bluuebunny/crossref_metadata_2025_split huggingface dataset:
Donor Specific Tolerance Of Renal Allografts Following Haploidentical In Utero Hematopoietic Cell Transplantation In The Canine Model
Authors: Pearson Erik G. , Vrecenak Jesse D , Bhatti Tricia R , Peranteau William H. , Flake Alan W. 
Published: October 2019

Abstract

Introduction
In utero hematopoietic cell transplantation (IUHCT) can result in allogeneic mixed hematopoietic chimerism and associated donor specific tolerance (DST). We have reported a 1-2% donor chimerism threshold for consistent DST in the murine model as defined by the ability to enhance engraftment postnatally with a same donor minimal conditioning BMT, and have confirmed this finding in the canine model of IUHCT. Recently, we have optimized the canine model and achieved higher levels of chimerism (average>10%). As prenatal tolerance induction for postnatal organ transplantation is one of the clinical goals of IUHCT, we hypothesized that the presence of donor chimerism (>2.0%) after haploidentical IUHCT in the canine model would be sufficient to allow same donor renal transplants without immunosuppression.

Method
Stable mixed hematopoietic macrochimerism was documented by VNTR after haploidentical IUHCT performed at 40 days gestation using maternal donor BM cells in 4 pups (chimerism levels 3-38%). One positive control canine with no detectable chimerism following IUHCT also underwent haploidentical renal transplantation. Renal transplantation was performed from the maternal donor at ages between 12 and 18 months, and the pups were serially followed by ultrasound of the graft, blood chemistry and urinalysis post transplant. At 60 days an open biopsy of the allograft was taken and at 6 months a graft nephrectomy was performed for histologic analysis.

Results
Following transplantation, all recipients demonstrated blood flow to the renal cortex and all laboratory values were within normal ranges. At 60 days and 6 months 3 of the 4 recipients demonstrated a graft without evidence of acute or chronic rejection. The recipient with the lowest level of chimerism (3%) demonstrated evidence of mild interstitial nephritis (Banff class 1 rejection) following transplantation at the time of renal biopsy which increased in severity to severe interstitial fibrosis and moderate tubular atrophy (Banff class 3 rejection) at the time of graft nephrectomy. The positive control canine without detectable chimerism demonstrated clinical and histologic evidence of acute rejection within one week of transplantation.

Conclusion
Our results support the ability of IUHCT to induce DST for haploidentical organ transplantation, in a large animal model, without the need for immunosuppression. In agreement with previous studies in the murine model there appears to be a threshold level of donor chimerism required for associated DST. Although our numbers are not adequate to establish absolute thresholds of chimerism predictive of DST for organ transplantation, it appears to be slightly higher than the 1-2% threshold established for cellular transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Immunologic Effects Of Mesenchymal Stem Cells In The Treatment Of Refractory Acute Graft-Versus-Host Disease
Authors: Liu Qifa , Zhao Ke , Liu Can , Wu Meiqing , Zhang Yu , Huang Fen , Fan Zhiping , Dai Min , Sun Jing 
Published: October 2019

Abstract

Background
Mesenchymal stem cells (MSCs) have been considered as a promising strategy for the prevention and treatment of acute graft-versus-host disease (aGVHD), but the mechanism of MSCs ameliorating GVHD is still not fully understood. A few studies suggested that MSCs ameliorated GVHD via protecting and repairing the function of thymus.

Methods
Twenty refractory aGVHD patients receiving MSCs treatment were enrolled in this study, and twenty grade II to IV aGVHD patients treated without MSCs were matched as non-MSCs group. MSCs were given at a median dose of 1×106 cells/kg once weekly until aGVHD got complete response (CR) or MSCs were infused for a total of 8 doses. Lymphocyte subsets of T-cell, B-cell, and NK-cell in peripheral blood were analyzed by flow cytometry before and 30, 60, 90, 180 and 360 days after the MSC infusion in MSC group and the corresponding period in the control group.

Results
A total of the 33 patients who survived more than 30 days after the study treatments were evaluated for the alterations in cellular immune compartment and cGVHD, including 15 cases in MSCs group and 18 in non-MSCs group. In MSCs group, patients had a significantly higher CD4+/CD8+ T-cell ratio at 60, 90 and 180 day after MSCs treatments, which subsequently equalized at 360 day compared with non-MSCs group. The MSC group presented higher percentages of CD4+CD25+ regulatory T cells (Treg) comparing with non-MSCs group, especially at 90 and 180 day, and approached at 360 day. The proportion of CD4+CD45RO+ and CD4+CD45RA+ naïve T-cells in MSC group were also higher than those in non-MSCs group at 60, 90 and 180 day, but not different at 360 day. The proportion of CD19+ and CD16+CD56+ was not detected striking difference between the two groups. Four patients (26.7%) experienced cGVHD in MSCs group, compared with twelve (66.7%) in non-MSCs group (p=0.02).

Conclusions
In conclusion, our data indicate that MSCs might ameliorate aGVHD and induce longer-lasting immune tolerance by altering cellular immune compartments in peripheral blood. The alteration of the cellular immune compartments is associated with the protecting and repairing role of MSCs to thymus.

Disclosures:
Liu: 863 Program (No. 2011AA020105): Research Funding; National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647): Research Funding; Science and Technology Program of Guangzhou of China (11A72121174) : Research Funding.
Circulating Endothelial Cells Enumeration Is a Helpful Tool In The Diagnosis Of GvHD In Patients Undergoing Allogeneic Hematopoietic Stem Cells Transplantation
Authors: Almici Camillo , Skert Cristina , Verardi Rosanna , Di Palma Andrea , Bianchetti Andrea , Russo Domenico , Marini Mirella 
Published: October 2019

Abstract
Allo-HSCT can be burdened by life-threatening complications, being GvHD the major cause of morbility and mortality. Clinical and physio-pathological evidences showed that vascular endothelium could be a target of GvHD in very early phase; therefore markers of endothelial damage are warranted as valuable support in GvHD diagnosis. We conducted a study with primary endpoint to identify and count circulating endothelial cells (CEC) in peripheral blood of patients undergoing allo-HSCT as a function of endothelial damage.
The CellSearch System® is used to capture and enumerate CEC. Enriched and stained cells are dispensed into a MagNest® cartridge that is scanned and individual images of cells are scored as CEC, based on CD146+, CD105+, DAPI+ and CD45- phenotype. Patients undergoing allo-HSCT were tested before (T1), after the conditioning regimen (T2), at engraftment (T3), at GvHD onset (T4) and at 1 weeks after steroids treatment (T5). Ten healthy subjects served as controls.
We enrolled 40 patients with hematologic neoplastic diseases (7 HD, 13 AML, 5 ALL, 8 MM, 3 CLL, 1 NHL, 1 CML, 2 SAA) undergoing allo-HSCT from either HLA-matched familial (n=12) or unrelated donor (n=28). GvHD (grade I-IV) manifested in 19/39 patients. No clinical and transplant characteristics differences were present between patients with and without GvHD. The median CEC/ml pre allo-HSCT was 20 (n=40, range 4-718), in comparison to a value of 2 (range 1-14) in the 10 healthy subjects. At time of engraftment CEC/ml were 47 (range 16-148) in patients with GvHD and 92 (range 23-276) in patients without GvHD (P=0.006). This difference remained significant in multivariate analysis by logistic regression model (OR 0.97, 95% C.I. 0.96-0.99; P=0.02). At GvHD onset, the relative increase of CEC counts (T4 vs T3) was 44% (range, -43 - 569%) in GvHD patients versus 0% (range, -49 – 2%) in patients without GvHD (P=0.003), being confirmed in multivariate analysis (OR 1.04, 95% C.I. 1.0-1.08; P=0.04).
Circulating endothelial cells can represent a promising marker to monitor endothelial damage in patients undergoing allo-HSCT. The confirmation of the clinical utility of CEC counts in a larger series of patients, together with the use of a semi-automatic, standardized and reproducible technology, will allow a valuable help in the diagnostic definition of GvHD in early phase, and moreover could be a valid complement in the prognostic stratification of patients candidates to allo-HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Adolescents and Young Adults With Hemophagocytic Lymphohistiocytosis Who Undergo Allogeneic Hematopoietic Cell Transplantation Are At Increased Risk Of Mortality Compared To Younger Patients
Authors: Chandrakasan Shanmuganathan , Marsh Rebecca , Grimley Michael , Bleesing Jack , Jordan Michael , Filipovich Alexandra H. 
Published: October 2019

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening disorder of immune deregulation characterized by overwhelming immune activation and inflammation. Primary HLH was once thought to affect predominantly infants and young children. However, with increasing awareness, HLH is being diagnosed in adolescents and young adults. Currently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy available for primary hemophagocytic lymphohistiocytosis (primary HLH). There is limited data on HCT outcome for adolescents and young adults with HLH. We reviewed the allogeneic HCT outcomes of 19 adolescents and young adults with HLH (12 males and 7 females) who underwent HCT from January 2000 to June 2013 at our center. The median age at transplantation was 18.2 years (range: 15.2 -27.2). The Majority (15/19) underwent reduced-intensity conditioning (RIC) regimen consisting of alemtuzumab, fludarabine, and melphalan. Thirteen patients received transplants from HLA- matched donors (10 MUD and 3 MSD). Bone marrow was the source of stem cells in 15 patients. The HCT outcome of this group was compared to outcome of children with HLH less than 15 years of age. Median follow up of adolescent and young adult patients following HCT is 280 days (range 9-1643 days). Mixed donor chimerism was noted in 20% (3/15) of patients who received RIC. Acute GVHD grade II-IV was noted in four patients. Overall survival for adolescent and young adult patients was 42.1% (8/19). In patients who received RIC, Kaplan Meier analysis revealed a long term estimated survival of 57%, compared to 75% for children less than 15 years of age (p=0.03). Cox proportional hazard modeling revealed a reduced risk of mortality in young patients undergoing RIC HCT compared to adolescent and young adult patients (HR 0.379 [0.154-0.933], p=0.035), controlling for donor match and source. Deaths in adolescent and young adult patients occurred from days +9 to +568 following HCT. The cause of death varied from fulminant bacterial sepsis (n=4), acute refractory GVHD (n=2), disseminated aspergillus and fungal sepsis (n=2), viral infection (n=2), and refractory chronic GVHD (n=1). In conclusion, adolescents and young adults with HLH who undergo allogeneic HCT are at increased risk of mortality compared to younger patients. Further studies are needed to identify risk factors and potential interventions to improve HCT outcome for adolescents and young adults with HLH.

Disclosures:
No relevant conflicts of interest to declare.
Association Of Health Care Expenditure With Results Of Allogeneic HSCT For Adults With ALL: An Analysis From Acute Leukemia Working Party Of The EBMT
Authors: Giebel Sebastian , Labopin Myriam , Ibatici Adalberto , Browne Paul , Czerw Tomasz , Socié Gérard , Unal Ali , Kyrcz-Krzemien Slawomira , Bacigalupo Andrea , Goker Hakan , Potter Michael N , McQuaker Grant , Beelen Dietrich , Milpied Noel , Campos Antonio , Craddock Charles , Mohty Mohamad 
Published: October 2019

Abstract

Background
Results of allogeneic hematopoietic stem cell transplantation (aloHSCT) depend on many patient-, donor- and procedure-related factors. In recent years, in a setting of AML we demonstrated that also socio-economic status of a country and center experience may influence outcome. The goal of the current analysis, focused on patients with acute lymphoblastic leukemia (ALL), was to evaluate specific effects on non-relapse mortality (NRM) related to health care expenditure (HCE) of a country as well as distribution of transplant centers in addition to previously studied human development index (HDI) and center activity.

Patients and methods
Results of myeloablative alloHSCT from HLA-identical siblings performed between 2004-2008 for adults with ALL in CR1 were analyzed. Among 983 individuals treated in 27 European countries the median age was 35 (18-55) years and the interval from diagnosis to alloHSCT – 158 (42-831) days. TBI was used for conditioning in 820 (83%) cases and peripheral blood was a source of stem cells in 656 (67%) cases. The following factors were studied for their impact on outcome: current HCE, HCE as % of gross domestic product, public HCE, private HCE, no. of teams per country area and population, HDI and center activity (no. of alloHSCT for ALL in a study period). All variables were categorized by medians. The median follow-up was 34 months.

Results
In a univariate analysis the probability of day 100 NRM was increased for countries with lower current HCE (p=0.06), lower HDI (p=0.02) and for centers with lower experience (p=0.04). Also overall NRM was affected by current HCE (p=0.09), HDI (p=0.03) and center activity (p=0.07). In a multivariate model adjusted for recipient age, interval from diagnosis to HSCT, source of stem cells, type of conditioning, and donor/recipient gender, the variables of interest were included separately due to strong internal correlations. The best predictive model for day 100 NRM included HDI < median (HR = 2.38, 95%CI = 1.3-4.35, p=0.005). The overall NRM was most strongly predicted by current HCE < median (HR = 2.56, 95%CI = 1.41-4.76, p=0.002). In a univariate analysis lower values of HDI and current HCE were also associated with decreased probability of the overall survival (p=0.004 and p=0.006, respectively).

Conclusion
Both macroeconomic factors and the socio-economic status of a country influence strongly non-relapse mortality and overall survival after alloHSCT for adults with ALL. Our findings should be considered in interpretation of clinical studies in the field of alloHSCT.

Disclosures:
No relevant conflicts of interest to declare.
Adverse Pregnancy Outcomes In High Risk Sickle Cell Women
Authors: Saraf Pankhoori , Jacoby Sari H , Shah Shailja , Nazir Habib , Gimovsky Martin , Cohen Alice J. 
Published: October 2019

Abstract

Background
Life expectancy in patients with sickle cell disease (SCD) has increased with the institution of newborn screening, antibiotics and Hydroxyurea (HU). Prior studies have reported maternal mortality rate to be 2.2 times that of normal pregnancies. With improved high risk obstetrical services and hematological care, more women with SCD are choosing to carry a pregnancy (P). In order to see if outcomes have improved, we performed a review of women with SCD who had recent P at our hospital with a focus on maternal and fetal outcomes.

Methods
Patients (pts) were identified by a chart review of all women of childbearing age followed at both the Comprehensive Sickle Cell Center and the high risk obstetrics clinic. Data included: genotypes of SCD, fetal complications, P outcomes, transfusions (T), hospital admissions, previous HU use.

Results
71 pregnancies were identified in 53 women from 2008 to 2013.

Pregnancy outcomes
See Table 1. Live births rates were equal in both GR I and GR II. The mean gestational age (weeks) in GR I was 35.13 and GR II 38.28 (p=0.0077) with more preterm births in GR I 16/36 (44%) compared to GR II 2/18 (11%). The most common mode of delivery was C-section in both GR I and II. Reasons for C- section were fetal distress 60% (20), repeat C-section 27% (9), other (5% or less) for breech, elective, preeclampsia, placenta previa. There were equal numbers of induced and spontaneous labor in each group. Complications in GR I 8/36 (22%) and GR II 2/18(11%) included PIH, Chorioamniotis, placenta previa, death (cardiac arrest).

Fetal outcomes
Low birth weight occurred in 20/33(61%) of GR I and 3/18(17%) of GR II (p= 0.0016) births. Other complications (41 % of births) including IUGR, meconium aspiration, oligohydramnios and Apgar scores <7 @ 1 min occurred equally in both GRs.
Maternal outcomes: During P mean values for events in GR I and GR II respectively were: transfusions 5.56 units (U) and 1.22 U (p=0.0022), admission for vasoocclusive crisis (VOC) 3.33/pt and 1.44/pt (p=0.0173). Other complications were urinary tract infection (7), pneumonia (4), acute chest syndrome (4), cardiomyopathy (1), renal failure (1), hepatic crisis (2), DVT (1). Six patients were on HU pre- pregnancy (PP). In these patients 13 simple blood T were required PP and 56 during P (p=0.0297). VOC events increased from 13 PP to 35 during P (p=0.1011). 2 patient required exchange T during P.

Conclusion
Despite improved antenatal care for SCD women, P remains a high risk event for mother and fetus, with lower birth weights and more preterm deliveries in SS/SB 0 thal pts compared to SC/SB+ thal. Prior use of HU PP was not protective. New insights and studies are warranted to understand the pathophysiology of SCD causing adverse pregnancy outcomes and possible effects of HU withdrawal.

Disclosures:
No relevant conflicts of interest to declare.
ADAMTS13 Expressed In Glioblastoma and Astrocytoma Cells Can Modulate Endothelial Cell Migration
Authors: Lee Manfai , Hoyt Courtney , Rodgers George M 
Published: October 2019

Abstract
ADAMTS13, the von Willebrand factor (vWF) cleaving protease, regulates platelet aggregation and microthrombi formation by cleaving high-molecular weight vWF multimers. It is expressed primarily in hepatic stellate cells, but is also found in endothelial cells. Recently, ADAMTS13 was reported to be expressed and regulated in astrocytes, microglial, neuroblastoma, and adult human brain endothelial cells. Previous in vitro studies by our group with human umbilical vein endothelial cells (HUVEC) showed that ADAMTS13 can promote angiogenesis via upregulating the secretion of VEGF and phosphorylation of VEGFR2, suggesting that ADAMTS13 may also be involved in physiological processes unrelated to vWF cleavage (Lee, M., et al. Microvasc Res. 2012, 84, 109-115). Herein, we report an additional possible role of ADAMTS13 secreted by brain tumor cells to modulate tumor cell angiogenesis.
Using a human ADAMTS13 immunoassay, we detected ADAMTS13 in U-87 and LN-229 glioblastoma cell lysates, SW-1088 astrocytoma cell lysates, as well as in the supernatants of all cell lines (> 2.0 ng/mL). Co-incubation of U-87, LN-229, and SW-1088 tumor cell conditioned media with recombinant vWF indicated that brain tumor-secreted ADAMTS13 is biologically active in cleaving vWF multimers (measured by ELISA). Secretion of VEGF was upregulated in LN-229 and SW-1088 cell lines by ADAMTS13. 939 pg/mL and 674 pg/mL of VEGF were measured in LN-229 and SW-1088 cell lysates, respectively, after incubation with 100 ng/mL ADAMTS13. Incubation of LN-229 glioblastoma cells with 10 – 500 ng/mL rh-ADAMTS13 or 50 ng/mL VEGF165 did not affect tumor cell proliferation. No change in tumor cell proliferation was observed when LN-229 cells were incubated with a polyclonal antibody against ADAMTS13 in serum free media supplemented with 10 ng/mL ADAMTS13 or media supplemented with 5% FBS, suggesting that ADAMTS13 secreted by brain tumor cells may be involved in extracellular signaling of endothelial cells.
Brain tumor cell secreted-ADAMTS13 induced HUVEC migration in a Matrigel invasion assay. Using a modified Boyden chamber fitted with a Matrigel-coated polycarbonate membrane, LN-229 glioblastoma cells increased HUVEC migration by 83%. LN-229 cells supplemented with 10 ng/mL ADAMTS13 further increased HUVEC migration by 190%, suggesting that tumor cell-secreted ADAMTS13 may modulate EC migration (Fig. 1). Combined with our previous findings suggesting that recombinant ADAMTS13 modulates EC angiogenesis, brain tumor-secreted ADAMTS13 may also be a regulator for tumor vasculature angiogenesis.

Disclosures:
No relevant conflicts of interest to declare.
Tacrolimus-Induced Refractory Immune Thrombocytopenia In Solid Organ Transplant Patients
Authors: Mathew Aju , Woytowitz Donald , Smith Roy E. , Mehta Rakesh P 
Published: October 2019

Background
Immune thrombocytopenia (IT) is an uncommon complication in patients who have undergone solid organ transplantation. A few case reports have suggested a role for tacrolimus in inducing IT in such patients.

Methods
A retrospective chart review was conducted in two major academic institutions with a high volume of transplant surgeries. We identified cases of refractory IT in solid organ transplant patients who were on tacrolimus as their graft-rejection immunosuppressant, in whom platelet counts recovered after discontinuation of the medication. Retrospective chart review was performed. All other etiologies for thrombocytopenia were excluded. Finally, descriptive statistical analysis was performed.

Results
Ten patients were identified of which five each were renal and liver transplantations. Median age was 48 years. The median time from transplantation to onset of IT was 5.9 years (range 2.1-20 years) (table 1). In all but one case, the nadir platelet count was less than 5000/μL. Multiple therapeutic strategies including intravenous immunoglobulin, steroids, chemotherapy, rituximab, splenectomy, and romiplostim were attempted without any response. Bone marrow biopsy was consistent with IT in 9 of these patients; one patient did not undergo the procedure. Two patients were treated for H.pylori IgG positivity without any platelet recovery response. After tacrolimus was discontinued, median time to platelet recovery to greater than 50,000/μL was 8.5 days (range 5-81; n=8) (table 2). Median time to platelet count recovery to greater than 100,000/μL was 14 days (range 5-88 days; n=10). Median follow-up duration after platelet recovery of greater than 100,000/μL was 30 months (range 2-60; n=10). One patient, who recovered counts after nearly 3 months of discontinuation of tacrolimus, was on romiplostim for 2 years. If this patient is excluded from the analysis, the median time to platelet count recovery of greater than 100,000/μL was 13 days (range 5-35; n=9). Of note, 6 patients were on a steroid taper at the time of discontinuation of the medication. All except one patient was transitioned to immunosuppression using cyclosporine A; one patient was safely taken off immunosuppression.

Conclusion
Tacrolimus appears to occasionally cause a refractory IT in solid organ transplant recipients, which only appears to resolve with cessation of the drug. The onset of the IT usually occurs after at least two years of taking the medication. A trial of tacrolimus discontinuation for at least a 3 month period, substituted by another immunosuppressant such as cyclosporine A, should be attempted when seeing these patients, especially if there is consideration to perform a more invasive procedure such as a splenectomy or splenic artery embolization.

Disclosures:
No relevant conflicts of interest to declare.