bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Linkage of the Dehydrated Hereditary Stomatocytosis Locus to Chromosome 16 in Two Kindreds and Refinement of the Candidate Gene Region to 16q24.2 - 16qter,
Authors: Houston Brett L. , Zelinski Teresa , Houston Donald S , Israels Sara J. , Coghlan Gail , Chodirker Bernie N. , Gallagher Patrick G. , Zarychanski Ryan 
Published: October 2019

Abstract
Abstract 3170

BACKGROUND:
The hereditary stomatocytoses are a rare, diverse group of clinical conditions associated with chronic red blood cell hemolysis and increased erythrocyte membrane permeability to monovalent cations. The most common form of hereditary stomatocytosis is dehydrated stomatocytosis (DHSt, also called hereditary xerocytosis) first reported by Miller et al. (Blood 38:184, 1971). We studied two genetically unrelated kindreds with DHSt, one from Western Canada and the other, the original DHSt kindred reported by Miller et al., from upstate New York. Although the DHSt causative gene is unknown, previous studies have mapped the DHSt locus to 16q23 – 16qter. OBJECTIVES: To define the chromosomal region carrying the disease locus in these two families using DNA linkage analysis. METHODS: PCR-based genotyping was performed on genomic DNA according to standard methods. Fine mapping was performed using markers on the telomeric end of chromosome 16. Linkage data was generated from both paternal and maternal meioses. LOD scores (logarithm (base 10) of odds) were determined at assumed recombination fractions (theta) 0.00, 0.05, 0.10, 0.20, 0.30 and 0.40. Continuous allelic alignments were manually generated. RESULTS: Based on reticulocyte count, MCHC, and osmotic fragility, disease phenotypes were identified in 29 individuals of the Canadian kindred, and 27 individuals of the New York kindred. Linkage data from both families confirmed that the disease-causing locus mapped to chromosome 16. In the Canadian kindred, significant LOD scores (> +3.00) were established between the disease-causing locus (DHSt) and D16S3074, D16S2621 and D16S3026. Three recombinants were observed between DHSt:D16S3074, two between DHSt:D16S2621 and none between DHSt:D16S3026. Significant LOD scores were also established between DHSt and D16S3074, D16S476, and D16S413 in the New York kindred, and recombination between DHSt:D16S3074 was also observed. Definition of critical recombination events allowed us to define the centromeric boundary of the region containing the disease-causing locus as D16S2621, a 2.4 cM region containing 51 known or predicted genes. CONCLUSIONS: Genetic linkage analysis has confirmed DHSt linkage to chromosome 16 in two unrelated kindreds and has refined the assignment of DHSt to chromosome 16q24.2 – 16qter.

Disclosures:
No relevant conflicts of interest to declare.
Superiority of Haploidentical Related Hematopoietic Stem-Cell Transplantation Over Chemotherapy Alone for Patients with Intermediate- or Poor- Risk Acute Myeloid Leukemia in First Complete Remission,
Authors: Chang Yingjun , Zhu Honghu , Xu Lanping , Jiang Hao , Liu Daihong , Jiang Qian , Liu Kaiyan , Lu Jin , Jiang Bin , Huang Xiaojun 
Published: October 2019

Abstract
Abstract 4161

Purpose:
The role of HLA-haploidentical related donors (HRD) hematopoietic stem-cell transplantation (HSCT) in first complete remission (CR1) for adults with intermediate and poor risk acute myeloid leukemia (AML) is still not clear.

Patients and Methods:
Totally 428 newly diagnosed AML patients between 15 and 60 years old were studied between Jan 2006 and May 2010. Among 240 patients with intermediate and poor risk cytogenetics, 191patients achieved CR1 and received chemotherapy alone or HSCT as post-remission treatment. Of these, 141 patients received chemotherapy alone (n=78) or HRD HSCT (n=63) were analyzed.

Results:
Up to last follow-up time of May 2011, 44 out of 141 patients died (36 died of relapse and 8 died of TRM) and 97 patients are still alive. 49 out of 141 patients experienced relapse and 84 patients are still in continuous CR1. The cumulative incidence of relapse (CIR) at 4 years was 37.4%±4.4%. Overall survival(OS) and disease-free survival(DFS) at 4 year was 63.8%±5.0% and 55.5%±4.9%, respectively. The CIR of HRD HSCT group was significantly lower than chemotherapy group(12.8%±6.1% vs.57.4%±5.6%, p<0.0001). HRD HSCT improved survival achieved by chemotherapy alone significantly (DFS at 4 years, 71.8%±6.9% v 42.6%±6.1%, p<0.0001;OS at 4 years,75.7% ±7.0% v 54.6%±6.1%, p=0.0014). Univariate and multivariate analysis showed post-remission treatment choice (HRD HSCT or chemotherapy) and high WBC at diagnosis were independent risk factor affecting relapse, DFS and OS.

Conclusion:
HRD HSCT in CR1 is superior to chemotherapy alone for adults with intermediate and poor risk AML patients.

Disclosures:
No relevant conflicts of interest to declare.
Enhanced Antitumor Efficacy of MUC-16 Targeted T Cells Further Modified to Constitutively Express the IL-12 Cytokine in a Syngeneic Model of Ovarian Cancer,
Authors: Chekmasova Alena A , Sandadi Samith , Spriggs David R , Brentjens Renier J 
Published: October 2019

Abstract
Abstract 4176
T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). We have constructed SFG retroviral vectors encoding first (4H11mz) and second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mzIRESmIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. This antigen is over-expressed on most ovarian carcinoma tumor cells. IL-12 is a potent inducer of a Th1 CD4+ T cell response and serves as a “signal 3” in concert with TCR activation (signal 1) and CD28 co-stimulation (signal 2) to CD8+ T cells, resulting in optimized clonal expansion and effector function. In order to mimic the clinical setting, we generated a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) cells. In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate advanced intraperitoneal ovarian tumors. The mechanism of IL-12 expressing MUC-CD targeted T cell antitumor efficacy was mediated through enhanced persistence and engraftment of modified T cells, as well as the ability of IL-12 secreting T cells to recruit endogenous T cells to the tumor site. Furthermore, we observed elevated secretion of the pro-inflammatory cytokines (IFN-g and TNF-a) in the serum of IL-12 treated mice, compared to 4H11m28mz and control CD19 targeted T cell treated groups. Treatment of B6 mice with MUC-CD targeted T cells expressing IL-12 gene was dependent upon recruitment of the NK and NKT cells to the tumor site. Finally, we demonstrated the ability of IL-12 secreting T cells to overcome the immunosuppressive tumor microenvironment by switching the phenotype of the tumor-associated macrophages (TAMs) from a predominately immunosuppressive M2 to an immunostimulatory M1 phenotype. These data, obtained in the context of a clinically relevant syngeneic tumor model supports the application of this approach in the treatment of the patients with relapsed ovarian carcinomas.

Disclosures:
No relevant conflicts of interest to declare.
Refractory / Relapsed Myeloid Leukemia of Down Syndrome Is Resistant to Second-Line Chemotherapy and Hardly Salvaged by Hematopoietic Stem Cell Transplantation: A Retrospective Study by the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)
Authors: Taga Takashi , Saito Akiko , Kudo Kazuko , Tomizawa Daisuke , Terui Kiminori , Moritake Hiroshi , Kinoshita Akitoshi , Iwamoto Shotaro , Nakayama Hideki , Takahashi Hiroyuki , Tawa Akio , Shimada Akira , Taki Tomohiko , Kigasawa Hisato , Koh Katsuyoshi , Adachi Souichi 
Published: October 2019

Abstract
Abstract 4276

Introduction:
Myeloid leukemia in Down syndrome patients (ML-DS) is known to have good sensitivity against cytotoxic agents, especially to cytarabine, and outcomes in recent clinical trials are favorable with more than 80 % probability of long-term event-free survival (EFS). However, little have been focused on refractory / relapsed cases, since most of the treatment failures consist of toxicities rather than resistant or recurrent leukemia. We present here a retrospective analysis of the patients with refractory / relapsed ML-DS.

Patients and Method:
Among the ML-DS patients diagnosed between 2000 and 2011 at the 120 hospitals in Japan, twenty-nine refractory / relapsed patients were enrolled in this retrospective study.

Result:
Median follow-up period for all 29 patients was 10.9 months (range, 2.8 –76.7 months). Male/Female ratio was 18/11. The age at initial diagnosis for ML-DS was between 7 months and 16 years old (median, 2 years old). All the patients were initially treated with one of the protocols specifically designed for ML-DS; twenty patients with AML99 Down protocol, eight with JPLSG AML-D05 protocol, and one with JCCLSG AML9805 Down protocol. There were 3 induction failures and 26 relapsed cases. Among the 26 relapsed cases, duration from initial diagnosis to relapse was 2.4 month to 71.8 months (median 8.6 months); Twenty-eight relapsed at bone marrow and one patient relapsed at skin site. Twenty-six out of the 29 patients received various re-induction chemotherapies and 13 of them achieved complete remission (CR). Eight of the 13 patients with CR subsequently received allogeneic stem cell transplantation (SCT) and 4 survived. On the other hand, five of the 13 cases with CR were treated with chemotherapy alone, and 4 were alive with no evidence of leukemia. All the 12 patients who failed to achieve CR and the 2 patients who only received palliative therapy eventually died. The 3-year overall survival rate was 22.6 ± 8.8 %. Achievement of CR with second-line chemotherapy and longer duration from initial diagnosis to relapse were significant favorable prognostic factors. SCT did not influence the prognosis even if performed after achieving further remission.

Conclusion:
The Japanese strategy treating ML-DS have been successful with very low-intensive chemotherapy regimen, however, rescue of refractory / relapsed patients with ML-DS seems difficult even with SCT.
No relevant conflicts of interest to declare.

Disclosures:
No relevant conflicts of interest to declare.
Treatment Related Mortality of AML Pediatric Patients in a Single Center in Saudi Arabia
Authors: Jastaniah Wasil , Abrar Mohammed Burhan , Khattab Taha 
Published: October 2019

Abstract
Abstract 4291
Despite minimal changes in therapeutic approach, the outcome of acute myeloid leukemia (AML) in pediatric patients has improved significantly in the past two decades. Supportive care measures may have contributed to this success by reducing treatment related mortality (TRM) and thereby improving the overall survival (OS) of patients. Yet their impact on outcome remained unknown and masked under protocol effect. To assess the impact of supportive care measures on outcome, we undertook a retrospective review of all pediatric patients diagnosed with AML between 1986 and 2011and treated in our institution, the Princess Norah Oncology Center, King Abdulaziz Medical City, Jeddah. A total of 87 patients were reviewed. Of these, two patients whose parents refused treatment and one lost to follow-up were excluded. A total of 84 patients were qualified for the study. These patients were treated with two different protocols based on treatment eras. Patients diagnosed between 1986 and 1995 (era 1) were treated following AML-BFM-78 protocol while patients diagnosed between 1996 and 2011 (era 2) were treated following the MRC AML10. The cumulative TRM incidence was 76% in era1 compared to 11.5% in era 2 (P = 0.0001). This resulted in an improved 5-year OS from 10.5% in era 1 to 56% in era 2 (P = 0.007). The protocols used in both eras were different and may have improved OS. Significant difference in TRM however, suggests that other factors contributed to the improved OS. To gain further insight of the contributing factors, patients who received only MRC AML10 protocol (in era2) were partitioned into two sub-eras based on supportive care measures introduced sequentially in our institution as follows: 1996 to 2002 (era 2a) and 2003 to 2011 (era 2b).The cumulative TRM incidence was 48.6% in era 2a and 4.7% in era 2b (P = 0.001). This also resulted in an improved OS from 33.3% in era 2a to 56.2% in era 2b despite using the same protocol (P = 0.007). Our findings highlight the importance of supportive care as a significant factor in outcome of children. Comparing protocols per se masks the importance of supportive care measures in impacting outcome. We suggest devising a standardized scoring system to evaluate center-specific supportive care measures to quantify the impact of supportive care on TRM and survival outcomes while simultaneously allowing us to distinguish the effect of supportive care from that of protocol and other factors such as ethnicity.

Disclosures:
No relevant conflicts of interest to declare.
Prevalence of Heparin Induced Thrombocytopenia Antibodies During the Period 2004–2011. Relevance to Heparin Contaminants
Authors: Fareed Jawed , Adiguzel Cafer , Hoppensteadt Debra , Jeske Walter , Walenga Jeanine M. , Lewis Bruce E , Messmore Harry L. , Bansal Vinod 
Published: October 2019

Abstract
Abstract 4326
In conjunction with an ongoing program to investigate the prevalence of HIT antibody (HIT Ab) in ESRD, blood samples were collected from patients (n=53–89) on maintenance hemodialysis and retrospectively analyzed for the presence of these antibodies during the period February-April 2004–2011. Specified cut off levels were used to determine the positive and negative results. Two ELISA methods (GTI. Brookfield, WI) and (Aniara, Mason, Ohio) were used to quantitate the HIT antibodies. The prevalence of the HIT Ab during the period 2004–2011 was < 15% with the exception of 2007 where it was 35% and in 2008 it was 30%. While the assay based differences were noted, overall there was a decreased prevalence during the period 2009–2011 (13–15%). The antibody titers as quantified by optical density measurement were relatively higher during the year 2007 and 2008. Moreover, the subtyping of these antibodies in 2007 and 2008 showed a higher proportion of IgG subtype. Interestingly the platelet counts did not differ in the different groups. Similar trends were noted in the prevalence of HIT antibodies when other methods to detect HIT antibodies were used. None of the patients recruited in this study exhibited any clinical signs of HIT syndrome. Moreover, the serotonin release assays were also negative on all these patients. Some of the batches of heparin and low molecular weight heparins used during the period 2007–2008 were found to contain varying amounts of dermatan sulfate (up to 30%) and OSCS (up to 30%). Thus the presence of these carry over products and intentionally added OSCS are most likely to contribute to this increased prevalence and seroconversion of HIT antibodies. In conclusion, these observations suggest that heparin contaminants may have contributed to the higher prevalence of HIT antibodies during the period 2007–2008.

Disclosures:
No relevant conflicts of interest to declare.
Functional Characterization of BAX 855, a PEGylated Recombinant FVIII
Authors: Schrenk Gerald , Varadi Katalin , Gritsch Herbert , Rottensteiner Hanspeter , Ehrlich Hartmut J. , Scheiflinger Friedrich , Turecek Peter L 
Published: October 2019

Abstract
Abstract 4359
Baxter and Nektar have developed BAX 855, a longer-acting PEGylated form of Baxter’s recombinant FVIII (ADVATE process) using stable PEG technology from Nektar. BAX 855 was functionally characterized in vitro and its features were compared with those of the unmodified parent rFVIII. The overall hemostatic potency of BAX 855 was assessed using a thrombin generation assay. Human FVIII-deficient plasma containing less than 1% of FVIII was supplemented with different concentrations of BAX 855 and unmodified rFVIII and coagulation was triggered by adding a small amount of recombinant human tissue factor complexed with phospholipid (PL) micelles to the plasma. Similar to unmodified rFVIII, BAX 855 corrected the impaired thrombin generation of the FVIII deficient plasma in a concentration-dependent manner. The role of FVIII within the tenase complex was determined by measuring the kinetics of FXa generation with a FIXa-cofactor activity assay, using either untreated or thrombin activated BAX 855. Comparison of the kinetic parameters and the maximum FXa generated revealed similar characteristics between BAX 855 and unmodified rFVIII. A similar approach revealed that BAX 855 fully retained its ability to be activated and inactivated by thrombin. The susceptibility of BAX 855 to activated protein C (APC) inactivation was also similar for BAX 855 and unmodified rFVIII. The binding affinities for VWF were similar for unmodified rFVIII (KD 0.6 nM) and BAX 855 (KD 0.8 nM) and the binding capacity of BAX 855 was also only slightly reduced. In contrast, the binding capacity of BAX 855 to the low-density lipoprotein-receptor-related protein (LRP) clearance receptor was 55% less than that of the unmodified rFVIII. In summary, the functional properties of BAX 855 were fully retained, indicating that PEGylation did not have an impact on the functional properties of rFVIII.

Disclosures:
Schrenk: Baxter Innovations GmbH: Employment. Varadi:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment.
Impact of the Approval of Eculizumab by the Food and Drug Administration on the Frequency of Patients Screened for Paroxysmal Nocturnal Hemoglobinuria
Authors: Munoz Javier , Younes Mohamad A. , Olarte-Merida Karen , Kuriakose Philip 
Published: October 2019

Abstract
Abstract 4377

Background:
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired complement-mediated hemolytic disorder. Eculizumab, a monoclonal antibody designed to inhibit terminal complement activation, reduces intravascular hemolysis while leading to improvements in anemia, fatigue, and quality of life as well as reductions in blood transfusions and thrombosis. This medication was approved by the Food and Drug Administration (FDA) in March 16, 2007. The intent of our study was to assess if the number of patients screened for PNH has increased after the approval of eculizumab by the FDA.

Methods:
Retrospective single institution chart review over a period of 6 years from January 2004 to June 2010. Our study population comprised 174 patients screened for PNH by flow cytometry.

Results:
Between January 2004 and March 16, 2007 (39 months), a total of 68 cases were screened for PNH. On the other hand, between March 17, 2007 (date of FDA approval) and June 2010 (39 months), a total of 106 cases were screened for PNH with an increase in the frequency of testing by 55.8% (Figure 1). 1 out of 68 cases (1.5%) screened before March 16, 2007 were positive for PNH. 6 out of 106 cases (5.6%) screened after March 16, 2007 were positive for PNH (Table 1). 74 patients were male (42.5%) and 100 were female (57.5%). Average age at screening for PNH was 53.3 years. Screening was most commonly requested by Hematology (151 cases; 86.7%) followed by Internal medicine (5 cases), Hepatology (3 cases), Neurology (1 case) and Pulmonary (1 case). We found no information available in 13 cases regarding the location of the patient or the service that requested PNH screening. The clinical indications to screen for PNH were cytopenias (110 cases; 63.2%), thrombotic events (39 cases; 22.4%), or a combination of cytopenia plus a thrombotic event (9 cases; 5.2%). No indication for PNH screening was documented in 16 cases.

Conclusion:
Our hypothesis is that an approval of a new medication can increase both, the awareness of a disease among physicians, and the frequency of ordering its diagnostic tests. The number of patients screened for PNH sharply increased after the approval of eculizumab by the FDA, confirming our hypothesis.

Disclosures:
No relevant conflicts of interest to declare.
Heme Oxygenase 1-Induced Resistance to Imatinib In Chronic Myelogenous Leukemia Cells
Authors: Tibullo Daniele , Barbagallo Ignazio , Branca Antonio , Giallongo Cesarina , La Cava Piera , Li Volti Giovanni , Palumbo Giuseppe A , Motterlini Roberto , Vanella Angelo , Di Raimondo Francesco 
Published: October 2019

Abstract
Abstract 4410
Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme degradation leading to the generation of free iron, biliverdin and carbon monoxide (CO). In this study, K562 cells were incubated for 24 h with imatinib (1 μM) alone or in combination with: 1) cobalt protoporphyrin (CoPP, 10 μM), a potent inducer of HO-1; or 2) tin mesoporphyrin (SnMP, 10 μM), an inhibitor of HO activity. CoPP was able to overcome the inhibitory effect of imatinib while SnMPP restored the cytotoxicity. Interestingly, neither bilirubin nor CO (using the CO-releasing agent CORM-3) were able to protect K562 cells from imatinib-induced toxicity. The protective effect of CoPP was mitigated by addition of a protease inhibitor (Ed64), which was able to stop HO-1 nuclear translocation. We also analyzed 96 kinase genes and found that addition of CoPP in combination with imatinib leads to at least seven kinases being significantly increased while the expression of these genes was reduced in cells treated with imatinib alone or in the presence of SnMP. All of them are able to activate mitogenic signals. We also found that 1 μM imatinib was able to increase the formation of cellular reactive oxygen species and this effect was inhibited by CoPP and restored in presence of SnMP. In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve the action of its catabolites, but rather a translocation of HO-1 to the nucleus after proteolytic cleavage. Migration to the nucleus activates several kinases able to induce mitogenic signals thus enabling HO-1 to reduce oxidative stress induced by imatinib.

Disclosures:
Di Raimondo: celgene: Honoraria.