bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relative Survival of Older Patients with Indolent Lymphoma–Analysis From the SEER Database
Authors: Prabhakar Mamatha , Kanapuru Bindu , Jemal Ahmedin , Hesdorffer Charles , Ershler William , Longo Dan L. , Yates Jerome W 
Published: October 2019

Abstract
Abstract 5214

Background:
Indolent lymphomas account for 35–40% of Non-Hodgkin's lymphomas (NHL). The treatment choices, and as a result, the overall outcome of these indolent lymphomas seem to be changing with the introduction of chemoimmunotherapy. However, the impact of these new treatment approaches on the survival in older patients has not been specifically studied.

Methods:
We used data from the Surveillance, Epidemiology and End Results database to determine survival for older patients diagnosed with indolent lymphomas. We compared trends in survival between 1977–86, 1987–96 and 1997–2006 in men and women, for three age groups 65–74, 75–84 and 85+ years. Survival rates were calculated up to 9 years post-diagnosis.

Results:
Between 1977 and 2006, survival rates increased for both men and women in all three age groups. The greatest improvement in survival was seen at 5 years. Between 1977–86 and 1997–2006, 5-year survival rates increased in men/women by 21%/22%, 23%/29% and 16%/24% in the 65–74, 75–84 and 85+ age groups respectively. Survival gains increased with each decade in all age groups for both sexes with the most marked improvements between 1987–1996 & 1997–2006. Women in the first two groups consistently demonstrated a better survival than men. The oldest old men (85+) had the lowest survival rate with the majority of the deaths occurring in the first year of diagnosis.

Conclusions:
Survival for older patients has increased considerably in the interval between 1977–2006 with the largest improvement seen in the 75–84 year old age group. Larger increases in the survival rates between 1987–1996 and 1997–2006 might be accounted for by the benefits of immunotherapy with the introduction of rituximab in 1998. The increased early deaths noted in men 85+, could be related to treatment toxicity. While earlier treatment is being advocated for patients diagnosed with indolent lymphoma, the data we present imply that more careful consideration should be given to the selection of patients above the age of 85 for such treatment. Male-female differences in survival are interesting and further study would seem important to elucidate the causes.

Disclosures:
No relevant conflicts of interest to declare.
Conditional C-Myc Inactivation Impacts on Chromosomal Translocation Mechanisms and B Lymphomagenesis
Authors: Yan Catherine T. , Muniandy Parames , Yang Xiaoli 
Published: October 2019

Abstract
Abstract 5238
The requirement for Myc oncogenes in cellular transformation and tumor progression in human cancers has been studied extensively. Others and we have shown that the spontaneous development and progression of B lymphomas involving translocations that activate c-Myc can be faithfully recapitulated in model systems. However, for other oncogenes that are the predominant translocation targets in hematopoietic malignancies in humans, such as Bcl6, animal models that spontaneously promote translocations involving them are still lacking. Importantly, the molecular basis for the recurrence of particular oncogene translocations remains undefined. We have shown that a breakdown in DNA double strand break (DSB) repair resulting from conditionally inactivating the essential non-homologous end-joining (NHEJ) repair gene XRCC4 in p53 (XcP) deficient mature B cells reproducibly leads to the development of mature B lymphomas. These lymphomas, termed CD21/XcP, routinely harbor a clonal translocation that fuses IgH switch (S) regions to exon 1 of c-Myc, which we showed are formed by the aberrant repair of AID-induced DSBs during IgH Class Switch Recombination (CSR). These lymphomas harbor also a second clonal translocation that fuses the Igl locus into various chromosomal locations, including c-Myc, which our studies showed were formed by aberrant V(D)J recombination. Juxtaposition of Ig heavy chain (IgH) sequences to the c-Myc oncogene is one of the most extensively modeled and well-studied translocations. It is a hallmark of Burkitts Lymphoma, a subset of other B lymphomas. By limiting or eliminating c-Myc via conditional c-Myc inactivation in peripheral naïve and GC B cells in wildtype, p53 deficient and combined XRCC4 and p53 deficient settings, our studies reveal new insights into normal, functional requirements for C-myc in peripheral B lymphocytes, selection mechanisms underlying its activation in B lymphomagenesis, and the identification of new oncogenic translocation partners resulting from its inactivation in the CD21/XcP model.

Disclosures:
No relevant conflicts of interest to declare.
Fibrinogen, Coagulation Times and Some Inflammation Markers In Patients with Different Stages of Sepsis
Authors: Mariscal Ignacio , Joanne Lim-Baga Grace 
Published: October 2019

Abstract
Abstract 5257
Fibrinogen, Coagulation Times and Some Inflammation Markers In Patients with Different Stages of Sepsis. Mariscal II MD, Lim-BagaGJ MD. Hospital Gómez Farias ISSSTE. Zapopan, México.
Inflammation and coagulation pathways, among others, are activated during sepsis (Sp). We tested a priori hypothesis that coagulation changes are related to clinical stages of Sp.

DESIGN.
Prospective non interventional study on patients with Sp, from November 2009–2010

SETTING.
Medicine hospitalization areas in a single third level hospital in western México

PATIENTS.
One hundred and eighty eight patients with Sp who were admitted to Medicine wards received standard critical care treatment.

INTERVENTION.
Patients were stratified into Sp, severe Sp and septic shock. Mortality was assessed at discharge and clotting test and inflammation markers were measured at admission and at discharge

MEASUREMENTS AND MAIN RESULTS.
Sp incidence was 9.6%. There were 114 patients with Sp, 57 severe Sp and 17 with septic shock; the mortality for the group was 23%; 6%, 34%, and 94% in Sp, severe Sp, and septic shock respectively. Initial fibrinogen (Fg) showed a trend to be higher as clinical stages of Sp advanced (346, 361,393 mg PNS), and final Fg decreased in Sp** and severe Sp* and shock (PNS). PT** and PTT** at discharge, were prolonged. Initial and final bands* were higher as the stages of Sp increased and decreased at discharge, except in those with septic shock. Comparing results by survivorship it was observed that initially and at discharge, non survivors had greater abnormalities of PT**, PTT**, and bands** than survivors. Fg**was lower in those who died

CONCLUSIONS.
The trend of the Initial Fg levels to increase as severity of Sp, its decrease at discharge, the prolongation of PT and PTT and the descend of platelets, suggest that the activation of the coagulation cascade increases as Sp progresses and, that this could be related to the severity of the inflammatory response and the vascular damage. The coagulopathy is suggestive of DIC andthat this participates in the prognosis. It would be important to set the clinical role of coagulation in the stages of Sp. A mayor numbers of patients must be studied and markers of DIC investigated.

Disclosures:
No relevant conflicts of interest to declare.
A Retrospective Review of the Management of Patients with Porphyria Cutanea Tarda At a Tertiary Care Centre
Authors: Yudin Jovana , Bacchus Farzana R. , Crowther Mark A. 
Published: October 2019

Abstract 5290
Porphyria Cutanea Tarda (PCT) is caused by a deficiency in uroporphyrinogen decarboxylase, an enzyme in the heme biosynthesic pathway. This leads to an excess of porphyrins, which cause blistering and skin fragility on sun exposure. The goals of treatment are iron depletion and reduction of plasma porphyrins to ameliorate skin symptoms.
We reviewed the management of all PCT patients at St. Joseph's Hospital followed by the Hematology service, with the objective of describing their treatment course and its efficacy. The type of treatment received as well as the number and volume of phlebotomies were recorded. Outcomes of interest were skin symptom resolution (clinical remission) and biochemical remission, as measured by serum ferritin. Target ferritin was set at 30–50 μg/L.
A total of 18 patients with PCT met our inclusion criteria; 14 males and 4 females. Three patients had the familial subtype of PCT while 15 had the sporadic form. Precipitants included alcohol, hepatitis C, hemochromatosis and estrogens. All patients received phlebotomy and three received hydroxychloroquine. Most patients were referred and initially diagnosed by dermatologists. The total volume of phlebotomies per patient ranged from 750–9500 mL for resolution of cutaneous symptoms which was achieved in 75% of patients. At the end of the study period, 15/18 (83%) patients were in clinical remission and 12/18 (67%) were in biochemical remission.
Follow-up of PCT patients by a hospital hematology service allows for symptomatic control and biochemical remission in the vast majority of patients through the use of phlebotomy and occasionally hydroxychloroquine.

Disclosures:
No relevant conflicts of interest to declare.
Use of Biosimilar G-CSF Is Effective After Autologous Bone Marrow Transplantation
Authors: Kotwica Katarzyna , Cioch Maria B. , Wach Malgorzata , Manko Joanna , Jawniak Dariusz , Walter-Croneck Adam , Legiec Wojciech , Dmoszynska Anna 
Published: October 2019

Abstract
Abstract 5321

OBJECTIVES:
Granulocyte colony-stimulating factors (G-CSFs) are widely used to accelerate haematopoietic recovery after bone marrow transplantation (BMT). Regulatory approval of biosimilar G-CSFs in Europe has been on the basis of comparable efficacy, safety and quality as the originator product. However, data are not presently available for all G-CSF clinical settings. This is the first reported use of a biosimilar G-CSF for neutrophil recovery after BMT.

METHODS:
A total of 23 consecutive patients (12 male, 11 female; mean ± SD age 47 ± 13 years) with haematological malignancy (multiple myeloma, n=12; Hodgkin’s lymphoma, n=6; non-Hodgkin’s lymphoma, n=4; acute myeloid leukaemia, n=1) were recruited at a single-centre. Nineteen patients were receiving their first BMT while it was the second autograft for 4 patients. Mobilisation chemotherapy consisted of high-dose (HD) VEP (n=14), ESHAP (n=4), HD Ara-C (n=3), HD cyclophosphamide (n=2) or ICE (n=1). Patients received biosimilar G-CSF (EP-2006, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BEAM or melphalan 140/200 mg/m2 +/− bortozemib) with or without radiotherapy followed by autologous BMT. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 109/l and was continued until ANC reached >1.5 × 109/l for 3 consecutive days. Response was evaluated after BMT using International Uniform Response Criteria.

RESULTS:
Mean ± SD number of CD34+ cells collected before transplantation was 10.1 ± 4.0 x106/kg/body weight. After BMT, one patient had a stringent complete response (CR), 7 patients had a CR, one patient a near CR, one patient a very good partial response (PR), 12 patients a PR, and one patient had progressive disease (overall response 96%). Mean recovery to ANC >0.5 × 109/l was 13.0 ± 4.0 days. Mean duration until platelet recovery >20 000/ml was 16.1 ± 4.4 days (not achieved in 5 patients at last available assessment). Mean duration of treatment with biosimilar G-CSF was 14.4 ± 5.1 days (range 6−23). Patients required antibiotics on a median of 4 days (range 1−6). Five patients (22%) experienced neutropenic events (neutropenic fever, n=4 and neutropenic enterocolitis and sepsis, n=1). Mean number of days in hospital was 28 ± 6.

CONCLUSION:
Biosimilar G-CSF appears to be effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by autologous BMT. The use of biosimilar G-CSFs may result in cost savings in cancer supportive care budgets.

Disclosures:
Dmoszynska: Mundipharma: Advisory Board; Roche: Honoraria.
Von Willebrand Factor Binds to the Endothelial Growth Factor Angiopoietin-2 Both within Endothelial Cells and Upon Release From Weibel Palade Bodies
Authors: Mckinnon Thomas A J , Starke Richard D , Ediriwickrema Kushani , Randi Anna Maria , Laffan Michael 
Published: October 2019

Abstract
Abstract 698
Von Willebrand Factor (VWF) is a large multimeric plasma glycoprotein essential for homeostasis, also involved in inflammation and angiogenesis. The majority of VWF is synthesised by endothelial cells (EC) and is either constitutively secreted or stored in Weibel-Palade bodies (WPB), ready to be released in response to endothelial stimulation. Several studies have shown that formation of WPB is dependent on the presence of VWF, and deletion of VWF in human umbilical vein EC (HUVEC) results in loss of WPB. Amongst the other proteins shown to co-localise to WPB is angiopoietin-2 (Ang2), a ligand of the receptor tyrosine kinase Tie-2. Ang2 regulates endothelial cell survival, vascular stability and maturation, by destabilizing quiescent endothelium and facilitating the response to inflammatory and angiogenic stimuli. VWF is required for storage of Ang2, and release of Ang-2 from EC is increased in VWF-deficient HUVEC. Recently, we have shown that VWF itself regulates angiogenesis, raising the hypothesis that some of the angiogenic activity of VWF may be mediated by Ang-2. In the present study we investigated the interaction between Ang2 and VWF. Binding analysis demonstrated that recombinant human Ang2 bound to purified plasma-derived VWF in a pH and calcium dependent manner, with optimal binding occurring at pH 6.5 and 10mM calcium, indicative of binding within the Golgi body. Generation of binding isotherms established that Ang2 bound to VWF with high affinity (KD∼3nM); furthermore binding affinity was not dependent on VWF conformation. Using an array of VWF constructs we determined that Ang2 bound predominantly to the VWF A1 domain, which also contains binding sites to the platelet receptor GPIb and extracellular matrix proteins. Co-immunoprecipitation experiments performed on TNFα- and ionomycin-stimulated HUVECs, to induce WPB exocytosis, confirmed that a portion of Ang2 remained bound to secreted VWF. Moreover, immunofluorescence staining of histamine-stimulated HUVECs to induce VWF release demonstrated the presence of Ang2 on VWF strings secreted from ECs. Finally we demonstrated that Ang2 bound to VWF was still able to interact with Tie-2. These data demonstrate that binding of Ang2 to VWF occurs within the cell; we propose that this is the mechanism mediating storage of Ang2 in WPB. Moreover, the finding that the Ang2-VWF interaction is preserved following secretion raises the intriguing possibility VWF may affect Ang2 function, possibly by localising Ang2 to the Tie 2 receptor under the shear forces experienced in flowing blood. Similarly, Ang-2 binding to VWF may modulate its interaction with receptors and extracellular matrix proteins, and ultimately influence the role of VWF in the angiogenic processes.

Disclosures:
No relevant conflicts of interest to declare.
Activation of the Canonical Notch Signaling Pathway in the Hematopoietic Microenvironment Is Required to Maintain Normal Hematopoiesis
Authors: Wang Lin , Rodriguez-Rodriguez Sonia , Zhang Huajia , Mumaw Christen , Cardoso Angelo A , Carlesso Nadia 
Published: October 2019

Abstract
Abstract 723
Recent studies demonstrated that the causes of Myeloproliferative syndromes (MPS) is not limited to factors intrinsic to hematopoietic cells, but include also non-cell autonomous mechanisms. Here, we demonstrate that loss of CSL-dependent Notch signaling in the hematopoietic microenvironment leads to a lethal myeloproliferative disorder. Following pIpC induction, Mx1-Cre+/RBP-Jlox/lox mice showed a significantly increase in granulocyte/macrophage progenitors and granulocytes in bone marrow (BM), peripheral blood, spleen and liver and died by week 16–20. Survival at 5 months was 12% for the RBPJ KO mice compared to 100% for the control mice. Transplant studies revealed that the myeloproliferative disorder occurred rapidly when WT-hematopoietic cells were transplanted into MX1-Cre+/RBP-Jlox/lox-recipients, whereas WT-recipients of MX1-Cre+/RBP-Jlox/lox hematopoietic cells did not show onset of diseases at 6 months of follow-up. Furthermore, the disease was not transplantable in WT-recipients, indicating that abnormal Notch signaling in the microenvironment is critical for the development and sustainment of MPS. Transplants conducted with Lys/GFP HSC as WT donor cells, showed that transplant of myeloid progenitors (LK) are sufficient for the development of disease, as documented by rapid expansion of LK-Lys/GFP cells into MX1-Cre+/RBP-Jlox/lox recipients by intravital microscopy of the BM niche. Levels of hematopoietic cytokines were not significantly different in MX1-Cre+/RBP-Jlox/lox recipients prior to transplantation. Histological analysis of BM and spleen showed increased microvascular density and increased CD31+ EC by IHC. To dissect the mechanisms, we analyzed different cellular components of the microenvironment. Mx1Cre driven deletion of RBP-J occurred in osteoblasts, endothelial progenitors and mesenchymal stem cells. Co-culture experiments of HSC with these different cell types suggested cooperative effects in altering proliferation and differentiation of myeloid cells. Crosses of RBP-Jlox/lox mice with mice bearing cell type promoter specific Cre are ongoing to determine the cellular type(s) critical for the myeloid expansion and to identify downstream molecular mediators. These studies will provide further insights on the role of the microenvironment in contributing to myeloid proliferative diseases and leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Distinct Metabolic Dependency of Normal and Leukemic Cells in a Mouse Model
Authors: Yusuf Rushdia Z. , Acharya Sanket S. , Yu Vionnie , Saez Borja , Duvet Mildred , Scadden Elizabeth , Warraich Gohar , Clish Clary , Churchill Michael , Doench John , Logan David J. , Cook Colleen , Das Sudeshna , Brown Adam , Sykes Stephen M. , Chattopadhyay Shrikanta , Carpenter Anne E. , Heiden Mathew Vander , Armstrong Scott A. , Mukherjee Siddhartha , Ebert Benjamin L. , Scadden David T. 
Published: October 2019

Abstract
Abstract 759
We hypothesized that metabolic differences between leukemia initiating cells and their normal counterparts represent a vulnerability in the leukemia initiating cell, which can be therapeutically exploited. To test this hypothesis, we used the MLL-AF9 acute myeloid leukemia (AML) model in mice. Actin-DsRed mouse bone marrow transduced with MLL-AF9 expressing retrovirus was used to produce serially transplantable leukemia. Leukemic granulocyte-monocyte precursors (L-GMPs), defined by others to be the leukemia initiating cells were flow sorted from secondary recipient mice and compared with normal GMPs (N-GMPs) from actin Ds-Red mice.
Gene expression profiling, metabolomic profiling via liquid chromatography- mass spectrometry and an in vitro shRNA screen were used to identify metabolic pathways preferentially activated in leukemia initiating cells. Of 1574 defined metabolic enzymes, 44 were found to be differentially expressed between L-GMPs and their normal counterparts (N-GMPs). These together with 117 classic rate limiting enzymes were subjected to shRNA knockdown in vitro. Metabolomic profiling of both cell populations was used to corroborate findings from shRNA knockdowns.
L-GMPs and N-GMPs were transduced with lentivirus expressing shRNAs of interest (5 shRNAs per gene) in a 384 well format, selected with puromycin and cultured for 72–96 hours in the presence of GFP-positive primary bone marrow stroma. The number of cells in each well at the end of this experiment was quantitated using an Image Xpress microscope. Genes, the knockdown of which by at least two independent shRNAs produced a two fold or more decrease in L-GMPs as compared to control wells and did not similarly decrease N-GMPs, were chosen for in vivo validation. Ten genes in the glycolysis pathway and TCA cycle, fatty acid metabolism and detoxification, and ketohexokinase were identified.
Ketohexokinase, a rate-limiting enzyme in fructose metabolism was particularly potent and of interest given its potential to be exploited therapeutically. In vivo assessment of its relative ability to inhibit malignant versus normal hematopoietic cells is ongoing. These studies provide preliminary support for the hypothesis that specific metabolic circuits are differentially active in leukemia initiating cells in MLL-AF9 AML and may represent unique points of vulnerability that can be targeted therapeutically.
Authors 1 and 2 contributed equally. Authors 3 and 4 contributed equally.

Disclosures:
No relevant conflicts of interest to declare.
The Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (LARG) Is Essential for Survival and Proliferation of AML1-ETO Associated AML Cells
Authors: Shen Shuhong , Zheng Yi , Mulloy James C. 
Published: October 2019

Abstract
Abstract 923
AML1-ETO (AE), the product of translocation 8;21, is the most frequently observed fusion gene in acute myeloid leukemia (AML). Although AE is not sufficient to induce leukemia by itself, it endows a significant survival and growth advantage to hematopoietic progenitors. In a search of various AML microarray databases, we found that the Leukemia-Associated Rho Guanine nucleotide exchange factor (LARG) gene expression is consistently upregulated in samples from AE-positive AML patients compared to other types of AML. This observation was confirmed in an independent cohort of AML samples by qPCR and Western Blot analysis, and in a pre-leukemia cell model generated by AE expression in CD34+ human cord blood (CB) cells compared with CB cells transduced with the MLL-AF9 (MA9) fusion gene or control retroviral vector. ChIP-PCR assays further indicate that AE directly binds to the LARG regulatory region through cis-elements containing AML1 (Runx1) binding sites. LARG, a RhoA GEF, can activate the RhoA pathway which is important for interaction between cells and their environment. We found that the AE cell lines were more adhesive to fibronectin than the MA9 cell lines. When we used lentiviral vectors expressing shRNA to suppress LARG expression in AE+ pre-leukemic cells, the cells showed a significant decrease in adhesion to fibronectin. In addition, knockdown of LARG also significantly interfered with the growth of AE cells in that the shRNA transduced cells displayed a competitive disadvantage relative to non-transduced or control-transduced cells in a proliferation assay. Cell cycle analysis revealed that LARG knockdown induced cell cycle exit, while Annexin V staining showed that LARG suppression promoted apoptosis of AE cells. Because LARG is a well-known guanine nucleotide exchange factor (GEF) for RhoA GTPase, we examined the downstream signaling events of the LARG/Rho axis, including phosphorylation of MLC and AURORA, targets of Rho-associated protein kinase (ROCK). pMLC and pAURORA were significantly down-regulated upon knockdown of LARG. Phosphorylation of Stat3, another protein downstream of RhoA signaling important for the proliferation and survival of myeloid cells, was also decreased upon LARG knockdown. These findings suggest that LARG is a transcriptional target of the AML1-ETO fusion protein and the LARG-RhoA signaling pathway plays an essential role in the proliferation and survival of AE cells. The LARG/RhoA pathway may serve as a new therapeutic target in t(8;21) AML.

Disclosures:
No relevant conflicts of interest to declare.