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  • 1
    In: Human Mutation, Hindawi Limited, Vol. 2023 ( 2023-6-2), p. 1-11
    Abstract: Current estimates suggest that up to 10% of patients with myeloid neoplasms (MN) harbor variants associated with a germline predisposition. A pathogenic variant in the runt-related transcription factor 1 gene (RUNX1) is a frequent cause of germline predisposition to MN. RUNX1 variants detected in tumor tissue at a VAF close to 50% are potentially germline and causative of RUNX1 familial platelet disorder with associated myeloid malignancies. Previous studies have found germline RUNX1 variants in 3% of patients with acute myeloid leukemia; however, the frequency of germline RUNX1 variants in less advanced myeloid neoplasms has not been examined. We screened 590 patients suspected of MN, excluding myeloproliferative neoplasms, for germline variants in RUNX1. We found RUNX1 variants in 83 patients (14%) by targeted sequencing of tumor tissue. In 40 patients (6.8%), the VAF of RUNX1 was above 30%. In 32 of the 40 patients, skin biopsies were available and used for Sanger sequencing to assess the germline status. Two of the tested variants (6.3%) were confirmed as germline, and both variants were curated as variants of unknown significance. To further explore the pathogenicity of these variants, we implemented a novel CRISPR-Select functional genetic assay. The assay demonstrated a profound effect on proliferation in K562 cells for a known pathogenic variant but no effect for the two germline variants detected in the study. We therefore propose that both germline variants are classified as likely benign. In this study, we show that RUNX1 germline variants are rare in Danish patients with MN and use a novel assay for functional classification of germline RUNX1 variants.
    Type of Medium: Online Resource
    ISSN: 1098-1004
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2023
    detail.hit.zdb_id: 1498165-8
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  • 2
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 607-607
    Abstract: Background: Somatic driver mutations in hematopoietic cells may lead to clonal hematopoiesis of indeterminate potential (CHIP). In patients with lymphoma CHIP has been associated with increased risk of therapy-related myeloid neoplasms (tMN) and inferior survival after autologous stem cell transplantation as demonstrated in a large single center study and in a case-control study (Gibson CJ et al., JCO 2017 and Berger G et al., Blood 2018). Here, we investigated the clinical impact of clonal hematopoiesis in a nation-wide population-based cohort of Danish lymphoma patients undergoing autologous transplant with prospective data from four national patient registries. Methods: Patients with lymphoma who had undergone leukapheresis at all danish transplant centers from 2000 to 2012 were identified. DNA and RNA was extracted from mobilized peripheral blood products. Targeted sequencing of all samples was performed using an Illumina TruSeq Custom Amplicon panel (Illumina, San Diego, CA, USA) designed to cover 〉 95% of mutations associated with CHIP (ASXL1, ASXL2, BCOR, BRCC3, CBL, CREBBP, DNMT3A, ETV6, GNB1, IDH1, IDH2, JAK2, KRAS, NRAS, PPM1D, RAD21, SF3B1, SRSF2, TET2, TP53). To allow detection of low-level mutations and secure variant calling, unique molecular identifiers (UMI's) were used. Filtering of variants was done by stringent criteria consistent with earlier studies. Assessment of mutations was performed blinded to the patients' clinical data. Prospective clinical patient data was obtained for all patients from four national registries, including the Danish Lymphoma Registry (diagnosis, involvement, lymphoma treatment, relapse and death), the Danish National Patient Registry (hospital admission diagnoses and treatments), the Danish Cancer Registry (primary and secondary cancer diagnoses) and the Danish Pathology Database (histopathological examinations and diagnoses), respectively. Results: Samples from 574 patients were included. The median age was 55.5 years (IQR: 45.3 - 62.2) and the median follow-up time for survivors was 9.2 years (IQR: 7.1 - 11.2). The lymphoma subtypes were typical of patients selected for autologous transplantation; diffuse large B-cell lymphoma (191 pts), follicular lymphoma (102 pts), mantle cell lymphoma (88 pts), Hodgkin's lymphoma (80 pts), peripheral T-cell lymphoma (77 pts) and other histologies (36 pts). Of the 574 patients analyzed, 191 (33.3%) of the patients had somatic mutations meeting CHIP criteria (total mutations called=210). The most commonly mutated genes were DNMT3A (n=59, 28%), TET2 (n=48, 23%), PPM1D (n=34, 16%), ASXL1 (n=21, 10%) and TP53 (n=18, 8%). As expected CHIP mutations were more frequent in patients above 60 years (p=0.002). Prevalence of CHIP was associated with an inferior overall survival (p=0.004) and event-free survival (p=0.03). It was also associated with increased risk of biopsy-confirmed tMN (p=0.03) and higher probability of receiving blood transfusions after autologous transplant (p=0.027). Especially patients with mutations in DNA damage response genes PPM1D and TP53 (found in 48 pts, 8.3%) had a significantly increased risk of adverse outcomes. Both overall survival and event-free survival were significantly poorer with the presence of DNA damage pathway mutations (p 〈 0.0001 for both, Figure 1A), as well as risk of tMN (p=0.01). In addition, PPM1D/TP53 mutations were associated with increased rates of any secondary cancer (p=0.004), including non-hematological cancer, and hospital admissions with severe infections (p=0.01, Figure 1B). The impact of low-level mutations and statistical modelling of interactions between parallel outcomes will be presented at the meeting. Conclusion: To our knowledge this is the first population-based study of clonal hematopoiesis in patients with lymphoma. We find that CHIP and particularly mutations in DNA damage response genes (PPM1D/TP53) are associated with increased mortality, which confirms findings from single center studies. These data support the evaluation of CHIP for risk assessment in lymphoma patients before high-dose chemotherapy. Our study also identifies increased rates of several clinically relevant adverse outcomes (severe infections, blood transfusions and secondary cancers) in lymphoma patients with clonal hematopoiesis. Figure 1. Figure 1. Disclosures Grønbæk: Janssen Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3105-3105
    Abstract: Introduction and aims The term ICUS is used to describe cases with persistent cytopenia (more than 6 months) without evidence of dysplasia in the bone marrow (BM) smear, and normal cytogenetics. Flow cytometry is currently a standard tool for the diagnosis of myelodysplastic syndromes (1). Our goal was to evaluate the efficacy of flow cytometry in detecting bone marrow dysplasia in the absence of abnormal morphology. Materials and methods A total of 79 patients with ICUS and 12 patients with MDS were analyzed with a standardized flow cytometry panel (2). Data were analyzed using two different algorithms; the Ogata algorithm (3) and Wells algorithm (4). For each of the algorithms, samples were classified as suggestive for dysplasia when scoring equal to or higher than 2. Furthermore, all ICUS patients were screened for mutations using targeted sequencing of 20 genes (DNMT31, TET2, EZH2, SRSF2, CBL1, SF3B1, UAF1, GATA2, IDH1, IDH2, CEBPa1, ZRSR2, TP53, KRAS, NRAS, ETV6, RUNX1, JAK2 and ASXL1) and 57/71 samples were additionally evaluated for signs of dysplasia by two independent hematopathologists. Results The diagnostic value of flow cytometry in MDS was confirmed by our data; the Wells algorithm was slightly superior to Ogata algorithm in predicting MDS (10/12 patients (83.3%) vs. 7/12 patients (58.3%) respectively, fig. 1A) and was therefore the main algorithm used for the further analysis of the ICUS patients. Flow cytometry was suggestive of dysplasia in 34/79 (43%) patients with ICUS. Interestingly, in patients with at least one detected mutation, flow cytometry was positive in 23/42 (54.8%) of the cases, while it was positive in 8/9 (88.9%) patients with more than two mutations (fig. 1C). There was no higher frequency of abnormal flow cytometry in patients with higher risk mutations. Additionally, for the 57 patients evaluated for dysplastic changes, flow cytometric abnormalities were more frequent (p= 0.05) in the 22 patients with moderate/severe dysplasia (15/22 patients or 68.2%, fig. 1D). After a median follow-up of 20 months (range: 3 - 90), a total of eight patients progressed to either MDS, CMML or AML. Interestingly, these eight patients had flow cytometric abnormalities suggestive of dysplasia before developing hematological malignancy. In conclusion, flow cytometry can identify a subgroup of ICUs patients with a higher mutational burden, dysplastic changes and a higher risk for progression to MDS or a more aggressive myeloid disease and has a place in the diagnostic evaluation of patients with idiopathic cytopenia. References: Porwit A, Van De Loosdrecht AA, Bettelheim P, Eidenschink Brodersen L, Burbury K, Cremers E, et al. Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes - Proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS. Leukemia. 2014;28(9):1793-8. van Dongen JJM, Lhermitte L, Böttcher S, Almeida J, van der Velden VHJ, Flores-Montero J, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia [Internet]. 2012 Sep [cited 2014 Nov 28] ;26(9):1908-75. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3437410 & tool=pmcentrez & rendertype=abstract Porta MGD, Picone C, Pascutto C, Malcovati L, Tamura H, Handa H, et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: Results of a European LeukemiaNET study. Haematologica. 2012;97(8):1209-17. Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood. 2003;102(1):394-403. Figure 1. Figure 1. Disclosures Hansen: Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees. Grønbæk:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Pharma: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 6 ( 2020-06), p. 1091-1098
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 5
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  HemaSphere Vol. 6, No. 9 ( 2022-08-26), p. e768-
    In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 9 ( 2022-08-26), p. e768-
    Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and has been reported to associate with accelerated epigenetic age (AgeAccel), especially intrinsic (ie, cell-type independent) AgeAccel and to a lesser degree extrinsic AgeAccel, which reflects the immune-cell composition of the peripheral blood. We investigated the association between CHIP occurrence and AgeAccel in 154 Danish twin pairs aged 73–90 years (mean 79), using both individual-level and intrapair analyses, the latter to control for shared genetic and environmental factors. Of 308 individuals, 116 carried a CHIP mutation. CHIP carriers had non-significantly increased AgeAccel compared with non-carriers; the strongest association was for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.4 years older, P = 0.052). In intrapair analyses, the extrinsic Hannum age estimator showed the strongest association (1.6 years older, P = 0.027). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.0 years older, P = 0.003) and intrapair analyses (2.8 years older, P = 0.05). DNMT3A mutations were associated with IEAA in individual-level (1.9 years older, P = 0.034) but not intrapair analysis (0.9 years, P = 0.41). Analyses of logit-transformed variant allele frequency were generally consistent with these results. Together, these observations indicate that different factors may be driving the expansion of DNMT3A and TET2 clones, respectively. Finally, CHIP carriers accelerated in both the Hannum and the GrimAge age estimators did not have an increased mortality risk in our cohort followed for 22 years (HR = 1.02, P = 0.93), hence not replicating the stratification model proposed by Nachun et al.
    Type of Medium: Online Resource
    ISSN: 2572-9241
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2922183-3
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  • 6
    In: European Journal of Haematology, Wiley, Vol. 101, No. 5 ( 2018-11), p. 595-603
    Abstract: We investigated mortality and long‐term development of malignant hematological disease, cancer, liver‐, renal‐, and rheumatic disease in patients with unexplained cytopenia ( UC ). Methods We screened all patients referred to the outpatient clinic at the Department of Hematology, Rigshospitalet, Copenhagen, with a suspected myeloid neoplasm from June 2009 to the end of 2012. Through registry linkage, we obtained information on hospital‐based ICD ‐10 diagnoses and survival. We estimated cumulative incidences of disease and hazard ratios of all‐cause mortality using the Aalen‐Johansen estimator and Cox regression. We compared incidences and mortality with a control cohort. Results Among 1820 referrals, 221 had UC . The UC group had a 5‐year cumulative incidence of malignant hematological disease of 8.91% ( CI 95%: 4.98‐12.84) compared to 0.93( CI 95%: 0.32‐1.55) in the matched controls. In addition, UC patients had higher incidences of cancer, liver, and rheumatic disease. Mortality was higher in UC patients compared to the matched controls with a HR of 1.43 [ P  = 0.038, CI 95%: 1.02‐2.00] adjusted for comorbidity, sex, and age. Most of the mortality and morbidity were ascribed to patients 50 years or older. Conclusions Unexplained cytopenia patients had a higher incidence of malignant hematological‐, cancer‐, liver‐, and rheumatic disease and increased mortality compared to the general population.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2027114-1
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  • 7
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1630-1630
    Abstract: Background: Extranodal disease is common in diffuse large B-cell lymphoma (DLBCL), and involvement of more than one extranodal site is associated with a worse outcome. 18F-fluorodeoxyglucose PET/CT (PET/CT) is the current state-of-the-art for staging of DLBCL, and has shown to be much more sensitive for the detection of extranodal involvement than a stand-alone CT scan. Therefore, a re-evaluation of the clinical significance of extranodal disease among PET/CT staged DLBCL patients is warranted. Patients and Methods: We retrospectively included patients from Aalborg (2007-2012), Copenhagen (2009-2012), and British Columbia (2011-2012) in the present study. The inclusion criteria were, i) newly diagnosed DLBCL, ii) R-CHOP or R-CHOP like first-line treatment, and iii) PET/CT staging. The written PET/CT files were reviewed for disease stage and extranodal sites of involvement. The relationship between number of involved sites, extranodal locations and outcome were assessed with simple Cox regression analyses. Extranodal locations with p 〈 0.1 in univariate analysis were entered in a multivariable Cox regression analysis together with the following International Prognostic Index (IPI) factors: age 〉 60 years, elevated LDH, ECOG performance score 〉 1. Results: A total of 444 patients with a median age of 65 years (range 16-90) and a male:female ratio of 1.3 were included in the study. Of these patients 28% (n=98) had Ann Arbor stage I disease, 16% (n=72) stage II disease, 16% (n=71) stage III disease, and 46% stage IV disease (n= 203). LDH was elevated in 51% (n=224), and 17% (n=74) had ECOG performance status 〉 1. B-symptoms were present in 37% (n=164) and 26% (n=114) had a bulky mass =/ 〉 10 cm. With a median follow-up of 2.4 years (range 0.5-6.5) in patients still alive at the time of analysis, the 3-year OS and PFS were 73% and 69%, respectively. Extranodal disease was diagnosed in 286 (64%) of the patients. The anatomic locations of extranodal disease and their relations to outcome are shown in Table I. Figure 1A and B show the PFS and OS curves when patients are grouped according to the number of involved extranodal sites. Patients with one or two extranodal sites of involvement had similar outcome (3-year PFS 68% vs. 70%), whereas all patients with involvement of more than three extranodal sites progressed. Conclusions: Extranodal involvement is diagnosed in more than half of all newly diagnosed DLBCL patients staged with PET/CT. Bone/bone marrow involvement was the most common site and associated with a worse outcome. Thus, detection of these lesions with PET/CT is clinically important. The presence of extranodal disease is generally associated with a worse outcome, but our data suggest that the optimal cut-off for prognostication in PET/CT staged patients may be more than two sites rather than more than one site, as according to the IPI. Abstract 1630 Table1: Extranodal DLBCL and their relationship with outcome in PET/CT staged patients treated with R-CHOP. Empty boxes represent variables not included in multivariate models. Site Frequency, n (%) HR, univariate HR, multivariate PFS OS PFS OS Lung 33 (7%) 1.56, p=0.002 1.46, p=0.26 Not significant Liver 34 (8%) 2.39, p=0.001 2.43, p=0.002 Not significant Not significant Bone/bone marrow (PET/CT) 127 (29%) 2.49, p 〈 0.001 2.53, p 〈 0.001 1.77, p=0.007 1.66, p=0.03 Bone marrow indolent NHL (biopsy) 28 (6%) 0.86, p=0.70 0.94, p=0.87 Bone marrow DLBCL (biopsy) 43 (10%) 2.55, p 〈 0.001 2.66, p 〈 0.001 Not significant Not significant Gastrointestinal 35 (8%) 1.27, p=0.43 1.02, p=0.96 Kidney 13 (3%) 2.10, p=0.06 1.63, p=0.29 Not significant Soft tissue and muscle 46 (10%) 1.18, p=0.58 1.17, p=0.64 Paranasal sinus 15 (3%) 1.57, p=0.28 1.69, p=0.25 Pleural fluid 16 (4%) 2.82, p=0.005 3.23, p=0.003 2.43, p=0.02 2.53, p=0.02 Testicular 13/252 (5%) 2.42, p=0.22 1.81, p=0.41 Female genitals 10/192 (5%) 3.38, p=0.006 3.76, p=0.003 Figure 1A and B: PFS (Figure 1A) and OS (Figure 1B) in patients grouped according to the number of extranodal sites involved: zero (blue), 1 (green), 2 (grey), 3 (purple), 〉 4 (red). Figure 1A and B:. PFS (Figure 1A) and OS (Figure 1B) in patients grouped according to the number of extranodal sites involved: zero (blue), 1 (green), 2 (grey), 3 (purple), 〉 4 (red). Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3079-3079
    Abstract: Introduction Hematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylsytosine (5hmC); the first step in active DNA demethylation. In tissue culture, we have shown that restoration of vitamin C to normal concentrations can potentiate the effect of DNA methyltransferase inhibitors (DNMTis) by activation of DNA demethylation and induction of genes in the viral defense pathway, so called 'viral mimicry' (Liu et al. PNAS 2016). Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the efficacy of active DNA demethylation and induce upregulation of genes in the viral defense pathway in patients with myeloid cancers treated with the DNMTi 5-azacytidine. Study Design and Methods A randomized, placebo-controlled clinical trial of myelodysplastic syndrome (MDS; n=9), chronic myelomonocytic leukemia (CMML; n=4) and acute myeloid leukemia (AML; n=7) patients was performed during 3 cycles/12 weeks of DNMTi treatment (5-azacytidine, 100mg/m2 day 1 to 5 in a 4-week cycle) supplemented by oral dose of 500mg vitamin C (n=10) or placebo (n=10) daily during the last 8 weeks (Figure 1). Blood samples were drawn on day 1 and 5 of each treatment cycle before 5-azacytidine was administered and on day 28 of the third treatment cycle. Total plasma vitamin C was measured by HPLC in samples that had been acidified by 10% meta-phosphoric acid immediately after blood drawn. Mutational status of the 20 most commonly mutated genes in MDS were conducted by targeted next-generation sequencing. Global levels of 5mC and 5hmC were measured with LC-MS/MS in DNA extracted from MACS-sorted malignant cells and quoted relative to total levels of deoxyguanine. Total RNA-seq was performed on 20 RNA samples from 6 patients; cDNA libraries were prepared using KAPA RNA HyperPrep Kits and sequencing on a NextSeq 500 instrument (Illumina). Results Fourteen patients were deficient in plasma vitamin C ( 〈 23 µM) and 4 of the remaining 6 patients took vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency ( 〈 11.4 µM; P=0.004) and borderline significantly higher in DNMTi naïve (n=11) compared to non-naïve patients (P=0.095). At baseline, global 5hmC/5mC levels were lower in the 7 patients with TET2 mutations (n=7; P= 0.013). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P 〈 0.0005). We show for the first time that active DNA demethylation, estimated as the change in global 5hmC/5mC levels, was significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Preliminary RNA sequencing data show increased upregulation of genes involved in the viral defense pathway, including IRF7 and IFIT1, in vitamin C supplemented patients that were DNMTi naïve at study inclusion. Conclusions The increase in active DNA demethylation, indicated by the elevation of 5hmC/5mC levels in myeloid cells from vitamin C supplemented patients compared to placebos, plus the increased expression of viral defense genes in vitamin C treated DNMTi naïve patients, suggest that the efficacy of 5-azacytidine might be increased by oral supplementation of vitamin C. We suggest that normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical relevance of vitamin C supplementation to DNMTis in a large randomized placebo controlled trial. Figure 1. Study design. Days 1, 5, and 28: before vitamin C/placebo exposure. Day 32: after short-term vitamin C/placebo exposure. Days 56, 60, and 84: after longer-term vitamin C/placebo exposure. C = cycle, D = day in cycle. Figure 1. Figure 1. Disclosures Jones: ZYMO Corporation: Consultancy. Grønbæk:Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharma: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Oncotarget, Impact Journals, LLC, Vol. 5, No. 20 ( 2014-10-30), p. 9798-9810
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2560162-3
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  • 10
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 11 ( 2022-06-14), p. 3541-3550
    Abstract: Bone marrow specimens are the core of the diagnostic workup of patients with cytopenia. To explore whether next-generation sequencing (NGS) could be used to rule out malignancy without bone marrow specimens, we incorporated NGS in a model to predict presence of disease in the bone marrow of patients with unexplained cytopenia. We analyzed the occurrence of mutations in 508 patients with cytopenia, referred for primary workup of a suspected hematologic malignancy from 2015 to 2020. We divided patients into a discovery (n = 340) and validation (n = 168) cohort. Targeted sequencing, bone marrow biopsy, and complete blood count were performed in all patients. Mutations were identified in 267 (53%) and abnormal bone marrow morphology in 188 (37%) patients. Patients with isolated neutropenia had the lowest frequency of both mutations (21%) and abnormal bone marrow morphology (5%). The median number of mutations per patient was 2 in patients with abnormal bone marrow morphology compared with 0 in patients with a nondiagnostic bone marrow morphology (P & lt; .001). In a multivariable logistic regression, mutations in TET2, SF3B1, U2AF1, TP53, and RUNX1 were significantly associated with abnormal bone marrow morphology. In the validation cohort, a model combining mutational status and clinical data identified 34 patients (20%) without abnormal bone marrow morphology with a sensitivity of 100% (95% confidence interval: 93%-100%). Overall, we show that NGS combined with clinical data can predict the presence of abnormal bone marrow morphology in patients with unexplained cytopenia and thus can be used to assess the need of a bone marrow biopsy.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 2876449-3
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