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Shi X, Wallach J, Ma X, Rogne T. Autoimmune Diseases and Risk of Non-Hodgkin Lymphoma: A Mendelian Randomisation Study. Cancer Med 2024; 13:e70327. [PMID: 39506244 PMCID: PMC11540836 DOI: 10.1002/cam4.70327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/12/2024] [Accepted: 09/28/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Non-Hodgkin lymphoma (NHL) is one of the most common haematologic malignancies in the world. Despite substantial efforts to identify causes and risk factors for NHL, its aetiology is largely unclear. Autoimmune diseases have long been considered potential risk factors for NHL. We carried out Mendelian randomisation (MR) analyses to examine whether genetically predicted susceptibility to ten autoimmune diseases (Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes) is associated with risk of NHL. METHODS Two-sample MR was performed using publicly available summary statistics from cohorts of European ancestry. For NHL and four NHL subtypes, we used data from UK Biobank, Kaiser Permanente cohorts, and FinnGen studies. RESULTS Negative associations between type 1 diabetes and sarcoidosis and the risk of NHL were observed (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.92-0.98, p = 5 × 10-3, and OR 0.92, 95% CI: 0.85-0.99, p = 2.8 × 10-2, respectively). These findings were supported by the sensitivity analyses accounting for potential pleiotropy and weak instrument bias. No significant associations were found between the other eight autoimmune diseases and NHL risk. CONCLUSION These findings suggest that genetically predicted susceptibility to type 1 diabetes, and to some extent sarcoidosis, might reduce the risk of NHL. However, future studies with different datasets, approaches, and populations are warranted to further examine the potential associations between these autoimmune diseases and the risk of NHL.
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Affiliation(s)
- Xiaoting Shi
- Department of Environmental Health SciencesYale School of Public HealthNew HavenConnecticutUSA
- Yale Center for Perinatal, Pediatric, and Environmental EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
| | - Joshua D. Wallach
- Department of Epidemiology, Rollins School of Public HealthEmory UniversityAtlantaGeorgiaUSA
| | - Xiaomei Ma
- Department of Chronic Diseases EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
| | - Tormod Rogne
- Yale Center for Perinatal, Pediatric, and Environmental EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Department of Chronic Diseases EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Department of Community Medicine and Global HealthUniversity of OsloOsloNorway
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Cotta CV, Bhavsar S, Robertson S, Cook JR. Patients with Classic Hodgkin Lymphoma and Follicular Lymphoma Compared to Single Malignancy Controls. Am J Surg Pathol 2024; 48:965-971. [PMID: 38600854 DOI: 10.1097/pas.0000000000002225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024]
Abstract
Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls.
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MESH Headings
- Humans
- Hodgkin Disease/pathology
- Hodgkin Disease/virology
- Hodgkin Disease/genetics
- Lymphoma, Follicular/pathology
- Lymphoma, Follicular/genetics
- Lymphoma, Follicular/virology
- Middle Aged
- Female
- Male
- Aged
- Adult
- Neoplasms, Multiple Primary/pathology
- Neoplasms, Multiple Primary/genetics
- Neoplasms, Multiple Primary/virology
- Proto-Oncogene Proteins c-bcl-2/genetics
- Neoplasm Grading
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Translocation, Genetic
- Aged, 80 and over
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/virology
- Epstein-Barr Virus Infections/pathology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/analysis
- In Situ Hybridization, Fluorescence
- Case-Control Studies
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Affiliation(s)
- Claudiu V Cotta
- Robert J. Tomsich Pathology and Laboratory Medicine Institute of the Cleveland Clinic, Cleveland, OH
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Orimoloye HT, Nguyen N, Deng C, Saechao C, Ritz B, Olsen J, Hansen J, Heck JE. Maternal autoimmune disease and its association with childhood cancer: A population-based case-control study in Denmark. EJC PAEDIATRIC ONCOLOGY 2024; 3:100145. [PMID: 38298419 PMCID: PMC10827341 DOI: 10.1016/j.ejcped.2024.100145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
Background Autoimmune diseases have been linked to an increased risk of pregnancy-related complications. A family history of autoimmune diseases may be related to the risk of childhood cancer based on similar histocompatibility antigens. We utilized data from national registries in Denmark to examine associations between maternal autoimmune disease and cancer in their offspring. Methods We linked data from several national registries in Denmark to identify childhood cancer cases in children <20 years diagnosed between 1977 to 2016. Controls were selected from the Central Population Register and matched to cases by birth year and sex (25:1). Mothers with autoimmune disease diagnosed in pregnancy or prior were identified from the National Patient Register. Multivariable conditional logistic regression analyses were used to estimate associations between maternal autoimmune diseases and childhood cancer in offspring. Results Autoimmune diseases (all types) were positively associated with all childhood cancers combined (Odds Ratio (OR) = 1.25, 95% CI 1.06, 1.47), acute lymphoblastic leukemia (OR =1.52, 95% CI 1.09, 2.13), Burkitt lymphoma (OR = 2.69, 95% CI 1.04, 6.97), and central nervous system tumors (OR = 1.45, 95% CI 1.06, 1.99), especially astrocytoma (OR = 2.27, 95% CI 1.36, 3.77) and glioma (OR = 1.75, 95% CI 1.13, 2.73). When we examined mothers with rheumatoid arthritis, we observed an increased association for all cancers (OR = 2.15, 95% CI 1.40, 3.30), acute lymphoblastic leukemia (OR = 3.55, 95% CI 1.69, 7.47), and central nervous system tumors (OR = 2.91, 95% CI 1.46, 5.82), especially glioma (OR = 3.58, 95% CI 1.40, 9.18) in offspring. Conclusion There is a positive association between maternal autoimmune disease and childhood cancer. This association is especially prominent in the offspring of women with rheumatoid arthritis.
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Affiliation(s)
- Helen T. Orimoloye
- College of Health and Public Service, University of North Texas, Denton, TX, USA
| | - Nicholas Nguyen
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
| | - Chuanjie Deng
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
| | - Chai Saechao
- UCLA Health, University of California, Los Angeles
| | - Beate Ritz
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jorn Olsen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
| | - Johnni Hansen
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Julia E. Heck
- College of Health and Public Service, University of North Texas, Denton, TX, USA
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
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Al-Hussaini I, White B, Varmeziar A, Mehra N, Sanchez M, Lee J, DeGroote NP, Miller TP, Mitchell CS. An Interpretable Machine Learning Framework for Rare Disease: A Case Study to Stratify Infection Risk in Pediatric Leukemia. J Clin Med 2024; 13:1788. [PMID: 38542012 PMCID: PMC10970787 DOI: 10.3390/jcm13061788] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 04/18/2024] Open
Abstract
Background: Datasets on rare diseases, like pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), have small sample sizes that hinder machine learning (ML). The objective was to develop an interpretable ML framework to elucidate actionable insights from small tabular rare disease datasets. Methods: The comprehensive framework employed optimized data imputation and sampling, supervised and unsupervised learning, and literature-based discovery (LBD). The framework was deployed to assess treatment-related infection in pediatric AML and ALL. Results: An interpretable decision tree classified the risk of infection as either "high risk" or "low risk" in pediatric ALL (n = 580) and AML (n = 132) with accuracy of ∼79%. Interpretable regression models predicted the discrete number of developed infections with a mean absolute error (MAE) of 2.26 for bacterial infections and an MAE of 1.29 for viral infections. Features that best explained the development of infection were the chemotherapy regimen, cancer cells in the central nervous system at initial diagnosis, chemotherapy course, leukemia type, Down syndrome, race, and National Cancer Institute risk classification. Finally, SemNet 2.0, an open-source LBD software that links relationships from 33+ million PubMed articles, identified additional features for the prediction of infection, like glucose, iron, neutropenia-reducing growth factors, and systemic lupus erythematosus (SLE). Conclusions: The developed ML framework enabled state-of-the-art, interpretable predictions using rare disease tabular datasets. ML model performance baselines were successfully produced to predict infection in pediatric AML and ALL.
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Affiliation(s)
- Irfan Al-Hussaini
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Brandon White
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Armon Varmeziar
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Nidhi Mehra
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Milagro Sanchez
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Judy Lee
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA (T.P.M.)
| | - Nicholas P. DeGroote
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA (T.P.M.)
| | - Tamara P. Miller
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA (T.P.M.)
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Emory University, Atlanta, GA 30332, USA
| | - Cassie S. Mitchell
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Machine Learning Center at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA
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Shi X, Wallach JD, Ma X, Rogne T. Autoimmune diseases and risk of non-Hodgkin lymphoma: A Mendelian randomisation study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.01.20.24301459. [PMID: 38343812 PMCID: PMC10854352 DOI: 10.1101/2024.01.20.24301459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Objective To examine whether genetically predicted susceptibility to ten autoimmune diseases (Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes) is associated with risk of non-Hodgkin lymphoma (NHL). Design Two sample Mendelian randomization (MR) study. Setting Genome wide association studies (GWASs) of ten autoimmune diseases, NHL, and four NHL subtypes (i.e., follicular lymphoma, mature T/natural killer-cell lymphomas, non-follicular lymphoma, and other and unspecified types of NHL). Analysis We used data from the largest publicly available GWASs of European ancestry for each autoimmune disease, NHL, and NHL subtypes. For each autoimmune disease, we extracted single nucleotide polymorphisms (SNPs) strongly associated (P < 5×10-8) with that disease and that were independent of one another (R2 < 1×10-3) as genetic instruments. SNPs within the human leukocyte antigen region were not considered due to potential pleiotropy. Our primary MR analysis was the inverse-variance weighted analysis. Additionally, we conducted MR-Egger, weighted mode, and weighted median regression to address potential bias due to pleiotropy, and robust adjusted profile scores to address weak instrument bias. We carried out sensitivity analysis limited to the non-immune pathway for nominally significant findings. To account for multiple testing, we set the thresholds for statistical significance at P < 5×10-3. Participants The number of cases and controls identified in the relevant GWASs were 437 and 3,325 for Behçet's disease, 4,918 and 5,684 for coeliac disease, 435 and 341,188 for dermatitis herpetiformis, 4,576 and 8,039 for lupus, 11,988 and 275,335 for psoriasis, 22,350 and 74,823 for rheumatoid arthritis, 3,597 and 337,121 for sarcoidosis, 2,735 and 332,115 for Sjögren's syndrome, 9,095 and 17,584 for systemic sclerosis, 18,942 and 501,638 for type 1 diabetes, 2,400 and 410,350 for NHL; and 296 to 2,340 cases and 271,463 controls for NHL subtypes. Exposures Genetic variants predicting ten autoimmune diseases: Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes. Main outcome measures Estimated associations between genetically predicted susceptibility to ten autoimmune diseases and the risk of NHL. Results The variance of each autoimmune disease explained by the SNPs ranged from 0.3% to 3.1%. Negative associations between type 1 diabetes and sarcoidosis and the risk of NHL were observed (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.92 to 0.98, P = 5×10-3, and OR 0.92, 95% CI: 0.85 to 0.99, P = 2.8×10-2, respectively). These findings were supported by the sensitivity analyses accounting for potential pleiotropy and weak instrument bias. No significant associations were found between the other eight autoimmune diseases and NHL risk. Of the NHL subtypes, type 1 diabetes was most strongly associated with follicular lymphoma (OR 0.91, 95% CI: 0.86 to 0.96, P = 1×10-3), while sarcoidosis was most strongly associated with other and unspecified NHL (OR 0.86, 95% CI: 0.75 to 0.97, P = 1.8×10-2). Conclusions These findings suggest that genetically predicted susceptibility to type 1 diabetes, and to some extent sarcoidosis, might reduce the risk of NHL. However, future studies with different datasets, approaches, and populations are warranted to further examine the potential associations between these autoimmune diseases and the risk of NHL.
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Affiliation(s)
- Xiaoting Shi
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA
- Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Joshua D. Wallach
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Xiaomei Ma
- Department of Chronic Diseases Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Tormod Rogne
- Department of Chronic Diseases Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
- Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
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Watanabe T. Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas. World J Gastroenterol 2023; 29:6179-6197. [PMID: 38186866 PMCID: PMC10768399 DOI: 10.3748/wjg.v29.i48.6179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/02/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023] Open
Abstract
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.
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Affiliation(s)
- Takuya Watanabe
- Department of Internal Medicine and Gastroenterology, Watanabe Internal Medicine Aoyama Clinic, Niigata 9502002, Japan
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Gupta DS, Gadi V, Kaur G, Chintamaneni M, Tuli HS, Ramniwas S, Sethi G. Resveratrol and Its Role in the Management of B-Cell Malignancies-A Recent Update. Biomedicines 2023; 11:221. [PMID: 36672729 PMCID: PMC9855921 DOI: 10.3390/biomedicines11010221] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/11/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023] Open
Abstract
The growing incidence of B cell malignancies globally has prompted research on the pharmacological properties of phytoconstituents in cancer management. Resveratrol, a polyphenolic stilbenoid widely found in nature, has been explored for its anti-inflammatory and antioxidant properties, and promising results from different pre-clinical studies have indicated its potential for management of B cell malignancies. However, these claims must be substantiated by a greater number of clinical trials in diverse populations, in order to establish its safety and efficacy profile. In addition to this, there is a need to explore nanodelivery of this agent, owing to its poor solubility, which in turn may impact its bioavailability. This review aims to offer an overview of the occurrence and pathogenesis of B cell malignancies with a special focus on the inflammatory pathways involved, the mechanism of actions of resveratrol and its pharmacokinetic profile, results from pre-clinical and clinical studies, as well as an overview of the marketed formulations. The authors have also presented their opinion on the various challenges associated with the clinical development of resveratrol and future perspectives regarding therapeutic applications of this agent.
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Affiliation(s)
- Dhruv Sanjay Gupta
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vile Parle-West, Mumbai 400056, India
| | - Vaishnavi Gadi
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vile Parle-West, Mumbai 400056, India
| | - Ginpreet Kaur
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vile Parle-West, Mumbai 400056, India
| | - Meena Chintamaneni
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vile Parle-West, Mumbai 400056, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali 140413, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
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8
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Shi X, Zhuo H, Du Y, Nyhan K, Ioannidis J, Wallach JD. Environmental risk factors for non-Hodgkin's lymphoma: umbrella review and comparison of meta-analyses of summary and individual participant data. BMJ MEDICINE 2022; 1:e000184. [PMID: 36936582 PMCID: PMC9978687 DOI: 10.1136/bmjmed-2022-000184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/31/2022] [Indexed: 02/06/2023]
Abstract
Objectives To summarise the range, strength, and validity of reported associations between environmental risk factors and non-Hodgkin's lymphoma, and to evaluate the concordance between associations reported in meta-analyses of summary level data and meta-analyses of individual participant data. Design Umbrella review and comparison of meta-analyses of summary and individual participant level data. Data sources Medline, Embase, Scopus, Web of Science Core Collection, Cochrane Library, and Epistemonikos, from inception to 23 July 2021. Eligibility criteria for selecting studies English language meta-analyses of summary level data and of individual participant data evaluating associations between environmental risk factors and incident non-Hodgkin's lymphoma (overall and subtypes). Data extraction and synthesis Summary effect estimates from meta-analyses of summary level data comparing ever versus never exposure that were adjusted for the largest number of potential confounders were re-estimated using a random effects model and classified as presenting evidence that was non-significant, weak (P<0.05), suggestive (P<0.001 and >1000 cases), highly suggestive (P<0.000001, >1000 cases, largest study reporting a significant association), or convincing (P<0.000001, >1000 cases, largest study reporting a significant association, I2 <50%, 95% prediction interval excluding the null value, and no evidence of small study effects and excess significance bias) evidence. When the same exposures, exposure contrast levels, and outcomes were evaluated in meta-analyses of summary level data and meta-analyses of individual participant data from the International Lymphoma Epidemiology (InterLymph) Consortium, concordance in terms of direction, level of significance, and overlap of 95% confidence intervals was examined. Methodological quality of the meta-analyses of summary level data was assessed by the AMSTAR 2 tool. Results We identified 85 meta-analyses of summary level data reporting 257 associations for 134 unique environmental risk factors and 10 subtypes of non-Hodgkin's lymphoma nearly all (79, 93%) were classified as having critically low quality. Most associations (225, 88%) presented either non-significant or weak evidence. The 11 (4%) associations presenting highly suggestive evidence were primarily for autoimmune or infectious disease related risk factors. Only one association, between history of coeliac disease and risk of non-Hodgkin's lymphoma, presented convincing evidence. Of 40 associations reported in meta-analyses of summary level data that were also evaluated in InterLymph meta-analyses of individual participant data, 22 (55%) pairs were in the same direction, had the same level of statistical significance, and had overlapping 95% confidence intervals; 28 (70%) pairs had summary effect sizes from the meta-analyses of individual participant data that were more conservative. Conclusion This umbrella review suggests evidence of many meta-analyses of summary level data reporting weak associations between environmental risk factors and non-Hodgkin's lymphoma. Improvements to primary studies as well as evidence synthesis in evaluations of evironmental risk factors and non-Hodgkin's lymphoma are needed. Review registration number PROSPERO CRD42020178010.
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Affiliation(s)
- Xiaoting Shi
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Haoran Zhuo
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Yuxuan Du
- Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA
| | - Kate Nyhan
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA
| | - John Ioannidis
- Department of Medicine, of Epidemiology and Population Health, of Biomedical Data Science, and of Statistics, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA
| | - Joshua D Wallach
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
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9
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Riller Q, Cohen-Aubart F, Roos-Weil D. [Splenic lymphoma, diagnosis and treatment]. Rev Med Interne 2022; 43:608-616. [PMID: 35691756 DOI: 10.1016/j.revmed.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/23/2022] [Indexed: 11/29/2022]
Abstract
Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia can lead to the diagnosis of splenic lymphoma. Splenic lymphoma is rare, mainly of non-hodgkinian origin, encompassing very different hematological entities in their clinical and biological presentation from an aggressive form such as hepato-splenic lymphoma to indolent B-cell lymphoma not requiring treatment such as marginal zone lymphoma, the most frequent form of splenic lymphoma. These entities can be challenging to diagnose and differentiate. This review presents different clinical and biological manifestations suspicious of splenic lymphoma and proposes a diagnosis work-up. We extended the strict definition of splenic lymphoma (lymphoma exclusively involving the spleen) to lymphoma thant can be revealed by a splenomegaly and we discuss the differential diagnosis of splenomegaly.
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Affiliation(s)
- Q Riller
- Service de médecine interne 2, Centre national de référence maladies systémiques rares, hôpital Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France.
| | - F Cohen-Aubart
- Service de médecine interne 2, Centre national de référence maladies systémiques rares, hôpital Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France
| | - D Roos-Weil
- Service d'hématologie clinique, hôpital Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France
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10
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Zhang M, Wang Y, Wang Y, Bai Y, Gu D. Association Between Systemic Lupus Erythematosus and Cancer Morbidity and Mortality: Findings From Cohort Studies. Front Oncol 2022; 12:860794. [PMID: 35600353 PMCID: PMC9115099 DOI: 10.3389/fonc.2022.860794] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/28/2022] [Indexed: 01/08/2023] Open
Abstract
Background Observational studies suggested that systemic lupus erythematosus (SLE) might be associated with increased cancer incidence and cancer-related death, however, the results are inconsistent. We aim to comprehensively estimate the causal relationships between SLE and cancer morbidity and mortality using a meta-analysis of cohort studies and Mendelian randomization. Methods A systematic search was conducted using PubMed to identify cohort studies published before January 21, 2021. Meta-analysis was performed to calculate relative risk (RR) and corresponding 95% confidence intervals (CI). In addition, we further evaluated the potentially causal relationships identified by cohort studies using two-sample Mendelian randomization. Results A total of 48 cohort studies involving 247,575 patients were included. We performed 31 main meta-analysis to assess the cancer risk and three meta-analyses to evaluate cancer mortality in SLE patients. Through meta-analyses, we observed an increased risk of overall cancer (RR=1.62, 95%CI, 1.47-1.79, P<0.001) and cancer-related death (RR=1.52, 95%CI, 1.36-1.70, P<0.001) in patients with SLE. Subgroup analysis by site-specific cancer showed that SLE was a risk factor for 17 site-specific cancers, including six digestive cancers (esophagus, colon, anus, hepatobiliary, liver, pancreatic), five hematologic cancers (lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, leukemia, multiple myeloma), as well as cancer in lung, larynx, cervical, vagina/vulva, renal, bladder, skin, and thyroid. In addition, further mendelian randomization analysis verified a weakly association between genetically predisposed SLE and lymphoma risk (odds ratio=1.0004, P=0.0035). Conclusions Findings from our study suggest an important role of SLE in carcinogenesis, especially for lymphoma. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, CRD42021243635.
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Affiliation(s)
- Min Zhang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yizhou Wang
- Department of Pathology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, China
| | - Yutong Wang
- Department of Epidemiology and Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Ye Bai
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Dongqing Gu
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
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11
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Wang SS, Vajdic CM, Linet MS, Slager SL, Voutsinas J, Nieters A, Casabonne D, Cerhan JR, Cozen W, Alarcón G, Martínez-Maza O, Brown EE, Bracci PM, Turner J, Hjalgrim H, Bhatti P, Zhang Y, Birmann BM, Flowers CR, Paltiel O, Holly EA, Kane E, Weisenburger DD, Maynadié M, Cocco P, Foretova L, Breen EC, Lan Q, Brooks-Wilson A, De Roos AJ, Smith MT, Roman E, Boffetta P, Kricker A, Zheng T, Skibola CF, Clavel J, Monnereau A, Chanock SJ, Rothman N, Benavente Y, Hartge P, Smedby KE. B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS. Cancer Epidemiol Biomarkers Prev 2022; 31:1103-1110. [PMID: 35244686 PMCID: PMC9081255 DOI: 10.1158/1055-9965.epi-21-0875] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/02/2021] [Accepted: 02/16/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. METHODS In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. RESULTS We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08-1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59-2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell-mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. CONCLUSIONS Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. IMPACT Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.
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Affiliation(s)
- Sophia S. Wang
- Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Monrovia, California
| | - Claire M. Vajdic
- Centre for Big Data Research in Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Martha S. Linet
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Susan L. Slager
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Jenna Voutsinas
- Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Monrovia, California
| | - Alexandra Nieters
- The Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - Delphine Casabonne
- Unit of Infections and Cancer, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program – Epibell, IDIBELL, Institut Català d’ Oncologia/IDIBELL, Barcelona, Spain
- The Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - James R. Cerhan
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Wendy Cozen
- Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California
| | - Graciela Alarcón
- Division of Clinical Immunology and Rheumatology, Department of Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Otoniel Martínez-Maza
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California
| | - Elizabeth E. Brown
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
- O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Paige M. Bracci
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
| | - Jennifer Turner
- Department of Histopathology, Douglass Hanly Moir Pathology, Sydney, New South Wales, Australia
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Henrik Hjalgrim
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Parveen Bhatti
- British Columbia Cancer Research Center, Vancouver, British Columbia, Canada
| | - Yawei Zhang
- Department of Cancer Prevention and Control at the National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Brenda M. Birmann
- Channing Division of Network Medicine, Department of Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Ora Paltiel
- Department of Hematology, The Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Hadassah University Medical Center, Jerusalem, Israel
| | - Elizabeth A. Holly
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
| | - Eleanor Kane
- Department of Health Sciences, University of York, York, United Kingdom
| | | | - Marc Maynadié
- Registry of Hematological Malignancies of Cote d'Or, INSERM U1231, Burgundy University and University Hospital, Dijon, France (Maynadie)
| | - Pierluigi Cocco
- Occupational Health Section, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Lenka Foretova
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Elizabeth Crabb Breen
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Qing Lan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Angela Brooks-Wilson
- Department of Biomedical Physiology and Kinesiology, Faculty of Science, Simon Fraser University, Vancouver, British Columbia, Canada
| | - Anneclaire J. De Roos
- Department of Environmental and Occupational Health, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania
| | - Martyn T. Smith
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California
| | - Eve Roman
- Department of Health Sciences, University of York, York, United Kingdom
| | - Paolo Boffetta
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Anne Kricker
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Tongzhang Zheng
- Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island
| | | | - Jacqueline Clavel
- Centre of Research in Epidemiology and Statistics (CRESS), UMR1153, INSERM, Université de Paris, Paris, France
| | - Alain Monnereau
- Centre of Research in Epidemiology and Statistics (CRESS), UMR1153, INSERM, Université de Paris, Paris, France
- Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, Paris, France
| | - Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Yolanda Benavente
- Unit of Infections and Cancer, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program – Epibell, IDIBELL, Institut Català d’ Oncologia/IDIBELL, Barcelona, Spain
- The Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Karin E. Smedby
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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12
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Oberoi M, Perinkulam Sathyanarayanan S, Akther J, Tantoush H. Diffuse Large B-cell Lymphoma of the Tibia in a Patient With Longstanding Seropositive Rheumatoid Arthritis on Methotrexate. Cureus 2022; 14:e23232. [PMID: 35449681 PMCID: PMC9012651 DOI: 10.7759/cureus.23232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2022] [Indexed: 11/27/2022] Open
Abstract
There has been an observance of increased occurrence of malignant lymphomas in patients with rheumatoid arthritis (RA). The increased risk of lymphoproliferative disorders has been linked to the severity of RA disease activity, the use of disease-modifying agents like methotrexate and certain genetic links between RA and lymphomas. This article outlines the case of an 88-year-old gentleman with a 13-year history of seropositive rheumatoid arthritis on methotrexate who presented with ankle pain and was subsequently found to have diffuse large B-cell lymphoma on further workup.
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13
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Barbu MC, Huider F, Campbell A, Amador C, Adams MJ, Lynall ME, Howard DM, Walker RM, Morris SW, Van Dongen J, Porteous DJ, Evans KL, Bullmore E, Willemsen G, Boomsma DI, Whalley HC, McIntosh AM. Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system. Mol Psychiatry 2022; 27:1647-1657. [PMID: 34880450 PMCID: PMC9095457 DOI: 10.1038/s41380-021-01412-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 10/11/2021] [Accepted: 11/26/2021] [Indexed: 12/28/2022]
Abstract
Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.
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Affiliation(s)
- Miruna C Barbu
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
| | - Floris Huider
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Carmen Amador
- MRC Human Genetics Unit, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Mark J Adams
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
| | | | - David M Howard
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Rosie M Walker
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Stewart W Morris
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Jenny Van Dongen
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - David J Porteous
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Kathryn L Evans
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Edward Bullmore
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Gonneke Willemsen
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Dorret I Boomsma
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Heather C Whalley
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
| | - Andrew M McIntosh
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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14
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Nicolò A, Linder AT, Jumaa H, Maity PC. The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia. Front Oncol 2022; 11:771669. [PMID: 34993136 PMCID: PMC8724047 DOI: 10.3389/fonc.2021.771669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/02/2021] [Indexed: 12/20/2022] Open
Abstract
Advanced genome-wide association studies (GWAS) identified several transforming mutations in susceptible loci which are recognized as valuable prognostic markers in chronic lymphocytic leukemia (CLL) and B cell lymphoma (BCL). Alongside, robust genetic manipulations facilitated the generation of preclinical mouse models to validate mutations associated with poor prognosis and refractory B cell malignancies. Taken together, these studies identified new prognostic markers that could achieve characteristics of precision biomarkers for molecular diagnosis. On the contrary, the idea of augmented B cell antigen receptor (BCR) signaling as a transforming cue has somewhat receded despite the efficacy of Btk and Syk inhibitors. Recent studies from several research groups pointed out that acquired mutations in BCR components serve as faithful biomarkers, which become important for precision diagnostics and therapy, due to their relevant role in augmented BCR signaling and CLL pathogenesis. For example, we showed that expression of a single point mutated immunoglobulin light chain (LC) recombined through the variable gene segment IGLV3-21, named IGLV3-21R110, marks severe CLL cases. In this perspective, we summarize the molecular mechanisms fine-tuning B cell transformation, focusing on immunoglobulin point mutations and recurrent mutations in tumor suppressors. We present a stochastic model for gain-of-autonomous BCR signaling and subsequent neoplastic transformation. Of note, additional mutational analyses on immunoglobulin heavy chain (HC) derived from non-subset #2 CLL IGLV3-21R110 cases endorses our perspective. Altogether, we propose a model of malignant transformation in which the augmented BCR signaling creates a conducive platform for the appearance of transforming mutations.
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Affiliation(s)
| | | | - Hassan Jumaa
- Institute of Immunology, Ulm University, Ulm, Germany
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15
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Abstract
In this issue of JEM, He et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211004) associate novel P2RY8 genetic variants to lupus, expanding the field of monogenic autoimmunity. The authors demonstrate that P2RY8 prevents the expansion of DNA-reactive B cells by restraining B cell mobility and activation within the germinal center.
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Affiliation(s)
- Maud Tusseau
- Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard, Lyon 1, Centre National de la Recherche Scientifique, UMR5308, ENS de Lyon, Lyon, France
| | - Alexandre Belot
- Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard, Lyon 1, Centre National de la Recherche Scientifique, UMR5308, ENS de Lyon, Lyon, France
- National Reference Centre for Rheumatic and AutoImmune and Systemic Diseases in Children (RAISE), Lyon, France
- Pediatric Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France
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16
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He MM, Lo CH, Wang K, Polychronidis G, Wang L, Zhong R, Knudsen MD, Fang Z, Song M. Immune-Mediated Diseases Associated With Cancer Risks. JAMA Oncol 2021; 8:209-219. [PMID: 34854871 PMCID: PMC8640951 DOI: 10.1001/jamaoncol.2021.5680] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Question What are the profiles of cancer risk associated with immune-mediated diseases? Findings In this cohort study of 478 753 participants, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers, and many immune-mediated diseases were associated with increased risk of cancer in the involved organs and in the near and distant organs or different systems. Meaning The findings suggest that immune-mediated diseases are associated with risk of cancer at the local and systemic levels, supporting the role of local and systemic immunoregulation in carcinogenesis. Importance Immune regulation is important for carcinogenesis; however, the cancer risk profiles associated with immune-mediated diseases need further characterization. Objective To assess the prospective association of 48 immune-mediated diseases with the risk of total and individual cancers and the prospective association of organ-specific immune-mediated diseases with the risk of local and extralocal cancers. Design, Setting, and Participants This prospective cohort study used data from the UK Biobank cohort study on adults aged 37 to 73 years who were recruited at 22 assessment centers throughout the UK between January 1, 2006, and December 31, 2010, with follow-up through February 28, 2019. Exposures Immune-mediated diseases. Main Outcomes and Measures The association of immune-mediated diseases with risk of cancer was assessed with multivariable hazard ratios (HRs) and 95% CIs after adjusting for various potential confounders using time-varying Cox proportional hazards regression. Heterogeneity in the associations of organ-specific immune-mediated diseases with local and extralocal cancers was assessed using the contrast test method. Results A total of 478 753 participants (mean [SD] age, 56.4 [8.1] years; 54% female) were included in the study. During 4 600 460 person-years of follow-up, a total of 2834 cases of cancer were documented in 61 496 patients with immune-mediated diseases and 26 817 cases of cancer in 417 257 patients without any immune-mediated diseases (multivariable HR, 1.08; 95% CI, 1.04-1.12). Five of the organ-specific immune-mediated diseases were significantly associated with higher risk of local but not extralocal cancers: asthma (HR, 1.34; 95% CI, 1.14-1.56), celiac disease (HR, 6.89; 95% CI, 2.18-21.75), idiopathic thrombocytopenic purpura (HR, 6.94; 95% CI, 3.94-12.25), primary biliary cholangitis (HR, 42.12; 95% CI, 20.76-85.44), and autoimmune hepatitis (HR, 21.26; 95% CI, 6.79-66.61) (P < .002 for heterogeneity). Nine immune-mediated diseases were associated with an increased risk of cancers in the involved organs (eg, asthma with lung cancer [HR, 1.34; 95% CI, 1.14-1.57; P < .001] and celiac disease with small intestine cancer [HR, 6.89; 95% CI, 2.18-21.75; P = .001]); 13 immune-mediated diseases were associated with an increased risk of cancer in the near organs (eg, Crohn disease with liver cancer: [HR, 4.01; 95% CI, 1.65-9.72; P = .002]) or distant organs (eg, autoimmune hepatitis with tongue cancer [HR, 27.75; 95% CI, 3.82-199.91; P = .001]) or in different systems (eg, idiopathic thrombocytopenic purpura with liver cancer [HR, 11.96; 95% CI, 3.82-37.42; P < .001]). Conclusions and Relevance In this cohort study, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers. The associations for individual immune-mediated diseases were largely organ specific but were also observed for some cancers in the near and distant organs or different systems. Our findings support the role of local and systemic immunoregulation in cancer development.
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Affiliation(s)
- Ming-Ming He
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Chun-Han Lo
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston
| | - Kai Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Georgios Polychronidis
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.,Study Centre of the German Surgical Society, University of Heidelberg, Heidelberg, Germany
| | - Liang Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Center of Gastrointestinal Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rong Zhong
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Markus D Knudsen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway.,Division of Surgery, Department of Transplantation Medicine, Inflammatory Diseases and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, Oslo, Norway
| | - Zhe Fang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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17
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Donzel M, Balme B, Dalle S. Mycosis fungoides in patients with multiple sclerosis: A report of two cases. Ann Dermatol Venereol 2021; 148:275-277. [PMID: 34210534 DOI: 10.1016/j.annder.2021.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/07/2021] [Accepted: 06/01/2021] [Indexed: 11/26/2022]
Affiliation(s)
- M Donzel
- Institut de pathologie multisite, hospices civils de Lyon, hôpital Lyon Sud, 69310 Pierre-Bénite, France.
| | - B Balme
- Institut de pathologie multisite, hospices civils de Lyon, hôpital Lyon Sud, 69310 Pierre-Bénite, France
| | - S Dalle
- Service de dermatologie, hospices civils de Lyon, hôpital Lyon Sud, 69310 Pierre-Bénite, France; Université Claude-Bernard, Lyon 01, 69100 Lyon, France
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18
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Han N, Oh JM, Kim IW. Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans. J Pers Med 2021; 11:33. [PMID: 33430289 PMCID: PMC7825650 DOI: 10.3390/jpm11010033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.
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Affiliation(s)
| | | | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea; (N.H.); (J.M.O.)
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Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin's Lymphomas from Genome-Wide Association Studies. Int J Mol Sci 2020; 22:ijms22010122. [PMID: 33374413 PMCID: PMC7795678 DOI: 10.3390/ijms22010122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/10/2020] [Accepted: 12/18/2020] [Indexed: 12/31/2022] Open
Abstract
B-cell non-Hodgkin’s lymphoma (NHL) risk associations had been mainly attributed to family history of the disease, inflammation, and immune components including human leukocyte antigen (HLA) genetic variations. Nevertheless, a broad range of genome-wide association studies (GWAS) have shed light into the identification of several genetic variants presumptively associated with B-cell NHL etiologies, survival or shared genetic risk with other diseases. The present review aims to overview HLA structure and diversity and summarize the evidence of genetic variations, by GWAS, on five NHL subtypes (diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, chronic lymphocytic leukemia CLL, marginal zone lymphoma MZL, and primary central nervous system lymphoma PCNSL). Evidence indicates that the HLA zygosity status in B-cell NHL might promote immune escape and that genome-wide significance variants can give biological insight but also potential therapeutic markers such as WEE1 in DLBCL. However, additional studies are needed, especially for non-DLBCL, to replicate the associations found to date.
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Abstract
Haematological malignancies induce important alterations of the immune system, which account for the high frequency of autoimmune complications observed in patients. Cutaneous immune-mediated diseases associated with haematological malignancies encompass a heterogeneous group of dermatoses, including, among others, neutrophilic and eosinophilic dermatoses, autoantibody-mediated skin diseases, vasculitis and granulomatous dermatoses. Some of these diseases, such as paraneoplastic pemphigus, are associated with an increased risk of death; others, such as eosinophilic dermatoses of haematological malignancies, run a benign clinical course but portend a significant negative impairment on a patient’s quality of life. In rare cases, the skin eruption reflects immunological alterations associated with an unfavourable prognosis of the associated haematological disorder. Therapeutic management of immune-mediated skin diseases in patients with haematological malignancies is often challenging. Systemic corticosteroids and immunosuppressive drugs are considered frontline therapies but may considerably augment the risk of serious infections. Indeed, developing a specific targeted therapeutic approach is of crucial importance for this particularly fragile patient population. This review provides an up-to-date overview on the immune-mediated skin diseases most frequently encountered by patients with onco-haematological disorders, discussing new pathogenic advances and therapeutic options on the horizon.
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Vera-Lastra O, Rojas-Milán E, Peralta-Amaro AL, Sánchez-Uribe M, Cruz-González LI, Hernández-Sánchez M, Tecayehuatl-Negrete L, Cruz-Dominguez MDP, Jara LJ. Autoimmune/inflammatory syndrome induced by methylmethacrylate associated to seronegative antiphospholipid syndrome and diffuse large B-cell non-Hodgkin's lymphoma. Lupus 2020; 29:1292-1296. [PMID: 32605524 DOI: 10.1177/0961203320936767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Autoimmune/inflammatory syndrome induced by adjuvants has been associated with different substances used for cosmetic purposes; for example, silicone, methylmethacrylate, autoimmune disorders and cancer. DISCUSSION A 40-year-old man with a prior history of methylmethacrylate injection in the buttocks for aesthetic purposes 8 years ago, presented with deep venous thrombosis in the left leg 6 months ago, accompanied with inflammation, hardening, changes in colour, ulceration in the buttocks, arthritis, myalgias and fever. Weak and moderate lupus anticoagulant and low levels of anticardiolipin antibodies were present. Thoracoabdominal tomography showed hepatosplenomegaly and a pulmonary nodule, the biopsy of which showed chronic granulomatous inflammation. After a month, a new chest tomography showed multiple nodular pulmonary lesions. The new pulmonary biopsy showed a diffuse large B-cell non-Hodgkin's lymphoma which was treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab for four cycles, with good response of the autoimmune/inflammatory syndrome, but partial response of the diffuse large B-cell non-Hodgkin's lymphoma. CONCLUSION We describe the first case of seronegative antiphospholipid syndrome and lymphoma associated with methylmethacrylate in a patient with autoimmune/inflammatory syndrome.
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Affiliation(s)
- Olga Vera-Lastra
- Internal Medicine Department, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico.,Division of Postgraduate Studies, Universidad Nacional Autónoma de México, México City, Mexico
| | - Eduardo Rojas-Milán
- Internal Medicine Department, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico
| | - Ana Lilia Peralta-Amaro
- Internal Medicine Department, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico
| | - Magdalena Sánchez-Uribe
- Pathological Anatomy Department, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico
| | | | - Mario Hernández-Sánchez
- Surgery Division, Hospital de Especialidades, "Dr Antonio Fraga Mouret", México City, Mexico
| | | | - María Del Pilar Cruz-Dominguez
- Internal Medicine Department, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico.,Research Division, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico
| | - Luis J Jara
- Division of Postgraduate Studies, Universidad Nacional Autónoma de México, México City, Mexico.,Direction of Education and Research, Hospital de Especialidades "Dr Antonio Fraga Mouret", México City, Mexico
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Camacho Castañeda FI, Dotor A, Manso R, Martín P, Prieto Pareja E, Palomo Esteban T, García Vela JA, Santonja C, Piris MA, Rodríguez Pinilla SM. Epstein-Barr virus-associated large B-cell lymphoma transformation in marginal zone B-cell lymphoma: a series of four cases. Histopathology 2020; 77:112-122. [PMID: 32145092 DOI: 10.1111/his.14101] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/07/2020] [Accepted: 03/02/2020] [Indexed: 12/11/2022]
Abstract
AIMS To present four examples of clonally related Epstein-Barr virus (EBV)-associated large-cell transformation of marginal zone lymphoma (MZL) (of nodal, extranodal and splenic types), occurring 120, 11 and 5 months after the initial diagnosis in three instances, and concurrently in one case; and to discuss several interesting features of EBV infection. METHODS AND RESULTS Somatic mutations were detected by use of a customised panel for next-generation sequencing and polymerase chain reaction studies of IgH in both low-grade and high-grade components of each case. In case 1, the initial biopsy of nodal MZL showed scattered EBV-positive cells, which might constitute an indication of EBV-induced progression. Case 2 showed heterogeneous EBV expression, a phenomenon attributable to loss of the EBV episomes during cell division, or to a secondary superinfection or reactivation of the virus. In case 3, p53 overexpression related to gene mutation and EBV-encoded small RNAs were identified in the same neoplastic component. In case 4, the mucosa-associated lymphoid tissue-type MZL and the high-grade component were identified concurrently in a patient previously treated with methotrexate for an autoimmune disorder. CONCLUSION These data suggest that the presence of EBV should be added to the list of potential markers to be analysed for MZL prognosis.
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Affiliation(s)
| | - Ana Dotor
- Pathology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | | | - Paloma Martín
- Pathology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
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Abstract
Systemic lupus erythematosus is associated with a small overall increased cancer risk compared with the general population. This risk includes a 4-fold increased risk of non-Hodgkin lymphoma, but a decreased risk of other cancers (such as breast cancer). The pathophysiology underlying the increased risk of hematologic cancer is not fully understood, but many potential mechanisms have been proposed, including dysfunction of the tumor necrosis factor and other pathways. A decreased risk of breast, ovarian, and endometrial cancer might be driven by hormonal factors or lupus-related antibodies, but these links have not been proved.
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Abstract
People living with rheumatic diseases frequently encounter cancer, either as a potential harm of antirheumatic therapies or as a comorbidity that alters the conversation about management. This article provides a general overview of the issues related to cancer and rheumatic disease and serves as a springboard for the remaining chapters in this issue. Several topics are reviewed, including epidemiology, bidirectional causal pathways, and issues related to medications. Although uncertainties remain, the issue of cancer is of great importance to patients with rheumatic diseases, and an individualized, person-centered approach to assessment and management is necessary.
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Affiliation(s)
- John Manley Davis
- Division of Rheumatology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
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Morton LM. Novel Insights Into the Long-Term Immune Health of Diffuse Large B-Cell Lymphoma Survivors. J Clin Oncol 2020; 38:1648-1650. [PMID: 32228357 PMCID: PMC7238492 DOI: 10.1200/jco.20.00361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2020] [Indexed: 11/20/2022] Open
Affiliation(s)
- Lindsay M. Morton
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Link BK. Immunologic dysfunction and Hodgkin lymphoma: Insight to better therapy? J Allergy Clin Immunol 2020; 145:780-781. [DOI: 10.1016/j.jaci.2019.12.914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/16/2019] [Accepted: 12/27/2019] [Indexed: 11/30/2022]
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Matsubayashi H, Ishiwatari H, Imai K, Kishida Y, Ito S, Hotta K, Yabuuchi Y, Yoshida M, Kakushima N, Takizawa K, Kawata N, Ono H. Steroid Therapy and Steroid Response in Autoimmune Pancreatitis. Int J Mol Sci 2019; 21:E257. [PMID: 31905944 PMCID: PMC6981453 DOI: 10.3390/ijms21010257] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/18/2019] [Accepted: 12/25/2019] [Indexed: 12/11/2022] Open
Abstract
Autoimmune pancreatitis (AIP), a unique subtype of pancreatitis, is often accompanied by systemic inflammatory disorders. AIP is classified into two distinct subtypes on the basis of the histological subtype: immunoglobulin G4 (IgG4)-related lymphoplasmacytic sclerosing pancreatitis (type 1) and idiopathic duct-centric pancreatitis (type 2). Type 1 AIP is often accompanied by systemic lesions, biliary strictures, hepatic inflammatory pseudotumors, interstitial pneumonia and nephritis, dacryoadenitis, and sialadenitis. Type 2 AIP is associated with inflammatory bowel diseases in approximately 30% of cases. Standard therapy for AIP is oral corticosteroid administration. Steroid treatment is generally indicated for symptomatic cases and is exceptionally applied for cases with diagnostic difficulty (diagnostic steroid trial) after a negative workup for malignancy. More than 90% of patients respond to steroid treatment within 1 month, and most within 2 weeks. The steroid response can be confirmed on clinical images (computed tomography, ultrasonography, endoscopic ultrasonography, magnetic resonance imaging, and 18F-fluorodeoxyglucose-positron emission tomography). Hence, the steroid response is included as an optional diagnostic item of AIP. Steroid treatment results in normalization of serological markers, including IgG4. Short- and long-term corticosteroid treatment may induce adverse events, including chronic glycometabolism, obesity, an immunocompromised status against infection, cataracts, glaucoma, osteoporosis, and myopathy. AIP is common in old age and is often associated with diabetes mellitus (33-78%). Thus, there is an argument for corticosteroid therapy in diabetes patients with no symptoms. With low-dose steroid treatment or treatment withdrawal, there is a high incidence of AIP recurrence (24-52%). Therefore, there is a need for long-term steroid maintenance therapy and/or steroid-sparing agents (immunomodulators and rituximab). Corticosteroids play a critical role in the diagnosis and treatment of AIP.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
- Genetic Medicine Promotion, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan
| | - Hirotoshi Ishiwatari
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Kenichiro Imai
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Yoshihiro Kishida
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Sayo Ito
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Kinichi Hotta
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Yohei Yabuuchi
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Masao Yoshida
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Naomi Kakushima
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Kohei Takizawa
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Noboru Kawata
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka 411-8777, Japan; (H.I.); (K.I.); (Y.K.); (S.I.); (K.H.); (Y.Y.); (M.Y.); (N.K.); (K.T.); (N.K.); (H.O.)
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