Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Treatment Options in Oncology
Published in: Current Treatment Options in Oncology 1/2020

01-01-2020 | Probiotics | Leukemia (PH Wiernik, Section Editor)

The Microbiota in Hematologic Malignancies

Authors: Yajing Song, PhD, Bryan Himmel, Lars Öhrmalm, MD, PhD, Peter Gyarmati, PhD

Published in: Current Treatment Options in Oncology | Issue 1/2020

Login to get access

Opinion statement

There are approximately 1.2 million new hematologic malignancy cases resulting in ~ 690,000 deaths each year worldwide, and hematologic malignancies remain the most commonly occurring cancer in children. Even though advances in anticancer treatment regimens in recent decades have considerably improved survival rates, their cytotoxic effects and the resulting long-term complications pose a significant burden on the patients and the health care system. Therefore, non-toxic treatment modalities are needed to decrease side effects. The human body is the host to approximately 40 trillion microbes, known as the human microbiota. The large majority of the microbiota is located in the gastrointestinal tract, and is primarily composed of bacteria. The microbiota plays several important physiological roles, ranging from digestive functions to immunological and neural development. Investigating the microbiota in patients with hematologic malignancies has several important implications. The microbiota affects hematopoiesis, and influences the efficacies of chemotherapy and antimicrobial treatments. Determination of the microbiota composition and diversity could be an important part of risk stratification in the future, and may also take part to personalize antimicrobial treatments. Modulation of the microbiota via probiotics or fecal transplant can potentially be involved in reducing side effects of chemotherapy, and eliminating multiple drug resistant strains in patients with hematologic malignancies.
Literature
1.
• Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361:k2179 A thorough introduction and review on the microbiota and its physiological functions.PubMedPubMedCentral
2.
National Research Council (US) Committee on Metagenomics: Challenges and Functional Applications. The new science of metagenomics: revealing the secrets of our microbial planet. Washington (DC): National Academies Press (US); 2007. 1, Why Metagenomics?
3.
DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, et al. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol. 2006;72(7):5069–72.PubMedPubMedCentral
4.
Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Opens external link in new window. Nucleic Acids Res. 2013;41(D1):D590–6.PubMed
5.
Cole JR, Wang Q, Fish JA, Chai B, McGarrell DM, Sun Y. etal. Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res. 2014;42(Database issue):D633–42.PubMed
6.
Brister JR, Ako-Adjei D, Bao Y, Blinkova O. NCBI viral genomes resource. Nucleic Acids Res. 2015;43(Database issue):D571–7.PubMed
7.
Tatusova T, Ciufo S, Fedorov B, O’Neill K, Tolstoy I. RefSeq microbial genomes database: new representation and annotation strategy [published correction appears in Nucleic Acids Res. 2015;43(7):3872]. Nucleic Acids Res. 2014;42(Database issue):D553–9.PubMed
8.
Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14(8):e1002533.PubMedPubMedCentral
9.
Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369–79.PubMed
10.
Khosravi A, Yáñez A, Price JG, Chow A, Merad M, Goodridge HS, et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe. 2014;15(3):374–81.PubMedPubMedCentral
11.
Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129:729–39.PubMedPubMedCentral
12.
• Staffas A, Burgos da Silva M, Slingerland AE, Lazrak A, Bare CJ, Holman CD, et al. Nutritional support from the intestinal microbiota improves hematopoietic reconstitution after bone marrow transplantation in mice. Cell Host Microbe. 2018;23(4):447–457.e4 A study highlighting the importance of the microbiota in hematopoiesis.PubMedPubMedCentral
13.
Jain S, Ward JM, Shin DM, Wang H, Naghashfar Z, Kovalchuk AL, et al. Associations of autoimmunity, immunodeficiency, lymphomagenesis, and gut microbiota in mice with knockins for a pathogenic autoantibody. Am J Pathol. 2017;187(9):2020–33.PubMedPubMedCentral
14.
15.
16.
Schloss PD, Westcott SL. Assessing and improving methods used in operational taxonomic unit-based approaches for 16S rRNA gene sequence analysis. Appl Environ Microbiol. 2011;77(10):3219–26.PubMedPubMedCentral
17.
Vijayvargiya P, Jeraldo PR, Thoendel MJ, Greenwood-Quaintance KE, Esquer Garrigos Z, Sohail MR, et al. Application of metagenomic shotgun sequencing to detect vector-borne pathogens in clinical blood samples. PLoS One. 2019;14(10):e0222915.PubMedPubMedCentral
18.
Dulanto Chiang A, Dekker JP. From the pipeline to the bedside: advances and challenges in clinical metagenomics. J Infect Dis. 2019; pii: jiz151.
19.
Song Y, Giske CG, Gille-Johnson P, Emanuelsson O, Lundeberg J, Gyarmati P. Nuclease-assisted suppression of human DNA background in sepsis. PLoS One. 2014;9(7):e103610.PubMedPubMedCentral
20.
21.
Gijavanekar C, Strych U, Fofanov Y, Fox GE. Willson RC Rare target enrichment for ultrasensitive PCR detection using cot-rehybridization and duplex-specific nuclease. Anal Biochem. 2012;421(1):81–5.PubMed
22.
Ten Hoopen P, Finn RD, Bongo LA, Corre E, Fosso B, Meyer F, et al. The metagenomic data life-cycle: standards and best practices. Gigascience. 2017;6(8):1–11.PubMedPubMedCentral
23.
•• Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, et al. Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia. Clin Infect Dis. 2018;67(4):541–8 A comprehensive study of the gut microbiome of pediatric ALL patients, indicating gut microbiota composition as a predictor for infectious outcome during chemotherapy.PubMedPubMedCentral
24.
25.
Han L, Zhang H, Chen S, Zhou L, Li Y, Zhao K, et al. Intestinal microbiota can predict aGVHD following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;pii: S1083–8791(19)30438–0.
26.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–31.
27.
Finucane MM, Sharpton TJ, Laurent TJ, Pollard KS. A taxonomic signature of obesity in the microbiome? Getting to the guts of the matter. PLoS One. 2014;9(1):e84689.PubMedPubMedCentral
28.
Duncan SH, Lobley GE, Holtrop G, Ince J, Johnstone AM, Louis P, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes. 2008;32(11):1720–4.
29.
Tims S, Derom C, Jonkers DM, Vlietinck R, Saris WH, Kleerebezem M, et al. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J. 2013;7(4):707–17.PubMed
30.
Nearing JT, Connors J, Whitehouse S, Van Limbergen J, Macdonald T, Kulkarni K, et al. Infectious complications are associated with alterations in the gut microbiome in pediatric patients with acute lymphoblastic leukemia. Front Cell Infect Microbiol. 2019;9:28.PubMedPubMedCentral
31.
Bindels LB, Neyrinck AM, Claus SP, Le Roy CI, Grangette C, Pot B, et al. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J. 2016;10(6):1456–70.PubMed
32.
33.
Montassier E, Gastinne T, Vangay P, Al-Ghalith GA. Bruley des Varannes S, Massart S, et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther. 2015;42(5):515–28.PubMed
34.
Shelburne SA, Ajami NJ, Chibucos MC, Beird HC, Tarrand J, Galloway-Peña J, et al. Implementation of a pan-genomic approach to investigate holobiont-infecting microbe interaction: a case report of a leukemic patient with invasive mucormycosis. PLoS One. 2015;10(11):e0139851.PubMedPubMedCentral
35.
van Vliet MJ, Tissing WJ, Dun CA, Meessen NE, Kamps WA, de Bont ES, et al. Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis. 2009;49(2):262–70.PubMed
36.
Kaysen A, Heintz-Buschart A, Muller EEL, Narayanasamy S, Wampach L, Laczny CC, et al. Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation. Transl Res. 2017;186:79–94.e1.PubMed
37.
Galloway-Peña JR, Smith DP, Sahasrabhojane P, Ajami NJ, Wadsworth WD, Daver NG, et al. The role of the gastrointestinal microbiome in infectious complications during induction chemotherapy for acute myeloid leukemia. Cancer. 2016;122(14):2186–96.PubMedPubMedCentral
38.
Galloway-Peña JR, Smith DP, Sahasrabhojane P, Wadsworth WD, Fellman BM, Ajami NJ, et al. Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients. Genome Med. 2017;9(1):21.PubMedPubMedCentral
39.
Kelly MS, Ward DV, Severyn CJ, Arshad M, Heston SM, Jenkins K, et al. Gut colonization preceding mucosal barrier injury bloodstream infection in pediatric hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2019;pii: S1083–8791(19)30451–3.
40.
Bindels LB, Neyrinck AM, Salazar N, Taminiau B, Druart C, Muccioli GG, et al. Non digestible oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice. PLoS One. 2015;10(6):e0131009.PubMedPubMedCentral
41.
de Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F, et al. Management of febrile neutropenia: ESMO clinical practice guidelines. Ann Oncol. 2010;21. Suppl. 2010;5:v252–6.
42.
Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007;30(Suppl 1):S51–9.PubMed
43.
Nørgaard M, Larsson H, Pedersen G, Schonheyder HC, Sorensen HT. Risk of bacteraemia and mortality in patients with haematological malignancies. Clin Microbiol Infect. 2006;12:217–23.PubMed
44.
Hersh EM, Bodey GP, Nies BA, Freireich EJ. Causes of death in acute leukemia: a ten-year study of 414 patients from 1954 – 1963. JAMA. 1965;193:105–9.PubMed
45.
Elting LS, Rubenstein EB, Rolston KV, Bodey GP. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis. 1997;25:247–59.PubMed
46.
Viscoli C, Bruzzi P, Castagnola E, Boni L, Calandra T, Gaya H, et al. Factors associated with bacteraemia in febrile, granulocytopenic cancer patients. The International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1994;30A:430–7.PubMed
47.
Klastersky J. Science and pragmatism in the treatment and prevention of neutropenic infection. J Antimicrob Chemother. 1998;41(Suppl D):13–24.PubMed
48.
Feld R. Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents. 2008;32(Suppl 1):S30–3.PubMed
49.
Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis. 2004;39(Suppl 1):S25–31.PubMed
50.
51.
Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2011;11(7):445–56.PubMedPubMedCentral
52.
Gyarmati P, Kjellander C, Aust C, Song Y, Öhrmalm L, Giske CG. Metagenomic analysis of bloodstream infections in patients with acute leukemia and therapy-induced neutropenia. Sci Rep. 2016;6:23532.PubMedPubMedCentral
53.
Wei W, Sun W, Yu S, Yang Y, Ai L. Butyrate production from high-fiber diet protects against lymphoma tumor. Leuk Lymphoma. 2016;57(10):2401–8.PubMed
54.
Piovan E, Tosello V, Amadori A, Zanovello P. Chemotactic cues for NOTCH1-dependent leukemia. Front Immunol. 2018;9:633.PubMedPubMedCentral
55.
56.
Min YW, Rhee PL. The role of microbiota on the gut immunology. Clin Ther. 2015;37(5):968–75.PubMed
57.
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.PubMedPubMedCentral
58.
Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019;10(1):89.PubMedPubMedCentral
59.
Wiest R, Rath HC. Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol. 2003;7(3):397–425.
60.
Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. 2016;167(5):1339–1353.e21.PubMedPubMedCentral
61.
Schniedel Y, Zimmerli S. Common invasive fungal diseases. Swiss Med Wkly. 2016;146:w14281.
62.
van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974;52:401–4.PubMed
63.
Lähteenmäki K, Wacklin P, Taskinen M, Tuovinen E, Lohi O, Partanen J, et al. Haematopoietic stem cell transplantation induces severe dysbiosis in intestinal microbiota of paediatric ALL patients. Bone Marrow Transplant. 2017;52(10):1479–82.PubMed
64.
Ingham AC, Kielsen K, Cilieborg MS, Lund O, Holmes S, Aarestrup FM, et al. Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation. Microbiome. 2019;7(1):131.PubMedPubMedCentral
65.
Kusakabe S, Fukushima K, Maeda T, Motooka D, Nakamura S, Fujita J, et al. Pre- and post-serial metagenomic analysis of gut microbiota as a prognostic factor in patients undergoing haematopoietic stem cell transplantation. Br J Haematol. 2019 Sep 30. https://​doi.​org/​10.​1111/​bjh.​16205.PubMed
66.
Abel GA, Klepin HD. Frailty and the management of hematologic malignancies. Blood. 2018;131(5):515–24.PubMed
67.
Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation. Clin Oncol. 2017;35(15):1650–9.
68.
Khoruts A, Hippen KL, Lemire AM, Holtan SG, Knights D, Young JH. Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota. Transl Res. 2017;179:116–25.PubMed
69.
Tunyapanit W, Chelae S, Laoprasopwattana K. Does ciprofloxacin prophylaxis during chemotherapy induce intestinal microflora resistance to ceftazidime in children with cancer? J Infect Chemother. 2018;24(5):358–62.PubMed
70.
Montassier E, Al-Ghalith GA, Ward T, Corvec S, Gastinne T, Potel G, et al. Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Med. 2016;8(1):49.PubMedPubMedCentral
71.
Montassier E, Batard E, Massart S, Gastinne T, Carton T, Caillon J, et al. 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation. Microb Ecol. 2014;67(3):690–9.PubMed
72.
Biagi E, Zama D, Rampelli S, Turroni S, Brigidi P, Consolandi C, et al. Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders. BMC Med Genet. 2019;12(1):49.
73.
Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.PubMedPubMedCentral
74.
Cabral DJ, Penumutchu S, Reinhart EM, Zhang C, Korry BJ, Wurster JI, et al. Microbial metabolism modulates antibiotic susceptibility within the murine gut microbiome. Cell Metab. 2019. pii: S1550–4131(19)30449–8.
75.
76.
Bindels LB, Beck R, Schakman O, Martin JC, De Backer F, Sohet FM, et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS On. 2012;7(6):e37971.
77.
Yamamoto ML, Maier I, Dang AT, Berry D, Liu J, Ruegger PM, et al. Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity. Cancer Res. 2013;73(14):4222–32.PubMedPubMedCentral
78.
Sulik-Tyszka B, Snarski E, Niedźwiedzka M, Augustyniak M, Myhre TN, Kacprzyk A, et al. Experience with Saccharomyces boulardii probiotic in oncohaematological patients. Probiotics Antimicrob Proteins. 2018;10(2):350–5.PubMed
79.
Avcin SL, Pokorn M, Kitanovski L, Premru MM, Jazbec J. Bifidobacterium breve sepsis in child with high-risk acute lymphoblastic leukemia. Emerg Infect Dis. 2015;21(9):1674–5.PubMedPubMedCentral
80.
Wardill HR, Van Sebille YZA, Ciorba MA, Bowen JM. Prophylactic probiotics for cancer therapy-induced diarrhoea: a meta-analysis. Curr Opin Support Palliat Care. 2018;12(2):187–97.PubMed
81.
Umesaki Y, Setoyama H, Matsumoto S, Okada Y. Expansion of alpha beta T cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology. 1993;79(1):32–7.PubMedPubMedCentral
82.
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases, Volume 66, Issue 7, 1 April 2018, Pages e1–e48.PubMedPubMedCentral
83.
Rashidi A, Zhu Z, Kaiser T, Manias DA, Holtan SG, Rehman TU, et al. Vancomycin-resistance gene cluster, vanC, in the gut microbiome of acute leukemia patients undergoing intensive chemotherapy. PLoS One. 2019;14(10):e0223890.PubMedPubMedCentral
84.
Innes AJ, Mullish BH, Fernando F, Adams G, Marchesi JR, Apperley JF, et al. Faecal microbiota transplant: a novel biological approach to extensively drug-resistant organism-related non-relapse mortality. Bone Marrow Transplant. 2017;52(10):1452–4.PubMed
85.
Biliński J, Grzesiowski P, Muszyński J, Wróblewska M, Mądry K, Robak K, et al. Fecal microbiota transplantation inhibits multidrug-resistant gut pathogens: preliminary report performed in an immunocompromised host. Arch Immunol Ther Exp. 2016;64(3):255–8.
86.
de Castro CG Jr, Ganc AJ, Ganc RL, Petrolli MS, Hamerschlack N. Fecal microbiota transplant after hematopoietic SCT: report of a successful case. Bone Marrow Transplant. 2015;50(1):145.PubMed
87.
Kaito S, Toya T, Yoshifuji K, Kurosawa S, Inamoto K, Takeshita K, et al. Fecal microbiota transplantation with frozen capsules for a patient with refractory acute gut graft-versus-host disease. Blood Adv. 2018;2(22):3097–101.PubMedPubMedCentral
Metadata
Title
The Microbiota in Hematologic Malignancies
Authors
Yajing Song, PhD
Bryan Himmel
Lars Öhrmalm, MD, PhD
Peter Gyarmati, PhD
Publication date
01-01-2020
Publisher
Springer US
Published in
Current Treatment Options in Oncology / Issue 1/2020
Print ISSN: 1527-2729
Electronic ISSN: 1534-6277
DOI
https://doi.org/10.1007/s11864-019-0693-7

Other articles of this Issue 1/2020

Current Treatment Options in Oncology 1/2020 Go to the issue

Lower Gastrointestinal Cancers (AB Benson, Section Editor)

Opioids in Cancer Development, Progression and Metastasis: Focus on Colorectal Cancer

Leukemia (PH Wiernik, Section Editor)

Use of Minimal Residual Disease in Acute Myeloid Leukemia Therapy

Palliative and Supportive Care (MP Davis, Section Editor)

Prognosticating for Adult Patients With Advanced Incurable Cancer: a Needed Oncologist Skill

Lower Gastrointestinal Cancers (AB Benson, Section Editor)

Locally Advanced Rectal Cancer: Treatment Approach in Elderly Patients

Leukemia (PH Wiernik, Section Editor)

Current and Future Molecular Targets for Acute Myeloid Leukemia Therapy

Palliative and Supportive Care (MP Davis, Section Editor)

Chemotherapy-Induced Sarcopenia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits