Skip to main content
Erschienen in: Die Innere Medizin 11/2022

19.09.2022 | Hämatologische Neoplasien | Schwerpunkt: Klonale Hämatopoese

Bedeutung der klonalen Hämatopoese für hämatologische Neoplasien

verfasst von: Prof. Dr. Katharina S. Götze, Prof. Dr. Claudia Lengerke

Erschienen in: Die Innere Medizin | Ausgabe 11/2022

Einloggen, um Zugang zu erhalten

Zusammenfassung

Hintergrund

Die klonale Hämatopoese von unbestimmtem Potenzial (CHIP) ist ein relativ neu beschriebenes Phänomen, bei dem mit myeloischen Neoplasien assoziierte somatische Mutationen im peripheren Blut von Personen ohne Anzeichen einer hämatologischen Erkrankung nachweisbar sind. Personen mit CHIP haben ein deutlich erhöhtes Risiko, eine hämatologische Neoplasie zu entwickeln, obwohl die Gesamtrate der Transformation gering ist.

Fragestellung

Wir geben hier einen Überblick über den aktuellen Wissensstand zu den Ursachen der klonalen Expansion von Blutzellen sowie zu den identifizierbaren Risikofaktoren für die Entwicklung einer hämatologischen Neoplasie.

Ergebnisse und Schlussfolgerung

Die CHIP gilt als prämaligner Zustand und prädisponiert für die Entwicklung einer hämatologischen Neoplasie. Da die Transformationsrate insgesamt niedrig ist, ist die eindeutige Identifizierung und anschließende Überwachung von CHIP-Patienten mit höherem Risiko von größter Bedeutung. In Zukunft könnten prospektive Studien zur Bewertung präventiver therapeutischer Strategien helfen, die Entwicklung von Blutkrebs bei Personen mit CHIP zu verhindern.
Literatur
1.
Zurück zum Zitat Jaiswal S, Fontanillas P, Flannick J et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498PubMedPubMedCentralCrossRef Jaiswal S, Fontanillas P, Flannick J et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498PubMedPubMedCentralCrossRef
2.
Zurück zum Zitat Genovese G, Jaiswal S, Ebert BL, McCarroll SA (2015) Clonal hematopoiesis and blood-cancer risk. N Engl J Med 372:1071–1072PubMedCrossRef Genovese G, Jaiswal S, Ebert BL, McCarroll SA (2015) Clonal hematopoiesis and blood-cancer risk. N Engl J Med 372:1071–1072PubMedCrossRef
3.
Zurück zum Zitat Xie M, Lu C, Wang J et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472–1478PubMedPubMedCentralCrossRef Xie M, Lu C, Wang J et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472–1478PubMedPubMedCentralCrossRef
4.
Zurück zum Zitat Young AL, Challen GA, Birmann BM, Druley TE (2016) Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7:12484PubMedPubMedCentralCrossRef Young AL, Challen GA, Birmann BM, Druley TE (2016) Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7:12484PubMedPubMedCentralCrossRef
5.
Zurück zum Zitat Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16PubMedPubMedCentralCrossRef Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16PubMedPubMedCentralCrossRef
6.
Zurück zum Zitat Zink F, Stacey SN, Norddahl GL et al (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–752PubMedPubMedCentralCrossRef Zink F, Stacey SN, Norddahl GL et al (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–752PubMedPubMedCentralCrossRef
7.
Zurück zum Zitat Hecker JS, Hartmann L, Rivière J et al (2021) CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood 138:1727–1732PubMedCrossRef Hecker JS, Hartmann L, Rivière J et al (2021) CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood 138:1727–1732PubMedCrossRef
8.
10.
Zurück zum Zitat Fuster JJ, Zuriaga MA, Zorita V et al (2020) TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity. Cell Rep 33:108326PubMedPubMedCentralCrossRef Fuster JJ, Zuriaga MA, Zorita V et al (2020) TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity. Cell Rep 33:108326PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat Agrawal M, Niroula A, Cunin P et al (2021) The association between clonal hematopoiesis and gout. Blood 138:595–595CrossRef Agrawal M, Niroula A, Cunin P et al (2021) The association between clonal hematopoiesis and gout. Blood 138:595–595CrossRef
13.
Zurück zum Zitat Jaiswal S, Natarajan P, Silver AJ et al (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111–121PubMedPubMedCentralCrossRef Jaiswal S, Natarajan P, Silver AJ et al (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111–121PubMedPubMedCentralCrossRef
14.
16.
Zurück zum Zitat Mitchell E, Spencer Chapman M, Williams N et al (2022) Clonal dynamics of haematopoiesis across the human lifespan. Nature 606:343–350PubMedPubMedCentralCrossRef Mitchell E, Spencer Chapman M, Williams N et al (2022) Clonal dynamics of haematopoiesis across the human lifespan. Nature 606:343–350PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Fabre MA, de Almeida JG, Fiorillo E et al (2022) The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606:335–342PubMedPubMedCentralCrossRef Fabre MA, de Almeida JG, Fiorillo E et al (2022) The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606:335–342PubMedPubMedCentralCrossRef
18.
Zurück zum Zitat Challen GA, Goodell MA (2020) Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136:1590–1598PubMedPubMedCentral Challen GA, Goodell MA (2020) Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136:1590–1598PubMedPubMedCentral
19.
Zurück zum Zitat Florez MA, Tran BT, Wathan TK, DeGregori J, Pietras EM, King KY (2022) Clonal hematopoiesis: mutation-specific adaptation to environmental change. Cell Stem Cell 29:882–904PubMedCrossRef Florez MA, Tran BT, Wathan TK, DeGregori J, Pietras EM, King KY (2022) Clonal hematopoiesis: mutation-specific adaptation to environmental change. Cell Stem Cell 29:882–904PubMedCrossRef
20.
Zurück zum Zitat van den Akker EB, Pitts SJ, Deelen J et al (2016) Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood 127:1512–1515PubMedPubMedCentralCrossRef van den Akker EB, Pitts SJ, Deelen J et al (2016) Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood 127:1512–1515PubMedPubMedCentralCrossRef
21.
Zurück zum Zitat Buscarlet M, Provost S, Zada YF et al (2017) DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–762PubMedCrossRef Buscarlet M, Provost S, Zada YF et al (2017) DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–762PubMedCrossRef
22.
Zurück zum Zitat Hinds DA, Barnholt KE, Mesa RA et al (2016) Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128:1121–1128PubMedPubMedCentralCrossRef Hinds DA, Barnholt KE, Mesa RA et al (2016) Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128:1121–1128PubMedPubMedCentralCrossRef
23.
Zurück zum Zitat Janiszewska H, Bąk A, Skonieczka K et al (2018) Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML. Leuk Res 70:74–78PubMedCrossRef Janiszewska H, Bąk A, Skonieczka K et al (2018) Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML. Leuk Res 70:74–78PubMedCrossRef
24.
Zurück zum Zitat Kennedy AL, Myers KC, Bowman J et al (2021) Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun 12:1334PubMedPubMedCentralCrossRef Kennedy AL, Myers KC, Bowman J et al (2021) Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun 12:1334PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Fuster JJ, MacLauchlan S, Zuriaga MA et al (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–847PubMedPubMedCentralCrossRef Fuster JJ, MacLauchlan S, Zuriaga MA et al (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–847PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Abegunde SO, Buckstein R, Wells RA, Rauh MJ (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp Hematol 59:60–65PubMedCrossRef Abegunde SO, Buckstein R, Wells RA, Rauh MJ (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp Hematol 59:60–65PubMedCrossRef
27.
Zurück zum Zitat Avagyan S, Henninger JE, Mannherz WP et al (2021) Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374:768–772PubMedCrossRef Avagyan S, Henninger JE, Mannherz WP et al (2021) Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374:768–772PubMedCrossRef
28.
Zurück zum Zitat Weeks LD, Marinac CR, Redd R et al (2022) Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 139:1246–1250PubMedCrossRef Weeks LD, Marinac CR, Redd R et al (2022) Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 139:1246–1250PubMedCrossRef
29.
Zurück zum Zitat Chen J, Nie D, Wang X et al (2021) Enriched clonal hematopoiesis in seniors with dietary vitamin C inadequacy. Clin Nutr ESPEN 46:179–184PubMedCrossRef Chen J, Nie D, Wang X et al (2021) Enriched clonal hematopoiesis in seniors with dietary vitamin C inadequacy. Clin Nutr ESPEN 46:179–184PubMedCrossRef
30.
Zurück zum Zitat Meisel M, Hinterleitner R, Pacis A et al (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580–584PubMedPubMedCentralCrossRef Meisel M, Hinterleitner R, Pacis A et al (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580–584PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Zeng H, He H, Guo L et al (2019) Antibiotic treatment ameliorates ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies. Cancer Lett 467:1–8PubMedPubMedCentralCrossRef Zeng H, He H, Guo L et al (2019) Antibiotic treatment ameliorates ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies. Cancer Lett 467:1–8PubMedPubMedCentralCrossRef
32.
Zurück zum Zitat Rodriguez-Meira A, Norfo R, Wen WX et al (2022) Deciphering TP53 mutant cancer evolution with single-cell multi-omics (bioRxiv)CrossRef Rodriguez-Meira A, Norfo R, Wen WX et al (2022) Deciphering TP53 mutant cancer evolution with single-cell multi-omics (bioRxiv)CrossRef
34.
Zurück zum Zitat SanMiguel JM, Eudy E, Loberg MA et al (2022) Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis (bioRxiv) SanMiguel JM, Eudy E, Loberg MA et al (2022) Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis (bioRxiv)
35.
Zurück zum Zitat Coombs CC, Zehir A, Devlin SM et al (2017) Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21:374–382.e4PubMedPubMedCentralCrossRef Coombs CC, Zehir A, Devlin SM et al (2017) Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21:374–382.e4PubMedPubMedCentralCrossRef
36.
Zurück zum Zitat Gillis NK, Ball M, Zhang Q et al (2017) Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol 18:112–121PubMedCrossRef Gillis NK, Ball M, Zhang Q et al (2017) Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol 18:112–121PubMedCrossRef
37.
Zurück zum Zitat Hsu JI, Dayaram T, Tovy A et al (2018) PPM1D mutations drive clonal Hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23:700–713.e6PubMedPubMedCentralCrossRef Hsu JI, Dayaram T, Tovy A et al (2018) PPM1D mutations drive clonal Hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23:700–713.e6PubMedPubMedCentralCrossRef
38.
Zurück zum Zitat Dawoud AAZ, Tapper WJ, Cross NCP (2020) Clonal myelopoiesis in the UK biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 34:2660–2672PubMedCrossRef Dawoud AAZ, Tapper WJ, Cross NCP (2020) Clonal myelopoiesis in the UK biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 34:2660–2672PubMedCrossRef
39.
Zurück zum Zitat Wong TN, Ramsingh G, Young AL et al (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552–555PubMedCrossRef Wong TN, Ramsingh G, Young AL et al (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552–555PubMedCrossRef
40.
Zurück zum Zitat Lindsley RC, Saber W, Mar BG et al (2017) Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 376:536–547PubMedPubMedCentralCrossRef Lindsley RC, Saber W, Mar BG et al (2017) Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 376:536–547PubMedPubMedCentralCrossRef
41.
Zurück zum Zitat Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwiński R, Rusin M (2015) Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer 112:1114–1120PubMedPubMedCentralCrossRef Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwiński R, Rusin M (2015) Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer 112:1114–1120PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Swisher EM, Harrell MI, Norquist BM et al (2016) Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol 2:370–372PubMedPubMedCentralCrossRef Swisher EM, Harrell MI, Norquist BM et al (2016) Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol 2:370–372PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat Bolton KL, Ptashkin RN, Gao T et al (2020) Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 52:1219–1226PubMedPubMedCentralCrossRef Bolton KL, Ptashkin RN, Gao T et al (2020) Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 52:1219–1226PubMedPubMedCentralCrossRef
44.
Zurück zum Zitat Yoshizato T, Dumitriu B, Hosokawa K et al (2015) Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 373:35–47PubMedPubMedCentralCrossRef Yoshizato T, Dumitriu B, Hosokawa K et al (2015) Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 373:35–47PubMedPubMedCentralCrossRef
45.
Zurück zum Zitat Kulasekararaj AG, Jiang J, Smith AE et al (2014) Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood 124:2698–2704PubMedPubMedCentralCrossRef Kulasekararaj AG, Jiang J, Smith AE et al (2014) Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood 124:2698–2704PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat Zhang CRC, Nix D, Gregory M et al (2019) Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients. Exp Hematol 80:36–41.e3PubMedPubMedCentralCrossRef Zhang CRC, Nix D, Gregory M et al (2019) Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients. Exp Hematol 80:36–41.e3PubMedPubMedCentralCrossRef
48.
Zurück zum Zitat Arends CM, Weiss M, Christen F et al (2020) Clonal hematopoiesis in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Haematologica 105:e264–7PubMedPubMedCentralCrossRef Arends CM, Weiss M, Christen F et al (2020) Clonal hematopoiesis in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Haematologica 105:e264–7PubMedPubMedCentralCrossRef
49.
Zurück zum Zitat Ertz-Archambault N, Kosiorek H, Taylor GE et al (2017) Association of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia. JAMA Oncol 3:936–943PubMedPubMedCentralCrossRef Ertz-Archambault N, Kosiorek H, Taylor GE et al (2017) Association of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia. JAMA Oncol 3:936–943PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat van Zeventer IA, de Graaf AO, Wouters HJCM et al (2020) Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals. Blood 135:1161–1170PubMed van Zeventer IA, de Graaf AO, Wouters HJCM et al (2020) Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals. Blood 135:1161–1170PubMed
51.
Zurück zum Zitat Malcovati L, Gallì A, Travaglino E et al (2017) Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129:3371–3378PubMedPubMedCentralCrossRef Malcovati L, Gallì A, Travaglino E et al (2017) Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129:3371–3378PubMedPubMedCentralCrossRef
52.
Zurück zum Zitat Rossi M, Meggendorfer M, Zampini M et al (2021) Clinical relevance of clonal hematopoiesis in persons aged ≥80 years. Blood 138:2093–2105PubMedCrossRef Rossi M, Meggendorfer M, Zampini M et al (2021) Clinical relevance of clonal hematopoiesis in persons aged ≥80 years. Blood 138:2093–2105PubMedCrossRef
53.
Zurück zum Zitat Abelson S, Collord G, Ng SWK et al (2018) Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 107:2099 Abelson S, Collord G, Ng SWK et al (2018) Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 107:2099
54.
Zurück zum Zitat Desai P, Mencia-Trinchant N, Savenkov O et al (2018) Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24:1–12CrossRef Desai P, Mencia-Trinchant N, Savenkov O et al (2018) Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24:1–12CrossRef
55.
Zurück zum Zitat Steensma DP, Bolton KL (2020) What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics. Blood 136:1623–1631PubMedPubMedCentral Steensma DP, Bolton KL (2020) What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics. Blood 136:1623–1631PubMedPubMedCentral
56.
Zurück zum Zitat Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131PubMedCrossRef Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131PubMedCrossRef
57.
Zurück zum Zitat Svensson EC, Madar A, Campbell CD et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol 7:521–528PubMedCrossRef Svensson EC, Madar A, Campbell CD et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol 7:521–528PubMedCrossRef
Metadaten
Titel
Bedeutung der klonalen Hämatopoese für hämatologische Neoplasien
verfasst von
Prof. Dr. Katharina S. Götze
Prof. Dr. Claudia Lengerke
Publikationsdatum
19.09.2022
Verlag
Springer Medizin
Erschienen in
Die Innere Medizin / Ausgabe 11/2022
Print ISSN: 2731-7080
Elektronische ISSN: 2731-7099
DOI
https://doi.org/10.1007/s00108-022-01401-0

Weitere Artikel der Ausgabe 11/2022

Die Innere Medizin 11/2022 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.