bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent Validation of Chronic Graft-Versus-Host Disease (GVHD) Grading System Proposed by the NIH Consensus Criteria in Terms of Prognostic Stratification of the Patients Developed Chronic Gvhd
Authors: Moon Joon Ho , Sohn Sang Kyun , Uhm Jieun , Gupta Vikas , Lipton Jeffrey H. , Messner Hans A. , Kuruvilla John , Kim Dennis Dong Hwan 
Published: October 2019

Abstract
Abstract 1946

Background:
A new grading system for graft-versus-host disease (GVHD) severity was established by the National Institute of Health (NIH)-consensus criteria (NCC) which was introduced since 2007. However, prognostic implications of the NCC grading system on GVHD-specific survival (GSS) are still on debate.

Methods:
A total of 425 consecutive patients who survived beyond 100 days following allogeneic hematopoietic stem cell transplantation (HSCT) at the Princess Margaret Hospital from Jan 1996 to Oct 2007 were reviewed retrospectively and reclassified using the NCC. The GVHD-specific survival was compared according to the severity at onset or at peak of cGVHD by the NCC.

Results:
Out of 425 patients, 346 patients (81.4%) were diagnosed to have chronic GVHD (cGVHD) by the Revised Seattle criteria (RSC). Among them, 317 patients were reclassified to have classic cGVHD (n=144, 41.6%) and overlap syndrome (n=173, 50.0%) by the NCC. Twenty nine patients (8.4%) were reclassified as late-onset/recurrent acute GVHD. Out of 317 patients diagnosed to have a classic chronic GVHD and overlap syndrome, the severity scores at the onset of cGVHD were as follows: mild (n=137, 43.2%), moderate (n=134, 42.3%) and severe (n=46, 14.5%), while more moderate and severe cGVHD was noted when severity score was assessed at the peak time of cGVHD as mild (41, 12.9%), moderate (n=176, 55.5%) and severe (n=100, 31.6%). With median follow-up duration of 34 months (range 4–93 months), 5 yrs GSS rate was significantly worse in the group with severe grade of cGVHD at onset and at peak: 50.9±7.8% in severe vs. 89.7±3.2% in moderate vs. 93.5±2.4% in mild (at onset, p<0.001) and 69.1±5.2% in severe vs. 93.2±2.1% in moderate vs. 97.3±2.7% in mild (at peak, p<0.001). No differences in GSS were noted between moderate and mild grades of cGVHD at onset and at peak. Multivariate analysis confirmed severe grade of cGVHD at onset (HR 5.18, 95% CI=1.97–13.6) and at peak (HR 3.79, 95% CI=1.79–8.07) by NCC is associated with poor survival.

Conclusion:
The present study has successfully validated the grading system of NCC. The NCC could predict long-term outcome in the patients with cGVHD and could potentially be used to develop risk-stratified approaches to treatment based on NCC grading. The group with severe grade cGVHD presented inferior long-term outcomes than those with mild/moderate grade cGVHD.

GVHD-specific survival according to chronic GVHD grading system
A. GSS according to the Revised Seattle Criteria, B. GSS according to the NIH Global score at onset, C. GSS according to the NIH Global score at peak

Disclosures:
No relevant conflicts of interest to declare.
The Outcome of Hematopoietic Cell Transplantation (HCT) for Myelodysplastic Syndrome (MDS) in Adults ≥65 Years of Age: First Report of the Coverage with Evidence Development (CED) in Medicare Beneficiaries
Authors: Atallah Ehab , Pedersen Tanya L. , Warlick Erica D. , Dircks Anne , Weisdorf Daniel , Horowitz Mary M. , Rizzo J. Douglas 
Published: October 2019

Abstract
Abstract 1983
Despite recent advances in treatment for MDS, allogeneic HCT remains the only curative therapy. Historically, patients (pts) ≥65 years with Medicare did not have coverage for HCT. On August 4th 2010, the Centers for Medicare and Medicaid services (CMS) approved coverage for HCT for MDS through coverage with evidence development (CED). A Center for International Bone Marrow Transplant Research (CIBMTR) study comparing outcomes of pts 55–64 vs. 65 and older was approved. Since the study initiation the number of HCT performed in pts≥65 years old has nearly doubled from a pre-study average of 75/year to 154 in 2011. As of May 2012, 220 pts have been enrolled; 120 have ≥100 days of follow-up. The median age at HCT was 67 (range 65–74); only 24% were >70 years old and 20% (n=23) had therapy related MDS. At the time of HCT, 45% had refractory anemia with excess blasts −1/2 and 32% had refractory anemia ± ringed sideroblasts/refractory cytopenia with multilineage dysplasia. The modified International Prognostic Scoring System (IPSS) score was low, intermediate-1 (INT-1), INT-2 and high risk in 17%, 36%, 32% and 5% of pts, respectively. Donors were an HLA identical sibling, unrelated adult donor (URD) or cord blood (UCB) in 25%, 73% and 2% respectively. Of the 88 patients who received an URD HCT, 70 (80%) were HLA 8/8 allele matched. Twenty five pts (21%) (95% CI, 14–29%) died before 100 days. Causes of death were graft rejection/failure (1), infection (5), interstitial pneumonitis (1), GVHD (3), relapse (6), organ failure (8) and unknown (1). The probability of death at 100 days after HCT in all patients' ages 55–64 transplanted for MDS in 2010–2011 reported to the CIBMTR is 17%. (95% CI, 15–20%).

Conclusion:
In pts ≥65, HCT for MDS results in similar early mortality compared to pts 55–64 years old. This study will be expanded to include 700 pts age 65 and older to facilitate analysis of effect of IPSS, cytogenetics and conditioning regimen on the critical HCT outcomes for MDS of survival and MDS-free survival. Importantly, the increased use of HCT after approval of the CED suggests that insurance and Medicare coverage is a significant barrier limiting access to this potentially curative treatment in older patients with MDS.

Disclosures:
No relevant conflicts of interest to declare.
Long-Term Remission After Hematopoietic Stem Cell Transplantation for Refractory Cutaneous T Cell Lymphoma
Authors: Galvin John P. , Monreal Joanne , Guitart Joan , Rosen Steve T. , Kuzel Timothy , Mehta Jayesh 
Published: October 2019

Abstract
Abstract 2028

Purpose:
Current treatment of advanced stage cutaneous T cell lymphoma (CTCL) includes a number of chemotherapy agents which provide good response rates, but with often short duration. Hematopoietic cell transplantation (HSCT) has the potential to offer a durable remission due to graft-versus-lymphoma effect. We conducted a retrospective study to report the outcome of HSCT in patients with refractory CTCL.

Methods:
From Feburary 1997 through May 2012, twenty-one patients (22–65 yo) with advanced, refractory CTCL underwent HSCT from HLA-identical sibling (n=13), unrelated donor (n=5), umbilical cord (n=1), syngeneic (n=1) and autolougous (n=1) sources. There were 7 tumor stage MF, 6 Sézary syndrome, 2 erythrodermic MF, 1 folliculotropic MF, 1 aggressive CD8+ T cell lymphoma (Berti's type), 2 γ-δ TCL, 1 α-β TCL and 1 CD30-negative large cell peripheral TCL. The intensity of the conditioning regimen was conventional in 10 and reduced in 11. At the time of HSCT, the median disease duration was 5.4 years (1–17 y). Most patients were heavily pretreated, having failed a median number of four (1–9) lines of therapy. The stage of the disease at the time of HSCT was IIB (n=9), III (n=2), IVA (n=9), and IVB (n=1).

Results:
For the 21 patients evaluated there was a median follow-up of 62 months (3–186 mo). 11 patients had relapse post-transplant: 5 patients had an early relapse (<100 days) and 6 patients had a late relapse (>100 days). Relapsed disease appeared to be of a lower grade clinically than at pre-transplantation and responded to therapies they had previously failed. 1 early relapse died of disease (SS, auto-SCT) and 1 late relapse died of disease (γ-δ TCL, RIC allo-SCT). Of the nine remaining relapsed patients, 1 has died of a cerebral hemorrhage. (CD30-neg large cell peripheral TCL, alloSCT) and 1 of GVHD (γ-δ TCL, RIC allo-SCT). Of the 7 remaining relapsed patients, 4 went into CR with reduction of immunosuppression. 14 patients developed acute GVHD (fatal in 3), and 10 developed chronic GVHD. Of the surviving patients (n=15) all are in CR. Overall survival was 71%, with a median OS of 27.1 months (range, 0.5–185.9). Progression free survival (PFS) was 43% with a median PFS of 4.1 months (range, 0.5–80).

Conclusions:
Our results suggest that HSCT can induce durable clinical remissions in patients with refractory CTCL through graft-versus-lymphoma effect.

Disclosures:
No relevant conflicts of interest to declare.
Interleukin-6, Hepcidin, and Other Biomarkers in Anemia of Chronic Disease (ACD) and Chemotherapy-Induced Anemia (CIA): Potential Therapeutic Targets.
Authors: Vadhan-Raj Saroj , Zhou Xiao , Bueso-Ramos Carlos E. , Patel Shreyaskumar , Benjamin Robert S , Ngyuen Martin 
Published: October 2019

Abstract
Abstract 2086

Background:
Anemia in patients with malignancies can be multifactorial including anemia of chronic disease (ACD), also known as anemia of inflammation (AI), and chemotherapy (CT)-induced anemia (CIA) from myelosuppression. Although, exact mechanism for ACD is not known, induction of hepcidin, a key iron-regulatory hormone, by Interleukin (IL)-6 and other pro-inflammatory cytokines with resulting hypoferremia and limitation of iron supply to the bone marrow appear to be major contributors to pathogenesis of anemia. Hepcidin reduces iron levels by inducing degradation of the cellular iron exporter, ferroportin. The objective of this study was to examine the levels of various cytokines/regulators that may play role in ACD.

Methods:
Chemo-naïve patients with sarcoma scheduled to initiate first-line doxorubicin-based chemotherapy had blood samples drawn at baseline, and following chemotherapy (post cycles1, 3 and 6) for analysis of pro-inflammatory cytokines/other biomarkers of anemia. Serum samples were analyzed for IL-1β, IL-6, TNF-α, Hepcidin, hemojuvelin, ferroportin, soluble transferrin receptor (sTFR), and C-reactive protein (CRP) using ELISA techniques (R&D Diagnostics, Uscn Life Science Inc, or Abnova). Correlations between these biomarkers and Hgb levels at baseline and during the study period were calculated by linear regression analysis (SAS 9.2).

Results:
Of the 49 patients enrolled on to the clinical trial, there were 26 (53%) women and 23 (47%) men, with median age 45 years (range 19–65 years). Twenty-five percent of the patients had Hgb less than 12g/dL (range, 8.9–15.9 g/dL) prior to CT. At baseline, 50% of the pts had hypoferremia with low serum iron and transferrin saturation <20%. Baseline serum levels of IL-6 (r= −0.73, p<0.0001), hepcidin (r= −0.46, p=0.005), CRP (r= −0.46, p=0.003), sTFR (r= −0.32, p=0.064) inversely correlated with hemoglobin levels prior to CT, supporting their role in ACD. During CT (median 4, range; 1–6 cycles), Hgb declined in all pts with 55% requiring PRBC transfusions (77% of pts starting with baseline Hgb < 12 g/dL vs 47% of pts with baseline Hgb > 12 g/dL). Interestingly, as shown below, Hepcidin, IL-6, and sTFR all significantly negatively correlated with Hgb levels during CT.
No significant correlation was found for IL-1β, TNF-α, ferroportin, or hemojuvelin levels with Hgb.

Conclusions:
IL-6 and Hepcidin pathway appears to play an important role in anemia in cancer patients before and during CT. Treatment with novel agents targeting this pathway may provide effective strategies for prevention and treatment of ACD and CIA.

Disclosures:
Vadhan-Raj: JNJ: Research Funding.
Prevalence and Risk Factors of Left Ventricular Noncompaction in Patients with β-Thalassemia.
Authors: Piga Antonio , Longo Filomena , Musallam Khaled M , Veltri Andrea , Davicino Lia , Bonamini Rodolfo 
Published: October 2019

Abstract
Abstract 2127
Left ventricular noncompaction (LVNC) is a rare cardiomyopathy with potentially serious outcomes. It results in multiple and excessive trabeculations, deep intertrabecular recesses, and a thickened ventricular myocardium with two distinct layers, compacted and noncompacted. The condition is most commonly congenital although acquired forms have been described. A recent report of LVNC detected in a β-thalassemia twin suggested an association with cardiac siderosis. In a cross-sectional study of 135 transfusion-dependent β-thalassemia patients (130 major and 5 intermedia, mean age 29.6 ± 7.7 year, 49.6% males) presenting for cardiac iron assessment by magnetic resonance imaging (MRI), we evaluated the prevalence and risk factors for LVNC. None of the patients had neuromuscular or congenital heart disease. Eighteen patients (13.3%, 95% CI: 8.6–20.1) fulfilled the pre-assigned strict criteria for LVNC on cardiac MRI. There were no statistically significant differences between patients with and without LVNC in respect to: demographics; hemoglobin levels; splenectomy status; systemic, hepatic and cardiac iron overload indices; hepatic disease and infection studies; or iron chelator type. Patients with LVNC were more likely to have heart failure (adjusted OR: 1.77, 95% CI: 0.29 to 10.89); although with high uncertainty. Patients with β-thalassemia have a higher prevalence of LVNC than normal individuals. As this finding could not be explained by conventional risk factors in this patient population, further investigating of the underlying mechanisms of LVNC is warranted. This remains crucial for an entity with adverse cardiac outcomes, especially in a β-thalassemia patients where cardiac disease remains a primary cause of mortality.

Disclosures:
No relevant conflicts of interest to declare.
The Role of Integrins aMb2 (CD11b/CD18) and aDb2 (CD11d/CD18) in Macrophage Fusion.
Authors: Wu YiFei , Kushchaeva Evgeniya , Ugarova Tatiana 
Published: October 2019

Abstract
Abstract 2138
Macrophage fusion leading to the formation of multinucleated giant cells (MGCs) is a hallmark of many chronic inflammatory reactions. MGCs are an invariable constituent of tuberculoid lesions and also found in a variety of conditions leading to granulomatous inflammation as well as the foreign body reaction. Despite the prominent phenotype, the molecular mechanisms underlying macrophage fusion are not well understood. MGCs originate from macrophages that are recruited to sites of chronic inflammation. The major myelo-monocytic integrin αMβ2 (CD11b/CD18, Mac-1), together with a related integrin αDβ2 (CD11d/CD18), mediate critical adhesive reactions of monocyte/macrophages. The function of β2 integrins in macrophage fusion remains controversial. Some studies using function blocking antibodies implicated αMβ2 in the cell/substrate adhesive interactions that are required for MGC formation, whereas one recent report indicated that this integrin plays a minor role. Moreover, the contribution of αDβ2, a receptor with recognition specificity overlapping that of αMβ2, to macrophage fusion is unknown. To evaluate the role of αMβ2 and αDβ2 in MGC formation, we examined fusion of inflammatory peritoneal macrophages isolated from wild-type mice and mice with deficiency of αM or αD integrin subunits. Macrophages were isolated at day 3 after thioglycollate injection and cultured for 24–72 hours in the presence of IL-4 to induce fusion. Percentage fusion was quantified as the number of giant cell nuclei (≥2 nuclei) to the number of total nuclei. The number of fused macrophages isolated from wild-type mice gradually increased and ∼40–50% macrophages formed MGCs after IL-4 stimulation by day 3. Analyses of fusion of αMβ2-deficient macrophages demonstrated that fusion was significantly reduced. By day 3, macrophage fusion of αMβ2-deficient macrophages was 23 ± 2% of wild-type macrophages. Fusion of αDβ2-deficient macrophages was also decreased and the change was statistically significant, albeit to a smaller degree (75 ± 4%). Using a mouse model of sterile peritonitis induced by thioglycollate injection, we also examined the formation of MGCs in vivo. In wild-type mice, the number of MGCs gradually increased from 2.5 ± 0.3% at day 0 (resident macrophages) to 17 ± 2% at day 18 (the resolution phase of inflammation). Moreover, expression of αMβ2 and αDβ2 on peritoneal macrophages increased by ∼2 and 1.6-fold, respectively, on 18th day after induction of inflammation. In αMβ2-deficient mice, the number of MGCs was reduced by 2.1-fold compared to wild-type mice. Furthermore, while the size of wild-type and αMβ2-deficient giant cells was the same, the number of cells with 3 and more nuclei in fused αMβ2-deficient MGCs was 4-fold less than in wild-type cells. The results indicate that both αMβ2 and αDβ2 integrins support macrophage fusion with αMβ2 playing a dominant role.

Disclosures:
No relevant conflicts of interest to declare.
Safety and Value of Bronchoalveolar Lavage and Lung Biopsy in Children with Leukemia: A Single Institution Experience.
Authors: Montoya Libby , Avent Yvonne , Wilder Keith , Pei Deqing , Cheng Cheng , Jeha Sima , Morrison R Ray , Elbahlawan Lama 
Published: October 2019

Abstract
Abstract 2153
Patients with hematological malignancies are at risk of developing life threatening opportunistic pulmonary infections. The value of bronchoalveolar lavage (BAL) and lung biopsy (BX) in the management of these patients is debatable. While some believe these procedures are relatively safe and often provide valuable information that can guide management in these patients, others question the benefit of the procedures or are concerned about the potential complications of the procedures. We reviewed the St Jude experience with bronchoalveolar lavage and lung biopsy in children with leukemia to assess the benefit and safety of these 2 procedures. Review of medical records from January 1, 1997 through December 31, 2007 identified 183 potential episodes of BAL or BX in patients with leukemia who were younger than 22 years at time of procedure. In 30 patients who had multiple procedures, only the initial procedure was included.
A total of 64 patients were included, 36 (56.3%) of which had lung biopsy and 28 (43.7%) who had BAL. (See Table 1 for Demographics). There was a trend of better yield with BAL as compared to BX (67% versus 44%, p=0.079). Better BAL yield was observed in: males versus females (88% versus 42%, p=0.017), ALL versus AML (79% versus 44%, p=0.097), non-neutropenic versus neutropenic children (90% versus 56%, p=0.098). Both procedures resulted in change in antimicrobial coverage (78% in lung biopsy, 89% in BAL). Although both procedures were relatively safe, patients with BX had more complications as compared to BAL. Bx resulted in new oxygen need in 4 patients, increased oxygen need in 1 patient, intubation in 2 patients, and bleeding in 1 patient. BAL resulted in new oxygen need in 2 patients and increase in need in 7 patients, but no intubation or bleeding was related to this procedure.
In summary, BAL and BX have a reasonable safety profile and contributed to the management of pulmonary infections in children with leukemia. Compared to BX, BAL was associated with higher yields and less complications.
Table 1. Demographics Variable BAL (28) BX (36) Sex M/F 16/12 19/17 Mean Age 11 years 11 years ALL patients 19 12 AML patients 9 24 Neutropenia (ANC≤500) 18 21 Intubated prior to procedure 13 4

Disclosures:
No relevant conflicts of interest to declare.
ADAMTS13 TSP1 Repeat Domains Promote HUVEC Angiogenesis Via Phosphorylation of VEGFR2.
Authors: Lee Manfai , Xiao Juan , Zheng X. Long , Baza Jonathan , Hoyt Courtney , Rodgers George M 
Published: October 2019

Abstract
Abstract 2182
The primary role of ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, 13) is to cleave unusually large von Willebrand factor (ULVWF) multimers under shear stress. Recently, we reported that ADAMTS13 may be a potent mitogen and chemoattractant, and it modulates angiogenesis in vitro (Microvas Res. 2012, 84, 109–115). However, the structural components and mechanism of ADAMTS13 modulating angiogenesis are not understood. Herein, we report the effect of ADAMTS13 variants on cell proliferation, migration, and, tube formation of human umbilical vein endothelial cells (HUVEC). In addition, we determined the signaling pathways by which ADAMTS13 promotes angiogenesis.
ADAMTS13 fragments containing TSP1 repeat (i.e. MDT, MDTCS, TSP1 2–8, TSP1 5–8 plus CUB, and TSP1 2–8 plus CUB) were used in this study. In the proliferation model, TSP1 2–8 at the concentration of 34.6 ng/mL (651 pM) increased endothelial cell proliferation by 267 %. In the chemotaxis assay, TSP1 2–8 at the concentration of 27.7 ng/mL (521 pM) increased endothelial cell migration across a gelatinized polycarbonate membrane by 71 %. Similarly, TSP1 2–8 at the concentration of 55.4 ng/mL (1.0 nM) induced endothelial cell tube formation in Matrigel by 45 %. In all three models, the TSP1 2–8 induced angiogenic responses with similar efficacy to full-length ADAMTS13. MDT and MDTCS fragments did not affect proliferation, migration, or tube formation significantly, as compared to the negative control.
To determine the mechanism by which ADAMTS13 induces angiogenesis, we incubated endothelial cells with ADAMTS13 at the concentration of 147 ng/mL (1.0 nM). We showed that ADAMTS13 increased the phosphorylation of VEGFR2, Akt, and, P44/42 MAPK, which may trigger downstream activation to promote cell proliferation and migration. Addition of anti-VEGF antibody in the culture system significantly blocked the ADAMTS13-induced effect, indicating that ADAMTS13 plays a role in promoting angiogenesis by inducing VEGF secretion from endothelial cells (Fig 1).
The biological role of ADAMTS13 in angiogenesis was further demonstrated in a chick embryo model. Collagen onplants supplemented with EBM-2 (as negative control), 40 ng/mL VEGF165 (2.1 nM) (as positive control), and 306 ng/mL ADAMTS13 (2.2 nM) were placed on the chorioallantoic membrane of day 8 fertilized white leghorn chicken embryos. Localized and sustained release of VEGF and ADAMTS13 over a course of 72 hours resulted in 8-fold increase in capillary migration into the collagen onplants. Together, our findings suggest that the TSP1 repeats of ADAMTS13 metalloprotease promote angiogenesis by inducing VEGF secretion and VEGFR2 phosphorylation.

Disclosures:
No relevant conflicts of interest to declare.