bluuebunny/crossref_metadata_2025_split huggingface dataset:
FCyIIIa Gene Polymorphisms as Response Predictor in Patients with Non-Hodgkin Lymphoma after Treatment with Anti-CD 20 Monoclonal Antibody (Rituximab).
Authors: Molnar Soledad , Nuñez Mariana , Rizzi Maria L. , Lavarda Marcelo , Balseiro Maria I. , Ryser Ricardo , Jarchum Gustavo 
Published: October 2019

Abstract
Background: The main mechanism of action of rituximab is through antibody-dependent cellular cytotoxicity via Fc receptors for immunoglobulin G. Recently a polymorphism of Fc was reported, which consists in the substitution of phenylalanine for valine in position 158. Patients with homozygous 158 valine/valine (V/V) alleles of Fc showed a higher response rate to rituximab treatment in contrast to patients with phenylalanine/valine (F/V) or homozygous phenilalanine (F/F). It would have clinical value to know which patients could have a greater benefit from the treatment with rituximab.
Aims: 1-to determine the Fc genotype in patients with Non-Hodgkin lymphoma (NHL) in our population. 2- to analyze the response rate to rituximab of these patients according to the Fc polymorphism.
Methods: DNA was isolated from peripheral blood. Genotyping of FCyIIIa polymorphism was performed using a polymerase chain reaction and were confirmed by direct sequencing of the region of interest. To analyse the results the patients were divided into two groups: with valine expression: V/V or V/F, and without valine expression F/F. The response was evaluated after 3 months of treatment and at the end of it. Chi-square and Fisher’s exact tests were used for statistical analysis.
Results: 34 patients with NHL: 19 follicular lymphoma, 12 diffuse large B-cell lymphoma, 3 mantle lymphoma. The FcyIIIa polymorphism expression was 11.8% V/V, 52.9% V/F and 35.3% F/F. The complete response (CR) after 3 months of treatment was 50% and 41.7% for V/V-V/F and F/F respectively (not statistically significant (ns)). After end of treatment CR was 86.7% in V/V-V/F and 72.7% in F/F(ns). In patients with follicular lymphoma the CR after end of treatment was 87.5% in V/V-V/F and 79% in F/F (ns). In patients with diffuse large B-cell lymphoma the CR was reached in all patients regardless of polymorphism.
Conclusions: FcyIIIa gene polymorphism did not help in predicting response after treatment with rituximab in our group of patients with NHL. A large number of patients would be necessary to draw conclusions, especially in the group with follicular lymphoma.
PTEN Regulates VEGF, VEGFR1 Expression and Its Clinical Significance in Myeloid Leukemia.
Authors: Cheng Zhiyong , Pan Lin , Guo Xiaoling , Zhang Xuejun , Wang Fuxu 
Published: October 2019

Abstract
Abstract 1001
Poster Board I-23
Phosphatase and tensin homology deleted on chromosome ten (PTEN) as a novel tumor suppressor gene, plays an important role in regulating proliferation, apoptosis, invasion and migration of many cancer cells. PTEN also modulates angiogenesis mediated by vascular endothelial growth factor (VEGF) via down-regulating the activity of PI3K/Akt pathway in many solid tumors. However, in myeloid leukemia, the effects of PTEN on VEGF and VEGFR1 (FLT1) mediated angiogenesis, migration, invasion of leukemia cells and its clinical significance are still unknown. Therefore, in the present study, we investigated the effect of PTEN on the activity of PI3K/Akt and VEGF/FLT1 pathways. Wild type PTEN gene was transfected into K562 cells, a cell line establish from a chronic myelogenous leukemia in blast crisis, to induce high expression of wild-type PTEN gene and protein by the cells. The correlation between the expression levels of PTEN and VEGF/FLT1 and its clinical significance in myeloid leukemia patients were also observed. We found that the expression reconstitution of wild-type PTEN had significance effect on inhibiting proliferation, migration and invasion ability of K562 cells via down-regulation of Akt phosphorylation and inhibition of VEGF/FLT1 expression. In myeloid leukemia patients, a negative correlation was found between the expression level of PTEN mRNA and that of VEGF and FLT1 mRNA. Low expression of PTEN mRNA and high expression of VEGF and FLT1 mRNA indicated a higher tendency of extramedullary disease in acute myeloid leukemia patients. Taken together, our findings indicated that PTEN could modulate the function of VEGF/VEGFR signaling pathway via down regulating Akt phosphorylation and that PTEN would be a candidate target for the treatment of myeloid leukemia.

Disclosures:
Pan: Nature science foundation of Hebei Province: Research Funding; Research Fund for the Doctoral Program of Higher Education of China: Research Funding; Emphases follow up pregram of Health Bureau of Hebei Province: Research Funding.
The Value of Post-Remission Therapy in Older Adults with Acute Myeloid Leukemia (AML).
Authors: Sekeres Mikkael A. , Fu Alex Z , Earl Marc , Kalaycio Matt , Advani Anjali , Saunthararajah Yogen , Sobecks Ronald , Copelan Edward 
Published: October 2019

Abstract
Abstract 1043
Poster Board I-65

Background:
In older (age 3 60) AML patients (pts) who are induced into complete remission, it is unclear whether post-remission therapy provides additional benefit.

Methods:
We examined all older AML pts treated with cytarabine-based induction chemotherapy at a single institution between 1997 and 2008. Data on known prognostic factors (age, white blood cell count (WBC) at diagnosis, cytogenetic risk groups (as defined by CALGB 8461) and AML etiology (de novo vs. secondary AML)) were collected. Of 240 pts identified, 25 had unknown post-remission status, leaving 215 pts for analyses: 81 receiving cytarabine-based post-remission therapy (PRT) for 1-2 cycles; 134 received no PRT. A cohort study using a propensity score method was conducted in which pts receiving PRT and those not receiving PRT were matched in a 1:1 ratio to address potential sample selection bias and to better balance patient characteristics. A logistic regression was used to predict the propensities of receiving PRT using individual characteristics: age, gender, race, WBC at presentation, AML cytogenetics, secondary AML, re-induction, FAB classification, and complete remission (CR). Overall survival (OS) was measured from the time of diagnosis; disease-free survival (DFS) from the time of CR. Individual characteristics and survival between groups were assessed by the routines of linear, categorical, and survival analyses.

Results:
Median age was 68 years (range, 60-81). Patients receiving PRT were more likely to be younger (67 vs 69 years, P=.003), male (67% vs. 52%, p=.04), have de novo AML (75% vs. 50%, p=.0012), favorable- or intermediate-risk cytogenetics (65% vs. 36%, p<.0001), to have M3 AML (5% vs. 0%), and to have achieved a CR (100% vs. 48%, p<.0001). There were no differences between groups in race, WBC at admission, reinduction rates, or comorbid conditions including renal dysfunction, hepatic dysfunction, and cardiac comorbidity. Median DFS and OS for those receiving PRT vs. no PRT were.45 and.34 years, and 1.13 and.69 years (p=.026 and p<.001, respectively, Figure 1). Only 3 patients underwent a bone marrow transplant after relapse, and there was no correlation between the total amount of chemotherapy received during induction for PRT, or OS. After 1:1 propensity score matching (n=88), there were no differences in baseline characteristics, re-induction, or CR rates, yet DFS and OSl remained significantly greater for pts receiving PRT vs. those who did not (Hazard Ratios.48 and.30, p=.05 and p<.0001, respectively).

Conclusions:
Even after adjusting for patient disease and treatment factors that could influence PRT administration, older AML pts receiving at least one cycle of PRT lived significantly longer than those who did not. PRT should be considered as a standard part of intensive therapy for older AML pts.

Disclosures:
No relevant conflicts of interest to declare.
Oridonin-Generated Cleavage Fragment of AML1-ETO Inhibits Its Oligomerization and Oncogenic Function Leading to Differentiation and Apoptosis of Leukemic Cells.
Authors: Wu Chuanfeng , Zhen Tao , Zhou Guangbiao , Liu Ping , Chen Zhu , Chen Saijuan 
Published: October 2019

Abstract
Abstract 1051
Poster Board I-73
Oligomerization through the NHR2 domain is essential for AML1-ETO's inhibition of granulocytic differentiation and enhanced clonogenic potential of primary bone marrow cells. We show here that Oridonin interferes with AML1-ETO oligomerization through its cleavage fragment DAML1-ETO, which consists of the amino acids (aa) 188-752 of the parental oncoprotein or aa 40-604s of the wild-type ETO. DAML1-ETO interacts with the parental AML1-ETO through NHR2 and exerts dominant negative effects on AML1-ETO with regard to DNA binding, transregulatory activity on target genes and regulation of leukemic cell survival, differentiation and proliferation both in vitro and in vivo. Moreover, Oridonin can activate retinoic acid and cAMP/PKA pathways, and potentiate differentiation induced by all-trans retinoic acid (ATRA) and G-CSF. Consistently, combined use of Oridonin, ATRA and G-CSF significantly prolongs lifespan of t (8;21) leukemic mice and, interestingly, we find that this treatment targets the Lin-/Sca-1+/C-KIT+ and Lin-/Sca-1-/C-KIT+ leukemia initiating cells. These data suggest that Oridonin, and potentially other small molecules, can inhibit AML1-ETO oligomerization and leukemogenic function, thus providing a targeted therapy that activates key regulatory pathways for myelomonocytic cell differentiation and apoptosis.

Disclosures:
No relevant conflicts of interest to declare.
Comparative Clinical and Biological Features of Primary Mediastinal B-Cell Lymphoma (PMBL) and Mediastinal Grey Zone Lymphoma (MGZL).
Authors: Dunleavy Kieron , Pittaluga Stefania , Tay Kevin , Grant Nicole , Chen Clara C , Shovlin Margaret , Steinberg Seth , Staudt Louis M , Jaffe Elaine S , Janik John E , Wilson Wyndham H 
Published: October 2019

Abstract
Abstract 106

Mediastinal B-cell lymphomas (MBCL) are a clinical-pathologically related group, putatively derived from thymic B-cells, and include PMBL, Nodular Sclerosis Hodgkin Lymphoma (NSHL) and MGZL. PMBL and NSHL contain significant molecular overlap, and MGZL has pathological features intermediate between PMBL and NSHL. Overlapping clinical features include young age, female predominance and localized mediastinal presentation. The risk of local failure after anthracycline-based therapy has led to routine mediastinal radiation (RT) in PMBL and bulky NSHL, suggesting relative chemo-resistance. Anecdotal reports also suggest MGZL is relatively resistant to Hodgkin-based chemotherapy. Thus, better systemic therapy is needed to avoid RT and its risk of secondary malignancies and cardiac disease, and to improve cure. Clinical studies suggest PMBL and NSHL are particularly responsive to dose-intense strategies. We prospectively compared untreated PMBL and MGZL for the first time and assessed if the dose-intense DA-EPOCH-R regimen would obviate the need for RT and improve cure. DA-EPOCH-R was administered 6-8 cycles and FDG-PET was used in pts with residual masses to assess need for biopsy and RT (n=31). PMBL and MGZL had similar clinical characteristics shown below. PMBL and MGZL IHC, respectively, had similar CD20+ 100% both; CD10+ 5% and 0%; BCL6+ 86% and 100%; and MUM1+ 58% and 67%; but different CD30+ 71% and 100% (P=0.14) and CD15+ 0% and 60% (P=0.0009). At 4 years median F/U, PFS and OS were 100% for patients with PMBL without RT (table below). Comparison to historical PMBL (n=17) treated with DA-EPOCH (PFS 65% and OS 77% at 10 years) indicated a significant benefit of rituximab (PFS: P=0.0012) and (OS: P=0.013). MGZL outcome with DA-EPOCH-R was significantly worse than PMBL (PFS 30% and OS 83% at 4 years) and 50% required mediastinal RT (figure below). FDG-PET + and - predictive value for relapse were 62% and 95%, respectively. In conclusion, DA-EPOCH-R is highly effective in PMBL and obviates RT whereas MGZL shows greater chemo-resistance. Rituximab adds significant benefit to PMBL. We hypothesize that MGZL and NSHL are more chemo-resistant than PMBL and may share molecular mechanisms of drug resistance. Novel therapeutic strategies, such as targeting the microenvironment, are needed in these diseases. Comparative gene expression profiling is underway.

Disclosures:
No relevant conflicts of interest to declare.
The Administration of Fondaparinux in Strongly Suspected Heparin-Induced Thrombocytopenia (HIT): Further Evidence of Its Safety and Efficacy, and Need for a Controlled Randomized Study.
Authors: Piovella Franco , Barco Stefano , Barone Marisa , Beltrametti Chiara , De Amici Mara 
Published: October 2019

Abstract
Abstract 1072
Poster Board I-94

Introduction:
Heparin-induced thrombocytopenia (HIT), alone or associated with thrombosis (HITT), may develop during anticoagulant treatment with unfractionated heparin (UFH) or low-molecular weight heparin (LWMH). Fondaparinux is a selective inhibitor of coagulation factor Xa which apparently does not react with anti-PF4/heparin antibodies in in vitro testing.

Methods:
From january 2005 to december 2007 we treated 44 patients who had strong suspect of HIT (12 patients) or HITT (32 patients, of whom 12 had both DVT and PE). Of these, 30 patients were previously exposed to unfractionated heparin (UFH) for major cardiac surgery. The remaining patients were admitted to medical or general surgery wards. In the 32 patients who developed HITT, we applied therapeutic dosages of fondaparinux, i.e. 7.5 mg QD or lower, in accordance with their bleeding risk. The remaining patients were treated with prophylactic dosages of fondaparinux, i.e. 2.5 mg QD. Switch to warfarin was performed as soon as possible. The mean of our patients 4T's score was 6.2, corresponding to high risk patients; the mean of anticorpal optical density (GTI Enhanced®) was 1.4; the mean platelet number was 45 × 109/L.

Results:
All patients but four showed sustained normalization of the platelet number. All patients but four showed a significant reduction of their thromboembolic burden. No death related to severe bleeding was recorded. Two episodes of major bleeding were recorded in post-surgical patients (4,5%); 4 episodes of minor bleeding were recorded (9,1%). Four patients underwent dialysis during fondaparinux without bleeding complications. One patient developed acute coronary syndrome during treatment with fondaparinux. Nine patients did not survive (20,5%), with a key role of primitive diseases (i.e. sepsis) causing delay in the diagnostic process of HIT (four of them had a diagnosis of HIT with a mean delay of 7 days). In 16 patients submitted to therapeutic dosages of fondaparinux, anti-PF4/heparin antibody titers were followed over time showing a constant decrease: in one case antibody levels did not decrease up to 6 months after stopping both heparin and fondaparinux. Thirty patients were easily switched from fondaparinux to VKAs without problems in reaching the appropriate INR target.

Conclusions:
This report provides further evidence supporting the safety and efficacy of fondaparinux in the treatment of HIT and underlines the importance of an early diagnosis. However, it shows the need of a randomized controlled study between fondaparinux and a registered comparator drug.

Disclosures:
Piovella: GlaxoSmithKline: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Boehringer Ingelheim: Honoraria, Speakers Bureau. Off Label Use: fondaparinux in the treatment of heparin-induced thrombocytopenia.
First Line Antiviral Therapy Significantly Improves Survival of Patients with Acute, Chronic and Smoldering ATL: a Worldwide Meta-Analysis.
Authors: Bazarbachi Ali , Plumelle Yves , Ramos Juan Carlos , Tortevoye Patricia , Otrock Zaher , Taylor Graham , Gessain Antoine , Harrington William J , Panelatti Gérard , Hermine Olivier 
Published: October 2019

Abstract
Abstract 108
HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small studies using zidovudine (AZT) and interferon-α (IFN) showed response in ATL patients. However, the global impact of this innovative antiviral treatment strategy on long-term survival of ATL patients in routine practice remains undetermined. We realized a worldwide meta-analysis on the use of AZT/IFN treatment. Charts of 254 ATL patients treated from 1994 to 2008 in the USA (59 patients), the UK (13 patients), Martinique (111 patients) and France metropolitaine (67 patients) were individually reviewed. Collected data included epidemiological, clinical and biological characteristics, ATL subtype, first line treatment, response to first line therapy, and overall survival. In 231 patients with available survival data, first line therapy was recorded in 207 patients only. Median age was 50 years (range 16 to 95). According to Shimoyama classification, there were 116 acute ATL, 18 chronic ATL, 11 smoldering ATL, 100 ATL lymphoma, and 9 patients with an unknown subtype. Hypercalcemia was present in 48% of patients. Five year overall survival rates were 20% for 77 patients who received chemotherapy alone, 46% for 75 patients who received first line antiviral therapy alone (p=0.012), and 12% for 55 patients who received chemotherapy followed by antiviral therapy. Response rate to first line antiviral therapy was 66%, including 35% complete remission (CR). When overall survival analysis was performed by ATL subtype, patients with acute, chronic, and smoldering ATL significantly benefited from first line antiviral therapy, whereas patients with ATL lymphoma had a better outcome with first line chemotherapy. Achievement of CR with first line antiviral therapy resulted in prolonged survival of more than 10 years in 82% of the acute ATL subgroup. Finally, first line antiviral therapy in chronic and smoldering ATL resulted in 100% overall survival at 10 years. Multivariate analysis using Cox regression showed that first line antiviral therapy significantly improves overall survival of ATL patients. In conclusion, these results confirm that treatment of ATL using AZT and IFN results in a high response and CR rates particularly in acute, chronic and smoldering ATL, but not in lymphoma, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy. Predictive factors of response are currently under investigations in order to improve prognosis of this still uncurable disease.

Disclosures:
No relevant conflicts of interest to declare.
DNA Double-Strand Break Formation Induced by Replication Arrest Depend On Artemis.
Authors: Takagi Masatoshi , Unno Junya , Kiyono Thoru , Honda Fumiko , Teraoka Hirobumi , Maeda Daisuke , Masutani Mitsuko , Morio Tomohiro , Mizutani Shuki 
Published: October 2019

Abstract
Abstract 1097
Poster Board I-119
Hydroxyurea (HU) is an antineoplastic drug used in hematological malignancies, specifically polycythemia vera, essential thrombocytosis or chronic myelogenous leukemia. HU targets cells that are actively replicating DNA by inhibit ing ribonucleotide reductase, which causes an imbalance in the deoxynucleotide triphosphate pool. Stalled replication forks lead to the production of single-stranded DNA (ssDNA), which in some cases is converted to DSBs by unknown mechanisms, an event that is termed replication fork collapse. however, the precise mechanism for DSB induction and the cellular response to persistent replication fork stalling are not fully understood. We show that DSBs are generated in an Artemis nuclease-dependent manner following prolonged stalling caused by exposure to HU, with subsequent activation of the ataxia-telangiectasia mutated (ATM) signaling pathway. DNA-dependent protein kinase (DNA-PK) activity, a prerequisite for the endonuclease activity of Artemis, is also required for DSB generation and subsequent ATM activation. Our findings indicate a novel function of Artemis as a molecular switch that converts single-stranded DNA lesions into DSBs, thereby activating an ATM-dependent fail-safe mechanism following prolonged replication fork stalling.

Disclosures
No relevant conflicts of interest to declare.
Base Excision Repair Deficiency in Acute Myeloid Leukemia.
Authors: Olipitz Werner , Scheer Nicole , Quehenberger Franz , Hiden Karin , Rankl Julia , Schlembach Dietmar , Sill Heinz 
Published: October 2019

Abstract
Abstract 1106
Poster Board I-128
Base excision repair (BER) is the main DNA repair mechanism for single DNA base lesions resulting from oxidative stress, chemical damage or ionizing radiation. We investigated BER in acute myeloid leukemia (AML), a disorder characterized by widespread genomic instability. AML cell lines were treated with H2O2 and DNA damage induction and repair were monitored using the alkaline comet assay. Significantly reduced single strand break (SSB) formation - representing BER intermediates - was observed in 5/10 cell lines. Significantly reduced SSB formation was also demonstrated in 15/30 leukemic samples from patients with therapy-related AML, 13/35 with de novo AML and 14/26 with AML following a myelodysplastic syndrome but only in 1/31 CD34+ hematopoietic stem and progenitor cell specimens isolated from umbilical cord blood (P=.0000056). Reduced SSB formation was not due to differences in intracellular ROS concentrations or selection for a damage resistant subpopulation. To determine whether initial steps of BER were impaired, incision assays with oligonucleotides harboring either 7,8-dihydro-8-oxoguanine or the AP site analog furan were performed. Significantly diminished cleavage for both substrates was observed in cell lines that did not exhibit SSB formation upon H2O2 treatment. These data demonstrate that BER is functionally impaired in a significant proportion of myeloid cell lines and leukemic cells from patients with AML.

Disclosures
No relevant conflicts of interest to declare.