bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copy Number Alterations of PAX5, CDKN2A/B Genes Rather Than IKZF1 gene Are Associated with Pathogenesis of Childhood ALL in Korean Assessed by Multiplex Ligation-Dependent Probe Amplification
Authors: Han Dong Kyun , Yu Li , Tran Huong Thi Thanh , Kim Hee Nam , Lee Il Kwon , Baek Hee Jo , Bae Sul Hee , Kim Hyeoung Joon , Kook Hoon , Hwang Tai Ju 
Published: October 2019

Abstract
Abstract 4231

Background:
Recent genomic studies have analyzed genetic alterations and gene expression in childhood acute lymphoblastic leukemia (ALL), and detected multiple new submicroscopic genetic abnormalities in key cellular pathways, and also identified new prognostic markers and therapeutic targets. More than 50 recurring genetic alterations have been identified, and these genes are known to play key or putative roles in lymphoid development and leukemogenesis. Multiplex Ligation-dependent Probe Amplification (MLPA) is a rapid multiplex PCR based technique that allows the comparative quantification of multiple sites. However, there have been no reports on the MLPA based copy number alterations (CNA) of childhood ALL in Asian countries. The aim of this study is to reveal the CNA of genes involved in lymphoid differentiation and cell cycle control in Korean children with ALL.

Patients and Methods:
Reference ranges for individual MLPA probes were established from a group of 30 healthy control subjects. The MLPA assay was performed for 121 children with ALL in Korea to target those genes including the lymphoid differentiation genes (BTG1, EBF1, IKZF1, and PAX); cell cycle control genes (CDKN2A/B and RB1); transcriptional factors regulating genes (ETV6); and those deleted from the PAR1 region (IL3RA, CRLF2 and CSF2RA). We also evaluated the prognostic impact of these abnormalities.

Results:
Out of the 121 patients analyzed in our study, 96 (79%) displayed CNA in at least one gene: PAX5, 49 (40%); CDKN2A, 42 (35%); CDKN2B, 35 (29%); IKZF1, 22 (18%); ETV6, 22 (18%); EBF1, 16 (13%); RB1, 16 (13%); BTG1, 14 (12%); CRLF2, 12 (10%); IL3RA, 12 (10%); CSF2RA, 11 (9%). Thirteen of 121 (11%) patients relapsed. There was no significant correlation between these CNA and the recurrence of ALL.

Conclusion:
These results suggest that CNA of PAX5, CDKN2A/B may play an important role in the pathogenesis of childhood ALL in Korea, contrasting to those findings from western countries showing a significant correlation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other possible genes are warranted in childhood ALL.

Disclosures:
No relevant conflicts of interest to declare.
Dexrazoxane Use in Pediatric Patients with Acute Lymphoblastic or Myeloid Leukemia: Analysis of a National Cohort of Patients in the Pediatric Health Information Systems Database From 1999 to 2009
Authors: Sepe Dana , Fisher Brian T. , Seif Alix E. , Huang Yuan-Shung V. , Li Yimei , Aplenc Richard 
Published: October 2019

Abstract
Abstract 4242

Background:
Acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) account for approximately 26% of all pediatric cancers. Anthracyclines are critical in the treatment of ALL and AML; however, their use is limited by cardiotoxicity. Dexrazoxane (DZX) is an FDA-approved cardioprotective agent that chelates intracellular free iron and iron bound to anthracyclines. Evidence for the efficacy of DZX as a cardioprotectant in children is limited, but available data support a short term cardioprotective effect in patients with ALL. The frequency of DZX use in pediatric cancer patients at high risk of developing cardiac toxicity is unknown.

Objective:
We sought to describe patterns of DZX use between 1999 and 2009 in a retrospective cohort study of pediatric patients diagnosed with ALL or AML in 43 pediatric hospitals across the United States in the Pediatric Health Information Systems (PHIS) database.

Methods:
Patients previously identified and validated as having de novo ALL and AML at these PHIS hospitals were included. Demographic data, as well as chemotherapy and DZX use were obtained from PHIS.

Results:
Of 8733 patients with de novo ALL and 2556 with de novo AML, 207 and 52 received DZX, respectively. The proportion of patients receiving DZX was higher in older children with ALL or AML and in African-Americans and males with ALL (Table 1). There was no trend in the proportion of patients receiving DZX per year in either group (Figure 1). DZX use varied by region in ALL, with 55% of the patients receiving DZX being treated in the northeast, but was not significantly different in AML. There was substantial variability in prescribing practices across institutions (Figure 2). Most patients with ALL and AML received the first dose of DZX in the first 30 days (67% and 31%, respectively) or >360 days from their first leukemia admission (23.5% and 31%, respectively).

Conclusions:
To our knowledge, this is the only description of DZX use in patients with ALL and AML using national, population-based data. Older children and those treated in the Northeastern U.S. were more likely to have received DZX, with the first dose being given either early or late in the study period. In general, DZX administration was relatively rare and was driven by only a few institutions, especially in ALL patients. This lack of universal acceptance of DZX is likely multi-factorial, including concerns about acute and long-term side effects, impact on the antitumor effect of anthracyclines, and risk for secondary malignant neoplasm. Work is ongoing to substantiate or refute these concerns using PHIS data.

Disclosures:
No relevant conflicts of interest to declare.
Multi-Course of Moderate Dose Cytosine Arabinoside and Fludarabin in the Consolidation Therapy of Patients with De Novo Acute Myeloid Leukemia
Authors: Qiu Huiying , Depei Wu , Sun Aining , Jin Zhengming , Miao Miao , Tang XiaoWen , Fu Chengcheng , Han Yue , He Guangsheng 
Published: October 2019

Abstract
Abstract 4251
To investigate the long-term outcome of multi-course of moderate dose cytosine arabinoside and fludarabin in the consolidation therapy of patients with de novo acute myeloid leukemia (AML). Sixty-seven consecutive de novo AML patients, 38 males, 29 females, including M1 (5 cases), M2a (34 cases), M4 (11 cases), M5 (13 cases), M6 (2 cases), unclassified AML (1 cases), HAL (1 case), were enrolled in this retrospective analysis between 2006 to 2011. Their median age was 32.28 years (range 13–64 years). Cytogenetic analysis showed that 27 patients with normal karyotype, 11 patients with t(8; 21), 4 patients with inv(16), 16 patients with other karyotype. Forty-two cases were classified as low and intermediate risk groups based on karyotype analysis and fusion gene detection. Thirty-eight cases and twenth-nine cases achieved complete remission (CR) after one course and two course induction chemotherapy (such as cytarabine with idarubicin or daunorubicin and mitoxantrone etc), respectively.
All patients received at least two-course consolidation therapy with moderate dose cytosine arabinoside (2g/m2) and fludarabin (30mg/m2) for 3 days (FA). Nineteen cases received two courses, 20 three courses, 20 four courses, 8 five courses and1 six courses. Quantitative RT-PCR and flow cytometry were used to detect minimal residual disease. Afterwards 3 patients underwent allogeneic stem cell transplantation. The median time for hematological recovery of neutrophils©ƒ500/microl and platelets©ƒ20,000/microl was 12 and 16 days, respectively. The median length of hospitalization was 18 days. Non-hematological toxicity consisted of mild gastrointestinal reaction and mild hepatic dysfunction, forty percent of patients experienced fever. There was no treatment-related mortality during consolidation. After follow up of 4–54 months, 10/19 (52.6%) cases were relapse-free survival (RFS) after two courses FA consolidation, 15/20 (75%) cases in three courses, 15/20 (75%) cases in four courses, respectively. 8 cases were all in RFS after five courses consolidation. 1 case was also in RFS after six courses FA consolidation. Three-year overall survival, event free survival and RFS was 67%, 67%, and 66%, respectively. Our results suggest that multi-course FA consolidation is effective in de novo AML patients with low-risk and moderate-risk diseases. To reduce the recurrence rate the number of courses should be increased. Non-hematological toxicity was mild and the toxicity is acceptable.

Disclosures:
No relevant conflicts of interest to declare.
Invasive Fungal Infections in Adults with Newly Diagnosed AML Undergoing Intensive Chemotherapy: Characterization, Risk Factors, and Outcomes in a Single Institution
Authors: Lu Kit , Neofytos Dionissios , Blackford Amanda , Seung Amy , Karp Judith E. 
Published: October 2019

Abstract
Abstract 4254

Background:
Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML) undergoing chemotherapy treatment. However, the epidemiology, risk factors, and outcomes of IFI in these patients have been poorly described.

Methods:
A single-center retrospective analysis was performed to study the epidemiology, risk factors, clinical outcomes, and mortality predictors of IFIs in AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST) between January 2005 and June 2010. Newly diagnosed AML patients, with exception of acute promyelocytic leukemia, were studied. IFIs were defined using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria.

Results:
254 consecutive patients (57% male; median age 54, range 20–78) were analyzed. 123 (48%) of patients had an IFI; of which, 15 patients (12%) had a proven candidal infection, and 108 patients (88%) had a mould infection (5 proven/probable (5%) and 103 (95%) possible mould infections). 237 (93%) patients received antifungal therapy during their treatment course (median day 8, range day -15 to 30). Of those, 63 (27%) received monotherapy (46% liposomal amphotericin, 44% voriconazole) and the rest received multiple antifungal agents.
Significant risk factors and trends for developing +IFI shown from univariate analyses are listed in Table 1. Prolonged neutropenia, duration of mucositis, and concurrent bacterial infections did not significantly affect the development of +IFI. Using multivariate analyses, mortality was impacted by patients’ baseline organ function (p=0.002 [1.3,3.1]), specifically, by bilirubin < 2 mg/dL (p=0.003 [1.38,4.57]) and creatinine < 1.5 mg/dL (p=0.01 [1.23,5.4]).
Patients with +IFI did not significantly impact overall survival. However, patients with candidal IFIs had a significantly lower overall survival compared to patients with mould IFIs and no IFI (HR 2.01 [1.06, 3.8]) (Figure 1). Candida colonization prior to or during the first week of chemotherapy, and development of mucositis were associated with the development of candidal IFIs (p=0.07).

Conclusion:
IFIs, particularly mould infections, remain a significant problem in patients with AML. Although overall survival did not appear to be significantly affected by mould infections, patients with candidal infections were more likely to die. Identification of risk factors for each type of IFIs may help to develop effective targeted preventive antifungal strategies.

Disclosures:
No relevant conflicts of interest to declare.
Clofarabine in Acute Myeloid Leukemia. the Spanish Experience
Authors: de la Fuente Adolfo , Deben Guillermo , Bethencourt Concha , Negri Silvia , Vilariño Dolores , Gonzalez Sonia , Olave Teresa , Martinez-Sanchez Pilar , Moscardo Federico , Caballero Mar , Fernandez Martinez Rosa , Bergua Juan , Gordillo Marina , Garcia Belmonte Daniel , Fernandez Fernandez Angeles , Solorzano Silvia , Santos Ana Belen , Roman Alejandro , Tormo Mar , Calabuig Marisa , Sastre Moral Jl , Lopez Lorenzo Jose Luis , Fernández-Abellán Pascual , Tomas Jose Francisco 
Published: October 2019

Abstract
Abstract 4279

Introduction:
Clofarabine (CLF) is a purine nucleoside analog approved by FDA and EMA in refractory pediatric ALL patients. Phase I and II studies have reported Clofarabine activity in AML.

Aims:
To evaluate the experience in Spain with (CLF) in the treatment of adult AML patients, analyzing effectiveness and toxicity profile.

Method:
This is a multicenter retrospective study including AML patients treated in Spain with CLF by compassionate use. Main points were complete remission as IWRv2003 criteria and toxicity as CTCAE v3.0 of NCI scale.

Result:
Between July 2007 ans April 2011 a total of 76 AML patients were treated with CLF based chemotherapy in Spain. We obtained clinical data from 64 cases. Median age at CLF treatment 52.4 years (18–77). Male/Female: 31/33. Previous Myelodisplastic syndrome 12 (18%). Cytogenetic data was available in 58 patients (90%), and 28 of them had high-risk cytogenetic.
CLF treatment: 56 patients received CLF as salvage therapy (23 in AML relapse and 33 in refractory disease), median previous lines 2 (0–7), were the remaining 8 patients were untreated patients. CLF was administered in combination with AraC in 94% patients and the 91% received a five days schedule. The most frequents CLF dose/day were: 40 mg/m2/day in 39 patients, 30 mg/m2/day in 11 patients, and 20 mg/m2/day in 9 patients.
Response and outcome: Nineteen (35.8%) patients achieved complete remission and 64.1% had resistant disease. Mean survival time 14.3 ± 1.4 months.
The statistical analysis shows a significant difference in the CR rate between first line therapy (CR 82%) and savage therapy in relapsed (CR 45%) and salvage therapy in refractory (CR 18%), (p0.012). Neither adverse cytogenetics nor previous MDS did influence CR. (p0.57 and p0.53 respectively).
Toxicity: All patients presented grade IV hematological toxicity with grade IV neuthopenia, grade IV trombopenia and transfusion depend anemia. The incidence of extra hematological toxic effects were low, creatinine >3 mg/dL: 4 cases (6%); bilirrubine > 3mg/dL: 9 cases (14%). Eleven (17%) patients died during Induction.

Conclusions(opcion1):
The revised experience in Spain with CLF as compassionate used in AML confirms the effectiveness of Clofarabine as a salvage regimen. Of note was that CLF could potentially overcome some adverse known factors as cytogenetics.

Disclosures:
Off Label Use: Clofarabine in AML is an off-label use.
Wogonoside Exerts Anti-Leukemia of AML Cells Via Restricting Phospholipid Scramblase 1 Gene Expression and Promoting Its Translocation Into Nuclear
Authors: Chen Yan , Chen Bao-An , Guo Qing-long 
Published: October 2019

Abstract
Abstract 4282

Objective:
To evaluate the antileukemic effect of wogonoside and reveal the underlying mechanism.

Method:
In this study trypan blue dye exclusion assay, MTT assay, and soft agar colony formation assay were used to analysis growth inhibition of wogonoside the on AML (acute human promyelocytic) cell lines. Propidium iodide (PI)-staining and cell cycle-regulatory proteins detecting by western blots were applied to exam whether wogonoside could induce cell cycle arrest. Then a series of experiment were used to assess the ability of wogonoside to overcome the AML associated differentiation block, by using Giemsa staining, Nitroblue tetrazolium (NBT) reduction assay, and cell-surface differentiation antigens expression analysis. Real time PCR, western blots, cycloheximide inhibition test and RNA interference, nuclear and cytoplasmic fractionation, immunofluorescent staining were used to investigate the underlying mechanism. In this point we mainly focus that wogonoside exerts antileukemic by modulating of PLSCR1 gene expression, as well as influence its subcellular localization to play a role in regulating gene transcription.

Result:
It was demonstrated that wogonoside have the capacity to decrease the growth of myeloid cell lines by induction of G0/1 phase cell cycle arrest and differentiation. This effect is mediated by the increasing in mRNA and up-regulating protein expression of phospholipids scramblase 1 (PLSCR1). Meanwhile wogonoside promoted PLSCR1 traffic into the nucleus, which let PLSCR1 to play a role in regulating cell cycle and differentiation-related genes transcription including p21, p27, c-myc and IP3R1.

Conclusion:
Wogonoside induced AML cell lines to undergo differentiation and G1 phase arrest by restricting phospholipid scramblase 1 gene expression and promoting its translocation into nuclear.

Disclosures:
No relevant conflicts of interest to declare.
The Analysis of Fe3O4 Nanoparticles Combined with Daunorubicin for Neurotoxicity of Rat Brain In Vivo
Authors: Xu Peipei , Chen Bao-An , Wang Xue-mei , Li Jingyuan , Cai Xiao-hui , Jiang Hui 
Published: October 2019

Abstract
Abstract 4287

Introduction□F
The safety of these nano-systems for human body should be carefully studied for the potential clinical application. Here in this report, we firstly study the effect of anticancer drug daunorubicin (DNR) and Fe3O4 nanoparticles (NPs) for the neurotoxicity of rat brain. The microdialysis experiment gave the precise and real-time method to investigate the effect.

Method:
SD rats(240–250 g) were randomly assigned to three groups containing three rats in each group. Microdialysis Probes were deployed corpus striatum. Then the animals were solitary breed to recovery the wound for about 24 h. The different drugs systems were administered by vena caudalis injection. Amino acids were measured in dialysates by HPLC.

Results:
The results indicated that the anticancer drug DNR had the serious bad effect for the rat brain to cause the neurotoxicity by influencing the concentration changes of amino acids in which some excitatory amino acids (such as Asp) and the inhibiting amino acid (such as Gly) especially decreased and the inhibiting amino acid GABA increased. For the system of nanocomposites for DNR conjugated with Fe3O4 NPs, the side effect of DNR for these amino acids was visibly cut down, and the time for DNR to affect the side neurotoxicity for the rat brain was shorten.

Conclusion□F
So these nanocomposites for DNR conjugated with Fe3O4 NPs had the better biocompatibility and biosecurity in the application of cancer therapy in vitro and in vivo. These nanocomposites system had the potential prospect to be further studied and utilized in the clinic therapy.

Disclosures:
No relevant conflicts of interest to declare.
Should Generic Versions of Low Molecular Weight Heparins Be Considered As Generic or Biosimilar Drugs. A Regulatory Dilemma
Authors: Fareed Jawed , Jeske Walter , Hoppensteadt Debra , Wahi Rakesh , Hull Russell D 
Published: October 2019

Abstract
Abstract 4328
The patent protections for the low molecular weight heparin (LMWHs) enoxaparin, dalteparin and tinzaparin have expired and their generic respective versions are available. Despite widespread clinical use the global regulatory pathways to develop and approve these products remain unclear. In South America and Southeast Asia generic versions of LMWHs are available without adequate regulatory oversight. The EMEA has considered these agents as biosimilars and require both pharmaceutical and clinical data for approval. Unlike the EMEA, the US FDA requires data on the basic, chemical, and pharmacologic profiles without any clinical validation. In July 2010, the FDA approved a generic version of enoxaparin for all of the clinical indications for which the branded enoxaparin is approved. On the other hand, Initially the FDA had approved the different branded LMWHs as distinct drug entities, requiring clinical trials for each individual clinical indication. Generic enoxaparins from various manufacturers are marketed under different trade names even when they are manufactured by the same company. Although in the pharmacopeial assays these agents exhibit comparability, in the pharmacodynamic studies assay based differences have been reported. In a study conducted on two batches of Sandoz’s enoxaparin and Lovenox®, while no differences were noted in the molecular profile and anti-FXa activity, significant differences were noted in other assays such as thrombin generation inhibition and PF4 titration. Moreover, pharmacodynamic differences in primates after sc administration were also noted which were more obvious in the release of tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor assays (TAFI).As the manufacturing process of these agents may differ from manufacturer to manufacturer it is likely that certain compositional variations are not detectable by chemical methods. Thus the requirement of clinical trials to assure the safety and efficacy of these agents is an important consideration. Of concern is the disharmonization of pathways between different regulatory bodies which contribute to the complexity of this issue. It is proposed that the EMEA, FDA and other regulatory bodies develop some common global guidelines for the rationale development of these drugs.

Disclosures:
No relevant conflicts of interest to declare.
Study of Octaplex Dosing Accuracy: An In Vitro Analysis
Authors: Patriquin Christopher Jordan , Chin-Yee Ian H. , Kovacs Michael J. , Lazo-Langner Alejandro , Keeney Michael , Hsia Cyrus C. 
Published: October 2019

Abstract
Abstract 4335

Background:
Supratherapeutic INRs are common with warfarin therapy, and increase serious bleeding risk. Octaplex is a prothrombin complex concentrates (PCC) that is recommended for urgent warfarin reversal. However, disagreement exists regarding proper dosing strategies (fixed versus weight-based).

Objectives:
We sought to measure the in vitro effect of Octaplex on INR and factor levels, and to characterize this relationship.

Methods:
Plasma samples from eligible patients on warfarin with stable INRs for ≥4 weeks were collected. Plasma volumes were calculated to approximate 1000, 2000 and 3000IU doses of Octaplex and these were added to the samples. INR and factor levels were measured pre- and post-Octaplex.

Results:
Twenty-three of the 30 subjects enrolled had complete data for analysis. INRs corrected <1.5 in all samples post-1000IU, and decreased further with subsequent doses (p<0.001). Similar changes occurred in factors II, VII, and X (p<0.01). Linear correlations were seen between INR and factors II, VII and X. Factor IX did not increase incrementally or show a correlation with INRs. Weight-based dosing was then estimated. All INRs were <1.2 (0.9–1.2), and factor levels >0.50IU for II, VII and X (0.96–1.52, 0.51–1.45 and 0.81–1.38, respectively). Factor IX did not uniformly correct >0.50IU (0.31–1.31).

Conclusion:
We confirmed in vitro that 1000IU of Octaplex was able to correct INR to <1.5 but factor activity for II, VII and X was not uniformly >0.50IU until 2000IU, and >1.00IU not until 3000IU. Our study suggests that INR correction alone may not appropriately reflect sufficient factor activity, and lends support for weight-based PCC dosing.

Disclosures:
No relevant conflicts of interest to declare.