bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study): Pronostic Consideration
Authors: Millot Frédéric , Guilhot Joelle , Suttorp Meinolf , Sedlacek Petr , de Bont Eveline S.J.M. , Li Chi Kong , Kalwak Krzysztof , Lausen Birgitte , Srdjana Culic , Dresse Marie-Francoise , Biondi Andrea , Baruchel Andre 
Published: October 2019

Abstract

Aims: An international registry (I-CML-Ped Study)was established to assess epidemiology, management and outcome of CML in the pediatric population.
Methods: All national pediatric study groups were invited to include newly diagnosed children and adolescents less than 18 years with CML diagnosed later than January 2000.
Results: Since January 2011, 351 patients from 12 countries have been registered. Clinical and biological data at initial diagnosis are available in 278 patients.There was a male preponderance (57%). The median age at diagnosis was 12.4 years (range, 9 months -17.5 years); 6% of the patients were younger than 4 years. At time of diagnosis 92% of the children were in chronic phase, 8% in accelerated phase and 1% in blastic phase according to the European Leukemia Net criteria. The Sokal risk group distribution was: 18% low, 31% intermediate and 51% high risk. The majority of the patients showed a Lansky score of 100 (59%) or 90 (21%). Splenomegaly was present in 76% of patients. The median of the spleen size below the costal margin was 11 cm (range: 1 to 25 cm). The median of the leukocyte count was 235x109/L (range: 5 to 1038). Additional chromosomal abnormalities in Ph-positive cells were observed in 6 % of the patients. The BCR-ABL transcript type was available in 227 patients: b3a2 54%, b2a2 38%, b3a2-b2a2 6% and b2a3 2%. The median follow-up time is 39 months (range, 0.5-161). Eight deaths were recorded. The estimated overall survival rate at 60 months is 95% (95%CI 89-97). Irrespective of treatment and follow-up, 124 (73%) of 169 assessable patients for cytogenetic response achieved complete cytogenetic response (CCyR). Exploratory analyses were performed in newly diagnosed patients regarding clinical and biological factors influencing the achievement of CCyR 12 months after starting imatinib. In univariate analyses, the Eutos score, the spleen size, the hematocrit level, the lymphocyte count and immature cells in peripheral blood, the percentage of granulocytes and monocytes in the marrow were identified as potential prognostic factors. However, only the percentage of the granulocytes in the marrow was identified as independent factor of achievement of CCyR at 12 months in multivariate analysis. Data collection and quality control regarding molecular assessment are ongoing.
Conclusion: The data indicates that children and adolescents with CML presented with clinical and biological differences compared to adult patients with CML. Identification of prognostic factors is needed to optimize the strategy in the pediatric population.
Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company

Disclosures
No relevant conflicts of interest to declare.
Artesunate Enhanced Apoptosis of Human High Risk MDS Cells Induced By the DNMT Inhibitor Decitabine
Authors: Ying Wang , Zhiyun Niu , Shupeng Wen , Fuxu Wang , Xuejun Zhang 
Published: October 2019

Abstract
Abstract: The present study evaluated whether the artesunate (ART) could enhance the apoptosis induced by decitabine (DAC) in SKM-1 cells, and to explore its potential mechanisms. Cytotoxicity of the combination of ART and DAC on SKM-1 cells was detected by CCK-8 assay and the apoptosis rate of high-risk myelodysplastic syndrome (MDS) cell line, SKM-1 cells was measured by flow cytometry. Protein expression levels of activated caspase-3, caspase-9, caspase-8, cleaved PARP and AIF in SKM-1 cells were measured by Western blot. Laser confocal microscope analysis showed AIF transfer to the nucleus. The growth inhibition rate and the apoptosis rate of SKM-1cells treated with the combination of ART and DAC was significantly increased compared with that of SKM-1 cells treated with the single agent (P<0.05). Both ART and DAC could induce caspase-dependent apoptosis, while ART, but not DAC, also induced caspase-independent apoptosis via AIF transfer from mitochondria to the nucleus. Additionally, the combination of the two agents induced cell death was not attenuated by caspase3,7 inhibitor Ac-DEVD-CHO. Our result suggested that the ART–DAC combination was more effective than single-agent therapy in vitro. Both compounds not only activated caspase-dependent pathway but also activated a caspase-independent mitochondrial pathway.

Disclosures
No relevant conflicts of interest to declare.
Establishment of TRAIL-Resistance Kasumi-1 Cell Line and the Analysis of It different mRNA Expression Profile with the Original Kasumi-1 Cell Line
Authors: Jiang Xuewei , Zengkai Pan , Jin Chen , Pengfei Yu , Liu Li-Gen 
Published: October 2019

Abstract
Introduction
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) can induce the apoptosis of many human leukemia cells while sparing of normal cells, but its resistance is also universal. Our previous study on apoptosis of t(8;21) positive acute myeloid leukemia cell line Kasumi-1 induced by rhTRAIL showed that the survival rate no longer decreased significantly when rsTRAIL reached a certain concentration which implied Kasumi-1 cells might have a resistant tendency to TRAIL. Then, we established a TRAIL-resistant Kasumi-1 cell line (Kasumi-1 TR) by intermittently escalating rsTRAIL concentration in culture media, and compared the mRNA expression profile with the original Kasumi-1 cell line by using Affymetrix Human Genome U133 Plus 2.0 Array.
Methods
Kasumi-1 TR cell line was established by intermittently treated Kasumi-1 cells with progressively escalating rsTRAIL concentration. Proliferation of leukemia cells were measured by CCK-8 assay, and rsTRAIL IC50 of cells and resistance index were calculated according to proliferation of cells treated with rsTRAIL at different concentrations. TRAIL and TRAIL receptors 1-4 on cells surface were detected by flow cytometry. Expression profiles of Kasumi-1 cells and Kasumi-1 TR cells were analyzed by Affymetrix Human Genome U133 Plus 2.0 Array to identify differentially expressed genes, and the search of genes possibly related with TRAIL-resistance were using by GO functional analysis and pathway enrichment analysis.
Results
1) Kasumi-1 TR cells proliferation was faster than that of Kasumi-1 cells(Fig 1A); 2) IC50 of 24 hours for Kasumi-1 cells was 756.833ng/ml (logIC50 2.879 ± 0.148), IC50 of 24 hours for Kasumi-1 TR cells was 1634646.005ng/ ml (logIC50 6.213 ± 0.637), the RI of 24h was 2159 (Fig 1B); IC50 of 48 hours for Kasumi-1 cells was 345.390ng/ml (logIC50 2.538 ± 0.153), IC50 of 48 hours for Kasumi-1 TR cells was 33642.641ng/ml (logIC50 is 4.257 ± 0.317), the RI for 48h was 97 (Fig 1C); 3) Cell surface expression of TRAIL and its receptors 1-4 had no difference between two cell lines(Fig 1D). 4) There were 1537 genes up regulated by more than 2 times while 487 genes down regulated by more than 2 times in Kasumi-1 TR cells compared with the original Kasumi-1 cells (Fig 1E). Of which BCL-2 family antiapoptotic gene BCL2 is increased by 3.153 times and BCL2A1 increased by 18.23 times, IFNAR1 involved in JAK/STAT pathway increased by 12.841 times and TRAIL death receptor TNFRSF10A down regulated by 3.256 times(Fig 1F).
Conclusions: The Kasumi-1 cell line with rsTRAIL resistance (Kasumi-1 TR) is established, and its resistance may be associated with the up expression of BCL2, BCL2A1, IFNAR1 and down regulated expression of DR4.
Acknowledgment
This work was supported by grants from NSFC (30672415) and STCSM (054119528).
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
The Outcome of Childhood High-Risk Acute Lymphoblastic Leukemia: 10 Years of Experience with the ALL-BFM 95 Protocol in Chinese Single Centre
Authors: Ruan Yongsheng , Wu Xuedong , Li Chunfu , Feng Xiaoqin 
Published: October 2019

Abstract
Objectives: To evaluate the effectiveness and the practicability of Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 95 (ALL-BFM 95) protocol in treating childhood high-risk (HR) acute lymphoblastic leukemia (ALL) in Chinese single centre.
Methods: A retrospective analysis of 47 children with novo high risk ALL from July 2003 and August 2013 was performed. These children treated by the ALL-BFM 95 protocol. Median follow-up time was 39 months (16~127months). Survival was evaluated by Kaplan Meier analysis and Log-Rank test.
Results:Relapse-related death occurred in 12 of 47 patients (25.5%), and 5 of 47 patients (10.6%) were treatment-related mortality. Five-year probability of event-free-survival (pEFS) were found to be 62.4%. High risk ALL children only with prednisone poor response(PPR) has good outcome who’s Five-year probability of event-free-survival (pEFS) could reach to 80%. Children with hematopoietic stem cell transplantation (HSCT) after chemotherapy achieved significantly better pEFS than only chemotherapy (77.3% vs 51.6%，p=0.035). pEFS for B-cell precursor and T-cell ALL was 64.5% and 57.1%, respectively（P=0.633）.
Conclusions: ALL-BFM 95 protocol can also improve the outcome of childhood high risk ALL in China. The leading causes of death were relapse. HSCT treatment had better outcome than only chemotherapy in high risk ALL children in CR1 phase.

Disclosures
No relevant conflicts of interest to declare.
The Prevalence of Congenital Trombophilia in Children Treated for Acute Lymphoblastic Leukemia with Thrombosis As a Complication
Authors: Smalisz-Skrzypczyk Katarzyna , Klukowska Anna , Pawelec Katarzyna , Matysiak Michal 
Published: October 2019

Abstract
The aim of the study was to evaluate factors predisposing to thrombosis, especially congenital trombophilia, in children treated for acute lymphoblastic leukemia according to ALL IC BFM 2002 and 2009.
An analysis of 36 cases of thrombosis in 242 children (15%) treated due to ALL in the Department in years 2007-2013 was carried out. Age at onset, location, cause and treatment methods were taken into consideration. All analyzed patients underwent screening for congenital thrombophilia.
The age of patients ranged from 1.5 to 17 years with the median of 8.5 years. Arterial thrombosis occurred in 2 persons (1%), venous thrombosis in 34 (99%) patients. Thromboembolism was usually related to the central venous catheter (n = 31, 91%). Massive thrombosis occurred in 7 patients (20%). Relapses occurred in 3 children.
The most common causes of thrombosis were: the presence of the central catheter (n = 31, 91%) and L-asparaginase treatment (n = 19, 55%). The factor V Leiden mutation was diagnosed in 1 patient, protein C deficiency in 1 patient as well, and elevated levels of factor VIII were detected in 4 cases.
The mean concentrations of factor VIII, von Willebrand factor and antithrombin were not different in the groups with and without thrombosis (table 1 ). The concentration of fibrinogen measured after finishing the chemotherapy was similar in both groups.
Conclusions 1. A risk factor for thrombosis in children with ALL is the treatment of L-asparaginase and the presence of central venous catheter.
2. Screening for congenital thrombophilia in children treated for ALL should not be done routinely because the coexistence of this two conditions is rare. Table 1FVIII (%)Fibrinogen ( g/l)AT (%)Patients with thrombosis1012,776Patients without thrombosis892,4382p0,45 ( ns)0,2 (ns)0,34 (ns)

Disclosures
No relevant conflicts of interest to declare.
Low Efficacy and High Mortality Associated with Clofarabine Treatment of Patients with Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes
Authors: Roberts Daniel A , Wadleigh Martha , McDonnell Anne , DeAngelo Daniel J , Stone Richard M. , Steensma David P. 
Published: October 2019

Abstract
Background: Clofarabine, a second-generation nucleoside analogue, has been shown in prospective studies to have activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of the drug in populations of patients not enrolled in clinical trials.
Methods: We reviewed clinical outcomes for 84 patients treated at our center off-study for relapsed or refractory AML (n=81) or MDS (n=3) with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Almost all patients (n=62) receiving combination therapy were administered cytarabine 1 g/m2/day on days 1-5 and clofarabine 40 mg/m2/day on days 2-6 (Faderl et al Blood 2005; 105:940), while monotherapy dosing ranged from 15-30 mg/m2/day x 5 days.
Results: Median age of patients was 51 years; 54% were male. The median prior salvage regimens received was 1 (range, 0-5). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR = CR + CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal significant variation in response rates when comparing age, performance status, or prior number of salvage regimens. 30-day mortality or induction death for all patients, combined therapy, and monotherapy was 21%, 23%, and 16% respectively. Overall median survival for all patients was 3 months; a subset of 12 patients who were able to go to allogeneic stem cell transplant had an 18-month median survival.
Conclusion: Clofarabine’s efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. Clofarabine's utility in relapsed/refractory AML/MDS may be primarily for cytoreduction in patients who have an allogeneic transplant option.

Disclosures
Off Label Use: Clofarabine- a second-generation nucleoside analogue approved for pediatric acute lymphoblastic leukemia..
Gene Expression Profiling in the Classification of Acute Leukemia Brazilian Patients
Authors: Melo Carolina Pereira de Souza , Campos Catharina Brant , Dutra Alvaro Pimenta , Atalla Angelo , Dudeque Pianovski Mara Albonei , Carbone Edna Kakitani , Quintão Lares Luciana , Souza Hélio Moraes , Silva Shirlei Octacilio , Ferreira Alessandro Clayton de Souza , Assumpcao Juliana Godoy 
Published: October 2019

Abstract
In the past few decades, genetic data has become increasingly important for acute leukemia diagnosis and patients stratification. Indeed, the present World Health Organization (WHO) leukemia classification system is largely based upon genetically defined subgroups. Gene expression profile (GEP) may correctly predict most genetic leukemia subtypes, but so far no GEP report has evaluate patients from Latin America. In the present study, we used gene expression microarray data to build an acute leukemia classifier. Bone marrow samples were collected from 231 individuals at diagnosis, 110 presented de novo acute myeloid leukemia (AML), 97 had de novo acute lymphoid leukemia (ALL) and the remaining 24 were controls who had other conditions including chronic leukemias or non-hematological diseases. GEP was evaluated based on mRNA expression signatures obtained with the Sure Print G3 Human GE (60k) system (Agilent Technologies). k-nearest neighbors prediction algorithm was applied and the top 60 informative genes were selected for each of the most prevalent genetic subtypes (T-ALL, B-ALL BCR-ABL, B-ALL ETV6-RUNX1, B-ALL TCF3-PBX1, AML PML-RARa, AML RUNX1-RUNX1T1, AML FLT3-ITD, AML NPM1mut). The less prevalent groups such as MLL rearranged and CBFB-MYH11 were not included in the classifier because of the low number of patients carrying these aberrations in our cohort. Performance of each prediction model was assessed by leave-one-out crossvalidation through the GenePattern platform (Broad Institute). The average classifier accuracy was 94.75%. Higher accuracy and precision were achieved for T-ALL (99%/96%) and AML PML-RARa (97%/97%). However, for ALL BCR-ABL, AML FLT3-DIT and AML NPM1mut the gene signature had low precision rates (74%, 66% and 80%, respectively). The data presented here confirm that a single platform of gene expression followed by bioinformatic analysis can correctly classify genetic subgroups, but a refinement of the classifier developed is needed in order to improve the detection of heterogeneous entities such as BCR-ABL or FLT3-ITD carriers.

Disclosures
No relevant conflicts of interest to declare.
Predictive value of therapeutic monitoring with plasma Epstein-Barr virus DNA in Extranodal NK/T cell lymphoma, nasal type
Authors: Guo Chengcheng , Huang He , Tian Ying , Li Xueying , Zhang Mengping , Hong Huangming , Fu Xiaohong , Lin Xiaoting , Li Shanshan , Prem Raj Shrestha , Xia Zhongjun , Lin Tongyu 
Published: October 2019

Abstract
Predictive value of therapeutic monitoring with plasma Epstein-Barr virus DNA in Extranodal NK/T cell lymphoma, nasal type
Background: Predictive tumor markers are essential for extranodal NK/T cell lymphoma, nasal type (ENKTL), which pursues an aggressive clinical course with poorer prognosis. This prospective study was conducted to evaluate the dynamic monitoring value of circulating EBV DNA concentration for the prediction of ENKL during treatment.
Method: Patients with untreated, centrally reviewed diagnosis of ENKTL were included in our study. Plasma Epstein-Barr virus (EBV) DNA levels were collected before and/or every 2 cycles of chemotherapies for circulating EBV DNA measurement by a real-time PCR assay.
Result: From Jan 2002 to Aug 2012, 113 newly diagnostic ENKTL patients enrolled. The positive rate of circulating EBV DNA is 61.9% (70/113) with a median concentration of 1.21×103copies/ml. Patients who had initial positive circulating EBV-DNA had more lymph nodes invasion, higher IPI and KPI score. The more advance of the stage, the higher rate of the circulating EBV-DNA positive. When divided the positive group as low and high-dose ones by the cut-off value as 2×104copies/ml, the CR rate of the high-dose group is much lower and the 5-year OS is significantly better than the low-dose group and the negative group. After two cycles of chemotherapy, 45 patients were tested circulating EBV-DNA and 53.33% (24/45) patients became negative EBV-DNA candidates. There were 87.5% (21/24) patients obtained complete remission at the end of the treatment, comparing as 42.86% (9/21) in the still positive EBV-DNA groups(P= 0.002). There is a tendency that the patients whose circulating EBV-DNA become negative after two cycles will have better prognosis (5-year OS: 75% vs 46%, P=0.074). The similar situation of CR rate and OS happened in the EBV-DNA detection of completion of total chemotherapy. 7 of 13 relapsed pts of ＞1×103copies/ml EBV-DNA at the time of recurrent, and the survival outcome was dismal for them compared to the other 6 pts of ≤1×103copies/ml（5- year OS: 0% vs 80%, P=0.001）
Conclusion: Circulating EBV-DNA level can predict the efficacy of treatment as a dynamic marker of ENKL. Patients with early positive detection of EBV-DNA after 2 cycles of chemotherapy maybe received more aggressive treatments.

Disclosures
No relevant conflicts of interest to declare.
Effect of High Body Mass Index on the Prognosis of Diffuse Large B-Cell Lymphoma
Authors: Hattori Yukako , Tomita Naoto , Suzuki Taisei , Ishiyama Yasufumi , Kishimoto Kumiko , Koyama Satoshi , Takahashi Hiroyuki , Miyashita Kazuho , Nakajima Yuki , Motohashi Kenji , Takasaki Hirotaka , Kawasaki Rika , Hashimoto Chizuko , Fujimaki Katsumichi , Sakai Rika , Fujisawa Shin , Motomura Shigeki , Ishigatsubo Yoshiaki 
Published: October 2019

Abstract
Background
Obesity has been pointed out as one of the risk factors for the development in several neoplastic diseases including malignant lymphoma. However the impact of obesity on the outcome of malignant diseases is unclear. L.Weiss et al have shown that high body mass index (BMI) is a significantly better prognostic factor in diffuse large B-cell lymphoma (DLBCL) (Increased body mass index is associated with improved overall survival in diffuse large B-cell lymphoma. Annals of Oncology 2014; 25: 171-176.). We evaluated this hypothesis in Japanese patients with DLBCL.
Patients and Methods
We analyzed 338 patients with newly diagnosed DLBCL who received full-dose (80% or more of the prescribed dose) R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) between April 2003 and December 2009 across 7 institutes. Patients of all stages were treated 6 or 8 cycles of full-dose R-CHOP therapy. All the patients were classified into 2 groups: high BMI (≥25 kg/m2 ) or low BMI (<25 kg/m2).
Results
The median patient age was 65 years (19–80 years); 192 were men and 146 were women. The median BMI was 22.9 kg/m2 (14.1–40.4 kg/m2); 66 patients (19.5%) were in the high BMI group (median, 27.4 kg/m2) and 272 (80.5%) were in the low BMI group (median, 21.6 kg/m2). The median follow-up of patients who were alive (n = 271) was 67.5 months (12.6–121.8 months). The 5-year progression-free survival (PFS) and overall survival (OS) of the high versus low BMI groups were 63.9% versus 74.0% (P = 0.196) and 77.2% versus 84.2% (P = 0.230), respectively (Figure1,2). Multivariate analysis considering the sex, International Prognostic Index, B symptoms, bulky mass, and BMI showed that high BMI (≥25 kg/m2) was a significant adverse prognostic factor for both OS (hazard ratio [HR], 1.906; 95% confidence interval [CI], 1.08-3.376; P = 0.027) and PFS (HR, 1.710; 95% CI, 1.054-2.774; P = 0.030).
Conclusion
The results of our study indicated that high BMI was an adverse prognostic factor of DLBCL. It is necessary to investigate BMI and its influence on patient background or treatment in much more cases.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Plasma DNA Methylation of p16 and shp1 in Patients with B-Cell Non-Hodgkin Lymphoma
Authors: Fu Rong , Chen Xiaoshuang , Shao Zonghong 
Published: October 2019

Abstract
To discuss the clinical implications of cell free DNA, methylation status of the p16 and shp1 genes in plasma DNA from patients with B-NHL were analyzed. Methylation specific polymerase chain reaction (MSP) was used to detect the methylation status of these genes in plasma, peripheral blood leukocytes (PBLs), and formaldehyde-fixed, paraffin-embedded (FFPE) tumor tissues of 73 B-NHL patients. Results showed methylation frequencies of p16 in plasma, PBLs, and FFPE tumor tissues of B-NHL patients were 37%(27/73), 16% (12/73), 39% (16/41); Whereas those of shp1 were 47% (34/73), 25% (18/73), 63% (26/41). High methylation consistencies of p16/shp1 were observed between plasma and FFPE tumor tissues. In plasma and FFPE tumor tissues, there was a higher frequency of methylated p16 in B-NHL patients who had later disease stage, while no similar association was observed in PBLs samples; Higher frequency of methylated p16 was observed in B-NHL patients who had B symptoms and lower platelet count (<100×109/L) in all three samples. Methylated shp1 was frequently detected in patients with high serum LDH level. In summary, DNA methylation in plasma may be promising biomarkers for B-NHL diagnosis, prognosis evaluation, and targeted therapy.

Disclosures
No relevant conflicts of interest to declare.