bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1428 GCSF ALONE STEM CELL MOBILIZATION IN MULTIPLE MYELOMA PATIENTS CANDIDATES TO HIGH DOSE CHEMOTHERAPY: A MONOCENTRIC RETROSPECTIVE EXPERIENCE
Authors: Bramanti S. , Magri F. , Giordano L. , Sarina B. , Morabito L. , Mariotti J. , De Philippis C. , Girardi D. , Timofeeva I. , Capizzuto R. , Mazza R. , Carlo‐Stella C. , Santoro A. , Castagna L. 
Published: June 2019

Background:Despite the introduction of several effective multidrug combination in the treatment landscape of multiple myeloma (MM), high dose chemotherapy (HDC) is still an important phase in the treatment of MM. On the other hand, chemotherapy used to mobilize stem cell (SC) do not contribute in disease control or long term survivalAims:To analyze the efficacy of granulocyte colony stimulating factor (GCSF) alone to mobilize SC, in a consecutive series of multiple myeloma patients candidate to HDC.Methods:From January 2016 to January 2019, 61 consecutive MM patients underwent GCSF alone stem cell mobilization in our institution. Every patients received GCSF at the dose of 10 mcg/kg/day for 5 days. Peripheral blood circulating CD34+/mcl were checked from day +4. Plerixafor was administered on demand when CD34+ cells were less than 20/mcl at day +4 or +5, or when CD34 harvested was less than 2  × 10^6/kg after the first or second apheresis. The stem cell harvest were performed processing 2.5 − 3 times total blood volume. After collection, the patients received single or double course of melphalan 200 mg/m2 or 1 course of melphalan 140 mg/m2 according to local guideline. The minimal CD34+ number to perform a single HDC was 2x106/kg.Results:Patient characteristics are listed in Table 1. All patients but 2 (3%) achieved the target to perform the planned HCD. Median total CD34+ × 106/kg harvested was 8.6. The proportion of patients able to achieve the goal with one apheresis was 50%. Only 1 patient underwent a third apheresis. Nine patients (14%) received plerixafor, 7 on day +4 and 2 on day +5. Median blood CD34+/mcl on day+4 and +5 was 33.5 (15–98), and 63 (10–171), respectively. Median total blood leucocyte counts (10^3/mm^3) on day 4+ and on day +5 was 41310 and 49250, respectively. Median CD34+ × 106/kg in the first and second apheresis was 6.4 (0,8–16) and 4.7 (1.5–8), respectively. Median total leucocyte count (106) in the graft on first and second apheresis was respectively 71280 and 49250. After HDC, all patients but one experienced engraftment.Summary/Conclusion:GCSF alone stem cell mobilization is an effective and safe approach after induction in MM patients candidate to HDC. The main advantages are the possibility to predict peak CD34+ level (4–5 days), to schedule apheresis in an outpatient program and to avoid unnecessary toxicity with chemotherapy.image
PS1429 LIVING ALONE WITH MULTIPLE MYELOMA: THE NEXT‐GENERATION CHALLENGE
Authors: Ríos‐Tamayo R. , Rodríguez D. Sánchez , Collado P. Garrido , Chan Y.L. Chang , Perez J. Sainz , Sierra P.A. González , Aguilar A. Romero , Ruiz A. García , Salas G. , Ballester J. Muñoz , Pérez M.J. Sánchez 
Published: June 2019

Background:According with the Spanish National Institute of Statistics (2017), 25.4% of Spanish households are formed by a single person and this trend is increasing in recent years. The outcome of patients with newly diagnosed multiple myeloma (NDMM) who live alone is not well known.Aims:To assess the impact in terms of overall survival (OS) and early mortality (EM) of NDMM patients who live alone, either voluntarily or not.Methods:All consecutive patients with the variable of interest available on clinical records and included in the population‐based Granada Myeloma Registry (Ríos‐Tamayo et al, 2015) until the end of 2018 are reported. Comparisons for categorical variables among different groups were made with the x2‐test. Comparisons of means of quantitative continuous variables between two groups were made with the t‐test. OS curves were estimated using the Kaplan‐Meier method, and comparisons among groups were carried out with the log‐rank test.Results:200 patients were evaluated, 117 men (58.5%) and 83 women. 35 patients (17.5%) lived alone at diagnosis, 19 men and 16 women. There was a trend to better OS for patients with some caregiver available with respect to patients who live alone (p = 0.074) (Figure 1). Median age for patients living alone was 68.74 vs 62.1 years (p = 0.006). Weight loss was documented in 18/35 (51.4%) vs 53/163 (32.5%) (p = 0.077). No statistical differences were shown between groups for other variables (body mass index, number of comorbidities, sex, ECOG, ISS, Light‐chain only MM and High‐Risk FISH). There were not statistically significant differences in EM at 6 months (6.8% vs 11.8%; p = 0.3).Summary/Conclusion:Patients with NDMM who live alone represent approximately 17.5% and have to face a huge challenge, showing a trend to poorer OS in comparison with patients who have a caregiver. This poor outcome may be due in part to a more advanced age. However, we cannot rule out other factors such as a poor adherence to the treatment.image
PS1454 CAG PROMOTER DRIVEN C‐MYC OVEREXPRESSION CAUSES RAPIDLY LETHAL CARDIOMYOPATHY
Authors: Kovacs S. Bojtine , Basu T. , Pahl H.L. 
Published: June 2019

Background:We have previously reported that mice expressing elevated levels of NFE2 display a myeloproliferative phenotype which spontaneously transforms to acute leukemia. Upon leukemic transformation, a high percentage of mice acquire duplications or amplification of the murine c‐myc locus. The CMV early enhancer/chicken‐beta‐actin (CAG) promoter has been reported to direct high level heterologous gene expression specifically to hematopoietic stem cells and myeloid progenitors.Aims:We hypothesized that elevated expression of both NFE2 and c‐myc synergize to induce leukemic transformation. Therefore, we compared the hematological phenotype of mice carrying either augmented NFE2 or c‐myc levels alone to mice overexpressing both genes.Methods:We crossed mice expressing a CAG‐driven tetracycline activator (CAG‐rtTA3) with the tet‐O‐myc mouse strain, in order to achieve high levels of doxycycline‐inducible c‐myc expression in the hematopoietic compartment. Double transgenic CAG‐myc mice were subsequently bred to heterozygous knock‐in mice expressing the NFE2‐D297–300 mutation of the endogenous promoter, generating both CAG‐myc‐NFE2‐wt and CAG‐myc‐NFE2mut mice. C‐myc expression was induced by doxycycline treatment administered through various routes, including drinking water, oral gavage and food pellets.Results:Unexpectedly both CAG‐myc and CAG‐myc‐NFE2 mice died rapidly, between 6 and 7 days following c‐myc induction, independent of the route of doxycycline administration. Autopsy and histological analysis revealed marked cardiomyocyte hypertrophy, with heart volume more than double the wt control (Fig. 1). In addition to hematopoietic stem and progenitor cells, the CAG promoter has been reported to direct expression to cardiomyocytes. C‐myc overexpression in adult cardiomyocytes by tet‐mediated c‐myc induction has previously been shown to cause cell cycle re‐entry that leads to cardiomyopathy and hypertrophy. However, it was not expected that the CAG promoter, seen as a “highly effective tool for probing hematopoietic development and disease”, would have a similarly cardiotoxic effect.Fig. 1: Pathology and histology of hearts following doxycycline induction of CAG‐myc expression. (A) representative autopsy finding from a wt control mouse (left) and a CAG‐myc‐NFE2‐wt mouse. Results are representative of n = 16 CAG‐myc mice. (B) Hematoxylin Eosin (H&E) staining of histological sections from CAG‐myc‐NFE2 wt and CAG‐myc‐NFE2mut mice before and after doxycycline induction. 200x magnification, size bars represent 50 mm.Summary/Conclusion:While our murine model did not allow us to investigate our hypothesized synergistic effect between c‐myc and NFE2 in leukemic transformation, the CAG‐myc mouse strain generated constitutes an excellent model for studying rapidly lethal cardiomyopathy. Moreover, our data serve to alert researchers in the hematopoietic field to possible side effects of using the CAG promoter to drive gene expression in hematopoietic stem and progenitor cells.image
PS1476 APPLICATION OF WHOLE EXOME SEQUENCING FOR PATIENTS WITH INHERITED PLATELET DISORDERS
Authors: Stevens‐Kroef M. , de Munnik S. , van Heerde W. , Brons P. , Saes J. , Schols S. , Simons A. 
Published: June 2019

Background:Inherited platelet disorders (IPDs) are disorders consisting of thrombocytopenia, thromobocytopathy or a combination of these. Diagnosis is often hampered by the lack of specificity and correct validation of current hematological assays. In addition, these disorders exhibit a genetic heterogeneity with over 50 genes involved.Aims:This study evaluates an upfront diagnostic strategy using whole‐exome sequencing (WES) with a targeted analysis of a panel of 145 genes involved in thrombosis and hemostasis in patients suspected for an IPD.Methods:Sixty‐Six patients suspicious for an IPD were subjected to WES, followed by targeted analysis of 145 genes (besides platelet genes also genes involved in coagulation and venous thrombosis embolism are analyzed). Variants were classified according to the five‐tier (class 1 to class 5) scheme.Results:Fourteen patients (21%) harbored (likely) pathogenic variants that explained the clinical spectrum in these patients. Genes affected in these patients were GP9, MYH9 (2 cases), NBEAL2, P2RY12, RUNX1 (3 cases), SLFN14 and VWF (2 cases), all these genes are involved in thrombocytopenia or thromobocytopathy. In the disorders with an autosomal recessive mode of inheritance either the mutation was homozygous (GP9 and P2RY12), or compound heterozygous (NBEAL2). Additionally, 2 patients with a mutation in the THPO gene and 1 patient with a mutation in SEPRINC1 were observed, both genes are known to be involved in venous thrombosis.In 4 (6%) other patients only one heterozygous (likely) pathogenic variant of an autosomal recessive disease gene was observed. In 12 patients (18%) a variant of unknown significance (VUS/class 3) was observed. Further segregation studies within the family and functional studies are required to fully solve these cases.Summary/Conclusion:We found that WES is a powerful tool in genetically diagnosing patients with IPD.
PS1566 HEMATOPOIETIC STEM CELL GRAFTS AS A SOURCE FOR RECONSTITUTING INNATE LYMPHOID CELLS FOLLOWING STEM CELL TRANSPLANTATION
Authors: Van Hoeven V. , Kroeze A. , Haverkate N. , Omar S. , Jachimowski L. , van Lier Y. , Franken S. , Zeerleder S. , Blom B. , Voermans C. , Hazenberg M. 
Published: June 2019

Background:Graft‐versus‐host disease (GvHD) is a common and life threatening complication of allogeneic stem cell transplantations (ASCT), and is thought to be initiated by chemotherapy‐induced tissue damage. Innate lymphoid cells are involved in tissue remodeling and repair and may therefore have a protective role in the development of GvHD. Indeed, in a previous study we observed that relatively high frequencies of activated ILC3 s before and/or after ASCT were associated with a lower risk to develop GvHD. While rapid reconstitution of ILCs thus seems favorable, ILCs in fact recover slowly and do not reach normal levels within 6 months post‐ASCT.Aims:By investigating the composition of stem cell grafts and the ILC‐development potential of graft‐derived multipotent hematopoietic progenitor cells (HPCs), we here aim to gain more insight into how ILCs reconstitute from stem cell grafts.Methods:Peripheral blood‐mobilized stem cell grafts of healthy adult donors were thawed and ILCs were phenotyped by flow cytometry. Lineage− CD34+ CD45RA+ HPCs were FACS‐sorted and cultured for a maximum of 4 weeks on JAG1‐expressing OP9 stromal cells in the presence of IL‐2, IL‐7, stem cell factor and Flt3‐ligand. This method was previously shown to support ILC development.Results:We detected mature ILC1 s, ILC2 s and ILC3 s in all grafts, and the median frequency of total CD127+ ILCs was 0.26% of the lymphocytes. The distribution of the ILC subsets differed substantially between stem cell grafts. HPCs isolated from human fetal liver successfully developed into ILCs within 4 weeks culture, however, HPCs derived from adult stem cell grafts did not have the capacity to develop into ILCs. We are currently investigating whether the age and the source of the isolated HPCs matters by testing the ILC developmental potential of cord‐blood and bone‐marrow derived HPCs. At the same time we are extending our graft and post‐ASCT analyses to be able to correlate our in vitro findings to in vivo ILC reconstitution.Summary/Conclusion:While mature ILCs present in stem cell grafts may be a good source for reconstituting ILCs, the ILC‐developmental potency of (adult) graft‐derived HPCs seems to be poor, possibly reflecting a decline in the potency of stem cells to develop into ILCs with increasing age. These results offer an explanation for the slow reconstitution of ILCs after ASCT.image
S1644 ASSOCIATION OF SYSTEMIC CYTOKINE LEVELS WITH RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH GLIOMA
Authors: Mir Seyed Nazari P. , Moik F. , Marosi C. , Riedl J. , Berghoff A.‐S. , Preusser M. , Hainfellner J.A. , Pabinger I. , Zlabinger G. , Ay C. 
Published: June 2019

Background:Venous thromboembolism occurs frequently in patients with primary brain tumors.Aims:Given the strong interplay between inflammation and haemostasis, the aim of the current study was to investigate the association of serum cytokine levels and risk of VTE development in patients with glioma.Methods:Within the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective and observational cohort study of patients with active cancer, we conducted an exploratory analysis. Patients were recruited at the time of cancer diagnosis or progression of disease after remission and followed for two years. Primary endpoint was symptomatic and objectively confirmed VTE. At study entry, a single blood draw was performed. Several cytokines (e.g. Interleukin (IL)‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL11, CCL3, TNF‐a, VEGF‐a) were measured in serum samples with the xMAP technology developed by Luminex.Results:In this study, 128 glioma patients were analyzed. Of those, 98/128 (76.6%) were diagnosed with glioblastoma (WHO grade IV), 24/128 (18.8%) with anaplastic glioma (WHO grade III) and 6/128 (4.7%) with diffuse glioma (WHO grade II). In total, 22/128 (17.2%) glioma had an IDH1 mutation. During follow‐up, 14/128 (10.9%) patients developed VTE. In univariable Cox‐regression analysis, CCL3 levels were significantly associated with risk of developing VTE (hazard ratio [HR] per 10 units increase: 0.629 [95% CI: 0.407–0.0.972], p = 0.037), while there was no significant association between the risk of VTE and serum levels of IL‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL‐11, TNF‐aand VEGF‐a, respectively. In multivariable analysis, adjusting for potential confounders (sex, age, glioblastoma), the association of CCL3 with the risk of VTE remained statistically significant (adjusted HR: 0.628 [0.397–0.992], p = 0.046). Cumulative incidence of VTE in reverse Kaplan‐Meier estimates was 22.8% in patients with low CCL3 serum levels (≤ 25thpercentile = 1.95 pg/ml) and 9.1% in patients with higher CCL3 serum levels (> 25thpercentile) (log‐rank, p = 0.017). (Figure 1)Summary/Conclusion:One out of 10 patients with glioma developed VTE in our study and low serum levels of CCL3 were associated with an increased risk of VTE. In conclusion, CCL3 might be useful as a potential biomarker for prediction of risk of VTE in patients with glioma.image
PB1659 WHOLE EXOME SEQUENCING IN ADULT PATIENT WITH PHILADELPHIA / BCR‐ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Lee P. Chin , Zubaidah Z. , Ranjeev H. , Fei K. Tsung , Ching N. Ching 
Published: June 2019

Background:BCR‐ABL1 gene fusion is detected at approximately 20% of adult acute lymphoblastic leukemia (ALL). Patients with Philadephia (Ph) / BCR‐ABL1 positive are a high risk group that associated with poor prognosis and short duration remission. Patients showed markedly improved with introduction of tyrosine kinase inhibitor combined with chemotherapy regimen but a small fraction of these patients remain refractory and poor response to treatment.Aims:The aim of this study was to determine the somatic mutations profile using whole exome sequencing of patient with Ph‐positive ALL.Methods:DNA from matched tumour‐normal samples for four patients with Ph‐positive ALL was extracted from peripheral blood or bone marrow leukemia cells by QIAamp DNA Mini kit. The exome library was enriched using the Nextera Rapid Capture Expended Enrichement kit (Illumina, San Diego, CA) according to the manufacturer's protocol and were subsequently sequenced on Illumina HiSeq 2500 system. Somatic mutations were separated from germline variants using Genome Analaysis Toolkits (GATK) best practices filtering strategy.Results:We identified a total of 14,804 intragenic somatic mutations (range from 2,948 to 4,165 in each). Of these 760 variants were passed through the variant caller. Among them 462 were single nucleotide variants (SNVs) and 298 were insertion/deletions (InDels). Total of 48 common variants were observed but failed Mutect caller. Among SNVs, 110 variants were nonsynonymous, 46 synonymous, 6 stopgain, 3 unknown and majority 297 (64.3%) null variants. A total of 53 nonsynonymous SNVs and 14 InDeLs (8 were frameshift deletion, 5 frameshift insertion and one stopgain) were identified as possible pathogeneic variants. The identified mutation genes in this study mostly also found in other malignancies disease and two alteration genes MCM7 and STAT5 were found in disease progression of CML.Summary/Conclusion:We have sequenced the whole coding sequence of four Ph / BCR‐ABL1 positive ALLs and corresponding normal samples that allows us to overview of candidate gene in the coding regions that driving Ph‐positive ALL development and as well as enhanced our understanding of the candidate genes in diagnosis testing and prognostic prediction of adult ALLs patient.
PB1669 RISK FACTORS FOR THROMBOEMBOLISM IN ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Boban A. , Mikulić M. , Serventi‐Seiwerth R. , Ostojić A. , Vrhovac R. , Duraković N. , Perić Z. , Bašić‐Kinda S. , Sertić D. , Rončević P. , Dujmović D. , Radman I. , Pulanić D. , Batinić J. , Zupančić‐Šalek S. , Aurer I. 
Published: June 2019

Background:Thromboembolism frequently complicates treatment of acute lymphoblastic leukemia (ALL).Aims:A single‐center retrospective study was conducted with the objective of assessing the risk factors for thromboembolism in adult patients with ALL.Methods:The study included 87 consecutive patients (aged 19–70 years; 57 males) treated for ALL; B‐cell (n = 40), T‐cell (n = 26), Ph+ (n = 13), byphenotypic (n = 3) and unclassified (n = 5) during the 10‐year period. All patients but one received intensive treatment, including L‐asparginase in 57 (65%) patients, while 23 (26%) underwent allogenic stem cell transplantation. Vast majority of patients (n = 80, 92%) had central venous catheters at least once during the treatment period, including peripherally inserted central catheter (PICC) placed in 18 (21%) patients.Results:Fourteen patients (16%) developed thrombosis during the study period. Deep venous thrombosis was described in 9(65%), pulmonary embolism in 2(14%), and cerebral sinus thrombosis in 3(21%) patients. One death was attributable to thromboembolism. The risk of thromboembolism was associated with the induction treatment, protocols including L‐asparginase, the use of central venous catheters, namely PICC, and non‐0 blood groups.Summary/Conclusion:Our results demonstrate high incidence of thromboembolic events in patients with ALL. The highest risk is attributed with the use of L‐asparginase, despite vigorous control of coagulation parameters and antithrombin substitution. Finally, our results strongly suggest against simultaneous use of L‐asparginase and PICC.
PB1709 TET 2 POLYMORPHISM AND MIRNA 22 EXPRESSION AMONG EGYPTIAN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: Dammag E. , Hamed N. , El Halawany N. , Kassem H. , Ayad M. 
Published: June 2019

Background:Acute myelogenous leukemia (AML) is a heterogeneous group of disease characterized by uncontrolled proliferation of myeloid progenitor cells. It is clear that TET2 polymorphisms are common among Egyptian AML patients and larger scale studies are needed to iinvestigate the role of this in both modulating treatment and prognostic impact of the disease. TET2 mutations are established poor prognostic molecular risk factors yet TET2 polymorphism status are not thoroughly studied. Role of miRNA22 and its impact on TET2 expression needs to be further studied to improve risk stratification of AML.Aims:The aim of this study is to evaluate the incidence of the TET2 single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) and its correlation to miRNA22 gene expression in Egyptian Adult Acute Myeloid Leukemia patients.Methods:Cases were selected from Alexandria Main University Hospital Internal Medicine Department (Hematology Unit) from March 2017‐December 2017; 52 patients diagnosed as AML and 30 healthy subjects matched for age and sex to determine SNPs genotype frequency among patients. DNA extraction by Invitrogen purelink genomic DNA minikit (Cat No. k1820‐01, Lot No 1510617) and real time PCR for TET2 SNP polymorphism using Taqman primers and probes of TET2 polymorphism (rs2454206, rs34402524, rs61744960) using an ABI Prism GeneAmp 7500 using peripheral or bone marrow blood. Micro RNA 22 Taqman quantitative Assay using real time PCR (Thermal Fisher Biosystems Taqman miRNA22 Cat. no. 4427975) and control miRNA was U6. Micro RNA extraction was done using Qiagen extraction kits (Cat No./ID: 217004). Written Informed consent was taken from every patient and approval of the Ethical committee (IRB No. 00008699, FWA No.00015712) was provided.Results:35 AML patients (14 females, 21 males) had mean age of 43.42 ± 14.0yrs are the subject of the study. SNP RS 34402524 ranged from heterozygous (23/52 46%) to homozygous (27/52 54%) in AML group but was mainly homozygous (24/30 80%) among the control group (p>0.05). As for RS 6843141, most AML patients had wild pattern (31/52 62%) and control group were homozygous (20/30 60%) (p < 0.0001). RS 2454206, and RS 61744960 showed no statistical significance between cases and controls (p > 0.05). miRNA22 were under‐expressed among AML most patients. This was of statistical significance compared to controls p < 0.0001. As for miRNA 22 and TET2 polymorphism, there was no statistical significance between the status of SNPs and miRNA22 expression p > 0.05.Summary/Conclusion:miRNA22 is markedly underexpressed in AML patients and may participate in hypermethylation and leukomogenesis. Confirmation of this finding could open a new therapeutic approach in AML and even in bone marrow transplant candidates.image