bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease
Authors: Li Yuan , Wang Qing Ya , Liang Ze Yin , Yin Yue , Liu Wei , Wang Qian , Dong Yujun , Sun YuHua , Xu Wei Lin , Ren Hanyun 
Published: November 2019

Objective: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate- and high-risk patients with MDS or AML.
Methods:Retrospective analysis of data pertaining to 76 intermediate and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabine containing conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine.
Results: Overa median follow up of 40 months(range, 1 to 155), the incidence of grade II to IV acute graft versus host disease was 12.5% in the Decitabine group and 41.7% in the non-Decitabine group (P=0.003). On multivariate analysis, Decitabine containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.275, 95% confidence interval 0.098-0.770,P=0.014). Incidence of respiratory infection in the Decitabine and non Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.837, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2 to 12) versus 3 months (range, 2 to 4), P=0.171]. Decitabine containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the between-group difference was not statistically significant (P=0.085).
Conclusions: Inclusionof Decitabine in the conditioning regimen for allo-HSCT in intermediate- and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time.

Disclosures
No relevant conflicts of interest to declare.
The Study of Thrombosis in JAK2V617F Mutated Myeloproliferative Neoplasms
Authors: Bai Jie , Zhang Yuhui , Wang Yingshao , Teng Guangshuai , Wang Yan , Du Chenxiao , Chen Yafang , Zhang Huiqin , Li Yanqi , Fu Lixia , Zhang Lei , Zhou Yuan 
Published: November 2019

Introduction: Thrombosis is the most important risk factor affecting event-free survival and overall survival (OS) of patients with myeloproliferative neoplasms (MPNs). To explore the risk factors of thrombosis in patients with JAK2V617F-mutated MPN, a cohort of 1537 Chinese patients with JAK2V617F-mutated MPN was retrospectively analyzed for clinical characteristics, laboratory characteristics, cytogenetics, thromboembolism, disease progression and OS.
Methods: The qualitative data were compared by the Chi-square test or Fisher's test, and continuous variables were compared with the Mann-Whitney U test or Kruskal-Wallis test. The Kaplan-Meier method and multivariate Cox analysis were used to study the risk factors of thrombosis in patients with JAK2V617F-mutated MPN.
Results: Among the 1537 MPN patients, 931, 468 and 138 had polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), respectively. The median follow-up time was 7 years (range 1-47), and 12.8% of patients (197/1537) died during this period. A total of 16.8% (259/1399) of PV and ET patients had secondary myelofibrosis, and 2.5% (38/1537) of patients developed acute myeloid leukemia (AML). Thrombosis events occurred in 43.9% (675/1537) of patients, among which 91.4%(617/675) were arterial thrombosis and 16.6% (112/675) were venous thrombosis. The number of thrombosis events in PV, ET and PMF patients was 439 (47.2%), 197 (42.1%) and 39 (28.2%), respectively. The multivariate analysis indicated that age≥60 years old (P=0.003, HR=1.76, 95% CI[1.214, 2.552]), HCT≥48% (P=0.022, HR=1.635, 95% CI[1.073, 2.492]), at least one cardiovascular risk factor (P=0.024, HR=1.559, 95% CI[1.061,2.291]), a history of thrombosis (P<0.0001, HR=2.313, 95% CI[1.573,3.401]), and JAK2V617Fallele burden (V617F%) ≥50% (P=0.003, HR=1.804, 95% CI [1.221, 2.665]) are risk factors for thrombosis in JAK2V617F-mutated MPN. According to the results of the multivariate analysis, a risk model of thrombosis was established and comprised low-risk (0 points), intermediate-risk (1 points) and high-risk (≥2 points) groups, among which the incidence of thrombosis was 9.1%, 33.7% and 72.9%, respectively.
Conclusions: The Chinese thrombosis risk model of JAK2V617F-mutated MPN established in this study suggests that elderly patients with a history of thrombosis should reduce V617F%, control HCT to less than 48% and mitigate cardiovascular risk factors, all of which are necessary measures to prevent thrombosis in patients with JAK2V617F-mutated MPN.

Disclosures
No relevant conflicts of interest to declare.
Examining the Role of CD30 in an Anaplastic Large Cell Lymphoma Mouse Model
Authors: Poggio Teresa , Graessel Linda , Kreutmair Stefanie , Miething Cornelius , Pfeifer Dietmar , Andrieux Geoffroy , Boerries Melanie , Follo Marie , Turner Suzanne , Zeiser Robert , Duyster Justus , Illert Anna Lena 
Published: November 2019

Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of T-cell non-Hodgkin lymphoma (NHL) mainly affecting children and young adults. About 70% of systemic ALCLs are associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in the NPM-ALK fusion gene, its over-expression and constitutive kinase activity. Immunophenotypic characterization of human ALCL revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on disease development remains unclear and the relationship between NPM-ALK and CD30 has been investigated mostly using cell line models. Syngeneic mouse models of cancer can serve as useful models since the tumors develop in situ where the contribution made by the immune system and the extracellular matrix can be investigated.
Here, we focus on the involvement of CD30 in a retroviral murine bone marrow transplantation model of ALCL. In this model, the BM of Lck-Cre-transgenic mice is infected with a MSCV-Stop-NPM-ALK-IRES-EGFP vector leading to expression of NPM-ALK in early T-cells. With a latency of 3-4 months, mice develop lymphomas and die from neoplastic T-cell-infiltration of BM and lymphatic organs. To investigate the impact of abrogation of CD30 signals on the development of NPM-ALK+ ALCL in our model, CD30 knockout mice were crossed with Lck-Cre mice. Both Lck-Cre NPM-ALK CD30 wt and Lck-Cre NPM-ALK CD30 ko recipients develop a human ALCL-like lymphoma with a pure T-cell phenotype characterized by Thy1.2+ cells infiltrating the thymus, lymph nodes, spleen and BM. First results from Lck-Cre NPM-ALK CD30 ko transplanted mice showed impaired disease induction and prolonged survival compared to CD30 wt animals. Moreover, secondary transplantation of NPM-ALK thymic lymphomas led to distinct deceleration of disease development upon CD30 deletion. Microarray analyses have shed some light on the mechanisms underlying the delayed lymphoma progression of CD30 deleted tumors with an upregulation of inflammatory pathways and proteins that are master players in inflammation and immune responses. Further characterization of the role of CD30-mediated immune response in disease progression using this mouse model and immunocompromised mice is ongoing. An improved understanding of how the immune system affects tumor progression will extend the rationale in translational strategies to use immunotherapies for patients with T-NHLs.

Disclosures
No relevant conflicts of interest to declare.
Use of Fluid and Oxygen Therapy in Normoaxaemic Paediatric Patients Presenting with Acute Sickle Vaso-Occlusive Episodes Requiring Hospital Admission and Analysis of Clinical Outcome
Authors: Butt Zain , Chakravorty Subarna 
Published: November 2019

Introduction: There is limited consensus on the optimal regime and benefit of fluid and oxygen therapy when treating vaso-occlusive episodes (VOEs) in children with sickle cell disease (SCD). The purpose of this study was to investigate the current prevalence of intravenous fluid and oxygen therapy when treating VOEs in children with SCD in a large tertiary hospital in London, UK and analyse the clinical outcome of these patients, in order to design a future study to determine optimum use of fluid and oxygen therapy in children presenting with VOE.
Methods: We studied a random selection of 100 vaso-occlusive events in paediatric sickle cell patients resulting in hospital admission between 2008-2019. All patients received assessment and initial treatment according to established hospital guidelines at the emergency department (ED) and were subsequently admitted to an inpatient ward. Baseline clinical and laboratory information, alongside data on the admission, duration, treatment and clinical outcome of each VOE were recorded. Data were compared between therapy and non-therapy groups.
Results: Out of 100 VOE events, 46 were given fluid therapy and 24 were given oxygen therapy. All cases of VOE on fluid therapy were treated with IV dextrose saline (0.5% dextrose and 0.45% NaCl), and the average rate of fluid given was 71.4 ml/kg/24hour (±20.7). No intravenous bolus of normal saline was administered. Fluid therapy was associated with a higher reduction in pain score points at discharge (5.4±2.3 vs 4.8±2.6). However, it was also associated with more chest x-rays (CXR) positive for consolidation (20% vs 7%) and more acute chest syndrome (ACS) diagnosis (9% vs 2%). The mean oxygen saturation in air of patients given oxygen therapy in ED was 96.6% (±4.8) and those that were not given oxygen therapy in ED was 98.2% (±1.6). Oxygen therapy was associated a higher reduction in pain score points at discharge (6.3±2.5 vs 4.7±2.4). However, in the oxygen therapy group, more CXRs were undertaken (71% vs 30%), more CXRs were positive for consolidation (42% vs 4%) and there was more (ACS) diagnoses (21% vs 0%).
Conclusion: These data reveal that about half of children presenting with VOEs received intravenous fluid therapy and about a quarter received oxygen therapy for the treatment of VOEs in this single-centre study. These therapies were associated with positive and negative impacts on clinical outcome. This highlights the need for randomised-controlled trials to evaluate the optimal regime for such therapies.

Disclosures
No relevant conflicts of interest to declare.
FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors
Authors: Li Yanan , Patel Riddhi M , Casey Emily , Magee Jeffrey A. 
Published: November 2019

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors.

Disclosures
No relevant conflicts of interest to declare.
Palmitoylation of GNA13 Is Essential for Its Tumor Suppressor Function and Its Inhibition Confers Hypersensitivity of B-Cell Lymphoma to BCL2 Inhibitors
Authors: Xia Zhizhou , Zhang Xiuli , Liu Ping , Jiao Bo , Ren Ruibao 
Published: November 2019

GNA13, encoding G alpha subunit 13 protein, is a major tumor suppressor gene frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) and Burkitt's lymphoma (BL). GNA13 is one of the key mediators of sphingosine-1-phosphate (S1P) signaling to confine B cells in germinal center. Inactivation of GNA13 coupled signaling could release tumor B cells from germinal center of lymphoid organs to peripheral blood and promote lymphomagenesis. Due to the "undruggable" nature of GNA13 as a tumor suppressor, targeted therapy remains an unsolved clinical issue.
Protein palmitoylation is a unique post-translational lipid modification in regulating protein trafficking, stability and functionality. Emerging evidence reveals that palmitoylation plays vital roles in control of G-protein-coupled receptor (GPCR) signaling transduction. In this study, we discovered that GNA13 protein relies on amino-terminal palmitoylation for its membrane association and signal transduction, which is essential for its tumor suppressor activities. By using a Isobaric iodoTMT switch labeling based mass spectrometry method, we firstly identified that palmitoylation mainly occurs on two cysteine residues, Cys14 and Cys18, one of which site was also found mutated in DLBCL patients. To validate this result, we genetically mutated the cysteine to serine residues on these two potential palmitoylation sites, respectively. We found that both single and double mutants could largely reduce the palmitoylation level of GNA13. We also found that the loss of palmitoylation dissociates GNA13 protein from cell plasma membrane. Similar results were obtained using a pan-palmitoylation inhibitor, 2-bromopalmitate (2-BP).
In order to examine the role of GNA13 palmitoylation in human DLBCL cells, we reintroduced either wildtype (wt) GNA13 or palmitoylation mutant GNA13 into Su-DHL-4 lymphoma cells after knocking down the endogenous wt GNA13 expression with short hairpin RNA interference. Our data show that the loss of palmitoylation promotes GCB-DLBCL cell proliferation and tumor growth both in vitro and in vivo, indicating that palmitoylation of GNA13 is essential to its tumor suppressor function. Mechanically, inactivation of GNA13, either by knocking down GNA13 expression or mutating the palmitoylation sites of GNA13, leads to phosphoinositide 3-kinase (PI3K)/AKT activation and BCL2 overexpression. Consistent to the increased BCL2 expression, we found that BCL2 inhibitors are among the most effective drugs to kill GNA13-deficient cells in a high-throughput chemical screen. Furthermore, we show that inhibition of palmitoylation by 2-BP enhances the drug sensitivity of GNA13 wildtype GCB-DLBCL cells to BCL2 inhibitors. These results indicate that the palmitoylation of GNA13 could serve as a target for treating B-cell lymphoma in combination with a BCL2 inhibitor.

Disclosures
No relevant conflicts of interest to declare.
TRAF1-ALK Fusion Predicts Poor Prognosis for ALK Positive Anaplastic Large Cell Lymphoma Patients with Chemotherapy and ALK Inhibitor
Authors: Huang Ling , Jiang Xinmiao , Guo Hanguo , Sichu Liu , Wei Xiaojuan , Feili Chen , Liang Zhanli , Li Wenyu 
Published: November 2019

Background: Relapsed/refractory anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas (ALCLs) respond to ALK inhibitors, but resistance, which bear a poor prognosis. No biomarkers were found to predict long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of ALCL. However, several distinct ALK fusions which result in highly different characteristics have also been described in lymphomas.
Methods: We retrospectively reviewed seven relapsed/refractory ALK positive ALCLs who received ALK inhibitors (six with Crizotinib and one with Alectinib) at Guangdong Provincial People's Hospital from June 2007 through March 2019. We did next generation sequencing (NGS) with paraffin-embedded tissue for two patients who quickly developed resistance.
Results: Of the seven patients, four were male and three were female, with a median age of 18 years (range 15-51) old. The median line of therapies was four (range 3-7) and that of ALK inhibitor usage was three (range 2-5). The overall response rate was 7 of 7 (100%) and the median overall survival of 21.2 months (8.5-86 months). Three patients obtained complete response (CR) on Crizotinib and then received autologous stem cell transplantation, and are still CR. One patient obtained CR, but died of serious infection five months after allogeneic stem cell transplantation. One patient is in CR under continuous crizotinib administration. One patient received Crizotinib obtained CR, but three months later got progression disease, the NGS showed TNF receptor-associated factor 1 gene (TRAF1) exon 6-ALK exon 20 fusion junction. The last patient was CR on alectinib, but quickly developed resistance, with a progression free survival of 1 month, the NGS indicated TRAF1 exon 7-ALK exon 20 fusion.
Conclusions: ALK inhibitors improved survival of relapsed/refractory ALK positive ALCLs. TRAF1-ALK fusion may predict poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend to aggressive behaviour in lymphomas.

Disclosures
Li: Guangdong Province Hospital: Employment.
What Can We Expect after Performing Allogeneic Stem Cell Transplantation for Adult T Lymphoma in Patients from Romania, Europe?
Authors: Tanase Alina Daniela Daniela , Craciun Oana Gabriela , Lipan Lavinia , Ranete Adela , Stefan Diana Laura , Varady Zsofia , Bumbea Horia , Colita Andrei , Hermine Olivier , Pasca Segiu , Teodorescu Patric , Tomuleasa Ciprian 
Published: November 2019

Introduction: Adult T lymphoma (ATL) is a rare and aggressive disease shown to be consistently caused by the human T lymphoma virus I (HTLV-I). It generally occurs in Japan and Africa, with a low incidence in Europe. Romania is an exception to this rule, presenting an endemic representation of ATL.
Aim: The aim of this study was to present our experience with allogeneic stem cell transplantation (alloSCT) for ATL.
Methods: The current study was a retrospective analysis of the ATL cases that received alloSCT in the Fundeni Clinical Institute. The patients were included between January 2016 to April 2019.
Results: A total of 7 patients were included in the present study, out of which 2 (28%) presented the acute form, while the rest presented the lymphomatous form. Four (57%) patients presented extranodal involvement, with 3 of those (75%), showing skin involvement. Of note, all patients presenting skin involvement also had bone marrow involvement. Thus, skin involvement was associated with a more advanced disease. Graft versus host disease (GvHD) was present in 4 (57%) patients, two of which were acute GvHD and two, chronic GvHD. Interestingly, the two patients that relapsed presented either acute or chronic GvHD, showing that the graft versus lymphoma (GVL) effect that can be observed in other lymphoma types is not observed in this cohort. Another noticeable observation is the fact that 4 out of the 6 patients tested for HTLV-I at 6 months post alloSCT presented a positive HTLV-I viral load. This event occurred, although, at 30 days, all patients presented 100% donor chimerism and the donor samples were negative for HTLV-I. This shows a possible imperfect jump of the HTLV-I from the recipient to the donor T lymphocytes or the possibility of a reinfection. Three (43%) patients presented a response less than complete remission (CR) after the first line of therapy, two of which progressed to death. The two deaths occurred at 14 and 15 months from the diagnosis, with the other follow-up periods in the cohort being higher than 26 months with the exception of one patient that had a follow-up of 6.8 moths from diagnosis. These two aforementioned patients were also the only ones to relapse thus far.
Conclusion: For ATL, alloSCT represents a viable and potentially curative approach when used in chemosensitive disease. This being said, there are clear differences from other lymphomas, ATL having to be considered separately.

Disclosures
Tanase: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy. Hermine:Novartis: Research Funding; Celgene: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding.
The Effect of Pyruvate Kinase M2: Inhibitor(shikonin) on the Function of Mdc in Severe Aplastic Anemia Mouse Model
Authors: Zheng Mengying , Liu Chunyan , Shao Yuanyuan , Fu Rong , Wang Huaquan , Wang Ting , Qi Weiwei , Shao Zonghong 
Published: November 2019

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Over-activated myeloid dendritic cells (mDCs) play an important role in the pathogenesis of SAA. In recent years, the role of pyruvate kinase M2 (PKM2) in DC function and autoimmune response has been gradually recognized. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation and lymphocyte infusion. The AA model mice showed pancytopenia, decreased ratio of CD4+/CD8+ cells, increased expression of cytotoxic molecules perforin and granzyme in CD8+ cells, increased levels of co-stimulatory molecules CD80 and CD86 in DCs and inadequate Treg number. In-vitro animal experiments confirmed the activation of PKM2 in mDCs, which promoted glycolytic metabolism. High levels of PKM2 in mice contributed to the poor survival rate. Additionally, intervention treatment with shikonin or cyclosporin A in the AA mouse model reduced the expression not only of co-stimulatory molecules CD80 and CD86 in mDCs but also of cytotoxic molecules in CD8+ cells. In conclusion, we confirmed the activation of PKM2 in mDCs in AA mouse models. PKM2 is involved in mDC activation and proliferation, which might contribute to activating the downstream cytotoxic T cells (CTLs). PKM2 is a possible novel target in SAA treatment.

Disclosures
No relevant conflicts of interest to declare.