bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Prasugrel In a Rat Model of Myocardial Infarction Induced by Thrombotic Coronary Artery Occlusion
Authors: Sugidachi Atsuhiro , Yamaguchi Shinji , Jakubowski Joseph A , Hashimoto Masami , Niitsu Yoichi 
Published: October 2019

Abstract
Abstract 3317

Purpose:
Prasugrel is the 3rd generation of thienopyridine with an antiplatelet profile distinct from clopidogrel. Its phase 3 study, TRITON-TIMI 38, demonstrated reduced rates of ischemic events relative to clopidogrel. However, effects of prasugrel in models of myocardial infarction (MI) have not yet been reported.

Methods:
Photochemical activation of rose bengal by laser activation at 540 nm is well established method for the induction of endothelial injury resulting in arterial thrombotic occlusion. Hirata et al. applied this approach in the rat to induce MI secondary to photochemically induced thrombosis (Jpn. J. Pharmacol., 67, 51–57, 1995). In the present study, the effects of prasugrel (1, 3 and 10 mg/kg, p.o., 2 hrs before photo-irradiation), were evaluated in this rat model of MI induced by photochemical insult to rat coronary arteries.

Results:
In a vehicle-treated control group of rats the mortality rate was 58.8% during 30-min photo-irradiation. In contrast, mortality rates of prasugrel-treated animals (1-10 mg/kg, p.o.) during the photo-irradiation were 0% for 1 mg/kg, 22.2% for 3 mg/kg and 0% for 10 mg/kg, indicating a protective effect of prasugrel. In surviving rats infarct sizes, the necrosis area/total left ventricular area (NA/TLV), at 24 hrs after irradiation was evaluated. In the control group, NA/TLV was 37.9 ± 6.8% (n=7). At all prasugrel doses tested, infarct size (NA/TLV) was smaller than that in control groups: 14.4 ± 4.0% for 1 mg/kg (p<0.01 vs. control, n=7), 19.8 ± 4.5% for 3 mg/kg (p<0.05 vs. control, n=7), and 14.8 ± 3.6% for 10 mg/kg (p<0.01 vs. control, n=7). We monitored blood pressure (BP), heart rate (HR), and the electrocardiogram in control and 10 mg/kg of prasugrel groups. And found no significant differences between the groups for BP and HR values 24 hrs after photo-irradiation. In contrast, arrhythmia was observed in 5 of 7 animals in the control group at 24 hrs, in contrast no arrhythmia was found in the group treated with prasugrel.

Conclusion:
The present results indicate that in this rat model prasugrel protected against both myocardial infarction and associated arrhythmia.

Disclosures:
Sugidachi: Daiichi Sankyo Co., Ltd.: Employment. Yamaguchi:Daiichi Sankyo Co., Ltd.: Employment. Jakubowski:Eli Lilly and Company: Employment. Hashimoto:DAIICHI SANKYO: Employment. Niitsu:Daiichi Sankyo Co., Ltd.: Employment.
Comparative Efficacy of First Line Treatment of Chronic Myeloid Leukaemia (CML): A Systematic Review and Meta-Analysis.
Authors: Mealing Stuart , Barcena Leticia , Hawkins Neil , Clark James , Davis Catherine 
Published: October 2019

Abstract
Abstract 3436

Introduction:
Historically, interferon-alpha, hydroxyurea or chemotherapy were used as first line therapy for individuals newly diagnosed with CML. Current practice, however, recommends that tyrosine-kinase inhibitors (TKIs) be used in this patient group, with imatinib (1st generation TKI) being the current standard of care. Recent publications provide data from randomized clinical trials on 2nd generation TKIs (dasatinib and nilotinib) in the first-line setting. In the absence of randomized head to head evidence for all three TKI's, a Bayesian mixed treatment comparison meta-analysis provides a means of indirectly estimating the treatment effect of one intervention relative to another.

Methods:
A systematic review identified RCTs that reported or summarized efficacy data for any of the treatments of interest in treatment-naive CML patients. In order to maximise the evidence network, RCT's of non-TKI's were also included in the review. Where reported, data was extracted for molecular, hematological and cytogenic response at three montly intervals. In addition, safety and progression free and overall survival data was extracted for all reported timepoints. Extracted data was analyzed in a Bayesian mixed treatment comparison using a fixed-effects model. The outputs from all analyses were expressed as odds ratios with Imatinib 400mg SID used as the baseline intervention in all analyses.

Results:
Overall, 44 articles arising from 19 distinct clinical trials were included in the review. The results for complete cytogenetic response (CCyR) at twelve months (expressed as both response probabilities and odds ratios) are presented in table 1.
High dose imatinib performed no better than standard dose imatinib. However, response with both 2nd generation TKIs was significantly better than with standard dose imatinib with the effect size being doubled on all endpoints. Head to head results for nilotinib and dasatinib showed no statistically significant differences (p=0.05) between the two products on all endpoints (see table 2).

Conclusions:
Compared to Imatinib, the use of 2nd generation TKI's for the treatment of newly diagnosed CML results in a significant improvement in complete cytogenic response. However, the current evidence base is not rich enough to distinguish between the two 2nd generation TKIs either in terms of response or progression free survival. The analyses presented will be strengthened by the inclusion of additional RCT data that may become available in the future.

Disclosures:
Mealing: Oxford Outcomes: Employment. Barcena:Oxford Outcomes: Employment. Hawkins:Oxford Outcomes: Employment. Clark:Oxford Outcomes: Employment. Davis:Bristol Myers-Squibb: Employment.
The Potential Role of Circulating IL-17 Levels During the Peri-Transplant Period as a Predictor for Early Leukemia Relapse After Allogeneic Stem Cell Transplantation.
Authors: Cho Byung Sik , Lim Ji-Young , Yahng Seung-Ah , Lee Sung-Eun , Eom Ki-Seong , Kim Yoo-Jin , Chung Nak-Gyun , Jeong Dae-Chul , Lee Seok , Kim Heeje , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Park Chong-Won , Min Chang-Ki 
Published: October 2019

Abstract
Abstract 3454
IL-17 is involved in inducing and mediating proinflammatory responses. The association of IL-17 with tumor growth or graft-versus-host disease (GVHD) has become the object of controversy. To determine the role of IL-17 levels during the peri-transplant period on alloreactive responses, serum IL-17 (sIL-17) levels of 95 patients with leukemia (52 AML, 38 ALL, 5 CML) who had undergone myeloablative allogeneic stem cell transplantation were measured using ELISA before conditioning and on day 0, day +7, and day +14 after transplantation. With the median follow-up of 17 months (range, 9–26), overall survival and disease-free survival rates were 70.9%±9.2% and 66.3±6.2%, respectively, and cumulative incidence of relapse and non-relapse mortality were 23.4%±5.7% and 10.3%±3.3%, respectively. Among 18 patients relapsed, 10 patients were relapsed within 180 days (range, 76–172) after transplants, and cumulative incidence of the early relapse was 10.5%±3.2%. The cumulative incidences of acute GVHD with grade II-IV and chronic GVHD were 55.8%±5.1%and 69%±5%, respectively. Analyses using repeated measures of ANOVA and mean values of sIL-17 revealed that patients relapsed within 180 days had higher sIL-17 levels during peri-transplant period, whereas no association was detected between sIL-17 levels and other clinical outcomes including acute GVHD. Receiver operating characteristic curve analysis also showed that sIL-17 levels at every time point were available for the prediction of the early relapse. Patients with advanced disease status at transplantation, one of factors associated with early relapse in univariate analyses, had higher sIL-17 levels at pre-conditioning and day 0. However, the result of multivariate analyses showing that sIL-17 levels at each time points were the only factor associated with early relapse suggests the importance of sIL-17 level itself than advanced disease status at transplantation. This study represents the first one demonstrating the early change of sIL-17 during the peri-transplant period and its association with early leukemic relapse in human. The predictive role of sIL-17 during the peri-transplant period for early leukemic relapse may be explained by the association of sIL-17 with tumor itself or tumor growth as well as possible inhibition of the function of graft-versus-leukemia effectors, such as natural killer cell, by sIL-17. Further studies are needed to precisely define the potential roles of IL-17.

Disclosures:
No relevant conflicts of interest to declare.
Influence of Glutathione S-Transferase A1 and P1 Polymorphisms on the Outcome of Hematopoietic Stem Cell Transplantation with Busulfan Based Conditioning Regimen In Children.
Authors: Lee Ji Won , Kang Hyoung Jin , Yuk Yen Ju , Jang Mi Kyoung , Han Eun Jong , Kim Nam Hee , Kim Hyery , Park Kyung Duk , Shin Hee Young , Ahn Hyo Seop 
Published: October 2019

Abstract
Abstract 3492

Introduction:
Busulfan has narrow therapeutic range. High exposure is associated with systemic toxicity such as veno-occlusive disease (VOD) while underexposure results in graft failure or relapse. In children, pharmacokinetic variability was found to be high even after the introduction of intravenous busulfan. Busulfan is metabolized via liver through conjugation with glutathione S-transferase (GST) family, and inter-individual variability may be explained by GST polymorphisms. Thus, we investigated the influence of GST polymorphisms on the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with busulfan based conditioning regimen in children.

Patients and methods:
We studied patients who underwent HSCT at Seoul National University Children's Hospital from November, 2001 to November, 2008. IV busulfan (0.8 mg/kg/dose for patients≥10 kg and 1.1 mg/kg/dose for patients <10 kg, q 6hr for 4 days) was used in combination with cyclophosphamide or fludarabine as conditioning regimen. Etoposide was added for acute lymphocytic leukemia (ALL). GST polymorphisms (GSTA1 375 A > G, -52 G > A, -567 G > T, -631 G > T, -69 C > T, GSTM1 deletion, GSTT1 deletion, and GSTP1 313 A > G) were analyzed by multiplex PCR amplification and SNP genotyping.

Results:
A total of 70 patients (48 male, 22 female) were analyzed. The diagnoses were ALL in 32, AML in 26, and other diseases in 12 patients. Median age at HSCT was 8.8 years (range 1.0–19.0 years). Bone marrow or peripheral blood stem cell transplantations (BMT/PBSCT) were conducted in 42 patients, and cord blood transplantations (CBT) in 28 patients. Graft failure occurred in 11 (15.7%) patients (1 (2.4%) in BMT/PBSCT, 10 (35.7%) in CBT) and relapse occurred in 15 (21.4%) patients (12 (28.6%) in BMT/PBSCT, 3 (10.7%) in CBT) after HSCT. Patients having GSTA1 *A/*A and GSTP1 313 A/A genotype (N=33) showed higher incidence of graft failure than the others (N=37) (27.3% vs 5.4%, P =.01). Conversely, the incidence of hyperbilirubinemia over grade 3 was significantly lower in the patients with GSTA1 *A/*A and GSTP1 313 A/A genotype than the other patients (6.1% vs 24.3%, P =.05). Event free survival (EFS) of patients with GSTA1 *A/*A and GSTP1 313 A/A genotype was significantly lower than the EFS of the other patients in both BMT/PBSCT and CBT, and the main causes of event were graft failure in CBT and relapse in BMT/PBSCT.

Conclusions:
In children undergoing HSCT with busulfan based conditioning regimen, GST A1 and P1 polymorphisms seem to have influence on the graft failure, relapse and complications. To confirm our results, further studies about the influence of GST A1 and P1 polymorphisms on the pharmacokinetics of busulfan are needed.

Disclosures:
No relevant conflicts of interest to declare.
Similar Overall Survival and Toxicity After CB Transplanation with Co-Infusion of CD34+ Cells From a Third Party Donor Compared to Myeloablative MUD Stem Cell Transplantation In High Risk Patients
Authors: Kwon Mi , Infante Maria , Balsalobre Pascual , Muñoz Cristina , Buno Ismael , Gayoso Jorge , Serrano David , Diez-Martin Jose L. 
Published: October 2019

Abstract
Abstract 3532
In the absence of an HLA matched sibling donor, an unrelated adult donor matched (MUD) at 8 of 8 alleles for HLA A, B, C, DRB1 is considered as first alternative. However, only 50% of patients in Europe have an available suitable donor in a median time of 4 months. For those patients without a suitable MUD, we have adopted CB (cord blood) stem cell transplantation with the co-infusion of CD34+ cells from a third party non HLA-identical donor (Dual transplantation). The objective of this study was to analyze toxicity and overall survival (OS) rates of patients who underwent this procedure and compare them with a cohort of patients who received a myeloablative MUD transplantation in a single centre and during a similar period of time.

Patients:
Between 2005 and 2010, 16 consecutive patients with high risk disease underwent a total of 18 dual transplants and 17 patients, with similar pre-SCT characteristics recieved a myeloablative MUD transplantation with 12/12 HLA identity in a single centre (Table 1). Transplants performed before 2005, those with manipulated grafts and with HLA mismatches were excluded.

Results:
There were no significant differences in age, gender, pre-SCT disease status and previous therapy lines between both groups. Three cases among the dual group showed primary graft failure (2 of them showing third party donor cells engraftment) who were rescued by a second CB transplant in two cases and a MUD in one case (succesfull in 2). There were no graft failures in the MUD group. GVHD rates are shown in table 1. OS was 50% in the dual group and 53% in the MUD group with a median follow-up of 33 (1-67) y 13 months (1,1-48,5) respectively (Figure 1). The cumulative relapse incidence at 2 years was 54% in the dual group and 53% in the MUD group. There were no relpses after 2 years in both groups. All the transplant related deaths (TRM) took place within the first year after transplantation with no significant differences in cumulative incidence between both groups (p=0,69).

Conclusions:
In our experience, CB transplantion together with the co-infusion of CD34+ cells from a third party HLA-mismatched donor offers OS and DFS rates comparable to those from myeloablative HLA 12/12 MUD trasnplantation with an acceptable TRM. Therefore, dual transplantion is still our first choice for patients without an available MUD or for whom trasplant is urgent.

Disclosures:
No relevant conflicts of interest to declare.
Minimal Residual Disease Status at Day +100 Post Allogeneic Hematopoietic Stem Cell Transplantation Is a Powerful Predictor for Post-Transplant Outcome In Patients with High Risk Acute Leukemia
Authors: Tang XiaoWen , Sun Xingwei , Xue Shengli , Shi Xiaolan , Zhu Mingqing , Shen Wenhong , Chen Li , Sun Aining , Depei Wu 
Published: October 2019

Abstract
Abstract 3550
Background and Objectives Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a major cause for the failure in treatment. It has been shown that there was a closely relationship between the level of minimal residual disease (MRD) and relapse in acute leukemia (AL) patients; However, the application of multiparameter flow cytometry (MFC) for MRD assessment in high risk patients with AL who undergoing allo-HSCT is little concerned. We retrospectively analysed the serial results of MRD of 52 high risk patients with AL to evaluates the prognostic value of MRD pre and post transplantation.

Methods
52 patients with a median age of 29 (13–55) years have been enrolled on this study in our hospital from January 2003 to September 2008.Diagnoses included AML (n=27) and ALL (n=25). The patients had been analyzed retrospectively the level of MRD pre-(day-30)and post-HSCT(day+30 and +100)using three color FCM with CD45/SSC gating and a comprehensive panel of monoclonal antibodies, at least one leukemia associated aberrant immunophenotype (LAIP) at diagnosis. According to the cutoff value 0.1%, two groups were defined based on the level of patient's MRD level< (low level group) or >= (high level group) 0.1%.

Results
The median follow up were 23 (range 1–60) months. 1.MRD level declines significantly (P=0.03) post transplant. 2. There were significantly difference between low level and high level group at day -30 before transplant with 3 years event free survival(EFS) and relapse free survival (RFS)(77.4% and 88.4% vs. 22.3% and 25.7%, p=0.007and p=0.001 respectively). 3. Concerning about MRD at day +100 after transplant, outcome was significantly better among patients with low level MRD group versus high group including 3 years OS,EFS and RFS(84.2%, 79.5% and 89.5% versus 22.9%, 9.5% and 11.2%).4. The median time from high level MRD detected first time to clinical relapse was 2.5 (range from 1 to 33) months in relapsed patients. 5. The patients with cGVHD had better 3 years OS and EFS than that without cGVHD(86.3% vs 12.1%, p<0.001 and 65.3% vs.14.8%, p< 0.001 respectively). 6. Multivariate Cox regression analysis revealed that MRD on day +100 as well as chronic GVHD were independent parameters predictive for OS and EFS.

Conclusions
MRD monitoring pre- and post-transplant is an important tool to predict the outcome of transplantation for patients with high risk AL. The MRD check point at day +100 should be considered crucial for subsequent therapeutic decisions after allogeneic transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Intensive Induction Chemotherapy Followed by Autologous Stem Cell Transplantation (ASCT) In Patients with Enteropathy-Associated T-Cell Lymphoma: a Prospective Study by the Nordic Lymphoma Group (NLG-T-01)
Authors: Jantunen Esa , Relander Thomas , Lauritzsen Grete Fossum , Hagberg Hans , Anderson Harald , Cavallin-Ståhl Eva , Holte Harald , Østerborg Anders , Merup Mats , Brown Peter De Nully , Kuittinen Outi , Erlanson Martin , Østenstad Bj∅rn , Fagerli Unn-Merete , Gadeberg Ole , Sundstrom Christer , Delabie Jan , Ralfkiaer Elisabeth , Vornanen Martine , d’Amore Francesco 
Published: October 2019

Abstract
Abstract 3565
Enteropathy-associated T-cell lymphoma (ETCL) is a rare lymphoma often, but not always, associated with celiac disease and characterized by poor prognosis when treated with conventional chemotherapy. In previous studies long-term survival has been achieved in only 10–20% of the patients. Limited data is available on the feasibility and efficacy of intensive induction chemotherapy followed by autologous stem transplantation (ASCT) in this rare lymphoma entity. We therefore specifically analysed the outcome of ETCL patients included in a large prospective phase II study (NLG-T-01) performed by the Nordic Lymphoma Group. The NLG-T-01 study included 160 patients with systemic alk-negative peripheral T-cell lymphoma over the period 2002–2007. The patients received CHOEP-14 × 6 followed by ASCT after BEAM or BEAC in responsive patients. The study included altogether 21 patients (13 %) with ETCL. There were 16 males and 5 females with a median age of 55 years (32-65) at diagnosis. Eighteen patients (86 %) had advanced disease, three patients (14 %) had a bulky tumour, nine patients (43 %) presented with B symptoms and four (19%) with elevated serum lactate dehydrogenase. Response status after three and six courses was CR or CRu in 67 % patients. Fourteen patients (67 %) received BEAM or BEAC supported by blood stem cell graft (median number of stem cells infused 5.4 × 106/kg). Of these, 6 patients relapsed with a median of 219 days from ASCT. Of the 7 patients (33%), who did not reach ASCT because of refractory/progressive disease, 5 died early due to lymphoma. At a median follow-up of 45 months, 10 patients (45 %) are alive. The progression-free survival is 40 %. One patient (5%) died due to early transplant-related cause (disseminated candidiasis). In this prospective study, intensive induction chemotherapy followed by ASCT was feasible in the majority of younger patients with EATL. In a subset of patients, who should clinically and biologically be further characterized, long-term outcome seems promising when compared to historical controls. Whether addition of other chemotherapeutic agents, antibodies such as alemtuzumab or other biologicals may further improve long-term outcome remains to be studied.

Disclosures:
No relevant conflicts of interest to declare.
C-Abl Regulates Mcl-1 Gene Expression In Chronic Lymphocytic Leukaemia Cells
Authors: Allen John C , Zuzel Mirko , Lin Ke , Slupsky Joseph R 
Published: October 2019

Abstract
Abstract 3579
Chronic lymphocytic leukaemia (CLL) is a prevalent malignancy characterised by the clonal expansion of mature B cells that are resistant to apoptosis. This resistance to apoptosis will partly be due to Mcl-1 expression because high levels of this protein in CLL cells correlate with poor disease prognosis and resistance to chemotherapy. Thus, understanding the mechanism(s) regulating Mcl-1 expression in CLL cells may be useful in the development of new therapies for this incurable disease. In the present study we show a strong relationship between c-Abl and Mcl-1 expression in CLL cells. We show that treatment of CLL cells with Abl-specific siRNA or with imatinib, to inhibit c-Abl activity, results in the downregulation of Mcl-1 protein and mRNA. A major regulator of Mcl-1 gene expression is STAT3. Our data show that CLL cells expressing high levels of c-Abl also show elevated levels of phospho-STAT3, and that STAT3 phosphorylation in CLL cells is dependent on c-Abl activity. However, STAT3 phosphorylation by c-Abl is not direct, and requires activation of NFkB, secretion of autocrine IL6 and active PKC. Taken together, our results provide clearer definition of the pathobiological role of c-Abl in CLL cells. Given that high NFkB activation, plasma IL6 levels and Mcl-1 all correlate with poor disease prognosis in CLL, our work potentially connects several features of CLL cells that are important to their pathophysiology by suggesting a central role of c-Abl in their regulation. Since CLL cells expressing high levels of c-Abl and Mcl-1 belong to the unmutated, poor prognostic group of CLL, c-Abl inhibition may have therapeutic application in the treatment of this disease, especially for those patients who are resistant to conventional chemotherapeutic agents.

Disclosures:
No relevant conflicts of interest to declare.