bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and Predictors of Pulmonary Arterial Hypertension in Hemoglobin E/ β-Thalassemia Patients.
Authors: Chuncharunee Suporn , Atichartakarn Vichai , Archararit Napaporn , Udomsubpayakul Umaporn , Ingsathit Atiporn , Lee Ratchanee , Tunhasiriwet Anusith , Tanomsup Supachai , Aryurachai Katcharin , Ungkanont Artit , Niparuck Pimjai , Angchaisuksiri Pantep 
Published: October 2019

Abstract
Abstract 2015
Poster Board I-1037

Introduction:
Pulmonary arterial hypertension (PAH) associated with thalassemia (Thal) hemoglobinopathy is now an accepted clinical entity. Most of the reports are in sickle cell disease and splenectomized β-Thal patients. Once manifested, it connotes poor prognosis. We herein present its prevalence and predictors in hemoglobin E/β-Thal (E/β-Thal) patients.

Patients and Methods:
One hundred and ten clinically stable E/β-Thal outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). PAH was defined as an estimated SPAP ≥36 mmHg. Clinical features and laboratory data were stratified according to the presence or absence of PAH, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value <0.05 as statistically significant. Predictors of PAH were considered in univariate analysis.

Results:
There were 110 patients, 56 of whom were female and 61 were asplenic. PAH was present in 41 patients (37.3%), all of whom had normal left ventricular ejection fraction. There was no gender difference between the 2 groups (p=0.055). Selected statistically significant results are shown in the table.

Conclusions:
Prevalence of PAH in E/β-Thal patients is 37.3% without gender preponderance. Predictors are asplenia, more severe hemolysis, higher number of circulating (activated) platelets and nucleated RBCs, increased chronic low grade inflammation and increased cellular adhesion between blood and endothelial cells. These changes could facilitate development of thrombotic pulmonary arteriopathy, the underlying basis of PAH. Serum NT pro BNP assay can be utilized as a predictor or a screener of PAH in these patients.

Disclosures:
No relevant conflicts of interest to declare.
Characteristics of Transfused Platelets Do Not Affect Bleeding Outcomes in Hypoproliferative Thrombocytopenia.
Authors: Triulzi Darrell , Assmann Susan , Strauss Ronald G. , Ness Paul M. , Hess John R. , Granger Suzanne , Slichter Sherrill J. 
Published: October 2019

Abstract
Abstract 21

Background:
A number of studies have examined the effect of various platelet (plt) characteristics on the efficacy of plt transfusion(tx) including; source (apheresis platelets [AP] vs pooled platelets [PP]), plt ABO matching (identical [ID], minor mismatch [Min], major mismatch [Maj]), and duration of plt storage. These studies have focused on post transfusion plt counts with some evidence to support that there are differences in plt recovery based on these factors. These studies have not however examined the effect of these factors on the clinical outcome of bleeding.

Methods:
The PLADO study enrolled subjects with thrombocytopenia caused by stem cell transplantation (SCT) or chemotherapy into a blinded RCT of three different dosing strategies (lower, medium, and higher dose plt tx) to assess the effect of dose on the primary outcome of bleeding. Patients could receive either AP or PP with an attempt to keep patients on the same type plts. ABO selection and duration of storage were left to local practices. Patients were assessed daily for bleeding and, if present, assigned a WHO grade 2-4. A time to event analysis strategy was used with the outcome defined as the number of days from the first platelet transfusion to first date of bleeding. Subjects were censored on the first date they received a plt tx which differed from the first plt tx for the characteristic of interest. Analyses used Cox proportional hazard models with an adjustment for treatment group.

Results:
1351 patients were enrolled of which 1272 actually received a plt tx. 489 (38%) patients were excluded (41 given HLA selected plts, 421 with WHO Grade 2 or higher bleeding before or on the day of the first plt tx, and 27 with missing data) leaving 783 evaluable patients. The platelet source did not affect the time to first grade 2 or higher bleeding. Duration of platelet storage did not affect time to first grade 2 or higher bleeding . Because few patients received platelets stored for fewer than 3 days or more than 5 days, the analysis is shown for 3, 4 or 5 days of storage. ABO matching status did not affect time to first grade 2 or higher bleeding. A multi-predictor model using all 3 characteristics and treatment arm showed that none was significantly related to the time to grade 2 or higher bleeding.

Conclusion:
Platelet characteristics including source (AP vs PP), duration of storage for 3 to 5 days, and ABO matching, do not affect the outcome of time to bleeding in patients with SCT or chemotherapy receiving prophylactic platelet transfusions.

Disclosures:
Triulzi: Fenwal: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ness:Northfield Laboratories: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caridian: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Influenzaviruses Are Inactivated by the Manufacturing Process of Plasma-Derived Products.
Authors: Groener Albrecht , Schäfer Wolfram 
Published: October 2019

Abstract
Abstract 2107
Poster Board II-84
The starting material of plasma-derived products, pooled human plasma, may contain the blood-borne viruses HIV, HCV and HBV as well as HAV and B19V. The presence of these viruses in blood has led to cases of virus transmission by blood transfusions and, in the past when these pathogens were incompletely inactivated or removed, also by plasma-derived products. There is a continuous concern for the safety of the starting material for plasma-derived products regarding emerging viruses potentially present in the donor population. These viruses may not be detected because (i) at the time of donation the donor is in the incubation period and appears healthy and (ii) no routine screening test is available to detect emerging viruses. Therefore, the manufacturing process of plasma-derived products must be able to inactivate or remove these pathogens with a high margin of safety. Currently, influenzaviruses are perceived as viruses of risk, especially the pandemic influenzavirus H1N1 and the avian influenzavirus H5N1.
We studied the inactivation of influenzaviruses by pasteurization (heat treatment at 60°C for 10 hours in aqueous solution), a virus inactivation method used in the manufacturing process of a range of plasma-derived products. The influenzavirus strains H1N1 (A/PR/8/34), H5/N2 (A/chick/Pennsylvania/1/83), H7N1 (FPV/Rostock/34) and H5N1 (A/Cygnus/Germany/06) were used in virus validation studies employing a laboratory scale of the manufacturing process. This scaled-down process was validated to mimic the production process as closely as possible, i.e. appropriate product intermediates were obtained from the production facility and spiked with virus stocks. The heat treatment was performed according to production parameters resulting in identical conditions of protein concentration, pH, temperature, time etc for different coagulation factor concentrates (VWF/FVIII; FVIII; FIX) as well as ATIII. The virus strains were propagated in a chicken cell line (CER-3, established at CSL Behring) and the virus infectivity was quantified on MDCK cells based on a cytopathogenic effect. The data demonstrate these strains of influenzaviruses are highly sensitive to heat treatment: after a heat treatment of 6 hours or less, no infectious virus could be detected. The pasteurization step demonstrated an inactivation factor for each strain of at least ≥ 4.4 log10. We plan to study additional influenzavirus strains, as well as further products, to increase the robustness of the data base showing the effective inactivation of influenzaviruses by this heat treatment method alone.

Disclosures:
Groener: CSL Behring: Employment. Schäfer:CSL Behring: Employment.
Prominin-1 Mobilisation, Collection and Immunoselection in Cancer Patients for Liver Regeneration.
Authors: Perotti Cesare , Fante Claudia Del , Viarengo Gianluca , Maestri Marcello , Salvaneschi Laura 
Published: October 2019

Abstract
Abstract 2141
Poster Board II-118

Background:
CD133+ (Prominin-1 positive) is a 5-transmembrane glycoprotein that identifies immature progenitor stem cells.
Immature hematopoietic stem cells retain the possibility to give origin to tissues different from hematopoietic cell lines (transdifferentiation).

Material and methods:
In this preliminary study we investigated the possibility to mobilize, collect, immunoselect and reinfuse autologous CD133+ immature stem cells in liver cancer patients. This approach was adopted to obtain, in a short time, an adequate volume increase of the disease free liver thus extending the resectability criteria of the liver, with the final goal to prolong survival.
We enrolled 4 patients with a large liver cancer and no chance of resection. The mobilization protocol consisted in: G-CSF administration (10 μg/kg/day ) for 3-5 days, peripheral blood stem cell (PBSC) monitoring starting from the 3rd day, leukapheresis (LKF) collection processing 3 blood volumes when CD133+ cells>15 μL. Patients were monitored during mobilization, collection and post collection phase for clinical status, blood pressure and bleeding. Positive CD133+ immunoselection (Miltenyi Clinimacs) was performed on LKF product after overnight storage. Quality controls on positive fraction consisted in viability and purity of CD133+ cells by cytofluorimetric analysis and clonogenic assays. Microbial tests were performed on the negative fraction.
After LKF, patients underwent right portal embolization and infusion of CD133+ cells into the opposite portal vein by a percutaneous access. Evaluation of liver regeneration was performed 30 days after stem cell infusion by spiral CT and galactose clearance. Liver resection was carried out if liver regeneration reached 30-40%.

Results:
Stem cell mobilization, LKF content and immunoselected cells are detailed in tab 1. No relevant side effects were observed. We obtained an efficient stem cell mobilization in all patients enrolled. No bacterial or fungal contamination was observed in cells infused. Results about liver regeneration and patients' follow up are detailed in table 2.

Conclusions:
Our approach to liver regeneration was feasible and safe with no relevant side effects. We observed an efficient stem cell mobilization comparable to healthy donors also in liver cancer patients. The infusion of CD133+ cells allowed a significant hepatic tissue regeneration in all patients. Controlled clinical trials are needed to confirm our preliminary results.

Disclosures:
No relevant conflicts of interest to declare.
Pentraxin-3: An Easily Measurable Soluble Factor to Improve Post-Transplant Graft Versus Host Disease Monitoring and Management.
Authors: Dander Erica , Cuccovillo Ivan , Vinci Paola , Bonanomi Sonia , Maio Lucia Di , Lucchini Giovanna , Migliavacca Maddalena , Perseghin Paolo , Rovelli Attilio , Balduzzi Adriana , Mantovani Alberto , Bottazzi Barbara , Biondi Andrea , D'Amico Giovanna 
Published: October 2019

Abstract
Abstract 2217
Poster Board II-194

Introduction:
Allogeneic haemopoietic-stem-cell transplantation (HSCT) is the treatment of choice for many malignant and non-malignant disorders. Despite the recent advances in post-transplantat immunosuppressive therapy, Graft-versus-Host Disease (GVHD) still represents the major life-threatening complication, developing in a substantial number of HSCT patients and resulting in poor outcome. The basis of GVHD pathophysiology are still poorly understood and its current diagnosis depends mainly on clinical manifestations and invasive biopsies. Specific biomarkers for GVHD would facilitate the early and accurate recognition of this invalidating disease as well as the monitoring of patient response to adopted anti-GVHD pharmacological treatment. With the aim to explore new reliable markers for predicting and monitoring GVHD course, we focused on pentraxin-3 (PTX-3), an acute-phase protein, that has been shown to play a crucial role in orchestrating inflammatory immune responses.

Patients and Methods:
Having obtained an informed consent, we collected plasma samples from 46 patients who received unmanipulated HSCT and from 9 healthy donors (HD) volunteers. After HSCT, 25/46 patients developed skin GVHD (18 acute GVHD and 7 chronic GVHD), while 21/46 never experienced it. Concerning GVHD patients, blood samples were collected at the day of GVHD onset/ flare, before the beginning of GVHD-specific drug therapy. PTX-3 plasma levels were monitored by ELISA assays.

Results:
Patients who did not develop GVHD after HSCT showed augmented PTX-3 plasma levels (mean=3.3 ng/ml, range=1.1-8.6 ng/ml) if compared to HD (mean=1.2 ng/ml, range=0.3-2.5 ng/ml, p<0.01). Interestingly, we observed a strong increase of PTX-3 plasma levels in patients with acute GVHD (mean=42.2 ng/ml, range=6.7-218.2 ng/ml) or with flair-ups of chronic GVHD (mean=15.8 ng/ml, range=9-44.3 ng/ml). The increase of PTX-3 levels in patients with acute and active chronic GVHD was statistically significant (p<0.01 and p<0.05 respectively) when compared to both HD and HSCT patients without GVHD.

Conclusions:
These preliminary results suggest that PTX-3 plasma levels increase very rapidly in patients experiencing active GVHD, thus candidating PTX-3 as an easily measurable soluble factor useful to corroborate clinical observations in a disease in which signs and symptoms are often protean. Further studies are needed to clarify if PTX-3 could represent a good diagnostic and/or prognostic factor rapidly indicating therapy responsiveness.

Disclosures:
No relevant conflicts of interest to declare.
Donor Statin Treatment Protects against Severe Acute Graft-Versus-Host Disease After Related Allogeneic Hematopoietic Cell Transplantation.
Authors: Rotta Marcello , Storer Barry E , Storb Rainer F , Martin Paul J , Heimfeld Shelly , Peffer Amanda , Sandmaier Brenda M , Maloney David G , Deeg H. Joachim , Appelbaum Frederick R , Mielcarek Marco 
Published: October 2019

Abstract
Abstract 2227
Poster Board II-204

Acute graft-versus-host disease (GVHD) contributes to morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) and more effective prevention and treatment strategies are needed. The 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) have been shown to possess immunomodulatory properties in vitro and in vivo. To determine whether donor or recipient statin use may affect the risk of GVHD, we retrospectively analyzed outcomes among 567 patients with hematologic malignancies who had hematopoietic cell transplantation from HLA-matched related donors at a single institution between 2001 and 2007. Compared to allografts where neither the donor nor recipient was treated with a statin at the time of transplant (n=464), statin use by the donor and not the recipient (n=75) was associated with a profoundly decreased risk of grade 3-4 acute GVHD (multivariate hazard ratio [HR], 0.28; 95= confidence interval [CI], 0.1-0.9; p=0.03) (Table). Statin use by both donor and recipient (n=12) was suggestively associated with a decreased risk of grade 3-4 acute GVHD (HR, 0.00; 95= CI, undefined; p=0.06), while statin use by the recipient and not the donor (n=16) did not confer GVHD-protection. Risks of chronic GVHD, recurrent malignancy, non-relapse mortality and overall mortality were not significantly affected by donor or recipient statin exposure. Statin-associated GVHD-protection was restricted to recipients with cyclosporine-based postgrafting immunosuppression (n=417; 74=) and was not observed among those given tacrolimus (significance of effect modification: cyclosporine vs. tacrolimus, p=0.009). These results suggest that donor statin treatment may be a promising strategy for preventing severe acute GVHD without compromising immunologic control of the underlying malignancy.

Disclosures:
No relevant conflicts of interest to declare.
Antifungal Therapy with Itraconazole Impairs Rituximab′s Anti-Lymphoma Effect by Inhibiting CD20 Recruitment to Lipid Rafts.
Authors: Bueschenfelde Christian Meyer zum , Feuerstacke Yvonne , Krainz Philipp , Herrmann Ken , Buck Andreas , Peschel Christian , Ringshausen Ingo 
Published: October 2019

Abstract
Abstract 2735
Poster Board II-711
Patients with hematologic malignancies have a high risk of developing invasive fungal infections. The higher risk is attributed to host defense impairment due to intensive cytotoxic chemotherapies, hematopoetic stem cell transplantation, and immunosuppressive agents. As early treatment initiation in patients with invasive fungal infections has a profound impact on mortality rates, different antifungal treatment strategies like prophylaxis, empirical, pre-emptive and targeted treatment after proven fungal infection have been developed. Azoles are the most broadly used antifungal drugs inhibiting CYP51. They play a pivotal role in the treatment and prophylaxis of systemic and dermal mycoses. Azoles inhibit the sterol 14a-demethylase activity and block sterol biosynthesis, which is lethal in unicellular organisms. However, in mammalian cells, it has been shown that they lower endogenous cholesterol production. As lipid rafts consist of sphingolipids and cholesterol and lipid rafts have been demonstrated to be crucial for rituximab induced cell death, we asked whether rituximab exhibits its full anti-lymphoma effect in the presence of azoles.
We now demonstrate that antifungal treatment with itraconazole impairs rituximab's anti-lymphoma effect both in vitro and in vivo. Using a mouse xenograft model, no tumor growth was observed in mice treated with rituximab. In contrast, in the presence of itraconazole there was tumor growth, indicating that the concentration was sufficient to antagonize rituximab′s anti-lymphoma effect. On the molecular level, CD20 raft recruitment was inhibited in the presence of itraconazole. Furthermore, the translocation of CD20 into lipid rafts has been shown to be crucial for calcium influx and apoptosis. Therefore, we tested the rituximab induced calcium flux in the absence and presence of itraconazole. Indeed, calcium flux was almost completely abolished in the presence of itraconazole. The fact that antibody treatment failure in the presence of itraconazole only affects targeted therapy against raft associated molecules i.e. CD20 and CD52 but not the non raft associated molecule CD33 further supports our proposed mechanism of action. Together, our data suggest that concomitant treatment of itraconazole and rituximab attenuates rituximab's anti-lymphoma effect. As chemotherapy by itself has high response rates in lymphoma, the loss of rituximab mediated cell death in the presence of itraconacole may be missed in our daily routine.

Disclosures:
No relevant conflicts of interest to declare.
Expression of S100A8 in Leukemic Cells Predicts Poor Survival in De Novo AML Patients.
Authors: Mossuz Pascal , Nicolas Emmanuelle , Ramus Claire , Berthier Sylvie , Arlotto Marie , Lefebvre Christine , Morel Françoise , Garin Jérome , Ifrah Norbert , Berger François , Cahn Jean-Yves 
Published: October 2019

Abstract
Abstract 276

Treatment strategies of acute myeloid leukaemia (AML) largely depend on their cytogenetic status. However this stratification remains insufficient for almost half of the patients, requiring subsequent molecular investigations. In our study, we used mass spectrometry-based proteomic approaches to characterize de novo-AML. Samples (blood mononuclear cells collected and frozen before any treatment) were retrospectively selected from two independent sets of newly diagnosed AML patients, included in prospective clinical trials of the GOELAMS (Groupe d'Etude Ouest-Est des Leucémies aigues). We showed that protein signature of leukemic cells defined 2 groups of patients that displayed significant variation of overall and disease free survival (Fig-1A). This proteomic classification refined cytogenetic classes. Combination of proteomic and cytogenetic allowed a new stratification highly correlated with outcome. In particular, AML with intermediate and high risk cytogenetic could be respectively subdivided according to their protein profiles in two subgroups with significantly different survival (Fig-1B). Interestingly in both type 2 and type 3 cytogenetic groups, a good proteomic profile identified subsets of patients with significantly increased probability of survival, suggesting that the weigh of a good proteomic risk might predominate over a bad predictive cytogenetic. Among proteins expressed by leukemic cells, we isolated a 10800 Da marker that retained the highest discriminative value between alive and deceased patients. The median intensity of the 10800 peak was 94.3 ± 97.7 (7.5-368.7) in living patients compared to 214.2 ± 163.7 (9.0-693.4) in dead patients (p= 0.009). Among normal cytogenetic patients, intensity levels of the marker was also significantly different between dead (217.4 ± 155.7 range 10.4-612.8) and alive patients (26.0 ± 73.1, range 6-168.1; p= 0.008) (Fig-1C). Using a thresholds of 100 (calculated by ROC curves) we were able to correctly identify 82% of patients who died (patients greater than 100) and 70% of patients who stayed alive (patients lower than 100) with a specificity of 65% and 82% respectively. These data were confirmed in a second independent set of patients. 10800 Da marker was identified by MS peptide sequencing as S100A8 (also designated MRP8 or calgranulin A), a cytosolic protein of mature granulocytes. Western blot analysis confirmed its expression mainly in AML patients with the worst prognostic but not in all AML patients, neither in some leukemic and lymphoma cell lines, arguing for a selective deregulation associated with poor prognosis. These results show that expression of S100A8 in leukemic cells at diagnosis might be considered as a predictor of low survival.

Disclosures:
No relevant conflicts of interest to declare.