bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-Marketing Safety Experience with Edoxaban in Japan for Thromboprophylaxis Following Major Orthopedic Surgery
Authors: Kuroda Yasufumi , Hotoda Hitoshi , Nishikawa Yasuhiro , Nishiwaki Akinori 
Published: October 2019

Abstract
Abstract 4697

Background
Edoxaban, an oral, selective, direct factor Xa inhibitor, is approved in Japan as a once-daily dose (15 mg or 30 mg tablets) for the prevention of venous thromboembolism (VTE) following major orthopedic surgery, including total knee arthroplasty, total hip arthroplasty, and hip fracture surgery. Currently, edoxaban is in phase 3 clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation as well as treatment and prevention of recurrence of VTE. This report describes the adverse drug reactions (ADRs) that were spontaneously reported during early post-marketing phase vigilance (EPPV) since the July 2011 commercial launch in Japan.

Methods
EPPV was conducted for the initial 6 months from launch: July 19, 2011, to January 18, 2012. All ADRs that were spontaneously reported, were collected and analyzed.

Results
The estimated exposure was approximately 20,000 patients. A total of 67 ADRs were reported in 56 patients, of which 15 (in 14 patients) were serious. The mean age of the patients was 74.1 years, mean weight was 59.4 kg, and approximately 70% of the patients were female. The majority of ADRs were bleeding events (51 ADRs in 42 patients), and serious ADRs included cerebral hemorrhage (n=1), gastric hemorrhage (n=1), gastric ulcer hemorrhage (n=1), and surgical site hemorrhage (n=12). Most of these ADRs occurred within the first week of treatment and there were no fatalities. The majority of non-serious adverse events associated with bleeding that occurred in more than one patient included subcutaneous hemorrhage (n=9), wound hemorrhage (n=5), post-procedural hematoma (n=4), anemia (n=4), and hemarthrosis (n=3). Other non-serious adverse events occurring in more than one patient included abnormal hepatic function (n=4) and diarrhea (n=2).

Conclusions
Preliminary data from EPPV for the first 6 months of commercial use of edoxaban did not identify any unforeseen safety signals. This evidence confirms the known safety profile of edoxaban—that edoxaban has been shown to be well tolerated.

Disclosures:
Kuroda: Daiichi Sankyo Pharma Development: Employment. Hotoda:Daiichi Sankyo Co., Ltd.: Employment. Nishikawa:Daiichi Sankyo Co., Ltd.: Employment. Nishiwaki:Daiichi Sankyo Co., Ltd.: Employment.
The Cost of Pediatric Unrelated Donor Transplantation
Authors: Barros Daniele Porto , Seber Adriana , Domingues Fernando , Antunes Luciana , Araujo Valeria , Felix Olga , Ibanez Adriane , Zecchin Victor , Gouveia Roseane , Ginani Valeria Cortez , Petrilli Antonio Sérgio , Vergueiro Carmen 
Published: October 2019

Abstract
Abstract 4711
Allogeneic unrelated hematopoietic stem cell transplants (HSCT) are complex procedures that need adequate hospital infrastructure, a competent team, high-cost procedures and medications. Most transplants that are performed in Brazil are paid by the government. The national health system reimburses the hospital U$ 35,801.00 as a flat rate. The government has recently increased this amount by 60% but there are not national studies to use to evaluate the appropriateness of this amount.
The objective of this study was to retrospectively evaluate the cost of ten consecutive unrelated donor HSCT performed in our institution.

Methods:
The project was approved by our IRB (CEP-UNIFESP #1875/11) and granted waiver to request consent. The costs were evaluated from the first appointment until one year after transplant or death divided as 1) pre-HSCT, 2) conditioning therapy, 3) from the day of transplant until first discharge, 4) until D+100, 5) until D+180, and 6) until D+360. The costs included medications, supplies, blood transfusions, laboratory, imaging and the cost of the ward. Housing and out-of pocket costs or loss of income were not evaluated. Patients were evaluated according to the Pediatric EBMT score (1–3).

Results:
Ten consecutive children 2–14 years of age underwent unrelated donor HSCT from June, 2010 to May, 2011. Diagnoses were ALL (4). AML (3), lymphoma (2), and aplastic anemia (1). Three patients had early disease and others were in advanced phases of the diseases. Eight were CMV positive. Five had marrow and five cord blood transplants. The median time was 3.7 years from diagnosis to transplant and 80 days from referral to transplant. The patients remained in the unit for a median of 80 days (21–50). Median time to engraftment was D+22 (12–56) and six had complications and needed Intensive Care support. Of the 10 children, seven were discharged but three relapsed; overall survival is 50%. The median total cost during the first year was U$112,130.00 (mean U$ 174,000.00) – 44% of that spent within the first 100 days post HSCT. The first admission had a median total cost of U$ 60,700.00 (13,580 – 157,840). Total costs were approximately 40% higher than the direct cost. The highest costs were blood products and medications. No relationship was found between cost and age, gender, graft source of Pediatric EBMT-score.

Conclusion:
Unrelated-donor HSCT are expensive procedures and the government only partially reimburses its cost. Even with the 60% increase in reimbursement there will be a deficit in more than half of the procedures. We are working to increase this amount paid in patients who have complications and will have to continue to find alternative resources to finance the transplants.

Disclosures:
No relevant conflicts of interest to declare.
Decreased Apoptosis in Bone Marrow of Pediatric Patients After HLA-Identical Stem Cell Transplantation for African Sickle Cell Anemia
Authors: Isgrò Antonella , Marziali Marco , Sodani Pietro , Gaziev Javid , Fraboni Daniela , Paciaroni Katia , Simone Maria Domenica , De Angelis Gioia , Alfieri Cecilia , Gallucci Cristiano , Roveda Andrea , Torelli Fabio , Cardarelli Luisa , Ribersani Michela , Lucarelli Guido 
Published: October 2019

Abstract
Abstract 4751

Background.
In thalassemia patients ineffective erythropoiesis appears to be caused by accelerated apoptosis, in turn caused primarily by deposition of a-globin chains in erythroid precursors. The bone marrow is the main site of the erythroid cell death. The occurrence of apoptosis at the polychromatophilic stage coincides with the stage where intensive hemoglobinization occurs and could be explained by the increase in a-globin production and precipitation. The mechanism of BM apoptosis is also observed in sickle cell anemia (SCA), but is reduced. We report our experience concerning 12 geno-identical hematopoietic stem cell transplantation (HSCT) for SCA-patients, to analyse the effect of transplant on “normalization” of intramedullary apoptosis.

Patients and Methods.
Twelve patients with a median age of 12 years (range, 2–16), affected by sickle cell anemia (SCA), received hematopoietic stem cell transplantations from HLA-identical, related donors following a myeloablative conditioning regimen. We studied Fas (CD95+) and caspases-3 expression on erythroblast subpopulation. Using both CD71 and FSC parameters, we obtain 3 principal populations, which we labelled A, B, C erythroblasts (Ery. A, Ery. B, Ery. C). Ery A (CD71high FSChigh) are basophilic, Ery. B (CD71high FSClow) are late basophilic and polychromatic, whereas Ery. C (CD71low FSClow) are orthochromatic erythroblasts and reticulocytes.

Results.
We observed an expansion of Ery A, Ery B and Ery C population at baseline, probably as an essential process needed to maintain a constant red cell production in SCA patients (42.4% Ery A; 24.7% Ery B; 35.6% Ery C). After BM transplant decreased levels was observed especially on Ery A and Ery B populations (12.9% Ery A; 7% Ery B; 35% Ery C). After BM transplant Fas expression was reduced in all 3 erythroid population, but significantly on more immature Ery A (17% vs 3.5% CD95+ on Ery A; 32.2 vs 24.4 on Ery B; 5% vs 3.3% on Ery C). This observation may suggest that Fas, expressed by early erythroblasts in vivo, might contribute to the cell death of erythroid precursors in bone marrow, but this was corrected after HSCT. In addition, only after transplant we observed an initial increase of caspases 3 on more mature Ery C population (2.3% at baseline vs. 15.3% after transplant), as observed during later steps of “normal” cell maturation.

Conclusion.
After HSCT in SCA we observed a “normalization” of erythroid populations, in parallel with decreased intramedullary apoptosis rate, suggesting normal erythroid maturation in ex-SCA patients.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation of Autonomic Function in Patients with Sickle Cell Disease in Relation to Nighttime Hypoxemia
Authors: Erin McGuire , Kato Roberta Miyeko , Bush Adam M , Zmyewski Heather , Detterich Jon , Gardner Daniel , Khoo Michael , Meiselman Herbert J , Coates Thomas D. , Wood John C 
Published: October 2019

Abstract
Abstract 4764

Background:
Sickle cell disease (SCD) is a genetic condition resulting from a homozygous hemoglobin S mutation of the beta globin gene. HbS polymerizes in the deoxygenated state, causing the red cell membrane to become rigid and obstruct blood flow. Ischemia results leading to early organ damage, impaired quality of life and short life expectancy. Patients with SCD die from many causes including infection, splenic sequestration, stroke, and pulmonary emboli, however; a number of deaths in this population are acute and unexplained. The increased risk of sudden death is hypothesized to be associated with autonomic dysfunction. Heart rate variability (HRV) is a measurement of autonomic function and predictor of risk of sudden death. Measures of HRV can be compared to other factors associated with autonomic dysfunction. Individuals with obstructive sleep apnea have increased sympathetic tone. We hypothesized that SCD subjects that experienced nighttime hypoxemia will have autonomic dysfunction.

Methods:
Subjects were fitted with an ambulatory electrocardiogram device (Acitheart, CamNTech, Inc) and monitored for 24 hours. High frequency power (HFP), a measure of cardiac parasympathetic tone, and low:high ratio (LHR), a measure of sympathovagal balance, were calculated from the HRV by the product software. During sleep, baseline oxyhemoglobin saturation (SpO2) and number of desaturations below 88% was monitored using an ambulatory pulse oximeter (WristOX, Respironics, Inc). Bivariate analysis of the median HFP and LHR values over a 24 hour period were compared to baseline SpO2and number of desaturation events. Sex, age and hematologic values including hemoglobin, CRP and lactate dehydrogenase values were also considered.

Results:
30 SCD subjects (mean age= 26.1 years+10.96, 36% male) were evaluated. Baseline nighttime SpO2 was 95.5+2.8% with 1 subject with a baseline SpO2 < 90%. Baseline SpO2 did not correlate with HF with R2 = 0.03 but did correlate with LHR with R2 = 0.46. There was a mean number of desaturation events of 16.6+38.3 with 4 subjects greater than 25 desaturation events. The number of desaturation events did not correlate with HF with R2 = 0.027 but did correlate with LHR with R2= 0.63. Stepwise multivariate analysis was performed including the baseline SpO2, number of desaturation events, sex, age and hematologic parameters showed that the number of desaturation events was the best predictor of LHR.

Conclusions:
SCD subjects that experienced nighttime hypoxemia and increased number of desaturation events during sleep have higher LHR ratios consistent with increased sympathovagal tone.

Disclosures:
Coates: Novartis: Speakers Bureau; Apopharma: Consultancy. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding.
Cerebral Venous Thrombosis in Adolescents and Young Adults with Classical Hodgkin Lymphoma
Authors: Kumar Poornima , Ahmed Rebekah , Riat Renu , Ardeshna Kirit M , Daw Stephen 
Published: October 2019

Abstract
Abstract 4784

Background
Patients with classical Hodgkin Lymphoma (cHL) have a relatively high risk of venous thrombo-embolism (VTE); reported incidence 4.6–7% in adults and up to 11.5% in children and adolescents. Most VTE episodes are peripheral or related to central venous catheters, with very limited data on central or life-threatening thromboses in adolescents. There is only 1 reported case series on cerebral venous thrombosis (CVT) in adolescents. We report 4 cases of CVT from our centre, all treated with chemo-radiotherapy. Chemotherapy comprised OEPA (vincristine, prednisolone, doxorubicin, etoposide) and COPP/COPDAC (cyclophosphamide, vincristine, prednisolone, procarbazine/dacarbazine respectively).

Results
All patients received involved field radiotherapy (IFRT) 19.8 – 30Gy on completing chemotherapy. All were female, aged 12–23. All received norethisterone contraception. All had indwelling central venous catheters (PICC). Patient 4 alone had a raised body mass index. All were exposed to steroids; Patient 4 completed steroid therapy several weeks before developing CVT symptoms. Patients 2 and 4 received treatment dose low molecular weight heparin (LMWH) for 6 weeks after diagnosis of PICC-associated thrombosis, and were not on anticoagulation or thromboprophylaxis when CVT was diagnosed. Regarding other risk factors, 3/4 had no documented prothrombotic tendency. Patient 4 was found to have a moderately positive IgM anti beta 2 glycoprotein antibody present 12 weeks apart, consistent with antiphospholipid syndrome.
All patients were therapeutically anticoagulated for 6 months to 1 year. LMWH of choice at our centre was dalteparin. Patient 1 was switched to warfarin upon completion of chemo-radiotherapy, and Patient 4 was commenced on warfarin with dalteparin cover at diagnosis of CVT as she had completed treatment.
Patients 1 and 2 had raised intracranial pressure on lumbar puncture, and required therapeutic lumbar punctures and acetazolamide.
Patients 2 and 3 both required anticonvulsant therapy for 1 year. Patient 2 was initially treated with phenytoin, and switched to carbamazepine. Patient 3 was also initially managed with phenytoin, and switched to levetiracetam. Neither patient had any subsequent seizures.
All 4 patients have recovered completely from CVT with no residual neurological deficits or further thromboses.

Conclusion
CVT is a rare and potentially life threatening complication in adolescents and young adults with cHL with paucity of data. The risk factors are unclear however all patients in our series were female, received steroids and were on norethisterone. Only 1 patient had a prothrombotic tendency detected on thrombophila screening. CVT is treatable, and complete resolution of signs and symptoms can be expected. More studies are required to elucidate risk factors which may help develop thromboprophylaxis guidance in this group of patients.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Characterization and Prognostic Factors of 144 Adult Acute Monocytic Leukemia
Authors: Wu Yingying , Ye Xiujin , Li Li , Zhu Jingjing , Xie Wanzhuo , Zhang Jie , He Jingsong , Cai Zhen , Huang He 
Published: October 2019

Abstract
Abstract 4798

Background:
Acute monocytic leukemia (M5) is one kind of acute leukemia with poor prognosis, which has the characterization of high number of white blood cells, high risk of extramedullary metastasis and abnormal chromosome karyotype.

Objective:
To analyze clinical characterization and prognostic factors of adult acute monocytic leukemia.

Methods:
Clinical data of 144 patients diagnosed between Jan 1st 2006 and Dec 31 2010 were collected. Clinical manifestation, cytogenetics, immunophenotyping and minimal residual disease (MRD) were analyzed respectively. The numeration data was tested by χ2 test, while the measurement data by Levene test to variance homogeneity and by T test to the mean difference. The data were analyzed by SPSS 17.0.

Results:
81.9% of 144 patients reached complete remission. 27.5% patients were abnormal in cytogenetics, including +8, −5/del (5q), −7/del (7q). Patients were divided into three groups according to chromosome karyotype. Intermediate prognostic group has better OS and DFS than poor prognostic group (P<0.05). 26 patients treated with SCT.These patients have higher OS rate for one year and low relapse rate than those who did not receive SCT.CR rate for old patients(≥55) and young patients (<55) were 69.4% and 86.1% respectively. Old patients had shorter OS and DFS than young patients, but no singnificant difference in FAB type, number of white blood cell and immunophenotyping. Old patients occur chromosome abnormalities more frequently than young patients. Relapse rate is 20.7% in MRD+ group versus 11.5% in MRD- group. Multivariate COX analysis showed that chromosome karyotype and MRD had most significant correlation with relapse.

Conclusion:
Chromosome karyotype, age, therapy, MRD were all prognostic factors of M5. Chromosome karyotype and MRD had most important significance in prognosis.

Disclosures:
No relevant conflicts of interest to declare.
High WT1 Expression in 2nd CR of AML Is Predictive for Early Relapse (prospective study)
Authors: Girshova Larisa , Romanova Ekaterina , Kholopova Irina , Nikulina Tatiana , Mirolubova Julia , Gorunova Elena , Motorin Dmitry , Zaritskey Andrey 
Published: October 2019

Abstract
Abstract 4812

Backgound:
The Wilms' tumor gene 1 (WT1), which is over-expressed in more than 90% of AML, is a useful marker for monitoring MRD. Quantification of WT1 transcript level in peripheral blood (PB) and bone marrow (BM) at recovery from chemotherapy reliably discriminates patients at different risks of relapse. It is known that WT1 expression may be a marker of future relapse in 1 CR AML patients, after allogenic BMT and WT1 reduction also is a prognostic during induction of the first episode of AML. But there no evidence of WT1 reduction value in AML relapse.

Patients and methods:
In our prospective study were 10 patients with the first AML relapse and 2nd bone marrow complete remission were studied. High level of WT1 at relapse and achieving 2nd remission were the main inclusion criteria. Median WT1 level at relapse was 4302,2 (range 540–13184) copies WT1/104 Abl. Monitoring of WT1 level were estimated in patients with median age 36,6 (range from 20 to 64). Median time from the first CR to the relapse was 16,47 months (range from 3 to 51 mo), so there were 6 patients with early relapse and 4 patients with late relapse respectively. Chemotherapy with high dose cytarabine (HiDAC, FLAG) used for 2nd CR induction.

Results:
Only 66,7% (6 patients) demonstrated WT1 normalization. All of patients (n=4) with high WT1 expression in bone marrow remission developed second relapse in a few months, median time to relapse was 4,45 months (range from 2,8 to 7,4 mo). While patients with normal WT1 level in 2nd remission had relapse free survival 83.3% at 20 months (p=0.048, Fisher exact test, two tailed). Only one of 6 patients developed an extramedullary relapse in 6 months. The groups of patients were comparable to cytogenetic and molecular risks.

Conclusion:
We have shown that high WT1 level in 2nd remission is predictive for early relapse. Thus, high WT1 level in 2nd remission is an indication for very early stem cell transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Eph-A4 Plays a Important Role in Metastasis and Invasive Activity of Myeloid Leukemia Cells
Authors: Xiaoli Liu , Zhou Xuan , Zuo Yuan , Xu Lulu , Zhang Jinfang , Xu Na , Huang Bintao , Xiao Xiaozhen , Huang Yuanlu , Du Qingfeng 
Published: October 2019

Abstract
Abstract 4819
The Eph receptors are found in a wide range of cancers and correlate with metastasis. However, their precise role in cancer has only started to be addressed. In this study, we investigated the role of Eph-A4 receptor in metastasis and invasive activity of myeloid leukemia cells. We fisr tested the expression of Eph-A4 in eight primary myeloid leukemias imclulding four with extramedullary metastasis and four without it, and leukemia cell line K562 by Real-time PCR and western blotting, then found that Eph- A4 was wildly expressed in myeloid Leukemia cells, especially in myeloid leukemia cells with high invasive activity. To further clarified the question, the stable over-expressing Eph-A4 cell line (K562-EphA4) based the wild K562 cell and pGC lentivirus vector were established to declare the metastasis and invasive activity in myeloid leukemia cells in vitro by trans-well migration assay. The results indicated that the mRNA level and protein expression of Eph-A4 were significantly increased in myeloid leukemias with extramedullary metastasis and K562 cells compared to those without it (P<0.05).After we successfully established the stable over-expressing Eph-A4 cell line, we verified its mRNA level and protein expression were both significantly increased ((P<0.05).Furthermore, RhoA and Rac1/cdc42, which are important adhesion molecules and related to metastasis and invasive activity were both highly expressed in K562-EphA4 cells compared to wild K562 cells (P<0.05). Moreover, the trans-well migration assay showed that cells that migrated to lower chambers and matrigel hydrogel were both increased in K562-EphA4 cells compared to wild K562 cells (5.22±2.11*104/ml vs 13.56±2.70*104 /ml P<0.000;18.07±3.15/cm2 vs 28.53±2.50/cm2P<0.000 respectively). Our findings suggest that Eph- A4 is likely to play an important role in the regulation the of myeloid Leukemia through the control of RhoA and Rac1/cdc42 associated signaling, migration and invasive activity, and therefore may represent a novel target for cancer treatment.

Disclosures:
No relevant conflicts of interest to declare.
More Sun Light Exposure May Be Associated with Improved Overall Survival in Diffuse Large B-Cell Lymphoma. A Population Based Swedish Lymphoma Registry Study
Authors: Jerkeman Mats , Székely Elisabeth , Hagberg Oskar , Linden Ola 
Published: October 2019

Abstract
Abstract 4847

Background
Low levels of circulating 25-hydroxyvitamin D [25(OH)D] has been associated with inferior EFS and OS in DLBCL[1]. Ultraviolet B radiation from the sun contributes strongly to the vitamin D status in humans. In Scandinavia, the difference in sun light exposure is highly dependent on season. Consequently, vitamin D levels in Norway have been found to be 15–50 % lower in winter compared to summer[2]. In this study we tested the hypothesis that diagnosis of DLBCL during the lighter period of the year may be related to superior overall survival in DLBCL.

Patients and materials
The study population was collected from the Swedish Lymphoma Registry 2000–2010.
A Cox regression model was analyzed for overall survival. Light exposure was defined as a continuous variable - cos((month of diagnosis -6)/12 × 2π) – varying between -1 in December and +1 in June. In addition, age, stage, year of diagnosis, performance status, number of extranodal sites, and LDH were included as cofactors.

Results
During this period, 5268 adult patients with DLBCL were identified.
In multivariate analysis, including all factors above, overall survival was significantly superior for patients diagnosed during the lighter part of the year, p = 0.032.
The hazard ratio for death due to all causes for patients diagnosed in June compared to December was 0.90. Monthly

Discussion
On a population level, seasonal differences in sun light exposure may contribute to differences in overall survival in DLBCL. However, to prove if normalizing vitamin D levels in this group of patients would improve survival; this will require testing in randomized trials.

Disclosures:
No relevant conflicts of interest to declare.