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  • 1
    Online Resource
    Online Resource
    Horizontal DNA Transfer from Donor to Host Cells as an Alternative Mechanism of Epithelial Chimerism after Allogeneic Hematopoietic Cell Transplantation
    Elsevier BV ; 2011
    In:  Biology of Blood and Marrow Transplantation Vol. 17, No. 3 ( 2011-03), p. 319-329
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 17, No. 3 ( 2011-03), p. 319-329
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2010.09.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
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  • 2
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    SNP Array Analysis In Unrelated HLA-Matched Transplanted Patients Reveals Loss of Patient- Specific Allele at the Mismatched Locus
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4692-4692
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4692-4692
    Abstract: Abstract 4692 Allogeneic hematopoietic cell transplantation (HCT) is the most effective curative therapy in patients acute myeloid leukemia (AML) and myelodisplastic syndromes (MDS). Despite improvements in the clinical management, relapse from the original disease is still one of the main causes of treatment failure. There is scarce available data on the influence of genomic changes in relapsed patients after HCT, in particular in HLA identical transplantation. Selective pressure mediated by T cells can result in genomic changes in the HLA region on chromosome 6, as shown by several animal models and in human haploidentical transplantation. In this study we examined genome wide DNA copy number changes and long contiguous stretches of homozygosity (LCSH) in 21 patients with a diagnosis of AML or MDS/AML undergoing HCT. SNP-chip analysis revealed a total of 162 genomic aberrations (GA) in 21 pairs of samples before allogeneic transplantation and at relapse in patients diagnosed with AML or AML/MDS. Total GA were significantly higher after transplant compared with the pre transplant samples (p 〈 0.05) only in the group of patients with normal cytogenetics. Within this last group of patients, only a small deletion was detected in the pre transplant sample not detected by conventional cytogenetics. In contrast, in the group of patients with abnormal/complex karyotype, 5 additional deletions and 2 duplications were detected in 5 patients before transplantation. The median number of GA per patient pre transplant was 3 (range 0–19), while the median number of GA at relapse post transplantation was 5 (range 1–20). The median copy number loss per patient was 1.6 before transplant and 2.8 at relapse, while the median number of LCSH at the same time points was 2 and 2.8 respectively. Copy number gains were significantly less common (p 〈 0.05) with a median of 0.5 per patient before transplant and 1 at relapse. Of 21 patients, eleven (52%) shared the same GA before transplant and at relapse indicating common clonality. Conversely 26 novel deletions, 9 LCSH and 6 duplications arose at relapse detected in 17 patients (76%). Of interest 3 out of 9 of these new LCSH involving chromosomes 6p, 20q and 22q, were recurrent GA at relapse detected in 2, 5 and 4 patients respectively. HLA typing of the blasts from patients with LCSH in chromosome 6p revealed a loss of the patient specific band at the mismatched locus leading to homozygosity for the HLA haplotype shared by the patient and the donor. LCSH was the most frequent lesion present in 81% of the patients followed by deletions (57%), trisomies (48%) and duplications (24%). All chromosomes had one or more GA, with significant differences among the 22 autosomes. Chromosome 2 had only 2 GA in the post transplant sample while chromosome 17 had 9 in the same time point. The most frequent lesion was LCSH in chromosome 20 q11.21 in the relapse sample, occurring in 5 of 21 patients (24%). Another recurrent GA was a deletion in chromosome 12 p13 detected in 4 patients (19%) at relapse. To confirm the SNP-chip results detected in allogeneic transplanted patients, extensive validation analysis was performed. FISH signal for probes TP53 (17q13.1), ETV6 (12p13) and ATM (11q 22.3) revealed one signal. These regions also showed hemizygous deletion by SNP-chips analysis. D8Z2 probe revealed three signals in patients with trisomy 8 detected with the array platform. Two patients with LCSH in the short arm of chromosome 9 p24 were homozygous for JAK2 mutation as detected by pyrosequencing. STR analysis using the polymorphic marker YNZ 22 confirm the allelic loss of at least one allele in the 17 p13.3 region. Results of SNP, FISH, pyrosequencing and STR analysis were completely congruent. These validation results suggest that SNP analysis reflected genomic changes. Patients with late onset GvHD ( 〉 day 100 post transplantation) had a significant higher number of GA after transplantation (p 〈 0.05). No significant association was found between acquired GA and the rest of the clinical variables analyzed including outcome. Our results indicate that GA in patients undergoing HCT are likely to play a role. LCSH in chromosome 6p can result in immune escape by leukemic cells from graft-versus-leukemia effect that can lead to relapse. In addition homozygosity in mutated genes such as FLT3 (13 q12) and JAK2 (9 p24) due to deletion or LCSH has important implication for selecting a treatment in patients that relapse after HCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4692.4692
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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    detail.hit.zdb_id: 80069-7
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  • 3
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    Frequent Genomic Alterations in Epithelium Measured by Microsatellite Instability Following Allogeneic Hematopoietic Cell Transplantation in Humans.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1117-1117
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1117-1117
    Abstract: While typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. Therefore, we examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at three tetranucleotide (SEE33, THO-1, D14S120) and three mononucleotide (ZP3, BAT26, SRY) microsatellite loci. All except two colon biopsies examined had histological signs of GvHD. No signs of mucositis or oral GvHD were present at the time of buccal sampling. Novel bands indicative of microsatellite instability (MSI) were detected in laser-capture microdissected (LCM) colonic crypts in 12 out of 16 patients (75%) and in buccal smears in 10 out of 24 (42%) allografted patients. In contrast to the allografted patients, no MSI was found in the LCM crypts obtained from 4 patients after intensive chemotherapy or from 7 control subjects with no history of either colon malignancy or chemotherapy, and in the buccal smears obtained from 8 patients after autologous HCT or from 9 healthy controls. MSI was found only at tetranucleotide markers but not at mononucleotides. There was no statistical correlation between the presence of MSI in colon and the underlying disease, the previous history of multiple ( & gt;=3) intensive chemotherapies before transplantation, the type of preparative regimen for HCT, the overall GVHD grade any time before sampling or the GvHD stage in colon at sampling. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins (MLH1, MSH2, MSH3, APE-1, XPA). There was no significant association between MSI in the buccal mucosa and patient age, gender, disease, type of conditioning, history of oral GvHD or overall GvHD occured at any point before buccal sampling. Interestingly, we found a significant association between the time of buccal sampling after transplantation and the presence of MSI (p=0.008). MSI was also found in three post-transplant squamous cell cancers examined. The frameshift alterations found in post-transplant tumors often differed from those in the associated non-malignant tissues. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT. This previously unacknowledged genomic instability after allogeneic HCT may be implicated in the evolution of post-transplant diseases, including secondary cancer.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1117.1117
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Comparison of reduced-toxicity conditioning protocols using fludarabine, melphalan combined with thiotepa or carmustine in allogeneic hematopoietic cell transplantation
    Springer Science and Business Media LLC ; 2021
    In:  Bone Marrow Transplantation Vol. 56, No. 1 ( 2021-01), p. 110-120
    Details
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 56, No. 1 ( 2021-01), p. 110-120
    Type of Medium: Online Resource
    ISSN: 0268-3369 , 1476-5365
    URL: Article
    DOI: 10.1038/s41409-020-0986-2
    RVK:
    XA 10000
    RVK:
    XA 33180
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2004030-1
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  • 5
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    Correction: Colon and liver tissue damage detection using methylated SESN3 and PTK2B genes in circulating cell-free DNA in patients with acute graft-versus-host disease
    Springer Science and Business Media LLC ; 2021
    In:  Bone Marrow Transplantation Vol. 56, No. 10 ( 2021-10), p. 2616-2616
    Details
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 56, No. 10 ( 2021-10), p. 2616-2616
    Type of Medium: Online Resource
    ISSN: 0268-3369 , 1476-5365
    URL: Article
    DOI: 10.1038/s41409-021-01405-8
    RVK:
    XA 10000
    RVK:
    XA 33180
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2004030-1
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  • 6
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    The impact of pulmonary function in patients undergoing autologous stem cell transplantation
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 21 ( 2021-11-09), p. 4327-4337
    Details
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 21 ( 2021-11-09), p. 4327-4337
    Abstract: High-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation (auto-HSCT), is an established therapy for patients with hematological malignancies. The age of patients undergoing auto-HSCT and, therefore, the comorbidities, has increased over the last decades. However, the assessment of organ dysfunction prior to auto-HSCT has not been well studied. Therefore, we retrospectively analyzed the association of clinical factors and lung and cardiac function with outcome and complications after conditioning with BEAM (BCNU/carmustine, etoposide, cytarabine, melphalan) or high-dose melphalan in patients undergoing auto-HSCT. This study included 629 patients treated at our institution between 2007 and 2017; 334 and 295 were conditioned with BEAM or high-dose melphalan, respectively. The median follow-up was 52 months (range, 0.2-152) and 50 months (range, 0.5-149), respectively. In the multivariate analysis, we identified that progressive disease, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, Karnofsky Performance Status (KPS) ≤ 80%, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score ≥ 4, and age & gt; 70 years were associated with decreased overall survival (OS) in patients treated with BEAM. Similarly, DLCOcSB ≤ 60% of predicted, HCT-CI score ≥ 4, and age & gt; 60 years were identified in patients treated with high-dose melphalan. Abnormalities in DLCOcSB ≤ 60% of predicted were associated with chemotherapy with lung-toxic substances, mediastinal radiotherapy, KPS ≤ 80%, current/previous smoking, and treatment in the intensive care unit. More often, patients with DLCOcSB ≤ 60% of predicted experienced nonrelapse mortality, including pulmonary causes of death. In summary, we identified DLCOcSB ≤ 60% of predicted as an independent risk factor for decreased OS in patients conditioned with BEAM or high-dose melphalan prior to auto-HSCT.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021004863
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 2876449-3
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  • 7
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    An internal validation approach and quality control on hematopoietic chimerism testing after allogeneic hematopoietic cell transplantation
    Walter de Gruyter GmbH ; 2013
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 51, No. 2 ( 2013-02-01), p. 363-369
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 51, No. 2 ( 2013-02-01), p. 363-369
    Abstract: Background: Hematopoietic chimerism analysis is important in the follow-up of patients undergoing allogeneic stem cell transplantation. PCR of short tandem repeats is mainly used for monitoring chimerism after transplantation. Validation studies and precision of assay’s performance with respect to different mixed chimerism stages is not fully addressed. The aim of the present study was to assess the impact of several microsatellite analytical parameters in the quantification of hematopoietic chimerism after allogeneic hematopoietic stem cell transplantation and to analyze the overall analytical process through the application of internal quality control procedures. Methods: Artificial DNA mixtures prepared in known proportions and patients samples were analyzed using three microsatellites, together with amplification of amelogenin gene and fluorescence in situ hybridization (FISH) for X and Y chromosomes. Limit of detection, analytical and clinical sensitivity, stochastic threshold and precision profiling was established. Levey-Jennings charts and Westgard rules were applied for quality control evaluation. Results: Analytical and clinical sensitivity of the microsatellite markers was between 0.5% and 1.6%. Amelogenin detection and FISH for X and Y chromosomes showed a similar sensitivity. Severe allelic imbalance resulted in up to 50% difference between the calculated and corrected mixed chimerism. Systematic errors were identified using Levey-Jennings charts and Westgard rules. Conclusions: Analysis of hematopoietic chimerism performance is a critical step to better understand potential intrinsic errors that may impact the final hematopoietic chimerism results. Implementing quality control tools, such as Levey-Jennings charts together with Westgard rules can identify systematic and random errors so corrective actions can be performed.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2012-0230
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2013
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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  • 8
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    Droplet digital PCR for the simultaneous analysis of minimal residual disease and hematopoietic chimerism after allogeneic cell transplantation
    Walter de Gruyter GmbH ; 2019
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 57, No. 5 ( 2019-04-24), p. 641-647
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 57, No. 5 ( 2019-04-24), p. 641-647
    Abstract: Minimal residual disease (MRD) and hematopoietic chimerism testing influences clinical decision and therapeutic intervention in patients after allogeneic stem cell transplantation (HSCT). However, treatment approaches to induce complete donor chimerism and MRD negativity can lead to complications such as graft-versus-host disease (GvHD) and marrow aplasia. Therefore, there is a need for comprehensive characterization of the molecular remission status after transplantation. Methods We analyzed 764 samples from 70 patients after HSCT for the simultaneous measurement of chimerism and molecular targets used for MRD testing with a digital PCR (dPCR) platform. Results Mixed chimerism (MC) was detected in 219 samples from 37 patients. The mean percentage of host derived DNA in these clinical samples was 4.3%. Molecular relapse with a positive MRD marker and/or increased WT1 expression was observed in 15 patients. In addition to WT1 overexpression, other MRD positive markers were: NPM1 (Type A, B, K), DNMT3A (R882H), MLL-PTD, IDH1 (R132H) and KRAS (G12S). Increasing MC was observed in 15 patients. This group of patients showed either a positive MRD marker, increased WT1 expression or both. Next, we analyzed whether MC or the molecular target for MRD was first detected. MC and MRD marker positivity in this group was first detected in six and two patients, respectively. In the remaining seven patients MC and MRD positivity was detected simultaneously. Conclusions The combination of MRD and chimerism markers in a dPCR platform represents a practical, sensitive and accurate diagnostic tool for the comprehensive assessment of the molecular remission status of patients undergoing HSCT.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2018-0827
    Language: Unknown
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2019
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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  • 9
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    Sensitive and accurate quantification of JAK2 V617F mutation in chronic myeloproliferative neoplasms by droplet digital PCR
    Springer Science and Business Media LLC ; 2016
    In:  Annals of Hematology Vol. 95, No. 5 ( 2016-4), p. 739-744
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 95, No. 5 ( 2016-4), p. 739-744
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-016-2623-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 1458429-3
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  • 10
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    Early mixed hematopoietic chimerism detection by digital droplet PCR in patients undergoing gender-mismatched hematopoietic stem cell transplantation
    Walter de Gruyter GmbH ; 2017
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 55, No. 8 ( 2017-07-26), p. 1115-1121
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 55, No. 8 ( 2017-07-26), p. 1115-1121
    Abstract: Clinical decision making after allogeneic stem cell transplantation (HSCT) is partially based on hematopoietic chimerism analysis. Polymerase chain reaction amplification of polymorphic short tandem repeats (STR-PCR) is currently considered the gold standard for chimerism surveillance after transplantation. Nevertheless, this method has shown several limitations. Emerging technologies such as digital PCR (dPCR) has been applied to detect hematopoietic chimerism. Despite previous reports, the clinical usefulness of dPCR is unclear because the studies were performed in limited patient populations with short follow-ups. Methods: In order to compare hematopoietic chimerism detection time and rate, we analyzed 591 samples from 155 patients undergoing gender-mismatched HSCT using STR-PCR and dPCR. We also established the correlation between both methods in artificial DNA mixtures prepared in known proportions and in clinical samples. Results: Depending on the artificial DNA mixture analyzed the correlation coefficient between both methods was 0.9946 and 0.9732. The limit of detection for dPCR was 0.01%. Of 157 samples with donor and recipient DNA, mixed chimerism (MC) was detected solely by dPCR in 66 samples. Within the group of patients relapsing after HSCT (n=32) MC was detected earlier in 15 of these patients with dPCR in comparison with STR-PCR. The mean time from MC detection to relapse was 155 days (range: 13–385 days) and 65 days (range: 0–203 days) for dPCR and STR-PCR, respectively. Conclusions: dPCR is a sensitive and accurate method for the quantification of hematopoietic chimerism allowing earlier MC detection compared to STR-PCR.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2016-0900
    Language: Unknown
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2017
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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