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Leotta S, Giammarco S, Mariotti J. Editorial: Allogenic hematopoietic cell transplant in hematological malignancies: controversies and perspective. Front Oncol 2025; 15:1582751. [PMID: 40177246 PMCID: PMC11961914 DOI: 10.3389/fonc.2025.1582751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 04/05/2025] Open
Affiliation(s)
- Salvatore Leotta
- Azienda Ospedaliero-Universitaria Policlinico “G-Rodolico”- San Marco - Catania, Catania, Italy
| | - Sabrina Giammarco
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Agostino Gemelli University Policlinic Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Jacopo Mariotti
- Humanitas Cancer Center, Humanitas Research Hospital, Rozzano, Italy
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Guo Z, He M, Shao L, Li Y, Xiang X, Wang Q. The role of fecal microbiota transplantation in the treatment of acute graft-versus-host disease. J Cancer Res Ther 2024; 20:1964-1973. [PMID: 39792405 DOI: 10.4103/jcrt.jcrt_33_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 09/02/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACT Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most important methods for treating a wide range of hematologic malignancies and bone marrow failure diseases. However, graft-versus-host disease (GVHD), a major complication associated with this method, can seriously affect the survival and quality of life of patients. Acute GVHD (aGVHD) occurs within 100 days after transplantation, and gastrointestinal aGVHD (GI-aGVHD) is one of the leading causes of nonrecurrent death after allo-HSCT. In recent years, fecal microbiota transplantation (FMT) has been attempted as an emerging treatment method for various diseases, including aGVHD after HSCT. Studies have shown encouraging preliminary clinical results after the application of FMT in aGVHD, particularly steroid-resistant aGVHD. Additionally, several studies have demonstrated that the gut microbiota plays an important immunomodulatory role in the pathogenesis of GVHD. Consensus guidelines recommend FMT as a secondary option for the treatment of aGVHD. This article aims to review FMT treatment for GI-aGVHD after allo-HSCT.
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Affiliation(s)
- Zhi Guo
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Department of Hematology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Mingxin He
- Department of Hematology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yue Li
- Department of Hematology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Xiaochen Xiang
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qiang Wang
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
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Biennier S, Fontaine M, Duquenoy A, Schwintner C, Doré J, Corvaia N. Narrative Review: Advancing Dysbiosis Treatment in Onco-Hematology with Microbiome-Based Therapeutic Approach. Microorganisms 2024; 12:2256. [PMID: 39597645 PMCID: PMC11596191 DOI: 10.3390/microorganisms12112256] [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: 09/30/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
This review explores the complex relationship between gut dysbiosis and hematological malignancies, focusing on graft-versus-host disease (GvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We discuss how alterations in microbial diversity and composition can influence disease development, progression, and treatment outcomes in blood cancers. The mechanisms by which the gut microbiota impacts these conditions are examined, including modulation of immune responses, production of metabolites, and effects on intestinal barrier function. Recent advances in microbiome-based therapies for treating and preventing GvHD are highlighted, with emphasis on full ecosystem standardized donor-derived products. Overall, this review underscores the growing importance of microbiome research in hematology-oncology and its potential to complement existing treatments and improve outcomes for thousands of patients worldwide.
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Affiliation(s)
- Salomé Biennier
- MaaT Pharma, 69007 Lyon, France; (S.B.); (A.D.); (C.S.); (N.C.)
| | | | - Aurore Duquenoy
- MaaT Pharma, 69007 Lyon, France; (S.B.); (A.D.); (C.S.); (N.C.)
| | | | - Joël Doré
- Université Paris-Saclay, INRAE, MetaGenoPolis, AgroParisTech, MICALIS, 78350 Jouy-en-Josas, France;
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Huang K, Yang M, Zhou Y, Cao Y, Pang G, Zhao J, Liu Y, Luo J. Application of CD25 and CTLA4 gene transcription levels in early prediction of acute graft-versus-host disease. Front Immunol 2024; 15:1410439. [PMID: 39072333 PMCID: PMC11272456 DOI: 10.3389/fimmu.2024.1410439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 07/01/2024] [Indexed: 07/30/2024] Open
Abstract
Introduction Our study investigated the potential of peripheral blood T cell CD25, CD28, and CTLA-4 gene transcription levels as predictive biomarkers for acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Real-time reverse transcription fluorescent quantitative PCR (RT-qPCR) analysis was conducted on day +7, +14, and +21 post-transplantation in patients undergoing allo-HSCT. Results Elevated levels of CD25 and CTLA-4 mRNA were found to be associated with the occurrence of aGVHD, as well as severe and gastrointestinal aGVHD. Receiver operating characteristic (ROC) curve analysis was utilized to assess the predictive value of each biomarker. Combined analysis of CD25 and CTLA-4 mRNA levels demonstrated promising predictive potential for aGVHD. Conclusion Our results confirmed that the transcription levels of CD25 and CTLA-4 genes could be used as early predictive biomarkers for aGVHD post-allo-HSCT.
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Affiliation(s)
- Ken Huang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pediatrics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Mengxin Yang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuhang Zhou
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Institute of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yaxuan Cao
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guanxiu Pang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jie Zhao
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yang Liu
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jianming Luo
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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5
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Seida I, Al Shawaf M, Mahroum N. Fecal microbiota transplantation in autoimmune diseases - An extensive paper on a pathogenetic therapy. Autoimmun Rev 2024; 23:103541. [PMID: 38593970 DOI: 10.1016/j.autrev.2024.103541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/31/2024] [Accepted: 04/04/2024] [Indexed: 04/11/2024]
Abstract
The role of infections in the pathogenesis of autoimmune diseases has long been recognized and reported. In addition to infectious agents, the internal composition of the "friendly" living bacteria, (microbiome) and its correlation to immune balance and dysregulation have drawn the attention of researchers for decades. Nevertheless, only recently, scientific papers regarding the potential role of transferring microbiome from healthy donor subjects to patients with autoimmune diseases has been proposed. Fecal microbiota transplantation or FMT, carries the logic of transferring microorganisms responsible for immune balance from healthy donors to individuals with immune dysregulation or more accurately for our paper, autoimmune diseases. Viewing the microbiome as a pathogenetic player allows us to consider FMT as a pathogenetic-based treatment. Promising results alongside improved outcomes have been demonstrated in patients with different autoimmune diseases following FMT. Therefore, in our current extensive review, we aimed to highlight the implication of FMT in various autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid and liver diseases, systemic lupus erythematosus, and type 1 diabetes mellitus, among others. Presenting all the aspects of FMT in more than 12 autoimmune diseases in one paper, to the best of our knowledge, is the first time presented in medical literature. Viewing FMT as such could contribute to better understanding and newer application of the model in the therapy of autoimmune diseases, indeed.
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Affiliation(s)
- Isa Seida
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Maisam Al Shawaf
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
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6
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Youngster I, Eshel A, Geva M, Danylesko I, Henig I, Zuckerman T, Fried S, Yerushalmi R, Shem-Tov N, Fein JA, Bomze D, Shimoni A, Koren O, Shouval R, Nagler A. Fecal microbiota transplantation in capsules for the treatment of steroid refractory and steroid dependent acute graft vs. host disease: a pilot study. Bone Marrow Transplant 2024; 59:409-416. [PMID: 38212672 DOI: 10.1038/s41409-024-02198-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/21/2023] [Accepted: 01/02/2024] [Indexed: 01/13/2024]
Abstract
Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.
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Affiliation(s)
- Ilan Youngster
- Shamir Medical Center, Beer Yaacov, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Eshel
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Mika Geva
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Ivetta Danylesko
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Israel Henig
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
| | - Tsila Zuckerman
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Shalev Fried
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Ronit Yerushalmi
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Noga Shem-Tov
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Joshua A Fein
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - David Bomze
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Division of Dermatology, Sourasky Medical Center, Tel Aviv, Israel
| | - Avichai Shimoni
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Roni Shouval
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel.
- Adult BMT Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
| | - Arnon Nagler
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
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Battipaglia G, Mooyaart JE, Meyer R, Mohty M, Sadowska-Klasa A, Goloshchapov O, Locatelli F, Styczynski J, Pavlu J, Dybko J, Bronin G, Salmenniemi U, Jindra P, Hoogenboom JD, Kuball J, Ruggeri A, Malard F. Current use of fecal microbiota transfer in patients with hematologic diseases: a survey on behalf of the Cellular Therapy and Immunobiology Working Party of the EBMT. Bone Marrow Transplant 2023; 58:1419-1421. [PMID: 37789073 DOI: 10.1038/s41409-023-02115-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/16/2023] [Accepted: 09/22/2023] [Indexed: 10/05/2023]
Affiliation(s)
- Giorgia Battipaglia
- Department of Clinical Hematology and Surgery, Division of Hematology, Federico II University of Naples, Naples, Italy.
| | | | - Ralf Meyer
- Dortmunder Centrum für Zelltransplantation (DCZ), Dortmund, Germany
| | - Mohamad Mohty
- Sorbonne Université; Centre de Recherche Saint-Antoine INSERM UMRs938; Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France
| | - Alicja Sadowska-Klasa
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdańsk, Poland
| | - Oleg Goloshchapov
- RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia
| | | | - Jan Styczynski
- Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland
| | | | - Jaroslaw Dybko
- Department of Hematology and Transplantology, Lower Silesian Center of Oncology, Wroclaw, Poland
| | | | - Urpu Salmenniemi
- Comprehensive Cancer Center, Stem Cell Transplantation Unit, Helsinki University Hospital, Helsinki, Finland
| | - Pavel Jindra
- Charles University Hospital, Pilsen, Czech Republic
| | | | - Jurgen Kuball
- Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Annalisa Ruggeri
- Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Florent Malard
- Sorbonne Université; Centre de Recherche Saint-Antoine INSERM UMRs938; Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France
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8
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Zhu G, Jin L, Shen W, Zhao M, Liu N. Intratumor microbiota: Occult participants in the microenvironment of multiple myeloma. Biochim Biophys Acta Rev Cancer 2023; 1878:188959. [PMID: 37488050 DOI: 10.1016/j.bbcan.2023.188959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/07/2023] [Accepted: 07/20/2023] [Indexed: 07/26/2023]
Abstract
More recently, microbiota was detected in several tumorous tissues including multiple myeloma (MM), but the roles of which is still under-studied as paucity of research on tumor biology. Moreover, we also detected the presence of microbiota in the bone marrow of patients with MM by 2bRAD-M sequencing technology, which is an incurable hematological malignancy characterized by accumulation of abnormal plasma cells in the bone marrow. However, the roles of intratumor microbiota in tumor disease remains poorly understood. In this review, we critically reviewed recent literature about microbiota in the tumorigenesis and progression of MM. Importantly, we proposed that the emergence of microbiota in the microenvironment of multiple myeloma may be attributed to microbial dysbiosis and impaired intestinal barrier, due to the increased prevalence of MM in patients with obesity and diabetes, of which the characteristic phenotype is gut microbial dysbiosis and impaired intestinal barrier. When the intestinal barrier is damaged, dysbiotic microbiota and their metabolites, as well as dysregulated immune cells, may participate in the reshaping of the local immune microenvironment, and play pivotal roles in the tumorigenesis and development of multiple myeloma, probably by migrating to the bone marrow microenvironment from intestine. We also discuss the emerging microbiological manipulation strategies to improve long-term outcomes of MM, as well as the prospective of the state-of-the-art techniques to advance our knowledge about the biological implication in the microbiome in MM.
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Affiliation(s)
- Gengjun Zhu
- Central Laboratory, The Second Hospital of Jilin University, Changchun, China
| | - Lifang Jin
- Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, China
| | - Weizhang Shen
- Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, China
| | - Meng Zhao
- Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, China
| | - Ning Liu
- Central Laboratory, The Second Hospital of Jilin University, Changchun, China; Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China.
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9
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Malard F, Holler E, Sandmaier BM, Huang H, Mohty M. Acute graft-versus-host disease. Nat Rev Dis Primers 2023; 9:27. [PMID: 37291149 DOI: 10.1038/s41572-023-00438-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 06/10/2023]
Abstract
Acute graft-versus-host disease (GVHD) is a common immune complication that can occur after allogeneic haematopoietic cell transplantation (alloHCT). Acute GVHD is a major health problem in these patients, and is associated with high morbidity and mortality. Acute GVHD is caused by the recognition and the destruction of the recipient tissues and organs by the donor immune effector cells. This condition usually occurs within the first 3 months after alloHCT, but later onset is possible. Targeted organs include the skin, the lower and upper gastrointestinal tract and the liver. Diagnosis is mainly based on clinical examination, and complementary examinations are performed to exclude differential diagnoses. Preventive treatment for acute GVHD is administered to all patients who receive alloHCT, although it is not always effective. Steroids are used for first-line treatment, and the Janus kinase 2 (JAK2) inhibitor ruxolitinib is second-line treatment. No validated treatments are available for acute GVHD that is refractory to steroids and ruxolitinib, and therefore it remains an unmet medical need.
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Affiliation(s)
- Florent Malard
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
| | - Ernst Holler
- University Hospital of Regensburg, Department of Internal Medicine 3, Regensburg, Germany
| | - Brenda M Sandmaier
- Fred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, WA, USA
- University of Washington School of Medicine, Division of Medical Oncology, Seattle, WA, USA
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- Engineering Laboratory for Stem Cell and Immunity Therapy, Institute of Hematology, Zhejiang University, Hangzhou, China
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, China
| | - Mohamad Mohty
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
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10
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Mohty M, Malard F. IL-22, a new beacon in gastrointestinal aGVHD. Blood 2023; 141:1369-1370. [PMID: 36951884 DOI: 10.1182/blood.2022018934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023] Open
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11
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Yoshikawa S, Taniguchi K, Sawamura H, Ikeda Y, Tsuji A, Matsuda S. Advantageous tactics with certain probiotics for the treatment of graft-versus-host-disease after hematopoietic stem cell transplantation. World J Hematol 2023; 10:15-24. [DOI: 10.5315/wjh.v10.i2.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) becomes a standard form of cellular therapy for patients with malignant diseases. HSCT is the first-choice of immunotherapy, although HSCT can be associated with many complications such as graft-versus-host disease (GVHD) which is a major cause of morbidity and mortality after allogeneic HSCT. It has been shown that certain gut microbiota could exert protective and/or regenerative immunomodulatory effects by the production of short-chain fatty acids (SCFAs) such as butyrate in the experimental models of GVHD after allogeneic HSCT. Loss of gut commensal bacteria which can produce SCFAs may worsen dysbiosis, increasing the risk of GVHD. Expression of G-protein coupled receptors such as GPR41 seems to be upre-gulated in the presence of commensal bacteria, which might be associated with the biology of regulatory T cells (Tregs). Treg cells are a suppressive subset of CD4 positive T lymphocytes implicated in the prevention of GVHD after allogeneic HSCT. Here, we discuss the current findings of the relationship between the modification of gut microbiota and the GVHD-related immunity, which suggested that tactics with certain probiotics for the beneficial symbiosis in gut-immune axis might lead to the elevation of safety in the allogeneic HSCT.
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Affiliation(s)
- Sayuri Yoshikawa
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Kurumi Taniguchi
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Haruka Sawamura
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Yuka Ikeda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Ai Tsuji
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
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12
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Qiao X, Biliński J, Wang L, Yang T, Luo R, Fu Y, Yang G. Safety and efficacy of fecal microbiota transplantation in the treatment of graft-versus-host disease. Bone Marrow Transplant 2023; 58:10-19. [PMID: 36167905 DOI: 10.1038/s41409-022-01824-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/24/2022] [Accepted: 09/01/2022] [Indexed: 01/10/2023]
Abstract
This article evaluates the efficacy and safety of FMT in the treatment of GVHD after HSCT using a systematic literature search to conduct a meta-analysis constructed of studies involving GVHD patients treated with FMT. 23 studies were included, among which 2 prospective cohort studies, 10 prospective single arm studies, 2 retrospective single arm studies, 2 case series and 7 case reports, comprise a total of 242 patients with steroid-resistant or steroid-dependent GVHD secondary to HSCT who were treated with FMT. 100 cases achieved complete responses, while 61 cases showed partial responses, and 81 cases presented no effect after FMT treatment. The estimate of clinical remission odds ratio was 5.51 (95% CI 1.49-20.35) in cohort studies, and the pooled clinical remission rate is 64% (51-77%) in prospective single arm studies and 81% (62-95%) in retrospective studies, case series and case reports. Five (2.1%) patients had FMT-related infection events, but all recovered after treatment. Other adverse effects were mild and acceptable. Microbiota diversity and composition, donor type, and other related issues were also analyzed. The data proves that FMT is a promising treatment modality of GVHD, but further validation of its safety and efficacy is still needed with prospective control studies.Clinical trial registration: Registered in https://www.crd.york.ac.uk/PROSPERO/ CRD42022296288.
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Affiliation(s)
- Xiaoying Qiao
- Peking University Health Science Center, Beijing, 100191, China.,Peking University People'hospital, Beijing, China
| | - Jarosław Biliński
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
| | - Leyi Wang
- Peking University Health Science Center, Beijing, 100191, China
| | - Tianyu Yang
- Peking University Health Science Center, Beijing, 100191, China
| | - Rongmu Luo
- Department of Hematology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China
| | - Yi Fu
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China
| | - Guibin Yang
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
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13
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The Crosstalk between the Gut Microbiota Composition and the Clinical Course of Allergic Rhinitis: The Use of Probiotics, Prebiotics and Bacterial Lysates in the Treatment of Allergic Rhinitis. Nutrients 2022; 14:nu14204328. [PMID: 36297012 PMCID: PMC9607052 DOI: 10.3390/nu14204328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/26/2022] Open
Abstract
Although massive progress in discovering allergic rhinitis (AR) aetiology has been made in recent years, its prevalence is still rising and it significantly impacts patients' lives. That is why further and non-conventional research elucidating the role of new factors in AR pathogenesis is needed, facilitating discoveries of new treatment approaches. One of these factors is the gut microbiota, with its specific roles in health and disease. This review presents the process of gut microbiota development, especially in early life, focusing on its impact on the immune system. It emphasizes the link between the gut microbiota composition and immune changes involved in AR development. Specifically, it elucidates the significant link between bacteria colonizing the gut and the Th1/Th2 imbalance. Probiotics, prebiotics and bacterial lysates, which are medications that restore the composition of intestinal bacteria and indirectly affect the clinical course of AR, are also discussed.
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14
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A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2124627. [PMID: 35571252 PMCID: PMC9098338 DOI: 10.1155/2022/2124627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.
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15
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Biliński J, Jasiński M, Basak GW. The Role of Fecal Microbiota Transplantation in the Treatment of Acute Graft-versus-Host Disease. Biomedicines 2022; 10:biomedicines10040837. [PMID: 35453587 PMCID: PMC9027325 DOI: 10.3390/biomedicines10040837] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 12/11/2022] Open
Abstract
The number of allogeneic hematopoietic stem cell transplantations conducted worldwide is constantly rising. Together with that, the absolute number of complications after the procedure is increasing, with graft-versus-host disease (GvHD) being one of the most common. The standard treatment is steroid administration, but only 40–60% of patients will respond to the therapy and some others will be steroid-dependent. There is still no consensus regarding the best second-line option, but fecal microbiota transplantation (FMT) has shown encouraging preliminary and first clinically relevant results in recent years and seems to offer great hope for patients. The reason for treatment of steroid-resistant acute GvHD using this method derives from studies showing the significant immunomodulatory role played by the intestinal microbiota in the pathogenesis of GvHD. Depletion of commensal microbes is accountable for aggravation of the disease and is associated with decreased overall survival. In this review, we present the pathogenesis of GvHD, with special focus on the special role of the gut microbiota and its crosstalk with immune cells. Moreover, we show the results of studies and case reports to date regarding the use of FMT in the treatment of steroid-resistant acute GvHD.
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Affiliation(s)
- Jarosław Biliński
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.J.); (G.W.B.)
- Human Biome Institute, 80-137 Gdansk, Poland
- Correspondence:
| | - Marcin Jasiński
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.J.); (G.W.B.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Grzegorz W. Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.J.); (G.W.B.)
- Human Biome Institute, 80-137 Gdansk, Poland
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16
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Bou Zerdan M, Niforatos S, Nasr S, Nasr D, Ombada M, John S, Dutta D, Lim SH. Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice. Cancers (Basel) 2022; 14:691. [PMID: 35158960 PMCID: PMC8833574 DOI: 10.3390/cancers14030691] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/28/2022] [Accepted: 01/28/2022] [Indexed: 11/28/2022] Open
Abstract
Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory Clostridioides difficile infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition. Therefore, they are an ideal population for exploring FMT as a therapeutic approach. However, there are inherent factors presenting as obstacles for the use of FMT in these patients. In this review paper, we discussed the principles and biologic effects of FMT, examined the factors rendering patients with hematologic and oncologic conditions to increased risks for relapsed/refractory CDI, explored ongoing FMT studies, and proposed novel uses for FMT in these groups of patients. Finally, we also addressed the challenges of applying FMT to these groups of patients and proposed ways to overcome these challenges.
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Affiliation(s)
- Maroun Bou Zerdan
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
| | - Stephanie Niforatos
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
| | - Sandy Nasr
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
| | - Dayana Nasr
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
| | - Mulham Ombada
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
| | - Savio John
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
- Division of Gastroenterology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
| | - Dibyendu Dutta
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
| | - Seah H. Lim
- Division of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (M.B.Z.); (S.N.); (S.N.); (D.N.); (M.O.); (S.J.); (D.D.)
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
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17
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Alexander T, Snowden JA, Burman J, Chang HD, Del Papa N, Farge D, Lindsay JO, Malard F, Muraro PA, Nitti R, Salas A, Sharrack B, Mohty M, Greco R. Intestinal Microbiome in Hematopoietic Stem Cell Transplantation For Autoimmune Diseases: Considerations and Perspectives on Behalf of Autoimmune Diseases Working Party (ADWP) of the EBMT. Front Oncol 2021; 11:722436. [PMID: 34745944 PMCID: PMC8569851 DOI: 10.3389/fonc.2021.722436] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/07/2021] [Indexed: 12/12/2022] Open
Abstract
Over the past decades, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory autoimmune diseases (ADs), where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. The intestinal microbiome plays an important role in host physiology including shaping the immune repertoire. The relationships between intestinal microbiota composition and outcomes after HSCT for hematologic diseases have been identified, particularly for predicting the mortality from infectious and non-infectious causes. Furthermore, therapeutic manipulations of the gut microbiota, such as fecal microbiota transplant (FMT), have emerged as promising therapeutic approaches for restoring the functional and anatomical integrity of the intestinal microbiota post-transplantation. Although changes in the intestinal microbiome have been linked to various ADs, studies investigating the effect of intestinal dysbiosis on HSCT outcomes for ADs are scarce and require further attention. Herein, we describe some of the landmark microbiome studies in HSCT recipients and patients with chronic ADs, and discuss the challenges and opportunities of microbiome research for diagnostic and therapeutic purposes in the context of HSCT for ADs.
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Affiliation(s)
- Tobias Alexander
- Department of Rheumatology and Clinical Immunology - Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health (BIH), Berlin, Germany.,Deutsches Rheuma-Forschungszentrum (DRFZ Berlin) - a Leibniz Institute, Berlin, Germany
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals Foundation NHS Trust, Sheffield, United Kingdom.,Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Joachim Burman
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Hyun-Dong Chang
- Deutsches Rheuma-Forschungszentrum (DRFZ Berlin) - a Leibniz Institute, Berlin, Germany.,Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany
| | | | - Dominique Farge
- Unité de Médecine Interne: (UF 04) CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Paris, France.,Universite de Paris, IRSL, Recherche Clinique Appliquee `à l'´hématologie, Paris, France.,Department of Medicine, McGill University, Montreal, QC, Canada
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Florent Malard
- Service d'hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, APHP, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Paolo A Muraro
- Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Rosamaria Nitti
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | | | - Basil Sharrack
- Department of Neuroscience, Sheffield Teaching Hospitals NHS, Foundation Trust, Sheffield, United Kingdom.,NIHR Neurosciences Biomedical Research Centre, University of Sheffield, Sheffield, United Kingdom
| | - Mohamad Mohty
- Service d'hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, APHP, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Raffaella Greco
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
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18
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Goeser F, Sifft B, Stein-Thoeringer C, Farowski F, Strassburg CP, Brossart P, Higgins PG, Scheid C, Wolf D, Holderried TAW, Vehreschild MJGT, Cruz Aguilar MR. Fecal microbiota transfer for refractory intestinal graft-versus-host disease - Experience from two German tertiary centers. Eur J Haematol 2021; 107:229-245. [PMID: 33934412 DOI: 10.1111/ejh.13642] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/17/2022]
Abstract
RATIONALE Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD. OBJECTIVES We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing. RESULTS Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis-each 3/11 and vomiting-1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT. CONCLUSIONS In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.
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Affiliation(s)
- Felix Goeser
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.,German Clinical Microbiome Study Group (GCMSG), Germany
| | - Barbara Sifft
- Department of Internal Medicine III, Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany
| | | | - Fedja Farowski
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.,German Clinical Microbiome Study Group (GCMSG), Germany.,Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.,Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, Frankfurt am Main, Germany
| | | | - Peter Brossart
- Department of Internal Medicine III, Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany
| | - Paul G Higgins
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.,Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany
| | - Christoph Scheid
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
| | - Dominik Wolf
- Department of Internal Medicine III, Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany.,UKIM 5, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
| | - Tobias A W Holderried
- Department of Internal Medicine III, Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany
| | - Maria J G T Vehreschild
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.,German Clinical Microbiome Study Group (GCMSG), Germany.,Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.,Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Marta Rebeca Cruz Aguilar
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.,German Clinical Microbiome Study Group (GCMSG), Germany.,Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
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19
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Bilinski J, Lis K, Tomaszewska A, Pechcinska A, Grzesiowski P, Dzieciatkowski T, Walesiak A, Gierej B, Ziarkiewicz-Wróblewska B, Tyszka M, Kacprzyk P, Chmielewska L, Waszczuk-Gajda A, Wiktor-Jedrzejczak W, Basak GW. Eosinophilic gastroenteritis and graft-versus-host disease induced by transmission of Norovirus with fecal microbiota transplant. Transpl Infect Dis 2021; 23:e13386. [PMID: 32574415 DOI: 10.1111/tid.13386] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/15/2020] [Indexed: 12/29/2022]
Abstract
Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic-resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft-versus-host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus-free FMT from another donor.
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Affiliation(s)
- Jaroslaw Bilinski
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Karol Lis
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Tomaszewska
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Pechcinska
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Tomasz Dzieciatkowski
- Department of Microbiology, Central Clinical Hospital, Medical University of Warsaw, Warsaw, Poland.,Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland
| | - Alicja Walesiak
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Beata Gierej
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | | | - Martyna Tyszka
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Kacprzyk
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Lidia Chmielewska
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Anna Waszczuk-Gajda
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Grzegorz W Basak
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
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20
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Pession A, Zama D, Muratore E, Leardini D, Gori D, Guaraldi F, Prete A, Turroni S, Brigidi P, Masetti R. Fecal Microbiota Transplantation in Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Systematic Review. J Pers Med 2021; 11:100. [PMID: 33557125 PMCID: PMC7913807 DOI: 10.3390/jpm11020100] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/25/2021] [Accepted: 02/02/2021] [Indexed: 12/29/2022] Open
Abstract
The disruption of gut microbiota eubiosis has been linked to major complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Various strategies have been developed to reduce dysbiosis and related complications. Fecal microbiota transplantation (FMT) consists of the infusion of fecal matter from a healthy donor to restore impaired intestinal homeostasis, and could be applied in the allo-HSCT setting. We conducted a systematic review of studies addressing the use of FMT in allo-HSCT patients. In the 23 papers included in the qualitative synthesis, FMT was used for the treatment of recurrent Clostridioides difficile infections or as a therapeutic strategy for steroid-resistant gut aGvHD. FMT was also performed with a preventive aim (e.g., to decolonize from antibiotic-resistant bacteria). Additional knowledge on the biological mechanisms underlying clinical findings is needed in order to employ FMT in clinical practice. There is also concern regarding the administration of microbial consortia in immune-compromised patients with altered gut permeability. Therefore, the safety profile and efficacy of the procedure must be determined to better assess the role of FMT in allo-HSCT recipients.
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Affiliation(s)
- Andrea Pession
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
| | - Daniele Zama
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
| | - Edoardo Muratore
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
| | - Davide Leardini
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
| | - Davide Gori
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy; (D.G.); (F.G.)
| | - Federica Guaraldi
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy; (D.G.); (F.G.)
- IRCCS Istituto delle Scienze Neurologiche di Bologna, 40126 Bologna, Italy
| | - Arcangelo Prete
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
| | - Silvia Turroni
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Patrizia Brigidi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy;
| | - Riccardo Masetti
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit—IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.P.); (D.Z.); (D.L.); (A.P.); (R.M.)
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21
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Devaux CA, Million M, Raoult D. The Butyrogenic and Lactic Bacteria of the Gut Microbiota Determine the Outcome of Allogenic Hematopoietic Cell Transplant. Front Microbiol 2020; 11:1642. [PMID: 32793150 PMCID: PMC7387665 DOI: 10.3389/fmicb.2020.01642] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Graft versus host disease (GVHD) is a post-transplant pathology in which donor-derived T cells present in the Peyer's patches target the cell-surface alloantigens of the recipient, causing host tissue damages. Therefore, the GVHD has long been considered only a purely immunological process whose prevention requires an immunosuppressive treatment. However, since the early 2010s, the impact of gut microbiota on GVHD has received increased attention. Both a surprising fall in gut microbiota diversity and a shift toward Enterobacteriaceae were described in this disease. Recently, unexpected results were reported that further link GVHD with changes in bacterial composition in the gut and disruption of intestinal epithelial tight junctions leading to abnormal intestinal barrier permeability. Patients receiving allogenic hematopoietic stem cell transplant (allo-HCT) as treatment of hematologic malignancies showed a decrease of the overall diversity of the gut microbiota that affects Clostridia and Blautia spp. and a predominance of lactic acid bacteria (LAB) of the Enterococcus genus, in particular the lactose auxotroph Enterococcus faecium. The reduced microbiota diversity (likely including Actinobacteria, such as Bifidobacterium adolescentis that cross feed butyrogenic bacteria) deprives the butyrogenic bacteria (such as Roseburia intestinalis or Eubacterium) of their capacity to metabolize acetate to butyrate. Indeed, administration of butyrate protects against the GVHD. Here, we review the data highlighting the possible link between GVHD and lactase defect, accumulation of lactose in the gut lumen, reduction of Reg3 antimicrobial peptides, narrower enzyme equipment of bacteria that predominate post-transplant, proliferation of En. faecium that use lactose as metabolic fuels, induction of innate and adaptive immune response against these bacteria which maintains an inflammatory process, elevated expression of myosin light chain kinase 210 (MLCK210) and subsequent disruption of intestinal barrier, and translocation of microbial products (lactate) or transmigration of LAB within the liver. The analysis of data from the literature confirms that the gut microbiota plays a major role in the GVHD. Moreover, the most recent publications uncover that the LAB, butyrogenic bacteria and bacterial cross feeding were the missing pieces in the puzzle. This opens new bacteria-based strategies in the treatment of GVHD.
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Affiliation(s)
- Christian Albert Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), Marseille, France
| | - Matthieu Million
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
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Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia 2020; 34:1229-1240. [PMID: 32242050 PMCID: PMC7192843 DOI: 10.1038/s41375-020-0804-2] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 03/03/2020] [Accepted: 03/12/2020] [Indexed: 02/06/2023]
Abstract
Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroid-refractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.
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Affiliation(s)
- Florent Malard
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), UMRS_938, AP-HP Hôpital Saint-Antoine, F-75012, Paris, France.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Joycelyn P Y Sim
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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23
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Zama D, Bossù G, Leardini D, Muratore E, Biagi E, Prete A, Pession A, Masetti R. Insights into the role of intestinal microbiota in hematopoietic stem-cell transplantation. Ther Adv Hematol 2020; 11:2040620719896961. [PMID: 32010434 PMCID: PMC6974760 DOI: 10.1177/2040620719896961] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/20/2019] [Indexed: 12/11/2022] Open
Abstract
The gut microbiota (GM) is able to modulate the human immune system. The development of novel investigation methods has provided better characterization of the GM, increasing our knowledge of the role of GM in the context of hematopoietic stem-cell transplantation (HSCT). In particular, the GM influences the development of the major complications seen after HSCT, having an impact on overall survival. In fact, this evidence highlights the possible therapeutic implications of modulation of the GM during HSCT. Insights into the complex mechanisms and functions of the GM are essential for the rational design of these therapeutics. To date, preemptive and curative approaches have been tested. The current state of understanding of the impact of the GM on HSCT, and therapies targeting the GM balance is reviewed herein.
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Affiliation(s)
- Daniele Zama
- Pediatric Oncology and Hematology Unit ‘Lalla
Seràgnoli,’ Sant’Orsola-Malpighi Hospital, University of Bologna, Via
Massarenti 11, Bologna, 40137, Italy
| | - Gianluca Bossù
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
| | - Davide Leardini
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
| | - Edoardo Muratore
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
| | - Elena Biagi
- Department of Pharmacy and Biotechnology,
University of Bologna, Bologna, Italy
| | - Arcangelo Prete
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
| | - Andrea Pession
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
| | - Riccardo Masetti
- Department of Pediatrics, ‘Lalla Seràgnoli,’
Hematology-Oncology Unit, University of Bologna, Italy
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24
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Goloshchapov OV, Olekhnovich EI, Sidorenko SV, Moiseev IS, Kucher MA, Fedorov DE, Pavlenko AV, Manolov AI, Gostev VV, Veselovsky VA, Klimina KM, Kostryukova ES, Bakin EA, Shvetcov AN, Gumbatova ED, Klementeva RV, Shcherbakov AA, Gorchakova MV, Egozcue JJ, Pawlowsky-Glahn V, Suvorova MA, Chukhlovin AB, Govorun VM, Ilina EN, Afanasyev BV. Long-term impact of fecal transplantation in healthy volunteers. BMC Microbiol 2019; 19:312. [PMID: 31888470 PMCID: PMC6938016 DOI: 10.1186/s12866-019-1689-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 12/17/2019] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes. RESULTS We have performed a combined analysis of three healthy volunteers before and after capsule FMT by evaluating their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene and shotgun sequencing. The data analysis demonstrated profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria and persistence of this effect for almost ∼1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events, however, one volunteer developed a systemic inflammatory response syndrome. CONCLUSIONS The FMT leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition and represents a relatively safe procedure to the recipients without long-term adverse events.
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Affiliation(s)
- Oleg V. Goloshchapov
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Evgenii I. Olekhnovich
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Sergey V. Sidorenko
- Pediatric Research and Clinical Center for Infectious Diseases, St. Petersburg, Russia
- Mechnikov North-West State Medical University, St. Petersburg, Russia
| | - Ivan S. Moiseev
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Maxim A. Kucher
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Dmitry E. Fedorov
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Alexander V. Pavlenko
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Alexander I. Manolov
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Vladimir V. Gostev
- Pediatric Research and Clinical Center for Infectious Diseases, St. Petersburg, Russia
- Mechnikov North-West State Medical University, St. Petersburg, Russia
| | - Vladimir A. Veselovsky
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Ksenia M. Klimina
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Elena S. Kostryukova
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Evgeny A. Bakin
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Alexander N. Shvetcov
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Elvira D. Gumbatova
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Ruslana V. Klementeva
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Alexander A. Shcherbakov
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Margarita V. Gorchakova
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | | | | | | | - Alexey B. Chukhlovin
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Vadim M. Govorun
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Elena N. Ilina
- Federal Research and Clinical Centre of Physical and Chemical Medicine of Federal Medical and Biological Agency of Russia, Moscow, Russian Federation
| | - Boris V. Afanasyev
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
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