bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monosomal Karyotype In Primary Myelofibrosis Is Prognostically Worse Than Otherwise Unfavorable Karyotype
Authors: Vaidya Rakhee , Caramazza Domenica , Begna Kebede , Gangat Naseema , Van Dyke Daniel L. , Hanson Curtis A. , Pardanani Animesh , Tefferi Ayalew 
Published: October 2019

Abstract
Abstract 3069

Background:
Monosomal karyotype (MK) is defined as the presence of two or more distinct autosomal chromosome monosomies or a single autosomal monosomy associated with at least one structural abnormality (Breems DA et al. J Clin Oncol 2008; 26: 4791). In acute myeloid leukemia (AML), MK has been shown to be prognostically worse than complex or other unfavorable karyotype (Breems DA et al. J Clin Oncol 2008; 26: 4791). In primary myelofibrosis (PMF), complex karyotype or isolated trisomy 8 predicts inferior survival (Hussein K et al. Blood 2010; 115: 496).

Objective:
To determine if MK in PMF is prognostically distinct from previously defined poor cytogenetic risk categories including complex karyotype and isolated trisomy 8.

Methods:
The Mayo Clinic database for PMF was used to identify consecutive patients with unfavorable karyotype including complex karyotype and sole trisomy 8. WHO criteria were used for PMF diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937).

Results:
Among 793 PMF patients with cytogenetic information at the time of their first time referral to the Mayo Clinic, 452 displayed a normal karyotype and 341 (43%) an abnormal karyotype. Of the latter, 41 (12%) displayed complex karyotype and 21 (6%) sole trisomy 8. Among the 41 patients with complex karyotype, 17 (42%) met the criteria for MK and 24 (58%) displayed complex karyotype without monosomies.
Overall survival was significantly inferior in patients with MK compared to those with either complex karyotype without monosomies (p=0.02; HR 2.3, 95% CI 1.1–4.8) or trisomy 8 (p=0.02; HR 2.4, 95% CI 1.2–5.1) (Fig. 1). Prognosis among all three groups was significantly worse than patients with normal karyotype (Fig. 1).
Leukemia-free survival was also significantly inferior in patients with MK compared to those with either complex karyotype without monosomies (p=0.02; HR 6.9, 95% CI 1.3–37.3) or trisomy 8 (p=0.02; HR 14.8, 95% CI 1.7–130.8) (Fig. 2). LFS in patients with normal karyotype was similar to those with either complex karyotype without monosomies (p=0.31) or trisomy 8 (p=0.86) (Figure 2).

Conclusions:
Monosomal karyotype in PMF is distinctly associated with extremely poor overall and leukemia-free survivals that are significantly worse than those seen in PMF patients with other unfavorable karyotype including complex karyotype without monosomies and sole trisomy 8 abnormalities.

Disclosures:
No relevant conflicts of interest to declare.
Down-Regulation of Signal Transducer and Activator of Transcription 3 Enhances Acute Myeloid Leukemia-Derived Dendritic Cell Function
Authors: Brady Michael T , Miller Austin , Sait Sheila , Ford Laurie A , Hans Minderman , Wang Eunice S. , Lee Kelvin P , Baumann Heinz , Wetzler Meir 
Published: October 2019

Abstract
Abstract 3140
Immunotherapies, including stimulating patients' immune system with acute myeloid leukemia (AML)-derived dendritic cell (DC) vaccines, are being sought for the treatment of AML. However, these vaccines have proven to be less successful than anticipated. We have previously shown that STAT3 is constitutively activated in the blasts of approximately half of AML patients and to correlate with poor prognosis. STAT3 regulates a variety of cellular events and has been shown to play a role in immunosuppression by inhibiting DC differentiation, resulting in induction of T cell tolerance rather than T cell activation. We hypothesize that AML-DC with constitutively activated STAT3 are impaired to fully differentiate and to efficiently stimulate T cells. The current study investigated the correlation between STAT3 activity, DC maturation and the ability to stimulate allogeneic T cells in primary AML-derived DCs. AML blasts differentiated to DCs regardless of the level of activated STAT3, however AML-DC with high levels of activated STAT3 elicited less T cell response than AML-DC with low levels of activated STAT3. Knock-down of STAT3 protein with inhibitory shRNAmirs in 4/4 patient AML-DCs increased stimulation of allogeneic T cells compared to control DCs without affecting the immunophenotype or endocytotic activity. Treatment of AML-DC with the STAT3 inhibitors AG490, arsenic trioxide (ATO), JSI-124 and NSC-74859 during early differentiation did not significantly enhance T cell stimulation. Treatment with ATO, but not the remaining inhibitors, during the last 24 hours of maturation led to more mature phenotype and enhanced T cell stimulation in 2/2 AML cell lines and 8/9 patient samples (p=0.0001) while having minimal effect on normal cord blood-derived DC. ATO-treated AML-DCs had an increased expression of the co-stimulatory markers CD80 and CD86, the mature DC marker CD83 and increased HLA-DR expression indicating more mature DCs. Four of six ATO-treated AML-DCs secreted higher amounts of the T cell stimulating cytokine interleukin (IL)-12p40 (average increase 2.5 fold); exogenous administration of IL-12 recapitulated ATO's effect. These data demonstrate that AML-DCs have improved immunogenicity after reducing STAT3 protein levels during differentiation. The observation that treatment with ATO is superior to the more targeted JAK/STAT inhibitors suggests that DC maturation is regulated by other pathways in addition to STAT3. We propose to use ATO-treated AML-DC vaccines in future clinical trials. ATO treatment would not only lead to more immunogenic vaccines, but would also increase the number of mature AML-DCs that could be differentiated from each patient, solving two of the major obstacles for the use of AML-DC vaccines.

Disclosures:
No relevant conflicts of interest to declare.
Dominant Negative Effect of Palmitoylation-Deficient NRAS In Suppression of BCR/ABL Leukemogenesis
Authors: Cuiffo Benjamin , Ren Ruibao 
Published: October 2019

Abstract
Abstract 3157
RAS mutations are found in ∼30% of all human cancers, with NRAS being the RAS isoform found most frequently mutated in hematological malignancies including acute myelogenous leukemia (AML) and chronic myelomonocytic leukemia (CMML). We have previously shown that expression of oncogenic NRAS efficiently induces a CMML- or AML-like disease in mice. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct cellular membrane microdomains. We have previously found that palmitoylation, in addition to prenylation, is an essential process for NRAS leukemogenesis. The results suggest that targeting RAS palmitoylation may be an effective therapy for hematological malignancies as well as other NRAS related cancers.
In addition to the direct activation by mutations, RAS can also be functionally activated by other oncogenic mutations, including activated protein tyrosine kinases such as BCR/ABL. While significant advances have been made in the treatment of chronic myelogenous leukemia (CML) by targeting the kinase activity of BCR/ABL, these treatments do not constitute a cure, as BCR/ABL-positive cells persist and eventually develop mutations that cause resistance to the kinase inhibitors. In addition, although advances have also been achieved in the treatment of BCR/ABL+ B-acute lymphoblastic lymphoma (B-ALL) through the use of combination chemotherapy along with the ABL kinase inhibitor imatinib, BCR/ABL+ B-ALL continues to pose a huge challenge; they are highly refractory to imatinib, and are still the least treatable subtype of ALL. The identification of molecular targets that impede the progression of BCR/ABL+ leukemias not relying on targeting the kinase activity of BCR/ABL is likely beneficial. Previous studies have shown that RAS is a critical downstream transducer of the oncogenic signaling by BCR/ABL. We have shown that palmitoylation-deficient oncogenic NRAS is mislocalized away from the plasma membrane yet still capable of binding GTP in cells. This finding suggests that palmitoylation-deficient, activated RAS may have a dominant negative effect in RAS signaling. As a proof-of-concept study for treating cancers driven by RAS regulators through blocking RAS palmitoylation, we evaluated the effect of blocking RAS palmitoylation in BCR/ABL leukemogenesis. We found that expression of palmitoylation-deficient oncogenic NRAS or palmitoylation-deficient wild type NRAS significantly impeded progression of BCR/ABL induced B-ALL- and CML-like diseases in mice. The palmitoylation-deficient NRAS suppresses the activation of downstream effectors of RAS, possibly by sequestrating RAS effectors away from the plasma membrane. The results suggest that targeting RAS palmitoylation may also constitute an effective therapy in cancers driven by oncogenes upstream of RAS.

Disclosures:
No relevant conflicts of interest to declare.
Prevalence of Thrombophilia In Patients with Sickle Cell Disease and Osteonecrosis
Authors: Al-Khabori Murtadha K. , Pathare Anil , Al Farsi Khalil , Al Huneini Mohammed , Alkindi Salam 
Published: October 2019

Abstract
Abstract 3184

Background:
Osteonecrosis (ON) of the femoral and humeral heads is frequently seen in patients with sickle cell disease (SCD). Earlier studies reported a high prevalence of thrombophilia in patients with ON.

Aims:
To study the prevalence of thrombophilia in patients of SCD with ON.

Methods:
Case records of SCD patients with ON were retrospectively reviewed for protein S, protein C, and anti-thrombin deficiency, along with activated protein C resistance (APCR).

Results:
A total of sixty-three patients were identified, 35 of whom were males, with a median age of 21 years (range 15to 46). Median haemoglobin, total white cell count and platelet counts were 10 g/dL (range 7.7to 13.3), 7.5 ×109/L (range 3.4 to 16.7) and 302 ×109/L (range 72 to 1101) respectively. Twenty-eight patients were on hydroxyurea. Thrombophilia testing showed that 29% (95% confidence interval: 17–40), 47% (95% CI: 29–64) and 79% (95% CI: 65–93) of the patients had low levels of functional (<60 unit/dl), total antigenic (<70 unit/dl) and free antigenic (<70 unit/dl) protein S respectively, while 21% (95% CI: 10–31) and 67% (95% CI: 46–87) had low levels of functional (<70 unit/dl) and antigenic (<70 unit/dl) protein C respectively. In addition, 14% (95% CI: 5–23) and 22% (95% CI: 0–56) of the patients had low levels of functional (<80 unit/dl) and antigenic (<80 unit/dl) anti-thrombin levels respectively. Only 2% (95% CI: 0–5) of these patients had an abnormally low APCR (APCR ratio ≤2.3).

Summary/Conclusions:
Patients with SCD and ON have a high prevalence of thrombophilia. These results indicate that a prospective study with more detailed thrombophilia work-up, along with confirmatory DNA analysis, as well as a study of the role of prophylactic anticoagulation in such patients is highly warranted.

Disclosures:
Pathare: Sultan Qaboos University: Employment, Research Funding. Alkindi:Sultan Qaboos University: Employment, Research Funding.
Detection of Lupus Anticoagulant In Women with Obstetric complications
Authors: Avigliano Andrea Laura , Galli Juan Carlos , Grand Beatriz 
Published: October 2019

Abstract
Abstract 3185

Introduction:
Lupus anticoagulant (LA) is one of the laboratory criteria for the diagnosis of antiphospholipid syndrome. To detect the presence of LA, ISTH recommends performing two assays based on different principles. Our LA profile includes dilute Russell viper venom time (dRVVT) and two different activated partial thromboplastin time (aPTT) reagents.
The aim of the study was to evaluate sensitivity and specificity of aPTT and dRVVT in women with a history of pre-eclampsia, intra-uterine growth restriction, early recurrent abortion, late fetal loss and placental abruption collectively termed “placenta mediated complications”.

Materials and Methods:
We studied a total of 247 patients and 287 samples in a 10 months period. Based on consensus criteria, samples were retested within a period of three months. 62/247 plasmas samples were collected during pregnancy.
Laboratory studies: Screening tests: aPTT was performed using PTT-LA (Stago) and an aPTT home made reagent with diluted cephalin. dRVVT was performed using Russel viper venom RVV (Stago) and diluted cephalin. Negative control plasma was prepared according to ISTH LA recommendations for the mixing tests. Confirmatory tests: We performed a home made reagent for platelet neutralization procedure (PNP)-aPTT and dRVVT; Rosner Index and % of Correction as criteria for mixing and confirmatory tests interpretation.
Statistical evaluation was performed by ROC method using EP Evaluator 9.9 software.

Results:
172/287 samples (59.9%) were negative, while 115/287 samples (40.1%) were positive for LA. 44/115 samples (38.26%) were positive for both tests (aPTT and dRVVT), 60/115 samples (52.17 %) were positive only for dRVVT and 11/115 samples (9.57%) were positive only for aPTT.
LA was confirmed in 9/62 pregnant women samples (14.5 %). 7 (11.3%) had abnormal dRVVT, the remaining 2 samples were positive for both tests.

Conclusions:
Our results demonstrated: 1- High prevalence of dRVVT positive plasmas 104/115 (90.43%); 2- Despite showing a low performance regarding sensitivity when compared to dRVVT, both aPTT tests were able to detect LA in 47.83% of the positive studies. 3- According to our experience, considering this initial cohort of selected patients, the use of dRVVT as the first and aPTT as the second screening test may help improve the performance for the diagnosis of LA.

Disclosures:
No relevant conflicts of interest to declare.
The Attitude of Canadian University Students towards a Behaviour-Based Blood Donor Health Assessment Questionnaire
Authors: Go Stephanie Lynn , Lam Cindy Tze-Yung , Lin Yahui Tammy , Wong Deborah Joanne , Lazo-Langner Alejandro , Chin-Yee Ian H. 
Published: October 2019

Abstract
Abstract 3342

Background:
As part of Canadian Blood Services policy (CBS), men who have sex with men (MSM) are indefinitely deferred from donating blood due to an increased risk for HIV infection. This policy has generated controversy, especially amongst student populations, due its perceived discrimination against homosexual men.

Objectives:
1) To determine the acceptability of a behaviour-based donor health questionnaire amongst Canadian university students and assess its suitability as an alternative to the current MSM policy. 2) To determine the perception of blood safety associated with specific risk behaviours.

Methods:
We conducted a survey amongst students at the University of Western Ontario in London, Ontario, Canada. A questionnaire was designed that included questions found on the current CBS donor health survey, and behaviour-based questions derived from studies assessing high risk factors for HIV. For each question, participants were asked to rate its acceptability and its perceived effect on blood safety using 7-point Likert scales. They were also asked whether the question would deter them from future donations. Data was analyzed using non-parametric tests.

Results:
741/3500 (21.2%) students participated in the study. Students rated both current and behavioural questions as equally acceptable and the majority (89-97%) would not be deterred from donating blood in the future by any question. The response scores for both sets of questions were significantly correlated. Questions on donor's sexual practices were rated less acceptable compared to those on high risk behaviours. Sexually transmitted infections, injection drug use and sex for money were considered high risk behaviours for blood safety (69-95% unsafe). In contrast, sexual practices (MSM, anal intercourse, condom use, knowledge of partner's sexual background) were rated less important for blood safety (30 to 62% unsafe). We found an inverse correlation between the perception of safety and the acceptability of questions (Table). 24.4% of students rated both questions on MSM status and a behaviour-based alternative as equally unacceptable.

Discussion:
A behaviour-based screening modification is unlikely to change opinions or satisfy those who object the current MSM policy. Acceptability of these questions might be related to a poor understanding of the effect of sexual practices on blood supply safety.

Disclosures:
No relevant conflicts of interest to declare.
Caphosol Mouth Rinse Diminishes Oral Mucositis In Allo-HSCT Recipients.
Authors: Markiewicz Miroslaw , Monika Dzierzak Mietla , Zielinska Patrycja , Kruzel Tomasz , Czerw Tomasz , Kyrcz-Krzemien Slawomira 
Published: October 2019

Abstract
Abstract 3498

Introduction:
Oral mucositis is a complication of conditioning treatment that produces pain and morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. The rationale of this study was to evaluate the efficacy of a calcium phosphate mouth rinse (Caphosol) vs standard regimen in 40 adult patients undergoing allo-HSCT.

Patients and Methods:
40 patients treated with allo-HSCT (31 from unrelated donors, 9 from siblings) performed in Hematology and BMT center in Katowice in 2009 were randomized and stratified by the conditioning regimen (busulfan-, treosulfan- or TBI- based), type of transplant (unrelated or related) and age into two equal groups. Treatment group received Caphosol washes 4 times daily from first day of conditioning until reaching ANC 0.2 G/l. Control group received standard topical mouth care with salvia, antibacterial and antifungal solutions. During the trial patients subjectively assessed level of pain in mouth and in pharynx using 0–10 scale and swallowing problems using 0–5 scale. Mucositis was judged by experienced physician. Nonparametric Mann-Whitney U-tests were used for statistical analysis.

Results:
Average oral toxicity in WHO scale in Caphosol vs control group was 0.9 vs 1.8 (p=0.02), duration of mucositis was 3.2 vs 7.1 days (p=0.02). Total parenteral nutrition (TPN) due to mucosits was required in Caphosol vs control group in 0 vs 6 pts, average duration of TPN was 0 vs 1.9 days (p=0.009). Analgetics were required, respectively, in 3 vs 9 pts and analgesy lasted for 1.1 vs 3.4 days (p=0.047). Average subjective peak pain in mouth was 0.85 vs 1.75 (p=0.005) and in pharynx 1.95 vs 2.2 (NS) in Caphosol vs control group, average pain intensity was lower in Caphosol group throughout the whole period of mucositis. Intensity of swallowing problems tended to be lower in Caphosol group (NS). Acute GVHD was observed in 7 vs 9 pts in Caphosol vs control group and its average degree was 0.5 vs 0.9 (NS).

Conclusions:
Caphosol mouth rinse in the allo-HSCT recipients is associated with decrease of oral toxicity, lower peak pain due to mucositis and its shorter duration. In consequence, comfort of life is improved and the incidence of acute GVHD is reduced, as well as the requirement of TPN and analgetics.

Disclosures:
No relevant conflicts of interest to declare.
The Impact of Center Experience on Results of Reduced Intensity – Allogeneic Hematopoietic Stem Cell Transplantation. A Survey From the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Giebel Sebastian , Labopin Myriam , Mohty Mohamad , Blaise Didier , Craddock Charles , Nagler Arnon , Frassoni Francesco , Sadus-Wojciechowska Maria , Rocha Vanderson 
Published: October 2019

Abstract
Abstract 3517
Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC-HSCT) is increasingly applied for the treatment of patients with acute myeloid leukemia. However, the procedure is heterogeneous with no standards based on randomized trials being elaborated so far. Hence, particular therapeutic decisions are in major part based on individual experience.
The goal of this study was to evaluate the impact of center experience on outcome of RIC-HSCT. Based on the registry of ALWP of the EBMT, we analyzed results of 1413 HLA-matched related (n=1058) or unrelated (n=355) transplantations performed in 203 European centers between 2001 and 2007. Only patients with AML in first complete remission were included. Median recipient age was 55 years (range, 18–77 y.). Centers were categorized by quintiles according to the number of RIC-HSCT procedures in a study period.
The 2 years probability of leukemia-free survival (LFS) after RIC-HSCT performed in centers with the lowest activity (1st quintile, ≤ 15 procedures/7 years) equaled 43% compared to 55% in the remaining ones (p<0.001). The incidence of non-relapse mortality (NRM) was 24% and 15%, respectively (p=0.004). In a multivariate model adjusted for other potential prognostic factors low RIC-HSCT activity was associated with decreased chance of LFS (HR=0.69, p<0.001) as well as increased risk of NRM (HR=1.69, p=0.001) and relapse (HR=1.37, p=0.01). No significant differences were found between centers belonging to the 2nd -5th quintile.
We conclude that center experience is a strong predictor of outcome and should be considered for future analyses evaluating results of RIC-HSCT.

Disclosures:
Off Label Use: Dasatinib as first line therapy in Ph ALL.
Critical Functions for Notch Dimerization In T Cell Transformation.
Authors: Liu Hudan , Chi Anthony , Arnett Kelly , Chiang Mark , Xu Lanwei , Shestova Olga , Wang Hongfang , Bhandoola Avinash , Aster Jon C , Blacklow Stephen C. , Pear Warren S. 
Published: October 2019

Abstract
Abstract 3647
Notch1 encodes an essential transmembrane receptor that is frequently mutated in T-ALL. Notch signaling regulates cell fate decisions, proliferation, survival and metabolism by activating transcription; yet the mechanism by which Notch selectively activates different transcriptional targets is poorly understood. After ligand-induced proteolysis, the intracellular part of Notch (ICN) generates signals by entering the nucleus and forming a transcriptional activation complex with the transcription factor CSL and the co-activator Mastermind (MAML). This complex can bind DNA as a monomer [1-3], however it can also dimerize on sites in which a pair of head-to-head CSL binding sites is properly spaced (so-called paired sites) [4, 5]. Whether Notch dimerization is physiologically important is unknown. Using T cell development and transformation as models, we now report that dimeric Notch transcriptional complexes are required for leukemic transformation but dispensable for T cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization within the T cell lineage result from the differential sensitivity of specific Notch target genes. One particularly important dimerization-dependent target of Notch, required for both T cell maturation and leukemogenesis, is the proto-oncogene c-Myc, whereas other well-characterized target genes, such as Hey1, show no dimerization-dependence. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Our data suggest that it may be possible to develop a new class of Notch inhibitors, which selectively block outcomes that are dependent on Notch dimerization (e.g., leukemogenesis).
References:
1. Nam, Y., et al., J Biol Chem, 2003. 278: 21232.
2. Nam, Y., et al., Cell, 2006. 124: 973.
3. Wilson, J.J. and R.A. Kovall, Cell, 2006. 124: 985.
4. Bailey, A.M. and J.W. Posakony, Genes Dev, 1995. 9: 2609.
5. Nam, Y., et al., Proc Natl Acad of Sci USA, 2007. 104: 2103.

Disclosures:
No relevant conflicts of interest to declare.