bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role and Mechanism Study of Lncrnas Involved in Glucocorticoid Resistance in Paediatric Acute Lymphoblastic Leukemia
Authors: Xiaowen Zhai , Fan Cuiqing , Wang Hongsheng 
Published: October 2019

Abstract
Objective: Glucocorticoids (GCs) are key components in the treatment of childhood acute lymphoblastic leukemia (ALL) and most ALL therapeutic failures can be explained by cellular resistance to GCs. However, the mechanisms of GC resistance are poorly understood. LncRNAs are involved in normal hematopoiesis and leukemia development, whereas the roles of lncRNAs in GC resistance are still unknown. Our goal was to investigate the role of lncRNAs involved in glucocorticoid resistance in paediatric acute lymphoblastic leukemia, and also elucidate the mechanism preliminarily.
Methods: In this study, lncRNA microarray was performed on GC-resistant cell line CEM-C1 and GC-sensitive cell line CEM-C7 to screen the differential expression of lncRNAs. Five up-regulated and five down-regulated lncRNAs were randomly chosen for validation by Real-time PCR. GO-Pathway analysis was done to investigate potential signaling pathways regulated by the lncRNAs.
Results: The microarray revealed that 4286 lncRNAs differed (p<0.05 and fold change>2.0) in GC-sensitive cell from those in GC-resistant cell. 826 lncRNAs changed more than 5-fold, while 356 lncRNAs changed more than 10-fold. Among them, 203 lncRNAs were up-regulated and 153 lncRNAs were down-regulated. Expression of ten selected lncRNAs was validated by Real-time PCR. GO analysis indicated that differentially expressed lncRNAs were involved in apoptotic process related GO terms. Pathway analysis revealed that these lncRNAs were involved in apoptosis, cell cycle, mTOR and some other signaling pathways.
Conclusions: Our study showed that lncRNA expression profile was altered in GC-sensitive and GC-resistant cells, indicating that differentially expressed lncRNAs may play important functional roles in GC resistance of ALL. And these lncRNAs may be involved in GC resistance by regulating signaling pathways associated with cell proliferation, differentiation and apoptosis. Our study provides new biological foundations for further mechanism study in GC resistance and also provides a new strategy for therapeutic development of ALL.

Disclosures
No relevant conflicts of interest to declare.
Phase I Study of Combination Chemotherapy Plus Ixazomib in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma (ALL)
Authors: Atallah Ehab , Michaelis Laura C , Carlson Karen B. , D'Souza Anita , Fenske Timothy S. , Pasquini Marcelo C. , Hamadani Mehdi , Baim Arielle , Guhl Jessica , Parameswaran Hari 
Published: October 2019

Abstract
Introduction: The outcome of adult patients with relapsed/refractory ALL remains dismal. In pediatric patients with relapsed/refractory ALL, the combination of vincristine, doxorubicin, pegaspargase, dexamethasone (VXLD) and bortezomib yielded significant response rates. Based on those results, this study was designed to test the safety of VXLD combined with the oral proteosome inhibitor Ixazomib in adult patients with relapsed/refractory ALL.
Study design: This was a phase I study combining vincristine 1.3 mg/m2 (maximum dose 2 mg) D1, 8, 15, and 22, doxorubicin 60 mg/m2 D1, PEGaspargase 2500 units/m2 (capped at 3750 mg) D2, D15, dexamethasone 10 mg/m2 D1-14, with escalating doses of ixazomib. Ixazomib dose was started at 2.3 mg D1, 8, and 15 aiming to increase the dose to 4 mg.
Results: Five patients were enrolled on the study between 10/1/13 and 2/26/16, prior to study termination. The median age was 49 years and 3 were female. Median number of prior regimens was 2 (range 2-3). At dose level one, 3 patients were enrolled. Of those patients, one developed grade 5 liver toxicity. That patient achieved complete remission, but died secondary to hyperbilirubinemia and liver failure. One patient developed grade 4 hyperbilirubinemia, did not respond to therapy and died from disease progression. The third patient developed transient grade 3 hyperbilirubinemia, had no response to treatment and went on to receive other therapies. Hepatic toxicities were attributed to pegaspargase. Based on that, the protocol was amended to remove pegaspargase (VXD + Ixazomib). Two patients were enrolled on dose level one (2.3 mg). One patient developed grade 5 infection. Due to increased toxicity in this population, the study was terminated.
Conclusion: In our experience, VXLD and VXD were poorly tolerated in adult patients with relapsed/refractory ALL. Ixazomib should be studied with other chemotherapy combinations in adults with relapsed/refractory ALL.
Table Table.

Disclosures
Atallah: Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Hamadani:Takeda: Research Funding. Parameswaran:Takeda: Consultancy.
Mesenchymal Stromal Cells Expressing Interferon α Limit the Development of Acute Myeloid Leukemia, Inducing Apoptosis In Vitro and In Vivo
Authors: Desbourdes Laura M , Guess Adam J , Hasgur Suheyla , Overholt Kathleen M , Yu Minjun , Otsuru Satoru , Horwitz Edwin M 
Published: October 2019

Abstract
Introduction
The 5-year survival for patients with acute myeloid leukemia (AML) has stagnated for over two decades at about 60% for children, 40% for young adults, and <15% for elderly patients. While most patients achieve remission, approximately 50% will relapse which is generally attributed to the persistence of leukemic stem cells. Interferon α (IFNα) is an effective therapy for patients with AML due to multiple mechanisms of action. However, high serum levels are associated with many adverse effects. In this proof-of-concept study, we used engineered mesenchymal stem/stromal cells (MSC) to deliver high concentrations of IFNα locally to an AML chloroma, potentially diminishing the poorly tolerated systemic side-effects.
Methods
Bone marrow MSCs from C57BL/6 mouse were isolated and transduced with a lentiviral vector expressing murine IFNα (IFNα-MSCs) and/or GFP (GFP MSCs). After measuring IFNα secretion by ELISA and confirming activity by the induction of the MHC I expression on the transduced cells, the anti-AML activity of these transduced MSCs was assessed by co-culture with the C57BL/6 AML cell line c1498 which expresses DsRed and firefly luciferase (FFluc). Apoptotic cell frequencies and cell cycle phase distributions of leukemia cells with or without MSCs were assessed by flow cytometry. The in vivo validation has been performed by subcutaneous injection of c1498 cells (chloroma) with or without GFP MSCs or IFNα MSCs in C57BL/6 mice. Tumor growth was monitored by bioluminescence imaging every 3 or 4 days.
Results
Flow cytometric analysis and ELISA confirmed the secretion of bio-active of IFNα by transduced MSCs (41.5 ng/1E06 MSCs/24h). In co-cultures, the presence of IFNα MSCs at the ratio 100:1 (c1498: MSC) significantly decreased the population of c1498 cells mainly by inducing apoptosis compared to MSC-free or GFP MSC co-cultures while no effect was observed on cell cycle distribution. The pro-apoptotic effect of IFNα MSCs was then investigated in vivo by subcutaneous injection of c1498 cells with or without MSCs (ratio 10:1) in C57BL/6 mice.The presence of IFNα MSCs significantly decreased leukemic cell mass as shown by the bioluminescence of the DsRed+ FFLuc+ c1498 cells. This result was confirmed by flow cytometric analysis of the percentage of DsRed + cells in the chloroma.
Conclusions
This study shows that IFNα MSCs present a strong anti-leukemic effect in vitro and in vivo promoting apoptosis and thus decreasing the leukemic burden. Further experiments will focus on a potential synergetic effect with Cytarabine treatment and a preclinical study using human IFNα MSCs in a xenograft murine model.

Disclosures
No relevant conflicts of interest to declare.
DNMT3A Mutation inChinese Childhood Acute Myeloid Leukemia
Authors: Li Weijing , Gao Chao , Cui Lei , Liu Shuguang , Zhao Xiaoxi , Zhang Ruidong , Zheng Huyong , WU Minyuan , Li Zhigang 
Published: October 2019

Abstract
Purpose DNMT3A mutation has been found in approximately 20% of adult acute myeloid leukemia (AML) patients and in 0~1.4% of children with AML, and the hotspots of mutations are mainly located in the catalytic methyltransferase domain, thereinto, mutation R882 accounts for 60%. Although the prognosis of adult patients with DNMT3A mutations is dismal, the prognosis of DNMT3A mutation in childhood AML is still unclear. Here, we tried to determine the incidence and prognostic significance of DNMT3A mutations in Chinese childhood AML.
Methods We detected the mutations in DNMT3A exon 23 by PCR and direct sequencing in 342 children with AML (0~16 years old) from January in 2005 to June in 2013, treated on BCH-2003 AML protocol. The correlation of DNMT3A mutations with clinical characteristics, fusion genes, other molecular anomalies (FLT3-ITD, NPM1, C-KIT and WT1 mutations), and treatment outcome were analyzed.
Results DNMT3A mutations were detected in 4 out of 342 (1.2%) patients. The mutations in coding sequences included S892S, V912A, R885G, and Q886R. Furthermore, there were two intronic mutations (c.2598-15C>T and c.2739+55A>C) found in one patient. No association of DNMT3A mutations with common clinical features was found. Two patients with DNMT3A mutations died of relapse or complications during treatment, one patient gave up treatment due to introduction failure in day33. Only one patient achieved continuous complete remission.
Conclusions DNMT3A mutations were rare in Chinese children with AML. The mutation positions were different from the hotspots reported in adult AML. DNMT3A mutations may have adverse impact on prognosis of children with AML.

Disclosures
No relevant conflicts of interest to declare.
Dynamics of Molecular Response in AML Patients with NPM1 and FLT3 Mutations Undergoing Allogeneic Stem Cell Transplant
Authors: Salem Rana , Massoud Radwan , Mahfouz Rami , Bazarbachi Ali , El Cheikh Jean 
Published: October 2019

Abstract
BACKGROUND: Concomitant NPM1 and FLT3 mutation occurs in 20% of AML patients. Molecular response and achievement of negative minimal residual disease (MRD) are strong predictors of long-term outcome. However, little is known about the dynamics of molecular response in NPM-1 and FLT-3 double positive mutations.
OBJECTIVE: To assess the dynamics of molecular response to treatment in AML adult patients with concomitant FLT3 and NPM1 mutations.
DESIGN: Retrospective single center study.
SETTING: This study was approved by the institutional review board of American University of Beirut Medical Center.
PATIENTS OR OTHER PARTICIPANTS:
Twelve consecutive newly diagnosed (n=11) or relapsed (n=1) AML patientsreceived Idarubicin/cytarabineinduction and one or two consolidation(s) (Table 1). Ten patients received allogeneic stem cell transplant (allo-SCT) followed by post-transplantsorafenibmaintenance. Median follow-up was 11.5 (6-27) months. All transplanted patients remain alive and disease free.
INTERVENTIONS: FLT3 mutation was tested on DNA using a qualitative method with a sensitivity of0.01%. NPM-1 mutation was tested on cDNA using a qualitative or a quantitative RT-PCR with a sensitivity of 0.01% and0.008 NCN respectively. Patients were tested at diagnosis, after induction, after each consolidation, before and at days 30, 60 and 100 afterallo-SCT.
MAIN OUTCOMES MEASURES: Kinetics of NPM1 and FLT3 molecular response.
RESULTS:
After induction, FLT3 became negative in all tested patients (n=10). After first consolidation, FLT-3 remained or became positive in 10/11 tested patients whereas a molecular relapse was noted in one patient who developed a hematological relapse and rapidly died. No molecular positivity for FLT-3 was noted later on, whether after second consolidation or post-transplant. Conversely, NPM-1 mutation became negative in 2 out of 12 tested patients after induction, in 1 additional patient after first consolidation and in 6 additional patients afterallo-SCT, mostly after startingsorafenib. NPM-1 MRD value remained elevated in 3 out of 4 patients with quantitative assessment at diagnosis and post induction.
CONCLUSION: FLT3 become negative early after induction while NPM1 negativity lags behind. Persistent NPM-1 MRD does not seem to predict post-transplant outcome and may indeed become negative after sorafenib. These results need confirmation in larger studies.
Figure Dynamics of NPM1 and FLT3 Molecular Response Figure. Dynamics of NPM1 and FLT3 Molecular Response

Disclosures
No relevant conflicts of interest to declare.
Leukemia Stem-like KG-1a Cells Escape the Synergistic Cytotoxic Effect of Arsenic Trioxide and Aclacinomycin: Regulated By Survivin
Authors: Ye Yongbin , Xu Xiaojun , Liu Qifa 
Published: October 2019

Abstract
Leukemia stem-like KG-1a cells escape the synergistic cytotoxic effect of arsenic trioxide and aclacinomycin: regulated by survivin
Yongbin YE1 , Xiaojun.XU1 , Liu Qifa2
Correspondence to: Xiaojun XU. E-mail: doctorxu@163.com
1Department of Hematology, Zhongshan Hospital of Sun Yat-sen University & Zhongshan City People Hospital, Zongshan 528403
2Department of Hematology, Nanfang Hospital of Southern Medical University, Guangzhou,510515
Abstract AIM OF STUDY: Arsenic trioxide combined with aclacinomycin has a synergistic cytotoxic effect on leukemia stem cell-like cells KG-1a in our pervious study, however, there are still a part of KG-1a cells escaped the synergistic cytotoxicity, survivin may plays in a key role in this process. In this study, we have studied the interaction and mechanism of survivin in regulating leukemia stem-like KG-1a cell escape the synergistic cytotoxic effect of arsenic trioxide and aclacinomycin. MATERIALS AND METHODS: The anti-proliferation effect was detected by CCK-8 and colony-forming assay, protein-protein chip assay was used to analysis the expression level of survivin before and after combination treatment. The induction of apoptosis and cell cycle arrest in KG-1a cell line were detected by FACS, the expression of related signal pathway protein was detected by western blot. RESULTS: The anti-proliferation of KG-1a cells caused by arsenic trioxide or aclacinomycin showed a time- and dose-independent manner. However, protein-protein chip assay showed that the expression of survivin had a significant increase after the combination treatment (p<0.05), but when survivin was suppressed, the apoptosis rate had a more significant increase than the single drug treatment. Meanwhile, more prominent cell cycle arrest was observed in the combination treatment, further study found that suppression of survivin combined with chemotherapy may activate the related apoptosis pathway protein but suppress the PI3K/AKT signal pathway. CONCLUSION: survivin play an important role in regulating leukemia stem cell escape the synergistic cytotoxic effect of arsenic trioxide and aclacinomycin. The mechanism of regulation process may through activate the related apoptosis pathway protein and supperss the PI3K/AKT signal pathway. This study may provide a further benefit for reversing chemotherapy resistant for acute leukemia
Key words: arsenic trioxide,aclacinomycin, Acute leukemia; survivin; chemotherapy resistant

Disclosures
No relevant conflicts of interest to declare.
Comparative Analysis Between RQ-PCR and Digital Droplet PCR of BCL2/IGH Rearrangement in the Peripheral Blood and Bone Marrow of Early Stage Follicular Lymphoma
Authors: Cavalli Marzia , De Novi Lucia Anna , Della Starza Irene , Cappelli Luca , Nunes Vittorio , Pulsoni Alessandro , Del Giudice Ilaria , Guarini Anna , Foa Robin 
Published: October 2019

Abstract
Figure Figure.

Disclosures
No relevant conflicts of interest to declare.
The Addition of Novel Agents to Front-Line Therapy Significantly Improve the Short-Term and Long-Term Therapeutic Effects of High Risk Waldenstrom's Macroglobulinemia Patients in China
Authors: Xiong Wenjie , Yi Shuhua , Li Heng , Li Zengjun , Lv Rui , Liu Wei , Xu Yan , Zou Dehui , Hao Mu , Qiu Lugui 
Published: October 2019

Abstract
Background: Waldenstrom's Macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltrated by B cell, lymphoplasmacytic cells and plasma cells. Some studies have shown that novel agents such as Rituximab and Bortezomib combined chemotherapy could improve WM patients' survival. However, few studies had focused on the efficiency of these agents on ISSWM intermediate or high risk group and no systematical investigations had been published for the Eastern WM patients.
Methods: We systematically reviewed the records of 91 WM patients with intermediate or high risk ISSWM group, who had been diagnosed at Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences& Peking Union Medical College.
Results: There was male predominant (75.8%) for the entire population, with a median age of 62 years (range32-87) at diagnosis. There were 36(39.6%) and 55(60.4%) patients in the intermediate or high risk ISSWM group, respectively. The percentage of hepatomegaly, splenomegaly, B symptomand elevated LDH were 16.9%, 34.1%, 33.3% and 18.6%, respectively. Among them, 36 patients received novel agents combination first-line chemotherapy and 55 patients received conventional chemotherapy. The complete remission (CR) rate and overall response rate(ORR) were 26.5% and 76.5% in the novel agent group respectively, which were higher than the conventional group( 26.5% v.s. 10%p=0.047; 76.5% v.s.56%, p=0.055). With a median follow-up of 35 months, The novel agent group induced a significantly longer progression-free survival (PFS) compared with the conventional group (77months v.s.45 months, p=0.04).The mediate overall survival (OS) in the novel agent group was not reached, which was also significantly longer than the conventional group(NR v.s. 62months,p=0.045).
Conclusion:Compared with the conventional therapy, the novel agent combination significantly improved the short-term and long-term therapeutic effects in intermediate/high risk patients of WM.

Disclosures
No relevant conflicts of interest to declare.
Post Transplant Brentuximab Maintenance Appears More Effective Than Post Transplant Salvage Brentuximab for Relapsed/Refractory Hogkin's Lymphoma
Authors: Chidiac Amanda , Massoud Radwan , Haidar Mohamad , Fares Elie , Bazarbachi Ali , El Cheikh Jean 
Published: October 2019

Abstract
POST TRANSPLANT BRENTUXIMAB MAINTENANCE APPEARS MORE EFFECTIVE THAN POST TRANSPLANT SALVAGE BRENTUXIMAB FOR RELAPSED /REFRACTORY HODGKIN LYMPHOMA
Amanda Chidiac1, Radwan Massoud 1, Mohamad Haidar1, Elie Fares1, Ali Bazarbachi1 and Jean El Cheikh1
1Bone Marrow Transplantation Program, American University of Beirut Medical Center, Beirut, Lebanon
Keywords: Hodgkin Lymphoma, Relapsed/Refractory, Brentuximab.
Context: Brentuximab Vedotin (BV) is a chimeric anti CD30 IgG1 antibody, conjugated to synthetic antitubulin momomethyl auristatin. BV is approved for the treatment of classical HL in relapse either after autologous stem cell transplantation (ASCT) or after two lines of combination chemotherapy in transplant ineligible patients. The AETHERA trial revealed increased PFS when BV is used as maintenance therapy after ASCT.
Objective: Compare the effectiveness of BV as maintenance or salvage therapy after ASCT for relapsed/refractory (R/R) HL.
Design: A retrospective analysis conducted on patients with R/R HL treated with BV after ASCT either as maintenance or salvage therapy. Analysis after a median follow up of 12 months is reported.
Setting: The study was conducted in a single institution; American University of Beirut Medical Center (AUBMC) after IRB approval.
Patients: The study included 15 adult patients with R/R HL treated with BV with the following indications:
á Maintenance therapy after ASCT in high risk patients
á Salvage therapy for relapse after ASCT or allo-SCT
Intervention: BV at 1.8mg/kg IV every 4 weeks for the above indications.
Main outcome measures: response rate (RR), overall survival (OS) and progression free survival (PFS).
Results: Nine high-risk patients (60%) received 4 cycles of BV as maintenance therapy post ASCT. Six additional patients (40%) in relapse after ASCT (n=5) or after allo-SCT (n=1) received BV as salvage therapy for an average of 4 cycles (range 3-21). Patients characteristics are listed on Table 1. RR was 33% in 6 patients who received BV as salvage post SCT. Two patients proceeded with allo-SCT in the salvage group. After a median follow up of 9 months, only 2 patients (22%) in the maintenance group progressed and all patients are still alive. Conversely, in the salvage group, 4 patients (67%) progressed and 1 patient developed secondary AML and died.
Conclusion: BV therapy showed an efficacy only as maintenance treatment after auto-SCT but was less successful when used as post-transplant salvage in R/R HL. Four cycles of maintenance may suffice. Prospective trials with larger samples are warranted to support these findings.

Disclosures
No relevant conflicts of interest to declare.
Treatment of Drug-Resistant Forms of Mycosis Fungoides/Sezary Syndrome
Authors: Gorenkova Liliya , Penskaya Ekaterina , Kravchenko Sergey , Kovrigina Alla , Savchenko Valeriy G. 
Published: October 2019

Abstract
Mycosis Fungoides (MF) and leukemic variant - Sezary Syndrome (SS) are the most frequent diseases among cutaneous T-cell lymphomas. These tumors have a chronic progradient nature. Up to present time there is no evident of effective therapy, particularly late-stage of diseases.
About 30% of patients have no effect from interferon, radiotherapy and combined treatment regimens. Older age (median age - ...) of such patients limits therapy options. Several lines of previous treatment lead to tumor resistance and higher accumulated toxicity. Thus, use of potentially effective chemotherapeutic agents in lower doses will reduce myelotoxicity and increase the cohort of patients. Gemcitabine is an effective medication in treatment of MF/SS. Its efficacy is preserved in small doses with prolonged duration of infusion and allows decreasing myelotoxicity. It was firstly discovered in therapy of solid tumors.
In current study were involved 14 patients with resistant forms of MF/SS (10 patients - GM 3 - SS, 1 case GM transformation into large cell lymphoma). We used 6-hour infusion of gemcitabine at dosage of 250 mg/m2. 86% of patients achieved a general response: 29% complete remission, 50% - partial remission, 21% - stabilization of disease, 14% (2 patients)-progression.
Present study showed promising results in treatment of patients with advanced stages of MF/SS which had at least two preceding lines of therapy without an effect. Common response (PR/CR) was received in high percent of cases. This treatment protocol is reproducible in elderly patients. For long-term conclusions further studies are needed.

Disclosures
No relevant conflicts of interest to declare.