bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Efficacy and Safety of a Catheter Removal Only Strategy for the Treatment of PICC Line Thrombosis Vs Standard of Care Anticoagulation: A Retrospective Review
Authors: Shatzel Joseph J. , Mart Dylan , Bien Jeffrey Y. , Maniar Ashray , Olson Sven R , Liem Timothy , Deloughery Thomas G. 
Published: October 2019

Abstract
Background: Peripherally-inserted central catheters (PICCs) are commonly used during hospitalization for ease of access with blood draws and fluid and medication administration. PICC use is frequently complicated by catheter-related thrombosis (CRT). Current guidelines recommend 3-6 months of anticoagulation for patients with CRT after catheter removal. This recommendation is based on extrapolation of data on lower extremity thrombosis, as data is lacking regarding the efficacy and safety of more specific management strategies in upper extremity cases. Retrospective data exists to suggest catheter removal without anticoagulation is a sufficient and reasonable treatment option, particularly for patients at risk for bleeding; no prospective randomized data have been reported in this population. We aimed to examine the incidence of progressive thrombosis and bleeding in a retrospective cohort of patients with PICCs.
Methods: We performed a retrospective analysis of hospitalized adult patients diagnosed with CRT at our center from 2012 to 2018. We determined rates of progressive thrombosis and bleeding in cohorts of patients who underwent catheter removal vs. those who had catheters removed and received anticoagulation.
Results: Among 83 total patients, 62 were treated with PICC removal alone, while 21 underwent PICC removal and received therapeutic anticoagulation. Patients treated with PICC removal alone were more likely to have hematologic malignancy, receive chemotherapy, develop thrombocytopenia, and have brachial vein thrombosis. No patients in the PICC removal plus anticoagulation arm developed progressive thrombosis, while 6.4% of patients treated with catheter removal alone developed a secondary VTE event, including one PE, three DVTs; this difference did not reach statistical significance. Five patients (8%) treated with catheter removal alone also developed progressive symptoms leading to initiation of anticoagulation. Major bleeding was significantly more common in the PICC removal + anticoagulation arm (28.5% vs 4.8% p=0.007).
Conclusions: Catheter-removal alone results in significantly reduced major bleeding compared with catheter-removal plus anticoagulation. In select patients, catheter removal alone may be considered as an option for CRT, though larger, prospective trials are needed to clarify whether this practice is effective at reducing rates of progressive thrombosis.

Disclosures
No relevant conflicts of interest to declare.
Heterogeneous Responses Among Ph+-B-ALLs to Imatinib with NRAS Mutant Being One Mechanism of Complete Resistance
Authors: An Xiaoyu , Liu Jinping , Wang Na , Wang Di , Huang Liang , Cai Jie , Zhou Demin , Li Henry 
Published: October 2019

Abstract
Background. Philadelphia Chromosome (Ph+) characterized by BCR-BAL fusion genes are one of the major leukemogenic drivers for a number of leukemia, including acute lymphoid leukemia (ALL) and chronic myeloid leukemia (CML). Experimental models are important to study disease mechanisms and assess pharmaceuticals, including drug resistances/mechanisms. Patient derived xenografts (PDXs) are stem cell driven diseases and considered to be the most closely resembling the original patients including leukemia [1], in terms of histo-/molecular pathology and pharmacology [2]. As far as we know, there has yet to be reported of PDXs of Ph+ leukemia, and thus such models could be particular useful for drug evaluation and study drug resistance.
Methods. Different B-lineage acute lymphoid leukemia (B-ALL) adult and pediatric patient bone marrow (BM) cells were engrafted into NOD/SCID mice or NSG-like mice, via IV injection (also intra-BM). The disease development is performed by monitoring peripheral blood for human CD45+ cells and cage-side clinical observations. At the terminal leukemia stage, the mice were gross-/histo-pathologically analyzed and immune-phenotyped for different affected tissues. The diseases are passed in mice by serially transplantations, and are by transcriptome sequenced-/pharmacologic-tested, enabling biomarker discovery.
Results. We achieved aggressive and serially transferrable full-blown ALL in mice for a number of patient samples that cause 100% mortality. The diseases of the established B-ALL-PDXs (patient-derived xenografts) start at BM followed by the quick expansion to peripherals, e.g. spleen and blood. The leukemic cells in mice have similar morphology, phenotypes and genotypes, including five ALLs with different forms of BCR-ABL fusion as seen in the original patients. The treatments of these five Ph+-ALLs with imatinib, a TKI targeting BCR-ABL fusion, caused heterogeneous remissions in peripheral blood, spleen and bone among the five PDXs, along with the correspondingly relief of the symptoms and extension of life. This is largely as anticipated and confirms that BCR-ABL fusion are likely key leukemogenic drivers to the majority of these PDXs. One of the five Ph+-ALLs, AL7267, displayed complete resistance to imatinib, which could potentially be explained by the identification of NRAS-G12S mutation that is absent in other 4 BCR-ABL bearing PDXs and likely responsible for AL7267's non-response to imatinib.
Conclusions. Our observations in the mouse trial of the five different Ph+ B-ALL-PDXs would suggest that individual patients of the same diseases could be greatly different in their response to TKIs targeting BCR-ABL, and NRAS mutation could be one of the important resistant mechanisms. These models could be useful tools to investigate drug resistance and the combination therapy to overcome the resistance.

Disclosures
No relevant conflicts of interest to declare.
DNA Damage in Haemopoeitic Stem Cells Impacts on Neutrophil and Platelet Engraftment Following Autologous Transplantation
Authors: Bai Lijun , Best Oliver Giles , Xia Wei , Peters Lyndsay , Wong Kelly , Ward Christopher , Greenwood Matthew 
Published: October 2019

Abstract
Background and Aim: Processing and cryopreservation is known to reduce the viability and absolute number of CD34+ haematopoetic stem cells (HSCs). DNA damage and subsequent apoptosis of stem cells may occur as a result of prior treatment regimens or from the accumulation of reactive oxygen species (ROS) during the freeze/thawing process. In our recent study we demonstrated that two distinct populations of HSCs are present in all cryopreserved patient samples, based on their ROS expression; these we defined as ROShigh and ROSlow. The significant correlation between the percentage of ROShigh HSCs in the graft and neutrophil recovery following transplant shown in our study suggests that some degree of ROS accumulation may play an important role in promoting neutrophil engraftment following autologous HSC transplantation (AHSCT) (Bai et al 2018). The current study examined the association between ROS levels and DNA damage in cryopreserved HSCs and whether these correlated with time to neutrophil and platelet engraftment following AHSCT.
Methods: Cryopreserved HSC samples from 51 patients who underwent AHSCT were studied. HSC's were defined as CD45+/CD34+. DNA damage and intracellular ROS levels were assessed using an antibody against the phosphorylated form of histone H2Ax (γH2Ax) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), respectively. Data acquisition and analysis were performed by flow cytometry.
Results: We observed a proportion of HSC in each sample that expressed elevated levels of gH2Ax. The median percentage of γH2Ax expressing CD34+ cells was 54.6% (range 3.4 - 98.4%). We observed a strong correlation between ROShigh and γH2Ax levels in terms of the dose of cells/kg infused (p < 0.001, r = 0.72). The ratio of ROShigh/γH2Ax-expressing HSCs was inversely associated with delayed neutrophil engraftment (p = 0.03, r = -0.31).
The cohort was divided into group 1 and group 2 based on ROShigh/γH2Ax ratios of >1 (n = 32) and ≤1 (n = 18) respectively. Median days to neutrophil engraftment were 12 (range 9-18), in group 1 and 15 (range 9-28) in group 2, (p = 0.007). Median days to platelet engraftment were 17 (range 10-28) in group 1 and 21.5 (range 14-55) in group 2, (p = 0.001). Median days to platelet count of >50 (plt50) was 18.5 (range 12-28) in group 1 and 22 (range 16-75) in group 2, (p = 0.001). In group 2, significant correlations were noted between the ROShigh/γH2Ax ratio and time to neutrophil engraftment (r = -0.54, p=0.025), plt20 (r = -0.64, p=0.004) and plt50 (r = -0.7, p = 0.002).
Conclusion: Our data suggest that DNA damage in CD34+ and accumulation of ROS may impact upon the time to engraftment of HSCs. Calculating a ratio of ROShigh/γH2Ax expression may be useful in predicting engraftment time following autologous transplantation.

Disclosures
No relevant conflicts of interest to declare.
Palliative Care Physicians' Views Toward Hematology and the Care of Patients with Hematologic Diseases: Results of a Nationwide Survey
Authors: Santivasi Wil L. , Wu Kelly M. , Litzow Mark R. , LeBlanc Thomas W. , Strand Jacob J. 
Published: October 2019

Abstract

Background: Palliative care specialists provide supportive care for patients with hematologic diseases. However, the degree of engagement by palliative care physicians may be limited by the views of both palliative care physicians and hematologists. Prior studies have surveyed hematologists to identify barriers to delivery of palliative care, however palliative care physician views are unclear. This study aimed to examine views of palliative care physicians toward hematology.
Methods: A survey was mailed to a random sample of the AAHPM physician contact list in 2017. Items focused on perceptions of their understanding of hematologic diseases, comfort providing care, opinions regarding palliative care and hospice involvement, and beliefs about hematologists. Anonymized responses were assessed on a Likert scale. Statistical testing was based on logistic regression models with generalized estimating equations to account for correlated data within respondents.
Results: 538 of 1000 surveys were completed. 51.9% of respondents were male. Community (37.2%), academic (36.7%) and hospice (26.2%) physicians were represented. Respondents were likelier to believe they understand the trajectories of lymphoma and myeloma than leukemia or patients undergoing hematopoietic stem cell transplantation (HSCT) (p < 0.001). They were more comfortable discussing prognosis (p =< 0.001) and managing symptoms (p < 0.001) in lymphoma and myeloma than leukemia and HSCT. They were likelier to believe that hematologists' perceptions of palliative care physicians limit collaboration rather than their own views of hematologists (p < 0.001). 80.2% agreed that hospice referrals are not made early enough.
Conclusions: Palliative care physicians' understanding of trajectories and comfort caring for patients varies by hematologic disease. They perceive that hematologists' perceptions are a larger barrier than their own and hospice referrals are delayed. These results provide insights into opportunities for better collaboration with hematologists.

Disclosures
No relevant conflicts of interest to declare.
PNH Clone Size By Flow Cytometry and Its Correlation with PIG Gene Mutation
Authors: Jeong Dajeong , Park Hee Sue , Choi Seongmin , Seo Heewon , Kim Sung-Min , Im Kyongok , Yun Jiwon , Kim Jung-Ah , Hwang Sang Mee , Kim Kwangsoo , Kim Ju Han , Lee Dong Soon 
Published: October 2019

Abstract
Background: Routine diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is based on flow cytometric measurement of PNH clone in RBC and granulocyte with sensitivity of 1%, and recent introduction of high-sensitive flow cytometry (FCM) makes it possible to detect 0.01% clone. However, the clinical significance of small PNH clone has not been elucidated, so even the necessity to treat or not is controversial. We investigated whether quantitative results of PNH clone size measured by FCM correlate with mutant burden of PIG gene.
Methods: A total of 44 specimens from 20 patients whose PNH clone size was >1% in either RBC or granulocyte by routine FCM were enrolled (classical PNH n=10, AA/PNH n=8, MDS/PNH n=2). To detect small quantity of cells with PIG gene mutation, we performed ultra-deep sequencing (average depth 3000X) for PIGA, PIGM, PIGT, and PIGX genes on these 44 consecutive specimens.
Results: Sixteen patients (80.0%) were found to harbor PIG gene mutations: 15 patients had PIGA mutation and 1 patient had PIGM mutation. Granulocyte PNH clone size and variant allele frequency (VAF) of PIG gene mutation showed higher correlation (Spearman's r=0.73, p=0.0002) than that of RBC (Spearman's r=0.61, p=0.0073). All patients harboring PIG gene mutation showed more than 10% PNH clone by FCM. In contrast, 4 patients who did not have PIG gene mutation showed less than 10% PNH clone by FCM.
Conclusion: Considering the mechanism of PNH development, the presence of PIG gene mutation is a definitive evidence supporting PNH diagnosis. PNH granulocyte clone size more than 10% by FCM seems to be clinically significant in relevance to PIG gene mutation. We suggest that neither high sensitivity FCM nor the detection of PIG gene mutation is a requisite for routine clinical diagnosis of PNH.

Disclosures
No relevant conflicts of interest to declare.
Perioperative Management of Hemophilia a Using Recombinant Factor VIII in Patients Undergoing Major or Minor Surgery
Authors: Okamoto Atsushi , Yamamoto Kenta , Eguchi Go , Kanai Yoshitaka , Yamaguchi Terufumi , Maeda Yasuhiro 
Published: October 2019

Abstract
[Introduction]
It has been known that Hemophilia needs careful management from the bleeding tendency in the perioperative period. In this study, we performed endoscopic nasal pituitary adenomatectomy for growth hormone-producing pituitary adenoma in patients with hemophilia A. There were no reports using efraloctocog alpha (ELOCTATE®, Bioverativ, Cambridge, MA, USA, rFVIIIFc) for perioperative management in major surgery, intracranial surgery, for a hemophilia A patient.
[Case]
A 28-year-old man admitted to our Hospital because of endoscopic nasal pituitary adenomasectomy for growth hormone-producing pituitary adenoma. rFVIIIFc was used as a management of hemophilia A at the perioperative period. And we created a regimen for administration of rFVIIIFc regarding the guidelines for hemostasis treatment for hemophilia patients without inhibitors (revised 2013) published by the Japan Thrombohemorrhagic Society. In our hospital, the results of factor VIII activity can not be obtained as an emergent examination, so we used APTT as an indicator.
[Result]
The surgery was terminated with 150 ml of intraoperative bleeding volume that was almost the same amount as expected bleeding volume. Despite a risk of nasal bleeding after surgery was expected, only a small amount of nasal bleeding was occurred twice. The course of factor VIII activity was also good with APTT.
[Conclusion]
We concluded that rFVIIIFc may be available reagent in perioperative management of intracranial surgery with hemophilia A without inhibitors. The advantage of perioperative management by the bolus administration method (=BI method, This involves repeated administration of a bolus injections.) using half-life extended drugs is that these drugs need to be administered intravenous injection only once a day, and such a treatment protocol is easy to perform at a hospital. Furthermore, the BI method is also economical as it reduces the amount and thus the cost of the drug, as compared with the continuous administration method (=CI method, A syringe pump continuously administers coagulation factors after an initial bolus administration.) using the existing coagulation factor preparations. For perioperative management using extended half-life drugs, we consider that further case studies are necessary to prepare dosing regimens. However, such drugs have the potential to impact not only periodic replacement therapy, but also perioperative management in hemophilia patients. As mentioned above, we feel that the extended half-life drugs have the potential to significantly impact hemophilia treatment.

Disclosures
No relevant conflicts of interest to declare.
Hematopoietic Stem and Progenitor Cell Proliferation and Differentiation Requires the Trithorax Protein Ash2l In Vivo
Authors: Chatain Nicolas , Lüscher-Firzlaff Juliane , Kuo Chao-Chung , Bochyńska Agnieszka , Ullius Andrea , Denecke Bernd , Costa Ivan , Koschmieder Steffen , Lüscher Bernhard 
Published: October 2019

Abstract
Gene transcription is controlled by post-translational modifications of core histones. Methylation of lysine 4 of histone H3 (H3K4), together with acetylation of H3K27, is closely associated with open chromatin and gene transcription. H3K4 methylation is catalyzed by KMT2 lysine methyltransferases that include the mixed-lineage leukemia 1-4 (MLL1-4) and SET1A and B enzymes. For efficient catalysis all six require a core complex of four proteins, WDR5, RBBP5, ASH2L, and DPY30.
In a newly-generated pIC-inducible Mx1-Cre mouse model, we report that targeted disruption of Ash2l in the hematopoietic system results in death of the mice due to a rapid loss of mature hematopoietic cells in the bone marrow and the spleen, associated with a significant reduction of the RBC, WBC and platelets. However, Lin-Sca1+Kit+ (LSK) cells, which are highly enriched in hematopoietic stem and multi-potent progenitor cells, were significantly increased in the bone marrow (18-fold increase). This increase was associated with a 15-fold loss of the myeloid progenitor (MP) population (p < 0.001). In detail, total cell number of granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs) and common-myeloid progenitors (CMPs) was significantly reduced, while the relative proportion remained essentially unchanged. In LSK cells, Ash2l loss interfered with H3K4 methylation and resulted in broadly deregulated gene expression, including down-regulation of mitosis-associated genes. As a consequence, LSK cells accumulated in the G2/M-phase of the cell cycle and were unable to proliferate and form colonies in semi-solid medium. Lentiviral complementation with human ASH2L in the lineage-negative population partly but not entirely restored colony forming capacity, suggesting that ASH2L-mediated shaping of hematopoietic differentiation is a very early process. In addition, we demonstrated that those genes that harbor H3K4me3 and H3K27ac marks at their promoters were preferentially transcriptionally down-regulated. In contrast, up-regulated genes were characterized by low H3K4me3 and H3K27ac. Thus, these findings suggest that H3K4me3 and H3K27ac are not essential for transcription of all genes and that other, so far unidentified chromatin marks, allow recruitment of the RNA polymerase complex and transcription. Together, our data identify Ash2l as a novel essential factor for balanced gene expression and for hematopoietic stem and multi-potent progenitor cell physiology. These data may have important implications for future therapies of hematopoietic malignancies, including epigenetic targeting of malignant stem cells.

Disclosures
No relevant conflicts of interest to declare.
Inhibition of DOT1L and PRMT5 Promotes Anti-Tumor Activity in a Human MLL Leukemia Model Induced By CRISPR/Cas9
Authors: Secker Kathy-Ann , Keppeler Hildegard , Duerr-Stoerzer Silke , Schmid Hannes , Schneidawind Dominik , Hentrich Thomas , Schulze-Hentrich Julia , Mankel Barbara , Fend Falko , Kanz Lothar , Schneidawind Corina 
Published: October 2019

Abstract
MLL rearrangements play a crucial role in leukemogenesis. They are associated with a poor prognosis and new treatment strategies are urgently needed. Here, we used the CRISPR/Cas9 system to generate an innovative leukemia model based on 100% pure MLL-AF4/-AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient leukemic cells faithfully mimicking the nature of the disease. Thus, it serves as ideal fundamental basis for pharmacological studies.
The catalytic activity of disruptor of telomeric silencing 1-like histone methyltransferase (DOT1L) is critical for the transforming potential of MLL oncogenes. Therefore, inhibition of DOT1L deals as one specific therapeutic approach for MLL-rearranged leukemias currently tested in clinical trials. However, the previous success was limited by restricted response warranting further investigation of DOT1L combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines in vitro and in MLL mouse models. Here, we used DOT1L (EPZ004777) and PRMT5 (EPZ015666) inhibitors alone or in combination in our human MLL-rearranged model demonstrating a dose-dependent reduced proliferation, impairment of cell cycle, upregulation of differentiation marker CD14 and apoptosis measured by flow cytometry and downregulation of known MLL target genes determined by qPCR. Strikingly, the combination of both compounds led to complementary anti-tumor effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias.

Disclosures
No relevant conflicts of interest to declare.
Incidence of Silent Thrombosis in Myeloproliferative Neoplasm Patients below 60 Years : Single Center Egyptian Study
Authors: Mattar Mervat , Nassef Sahar , El Husseiny Noha M , Morad Mohamed Abdel Kader , Salah Marwa , El Masry Mohamed Roshdy , Abdul Gawad Ahmed 
Published: October 2019

Abstract
Background : Identification of JAK-2 mutation even in absence of myeloproliferative disorders was found to be related to venous thromboembolism occurrence. The aim of this work is to screen myeloproliferative neoplasm ( MPN) patients for venous thrombosis and study its correlation with both JAK 2 allele burden and with symptoms the patients presented with. Methods: We enrolled 73 cases with JAK2 positive MPN in the period between August 2015 till Feb 2017. All patients were screened for thrombosis in venous system in neck, upper and lower limbs, superior and inferior Venae Cavae and portal and mesenteric venous systems system using color Doppler Ultrasound. Results: 53 patients (72.6%) were below 60 years. Forty even (64.4%) were females and 26(35%) were males. Twenty two (30%) of cases were Essential Thrombocytosis (ET), 35(248%) were Polycythemia Vera (PV) and 16 (22%) were Myelofibrosis (MF). Twenty seven venous thrombotic attacks were reported in twenty two patients (30.1%). Seventeen patients (23%) had mesenteric and portal vein thrombosis,six patients had iliofemoral (8%) and 4 (5%) had combined lower limb and portal thrombosis. Eight patients (10.8%) had active thrombosis at screening. Only three (4%) patient were symptomatising with pain during screening. Sixteen patients with thrombosis were below 60 (30% of those below 60 years) and 6 were above sixty years (also 30% of those above sixty years). Correlation analysis between JAK2 allele burden and thrombosis was not statistically significant (r=0.3 ,p value=0.5). However, JAK 2 allele burden was statistically higher in those above sixty years in both thrombosed and non-thrombosed cases in comparison to those below sixty years (p= 0.03, 0.017 respectively). The incidence of pruritis (p =0.02) and of abdominal pain (p=0.039) was significantly different between thrombosed and non-thrombosed cases. Comparison of 8 cases with active thrombosis to old thrombosis revealed no statistical difference in the MPN10 score (p>0.05). Conclusion: We recommend routine screen for venous thrombosis in any case of MPNs once diagnosed and screening for MPNs in any case with venous thrombosis . Further research in MPN group age below 60 years of age is highly recommended.

Disclosures
No relevant conflicts of interest to declare.