bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome Of Hematopoietic Cell Transplantation (HCT) In Pediatric Patients With Hodgkin Lymphoma (HL): Single Institution Results From Saudi Arabia
Authors: Sumaili Hassan A , Belgaumi Asim F , Al-Kofide Amani A , Al-Seraihy Amal , El-Solh Hassan , Al-Jefri Abdallah , Al-Ahmari Ali , Mohamed Amal , Anas Mohammed , Ayas Mouhab 
Published: October 2019

Abstract
Most pediatric patients with Hodgkin lymphoma are cured of their disease with standard combined-modality first-line therapy. Those who relapse are subjected to salvage chemo-radiotherapy, and patients who respond often undergo either autologous or allogeneic HCT, with a reported outcome ranging from 40%-60%. Variables affecting the outcome of such patients are not clearly defined.
This study retrospectively reviewed the clinical characteristics and outcome of patients who underwent HCT at our institution.
Between 1995 and 2012, 29 pediatric (age <14 years) patients with HL underwent HCT. This cohort included 24 boys and 5 girls. Their median ages at initial diagnosis and at HCT were 9.85 years (mean 8.85; range 3.6-13.75) and 12.18 years (mean 11.24; range 5.6-14.9), respectively. 28 patients had classic HL (23 nodular sclerosis, 3 mixed cellularity, 1 lymphocyte-depleted, and 1 lymphocyte-rich) and one patient had nodular lymphocyte-predominance HL. Ten had persistent/progressive disease following first line therapy, while 19 had relapsed following achievement of complete response (CR). For these patients median time to relapse from completion of first-line therapy was 16.9 months (mean 20.1; range 1.9-53.1). All patients received salvage chemotherapy and/or radiotherapy prior to HCT; fifteen patients achieved CR, 13 had a partial response and one had progressive disease. Two patients had allogeneic bone marrow (BM) grafts from matched-related donors, while the rest had autologous grafts (16 BM; 10 PBSC; 1 BM+PBSC) following chemotherapy-based myeloablative conditioning. Twelve patients have relapsed/progressed post-HCT at a median of 6.04 months (mean 11.8; range 1.02-71.4). Nine patients have died; eight because of disease progression and one due to sepsis post HCT. Only two patients died within the first 100 days post HCT, giving a Day-100 mortality rate of 6.8%. Two patients who relapsed after HCT were salvaged with chemo/radiotherapy and remain disease free 2.8 and 9.7 years later. The 5-year estimated overall survival (OS) from HCT for the whole cohort is 61.6%, with an event free survival (EFS) of 57.9%. Patients who had persistent/progressive disease at the end first-line therapy or relapsed <6months off therapy had a worse OS and EFS as compared to those who relapsed later (OS 42.9% v. 75.3%, p=0.047 [Taron-Ware]; EFS 41.7% v. 60.8%, p=0.052 [Taron-Ware]).
The outcome of patients with relapsed/refractory HL following HCT is encouraging, as a majority of patients survive free of their lymphoma. Timing of relapse/progression remains an important prognostic factor and patients who fail early may be considered for novel therapeutic approaches.

Disclosures:
No relevant conflicts of interest to declare.
Salvaged Cord Blood Transplantation For 19 Patients With Progressive Hematologic Malignancies
Authors: Zimin Sun , Wen Yao , Changcheng Zheng , Juan Tong , Huilan Liu , Liangquan Geng , Tang Baolin , Xiaoyu Zhu , Kaidi Song , Ding Kaiyang 
Published: October 2019

Abstract
Few clinical studies have investigated the role of salvaged unrelated cord blood transplantation (CBT) for progressive hematologic malignancies. The aim of this report is to identify the potential benefits of unrelated CBT in progressive hematologic malignancies.19 consecutive patients with progressive myeloid and lymphoid malignancies who received salvaged CBT following myeloablative conditioning regimens (12 TBI/CY/Ara-C, 6 Bu / CY / Ara-C, and 1 Bu /CY) from July 2005 to December 2012 were analyzed retrospectively. Of the 19 patients, 6 suffered from acute myeloid leukemia(AML), 5 acute lymphoid leukemia(ALL),：1 acute mixed lineage leukemia (AMLL), 1 myelodysplastic syndrome-refractory anemia with excess blasts(MDS-RAEB), 2 acute myeloid leukemia transformed from myelodysplastic syndrome, and 4 lymphoma, all of them in non-remission (NR) before transplantation. Median age of them were 13（range 6-32）years and median body weight were 45 (range 18–73 ) kg. All patients received 1 CBT unit ≤2 loci HLA-mismatched with the recipient. Infused TNC was 4.07（range 2.76-6.02）×107/kg and CD34+ stem cell 2.08（range 0.99-8.65）×105/kg. All patients were engrafted with neutrophil exceeded 0.5×109/L on median day +17（range 14-37d）and plt counts of＞20×109/L on median day +35 (range 17-70d). 10 patients (52.6%) experienced pre-engraftment syndrome (PES) and 3 (15.8%) patients progressed to acute GVHD. The incidence of Ⅱ-Ⅳ aGVHD and cGVHD were 10.5% and 21.1%. With a median follow up of 10(range 1-58) months，10 cases survived and 2 relapsed．The estimated 2 year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM) rate was 45.6%, 34.2% and 39.8%. Salvaged CBT might be a promising modality for treatment of progressive hematologic malignancies, even with high leukemia burden.

Disclosures:
No relevant conflicts of interest to declare.
The Mechanisms Of Damage To Bone Marrow By Iron Overload In Patients With Immuno-Related Pancytopenia
Authors: Fu Rong , Huang Lei , Shao Zonghong 
Published: October 2019

Abstract

Objective
To investigate the mechanisms of iron overloading bone marrow damage in patients with immuno-related pancytopenia.

Methods
Forty-seven IRP patients (21 iron overloading IRP patients) and 10 normal controls were enrolled in this study. The expression of ROS, apoptosis, Bcl-2 and Caspase-3 of the bone marrow mononuclear cells (BMMNC) were analyzed by flow cytometry. Antioxidants were added to the iron overloading IRP BMMNC, and then the changes were detected by FCM. The number and apoptosis of the T lymphocytes of IRP patients were detected.

Results
The ROS and apoptosis of the BMMNC, myelocytes, erythrocytes and stem cells in the bone marrow were significantly higher than those of non iron overloading IRP patients and normal controls(P<0.05). The expression of Bcl-2 in BMMNC, erythrocytes and stem cells of the iron overloading IRP patients were significantly lower than those of non iron overloading IRP patients (P<0.05). The levels of Caspase-3 in myelocytes, erythrocytes and stem cells of the iron overloading IRP patients were significantly higher than those of non iron overloading IRP patients or normal controls (P<0.05). After being treated with antioxidants, the expression of ROS, Caspase-3 and apoptosis of the iron overloading IRP BMMNC significantly decreased, the opposite of the Bcl-2. The percentage of the CD4+ lymphocytes (40.86±8.74)% and CD4+/CD8+ (1.44±0.36) in PB of the iron overloading IRP patients were significantly higher than those of non iron overloading IRP patients (35.96±7.03)% and (1.13±0.37)and normal controls(28.00±6.73)% and (0.79±0.21) (P<0.05), the opposite of CD8+ lymphocytes (P<0.05). The apoptosis of CD8+ lymphocytes (27.35±10.76)% and the ratio of CD8+ apoptosis /CD4+ apoptosis (2.51±0.80) in BM were significantly higher than those of the non iron overloading IRP patients (15.47±8.99)% and (1.39±0.47) (P<0.05). The apoptosis of the erythrocytes and stem cells coated with auto-antibodies in BM of the iron overloading IRP patients were significantly higher than those of the non iron overloading IRP patients.

Conclusion
Iron overload damaging the bone marrow hematopoiesis might be through the following mechanisms. 1. The increased ROS induced by iron overload affected the expression of Caspase-3 and Bcl-2, which caused the higher BMMNC apoptosis; 2. The abnormal number and ratio of T lymphocytes caused by iron overload aggravate the abnormality of immunity of IRP; 3. Iron overload may increase the damage to erythrocytes and stem cells coated with auto-antibodies.

Disclosures:
No relevant conflicts of interest to declare.
Pulmonary Irradiation Fibrosis Is Preceded By Increased Endothelial Cell Gene Expression
Authors: Kalash Ronny , Au Jeremiah , Epperly Michael W. , Goff Julie P. , Dixon Tracy M. , Franicola Darcy , Greenberger Joel S. 
Published: October 2019

Abstract
Irradiation of the C57BL/6NHsd mouse lung results in pulmonary fibrosis. An acute phase (days 1 to 28) following irradiation recognized by an inflammatory response is followed by a latent phase (day 28 to day 125) where lung appears normal. Fibrosis occurs from day 125 till death characterized by bone marrow stromal cell migration to and proliferation in lung and increased collagen deposition. To investigate the role of endothelial cells, C57BL/6NHsd female mice were irradiated to 20 Gy to the pulmonary cavity shielding the rest of the body. Lung was excised at serial times, endothelial cells separated and tested for expression of endothelial genes vWF, VEGF, FGF1, CCL13 and CTGF; inflammatory genes IL-6; IGFbp7 and genes associated with fibrosis including MnSOD, Nrf2, NfkB, TLR4 and TGF-B. Endothelial cells were separated by using antibodies to CD45, or PECAM and sorting using flow cytometry. RNA was extracted using Triazol and gene expression determined using Real Time Polymerase Chain Reaction (RT-PCR). In irradiated total lung there was significant increase in endothelial cell markers at all times, compared to nonirradiated lung. Transcripts for vWF increased by 474.1 ± 388.5% (p = 0.017) by 2 days after irradiation, 520 ± 55.4% (p < 0.0001) at day 50, and 484.8 ± 26.8% (p < 0.0001) by day 200. VEGF and CTGF also remained elevated. In contrast, total lung MnSOD gene expression increased by 140.6 ± 46.1% at day 2 (p = 0.0185), decreased at day 50 to 17.9 ± 11.2% (p = 0.2808), and increased to 31.5 ± 11.4% by day 200 (p = 0.023). However, purified endothelial cells compared to alveolar cells, showed increased expression of not only the endothelial cell genes but also MnSOD, Nrf2, NfkB, and TGF-B. MnSOD expression in endothelial compared to alveolar cells at day 28 after irradiation was higher at 244.5 ± 7.8 vs 80.5 ± 4.9 (p = 0.0016), at day 150 expression was 140.1 ± 25.0 vs 5.4 ± 1.2 (p < 0.0001) and day 200 expression was 368.5 ± 6.4 vs 51.8 ± 10.3 (p = 0.0007). Lung endothelial cells display critical biomarkers of irradiation injury leading to fibrosis.

Disclosures:
No relevant conflicts of interest to declare.
Bendamustine + Rituximab-Combinations and R-CHOP Achieve a Major Survival Improvement Of Patients With Follicular Lymphoma In Routine Care
Authors: Weide Rudolf , Feiten Stefan , Friesenhahn Vera , Heymanns Jochen , Kleboth Kristina , Thomalla Jörg , van Roye Christoph , Köppler Hubert 
Published: October 2019

Abstract

Introduction
Progress has been made in diagnosis and treatment of patients with follicular lymphoma who receive their treatment within prospective clinical trials. Due to necessary inclusion and exclusion criteria only a very limited number of patients are treated in studies. Therefore results from clinical trials can't be transferred into routine care. Little practice data are available how patients with follicular lymphoma are diagnosed and treated in routine care and whether improvements in survival are achieved.

Methods
A retrospective analysis of all patients with follicular lymphoma who were treated in an oncology group practice in Germany between 1995-2012. Relevant clinical data concerning diagnosis, treatment and survival were transferred from clinical files into a database and analyzed statistically using SPSS and SURVSOFT.

Results
174 patients with a median age of 60 (27-87) were identified. 43.7% were male and 56.3% female. Stage distribution at initial diagnosis was as follows: Stage I 45 patients (25.9%), stage II 23 patients (13.2%), stage III 32 patients (18.4%), stage IV 62 patients (35.6%), in 12 patients (6.9%) initial stage could not be retrieved. 90.8% needed therapy with a median of 2 different therapies (1-12). Regimens most frequently applied were: Rituximab-containing (67.1%), Bendamustine-containig (41.8%), Bendamustine+Rituximab-combinations (39.9%) and R-CHOP (27.8%). 15 patients (9.5%) received radiotherapy only. 13.3% of patients were treated within a clinical trial. 5 and 10 year absolute overall survival was 88.9% and 73.9%. Relative survival after 5 and 10 years was 94.4% and 86.6%. Median overall survival according to stage was 28 years for stage I, median not reached for stage II, 21 years for stage III and 16 years for stage IV. Median relative survival was 17.4 years for stage IV and has not been reached for stages I-III.

Conclusions
Systemic treatment of patients with follicular lymphoma in routine care consisted mainly of Bendamustine+Rituximab-combinations and R-CHOP. Employment of the most active chemoimmunotherapies leads to a marked prolongation of survival compared to historical controls and registry data.

Disclosures:
No relevant conflicts of interest to declare.
HLA Haplotype Frequency Analysis Within India: Pre-Requisite For Bone Marrow Donor Registry and Cord Blood Bank Planning
Authors: Maiers Martin , Halagan Michael , Leahy Nicole , Joshi Sangeeta , Ballal H Sudarshan , Jagannathan Latha , Damodar Sharat , Srinivasan Periathiruvadi , Narayan Saranya , Khattry Navin , Malhotra Pankaj , Shah Sandip A , Rajagopal Raghu , Cereb Nezih , Yang Soo Young , Dedhia Leenam , Parekh Sunil , Mammen Joy J , Daniels Dolly , Weisdorf Daniel J. 
Published: October 2019

Abstract
To better plan recruitment of volunteer adult unrelated donors for a registry and umbilical cord blood donations for cord banks to supply grafts for hematopoietic cell transplantation to serve Indian transplant candidate patients, we analyzed existing HLA typing data to estimate Indian national and regional populations’ HLA haplotype frequencies.
Indian BMT centers, renal transplant centers, adult donor registries and cord blood banks collaborated to collect HLA typing and demographic data. We have produced a catalogue of the frequency, and regional diversity, of HLA haplotypes in the Indian population. Haplotype frequency analysis was performed on the registry datasets (N=26,239) using a maximum-likelihood method capable of providing high-resolution estimates from typing data with ambiguities. These frequencies were generated for 20 regional subgroups into cohorts defined by either geographic state or by native language; and the 14 largest groups were used to develop a computational model of match rates. Patient family typing data was used to set phase for a group of N=485 patients that was used to run searches against the NMDP registry.
The match rates for Indian patients searching the NMDP USA database (over 11 million donors including DKMS) were 39.7% at the 8/8 allele level (A, B, C, DRB1 high-resolution) and 92.2% at the 7/8 level. Matching models for patients (averaged across the 14 regional subgroups) showed a match rate within India at the current registry sizes of 13.7% at the 8/8 level and 38.2% at the 7/8 level. Increasing the registry to 1,000,000 would raise this to 55.0% for 8/8 and 84.1% for 7/8. A cord blood inventory of 50,000 units would provide a match rate of 22.2% at the 6/6 level and 78.9% at the 5/6 level. Increasing to a cord blood inventory of 250,000 units would increase these match rates to 42.5% at the 6/6 level and 90.3% at the 5/6 level.
These data will define the needs and serve as critical planning data to define and direct donor recruitment goals to establish an effective Donor Registry and cord blood banking facilities able to serve the needs of Indian patients who could benefit from the curative potential of transplantation. Developed data will be shared with the broader scientific community to facilitate future studies of HLA in areas such as disease association, anthropology and transplantation.

Disclosures:
Joshi: Manipal Hospital, Bangalore: Employment. Damodar:NARAYAN HRUDAYALAYA: Employment. Cereb:Histogenetics: Employment. Young Yang:Histogenetics: Employment. Dedhia:Marrow Donor Registry (India): Employment.
An Internet-Based Registry For The Documentation Of Neoplastic Meningitis
Authors: Strik Herwig , Rock Hans 
Published: October 2019

Abstract
Neoplastic involvement of cerebrospinal fluid (CSF) and meninges is a relatively rare and highly heterogeneous disease. Only few randomized studies investigated different treatment strategies and achived no conclusive results. New prospective studies with homogeneous entities are difficult to establish and some initiatives failed recently. Therefore, an open, multicentric registry may be an adequate alternative for a prospective documentation and analysis of a large number of cases of neoplastic meningitis from different primary neoplasms.
To enable an easy multicentric access, an internet-based database was chosen. Secutrial is a professional database which enables pseudonymized registration of clinical courses and meets all requirements for the protection of personal data. Predefined routines enable an immediate analysis of data like survival or toxicity including the most recently documented data. The internet-based access enables a multicentric, international documentation of cases of neoplastic meningitis. Analysis of these data may allow for conclusions on efficacy and toxicity of different treatment strategies in the separate tumor entities.
The configuration of the database provides a separate documentation of the course of primary neoplasm, systemic and central nervous system metastases as well as neoplastic meningitis. Operative, medical treatment and radiotherapy can be assessed as well as results of radiological, histological and cytological examinations including diagnostic and prognostic markers. Also, complications of the disease and toxicity of treatment can be documented. By such, the database is able to discriminate between different causes of clinical deterioration and death. The system is flexible enough to enable the addition of newly established items like biomarkers if needed. Dicomm data of radiological examinations can be uploaded and shared if needed and biobanking organized. The results of tumor boards can be documented as well.
Since multicentric prospective trials are difficult to perform for this rare and heterogeneous disease, an internet based registry appears to be an adequate alternative to collect data on treatment results. We think that the structure and content of the database presented here provides an adequate tool to collect and analyse a large number of cases with neoplastic meningitis.

Disclosures:
Strik: Mundipharma: Consultancy, Honoraria, Speakers Bureau; Medac: Consultancy, Honoraria; Micromet: Consultancy.
N-Glycosylation Of Human ITP Autoantibodies Affects Complement Activation, Platelet Phagocytosis, and Platelet Survival In a Murine Model
Authors: Sachs Ulrich J. , Walek Kathrin , Krautwurst Annika , Rummel Mathias J. , Bein Gregor , Santoso Sentot , Bakchoul Tamam 
Published: October 2019

Abstract

Introduction
Immune thrombocytopenia (ITP) is a bleeding disorder caused by IgG autoantibodies (AAbs) directed against platelets. The IgG effector functions of autoantibodies depend on their Fc-constant region which undergoes posttranslational glycosylation. We investigated the role of Asn279-linked N-glycan of AAbs in vitro and in vivo.

Material and Methods
AAbs were purified from ITP patients (n=15) and controls (n=10) and N-glycans were enzymatically cleaved by endoglycosidase F. The effects of native AAbs and deglycosylated AAbs (deAAbs) were compared in vitro on enhancement of phagocytosis of platelets by monocytes and complement fixation and activation applying flow cytometry, laser scanning microscopy, and a complement consumption assay. The capability of AAbs and deAAbs to eliminate human platelets in vivo was studied in a NOD/SCID mouse model in presence and absence of a complement source.

Results
AAb-induced platelet phagocytosis was inhibited by N-glycan cleavage (median phagocytic activity: 8% vs. 0.8%, p=0.004). Seven out of 15 native AAbs bound C1q and induced complement consumption. N-glycan cleavage significantly reduced C1q binding (MFI 16.4 vs. 4.9, p=0.017) and complement consumption. In vivo survival of human PLTs was assessed after cotransfusion with native or deAAbs in NOD/SCID mice. Injection of AAbs resulted in rapid clearance of human platelets compared to control (platelet clearance after 5h (CL5h) 75% vs. 30%, p<0.001). AAbs that were able to activate complement induced more pronounced platelet clearance in the presence of complement compared to the clearance in the absence of complement (CL5h 82% vs. 62%, p=0.003). AAbs lost their ability to destroy platelets in vivo after deglycosylation (CL5h42%, p<0.001).

Conclusion
Removal of N-glycan from AAbs interferes with Fc-mediated phagocytosis and complement activation and thereby prolongs platelet survival in vivo. Our study provides tools for better characterizing ITP AAbs and sheds light on the heterogeneity of AAbs in ITP. Clinical studies should aim to assess such additional characteristics, since this could lead to the identification of ITP patient subgroups with increased responses to specific or new interventions such as, targetting complement factors.

Disclosures:
No relevant conflicts of interest to declare.
Role Of Monocyte Fcγ Receptors In The Prothrombotic State Of Heparin Induced Thrombocytopenia (HIT)
Authors: Rauova Lubica , Madeeva Daria , Tutwiler Valerie , Bailey Shahara , Hayes Vincent M. , Cines Douglas B. , Poncz Mortimer 
Published: October 2019

Abstract
HIT is an antibody-mediated disorder characterized by thrombocytopenia and thrombosis. Activation of platelet via FcγRIIA by HIT antibodies complexed to surface-bound platelet factor 4 (PF4) contributes to the prothrombotic state. However, using an in vitro microfluidic whole human blood model of HIT, we have found through depletion and repletion studies that activation of monocytes through Syk-kinase is a key step in generating a prothrombotic milieu. Here we define the Fcγ receptor(s) upstream of Syk that mediate the thrombotic signal in monocytes. Monocytes isolated from normal healthy volunteers were incubated with 50 µg/ml of blocking antibodies against FcγRIIA (CD32, clone IV.3) and/or against FcγRI (CD64, clone 10.1) or against FcγRIII (CD16, clone 3G8), washed to remove unbound antibody and added to monocyte depleted-whole blood. These monocyte-repleted samples were then stimulated with PF4 (10 µg/ml) and the HIT like monoclonal antibody KKO (50 µg/ml) for 30 min. After recalcification (5 mmol CaCl2), samples were perfused over a von Willebrand factor-coated BioFlux microfluidic channel at a shear stress of 20 dyne/cm2 at 37°C for 15 min. Platelet adhesion was quantified by fluorescence microscopy after adding Calcein-AM (3 µM), and fibrin was visualized by adding Alexa 561-labeled fibrinogen (1.5 μg/ml) to the whole blood prior to the perfusion. Selective inhibition of FcγRIIA on monocytes led to an ∼40% inhibition of fibrin deposition and comparable reduction in the formation of “coated” platelets relative to samples repleted with non-inhibited monocytes. Flow cytometry studies showed that these observations were not due to leaching of IV.3 antibody off the monocytes with subsequent blocking of platelet FcγRIIA. In contrast, selective blockade of FcγRI or FcγRIII in depletion/repletion studies or in whole blood did not significantly reduce platelet adhesion, formation of coated platelets, or fibrin accumulation. However, blocking FcγRI did decrease tissue factor (TF) activity on monocytes stimulated with PF4 and KKO and this effect was additive to FcγRIIA inhibition. In summary, our data show that monocyte-bound HIT IgG antibodies contribute to the prothrombotic state by activating FcγRIIA directly and indirectly by generating TF though FcγRI. We speculate that this activation of monocytes contributes to platelet activation and monocyte microparticle formation demonstrated previously. Drugs that target FcγRI and FcγRIIA on monocytes may help prevent thrombosis in HIT without causing platelet dysfunction or increasing the risk of bleeding.

Disclosures:
No relevant conflicts of interest to declare.