bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Prognostic Index for Ocular Adnexal Lymphoma
Authors: Meeks Marshall W. , Park Henry S. , Yu James B. , Roberts Kenneth B. , Foss Francine , Wilson Lynn D. 
Published: November 2019

Abstract
Background: Ocular adnexal lymphoma (OAL) is a rare malignancy with a heterogeneous patient population. We sought to identify prognostic factors for OAL and to incorporate them into a novel prognostic index by using a large national database.
Methods: We identified patients diagnosed with histologically confirmed OAL in 1973-2013 using all registries of the Surveillance, Epidemiology, and End Results database. Patients with regional or distant disease at diagnosis were excluded. Indolent histologies were defined as follicular, marginal zone, small lymphocytic not otherwise specified, and lymphoplasmacytic. We determined the association between OAL histology, orbital site, and overall survival (OS) using adjusted proportional hazards analysis and Kaplan-Meier estimates. Relative survival (RS) was calculated relative to a matched cohort of patients categorized by race, gender, and age using the SEER*Stat Program.
Results: Among the 3,070 patients included, 941 (30.6%) had conjunctival tumors, 418 (13.7%) had lacrimal gland tumors, and 1711 (55.7%) had orbital-not otherwise specified tumors. Indolent histology was present in 2,073 (67.5%) patients. The 10-year OS and RS were 61% and 86%, respectively. In univariable and multivariable models, conjunctival site location (P<0.001) and indolent histology (P<0.001) were both associated with superior OS. Three primary OAL prognostic groups were identified: Group I (indolent histology, conjunctival location), Group II (indolent histology, non-conjunctival location or aggressive histology, conjunctival location), and Group III (aggressive histology, non-conjunctival location). The adjusted 10-year hazard ratios for OS were 1.4 (95% CI, 1.1-1.7, P<0.001) and 3.1 (95% CI, 2.5-4.0, P<0.001) for groups II and III, respectively, compared to group I. Groups I, II, and III had 10-year OS of 75%, 61%, and 37%, respectively, and 10-year RS of 96%, 89%, and 55%, respectively.
Conclusions: Both conjunctival location and aggressive histology were independent predictors of survival. Our proposed prognostic index could have implications on OAL staging and management, though it must first be externally validated.

Disclosures
No relevant conflicts of interest to declare.
Chemotherapy-Induced Nausea and Vomiting (CINV) - First Results of a German Non-Interventional Study with NEPA - a Netupitant/Palonosetron Fixed Dose Combination
Authors: Karthaus Meinolf , Klare P , Heilmann V , Klausmann G , Schilling Joerg 
Published: November 2019

Abstract
Introduction: Platinum and anthracyclin chemotherapy regimens are frequently used in hematology pts and compromised by severe acute and delayed CINV. NEPA, a fixed dose combination of the long lasting NK1-receptor antagonist (RA) netupitant and the pharmacological distinct 5HT3-RA palonosetron, has been approved by FDA and EMA for the prevention of acute and delayed CINV receiving highly emetogenic cisplatin- and AC-based as well as moderately emetogenic chemotherapy. A German non-interventional study is currently investigating NEPA's efficacy and impact on quality of life in adult cancer patients by PRO and physicians' personal assessment under real life conditions.
Objectives: Primary objective is to evaluate quality of life (QoL) in adult patients receiving NEPA for CINV prevention. Secondary endpoints are efficacy and safety of NEPA.
Methods: This open label, non-interventional, prospective, national, multicenter study evaluates CINV prevention and patients' QoL with NEPA in 2,500 pts receiving either highly or moderately emetogenic cytostatics on up to 2 consecutive days. NEPA is prescribed in accordance with the EU marketing authorization. QoL is evaluated by the validated FLIE questionnaire for 3 chemotherapy cycles 24 hours before, within 24 hours after and additional 4 days after chemotherapy. Efficacy is documented via patient diaries for the same time period. Safety and physicians' overall satisfaction is reported via eCRF. The interim analysis reports on the first 20% of the pre-planned number of patients.
Results: Between June 2015 and July 2016 a total of 583 patients were enrolled. Median age was 56 (range of 28-88) with 521 out of 583 patients that completed documentation. A total of 291 patients (56%) received AC-based chemotherapy. Efficacy, evaluated by physicians' personal assessment on a 4-point scale, was rated very good or good for 486 (90.7%), 409 (93.4%) and 350 (92.9%) patients in cycle 1, 2 and 3, respectively. Complete response was analyzed based on 87 completed patient diaries. Here, 88.5% reported no emesis and no rescue medication in the acute phase (0-24h post chemotherapy), while 85.1% and 79.3% reported complete response in the delayed (>24-120h post chemotherapy) and overall phase (0-120h post chemotherapy). A high percentage of patients did not suffer from any emesis (94%, 99% and 93% in acute, delayed and overall phase). The study is ongoing.
Conclusions: NEPA proved to be highly effective for prevention of chemotherapy-induced emesis and nausea. Patient reported outcome was rated very good or good in more than 90% of Ctx cycles in the acute as the delayed phase of highly and moderately emetogenic Ctx including cisplatin or anthracyclin based therapy.

Disclosures
Karthaus: HELSINN: Honoraria; RIEMSER: Honoraria. Schilling:RIEMSER: Honoraria.
Regulation of the Erythroid Iron Deprivation Response By a TfR2-Scribble-Epor Integrated Module Coupling Iron Sensing with Receptor Presentation
Authors: Khalil Shadi , Delehanty Lorrie L , Holy Maja , Grado Stephen , Bullock Grant C. , Goldfarb Adam 
Published: November 2019

Abstract
Iron deficiency in humans causes desensitization of erythroid progenitors to erythropoietin, the principal cytokine for erythroid survival, proliferation, and differentiation. This nutrient deprivation response acts in a lineage-selective, non-apoptotic manner to restrain expansion of the tissue responsible for the majority of iron consumption, thereby triaging iron utilization under conditions of deficiency. The molecular basis for this response is incompletely understood but involves transferrin receptor 2 (TfR2) and aconitase enzymatic activity as extra- and intracellular iron sensors. Here, we identify a multi-component, integrated module connecting these two elements of erythroid iron sensing with endo-lysosomal trafficking, receptor surface delivery, and configuration of EpoR signaling. Specifically, iron and aconitase activity modulate the rate of TfR2 catabolism by cathepsin protease activity. Scribble, a conserved regulator of receptor transport and signaling, binds TfR2 and serves as a downstream effector through to its co-catabolism. Scribble levels in turn influence surface delivery of the erythropoietin receptor (EpoR), which physically interacts with both Scribble and TfR2. The TfR2-dependent downregulation of Scribble associated with iron deprivation diminishes surface EpoR density and skews its signaling from JAK-STAT to Akt pathways. Mice with surface-trapped, endocytosis-defective EpoR fail to develop anemia in response to iron deficiency. These findings establish a tissue-specific nutrient sensing pathway relevant to the pathogenesis of human anemias and their resistance to erythropoietin therapy.

Disclosures
No relevant conflicts of interest to declare.
The Prognostic Role of Hypertrabeculation By Cardiac Magnetic Resonance in Thalassemia Intermedia Patients
Authors: Pepe Alessia , Macaione Francesca , Giuliano Pietro , Pistoia Laura , Barone Angelica , Sarli Roberto , Roccamo Gaetano , Maggio Aurelio , Positano Vincenzo , Renne Stefania , Assennato Pasquale , Meloni Antonella 
Published: November 2019

Abstract
Background. Differentiation of left ventricle non-compaction (LVNC) from hypertrabeculated LV due to a negative heart remodeling in thalassemia intermedia (TI) can depends on the selected CMR criterion. The recently proposed Piga's criterion (NC/C ratio threshold of >2.5, Am J Haem 2012) seems to have a low specificity to identify the true LVNC in TI. Anyway, the Piga's criterion could well detect easy a negative heart remodeling in TI patients.
Purpose: To assess prospectively whether the Piga's criterion has a prognostic role for adverse cardiovascular outcomes in TI patients.
Methods. We studied prospectively by CMR 168 TI patients (81 males, mean age 38.32 ±11.61 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. Eight patients were excluded because a cardiac complication was present at the first CMR.
Using Piga's criterion the study population was divided into two groups: patients with Piga's positive criterion (n=18, 11.2%) and with Piga's negative criterion (n=143, 88.8%).
Results. Mean follow-up time was 57.50 ± 21.87 months. Sixteen cardiac new events were recorded: 1 heart failure (HF), 10 supraventricular arrhythmias and 5 pulmonary hypertension (PH). The patients with Piga's positive criterion had a significant higher risk of developing arrhythmias (hazard ratio-HR= 5.35 ; 95%CI=1.51-18.98; P=0.009). The figure shows the Kaplan-Meier survival curve.The positivity for the Piga's criterion was not predictive for PH or for cardiac complications globally considered.
Conclusions. Based on our data a NC/C ratio >2.5 provides
Figure Figure.

Disclosures
Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..
The Methylcytosine Dioxygenase TET2 Regulates CD8+ T Cell Memory Differentiation
Authors: Carty Shannon A. , Gohil Mercy , Banks Lauren B. , Johnson Matthew E , Stelekati Erietta , Wells Andrew D , Wherry E. John , Koretzky Gary A. , Jordan Martha S 
Published: November 2019

Abstract
DNA methylation is one of the major epigenetic mechanisms that control T cell differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines, intermediates in active DNA demethylation. Here we demonstrate that TET2 regulates CD8+ T cell differentiation in vivo following acute viral infection. At steady-state, mice with a T-cell specific deletion of TET2 have intact thymic and peripheral T cell populations. However, following acute viral infection with LCMV-Armstrong, TET2 loss promotes early acquisition of a memory CD8+ T cell fate in a cell-intrinsic manner without disrupting antigen-driven cell expansion or effector function. Integration of genome-wide methylation analysis and expression data suggest that TET2 loss leads to hypermethyation of the PRDM1 genomic locus (encoding Blimp-1) and alters the relative expression of Blimp-1 and Bcl-6, two antagonistic transcriptional repressors known to direct CD8+ T cell memory differentiation. Together, our data indicate that TET2 is an important regulator of CD8+ T cell fate decisions.

Disclosures
No relevant conflicts of interest to declare.
Are Direct Oral Anticoagulants Plasma Concentrations Associated with the Risk of Postoperative Bleeding? Results from the Real Life Cohort
Authors: Olivera Pável , Cortina Vicente , Pons Verónica , Canals Tania , Johansson Erik , Bosch Francesc , Santamaría Amparo 
Published: November 2019

Abstract

Background
The perioperative management (PM) of direct oral anticoagulants (DOACs) is controversial. The role of assessing DOAC plasma levels in order to ensure a safe use of these anticoagulants is still unknown.
Aims
To examine the association between DOACs plasma concentrations obtained before surgery and the risk of postoperative bleeding in the perioperative setting.
Methods
From June 2014 to December 2015 we have consecutively included 99 patients treated with DOACs and referred to our Unit for PM. Management was performed following the PM recommendations from the Catalan Thrombosis Working Group (Tromboc@t) . Bleeding events were classified following the ISTH criteria. Plasma concentrations were measured in the day of invasive procedure using the Technoclone anti-Xa assay from Technoclone (Vienna-Austria) for Rivaroxaban and Apixaban, and the Direct Thrombin Inhibitor Assay from IL (Bedford-MA-USA) for Dabigatran; in each case, specific calibrators were used. Patients were systematically followed 30 days after the surgical procedure.
Results
A total of 99 patients were recruited. Median age was 76 years (range: 61-94) and 51 (51.5%) were female. Among them, 23 patients received dabigatran, 40 rivaroxaban and 36 apixaban. As per the risk scores, 66.7% of the patients had a CHA2DS2-VASc score >3, 57.6% had a HAS-BLED score >3, and 51 (51.5%) were considered high-risk procedures. Total bleeding events occurred in 23 patients (47.8% minor, 30.4% non-major clinically relevant, and 21.7% major bleeding). The median plasma NOACs concentration was 38.3 ng/ml (0.8-226 ng/ml), with 32 patients having levels >30 ng/mL. HASBLED score > 3 was associated with an increased risk of bleeding events within 30 days (hazard ratio (HR)= 3.9, 95% CI= 1.14-13.4, P=0.03). Plasma DOAC levels > 30 ng/ml were not significantly associated with an increased risk of bleeding events (HR=2.17, 95% CI=0.862-6.67, P=0.10). Major bleeding (n=5) was probably associated with the risk of the procedure than to the DOAC plasma concentrations.
Conclusion
In our cohort we found significant association between the individual bleeding risk before surgery with the risk of postoperative bleeding. In spite of that, this study will continue to reevaluate PM in high-risk procedures according to plasma DOAC levels.

Disclosures
No relevant conflicts of interest to declare.
More Efficient Exchange of Sickle Red Blood Cells Can be Achieved By Exchanging the Densest Red Blood Cells
Authors: Thibodeaux Suzanne , Irwin Leah , Jamensky Lita , Schell Kevin , O'Doherty Una 
Published: November 2019

Abstract
Background: In sickle cell disease, it is well established that cells containing two mutated hemoglobins (SS) are denser than cells containing wild-type hemoglobin. We asked whether we could more efficiently exchange red blood cells (RBCs) in sickle cell anemia patients by exploiting the denser property of RBCs containing hemoglobin SS compared to wild-type RBCs.
Methods: To probe this question, we performed a series of experiments using the waste bags from sickle cell patients as simulated patients. We exchanged the simulated patient with one RBC volume using recently expired ABO compatible RBC units on a COBE Spectra apheresis instrument. We measured hematocrit and hemoglobin S levels in the simulated and control patient bag before and after the exchange. In the experimental scenario, we programmed the COBE Spectra to exchange the bottom half of the RBCs by indicating that the hematocrit was half of the true hematocrit (e.g. 21% when the hematocrit of the bag was 42%). For control exchanges we programmed the COBE Spectra to exchange the entire RBC volume by programing the hematocrit to be the true one (for this example 42%).
Results: The percentage of hemoglobin S was more effectively diminished in our modified exchanges that targeted dense RBCs than in control exchanges. Our experimental exchanges were also more effective than expected for a 1 red blood cell volume exchange by Poisson calculation (n=5). In an optimized experiment, hemoglobin S was reduced from 23.7% to 1.3 % after exchanging 1 RBC volume using our modified approach while it was reduced from 23.2 to 5.4% using the control or routine exchange parameters. The same volume of donor RBCs (1 RBC volume) was used to exchange our experimental and control simulations. We obtained a 95% reduction of hemoglobin S in our experimental conditions and a 77% reduction in our control conditions. The instrument was programmed to compensate for RBC depletion with the modified RBC exchange. The compensation is necessary to maintain a constant hematocrit since more RBCs are present in the bottom half than top half of the centrifuged RBCs.
Conclusions: It is possible to exchange sickle cell anemia patients more effectively by taking advantage of the fact that RBCs containing hemoglobin SS are denser than normal RBCs. Using waste products from sickle cell anemia exchanges provides an opportunity to safely optimize exchange parameters. This approach should allow us to: 1) achieve a higher reduction in hemoglobin S in patients, 2) achieve the previous levels of reduction using fewer donor units and/or 3) combine red cell exchange with other therapies for sickle cell disease, such as hydroxyurea, by taking advantage of the differential densities and selective depletion of red blood cells containing different levels of hemoglobin F.

Disclosures
No relevant conflicts of interest to declare.
Chromatin Accessibility Identifies CTCF As a Gatekeeper of Stemness Functions in Human Hematopoietic Development
Authors: Takayama Naoya , Murison Alex , Takayanagi Shin-ichiro , Zandi Sasan , Penrod Nadia , Mitchel Amanda , Kennedy James A. , Ng Stanley W.K. , Xie Stephanie Zhi-Juan , Minden Mark D. , Dick John E. , Lupien Mathieu 
Published: November 2019

Abstract
Hematopoietic stem cells (HSC), at the apex of the blood hierarchy, generate a series of increasingly committed progenitors and ultimately produce terminally differentiated cells at the bottom of the hierarchy. Although HSC and their immediate downstream, multipotent progenitors (MPP) have full multilineage differentiation capacity, only HSC have the capacity for long term self-renewal. Thus comparison of HSC with downstream progenitors that exhibit gradual fate restriction by assuming the identity of a mature blood cell is central to defining how the stemness state is established and how lineage commitment is executed. Interestingly, few genes are differentially expressed between human HSC and MPP, suggesting that some important stem cell mechanisms are in a permissive state and therefore difficult to identify simply by differential gene expression analysis. We hypothesized that these permissive genetic regions could be identified by chromatin analysis. To identify permissive genomic regions, we delineated regions of accessible chromatin through ATAC-seq assays in HSC, MPP, committed progenitors and seven mature lineages from human Cord Blood. DNA recognition motif analysis across accessible chromatin in each developmental stage identified both known and unknown candidate master regulatory transcription factors for each step of lineage development.
The DNA recognition motif for CTCF, a crucial effector of chromatin interactions, is enriched in accessible chromatin associated with progenitors but not in HSC, even though CTCF expression is not significantly different among stem and progenitor populations. Knockdown of CTCF in HSC by lentiviral vector system increased the proportion of HSC in G0 cell cycle and consequently reduced the number of mature cells generated in both conventional and high sensitivity single cell assays. The development of differentiated lymphoid and megakaryocytic lineages was affected. Few effects were seen when CTCF was silenced in MPP or more downstream progenitors. Collectively, our results suggest that CTCF is a "gate keeper factor" that regulates transition from dormant to active stages in HSC, and might control stem cell pool throughout life.
In parallel to normal blood hierarchies, AML is also composed of a hierarchy with leukemia stem cells and non-stem-like leukemia cells; LSC and non-LSC fractions sorted from 24 AML patients have also been subjected to ATAC-seq. Currently we are comparing HSC and non-HSC with LSC and non-LSC fractions to identify the similarity and differences between normal HSC and LSC. Overall, our study is revealing insights into the stemness state of normal and leukemic stem cells in primary human tissues.

Disclosures
Takayanagi: Kyowa Hakko Kirin: Employment.
Hospital Volume Does Not Influence in-Hospital Mortality of Autologous Hematopoietic Cell Transplant Among Multiple Myeloma Patients in the United States
Authors: Giri Smith , Dhakal Prajwal , Mehta Kathan Dilipbhai , Bhatt Vijaya R. 
Published: November 2019

Abstract
Introduction:
Hospital volume and provider experience affects survival among patients with hematologic malignancies (Giri et al Blood 3359-60). Whether hospital volume affects outcomes of autologous hematopoietic cell transplant (autoSCT) among patients with multiple myeloma (MM) remains unclear.
Methods:
We utilized the Nationwide Inpatient Sample (NIS) database to identify all adults >18 years diagnosed with MM who underwent autoSCT in 2009-2011. NIS is the largest all-payer inpatient database in the US that captures about 20% of all US hospitalizations. Hospitals were divided into quartiles, based on the annual number of autoSCT performed, and classified into high volume (above 75th percentile) and low volume centers (below 25th percentile). In-hospital outcomes including inpatient mortality, infection, mechanical ventilation, and costs of hospitalization were compared between the two groups. All p-values were 2 sided, and the level of significance was chosen at 0.05. Statistical analysis was done using STATA 13.0 (StataCorp, College Station, TX).
Results:
A total of 2,750 autoSCTs were reported among patients with MM during the study period. The characteristics of study population included mean age of 58.7 ± 8.7 years, 56% males (n=1547) and 72% whites (n=1822). No significant difference existed in in-hospital mortality rate (0.86% vs. 1.59%; p=0.183) between high volume (≥178 autoSCTs per year) versus low volume centers (≤56 autoSCTs per year). The rate of fungal infection (5.32% vs. 4.94%; p=0.75), herpes simplex virus infection (1.58% vs. 1.59%; p=0.98), and the need for mechanical ventilation (1.87% vs. 1.27%) was similar between the high volume and low volume centers. Higher rates of stomatitis (57% vs. 46%; p<0.01), use of total parenteral nutrition (12.37% vs. 6.21%) and neutropenic fever (33.6% vs. 23.5%; p <0.01) were noted in high volume versus low volume centers. The cost of initial hospitalization was similar in the two groups (mean $ 161,085 vs. $ 154,161; p value 0.17).
Conclusion:
Our study demonstrates a low risk of inpatient mortality without center effect for autoSCT in MM in the recent years. The risks of fungal and herpes simplex virus infection were also similar between high volume and low volume centers. Higher rates of stomatitis, use of total parenteral nutrition and neutropenic fever were noted in high volume versus low volume centers. The reasons for these differences are not clear from our study but may relate to possible differences in patient characteristics or conditioning chemotherapy.

Disclosures
No relevant conflicts of interest to declare.