bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful Hematopoietic Stem Cell Transplantation In a Child With Paroxysmal Nocturnal Hemoglobinuria
Authors: Karasu Gulsun , Ay Yilmaz , Akbayram Sinan , Kilic Suar Caki , Pekün Fügen , Yesilipek M. Akif 
Published: October 2019

Abstract

Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure. The clinical manifestations of PNH are usually seen in adulthood and are very rarely reported in children. The experience with transplantation in the management of children with PNH is also very limited. Here in this paper, we report a child with PNHpresenting with an episode of hemolytic anemia who was treated successfully with hematopoietic stem cell transplantation (HSCT).

Case Presentation
An eleven-year-old patient presented with a history of fatigue. On physical examination, there was no lymphadenopathy, and liver and spleen were not palpable. Laboratory analysis revealed a hemoglobin of 5.7 g/dL, platelets of 124.000/mL, and white blood cells were 1420/ml. She had increased lactate dehydrogenase and reticulocyte count and decreased haptoglobulin level. Bone marrow biopsy showed erythroid hyperplasia and relative hypocellularity in myeloid cell lines. Chromosomal karyotyping of bone marrow cells was normal. To look for PNH, immunophenotyping was performed. Flow cytometric analysis showed a PNH clone within the RBCs, granulocytes and monocytes. These findings were consistent with a diagnosis of PNH and she was started on anti-complement therapy with eculizumab. Since matched sibling donor was available, she was referred to our center for transplantation. The conditioning regimen of HSCT consisted of fludarabine (40 mg/m2day -9 to -6) and busulphan (4 mg/kg, day -5 to -2) combined with anti-thymocyte globulin (ATG) (Fresenius, Munich, Germany) (5 mg/kg, day -2 to 0). GVHD prophylaxis consisted of metotrexate plus cyclosporin. The infusion of bone marrow stem cells contained 11.8x106 CD34+ cells/kg and 7.9 x108total nucleated cells/kg. The patient had no significant complications in the post-transplant period. Neutrophil and platelet engraftment occurred on posttransplant day 11 and day 18, respectively. She is alive and is doing well over 14 months following BMT. Recovery is complete with full donor chimerism and the eradication of PNH clone.

Conclusion
PNH can occur in children but is often misdiagnosed and mismanaged. Although with the advent of anti-complement therapy, pure hemolytic anemia is no longer a clear indication for HSCT in adult patient, it is not licensed for use in pediatrics. HSCT is the only curative option for patients with PNH and if suitable matched sibling donor is available, transplant should be considered. However, the experience with tranplantation is also very limited. This case is worth mentioning as it shows that busulphan, fludarabine and ATG can be safely and effectively used for conditioning in PNH in children.

Disclosures:
No relevant conflicts of interest to declare.
Post-Transplantation Cyclophosphamide and Mesenchymal Stem Cells Infusion For Graft-Versus-Host Prophylaxis For Patients With Advanced Disease After Allogenic Bone Marrow Transplantation
Authors: Drokov Mikhail , Parovichnikova Elena , Kuzmina Larisa , Vasilyeva Vera , Karyakina Alexandra , Galstian Gennadyi , Savchenko Valeri G. 
Published: October 2019

Abstract

Introduction
Allogenic bone marrow transplantation (allo-BMT) with high-dose, post-transplantation cyclophosphamide (CY) to promote graft-host tolerance has become an alternative for standard immunosuppression. This post-BMT CY-based immunosuppression regimen has comparable efficacy with other immunosuppressive regimens including cyclosporine A and mycophenolate mofetil. Previously we reported a significant reduction of acute GVHD rate by using MSC infusion for GVHD prophylaxis (n=19, p=0.009) [Abstract 1256, 52nd ASH Annual Meeting abstract]. So we studied high-dose, post-transplantation cyclophosphamide and mesenchymal stem cells (MSC) infusion for graft-versus-host (GVHD) prophylaxis for patients with advanced disease after FLAMSA (where amsacrin was substituted for idarubicin) and FluBuATG conditioning regimen.

Patients and methods
7 patients with a median age 38 years (24-59 years; 5 males, 2 females; 4 donors/recipient pairs was sex matched, 3 was sex mismatched). All patients with advanced disease (relapsed or refractory AML n=4, ALL n=2, MM n=1) with a median blast cells 17.4%, underwent allo-BMT (n=5 from HLA-identical related donor, and n=2 from unrelated donor). Conditioning regimen was composed of fludarabine, busulfan, and horse anti-thymocyte immunoglobuline for 2 patients, in 4 patients FLAMSA was applied, and 1 patient has no conditioning regimen at all (he was in profound prolonged aplasia after previous course of chemotherapy). For GVHD prophylaxis CY at dose 50 mg/kg daily at day +3 (n=2) and at day +3,+4 (n=5) was used. All patients also received MSC for acute GVHD prophylaxis at day of recovery (WBC>1*109/l) at dose 1*106/kg. No other immunosuppression was used.

Results
Neutrophil engraftment was achieved at a median day +20 (range from 17 to 44 days). Acute GVHD occurred in 3 patients (43%) at a median day +45; all cases were Grade 2-3 (with only skin n=2; and with skin and liver involvement n=1); there was only 1 patient with late refractory GVHD in this study treated with prednisone at a dose 2 mg/kg; all other patients responded to initial treatment with cyclosporine A at 3 mg/kg. Overall mortality rate was 42.6%. 1 patient died in CR at day +60 due veno-occlusive disease (TRM - 14%). Relapses occurred in 2 patients (28.6%) at a 3,8 and 2.4 months. The overall survival is 51.4% with a median of follow-up 3,9 month.

Conclusion
Despite the fact that we study small group use of cyclophosphamide with MSC for GVHD prophylaxis is a very attractive approach for patients with advanced disease, and needs further investigation.

Disclosures:
No relevant conflicts of interest to declare.
The Comparison of Immune Components in Three Grafts for Stem Cell Transplantation
Authors: Fan Qian , Liu Hui , Liu Can , Ling Yiwen , Dai Min , Zhang Yu , Fan Zhiping , Xuan Li , Sun Jing , Liu Qifa 
Published: October 2019

Abstract

Background
Recently, a few data showed that Granulocyte-colony-stimulating factor (G-CSF) modified bone marrow (G-BM) grafts leaded a lower morbidity and mortality of graft-versus-host disease(GVHD), compared with G-CSF mobilized peripheral blood stem cells (G-PBSCs) and steady state bone marrow (SS-BM) grafts. However, the mechanism of this difference is not fully understood. In this study, we compared the immune components in the three grafts.

Methods
Twenty patients undergoing HLA-matched sibling donor stem cell transplantation(SCT) were enrolled in this study. Patients were randomized to receive G-BM (n=10) or G-PBSCs (n=10) transplantation. Immune components, including Human leucocyte antigen-G (HLA-G), Myeloid-derived suppressor cells (MDSCs) and T cell subsets, were detected in bone marrow (BM) and peripheral blood (PB) of donors before and at day 5 after G-CSF mobilization.

Results
Among 20 patients, 2 patients developed acute GVHD (aGVHD) and 5 developed chronic GVHD (cGVHD) in G-PBSCs group, and no patients developed aGVHD and only 1 developed limited cGVHD in G-BM group. For the grafts, the proportion of MDSCs in PB and BM was 1.47% ± 0.12% and 2.26% ± 0.35% (P=0.001), respectively, before mobilization. After 5 days of G-CSF mobilization, the proportion of MDSCs in PB and BM increased to be 2.73% ± 0.68% and 2.56% ± 0.12%, respectively. The increase is significant both in PB and BM (P=0.000,P=0.002, respectively), while no significant difference was found between the proportion of MDSCs in G-PB and G-BM graftes (P=0.115). The levels of HLA-G (both soluble and membrane bound) in PB and BM all increased significantly after G-CSF mobilization (all P<0.05). And the levels of HLA-G (both soluble and membrane bound) in BM were all higher than that in PB, including before and after G-CSF mobilization (all P<0.05). The total numbers of CD3+ cells were similar in BM before and after mobilization, both significantly lower than that in PB (both P<0.001). However, the lowered CD4+ cells and increased CD8+ cells in G-BM leaded to a significantly lower CD4:CD8 ratio than that in SS-BM and G-PB (both P<0.001).

Conclusions
The differences of immune components in the grafts might play a part in the different morbidity and mortality of GVHD. The higher expression of HLA-G in the grafts might be the main reason for the lower morbidity and mortality of GVHD in G-CSF-primed bone marrow transplantation.

Disclosures:
Liu: It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.
Intraoral GS-Nitroxide (JP4-039) Reduces Local Mucositis and Distant Marrow Suppression Toxicities In Head and Neck Irradiated Fancd2-/- (FVB/N) Mice
Authors: Berhane Hebist , Xu Karen , Goff Julie P. , Kalash Ronny , Epperly Michael W. , Dixon Tracy M. , Shields Donna , Franicola Darcy , Li Song , Gao Xiang , Wipf Peter , Greenberger Joel S. 
Published: October 2019

Abstract
The DNA repair defect in Fanconi Anemia patients limits effective radiotherapy. We quantitated oral cavity tissue damage in Head and Neck irradiated FancD2-/-, Fancd2+/- and FancD2+/+ mice, parameters of femoral bone marrow hematopoiesis and the effect of intraoral administration of mitochondrial targeted JP4-039 delivered in novel F15 liposomes. Adult 10-12 week mice were irradiated to the head and neck to 24, 26 or 28 Gy, shielding all tissue below the cervical spine. JP4-039/F15 was administered to a subgroup intraorally 10 min before irradiation. On day 2 or 5 post irradiation, mice were sacrificed, tongue and femur marrow harvested for histopathology, and marrow was assayed for hematopoietic colony formation. At 5 days post 26 Gy, FancD2 +/- and Fancd2 -/- mice had significantly greater tongue ulceration (52.8 ± 6.5%, p=0.0014 and 59.4 ± 3.4%, p=0.0001, respectively) compared to FancD2 +/+ mice (21.7±4.7%). JP4-039/F15 significantly reduced local tongue ulceration in all genotypes: FancD2 +/+ reduced to 12.2 ± 1.0 (p = 0.0049), FancD2 +/- reduced to 10.6 ± 3.5 (p < 0.0001) and FancD2 -/- reduced to 11.0 ± 2.5 (p < 0.0001). FancD2 -/- and FancD2 +/- mice showed “bystander-effect” reduction in femur marrow CFU-GM at 2 days after 26 Gy compared to nonirradiated controls (p=0.007). FancD2 -/- mice showed decreased BFU-E at day 2 after 24 Gy (p=0.009), CFU-GEMM after 26 Gy (p=0.048), BFU-E after 26 Gy and significantly less CFU-GM after 26 Gy or 28 Gy (p=0.017 and p=0.028, respectively). Intraoral JP4-039 prevented the marrow cytoreductive effects of head and neck irradiation. No reduction in femur marrow CFU-GM, BFU-E or CFU-GEMM was detected in FancD2+/+ mice. Biallelic or monoallelic loss of the Fancd2 gene renders mice sensitive to head and neck irradiation and is accompanied by distant femur marrow suppression. Both local and distant irradiation toxicities are ameliorated by intraoral administration of JP4-039. FancD2-/- mice are an excellent model for testing new agents to control local and distant “bystander effect” toxicities of ionizing irradiation.

Disclosures:
No relevant conflicts of interest to declare.
Impact Of a Federal Program On response Rate & Survival, In a Cohort Of Patients With Diffuse Large B- Cell Lymphoma. Analysis In a Single National Reference Institution In Mexico
Authors: Candelaria Myrna , Labardini Juan , Ramirez Ana Florencia , Aviles Alejandro , Estrada-Lobato Enrique , Meneses-Garcia, Md Abelardo , Mohar Alejandro 
Published: October 2019

Abstract
The actual standard of care of Diffuse Large B-Cell Lymphoma (DLBCL) includes rituximab in combination with chemotherapy, with overall response rates up to 76 %. However, this treatment may not be accessible to many patients because of limited economical resources, particularly in developing countries, where most of the treatment must be paid from the pocket of patients or their families. In Mexico, since 2011 a Federal program has fully covered the treatment of patients with DLBCL. At the Instituto Nacional de Cancerología (INCan) in Mexico city 214 patients with ths disease have been treated without cots with the standard of care. The mean age at diagnosis was 56.7 +15.9 (22-91). This series of cases was compared with a retrospective analysis of cases with DLBCL seen at the INCan between 2006-2008 None A total of 264 cases were retrospectively analyzed. No differences were found in demographic and clinical characteristics at the time of diagnosis. However, a clear positive impact was found in the group that received full treatment thanks to this new social coverage by this new social security program. The follow-up and completion of treatment was 99%., In contrast: from 264 in the retrospective group, 209 (79 %) were treated, but only 29 (10.9 %) were able to receive an optimal treatment, including rituximab. These differences in treatments had a clearly impact on the response rate, as shown in the following table:A: Retrospective cases.N (%) B: Cohort.N (%) p Patients. 264 214 -- Treatment:CHOP-R (standard of care)CHOP0-2 cycles** 2918055** 20410*-- 0.001 Response (all patients) :CompletePartialStable diseaseProgressiveNot evaluable, lost of follow up 103 (39)31 (11.7)11 (4.1 )24 (9)95 (36) 124 (58)19 (8.8)0 --29 (13.5)-- 0.001 Relapse rate (%) 93 (35 %) 43 (20%) 0.0001 *7 patients did not received rituximab because of HBV & 3 HIV positive had < 100 absolute CD4 counts.**Patients who abandoned treatment because of reduced economical resources.
These results demonstrate the importance of social programs that may accessible standard treatment options in countries with limited resources.

Disclosures:
No relevant conflicts of interest to declare.
Fatal and Serious Anaphylaxis Following Peginesatide Administration
Authors: Bennett Charles L. , Jacob Sony , Macdougall Iain C , Moore Tom , Georgantopoulos Peter , Nichols Judy , Yarnold Paul , Sartor Oliver , Raisch Dennis W. , Mikhail Ashraf , Norris LeAnn , Kessler Samuel , Magwood Jametta , Goldsmith David 
Published: October 2019

Abstract

Background
In March 2012, the Food and Drug Administration (FDA) approved peginesatide as anemia therapy for chronic kidney disease patients. In December, the manufacturer warned that a large dialysis organization identified eight patients with peginesatide-associated anaphylaxis. In February 2013, the organization again reported five anaphylaxis events, including three deaths, and discontinued administering peginesatide. After a manufacturer’s review identified five peginesatide-associated anaphylaxis deaths, the manufacturer discontinued marketing the drug.

Methods
We reviewed peginesatide-associated anaphylaxis in FDA’s Adverse Event Reporting System (FAERS). Clinical findings and product lot numbers were analyzed. Inclusion criteria included peginesatide administration and toxicity within thirty minutes of administration.

Results
Between July 2012 and February 2013, 38 CKD patients developed anaphylaxis within a median of five minutes following peginesatide administration (range, zero to 20 minutes). Findings included dyspnea (25 patients), chest pain (10), hypotension (18), diaphoresis (9), pruritis (11), rash (3), angioedema (5), and vomiting (9). Five deaths from cardio-respiratory arrests occurred. Exposure-adjusted incidence was 1.5 cases of anaphylaxis per 1,000 peginesatide-treated patients. Of five FAERS reports for anaphylaxis occurring in February 2013, three included the product lot number C18881 while two did not have lot numbers. Of 33 FAERS anaphylaxis events reported prior to December 4, 2012; 18 included the lot number C18685, two reports included the lot number C18696, one included the lot number C18881, and lot numbers were not identified for the remaining 12 reports.

Conclusion
Anaphylaxis can occur within minutes of initiating peginesatide therapy. Production or supply chain management problems may be the underlying etiology.

Disclosures:
Macdougall: Affymax and Takeda: Consultancy, Research Funding. Mikhail: Affymax and Takeda: Consultancy, Research Funding. Goldsmith: Affymax and Takeda: Consultancy, Research Funding.
Expansion, Differentiation and Transplantation of Human Endothelial Progenitor Cells Derived from Umbilical Cord Blood CD34+ Cells
Authors: Qin Meng , Zhang Qing-Yu , Ma Yupo , Dai Wei , Jiang Yongping 
Published: October 2019

Abstract
Transplantation of endothelial progenitor cells (EPCs)/endothelial cells (ECs) has been developed as a cell therapy for ischemic diseases and hemophilia A, due to the capacities of these cells to repair vascular damage and produce factor VIII. The strategies and the mechanisms of this type of cell therapy have been extensively investigated in the past decades. However, given the problems associated with host immune responses to grafts in allotransplantation, the difficulties in obtaining adequate numbers of suitable cells for transplantation represent additional obstacles for a successful cell therapy. In the present study, human umbilical cord blood CD34+ mesenchymal cells (MCs), which generate low immune response, have been adopted as the source of endothelial progenitors. Our major goal is to establish a highly efficient approach to stimulate the expansion and subsequent differentiation of human endothelial progenitor cells (EPCs), in order to obtain sufficient quantities of healthy cells for therapeutic use. The CD34+ cells isolated from human umbilical cord blood were cultured for 6 days in a customized basal medium supplemented with a modified cytokine cocktail, including SCF, Flt-3L, TPO, IL-3, and GM-CSF. At the end of proliferation stage, cell number was calculated with Flow Cytometry, and cell morphology was characterized as well. The numbers of CD34+ cells and CD34+/CD133+/VEGFR-2+ early EPCs cells were found to be increased by approximately 108-fold and 41.9-fold, respectively, on day 6. In the differentiation stage, the attached cells were transferred to EGM-2 basal medium supplemented with FBS and additional nutrients, including VEGF, IGF, EGF, and FGF, for another 15 days. Following this two-step culture, the generated adherent cells were found to have proliferated more than 1200 folds over the initial EPCs, and they were identified as mature endothelial cells expressing CD31, vWF and FVIII. Furthermore, we developed a nonobese diabetic, severe combined immunodeficient (NOD/SCID) mouse model with portal sinusoidal endothelium injury. The NOD/SCID mice were treated with the produced EPCs/ECs through hepatic portal vein injection at the dose of 6x10^6 cells. Tissue examination demonstrated that GFP-labeled transplanted cells migrated and integrated into liver structure, where they expressed specific endothelial cell markers. Therefore, through our unique approach, we can provide an excellent source of healthy endothelial progenitors for cell therapy.

Disclosures
Qin: Biopharmagen corp: Employment. Jiang:Biopharmagen.corp: Employment.
Low ADAMTS13 Activity Is a Strong Risk Factor for Ischemic Stroke: A Prospective Cohort Study - the Rotterdam Study
Authors: Sonneveld Michelle Alida Helena , Maat Moniek de , Portegies Marileen L.P. , Hofman Albert , Turecek Peter L , Rottensteiner Hanspeter , Scheiflinger Friedrich , Koudstaal Peter J. , Ikram Mohammed A. , Leebeek Frank 
Published: October 2019

Abstract
Introduction.ADAMTS13 has antithrombotic properties because it cleaves Von Willebrand factor (VWF) in smaller, less active multimers. Low ADAMTS13 activity may therefore increase the risk of arterial thrombosis, including ischemic stroke. We prospectively studied the association between ADAMTS13 activity, VWF antigen (VWF:Ag) levels and ischemic stroke in the Rotterdam Study, a population-based cohort study among subjects ≥ 55 years.
Methods.We included 5941 individuals without a history of stroke or TIA. Blood was drawn at baseline and ADAMTS13 activity (expressed as % of normal plasma) was measured using the FRETS-VWF73 assay and VWF:Ag levels by ELISA. All individuals were followed for development of stroke or TIA. The association between ADAMTS13 activity, VWF:Ag levels and ischemic stroke were assessed by Cox proportional hazard regression analysis.
Results.Over an average follow-up time of 9.5 years, 461 participants suffered from a stroke, 306 of which definitely classified as ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (HR 1.65, 95% CI 1.16 – 2.32) than those in the reference highest quartile. In individuals with low ADAMTS13 activity and high VWF:Ag levels the risk of ischemic stroke risk was 3.5 fold increased (HR 3.51, 95% CI 1.60 – 7.70).
Conclusions.In this large prospective population study, low ADAMTS13 activity predicts the risk of ischemic stroke, independently of age, sex, and established cardiovascular risk factors. This risk was even higher in individuals with both low ADAMTS13 activity and high VWF antigen levels.
Figure 1 Figure 1.

Disclosures
Turecek: Baxter Innovations GmbH, Vienna, Austria: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Leebeek:CSL Behring and Baxter: Membership on an entity's Board of Directors or advisory committees.