bluuebunny/crossref_metadata_2025_split huggingface dataset:
EARLY Post-Transplant Events , Cost of Admission and Mortality, in Patients Undergoing Allogeneic Transplants from Identical Siblings, Unrelated Donors or Haploidentical Donors
Authors: SORA Federica , Chiusolo Patrizia , Laurenti Luca , Giammarco Sabrina , Autore Francesco , Innocenti Idanna , Sica Simona , Elisabetta Metafuni , Bacigalupo Andrea 
Published: October 2019

Abstract
Background. The outcome of allogeneic hemopoietic stem cell transplantation (HSCT) is measured in terms of graft versus host disease (GvHD), non-relapse mortality (NRM) and survival. Days of Hospital stay and number of re-admissions, are important surrogates of outcome, quality of life, and also of costs, but are usually not reported.
Aim of the study . Assess the number of days alive and outside the Hospital (DAOH) , together with the frequency of a new re-admission, in the first 100 days after transplant. Patients. We analyzed 212 patients who received an allogeneic HSCT from matched sibling (SIB) (n=64), unrelated donors (UD) (n=74) and family haploidentical donors (HAPLO) (n=74). Median age was 49 years (19-71), disease phase was in remission in 53%; diagnoses was acute leukemia (66%) , MDS (14%) chronic disorders 20%.
DAOH. The median DAOH for SIB, HAPLO and UD grafts was 78, 72 and 66 days (p=0.0001). The median DAOH for SIB patients was significantly longer than for UD patients (p=0.00002) and for HAPLO grafts (p=0.0008); the median DAOH for UD and HAPLO patients were comparable (p=0.4). Donor type was the strongest predictor of DAOH , followed by a Sorror score >2 (p=0.04).
Re-admission. Fifty four patients, of 185 discharged, required a re-admission for complications. the first cause for readmission was fever of unknown origin (54%), followed by GvHD (18,5% ) ,cystitis (8%) , relapse (7%) and respiratory problems (7%). The only factor predicting re-admission was advanced disease (p=0.01). Patients who were re-admitted to hospital within 100 days had a significantly higher risk of non relapse mortality (NRM) (25%) as compared to patient non re-admitted (5%) irrespective of the cause for re-admission (p=0.0001). In a multivariate analysis re-admission was the strongest predictor of NRM, with a risk ratio of 10.9 (p=0.0002).
Days of admission and cost. The average number of days in hospital within 100 days from transplant, was 37,6 for UD, 35,0 for HAPLO and 25,0 for SIBS (p=0.0002). The average cost of admission within 100 days from HSCT, was €69522 for UD, €64715 for HAPLO and €46225 euros for SIBS.
Conclusion. HAPLO transplants with PT-CY and UD transplants , have lower numbers of DAOH, as compared to SIB grafts, which implies longer stay in hospital and greater cost. Re-admission to Hospital within 100 days is predicted by disease phase and has a very strong impact on non relapse mortality.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Rituximab Maintenance Treatment for a Maximum of 5 Years in Follicular Lymphoma: Final Results of the Randomized Phase III Trial SAKK 35/03
Authors: Taverna Christian , Martinelli Giovanni , Hitz Felicitas , Mingrone Walter , Pabst Thomas , Cevreska Lidija , del Giglio Auro , Vanazzi Anna , Laszlo Daniele , Raats Johann , Rauch Daniel , Vorobiof Daniel , Lohri Andreas , Zucca Emanuele , Rueegsegger Celine , Rondeau Stephanie - , Rusterholz Corinne , Ghielmini Michele 
Published: October 2019

Abstract
Background: Follicular lymphoma is usually a disase with a prolonged course and a chemotherapy-free regimen might be a favourable treatment strategy. SAKK 35/03 investigated two different durations of rituximab maintenance (5 years vs. 6 months) in patients with follicular lymphoma after induction with 4 weekly doses of rituximab monotherapy. With a median follow-up of 6.4 years we were not able to show a benefit with long-term rituximab maintenance up to five years in event-free survival (EFS) or overall survival (OS ). Here we report the final results with a median follow-up of 10 years.
Methods: 270 patients (median age 57 years: range 25-82) with untreated, relapsed, stable or chemotherapy resistant follicular lymphoma were treated with 4 doses of rituximab monotherapy in weekly intervals (375 mg/m²). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of five years or until disease progression or unacceptable toxicity). The primary endpoint was EFS . Progression-free survival (PFS), OS, and toxicity were secondary endpoints. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints.
Results: 165 patients were randomly assigned to short-term (n=82) or long-term (n=83) maintenance. At a median follow-up period of 10 years, the median EFS is 3.4 years (95% CI 2.1-5.5) in the short-term arm and 5.3 years (95% CI 3.5-7.5) in the long-term arm. Using the pre-specified log-rank test this difference is statistically not significant (p=0.39 ). There is no significant difference in PFS and OS. Median OS in the short-term arm is 11.0 years (95% CI 11.0, NA ) and not reached in the long-term arm (p=0.80). The incidence of subsequent cancers increased in both arms over time, nine patients developed a subsequent cancer in the short-term maintenance arm and 10 in the long-term maintenance arm. There was no major additional toxicity with longer follow-up.
Conclusions : Even with a long follow-up of 10 years we were not able to show a significant benefit of long-term compared to short-term rituximab maintenance in EFS, PFS and OS. Treatment strategies and study designs need to take these results into consideration in order to guarantee optimal medical and scientific results.

Disclosures
Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.
Impact of Immune Thrombocytopenia in Patients Admitted with Coronary Artery Disease: Results from National Inpatient Sample 2009-2011
Authors: Aryal Madan , Basnet Sijan , Dhital Rashmi , Gosain Rohit , Donato Anthony 
Published: October 2019

Abstract
Background
Patients with immune thrombocytopenia (ITP) may be at increased risk of thromboembolism related to different causes, including the use of thrombopoietin receptor agonists and splenectomy. Patients with ITP who develop coronary artery disease (CAD) can be a further challenge given their risk of both thromboembolism and bleeding, which may significantly increase the risk of mortality and length of stay (LOS) compared to patients who do not have ITP. We aimed to study the impact of ITP in hospital outcomes of patients with CAD.
Methods
We utilized the National Inpatient Sample database from years 2009 - 2011. We selected non-pregnant inpatients over the age of 18 with history of CAD. We selected patients with CAD and ITP based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We used STATA version 13.0 (College Station, TX) for database analysis.
Results
A total of 4,777 cases of ITP with CAD were identified compared to 2,614,008 without ITP (Table 1). Logistic multivariable analyses found that patients with ITP had higher in-hospital mortality (95% CI: 1.21 to 1.55, p=0.0001) and LOS (95% CI: 1.32 to 1.72, p<0.0001) after adjustment for age, sex, race, smoking, obesity, dyslipidemia, diabetes, hypertension, chronic kidney disease, peripheral vascular disease, smoking, obesity, stroke, and Charlson comorbidity index (Table 2).
Conclusion: Our study shows that in patients with coronary artery disease-associated ITP, adjusted LOS and mortality was significantly higher compared to patients without ITP.

Disclosures
No relevant conflicts of interest to declare.
Long Term Survival Analysis of Multiple Myeloma Patients Receiving Induction Therapy+ Autologous STEM CELL Trasplantation, Comparing Velcade-Dexametasone to Alkylating Polichemotherapy As Induction Therapy
Authors: Caceres Sara , Cardesa Rocio , Cabrera Carmen , Bañas M. Helena , Ibañez Fatima , Prieto Julio , Groiss Jorge , Toran Damian , Hernandez Carmen , Sergio Ortegon , Elena Duvos , Casado Maria Soledad , Cerezo Esperanza , Siguenza Raul , Suarez-Varela Sara , Carnicero Fernando , Martin Mateos Maria Luisa , Arcos Maria J. , Rodriguez Angel , Moriano Baldomero , Casas Ignacio , Perez Leal Francisco , Vazquez Godoy Teresa , Bagace Jose M. , Sanz Miguel A. , Bergua Burgues Juan Miguel Miguel 
Published: October 2019

Abstract
Introduction: Multiple Myeloma (MM) is an incurable disease. In young patients, autologous bone marrow transplantation (ABMT) remains a cornerstone treatment after induction therapy. Induction therapy has varied during time, from alkylating polychemotherapy (VBAD,VCMP) or VAD chemotherapy (AVAD) to Velcade-Dexametasone based regimens (VD). We present results of follow-up of a large cohort of patients treated with ABMT. We described overall survival (OS; from transplant to death by any cause) and progression free survival (PFS; from transplant to death by any case or progressive disease defined by reappearance by inmunofixation, or duplication of monoclonal peak after ABMT) , and the impact of induction therapy regiments.
Patients: 183 patients transplanted from 2002 to 2017. The median age of the patients was 59 years (33-72). Before 2008 all the patients were treated in alkylating based chemotherapy (42 patients). After 2008 patients were treated with VD based regimens (141patients). Only 12 patients received maintenance therapy based in PETHEMA trials 2005 and 2012. No one patient received a planed second transplant; only 32 patients received a second transplant after relapse as consolidation therapy.
Results: Median follow-up of patients still alive is 3.65 years (0.15-14.77). Median OS of all patients was 9.12 years (95% confidence interval (CI): 6.28-NR); Median PFS was 3.02 years(95% CI: 2.46-3.76). At 13 years only 2% of patients remains progression free (CI: 0.00-17%). There were significant differences between patients treated before and after VD regimens. The median OS of patients treated with APVAD was significantly shorter compared to VD (6.22 years, CI[3.39-12] vs. NR, CI[6.28-NR], p=0.025) (HR=0.49, p=0.01).
Conclusions: VD schemes of induction before ABMT have improved remarkably OS inpatients with Myeloma; nonetheless, plateau is not observed in EFS. Further analysis must address if EFS could represent a strong indicator of OS, mainly due to novel effective salvage therapies after relapse/refractoriness could be a confounding factor.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Development of a Clinical Prediction Rule for the Risk of Venous Thromboembolism in Patients with Acute Leukemia
Authors: Al-Ani Fatimah , Wang Yimin Pearl , Lazo-Langner Alejandro 
Published: October 2019

Abstract
Background: The impact of venous thromboembolism (VTE) on morbidity and mortality is significant in hematological cancer patients, including acute leukemia (AL). However, VTE in AL receives little attention in comparison to other more frequently occurring complications. Identifying risk factors for the development of VTE among patients with AL will enable clinicians to stratify their patients according to their VTE risk and consider them accordingly for tailored surveillance or prophylaxis strategies.
Methods: We aimed to derive a prediction rule for assessing VTE risk in AL patients. We conducted a retrospective cohort study of consecutive adult patients diagnosed with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) diagnosed between June 2006 and June 2017 at the London Health Sciences Centre, a tertiary care center in London, Ontario, Canada. Included participants were followed from diagnosis until last follow up, the occurrence of VTE, or death. Potential predictors were compared between groups using χ2 or Fisher's exact tests for categorical variables and T tests for continuous variables. Potentially significant predictors were evaluated using logistic regression and Cox regression analysis. A risk score was derived based on weighed variables included in the final model and compared using Kaplan-Meier survival analysis.
Results: A total of 396 patients with AL (335 AML and 61 ALL) were included in the preliminary analysis. Population characteristics are shown in the Table. VTE occurred in 68 (17%) patients. Median time to VTE was 3 months (Interquartile range 1-5). In univariate analysis a diagnosis of ALL, prior history of VTE, platelet count at presentation and the number of attempts for line insertion were potential predictors. However, in multivariate analysis only ALL diagnosis and prior history of VTE remained significant. A score was derived based on these predictors (ALL 1 point; Prior VTE 2 points). Kaplan-Meier analysis showed good discrimination between categories (Figure; Log-rank p<0.001).
Conclusion: We derived a score predictive of VTE in acute leukemia patients. Further confirmatory and validation studies are ongoing.
Disclaimer. FA-A is a fellow of the CanVECTOR Network; ALL-L is an investigator of the CanVECTOR Network. This study was funded by the CanVECTOR Network which receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654).
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Inhibition of Autophagy with 3-Methyladenine Potentiates Bortezomib-Induced Apoptosis of Myeloma Cell Via up Regulation of Mitochondrial Reactive Oxygen Species
Authors: Mun Yeung-Chul , Ahn Jee Young , Yoo Eun Sun , Lee Kyoung Eun , Nam Eunmi , Lee Soon Nam , Woo Hyun Ae , Rhee Sue Goo , Seong Chu Myong 
Published: October 2019

Abstract
Backgrounds : Autophagy plays an important role in the pathogenesis of multiple myeloma. Autophagy usually acts on a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death and could synergize with proteasome inhibitors in myeloma cells. In this study, we investigated the synergistic mechanism of apoptosis with bortezomib (BTZ) and autophagy inhibitors in the MM cells.
Methods : We evaluated the change of autophagy, apoptosis, mitochondrial ROS and cellular level of redox enzymes, including peroxiredoxin (Prx), thioredoxin (Trx), thioredoxin reductase (Trx-R) using human myeloma cell lines, MM.1S and MM.1R during BTZ treatment. To study the status of oxidation for redox enzyme, sulfinic acid (SO2) or multimeric form of Prx, Trx and Trx-R by western blot were measured using non-reducing or reducing gel.
Results : Mitochondrial over cytosolic ROS of MM cells was increased significantly after 24 hour of BTZ (2.5 nM) treatment. Apoptosis of MM cell after BTZ treatment was increased in concordance with mitochondrial ROS increment of MM cells. N-acetylcystein (NAC) reversed BTZ-induced mitochondrial ROS elevation and apoptosis of MM cells as well. Increased expressions of cleaved caspase-9 and cleaved caspase-3 were also observed during BTZ-induced MM cell apoptosis. LC3-II expression was elevated along with increment of mitochondrial ROS and apoptosis of MM cells after BTZ treatment. Oxidation of PRX4 and TRX2 was observed during BTZ-induced apoptosis of MM cells. After treatment of NAC, LC3-II and PRX4/TRX2 expression was reversed. Inhibition of autophagy with 3-Methyladenine (3-MA) not only resulted in a further increase in BTZ-induced apoptosis but also induced mitochondrial ROS in MM cells.
Conclusions : Autophagy is induced during BTZ treatment in MM cells. Our experiment showed crosstalk between autophagy and mitochondrial ROS and its redox enzymes during BTZ-induced MM cell apoptosis. Inhibition of autophagy with 3-MA potentiates BTZ-induced apoptosis of MM cells via up regulation of mitochondrial ROS. Our results provide new perspective on the cellular mechanism of action of BTZ and support the synergism of BTZ with autophagy inhibitor for an improved therapy of the multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.
Reduction of Graft Rejection By Fludarabine Combined Busulfan, Cyclophosphamide and Antithymocyte Globulin Conditioning in Cord Blood Transplantation for Children with Wiskott-Aldrich Syndrome
Authors: Xiao Peifang , Lu Jun , Li Jie , Zheng Defei , Gao Li , Guo Ailian , Liu Hu , Liu Suxiang , He Hailong , Hu Shaoyan 
Published: October 2019

Abstract
Background and Objectives: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency with microthrombocytopenia. Hematopoietic stem cell transplantation is a curative treatment for WAS. Unrelated cord blood transplantation (UCBT) become a more successive alternative donor transplantation for WAS with the improvement of high resolution HLA-typing method. However, graft rejection is the primary cause for mortality of WAS after UCBT. We hypothesized that the addition of fludarabine to a myeloablative conditioning regimen with antithymocyte globulin (ATG) would support engraftment for these children.
Methods: Seventeen Children with WAS underwent UBCT matched 6-10/10 at higher resolution (HLA-A, -B, -C, -DRB1and DQB1) in our center between 2013 and 2018. The conditioning regimen consisted of fludarabine 160 mg/m2 , busulfan (BU)12.8 mg/kg, cyclophosphamide (CY)120 mg/kg, ATG 7.5 mg/kg, and cyclosporine and mycophenolate for GVHD prophylaxis. Median follow-up time is 2.5 years (range, 0.2 to 3.5 years).
Results: All children had sustained donor cell engraftment and are stable engraftment. Twelve (71%) patients had cytomegalovirus (CMV) antigenemia and no one developed into CMV disease. Six (35%) children underwent acute Graft-versus-host disease (GVHD) (grade II-IV) and four (24%) children developed into chronic GVHD (cGVHD). Among these cases, only one child with HLA matched 6/10 died of kidney failure because of cGVHD. He experienced aGVHD with skin bullosa. Sixteen (94%) children are survival.
Conclusion: Conditioning regimen consisted of Fludarabine combined BUCY and ATG was able to reduce graft rejection in the WAS children after UCBT without increasing infection related mortality. Future efforts will focus on further reducing rates of acute GVHD and extensive cGVHD.

Disclosures
No relevant conflicts of interest to declare.
Silencing HDAC3 Enhances Apoptosis of Acute B Lymphoblastic Leukemia Cells smurf2 Inducing By Inhibiting JAK/STAT3 Signal Pathway
Authors: Guo Yongling , Ma Dan , He Zhengchang , Xiong Jie , Kuang Xingyi , Wang Weili , Yu Kunling , Zhang Zhaoyuan , Wang Jishi 
Published: October 2019

Abstract
Purpose Smad ubiquitin regulatory factor 2(Smurf2) as a member of ubiquitinated E3 ligase was certificated to regulate the ubiquitination level of target gene. In this study, smurf2 as tumor suppressor was studied in acute B lymphoblastic leukemia, Histone deacetylases 3(HDAC3) which was connected with smurf2 was related with poor prognosis. It is further proved that smurf2 and HDAC3 were expected to be therapeutic targets for B-ALL cells and improve the prognosis of patients with B-ALL.
Methods Realtime-PCR and westernblot were used to detect the expression of smurf2 and HDAC3 in healthy donors and B-ALL patients by us. Sup-B15 and CCRF-SB were treated with MG-132, small interfering RNA of smurf2 or HDAC3. Up-regulating smurf2 plasmid was also transfected to B-ALL cells by lipo3000. Flow cytometry and westernblot were used to validate the difference of apoptosis and cell cycle.
Results Smurf2 mRNA in B-ALL patients was significantly lower than that in healthy donors. HDAC3 was higher in B-ALL patients than that in healthy donors. Protein level of smurf2 and HDAC3 was consistent with mRNA level. Up-regulating smurf2 by plasmid or MG-132 and silencing smurf2 could influence HDAC3, which further depressed JAK/STAT3 signal pathway inducing apoptosis of B-ALL cells. Sup-B15 and CCRF-SB were treated with siHDAC3 and MG-132 for 24h, we discovered that silencing HDAC3 enhanced the apoptosis level of B-ALL cells MG-132 inducing by depressing JAK/STAT3 pathway. It was expected to become a therapeutic target for improving the clinical prognosis of B-ALL patients. On the other hand, we found that MG-132 caused G2/M phase arrest in B-ALL cells and successfully inhibited the JAK/STAT3 pathway leading to apoptosis.
Conclusions Silencing HDAC3 inhibited the JAK/STAT3 pathway and further enhanced apoptosis in B-ALL cells MG-132 inducing. HDAC3 and smurf2 were expected to become therapeutic targets for clinical treatment of acute B lymphocytic leukemia and improve survival rate of leukemia patients.
Key words Smurf2; HDAC3; Apoptosis; Prognosis;

Disclosures
No relevant conflicts of interest to declare.
Preclinical Evaluation of an Engineered AAV Capsid in Non-Human Primates for the Treatment of Haemophilia B
Authors: Dane Allison , McIntosh Jenny , Lee Doyoung , Sheridan Rose , Maginn Mark , Corbau Romuald , Davidoff Andrew M. , Nathwani Amit C 
Published: October 2019

Abstract
Introduction
Over recent years, proof-of-concept academic and early phase commercial trials have demonstrated long-term therapeutic benefit of liver directed AAV-mediated gene transfer of human FIX (hFIX). Extending this success to a greater number of haemophilia B patients is hampered by the need for large vector doses required for efficient gene transfer and associated liver toxicity. To improve potency, we focused on developing a novel synthetic capsid, AAVS3, to increase human hepatocyte transduction.
Here we present the preclinical in vitro and in vivo evaluation of AAVS3 pseudotyped vectors. In addition to showing strong liver tropism we demonstrate clinically relevant expression levels of hFIX expression in non human primates.
Methods
Primary human hepatocyte cultures were used to compare transduction efficiency of our novel capsid with AAV5 and AAV8, variants currently in the clinic. To extend this data in vivo, a humanised mouse liver model was utilised. Subsequently, fourteen Rhesus macaques were dosed with AAVS3 pseudotyped FIX vectors, via saphenous vein injection. Levels of hFIX were determined using an ELISA assay that is able to distinguish hFIX protein from the native Rhesus macaque FIX protein. At harvest biodistribution of vector was detected by quantitative PCR.
Results
We demonstrate that gene transfer efficiency with AAVS3 was up to 10-fold higher in primary human hepatocytes, when compared to vectors pseudotyped with AAV serotype 5 or 8 capsids. In addition, studies in a chimeric human-murine liver model revealed AAVS3 was 6-fold more efficient at transducing human hepatocytes compared with an AAV8 vector. Using two distinct optimised FIX expression cassettes, we demonstrate highly efficient gene transfer in Rhesus macaques. Indeed, AAVS3 FIX vectors injected at clinically relevant doses of 0.93 x1012 to 2.56 x1013 vg/kg achieved mean peak levels of 0.546 and 21.7µg/ml of hFIX respectively (~11% to ~430% of normal levels). Biodistribution studies showed strong liver tropism following peripheral vein administration with minimal distribution to other organs at or below the level of detection. No vector associated lesions or adverse events were observed in the liver.
Conclusion
Collectively, these data support further evaluation of an AAVS3 pseudotyped vector in humans with the aim of achieving transduction of a larger proportion of hepatocytes using a lower, potentially safer dose of vector than achieved with AAV8.

Disclosures
Dane: Freeline: Employment. Sheridan:Freeline: Employment, Equity Ownership. Maginn:Freeline: Consultancy, Equity Ownership. Corbau:Freeline: Employment, Equity Ownership. Nathwani:Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties.