans and dogs with lymphoma., Aim: To compare hematological parameters and complete blood count ratios between a population of dogs affected by lymphoma and healthy dogs to identify potential prognostic markers for lymphoma., Methods: This retrospective case-control study compares hematological parameters and complete blood count ratios between a population of 114 dogs affected by multicentric large B-cell lymphoma (LBCL) and 60 healthy dogs., Results: The study found several statistically significant differences between the hematological indices of LBCL dogs and healthy dogs, but no correlation between these parameters and the survival times of 78 dogs treated with chemotherapy Madison Wisconsin protocol. In addition, hematological alterations were evaluated such as anemia, leukocytosis, and thrombocytopenia., Conclusion: Hematological ratios have been suggested as potential prognostic markers for canine LBCL but their real prognostic value remains controversial and requires future investigation., Competing Interests: The authors declare that there is no conflict of interest.
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- 2024
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5. Impact of anti-CD20 monoclonal antibodies on serologic response to BNT162b2 vaccine in B-cell Non-Hodgkin's lymphomas.
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Marchesi F, Pimpinelli F, Giannarelli D, Ronchetti L, Papa E, Falcucci P, Pontone M, Di Domenico EG, di Martino S, Laquintana V, Mandoj C, Conti L, Cordone I, La Malfa A, Viggiani C, Renzi D, Palombi F, Romano A, Pisani F, Gumenyuk S, Di Bella O, Vujovic B, Morrone A, Ciliberto G, Ensoli F, and Mengarelli A
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Follow-Up Studies, Prognosis, Antibodies, Monoclonal therapeutic use, Antigens, CD20 immunology, BNT162 Vaccine administration & dosage, COVID-19 immunology, COVID-19 prevention & control, Lymphoma, B-Cell blood, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell virology, Lymphoma, Non-Hodgkin blood, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin virology
- Published
- 2022
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6. Clinical Efficacy of Bendamustine Plus Rituximab (BR) for B-cell Relevant Indolent Non-Hodgkin's Lymphoma and Role of β 2-MG in Predicting the Efficacy of BR Regimen: A Real-World Retrospective Study in China.
- Author
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Zhang Y, He D, He J, Huang W, Yang Y, Cai Z, and Zhao Y
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- Aged, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Biomarkers, Tumor blood, China, Computational Biology, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Proportional Hazards Models, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bendamustine Hydrochloride administration & dosage, Lymphoma, B-Cell blood, Lymphoma, B-Cell drug therapy, Rituximab administration & dosage, beta 2-Microglobulin blood
- Abstract
Background: Domestic bendamustine has been approved for appearing on the market in China in the past two years. The report on bendamustine plus rituximab (BR) in the treatment of Chinese B-cell-associated indolent non-Hodgkin's lymphoma (iNHL) has not yet been published. This study probed into clinical efficacy of the BR regimen for B-cell-associated iNHL in China as well as the value of β 2-microglobulin ( β 2-MG) as a prognostic factor., Methods: We retrospectively analyzed clinical data of 73 B-cell-associated iNHL patients who received BR treatment in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 2020 to January 2021, including clinical characteristics, therapies, therapeutic efficacy, and prognosis-related factors. Thirty-three patients (45.2%) did not receive any other treatment before the BR regimen, and other patients received CHOP, R-CHOP, and other regimens in the past. The cutoff date for follow-up was May 2021. Clinical characteristics of patients were analyzed. The clinical efficacy of the BR regimen was evaluated. Differences of β 2-MG expression before and after treatment were analyzed between the CR+PR group and the SD+PD group. Main outcomes were progression-free survival (PFS) and overall survival (OS). A multivariate Cox regression model was taken to analyze prognostic factors relative to survival rate of patients, and adverse events (AEs) during treatment., Results: The objective response rate (ORR) of B-cell-associated iNHL patients who received BR regimen as first-/multiline treatment was 79.5%, with complete response (CR) of 37.0%, partial response (PR) of 42.5%, median PFS of 12.1 months (95% confidence interval (CI): 10.9-13.2), and median OS of 15.5 months (95% CI: 14.8-16.1). Before treatment, there was no statistical significance in the β 2-MG level between the CR+PR group and the SD+PD group ( p > 0.05). After treatment, the β 2-MG level in the CR group was noticeably lower than that in the SD+PD group ( p < 0.05). The β 2-MG level in the CR+PR group decreased conspicuously after treatment ( p < 0.05). The β 2-MG level in the SD+PD group after treatment was not notably different from that before treatment ( p > 0.05). According to the median expression level of β 2-MG before treatment, patients were divided into two groups. The average PFS of the low expression group was 12.69 ± 0.77 months, which was longer than the high expression group (10.13 ± 0.74 months), but the difference between the groups was not statistically significant ( p > 0.05). Multivariate Cox regression analysis showed that B-cell-associated iNHL subtype was the independent prognostic marker most likely to affect PFS of patients ( p = 0.051). Incidence of any grade of AEs in all patients was 32.9% (24/73)., Conclusion: B-cell-associated iNHL patients who received BR regimen had favorable clinical efficacy and were tolerable to AEs. Though the β 2-MG level in this study could not be used to predict clinical outcome, a lower level before treatment seemed to be implicated in better survival outcomes of patients. Our research also unraveled that B-cell-associated iNHL subtype may be a key factor to patient's prognosis. Overall, this study offers some important insights into clinical application of the BR regimen for Chinese B-cell-associated iNHL patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Yujie Zhang et al.)
- Published
- 2022
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7. cfDNA-Based NGS IG Analysis in Lymphoma.
- Author
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Pott C, Kotrova M, Darzentas N, Brüggemann M, and Khouja M
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- Biomarkers, Tumor blood, Clone Cells, Humans, Immunoglobulins genetics, Liquid Biopsy methods, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics, Cell-Free Nucleic Acids blood, Cell-Free Nucleic Acids genetics, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Gene Rearrangement genetics, Genes, Immunoglobulin genetics, Lymphoma blood, Lymphoma diagnosis, Lymphoma genetics, Neoplasm, Residual blood, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics
- Abstract
Liquid biopsy is a novel diagnostic approach at first developed to characterize the molecular profile of solid tumors by analyzing body fluids. For cancer patients, it represents a noninvasive way to monitor the status of the solid tumor with respect to representative biomarkers. There is growing interest in the utilization of circulating tumor DNA (ctDNA) analysis also in the diagnostic and prognostic fields of lymphomas. Clonal immunoglobulin (IG) gene rearrangements are fingerprints of the respective lymphoid malignancy and thus are highly suited as specific molecular targets for minimal residual disease (MRD) detection. Tracing of the clonal IG rearrangement patterns in ctDNA pool during treatment can be used for MRD assessment in B-cell lymphomas. Here, we describe a reproducible next-generation sequencing assay to identify and characterize clonal IG gene rearrangements for MRD detection in cell-free DNA., (© 2022. The Author(s).)
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- 2022
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8. PCR-Free Shallow Whole Genome Sequencing for Chromosomal Copy Number Detection from Plasma of Cancer Patients Is an Efficient Alternative to the Conventional PCR-Based Approach.
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Beagan JJ, Drees EEE, Stathi P, Eijk PP, Meulenbroeks L, Kessler F, Middeldorp JM, Pegtel DM, Zijlstra JM, Sie D, Heideman DAM, Thunnissen E, Smit L, de Jong D, Mouliere F, Ylstra B, Roemer MGM, and van Dijk E
- Subjects
- Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Blood Specimen Collection methods, Carcinoma, Non-Small-Cell Lung diagnosis, Case-Control Studies, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Feasibility Studies, Humans, Leukemia, Myeloid, Acute diagnosis, Limit of Detection, Liquid Biopsy, Longitudinal Studies, Lung Neoplasms diagnosis, Lymphoma, B-Cell diagnosis, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung genetics, DNA Copy Number Variations, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute genetics, Lung Neoplasms blood, Lung Neoplasms genetics, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Polymerase Chain Reaction methods, Whole Genome Sequencing methods
- Abstract
Somatic copy number alterations can be detected in cell-free DNA (cfDNA) by shallow whole genome sequencing (sWGS). PCR is typically included in library preparations, but a PCR-free method could serve as a high-throughput alternative. To evaluate a PCR-free method for research and diagnostics, archival peripheral blood or bone marrow plasma samples, collected in EDTA- or lithium-heparin-containing tubes, were collected from patients with non-small-cell lung cancer (n = 10 longitudinal samples; 4 patients), B-cell lymphoma (n = 31), and acute myeloid leukemia (n = 15), or from healthy donors (n = 14). sWGS was performed on PCR-free and PCR library preparations, and the mapping quality, percentage of unique reads, genome coverage, fragment lengths, and copy number profiles were compared. The percentage of unique reads was significantly higher for PCR-free method compared with PCR method, independent of the type of collection tube: EDTA PCR-free method, 96.4% (n = 35); EDTA PCR method, 85.1% (n = 32); heparin PCR-free method, 94.5% (n = 25); and heparin PCR method, 89.4% (n = 10). All other evaluated metrics were highly comparable for PCR-free and PCR library preparations. These results demonstrate the feasibility of somatic copy number alteration detection by PCR-free sWGS using cfDNA from plasma collected in EDTA- or lithium-heparin-containing tubes and pave the way for an automated cfDNA analysis workflow for samples from cancer patients., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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9. Characterizing circulating nucleosomes in the plasma of dogs with lymphoma.
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Dolan C, Miller T, Jill J, Terrell J, Kelly TK, Bygott T, and Wilson-Robles H
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- Animals, Case-Control Studies, Dogs, Lymphoma, B-Cell blood, Lymphoma, T-Cell blood, Dog Diseases blood, Lymphoma, B-Cell veterinary, Lymphoma, T-Cell veterinary, Nucleosomes
- Abstract
Background: Nucleosomes consist of DNA wrapped around a histone octamer core like beads on a string so that DNA can be condensed as chromatin into chromosomes. Diseases such as cancer or inflammation lead to cell death where chromatin is fragmentated and released as mononucleosomes into the blood. The Nu.Q™ H3.1 assay measures total nucleosome concentration in plasma of humans and has been used to detect and identify cancer even at early stages. The objectives of this study were to determine if nucleosome levels could be used to distinguish between healthy dogs and dogs with various stages of lymphoma (LSA) using the Nu.Q™ H3.1 assay. A total of 126 dogs diagnosed with LSA and 134 healthy controls were recruited for this study. Plasma was collected from each dog and stored in K2-EDTA tubes. The LSA patient samples were recruited from TAMU or purchased from various biobanks. All control cases were recruited from TAMU., Results: Dogs with LSA had an approximately 7-fold increase in their plasma nucleosome concentrations compared to controls (AUC 87.8%). Nucleosome concentrations increased with cancer stage and dogs with B cell lymphomas had significantly higher nucleosome concentrations than dogs with T cell lymphomas., Conclusions: The Nu.Q™ H3.1 assay was able to reliably detect elevated nucleosome concentrations in the plasma of dogs with LSA. Furthermore, it appears that nucleosomes are useful for differentiating cancer from healthy individuals in canines., (© 2021. The Author(s).)
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- 2021
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10. Soluble programmed cell death protein 1 (sPD-1) and the soluble programmed cell death ligands 1 and 2 (sPD-L1 and sPD-L2) in lymphoid malignancies.
- Author
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Mortensen JB, Monrad I, Enemark MB, Ludvigsen M, Kamper P, Bjerre M, and d'Amore F
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- Adult, Apoptosis, B7-H1 Antigen chemistry, Blood Donors, Case-Control Studies, Cell Count, Diagnostic Tests, Routine, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunotherapy, Ligands, Lymphoma, B-Cell immunology, Lymphoma, B-Cell metabolism, Male, Middle Aged, Prognosis, Programmed Cell Death 1 Ligand 2 Protein chemistry, Programmed Cell Death 1 Receptor chemistry, B7-H1 Antigen blood, Biomarkers, Tumor blood, Gene Expression Regulation, Leukemic, Leukemia blood, Lymphoma, B-Cell blood, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, T-Cell blood, Programmed Cell Death 1 Ligand 2 Protein blood, Programmed Cell Death 1 Receptor blood
- Abstract
Background: The programmed cell death protein 1 (PD-1) and its ligand 1 and 2 (PD-L1/PD-L2) regulate the immune system, and the checkpoint pathway can be exploited by malignant cells to evade anti-tumor immune response. Soluble forms (sPD-1/sPD-L1/sPD-L2) exist in the peripheral blood, but their biological and clinical significance is unclear., Method: Time-resolved immunofluorometric assay (TRIFMA) and enzyme-linked immunosorbent assay (ELISA) were used to measure sPD-1, sPD-L1, and sPD-L2 levels in serum from 131 lymphoma patients and 22 healthy individuals., Results: Patients had higher sPD-1 and sPD-L2 levels than healthy individuals. In diffuse large B-cell lymphoma, patients with high International Prognostic Index score had higher sPD-1 levels and sPD-L2 levels correlated with subtype according to cell of origin. Compared to other lymphoma types, follicular lymphoma displayed higher sPD-1 and lower sPD-L1 levels along with lower ligand/receptor ratios., Conclusion: This is the first study to simultaneously characterize pretherapeutic sPD-1, sPD-L1, and sPD-L2 in a variety of lymphoma subtypes. The relation between higher sPD-1 levels and adverse prognostic factors suggests a possible biological role and potential clinical usefulness of sPD-1. Moreover, the reverse expression pattern in follicular lymphoma and T-cell lymphoma/leukemia may reflect biological information relevant for immunotherapy targeting the PD-1 pathway., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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11. Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma.
- Author
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Liu M, Deng H, Mu J, Li Q, Pu Y, Jiang Y, Deng Q, and Qian Z
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- Adenine therapeutic use, Adult, Aged, Combined Modality Therapy methods, Disease Progression, Drug Resistance, Neoplasm, Female, Humans, Immunotherapy, Adoptive adverse effects, Interleukin-6 blood, Interleukin-8 blood, Lymphoma, B-Cell blood, Lymphoma, B-Cell therapy, Lymphoma, Follicular blood, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Mantle-Cell blood, Male, Middle Aged, Receptors, Interleukin-2 blood, Remission Induction methods, Retreatment, Treatment Outcome, Adenine analogs & derivatives, Immunotherapy, Adoptive methods, Lymphoma, Follicular therapy, Lymphoma, Mantle-Cell therapy, Piperidines therapeutic use, Receptors, Chimeric Antigen genetics, Salvage Therapy
- Abstract
The efficacy and side effects of the second-time humanized CD19 chimeric antigen receptor (CD19-CAR) T-cell therapy after unsuccessful first-time anti-CD19-CAR T-cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B-cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first-time humanized anti-CD19-CAR T-cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7-16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second-time humanized anti-CD19-CAR T-cell therapy, which was the same as their first-time anti-CD19-CAR T-cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second-time anti-CD19-CAR T-cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti-CD19-CAR T-cell therapy. However, the second-time anti-CD19-CAR T-cell therapy led to higher peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second-time anti-CD19-CAR T-cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti-CD19-CAR T cells., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2021
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12. Circulating tumour DNA in B-cell lymphomas: current state and future prospects.
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Lakhotia R and Roschewski M
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- Biomarkers, Tumor genetics, Circulating Tumor DNA genetics, Disease Progression, Humans, Lymphoma, B-Cell genetics, Lymphoma, B-Cell therapy, Monitoring, Physiologic, Biomarkers, Tumor blood, Circulating Tumor DNA blood, Lymphoma, B-Cell blood
- Abstract
Circulating tumour DNA (ctDNA) is a highly versatile analyte and an emerging biomarker for detection of tumour-specific sequences in lymphoid malignancies. Since ctDNA is derived from tumour cells throughout the body, it overcomes fundamental limitations of tissue biopsies by capturing the complete molecular profile of tumours, including those from inaccessible anatomic locations. Assays for ctDNA are minimally invasive and serial sampling monitors the effectiveness of therapy and identifies minimal residual disease below the detection limit of standard imaging scans. Dynamic changes in ctDNA levels measure real-time tumour kinetics, and early reductions in ctDNA during treatment correlate with clinical outcomes in multiple B-cell lymphomas. After therapy, ctDNA can effectively discriminate between patients who achieved a complete molecular remission from those with residual treatment-resistant disease. Serial monitoring of ctDNA after therapy can detect early molecular relapse and identify drug-resistant clones that harbour targetable mutations. In order for ctDNA to reach its full potential, the standardization and harmonization of the optimal pre-analytical and analytical techniques for B-cell lymphomas is a critically necessary requirement. Prospective validation of ctDNA within clinical studies is also required to determine its clinical utility as an adjunctive decision-making tool., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2021
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13. C-reactive protein and ferritin levels and length of intensive care unit stay in patients with B-cell lymphomas treated with axicabtagene ciloleucel.
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Melody M, Rahman ZA, Saunders H, Diaz PL, Gannon N, Rosenthal A, Ayala E, Tun HW, Murthy H, Roy V, Foran J, Castro JE, Guru P, and Kharfan-Dabaja MA
- Subjects
- Adult, Aged, Biological Products, Female, Hospitalization, Humans, Immunotherapy, Adoptive, Intensive Care Units, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Male, Middle Aged, Prognosis, Retrospective Studies, Young Adult, Antigens, CD19 therapeutic use, C-Reactive Protein analysis, Ferritins blood, Lymphoma, B-Cell therapy
- Abstract
Objective/background: Chimeric antigen receptor (CAR) T-cell is an effective therapy in relapsed/refractory large B-cell lymphomas that, due to its unique toxicities, often requires escalation of care to the intensive care unit (ICU) setting. C-reactive protein (CRP) and ferritin are serum inflammatory markers associated with onset and persistence of CAR T-cell-related toxicity., Methods: We retrospectively analyzed 34 patients treated with axicabtagene ciloleucel (axi-cel) who were divided into two groups: patients requiring admission to the ICU during initial hospitalization (n = 13, 38%) and those who did not (n = 21, 62%). Primary objective was to examine possible relationships between serum ferritin and/or CRP levels with the need for, and length of, ICU stay between these groups., Results: All 13 patients admitted to the ICU developed cytokine release syndrome (CRS) and 11 of them also developed neurotoxicity (NT). Of the 21 patients in the non-ICU group, 18 developed CRS and 5 patients developed NT. Grade of CRS and NT were higher in ICU versus non-ICU patients (p = .03 and .001, respectively). There was no correlation between CRP levels at time of ICU admission and length of ICU stay (correlation of 0.41, p = .17). Yet, there was an association between serum ferritin levels and length of ICU stay (R
2 = 0.73) which did not reach statistical significance (correlation of 0.21, p = .49)., Conclusion: Notwithstanding the limitations of the small sample size, our study suggests that an elevated ferritin level at the time of escalation of medical care may be possibly indicative of anticipated prolonged ICU hospitalization in patients treated with axi-cel. A large multicenter study is certainly needed to confirm this observation., Competing Interests: Declaration of Competing Interest M.A.K-D declares consultancy for Daiichi Sankyo and Pharmacyclics. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)- Published
- 2021
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14. Biomarkers involved in evaluation of platelets function in South-Eastern Romanian patients with hematological malignancies subtypes.
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Matei E, Aschie M, Mitroi AF, Ghinea MM, Gheorghe E, Petcu L, Dobrin N, Chisoi A, and Mihaela M
- Subjects
- Aged, Biomarkers, Tumor metabolism, Blood Platelets immunology, CD3 Complex blood, Cell Adhesion immunology, Cell-Derived Microparticles, Female, Flow Cytometry, Humans, Integrin beta3 blood, Leukemia, Myeloid, Acute blood, Lymphocyte Activation, Lymphocyte Count, Lymphoma, B-Cell blood, Male, Middle Aged, Platelet Activation immunology, Platelet Count, Platelet Glycoprotein GPIb-IX Complex analysis, Romania, T-Lymphocytes, Helper-Inducer immunology, Biomarkers, Tumor blood, Blood Platelets metabolism, Leukemia, Myeloid, Acute immunology, Lymphoma, B-Cell immunology, T-Lymphocytes, Helper-Inducer metabolism
- Abstract
Abstract: At present, various researches presented how subtypes of hematological malignancies are related to stages of the immune response, because the activated immune system represents a promising form in cancer treatment. This study explores the relationship between the adaptive immune system (T cells), and the coagulation system (platelets, platelet membrane glycoproteins, platelets derivate microparticles) which seems to play an important role in host immune defense of patients with acute myeloblastic leukemia (AML) or B cell lymphoma (BCL), 2 of the most common hematological malignancies subtypes.Blood samples (n = 114) obtained from patients with AML or BCL were analyzed for platelet membrane glycoproteins (CD42b, CD61), glycoprotein found on the surface of the T helper cells (CD4+), protein complex-specific antigen for T cells (CD3+), platelet-derived microparticles (CD61 PMP) biomarkers by flow cytometry, and hematological parameters were quantified by usual methods.In patients with AML, the means of the percentage of the expressions of the molecules on platelet surfaces (CD61 and CD42b, P < .01; paired T test) were lower as compared to both control subgroups. The expression of cytoplasmic granules content (CD61 PMP) had a significantly higher value in patients with AML reported to controlling subgroups (P < .01; paired T test), which is suggesting an intravascular activation of platelets.The platelet activation status was presented in patients with low stage BCL because CD61 and CD42b expressions were significantly higher than control subgroups, but the expression of CD 61 PMP had a significantly decreased value reported to control subgroups (all P < .01; paired T test). T helper/inducer lineage CD4+ and T lymphoid lineage CD3+ expressions presented significant differences between patients with AML or low stage BCL reported to control subgroups (all P < .01; paired T test).Platelet-lymphocyte interactions are involved in malignant disorders, and CD61, CD42b present on platelet membranes, as functionally active surface receptors mediate the adhesion of active platelets to lymphocytes, endothelial cells, and cancer cells., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2021
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15. Peripheral eosinophil counts predict efficacy of anti-CD19 CAR-T cell therapy against B-lineage non-Hodgkin lymphoma.
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Jia Q, Qin D, He F, Xie Q, Ying Z, Zhang Y, Song Y, Cheng JN, Zuo X, Xu L, Fang H, Hu C, Peng L, Jin T, Shi Z, Alexander PB, Wang Y, Liu Y, Han W, Zhu J, Wang P, Li QJ, and Zhu B
- Subjects
- Adult, Aged, Animals, Antigens, CD19, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Leukocyte Count, Lymphoma, B-Cell blood, Male, Mice, Middle Aged, Prognosis, Progression-Free Survival, Young Adult, Eosinophils, Immunotherapy, Adoptive, Lymphoma, B-Cell therapy, Receptors, Chimeric Antigen
- Abstract
Rationale: The onset of cytokine release syndrome (CRS) and in vivo persistence of anti-CD19 chimeric antigen receptor T (CAR-T) cells after infusion correlate with clinical responsiveness. However, there are no known baseline biomarkers that can predict the prognosis of patients with B-lineage non-Hodgkin lymphoma (B-NHL). The aim of this study was to identify blood cell populations associated with beneficial outcomes in B-NHL patients administered CAR-T cell immunotherapies. Methods: We enumerated peripheral blood and CAR-T cells by retrospectively analyzing three CAR-T cell trials involving 65 B-NHL patients. We used a preclinical model to elucidate the eosinophil mechanism in CAR-T cell therapy. Results: During an observation period up to 30 mo, B-NHL patients with higher baseline eosinophil counts had higher objective response rates than those with low eosinophil counts. Higher baseline eosinophil counts were also significantly associated with durable progression-free survival (PFS). The predictive significance of baseline eosinophil counts was validated in two independent cohorts. A preclinical model showed that eosinophil depletion impairs the intratumoral infiltration of transferred CAR-T cells and reduces CAR-T cell antitumor efficacy. Conclusion: The results of this study suggest that peripheral eosinophils could serve as stratification biomarkers and a recruitment machinery to facilitate anti-CD19 CAR-T cell therapy in B-NHL patients., Competing Interests: Competing Interests: The authors declare the following financial interests/personal relationships that may be considered potential competing interests: Q-J.L. and P.W. are scientific cofounders of HRAIN Biotechnology Co., Ltd., Shanghai, and hold shares in this company., (© The author(s).)
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- 2021
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16. Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B-Cell Malignancies.
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Ou YC, Liu L, Tariq B, Wang K, Jindal A, Tang Z, Gao Y, and Sahasranaman S
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- Adult, Aged, Aged, 80 and over, Biological Variation, Population, Case-Control Studies, Clinical Trials as Topic, Dose-Response Relationship, Drug, Female, Healthy Volunteers, Humans, Leukemia, B-Cell blood, Lymphoma, B-Cell blood, Male, Middle Aged, Models, Biological, Piperidines administration & dosage, Protein Kinase Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyrimidines administration & dosage, Waldenstrom Macroglobulinemia blood, Young Adult, Leukemia, B-Cell drug therapy, Lymphoma, B-Cell drug therapy, Piperidines pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics, Pyrazoles pharmacokinetics, Pyrimidines pharmacokinetics, Waldenstrom Macroglobulinemia drug therapy
- Abstract
Zanubrutinib is a potent, second-generation Bruton's tyrosine kinase inhibitor that is currently being investigated in patients with B-cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B-cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed-effects modeling. Zanubrutinib PKs were adequately described by a two-compartment model with sequential zero-order then first-order absorption, and first-order elimination. A time-dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B-cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft-Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid-reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors., (© 2020 BeiGene. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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17. Study on Relationships of Tumor Status and Gene Polymorphism With Blood Concentration of MTX and Toxicities in 63 Pediatric Mature B Cell Lymphoma in Chinese Population.
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Huang S, Jin L, Yang J, Duan LY, Zhang M, Zhou JC, and Zhang HY
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- Adolescent, Anemia chemically induced, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Bone Marrow pathology, Chemical and Drug Induced Liver Injury genetics, Child, Child, Preschool, China, Female, Genotype, Humans, Infant, Liver physiopathology, Lymphoma, B-Cell blood, Lymphoma, B-Cell drug therapy, Male, Methotrexate administration & dosage, Methotrexate adverse effects, Neoplasm Staging, Neutropenia chemically induced, Neutropenia genetics, Polymorphism, Single Nucleotide, Retrospective Studies, Stomatitis chemically induced, Thrombocytopenia chemically induced, Antimetabolites, Antineoplastic blood, Liver-Specific Organic Anion Transporter 1 genetics, Lymphoma, B-Cell pathology, Methotrexate blood, Methylenetetrahydrofolate Reductase (NADPH2) genetics
- Abstract
Objective: This study investigated the relationships of tumor status (stage, renal involvement, bone marrow status, bulky disease, liver function), tumor gene polymorphism, and methotrexate (MTX) dosage (stratified by treatment group) with blood MTX levels and adverse reactions (ADR)., Methods: We retrospectively reviewed 63 mature B cell lymphoma patients who were treated in our center. Genotyping of the MTHFR 677 and SLCO1B1 genes was carried out, and the relationships between tumor status, polymorphism of the genes, MTX level, and ADR were analyzed., Results: Altogether, 63 children were included. The mean blood MTX concentration was 0.25 ± 0.2 umol/L at 45 h. Liver dysfunction and bulky disease were both correlated with MTX level (both P < 0.05). ADRs were higher among patients with blood MTX > 0.5 mmol/l at 45 h than for the groups with lower blood MTX. The MTHFR 677 CT genotype was correlated with liver function damage (P = 0.04); the rs11045879 locus CC genotype of SLCO1B1, stage IV, and bulky disease at the time of diagnosis were correlated with 4° neutropenia (P < 0.05). Stage IV, bulky disease, leukemia stage at the time of diagnosis, and C2 treatment group were correlated with severe anemia (P < 0.05). Stage IV, bulky disease, leukemia stage, renal invasion at the time of diagnosis, and C2 treatment group were associated with severe thrombocytopenia (P < 0.05). Bulky disease and renal invasion at the time of diagnosis were associated with severe mucositis and severe infection (P < 0.05)., Conclusion: Taken together, our data demonstrate that gene polymorphism, MTX levels, tumor status, and treatment group might be useful to optimize MTX therapy and estimate toxicity.
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- 2021
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18. Lymphocyte-depleting chemotherapy for aggressive hematologic malignancies in two patients with positive SARS-CoV-2 PCR.
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Pelcovits A, Pandita A, Farmakiotis D, and Egan P
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- Adult, COVID-19 blood, COVID-19 diagnostic imaging, COVID-19 genetics, COVID-19 therapy, Female, Humans, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, COVID-19 Nucleic Acid Testing, Hematologic Neoplasms blood, Hematologic Neoplasms diagnostic imaging, Hematologic Neoplasms therapy, Hematologic Neoplasms virology, Lymphocyte Depletion, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics, Lymphoma, B-Cell therapy, Polymerase Chain Reaction, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, SARS-CoV-2 genetics, SARS-CoV-2 metabolism
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- 2021
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19. Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.
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Dugué PA, Bassett JK, Wong EM, Joo JE, Li S, Yu C, Schmidt DF, Makalic E, Doo NW, Buchanan DD, Hodge AM, English DR, Hopper JL, Giles GG, Southey MC, and Milne RL
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- Adult, Age Factors, Aged, Aging genetics, Biomarkers blood, Case-Control Studies, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, Confidence Intervals, DNA blood, Epigenesis, Genetic, Female, Humans, Kidney Neoplasms blood, Kidney Neoplasms genetics, Logistic Models, Lung Neoplasms blood, Lung Neoplasms genetics, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Male, Middle Aged, Neoplasms genetics, Prospective Studies, Prostatic Neoplasms blood, Prostatic Neoplasms genetics, Risk Factors, Smoking, Stomach Neoplasms blood, Stomach Neoplasms genetics, Telomere Homeostasis, Urologic Neoplasms blood, Urologic Neoplasms genetics, Aging blood, DNA Methylation, Neoplasms blood, Telomere
- Abstract
Background: We previously investigated the association between 5 "first-generation" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: PhenoAge , GrimAge , and predicted telomere length., Methods: We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and we investigated potential nonlinearity., Results: We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per SD was approximately 1.2-1.3). Similar findings were obtained for age-adjusted GrimAge , but the association with lung cancer risk was much larger (RR per SD = 1.82, 95% confidence interval [CI] = 1.44 to 2.30), after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables. For cancer overall, the comprehensively adjusted rate ratio per SD was 1.13 (95% CI = 1.07 to 1.19) for PhenoAge and 1.12 (95% CI = 1.05 to 1.20) for GrimAge and appeared larger within 5 years of blood draw (RR = 1.29, 95% CI = 1.15 to 1.44 and 1.19, 95% CI = 1.06 to 1.33, respectively)., Conclusions: The methylation-based measures PhenoAge and GrimAge may provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer., (© The Author(s) 2020. Published by Oxford University Press.)
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- 2020
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20. Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy.
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Cappell KM, Sherry RM, Yang JC, Goff SL, Vanasse DA, McIntyre L, Rosenberg SA, and Kochenderfer JN
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- Adult, Aged, B-Lymphocytes immunology, B-Lymphocytes pathology, Female, Follow-Up Studies, Humans, Immunoglobulins immunology, Immunotherapy, Adoptive adverse effects, Lymphoma, B-Cell blood, Lymphoma, B-Cell immunology, Male, Middle Aged, Receptors, Chimeric Antigen blood, Receptors, Chimeric Antigen immunology, Survival Rate, Antigens, CD19 immunology, Immunotherapy, Adoptive methods, Lymphoma, B-Cell therapy
- Abstract
Purpose: Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy., Methods: Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells., Results: The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051)., Conclusion: Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.
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- 2020
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21. Circulating miRNAs as Biomarkers in Aggressive B Cell Lymphomas.
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Drees EEE and Pegtel DM
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- Biomarkers, Tumor metabolism, Carcinogenesis genetics, Circulating MicroRNA metabolism, Gene Expression Regulation, Neoplastic, Humans, Liquid Biopsy methods, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Reproducibility of Results, Specimen Handling methods, Biomarkers, Tumor blood, Circulating MicroRNA blood, Extracellular Vesicles metabolism, Lymphoma, B-Cell diagnosis
- Abstract
B cell lymphomas are heterogeneous malignancies of hematological origin with vastly different biology and clinical outcomes. Histopathology of tissue biopsies and image-based assessment guide clinical decisions. Given that tissue biopsies cannot be frequently repeated and will not inform on systemic responses to the treatment, more accessible biomarkers, such as circulating miRNAs, are considered. Aberrant miRNA expression in lymphoma tissues and ongoing immune reactions may lead to miRNA alterations in circulation. miRNAs bound to extracellular vesicles (EVs) are of interest because of their role in intercellular communication and organ crosstalk. Herein, we highlight the role of miRNAs and EVs in B cell lymphomagenesis and explain how circulating miRNAs may be turned into robust liquid biopsy tests for aggressive B cell lymphoma., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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22. A case report of lineage switch from T-cell acute leukemia to B-cell acute leukemia.
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Zhu Y, Liu H, Zhang S, Liang Y, Xiao M, Hao Y, and Guan Y
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- Acute Disease, Adult, B-Lymphocytes, Cell Lineage, Humans, Leukemia, Biphenotypic, Acute drug therapy, Lymphoma, B-Cell drug therapy, Lymphoma, T-Cell drug therapy, Male, T-Lymphocytes, Leukemia, Biphenotypic, Acute blood, Lymphoma, B-Cell blood, Lymphoma, T-Cell blood
- Abstract
Rationale: ALL is the most common form of leukemia (75% to 80%), it is characterized by clonal expansion of the lymphoid blasts in bone marrow, blood, and other tissues, which can be divided into T lineage and B lineage. Although relapse of acute leukemia is common, a change of immunophenotype at relapse only occurs rarely. Some of these cases have been labeled "lineage switch"., Patient Concerns: A 31-year-old man had multiple lymph nodes in the neck, and the lymph nodes on the right side adhered to the surrounding tissues. His lymphocytes ratio in blood was up to 86.3%. Flow cytometry of the bone marrow aspirate showed positive results for CD2, CD5, CD7, cCD3, TDT, CD4, CD8, and CD10, negative results for CD34, CD117, CD33, HLA-DR, CD19, and CD20. Twenty six months later, the patient felt pain in the neck and shoulder after touching. His lymphocytes of blood were 109.9×109 /L. 43 fusion genes and positive BCR/ABL was detected. Flow cytometry of the bone marrow aspirate showed pro B lymphocytes accounted for 85.54%, and positive expression of CD38, CD10, CD34, CD33, TDT, CD9, and HLA-DR. Moreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors., Diagnoses: Upon examination, the patient was initially diagnosed with T-lineage pro cell ALL. BM morphologic analysis presented complete remission (CR) after systemic chemotherapy. Twenty six months later, we discovered the patient was diagnosed with B-lineage acute lymphocytic leukemia., Interventions: Systemic chemotherapy is first given when a patient was diagnosed with T-cell acute lymphoblastic leukemia. After the patient happened linage switch, we adjusted the treatment plan, and the patient was complete remission after 1 course of treatment., Outcomes: Our case provides information of lineage switch from T-ALL to B-ALL in this report, which is never seen in our knowledge., Lessons: This lineage switch from T-ALL to B-ALL is never reported beforemoreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors. Its early recognition can let doctor provides appropriate therapy to patient.
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- 2020
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23. Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.
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Kroschinsky F, Middeke JM, Janz M, Lenz G, Witzens-Harig M, Bouabdallah R, La Rosée P, Viardot A, Salles G, Kim SJ, Kim TM, Ottmann O, Chromik J, Quinson AM, von Wangenheim U, Burkard U, Berk A, and Schmitz N
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized blood, Antibodies, Monoclonal, Humanized pharmacokinetics, Antigens, Neoplasm, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Agents, Immunological blood, Antineoplastic Agents, Immunological pharmacokinetics, Drug Resistance, Neoplasm, Female, Humans, Infusions, Intravenous, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Lymphoma, B-Cell metabolism, Male, Maximum Tolerated Dose, Middle Aged, Receptors, IgG genetics, Recurrence, Treatment Outcome, beta 2-Microglobulin blood, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Lymphoma, B-Cell drug therapy, Tetraspanins antagonists & inhibitors
- Abstract
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.
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- 2020
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24. Camrelizumab Plus Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin in Relapsed/Refractory Primary Mediastinal B-Cell Lymphoma: A Single-Arm, Open-Label, Phase II Trial.
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Mei Q, Zhang W, Liu Y, Yang Q, Rasko JEJ, Nie J, Liu J, Li X, Dong L, Chen M, Zhang Y, Shi L, Wu H, and Han W
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor blood, Doxorubicin administration & dosage, Doxorubicin adverse effects, Doxorubicin analogs & derivatives, Drug Resistance, Neoplasm, Female, Humans, Interferon-gamma blood, Interleukin-10 blood, Lymphoma, B-Cell blood, Lymphoma, B-Cell mortality, Lymphoma, B-Cell pathology, Male, Mediastinal Neoplasms blood, Mediastinal Neoplasms mortality, Mediastinal Neoplasms pathology, Middle Aged, Neoplasm Recurrence, Local, Polyethylene Glycols administration & dosage, Polyethylene Glycols adverse effects, Prognosis, Progression-Free Survival, Vinorelbine administration & dosage, Vinorelbine adverse effects, Young Adult, fas Receptor blood, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Lymphoma, B-Cell drug therapy, Mediastinal Neoplasms drug therapy
- Abstract
Purpose: Patients with relapsed/refractory primary mediastinal B-cell lymphoma (rrPMBCL) represent a particularly challenging population to treat, with few life-saving treatment options in the context of a dismal prognosis., Patients and Methods: In this open-label, single-arm, phase II study, the safety and efficacy of combined regimen of chemotherapy consisting of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) plus anti-PD-1 antibody camrelizumab was assessed in rrPMBCL. Patients received chemo-immunotherapy every 3 weeks until the second confirmed complete response (CR) or up to 12 cycles, followed by camrelizumab monotherapy for up to 1 year. The primary endpoints were objective response rate (ORR) and safety., Results: Twenty-seven response evaluable patients were enrolled, who received a median of three first-line therapies, 59% with bulky disease. The ORR was 74%, including 56% with a CR. A median time of 1.7 months to response was observed, with 78% exhibiting tumor shrinkage at the first evaluation. After 24.8 months median follow-up, the median duration of response was not reached, with a 65% 2-year estimated response rate. Thirteen responders remained in sustained complete remission. Estimated 24-month progression-free survival and overall survival rates were 48.2% and 81.5%, respectively. Any grade and grade 3 treatment-related adverse events (AE) occurred in 93% and 33% of patients, respectively; with no grade 4 or 5 AEs. Baseline levels of IL10, IFNγ, and soluble Fas were associated with objective response., Conclusions: Camrelizumab plus GVD chemotherapy offers a potent option as life-saving chemo-immunotherapy with promising efficacy and a manageable safety profile for patients with rrPMBCL, especially with bulky aggressive disease., (©2020 American Association for Cancer Research.)
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- 2020
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25. Lymphocyte-monocyte ratio (LMR) can predict bendamustine therapeutic efficacy in low-grade B-cell lymphoma.
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Shimono J, Izumiyama K, Ito S, Tsutsmi Y, Kondo T, Kakinoki Y, and Teshima T
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- Adult, Aged, Aged, 80 and over, Female, Humans, Lymphocyte Count, Male, Middle Aged, Recurrence, Retrospective Studies, Bendamustine Hydrochloride administration & dosage, Lymphocytes metabolism, Lymphocytes pathology, Lymphoma, B-Cell blood, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell pathology, Lymphoma, Follicular blood, Lymphoma, Follicular drug therapy, Lymphoma, Follicular pathology, Monocytes metabolism, Monocytes pathology
- Abstract
Introduction: Bendamustine has been reported to be effective against low-grade B-cell lymphoma. We examined the effect of bendamustine on the lymphocyte-monocyte ratio (LMR) in low-grade B-cell lymphoma patients., Methods: We retrospectively reviewed 127 cases of first line or relapse/refractory low-grade B-cell lymphoma in three individual institutions (Asahikawa Municipal Hospital, Aiiku Hospital, and Hakodate Municipal Hospital). Only patients who had received at least three courses of bendamustine therapy were selected; the LMR was evaluated at starting the initial course of bendamustine therapy. Time to next treatment (TTNT) was used to ascertain the efficacy of bendamustine therapy., Results: Follicular lymphoma (FL), at 68.5% (87/127), is the most common histological subtype of low-grade B-cell lymphoma. The receiver operating characteristic (ROC) curve for the LMR showed a cutoff value of 2.0, and 33 cases (26.0%) had an LMR ≤2.0. Cases with LMR ≤2.0 had a significantly earlier progression than those with LMR > 2.0, based on the TTNT (P = .0007). Additionally, LMR ≤2.0 indicates earlier progression in TTNT when comparing only FL and low-grade B-cell lymphoma cases without FL (P = .007, 0.002). For multivariate analysis, the factors associated with an LMR ≤2.0 (HR, 2.741; 95% CI, 1.4330-5.245; P = .002) were considered as early progression factors with regard to the TTNT., Conclusion: Lymphocyte-monocyte ratio effectively predicts the efficacy of bendamustine therapy for low-grade B-cell lymphoma, particularly FL; its application may improve treatment strategies for this disease., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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26. Analysis of IL-6 serum levels and CAR T cell-specific digital PCR in the context of cytokine release syndrome.
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Pabst T, Joncourt R, Shumilov E, Heini A, Wiedemann G, Legros M, Seipel K, Schild C, Jalowiec K, Mansouri Taleghani B, Fux M, Novak U, Porret N, Zeerleder S, and Bacher U
- Subjects
- Adult, Aged, Cytokine Release Syndrome etiology, Female, Humans, Male, Middle Aged, Polymerase Chain Reaction, Cytokine Release Syndrome blood, Immunotherapy, Adoptive, Interleukin-6 blood, Lymphoma, B-Cell blood, Lymphoma, B-Cell pathology, Lymphoma, B-Cell therapy, Receptors, Chimeric Antigen blood
- Abstract
Introduction: Chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used to treat relapsed B-cell lymphomas and acute lymphoblastic leukemia. Considering the frequency of cytokine release syndrome and CAR-T-related encephalopathy syndrome (CRS/CRES) after CAR-T administration, strategies enabling timely prediction of impending CRS/CRES are a clinical need., Methods: We evaluated the dynamics of serum interleukin (IL)-6 levels and CAR-T transgene copy numbers by digital droplet polymerase chain reaction in the peripheral blood of 11 consecutive patients with aggressive B-cell malignancies., Results: Four of 11 patients developed CRS, and 3 patients had CRES (33%), 2 of them had previous CRS. IL-6 levels increased on the day of clinical manifestation of CRS. All CRS patients had increased IL-6 peak levels (median IL-6 peak 606 pg/mL in CRS patients vs. 22 pg/mL in non-CRS patients, p = 0.0061). Different patterns emerged from the dynamics of CAR-T/µg genomic DNA: "rapid increase and rapid decrease with complete disappearance," "rapid increase and slow decrease with higher persistence," "rapid increase and rapid decrease with lower persistence," and "slow increase and rapid decrease with almost disappearance." Patients with the pattern "rapid increase and slow decrease with higher persistence" of CAR-T/µg genomic DNA concentration seemed to be at higher risk of developing CRS/CRES., Conclusion: Thus, the dynamics of CAR-T transgene copy numbers merits further evaluation for a possible association with manifestation of CRS. Increased IL-6 serum levels at CRS manifestation may contribute to the interpretation of symptoms., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
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- 2020
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27. The value of circulating microRNAs for early diagnosis of B-cell lymphoma: A case-control study on historical samples.
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Jørgensen S, Paulsen IW, Hansen JW, Tholstrup D, Hother C, Sørensen E, Petersen MS, Nielsen KR, Rostgaard K, Larsen MAH, Brown PN, Ralfkiær E, Homburg KM, Hjalgrim H, Erikstrup C, Ullum H, Troelsen J, Grønbæk K, and Pedersen OB
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Circulating MicroRNA genetics, Early Diagnosis, Female, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, ROC Curve, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Circulating MicroRNA blood, Lymphoma, B-Cell diagnosis
- Abstract
MicroRNAs are small regulatory RNAs that are deregulated in a wide variety of human cancers, including different types of B-cell lymphoma. Nevertheless, the feasibility of circulating microRNA for early diagnosis of B-cell lymphoma has not been established. To address the possibility of detecting specific circulating microRNAs years before a B-cell lymphoma is diagnosed, we studied the plasma expression of microRNA first in pre-treatment samples from patients with diffuse large B-cell lymphoma and subsequently in repository samples from blood donors who later developed B-cell lymphomas. In addition, we studied the microRNA expression in the diagnostic lymphoma biopsy. The most strongly induced (miR-326) and suppressed (miR-375) plasma microRNA at diagnosis, when compared with healthy blood donors, were also substantially up- or down-regulated in plasma repository samples taken from several months to up to two years before the blood donors were diagnosed with B-cell lymphoma. Importantly, at these time points the donors had no signs of disease and felt healthy enough to donate blood. In conclusion, this first study of plasma microRNA profiles from apparently healthy individuals, taken several years before B-cell lymphoma diagnosis, suggests that plasma microRNA profiles may be predictive of lymphoma development.
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- 2020
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28. Elderly woman with subacute lower limb weakness and rapid systemic decline.
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Wong C, Wills AJ, Samarasekera N, Noble D, Smith C, and Davenport R
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- Aged, Fatal Outcome, Female, Humans, Lower Extremity pathology, Lymphoma, B-Cell blood, Lymphoma, B-Cell complications, Muscle Weakness blood, Muscle Weakness etiology, Paraplegia blood, Paraplegia etiology, Time Factors, Disease Progression, Lymphoma, B-Cell diagnostic imaging, Muscle Weakness diagnostic imaging, Paraplegia diagnostic imaging
- Abstract
A 74-year-old woman developed bilateral leg weakness, with fluctuating cognitive and systemic symptoms that progressed despite treatment. Her diagnosis was confirmed at autopsy. Her case was discussed at the Edinburgh Clinical Neurology Course 2019 Clinicopathological Conference., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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29. Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia.
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Kiyoi H, Morris JD, Oh I, Maeda Y, Minami H, Miyamoto T, Sakura T, Iida H, Tuglus CA, Chen Y, Dos Santos C, Kalabus J, Anderson A, Hata T, Nakashima Y, and Kobayashi Y
- Subjects
- Adult, Aged, Antibodies, Bispecific adverse effects, Antibodies, Bispecific blood, Antibodies, Bispecific pharmacokinetics, Antigens, CD19 genetics, Antigens, CD19 immunology, B-Lymphocytes pathology, CD3 Complex genetics, CD3 Complex immunology, Dexamethasone administration & dosage, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Interferon-gamma blood, Kaplan-Meier Estimate, Lymphoma, B-Cell blood, Lymphoma, B-Cell pathology, Male, Middle Aged, Neoplasm, Residual blood, Neoplasm, Residual pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Remission Induction, T-Lymphocytes immunology, Antibodies, Bispecific administration & dosage, Lymphoma, B-Cell drug therapy, Neoplasm, Residual drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2020
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30. Reverse pseudohyperkalemia and pseudohyponatremia in a patient with B-cell non-Hodgkin lymphoma.
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Moreno G and Gunsolus IL
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- Aged, False Negative Reactions, False Positive Reactions, Humans, Hyperkalemia etiology, Hyponatremia etiology, Lymphoma, B-Cell blood, Lymphoma, Mantle-Cell blood, Male, Lymphoma, B-Cell complications, Lymphoma, Mantle-Cell complications, Potassium blood, Sodium blood
- Abstract
Objectives: Investigate concomitant and spurious high potassium and low sodium results in heparinized plasma., Methods: Potassium and sodium values were measured from heparinized plasma and serum in a patient with B-cell non-Hodgkin lymphoma using both an automated chemistry analyzer (indirect ion selective electrode) and blood gas analyzer (direct ion selective electrode)., Results: Potassium levels were significantly increased while sodium levels were significantly decreased in heparinized plasma compared to serum on several occasions., Conclusions: To our knowledge, concomitant reverse pseudohyperkalemia and pseudohyponatremia has not been reported previously. We postulate the discrepancy between plasma and serum sodium (pseudohyponatremia in plasma) may be unique to cases of reverse pseudohyperkalemia with extreme potassium elevations., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
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- 2020
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31. Serum CXCL13 levels are associated with lymphoma risk and lymphoma occurrence in primary Sjögren's syndrome.
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Traianos EY, Locke J, Lendrem D, Bowman S, Hargreaves B, Macrae V, Tarn JR, and Ng WF
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- Adult, Aged, Biomarkers blood, Case-Control Studies, Female, Germinal Center immunology, Humans, Lymphoma, B-Cell blood, Male, Middle Aged, Risk Assessment, Sjogren's Syndrome blood, Sjogren's Syndrome immunology, Chemokine CXCL13 blood, Lymphoma, B-Cell etiology, Sjogren's Syndrome complications
- Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease characterised by an increased risk for non-Hodgkin lymphoma (NHL) development. Ectopic germinal centre (GC) in the salivary gland is associated with increased NHL risk in pSS, and the chemokine CXCL13 is implicated in B-cell migration and GC formation. Serum CXCL13 concentrations were quantified by ELISA in 48 healthy individuals, 273 pSS patients without NHL (pSS-nonL), and 38 pSS patients with NHL (pSS-NHL+) from the United Kingdom Primary Sjögren's Syndrome Registry cohort. PSS-nonL patients were stratified into low risk (LR), moderate risk (MR) and high risk (HR) groups according to the lymphoma risk score proposed by Fragkioudaki et al. Differences in serum CXCL13 levels among groups were analysed using the Wilcoxon method. Also, changes in serum CXCL13 over a time period of at least 1 year and a median 4 years were assessed for 200 pSS-nonL and 8 pSS-NHL+ patients. In addition, associations of serum CXCL13 with B-cell and inflammatory markers were investigated by correlation analyses and logistic regression. Serum CXCL13 levels were higher in all pSS groups compared to controls (p < 0.0001), and in pSS-NHL+ compared to pSS-nonL patients (p = 0.0204). LR patients had lower CXCL13 levels than MR patients (p < 0.0001) and pSS-NHL+ patients (p = 0.0008). CXCL13 levels remained stable over the study period for all pSS groups. CXCL13 was associated (p < 0.0005) with Immunoglobulin G (IgG), B-cell activating factor, β2 microglobulin, combined free light chains, κ and λ light chains, anti-Ro/SSA, anti-La/SSB, and erythrocyte sedimentation rate. IgG and C3 controlled for age and gender were significantly associated with NHL risk in pSS. Serum CXCL13 levels were elevated in pSS-NHL+ and MR patients compared to LR patients and remained stable over time. Further study is required to investigate the role of CXCL13 in pSS-associated NHL risk.
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- 2020
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32. Molecular and phenotypic characterization of an early T-cell precursor acute lymphoblastic lymphoma harboring PICALM-MLLT10 fusion with aberrant expression of B-cell antigens.
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Khurana S, Melody ME, Ketterling RP, Peterson JF, Luoma IM, Vazmatzis G, Tun HW, Foran JM, and Jiang L
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- Adult, B-Lymphocytes metabolism, Biopsy, CD79 Antigens analysis, CD79 Antigens immunology, Diagnostic Errors, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics, Lymphoma, B-Cell immunology, Male, Mediastinal Neoplasms blood, Mediastinal Neoplasms genetics, Mediastinal Neoplasms immunology, Mediastinum diagnostic imaging, Mediastinum pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology, Tomography, X-Ray Computed, B-Lymphocytes immunology, CD79 Antigens metabolism, Mediastinal Neoplasms diagnosis, Oncogene Proteins, Fusion genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis
- Abstract
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is usually diagnosed based on the presence of immature lymphoid marker terminal deoxynucleotidyl transferase (TdT), and T-cell specific markers, specifically CD3, by immunohistochemistry (IHC) staining on bone marrow and/or extramedullary tissue. We present a novel, TdT and CD3 negative, aggressive early T-cell precursor LBL (ETP-LBL) initially misdiagnosed as a high grade B-cell lymphoma due to expression of CD79a and the erroneous detection of BCL2/IGH fusion. The patient was eventually evaluated using molecular diagnostic techniques, including fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) assays that demonstrated PICALM-MLLT10 fusion and a NOTCH1 mutation in the absence of BCL2/IGH fusion. The use of NGS, specifically mate-pair sequencing (MPseq), subsequently confirmed an in-frame PICALM-MLLT10 fusion. Our retrospective analysis showed that PICALM-MLLT10 fusion has no association with CD3/TdT negativity, as 6/49 T-ALL/LBL cases from Mayo Clinic database (01/1998-09/2018), including this case, were noted to have PICALM-MLLT10 fusion; however, none of the other cases were associated with CD3/TdT negativity. We emphasize the importance of a comprehensive hematopathologic evaluation including multiple molecular studies for the appropriate interrogation and classification of a difficult acute leukemia diagnosis, and to prevent potential diagnostic errors of clinical significance., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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33. A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells.
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Shen JC, Kamath-Loeb AS, Kohrn BF, Loeb KR, Preston BD, and Loeb LA
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- Adult, Cell Line, Cytidine Deaminase genetics, DNA Mutational Analysis methods, DNA-Directed DNA Polymerase genetics, Gene Frequency, Genetic Loci genetics, Healthy Volunteers, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics, Middle Aged, Mutation Rate, Proto-Oncogene Proteins c-bcl-6 metabolism, Young Adult, B-Lymphocytes metabolism, Enhancer Elements, Genetic genetics, Proto-Oncogene Proteins c-bcl-6 genetics
- Abstract
The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell SEs at single-nucleotide resolution from 10 healthy individuals across diverse ethnicities. We detected a total of approximately 9,000 subclonal mutations (allele frequencies <0.1%); of these, approximately 8,000 are present in the BCL6 SE alone. Within the BCL6 SE, we identified 3 regions of clustered mutations in which the mutation frequency is ∼7 × 10
-4 Mutational spectra show a predominance of C > T/G > A and A > G/T > C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase η, respectively, in mutagenesis in normal B cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signatures SBS85, SBS37, and SBS39 were found in the BCL6 SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations., Competing Interests: Competing interest statement: L.A.L. is a founder and equity holder at TwinStrand Biosciences.- Published
- 2019
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34. Prediction of delayed platelet engraftment after autologous stem cell transplantation for B-cell non-Hodgkin lymphoma.
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Yamaguchi J, Chinen Y, Takimoto-Shimomura T, Nagata H, Muramatsu A, Kuriyama K, Ohshiro M, Hirakawa Y, Iwai T, Uchiyama H, Uoshima N, Kaneko H, Nakao M, Tsukamoto T, Shimura Y, Kobayashi T, Horiike S, Yokota I, and Kuroda J
- Subjects
- Adult, Aged, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Transplantation Conditioning, Transplantation, Autologous, B-Lymphocytes pathology, Blood Platelets cytology, Hematopoietic Stem Cell Transplantation methods, Lymphoma, B-Cell therapy, Platelet Transfusion statistics & numerical data, Thrombopoiesis
- Abstract
Delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment after autologous peripheral blood stem cell transplantation (auto-PBSCT). To identify risk factors for DPE and to develop a simple and clinically applicable system for predicting the time required for platelet recovery, we conducted a multi-institutional retrospective study in 144 patients with B-cell non-Hodgkin lymphoma who underwent auto-PBSCT. In a median observation period of 930 days (range: 25-5272 days), 139 patients successfully achieved platelet engraftment (≥50.0 × 10
9 /L). The median duration for platelet engraftment was 19 days, and 130 patients had platelet engraftment within 40 days after auto-PBSCT; however, the other 14 patients failed to achieve platelet engraftment within 60 days. These 14 patients with DPE required a significantly greater number of apheresis procedures and had a lower pre-apheresis absolute lymphocyte count (PA-ALC) compared to those without DPE. Importantly, multivariate analysis revealed that the number of transplanted CD34+ cells (≤2.0 × 106 /kg), number of required apheresis procedures (≥3 days), and PA-ALC (≤1.0 × 109 /L) were independently associated with a longer time for platelet engraftment after auto-PBSCT. By incorporating these three independent factors as variables, we generated a new scoring system for prediction of the time and probability for platelet engraftment after auto-PBSCT.- Published
- 2019
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35. Simultaneous evaluation of diagnostic marker utility for enzootic bovine leukosis.
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Konishi M, Kobayashi S, Tokunaga T, Chiba Y, Tsutsui T, Arai S, Kameyama KI, and Yamamoto T
- Subjects
- Animals, B-Lymphocytes, Biomarkers, Cattle, Enzootic Bovine Leukosis virology, Female, Isoenzymes blood, L-Lactate Dehydrogenase blood, Leukemia Virus, Bovine, Leukocyte Count veterinary, Lymphoma, B-Cell blood, Lymphoma, B-Cell diagnosis, Male, Sensitivity and Specificity, Thymidine Kinase blood, Enzootic Bovine Leukosis blood, Enzootic Bovine Leukosis diagnosis, Lymphoma, B-Cell veterinary
- Abstract
Background: Enzootic bovine leukosis (EBL) is a disease of cattle caused by bovine leukemia virus (BLV). More than 60% of BLV-infected cattle remain subclinical and are thus referred to as aleukemic (AL) cattle. Approximately 30% of infected cattle show a relatively stable increase in the number of B lymphocytes; these cattle are termed persistent lymphocytosis (PL) cattle. A small percentage of infected cattle develop BLV-induced B cell lymphoma (EBL) and are called EBL cattle. Due to the increase in the number of BLV-infected cattle, the number of EBL cattle has featured a corresponding increase over recent years in Japan. Several diagnostic criteria for EBL (e.g., enlarged superficial lymph nodes, protrusion of the eye, increased peripheral blood lymphocyte, etc.) are used for on-farm diagnosis and antemortem tests at slaughterhouses. Since the slaughter of EBL cattle for human consumption is not allowed, on-farm detection of EBL cattle is important for reducing the economic loss incurred by farms. Therefore, establishing new diagnostic markers to improve the efficiency and accuracy of the antemortem detection of EBL cattle is a critical, unmet need. To simultaneously evaluate the utility of candidate markers, this study measured the values of each marker using the blood samples of 687 cattle with various clinical statuses of BLV infection (EBL, PL, AL and non-infected cattle)., Results: Sensitivity (Se) and specificity (Sp) were highest for the serum thymidine kinase (TK) followed by the serum lactate dehydrogenase (LDH) isozyme 2. The number of peripheral blood lymphocytes and proviral load in peripheral blood had the lowest Se and Sp. The values of all markers other than TK were influenced by the sex of the tested cattle., Conclusions: Although tLDH and its isozymes (LDHs) may be influenced by the sex of the tested cattle, the high accuracy of TK and LDH2 as well as accessibility and simplicity of the protocol used to measure these enzymes recommend the utility of TK and LDHs for EBL cattle detection. Using these markers for screening followed by the application of existing diagnostic criteria may improve the efficiency and accuracy of EBL cattle detection on farms, thereby contributing to the reduction of economic losses in farms.
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- 2019
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36. Fungal spore contamination mimicking parasitic infection.
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Blum S and Cairoli A
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- Animals, Diagnosis, Differential, Hematologic Tests methods, Histological Techniques instrumentation, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell complications, Male, Middle Aged, Parasitic Diseases blood, Parasitic Diseases complications, Spores, Fungal physiology, Equipment Contamination, Hematologic Tests instrumentation, Microfilariae isolation & purification, Parasitic Diseases diagnosis, Spores, Fungal isolation & purification
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- 2019
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37. Depletion of B cells rejuvenates the peripheral B-cell compartment but is insufficient to restore immune competence in aging.
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Avivi I, Zisman-Rozen S, Naor S, Dai I, Benhamou D, Shahaf G, Tabibian-Keissar H, Rosenthal N, Rakovsky A, Hanna A, Shechter A, Peled E, Benyamini N, Dmitrukha E, Barshack I, Mehr R, and Melamed D
- Subjects
- Adolescent, Adult, Aged, Animals, Antigens, CD20 genetics, Antigens, CD20 immunology, Antineoplastic Agents, Immunological therapeutic use, Bone Marrow Cells immunology, Female, Healthy Volunteers, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell drug therapy, Lymphopoiesis immunology, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Middle Aged, Prospective Studies, Rituximab therapeutic use, Young Adult, Aging immunology, B-Lymphocytes immunology, Lymphocyte Depletion methods, Rejuvenation physiology
- Abstract
Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B-cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B-cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B-cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals, were vaccinated against hepatitis B (HBV) after undergoing a detailed analysis for B-cell compartments. B-cell depletion in old mice resulted in rejuvenated B-cell population that was derived from de novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"-like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B-cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly depleted patients showed a "young"-like repertoire, population dynamics, and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and nondepleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B-cell compartment in aging, through B-cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
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- 2019
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38. CD5/CD20 expression on circulating B cells in HCV-related chronic hepatitis and mixed cryoglobulinemia.
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Russi S, Vincenti A, Vinella A, Mariggiò MA, Pavone F, Dammacco F, and Lauletta G
- Subjects
- Adult, Aged, Case-Control Studies, Cryoglobulinemia complications, Cryoglobulinemia virology, Female, Hepatitis C, Chronic complications, Hepatitis C, Chronic immunology, Humans, Logistic Models, Lymphoma, B-Cell complications, Lymphoma, B-Cell virology, Male, Middle Aged, Antigens, CD20 metabolism, B-Lymphocytes metabolism, CD5 Antigens metabolism, Cryoglobulinemia blood, Hepatitis C, Chronic blood, Lymphoma, B-Cell blood
- Abstract
The role of CD5
+ B cells in patients with HCV infection and HCV-related disorders, including mixed cryoglobulinemia (MC), has been addressed in previous reports with conflicting results. We established a correlation between CD5/CD20 expression on circulating B lymphocytes, characterizing monoclonal B cell lymphocytosis (MBL), and clinical features in a cohort of 45 patients with chronic HCV hepatitis [without MC: 23 patients (MC- group); with MC: 22 patients (MC+ group)], and 45 HCV-negative healthy subjects as controls. By flow cytometry analysis, three B cells phenotypes were singled out: 1) CD5+ CD20dim (CLL-like phenotype); 2) CD5+ CD20bright (atypical phenotype); and 3) CD5- CD20+ phenotype. CD5+ CD20bright cells were reduced in MC- patients (p=0.049). CD5+ CD20dim B cells were significantly higher in group B than in the control group (p=0.003). ROC curve analysis in MC+ patients showed the highest positive likelihood ratio at ≥7.35% (p=0.008) for CLL-like phenotype and at ≤63.6% (p=0.03) for the CD5- CD20+ B cell phenotype. HCV infection was associated with a higher frequency of CLL-like (odds ratio=16, p=0.002) and a lower frequency of atypical (odds ratio: 3.1, p=0.02) and CD5- CD20+ (odds ratio: 11, p=0.01) phenotypes. The association with higher levels of CLL-like phenotype progressively increased from group of MC- patients (odds ratio: 9.3, p=0.04) to the group of MC+ patients (odds ratio: 25.1, p=0.0003). CONCLUSIONS: The occurrence of a CLL-like pattern may allow to identify HCV-infected patients at risk of developing MC and eventually non-Hodgkin lymphoma, who should require a closer surveillance and a longer follow-up., (Copyright © 2019. Published by Elsevier B.V.)- Published
- 2019
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39. Donor lymphocyte infusions for B-cell malignancies relapse after T-cell replete allogeneic hematopoietic cell transplantation.
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Ortí G, García-Cadenas I, López-Corral L, Pérez A, Jimenez MJ, Sánchez-Ortega I, Alonso L, Sisinni L, Fox L, Villacampa G, Badell I, de Heredia CD, Parody R, Ferrà C, Solano C, Caballero D, Martino R, Querol S, and Valcárcel D
- Subjects
- Adult, Aged, Allografts, Female, Follow-Up Studies, Humans, Male, Middle Aged, Blood Donors, Graft vs Host Disease blood, Graft vs Host Disease mortality, Graft vs Host Disease therapy, Hematopoietic Stem Cell Transplantation, Lymphocyte Transfusion, Lymphoma, B-Cell blood, Lymphoma, B-Cell mortality, Lymphoma, B-Cell therapy, T-Lymphocytes
- Published
- 2019
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40. Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients.
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Amini RM, Enblad G, Hollander P, Laszlo S, Eriksson E, Ayoola Gustafsson K, Loskog A, and Thörn I
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological therapeutic use, Blood Cell Count, CD3 Complex metabolism, Case-Control Studies, Disease-Free Survival, Female, Flow Cytometry, Healthy Volunteers, Hodgkin Disease drug therapy, Hodgkin Disease immunology, Hodgkin Disease mortality, Humans, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell immunology, Lymphoma, B-Cell mortality, Male, Middle Aged, Prognosis, Prospective Studies, Young Adult, Hodgkin Disease blood, Killer Cells, Natural, Lymphoma, B-Cell blood, Monocytes, Myeloid-Derived Suppressor Cells, T-Lymphocytes
- Abstract
Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome., Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome., Results: The percentage of CD3-positive T-cells was lower (p = 0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p = 0.2) nor the T-cell/monocyte ratio (p = 0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7
+ /CD3- /CD56bright /CD16dim/- ) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p = 0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p = 0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p = 0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p = 0.04)., Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.- Published
- 2019
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41. Monoclonal B-cell lymphocytosis and prostate cancer: incidence and effects of radiotherapy.
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D'Auria F, Valvano L, Rago L, Statuto T, Calice G, D'Arena G, Fusco V, and Musto P
- Subjects
- Aged, B-Lymphocytes immunology, Case-Control Studies, Humans, Incidence, Leukocyte Count, Lymphoma, B-Cell blood, Male, Prostatic Neoplasms blood, Lymphoma, B-Cell complications, Lymphoma, B-Cell epidemiology, Prostatic Neoplasms complications, Prostatic Neoplasms radiotherapy
- Abstract
Monoclonal B-cells lymphocytosis (MBL) is a benign condition that may precede chronic lymphocytic leukemia (CLL), not rarely present in peripheral blood of healthy elderly people, among which there is also a male prevalence. Though CLL has been associated with various types of solid tumors, including prostate cancer (PC), no data exist about the relationship between PC and MBL. We studied the frequency of CLL-like MBL clones in a group of 48 patients affected by PC and followed them during and after whole-pelvis radiotherapy (WPRT) treatment. We found four MBL clones (8.3%), two of which (4.2%) had a B-cell clonal count >1000 cells/µL ('clinical MBL'). A single case (1.8%) of 'low-count' MBL occurred in a control group of 54 healthy males. Notably, normal B-lymphocytes were consistently affected by WPRT, while MBL clones were less radiosensitive. Our results suggest a possible association between 'clinical' MBL and PC and show a different impact of the radiation on monoclonal respect to normal B-cells, which could also imply a greater risk of clonal transformation., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2019
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42. [B-cell non-Hodgkin lymphoma discovery after observation of a platelet satellitism around atypical lymphocytes].
- Author
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Gatignol A, Amirault M, Legac É, and Decker J
- Subjects
- Aged, 80 and over, Blood Cell Count, Diagnosis, Differential, Female, Humans, Immunophenotyping, Lymphoma, B-Cell blood, Lymphoma, B-Cell pathology, Lymphoma, Non-Hodgkin blood, Lymphoma, Non-Hodgkin pathology, Blood Platelets pathology, Lymphocytes pathology, Lymphoma, B-Cell diagnosis, Lymphoma, Non-Hodgkin diagnosis
- Abstract
We report the case of an 83-year-old woman admitted to the accident and emergency unit for pneumopathy. The blood cell count on the DXH automaton (Coulter® ™ UniCel® DxH) found a normochromic and normocytic anemia, anormal platelet count and subnormal leukocyte formula. The only alarm raised by the automaton was the presence of a basocytosis. A control of the leucocyte count by flow cytometry and blood smear has been done. It revealed there was no basocytosis, but showed the presence of an atypical monomorphic lymphocytes B population (T/B < 1 ratio in flow cytometry), around which platelets aggregated. The lymphocytic immunophenotyping allowed us to highlight the presence of a CD5+ B clonal subpopulation.
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- 2019
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43. Single-cell RNA-Seq of follicular lymphoma reveals malignant B-cell types and coexpression of T-cell immune checkpoints.
- Author
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Andor N, Simonds EF, Czerwinski DK, Chen J, Grimes SM, Wood-Bouwens C, Zheng GXY, Kubit MA, Greer S, Weiss WA, Levy R, and Ji HP
- Subjects
- Biopsy, CCAAT-Enhancer-Binding Proteins genetics, CD4-Positive T-Lymphocytes cytology, CD52 Antigen genetics, Cell Lineage, Flow Cytometry, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells cytology, Histocompatibility Antigens Class II metabolism, Humans, Immune System, Immunoglobulin G, Lectins, C-Type genetics, Leukocytes, Mononuclear cytology, Lymphoma, B-Cell blood, Lymphoma, Follicular blood, Palatine Tonsil metabolism, Receptors, IgE genetics, Sequence Analysis, RNA, Transcriptome, Tumor Microenvironment, beta 2-Microglobulin genetics, Lymphoma, B-Cell genetics, Lymphoma, Follicular genetics, T-Lymphocytes, Regulatory cytology
- Abstract
Follicular lymphoma (FL) is a low-grade B-cell malignancy that transforms into a highly aggressive and lethal disease at a rate of 2% per year. Perfect isolation of the malignant B-cell population from a surgical biopsy is a significant challenge, masking important FL biology, such as immune checkpoint coexpression patterns. To resolve the underlying transcriptional networks of follicular B-cell lymphomas, we analyzed the transcriptomes of 34 188 cells derived from 6 primary FL tumors. For each tumor, we identified normal immune subpopulations and malignant B cells, based on gene expression. We used multicolor flow cytometry analysis of the same tumors to confirm our assignments of cellular lineages and validate our predictions of expressed proteins. Comparison of gene expression between matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin (Ig) light chain expression (either Igκ or Igλ), as well the expected upregulation of the BCL2 gene, but also downregulation of the FCER2 , CD52 , and major histocompatibility complex class II genes. By analyzing thousands of individual cells per patient tumor, we identified the mosaic of malignant B-cell subclones that coexist within a FL and examined the characteristics of tumor-infiltrating T cells. We identified genes coexpressed with immune checkpoint molecules, such as CEBPA and B2M in regulatory T (Treg) cells, providing a better understanding of the gene networks involved in immune regulation. In summary, parallel measurement of single-cell expression in thousands of tumor cells and tumor-infiltrating lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development., (© 2019 by The American Society of Hematology.)
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- 2019
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44. SERS-based dynamic monitoring of minimal residual disease markers with high sensitivity for clinical applications.
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Wang Y, Zong S, Li N, Wang Z, Chen B, and Cui Y
- Subjects
- Antigens, CD19 metabolism, Antigens, CD20 metabolism, Flow Cytometry, Humans, K562 Cells, Leukemia, B-Cell blood, Limit of Detection, Lymphoma, B-Cell blood, Prognosis, Reproducibility of Results, Sensitivity and Specificity, Biomarkers, Tumor blood, Immunoassay methods, Neoplasm, Residual diagnostic imaging, Neoplasms diagnostic imaging, Spectrum Analysis, Raman methods
- Abstract
Minimal residual disease (MRD) measurement is important for the diagnosis and prognosis of B cell hematological malignancies in the clinic. Thus, a sensitive and accurate method for monitoring the corresponding surface markers is in high demand for early diagnosis and treatment instruction. Herein, we developed a surface enhanced Raman scattering (SERS)-based sandwich-type immunoassay for the simultaneous detection of two surface markers (i.e., CD19 and CD20) in Raji cell lines as well as in clinical blood samples. First, to compare with the results obtained by flow cytometry, we evaluated the sensitivity and reproducibility of the SERS immunoassay for real-time detection of CD19 and CD20 expressions in Raji cells and blood samples. Then, we conducted follow-up tests on 13 B cell hematological malignancy patients for one month and dynamically monitored their CD19 and CD20 expressions by the SERS immunoassay. In addition to the improved sensitivity of the SERS method, good linear correlations between the SERS intensities and flow cytometry results were also observed for both CD19 and CD20, which indicated the accuracy of this SERS-based strategy. Therefore, this SERS-based simultaneous detection approach shows great potential for accurate and early diagnosis of MRD in B cell hematological malignancies.
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- 2019
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45. Plasma Exchange Can Be an Alternative Therapeutic Modality for Severe Cytokine Release Syndrome after Chimeric Antigen Receptor-T Cell Infusion: A Case Report.
- Author
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Xiao X, He X, Li Q, Zhang H, Meng J, Jiang Y, Deng Q, and Zhao M
- Subjects
- Adult, Antigens, CD19 blood, Antigens, CD19 therapeutic use, Cytokine Release Syndrome blood, Cytokine Release Syndrome pathology, Cytokines immunology, Glucocorticoids therapeutic use, Humans, Immunotherapy, Adoptive methods, Lymphoma, B-Cell blood, Lymphoma, B-Cell pathology, Male, Plasma Exchange methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen therapeutic use, Cytokine Release Syndrome therapy, Lymphoma, B-Cell therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Antigen, T-Cell therapeutic use
- Abstract
Background: Tumor immunotherapy with chimeric antigen receptor-T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening., Case Presentation: A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1 × 10
6 /kg of engineered anti-CD19 CAR-T cells was administered. After infusion of CAR-T cells (day 0), the patient underwent a typical CRS reaction, with increases in fever, muscle soreness, and inflammatory cytokines. He was treated with antiallergic and antipyretic drugs, glucocorticoids, and tocilizumab (4 mg/kg, days 3 and 5). However, CRS was not under control, and his condition rapidly deteriorated. He was transferred to the intensive care unit, where dexamethasone 10 mg q6h was administered, and plasma exchange was performed, with 3,000 mL of plasma replaced by fresh frozen plasma per day for 3 consecutive days. His symptoms gradually improved, and the CRS-related symptoms were relieved. Additionally, a bone marrow smear showed no lymphoblast cells, and minimal residual disease was negative on day 28. The patient was eventually discharged in a normal condition., Conclusions: CRS is caused by an exaggerated systemic immune response, potentially resulting in organ damage that can be fatal. Although therapeutic plasma exchange is not included in CRS management guidelines, this case shows that plasma exchange is feasible in at least some patients with severe CRS., (©2018 American Association for Cancer Research.)- Published
- 2019
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46. An integrated flow cytometry analysis of 286 mature B cell neoplasms identifies CD13 as a useful marker for diagnostic subtyping.
- Author
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Lau H, Nagy A, Atwater SK, Cascio MJ, and Ohgami RS
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Disease-Free Survival, Female, Hematologic Neoplasms mortality, Humans, Leukemia, B-Cell mortality, Lymphoma, B-Cell mortality, Male, Middle Aged, Survival Rate, Biomarkers, Tumor blood, CD13 Antigens blood, Flow Cytometry instrumentation, Flow Cytometry methods, Hematologic Neoplasms blood, Leukemia, B-Cell blood, Lymphoma, B-Cell blood, Neoplasm Proteins blood
- Abstract
Introduction: CD13 is a myeloid associated antigen, which may be expressed by a subset of B cell lymphomas; however, the significance of its expression along with other B cell associated antigens is not well characterized., Methods: Two hundred and eighty-six mature B cell neoplasms with flow cytometric analysis performed at the time of diagnosis were identified. Expression of CD13, CD45, CD19, CD20, CD5, CD10, CD38, CD22, CD23, FMC7, and kappa and lambda light chains was assessed for each case and correlated with clinicopathologic features., Results: CD13 expression was associated specifically with cases of lymphoplasmacytic lymphoma (LPL) (16/26)- and FMC7-positive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (11/30). No cases of follicular lymphoma (FL) expressed CD13 (0/48). Across all B cell neoplasms, CD13 expression positively correlated with FMC7 co-expression and kappa light chain restriction and negatively correlated with CD10 co-expression and lambda light chain restriction. No significant association of CD13 with overall or disease free survival in B cell neoplasms was seen., Conclusion: CD13 expression is present more often in LPL- and FMC7-positive CLL/SLL than other mature B cell lymphoma subtypes and absent in cases of FL and may be a useful feature for diagnostic subtyping., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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47. Elevated soluble CD23 level indicates increased risk of B cell non-Hodgkin's lymphomas: evidence from a meta-analysis.
- Author
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Huang YS, Zhou X, Yang ZF, and Lv ZT
- Subjects
- Female, Humans, Male, Risk Factors, HIV Infections blood, HIV-1, Lymphoma, B-Cell blood, Neoplasm Proteins blood, Receptors, IgE blood
- Abstract
The aim of the present study was to determine whether circulating soluble CD23 (sCD23) was associated with B cells non-Hodgkin's lymphomas (B-NHL). PubMed, EMBASE, and ISI Web of Science were extensively searched without language restriction. Data was extracted in a standardized data collection sheet after two reviewers scanned studies independently. The association between sCD23 and NHL was indicated as odds ratio (OR) along with its related 95% confidence interval (95% CI). Meta-analysis was conducted via RevMan 5.3. A total of five studies, which included 964 B-NHL patients and 1243 matched controls without B-NHL, among which 257 were HIV-positive donors and 986 were general controls, were included in our study. Meta-analysis revealed a significant association between peripheral sCD23 level and B-NHL in HIV-positive samples (OR 1.66, 95% CI 1.25, 2.20; P = 0.0005) as well as the general population (OR 2.51; 95% CI 1.71, 3.86; P < 0.00001). Meta-analysis, stratified by sampling time prior to diagnosis, indicated potential HIV-NHL patients are 2.34-folds more likely to have higher blood sCD23 level, although this association is statistically meaningful only during 3-5 years prior to diagnosis (95% CI 1.27, 4.33). Subgroup analysis based on B-NHL type demonstrated a significant association between sCD23 level and diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and follicular lymphoma (FL). The findings of our study indicate a positive association of circulating sCD23 level and B-NHL risks and highlight the possibility of sCD23 as a predictive marker of B-NHL. However, to better understand the underlying mechanism, further studies are needed.
- Published
- 2018
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48. Development of B-cell prolymphocytic leukemia in a patient with splenic diffuse red pulp small B-cell lymphoma.
- Author
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Cheng WY, Zhu YM, Cheng S, Chen YS, and Shen Y
- Subjects
- Humans, Leukemia, Prolymphocytic, B-Cell blood, Lymphoma, B-Cell blood, Lymphoma, B-Cell surgery, Male, Middle Aged, Splenectomy, Splenic Neoplasms blood, Splenic Neoplasms surgery, Cell Transformation, Neoplastic pathology, Leukemia, Prolymphocytic, B-Cell pathology, Lymphoma, B-Cell pathology, Splenic Neoplasms pathology
- Published
- 2018
- Full Text
- View/download PDF
49. Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma.
- Author
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Tagawa M, Kurashima C, Takagi S, Maekawa N, Konnai S, Shimbo G, Matsumoto K, Inokuma H, Kawamoto K, and Miyahara K
- Subjects
- Animals, Biomarkers, Tumor blood, Dogs, Female, Lymphocytes immunology, Lymphoma, B-Cell blood, Lymphoma, B-Cell immunology, Male, Neoplasm Grading, Prospective Studies, Dog Diseases blood, Dog Diseases immunology, Lymphoma, B-Cell veterinary
- Abstract
B cell high grade lymphoma is the most common hematopoietic malignancy in dogs. Although the immune checkpoint molecules, programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and immune checkpoint inhibitors have been evaluated for the treatment of various human lymphoid malignancies, the expression of those molecules and their relationship with prognosis remain unknown in canine lymphoma. The objective of this study was to evaluate the expression of costimulatory molecules on peripheral blood lymphocytes and tumor infiltrating lymphocytes, in addition to associated ligand expression in the lymph nodes of patients with B cell multicentric high grade lymphoma. Eighteen patients diagnosed with B cell high grade lymphoma and nine healthy control dogs were enrolled. Flow cytometric analysis revealed that the expression of PD-1 on CD4+ peripheral and tumor infiltrating lymphocytes and CTLA-4 on CD4+ peripheral lymphocytes was significantly higher in the lymphoma group than in the control group. The expression level of CD80 mRNA was significantly lower in the lymphoma group than in the control group. In contrast, there were no significant differences in PD-L1, PD-L2, and CD86 expression between the groups. Dogs with CTLA-4 levels below the cutoff values, which were determined based on receiver operating characteristic curves, on peripheral CD4+, CD8+, and tumor infiltrating CD4+ lymphocytes had significantly longer survival than dogs with values above the cutoff. Although it is uncertain whether the expression of immune checkpoint molecules affect the biological behavior of canine lymphoma, one possible explanation is that PD-1 and CTLA-4 might be associated with the suppression of antitumor immunity in dogs with B cell high grade lymphoma, particularly through CD4+ T cells., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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50. Cryoglobulin-induced red blood cell morphologic changes.
- Author
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Winer A and Bains A
- Subjects
- Bone Marrow pathology, Cryoglobulinemia blood, Cryoglobulinemia complications, Cryoglobulins analysis, Hemolysis, Hepatitis C blood, Hepatitis C complications, Hepatitis C pathology, Humans, Lymphoma, B-Cell blood, Lymphoma, B-Cell complications, Lymphoma, B-Cell pathology, Male, Middle Aged, Cryoglobulinemia pathology, Erythrocytes pathology
- Published
- 2018
- Full Text
- View/download PDF
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