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Prognostic Impact of the CD34+/CD38- Cell Burden in Patients with Acute Myeloid Leukemia receiving Allogeneic Stem Cell TransplantationJentzsch, Barbara Madlen 02 February 2018 (has links)
Introduction: In acute myeloid leukemia (AML), leukemia initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse.
Purpose: We evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in AML patients receiving an allogeneic stem cell transplantation (HSCT) in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects.
Methods: Percentage of bone marrow CD34+/CD38- cell burden in 169 AML patients at diagnosis was measured using flow cytometry. The optimal cutoff of 6% was applied and used to evaluate the impact of a high CD34+/CD38- cell burden on outcome.
Results: The CD34+/CD38- cell burden and was highly variable (median 0.5%, range 0-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival, which may be mediated by residual leukemia initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic HSCT.
Conclusion: Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic HSCT. Further studies to understand leukemia initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed.:Bibliographische Beschreibung / Bibliographic description 1
Einleitung / Introduction 2
Epidemiology and AML diagnosis 2
Therapeutic options in AML 3
Genetic risk classification for therapeutic decisions in AML 6
Immunophenotyping in AML 10
Leukemia Initiating Cells 11
Objectives of the here presented study 13
Publikation / Publication 14
Anlage / Supplemental Material 23
Zusammenfassung / Summary 48
Weiterführende Arbeiten / Future developments
GPR56 as new LIC marker 52
Referenzen / References 55
Referenz der Publikation / Reference of the publication 60
Erklärung über die eigenständige Abfassung der Arbeit 61
Curriculum Vitae 62
Komplette Publikationsliste 65
Danksagung 74
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Anti-CD20 Monoclonal Antibody (Rituximab) and Cidofovir as Successful Treatment of an EBV-Associated Lymphoma with CNS InvolvementHänel, Mathias, Fiedler, Friedrich, Thorns, Christoph January 2001 (has links)
Background: Epstein-Barr virus(EBV)-associated posttransplant lymphoproliferative disease (PTLD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Especially in cases with involvement of the central nervous system (CNS) treatment is difficult because the efficacy of most chemotherapeutic agents as well as EBV-specific cytotoxic donor T cells in liquor is uncertain. In the last years the anti-CD20 monoclonal antibody Rituximab was intensively investigated in the treatment of EBV-PTLD. However, only 8 patients with B-cell lymphoma and CNS involvement treated with Rituximab were reported. Case Report: A 24-year-old female patient with acute T-lymphoblastic leukemia in second complete remission had received allogeneic, unrelated, T-cell depleted HSCT. 10 months later an EBV-associated PTLD was diagnosed. Beside peripheral lymphomas and B symptoms the patient showed neurological symptoms. Examination of the cerebrospinal fluid (CSF) revealed a meningeosis lymphoblastica caused by the EBV lymphoma. Treatment with Rituximab and the antiviral drug Cidofovir led to complete remission with regression of the peripheral lymphomas and disappearance of the neurological symptoms. In addition, the PCR control on EBV DNA became negative in the plasma as well as in CSF. Conclusion: The combination of Rituximab and Cidofovir appears as an interesting alternative treatment in patients with EBV-associated PTLD and CNS involvement. / Hintergrund: Die Epstein-Barr-Virus(EBV)-assoziierte Posttransplantations-lymphoproliferative Disease (PTLD) ist eine gefürchtete Komplikation nach allogener hämatopoetischer Stammzelltransplantation (HSCT). Insbesondere bei Befall des zentralen Nervensystems (ZNS) ist die Behandlung auf Grund der unsicheren Liquorwirksamkeit der meisten Chemotherapeutika als auch von EBV-spezifischen zytotoxischen T-Spenderzellen schwierig. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in den letzten Jahren bei Patienten mit EBV-PTLD intensiv untersucht. Allerdings wurde bislang lediglich von 8 Patienten mit ZNS-Befall eines B-Zell-Lymphoms berichtet, bei denen eine Therapie mit Rituximab erfolgte. Kasuistik: Eine 24-jährige Patientin hatte wegen einer akuten T-lymphoblastischen Leukämie in zweiter kompletter Remission eine allogen-unverwandte, T-Zelldepletierte HSCT erhalten. 10 Monate später wurde eine EBV-assoziierte PTLD diagnostiziert. Neben peripheren Lymphomen und B-Symptomen zeigte die Patientin neurologische Symptome. Die Liquoruntersuchung erbrachte den Befund einer Meningeosis lymphoblastica im Rahmen des EBV-Lymphoms. Die Behandlung mit Rituximab und dem Virustatikum Cidofovir führte zu einer kompletten Remission mit Rückbildung der peripheren Lymphome und Verschwinden der neurologischen Symptomatik. Außerdem wurde die PCR-Kontrolle auf EBV-DNA sowohl im Plasma als auch im Liquor negativ. Schlussfolgerung: Die Kombination von Rituximab und Cidofovir erscheint als eine interessante Therapiealternative für Patienten mit EBV-assoziierter PTLD und ZNS-Befall. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Validation of a Next Generation Sequencing based method for chimerism analysis in clinical practiceHögberg, Maria January 2022 (has links)
Hematopoietic stem cell transplantation (HSCT) is used to treat patient with hematological diseases such as leukemia and genetic conditions such as sickle cell anemia. After HSCT the patients are supervised for signs of relapse of disease or rejection of transplanted cells. This is done by using chimerism analysis. At the department of clinical genetics at Akademiska sjukhuset fragment analysis of short tandem repeats is used for chimerism analysis, which is to be replaced by a Next generation sequencing (NGS) based method called Devyser chimerism, which includes an IVDR labelled kit. The aim of this project was to validate the new method for chimerism analysis. DNA samples from twelve HSCT patients and their donors were analyzed with Devyser chimerism and the results were compared to the results from the current method. The sensitivity of the new method was tested by analysis of artificial chimerism samples from blood donors. The results from the comparison showed a good correlation between methods (R2 = 0,9864) and the sensitivity of the method was confirmed to be 0,1% mixed chimerism. There was some difficulty in identifying enough informative markers for re-transplanted patients two had separate donors. This is a known problem for chimerism analysis in general and not a specific problem to the new method and will not be a hindrance for the implementation of Devyser chimerism at the clinical laboratory.
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Lipidomic profiling of multiple sclerosis patients undergoing autologous hematopoietic stem cell transplantationVaivade, Aina January 2021 (has links)
Background: Multiple sclerosis (MS) is a neurological, autoimmune disease which mainly affects people in the age of 20 to 40. The disease course is unpredictable affecting each patient differently, leading to progressiveand irreversible degradation of the central nervous system. There is no treatment that cures this disease, however, there are treatments that either slows down the disease course or prevents progressive disabilities. A treatment called autologous hematopoietic stem cell transplantation (AHSCT) is thought to reset the immune system and induce a new, more tolerant one, thus haltering the disease course. However, the knowledge about the effects causing the improvement seen in patients treated with AHSCT is limited. Methods: To investigate the effect of AHSCT in MS patients, serum lipidomics data from 16 patients was collected at ten timepoints. The lipidomics data was collected for both positively and negatively charged molecules separately as well as within a single experiment called polarity switching, using mass spectrometry. Since the standard method requires two separate experiments to analyze both positively and negatively charged lipids it requires twice the time and resources compared to polarity switching. Results: Comparing the two mass spectrometry protocols showed that the coefficient of variation (CV) was slightly higher for polarity switching compared to the standard method. Nevertheless, the difference was not significant and both methods had in general a good CV, indicating low technical variation. In addition, this thesis showed that polarity switching has a slightly higher percentage of lipids with zero carryover compared to the standard method. The results also indicated that the expression levels of differentially expressed lipids follow two distinct patterns throughout the AHSCT treatment. The largest intensity variation arises after stem cellreinfusion and the lipid intensities are back to nearly initial levels atthe three month follow-up. Finally, many lipids were found to be associated with the change in c-protein levels as well as erythrocyte, leukocyte, and thrombocyte levels that occurred during treatment. Conclusions: This master thesis showed that polarity switching is a good alternative to the standard method, saving both time and resources without losing too much in specificity. In addition, this thesis has shown that differentially expressed lipids follow two distinct expression patterns through the treatment. The lipids levels for both differentially expressed lipids and lipids associated with clinical data were nearly back to baseline levels three months after AHSCT. Hence, AHSCT has a major but short-lasting impact on the lipid levels in peripheral blood.
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GVHD amelioration by human bone marrow mesenchymal stromal/stem cell-derived extracellular vesicles is associated with peripheral preservation of naive T cell populations / ヒト骨髄間葉系幹細胞由来細胞外小胞は末梢のナイーヴT細胞分画を保持することにより急性移植片対宿主病を緩和するFujii, Sumie 26 March 2018 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21018号 / 医博第4364号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 誠司, 教授 柳田 素子, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Génération de lymphocytes T CAR-T multi-virus spécifiques résistants à l'action du tacrolimusGuettouche, Sabrina 12 1900 (has links)
Le transfert adoptif de lymphocytes T virus-spécifiques ou ‘’Chimeric Antigen Receptors’’ (CAR) s’est avéré efficace pour le traitement de plusieurs types d’infections virales et certains cancers à la suite d’une greffe de cellules souches hématopoïétiques. Cependant, l’immunosuppression administrée pour la prévention du rejet de greffe et de la maladie du greffon contre l’hôte limite l’efficacité et la persistance à long terme des réponses médiées par ces lymphocytes. L’agent immunosuppresseur Tacrolimus (FK506) est parmi les plus utilisés, et fonctionne en liant la protéine FK506-Binding protein (FKBP12) afin d’exercer ses effets immunosuppresseurs sur les lymphocytes T. Dans le but de fournir une protection anti-virale, mais également anti-lymphoprolifératif des lymphocytes B et permettre la poursuite de cette immunosuppression préventive, nous avons pour objectif de générer des lymphocytes CAR-T et virus-spécifiques résistants à l’action du FK506 par l’invalidation du FKBP12. En utilisant la méthode d’édition génique basée sur les CRISPR ciblés par la nucléase Cas9, nous avons pu invalider le gène du FKBP12 sur des lymphocytes T stimulés par CD3-CD28. L’efficacité du knockout a été validée par Western Blot et TIDE sequencing. Le knock-out du gène du FKBP12 a conféré un maintien de la croissance cellulaire et des fonctions effectrices telles que la synthèse de cytokines IL-2, TNFα et IFN γ en présence de Tacrolimus comparativement aux cellules contrôles. Par la même méthode, nous avons pu invalider le gène du FKBP12 sur des lymphocytes T multivirus-spécifiques dont l’efficacité a été validée par cytométrie en flux. Les fonctions effectrices ont également été maintenues en présence de tacrolimus et ont été évaluées par ELISpot. Enfin, des lignées de lymphocytes T multivirus spécifiques dont le gène du FKBP12 a été invalidé ont été transduites avec un vecteur lentiviral dans le but d’exprimer un CAR CD19 dont l’expression a été validée par cytométrie en flux et la réactivité maintenue en présence de tacrolimus. En conclusion, ces résultats nous ont permis de démontrer la faisabilité de génération de lymphocytes T « triple fonction » anti-tumorales, anti-virales et résistantes au tacrolimus. L’application de cette approche semble prometteuse dans un contexte d’une immunothérapie adoptive anti-virale et anti-tumorale post-transplantation de moelle osseuse. / Adoptive transfer of virus-specific T lymphocytes or CAR-T cells has been shown to be effective for the treatment of several types of viral infections and certain cancers following hematopoietic cell transplantation. However, immunosuppression administered for the prevention of transplant rejection and graft-versus-host disease limits the efficacy and long-term persistence of responses mediated by these lymphocytes. The widely used immunosuppressive agent Tacrolimus (FK506) requires FK506-Binding protein (FKBP12) to exert its immunosuppressive effects on T cells. We undertook to engineer a multifunctional T-cell therapy to both optimally prevent viral reactivation and relapse of B-cell malignancies post-transplant in the context of immunosuppression. The objective of our work is to generate tacrolimus resistant, multivirus-specific T-cell lines expressing an anti-CD19 CAR. Using the gene editing method based on Clustered Regular interspaced short palidromic repeats (CRISPR) targeted by the CRISPR-associated protein 9 (Cas9) nuclease, we were able to invalidate the FKBP12 gene on activated T cells (confirmed by TIDE sequencing and western blotting). Invalidation of FKBP12 conferred maintenance of cell growth and effector functions such as the synthesis of cytokines IL-2, TNFα and IFNγ in the presence of Tacrolimus. Using the same method, we were able to delete the FKBP12 gene in virus-specific T lymphocytes. Effector functions were also maintained in the presence of tacrolimus. Finally, we integrated an anti-CD19 CAR by lentiviral transduction into FKBP12-edited multi-virus T-cell lines, and the efficiency of transduction was determined by flow cytometry. The cells maintained their viral reactivity in the presence of tacrolimus. In conclusion, we were able to confirm the feasibility of generation of ‘’triple function’’ T cells (anti-viral, anti-tumoral and tacrolimus resistant). Multifunctional T-cell product manufacturing is a promising approach to optimize post-transplant T-cell immunity against opportunistic pathogens and underlying malignancies.
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The Role of Genetic Variant and Genomic Features in Outcomes Following TransplantationWang, Yiwen 07 September 2022 (has links)
No description available.
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A high hematopoietic cell transplantation comorbidity index (HCT-CI) does not impair outcomes after non-myeloablative allogeneic stem cell transplantation in acute myeloid leukemia patients 60 years or olderBackhaus, Donata Elisabeth 29 January 2024 (has links)
No description available.
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Identification of the Minimum Requirements for Successful Haematopoietic Stem Cell Transplantation / 造血幹細胞移植成立のための必要最小条件の同定Nishi, Katsuyuki 23 March 2022 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23794号 / 医博第4840号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 小川 誠司, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Patienters upplevelser av diagnos och behandling vid akut myeloisk leukemi : En kvalitativ litteraturöversikt / Patients' experiences of diagnosis and treatment in acute myeloid leukemiaJohansson, Elvira, Åström, Elenore January 2023 (has links)
Titel: Patienters upplevelser av diagnos och behandling vid akut myeloisk leukemi Bakgrund: Akut myeloisk leukemi (AML) är den vanligaste formen av akut leukemi. Behandlingen och symtomen är påfrestande och långvariga, vilket inverkar på patienters livskvalitet. Genom god personcentrerad vård kan sjuksköterskan försöka tillgodose många av behoven som patienten kan få under vårdtiden. Syfte: Att beskriva patienters upplevelser av att diagnostiseras med och genomgå behandling mot akut myeloisk leukemi. Metod: En litteraturöversikt med kvalitativ metod och induktiv ansats. Efter sökning i databaserna Cinahl, PubMed och PsyINFO samt artikelgranskning inkluderades tolv artiklar. Artiklarna analyserades genom Fribergs fem steg. Resultat: Genom en sammanställning av artiklarna framkom det två olika teman (känslomässiga reaktioner och förändrad kroppsuppfattning) och sex olika subteman (att få ett obegripligt besked, känsla av att få svår och komplex information, känsla av isolering, förändrat utseende relaterat till symtom, fysiska symtom relaterat till behandling och känsla av att vara en börda). Slutsatser: I litteraturöversikten framkom det att beskedet om diagnosen var obegripligt. Patienterna upplevde att sjuksköterskan hade svårt att förmedla den komplexa informationen personcentrerat. Behandlingstiden orsakade att patienterna upplevde sig isolerade och att symtomen (illamående, trötthet och håravfall) påverkade patienternas vardagliga liv negativt. Sjuksköterskans stöd och undervisning relaterat till symtomhantering och omvårdnadsåtgärder till såväl patient och anhöriga är avgörande för att minska de negativa känslorna som framkom i resultatet. Nyckelord: Cancer, cytostatikabehandling, personcentrerad vård, stamcellstransplantation
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