bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the Timing and the Type of Venous Thromboembolic Events On Survival in Patients with Pancreatic Cancer
Authors: Kesari Vivek , Shethia Maithili , Zhou Xiao , Overman Michael , Vadhan-Raj Saroj 
Published: October 2019

Abstract
Abstract 1151

Background:
Patients (pts) with pancreatic cancer are at high risk for venous thromboembolic events (VTE) and the occurrence of VTE can adversely affect prognosis. However, it is unclear if the type of VTE such as symptomatic vs incidental, deep vein thrombosis (DVT) vs pulmonary embolism (PE), the location of VTE [DVT of extremities vs visceral veins (abdominal/pelvic veins)] or the timing of VTE from diagnosis can influence the survival. The purpose of this study was to evaluate the incidence of different types of VTE, the impact of types and timing of VTE (early vs late) on survival.

Methods:
Medical records of 260 pts with pancreatic cancer, newly referred to MDACC in 2006, were reviewed for cancer diagnosis, patient demographics (age, gender), presence of metastasis, the date of diagnosis of VTE, timing of VTE, type of VTE, the site of VTE, the incidence of VTE during 2 years of follow up from the date of diagnosis. Clinical and laboratory parameters predictive for survival were also reviewed. All VTE episodes, including symptomatic as well as incidental VTEs were confirmed by the radiological studies using CT ANGIO, CT scan, Doppler compression ultrasound or V/Q perfusion scans. The survival time was calculated from the date of cancer diagnosis to the date of last follow up. Survival analysis was conducted using Kaplan-Meier method and Cox proportional hazard models. The stepwise selection method was employed to build a multivariate model using variables with p<0.15 in univariate analysis.

Results:
Of the 260 pts referred, 235 were confirmed to have the diagnosis of pancreatic carcinoma. During the 2-year follow-up, 80 pts (34%) had 109 episodes of VTE, including symptomatic and incidental episodes. The median age of the pts with VTE was 59 years (range: 28–86) and 51% were males. Of the 80 pts with VTE, 21 (26%) had PE, 18 (23%) had DVT of extremities, 28 (35%) had DVT of visceral veins and 13 (16%) had concurrent PE/DVT (diagnosed on the same day). Of the 80 pts, 25 (31%) had 29 recurrent episodes. Kaplan-Meier survival analysis, as shown in the table below, indicated that the pts who had early VTE (defined as VTE diagnosed within 30 days from the date of diagnosis of pancreatic cancer) vs late VTE (> 30 days) and pts with metastasis vs no metastasis had statistically poor 1 year survival (log-rank test).

Conclusions:
These findings suggest that timing of VTE is an important indicator of prognosis, regardless of whether symptomatic or incidental. Patients with VTE within 30 days of diagnosis have shorter survival.

Disclosures:
No relevant conflicts of interest to declare.
Primary Venous Thromboembolism Prophylaxis in Patients with Solid Tumors Receiving Chemotherapy: A Meta-Analysis
Authors: Phan Minh , John Sonia , Casanegra Ana Isabel , Tafur Alfonso 
Published: October 2019

Abstract
Abstract 1157

Background:
Venous thromboembolism [VTE] is the second highest cause of mortality among patients with cancer. However, pharmacological thromboprophylaxis for patients with solid tumor is only recommended during hospitalization. Primary outpatient thromboprophylaxis is not a widely accepted practice.

Objective:
Determine safety and efficacy of outpatient primary VTE prophylaxis in patients with solid tumors.

Data sources:
A systematic review was conducted using MEDLINE and EMBASE up to June 2012. Key search words included venous thromboembolism, malignancy, anticoagulants, and chemotherapy. Studies were considered for our meta-analysis if they included outpatient primary pharmacological thromboprophylaxis in adult patients with active solid cancer. All the information was independently reviewed by 2 of the authors [MP, SJ] and a third reviewer resolved discrepancies. The measure of association was calculated with R (R: A Language and Environment for Statistical, R Development Core Team, www.R-project.org), R META package (Version 0.8–2, Author: Guido Schwarzer). The Q statistic was calculated and a formal test of homogeneity was conducted. Random-effects model was preferred in case of heterogeneity.

Results:
A total of 1371 abstracts were reviewed and 29 manuscripts were fully abstracted. Eight randomized controlled trials including 6706 patients were analyzed. There were less VTE events with outpatient prophylaxis: odds ratio [OR] of 0.53 (95% CI, 0.40–0.70). Six studies used low or ultra-low molecular weight heparin and two studies used warfarin. In the subgroup analysis of heparin based primary prophylaxis, there was a significant reduction in VTE events [OR 0.47, 95% CI, 0.34–0.64], no significant heterogeneity [FIG 1]. In addition, there was no difference in major bleeding events between groups [OR 1.48, 95% CI, 0.89–2.46]. Five studies reported mortality data; there was significant heterogeneity between studies.

Conclusions:
Heparin based outpatient VTE prophylaxis in patients with solid tumors reduced by half the risk of VTE with no significant differences in major bleeding events. The current publications do not allow a meaningful grouped analysis of survival data, improved patient selection is necessary in order to adequately target VTE prevention strategies.

Disclosures:
No relevant conflicts of interest to declare.
Critical Role for Mouse Marginal Zone B Cells in PF4/Heparin Antibody Production
Authors: Zheng Yongwei , Yu Mei , Podd Andrew , Newman Debra K. , Wen Renren , Arepally Gowthami M , Wang Demin 
Published: October 2019

Abstract
Abstract 1175
Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of platelet factor 4 (PF4), heparin and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, the B-cell origin of HIT antibody production is not known. Here we show that upon challenge with PF4/heparin complexes, anti-PF4/heparin antibody production is severely impaired in B cell-specific Notch2-deficient mice (CD19CreNotch2fl/fl) that specifically lack marginal zone (MZ) B cells, and that antibody production is readily generated in wild-type mice (CD19CreNotch2+/+). As expected, Notch2-deficient mice responded normally to challenge with T cell-dependent antigen NP-CGG but not T cell-independent antigen TNP-Ficoll, in agreement with the lack of MZ B cells in the mutant mice. PF4/heparin-specific antibodies produced by wild-type mice on a C57BL/6 background were IgG2b and IgG3 isotypes. An in vitro class-switching assay showed that MZ B cells from wild-type C57BL/6 mice were capable of producing antibodies of IgG2b and IgG3 isotypes. Lastly, MZ, but not follicular (FO), B cells adoptively transferred into B cell-deficient muMT mice responded to PF4/heparin complex challenge by producing PF4/heparin-specific antibodies of IgG2b and IgG3 isotypes. Taken together, these data demonstrate that MZ B cells play a critical role in production of PF4/heparin-specific antibodies.

Disclosures:
Arepally: Teva Pharmaceuticals: Research Funding.
Generation of Human Hematopoietic Stem/Progenitor Cells From Pluripotent Stem Cells Through Modulating Retinoic Acid Signaling
Authors: Rönn Roger Emanuel , Guibentif Carolina , Moraghebi Roksana , Woods Niels-Bjarne 
Published: October 2019

Abstract
Abstract 1203
Hematopoietic stem and progenitor cells generated from patient derived induced pluripotent stem (iPS) cells could provide an unlimited supply of HLA matched transplantable cells for the treatment of both hematological disorders and malignancies. The goal of this project is to identify novel pathways involved in hematopoietic stem and progenitor cell generation and expansion from human ES and iPS cells. By using small molecules to modulate retinoid signaling, we report enhanced in vitro generation of hematopoietic progenitors cells (CD45/43+CD34+) and cells with an adult hematopoietic stem cell phenotype (CD45/43+CD34+CD38-CD90+CD45RA-). By inhibiting the cellular synthesis of retinoic acid (RA) and subsequent retinoid signaling we significantly increased the output of cells generated possessing an adult HSC surface phenotype by 2.7-fold (p-value: 0,024, n=7) compared to DMSO carrier controls, and increased clonogenic progenitors (CFUs) by 2.5-fold (p-value: 0,065, n=7). This improvement is consistent when using both a human ES line (Hues3) and a human iPS-line (RB9-CB1 generated from cord-blood derived endothelial cells). We also increased total blood cell output by increasing the frequency of embryoid bodies (EB) that successfully give rise to blood generating colonies. Conversely, and in support of our findings, directly adding RA was found to severely decrease the blood generation efficiency of our protocol. When comparing the colony forming potential of sorted cells gated on umbilical cord blood (CB), our system enabled the generation of CFU's at efficiencies on par with that of CB (preliminary data). Following plating equal numbers of sorted CD45/43+CD34+ blood progenitors, we saw 79 CFU/500 cells for the CB control, 65 CFU/500 cells from iPS + retinoic acid signaling inhibition, and 23 CFU/500 cells from iPS + DMSO control. The hematopoietic cells generated with our ES/iPS-2-Blood system also possess lymphoid lineage potential following plating of CD45/43+CD34+ cells into an in vitro based lymphoid assay, generating cells expressing markers of T-cells, B-cells, and NK-cells. We are currently performing transplantation experiments to assess the repopulating potential of these cells. We are also investigating additional factors that also have demonstrated significant increases in hematopoietic stem/progenitor cell output, with one additional modulator of RA signaling showing additive improvement together with the first molecule. We are further investigating the molecular mechanisms of these different factors for hematopoietic stem and progenitor cell generation with the aim to advance iPS cell technology towards treatments for hematological diseases and malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Profilin 1 Is Essential for Retention and Metabolism of Hematopoietic Stem Cells in Bone Marrow
Authors: Zheng Junke , Zhang Chengcheng 
Published: October 2019

Abstract
Abstract 1224
How stem cells interact with the microenvironment to regulate their cell fates and metabolism is largely unknown. Here we show that, in a hematopoietic stem cell (HSC) -specific inducible knockout model, the cytoskeleton-modulating protein profilin 1 (pfn1) is essential for the maintenance of multiple cell fates and metabolism of HSCs. The deletion of pfn1 in HSCs led to bone marrow failure, loss of quiescence, increased apoptosis, and mobilization of HSCs in vivo. In reconstitution analyses, pfn1-deficient cells were selectively lost from mixed bone marrow chimeras. By contrast, pfn1 deletion did not significantly affect differentiation or homing of HSCs. When compared to wild-type cells, levels of expression of Hif-1a, EGR1, and MLL were lower and an earlier switch from glycolysis to mitochondrial respiration with increased ROS level was observed in pfn1-deficient HSCs. This switch preceded the detectable alteration of other cell fates. Importantly, treatment of pfn1-deficient mice with the antioxidant N-acetyl-l-cysteine reversed the ROS level and loss of quiescence of HSCs, suggesting that pfn1 maintained metabolism is required for the quiescence of HSCs. Furthermore, we demonstrated that expression of wild-type pfn1 but not the actin-binding deficient or poly-proline binding-deficient mutants of pfn1 rescued the defective phenotype of pfn1-deficient HSCs. This result indicates that actin-binding and proline-binding activities of pfn1 are required for its function in HSCs. Thus, pfn1 plays an essential role in regulating the retention and metabolism of HSCs in the bone marrow microenvironment.

Disclosures:
No relevant conflicts of interest to declare.
Wnt Signaling Is Associated with Anti-Apoptosis in the Interaction Between Acute Myeloid Leukemia Cells and Stromal Cells
Authors: Minami Yosuke , Niwa Yosuke , Abe Akihiro , Hayakawa Fumihiko , Naoe Tomoki 
Published: October 2019

Abstract
Abstract 1366
Recent studies have revealed that strength of the Wnt signaling pathway regulates normal hematopoiesis including hematopoietic stem cells, and aberrant activation of the pathway is involved in the development of several types of leukemias. In the bone marrow microenvironment, stromal cells are rich sources of cytokines and some secreted cytokines have been observed to block induction of cell death in myeloid leukemia cells exposed to chemotherapy. Here, we examined the role of the Wnt signaling pathway on cell-adhesion, proliferation and survival of the stroma-dependent human AML cell line, TRL-01 cells, which we previously established (Ninomiya, et al. Cancer Gen Cyto, 2006). TRL-01 cells were maintained in the co-culturing with the hTERT-transduced human bone marrow stroma cell line, HTS cells, and cell death of TRL-01 cells was induced after removal of HTS cells. Treatment with the Wnt-receptor competitor, secreted Frizzled related protein (sFRP)-1, or the Rho kinase inhibitor, Y29632 (previously reported as an inhibitor of the non-canonical Wnt downstream pathway), but not with the specific inhibitor of the canonical Wnt pathway (DKK-1) induced apoptosis in dose-dependent manners in TRL-01 cells co-cultured with HTS cells. These results suggested that the non-canonical pathway of Wnt signaling might regulate survival of TRL-01 on the stromal cells. Next, we comprehensively investigated transcripts of the Wnt pathway components (10 Frizzleds, 2 LRPs, and 18 Wnts) in TRL-01 cells and HTS cells using RT-PCR. Transcripts of Wnt5A and Wnt9A were expressed in TRL-01 cells, but not in HTS cells. Moreover, the cell death of TRL-01 cells after removal of HTS cells was partially prevented by additional treatment with Wnt5A or Wnt9A not by other Wnt molecules such as Wnt5B. On the other hand, treatment with Wnt3A induced activated nuclear beta-catenin using Western-blotting, however, did not contribute to the survival of TRL-01 cells without the stromal co-culturing. Moreover, we are investigating regulation of the anti-apoptotic downstream pathway molecules in TRL-01 cells as well as effects of other inhibitors targeted for the Wnt signaling. We are also examining expressions of Wnt pathway components in primary AML bone marrow cells and other human bone marrow stroma cell lines such as HS-5 cells. These results imply association of Wnt5A and Wnt9A with anti-apoptosis in the interaction between AML cells and stromal cells, and a possible therapeutic target of AML for overcoming the resistance to chemotherapy in the bone marrow microenvironment.

Disclosures:
Naoe: Chugai Pharma: Research Funding; Novartis Pharma: Research Funding; Kyowa-Hakko Kirin: Research Funding.
Acquisition or Loss of Gene Mutations Occurs in Relapsed Pediatric Acute Myeloid Leukemia: A Comparative Analysis of Paired Matched Diagnosis and Relapse Bone Marrow Samples
Authors: Liang Der-Cherng , Lui Hsi-Che , Yang Chao-Ping , Jaing Tang-Her , Hung Iou-Jih , Yeh Ting-Chi , Shih Yu-Shu , Huang Yu-Hui , Lin Tung-Huei , Shih Lee-Yung 
Published: October 2019

Abstract
Abstract 1389

Background and purpose:
Relapse is the major cause of treatment failure in patients with acute myeloid leukemia (AML). The molecular pathogenesis in the relapse of AML is not well understood. A better understanding of molecular aberrations of relapsed AML will further improve the treatment outcome. In the present study, we aimed to determine the role of gene mutations in the relapse of de novo pediatric AML by comparative analysis of the paired matched diagnosis and relapse samples for the mutational status of 18 known mutated genes involved in myeloid neoplasms.

Patients and Methods:
Two hundred and six children aged below 18 with de novo AML were diagnosed at Chang Gung Children's Hospital, Taoyuan, Taiwan and MacKay Memorial Hospital, Taipei, Taiwan, between 1996 and 2011. They were treated with Taiwan Pediatric Oncology Group AML-97 Protocol (Leukemia 2006). Sixty patients had relapses of leukemia, 46 of them had paired diagnosis and relapse bone marrow samples available for examination on the 18 mutated genes, including FLT3-ITD, FLT3-TKD, C-KIT, C-FMS, NRAS, KRAS, PTPN11, JAK2V617F, RUNX1, CEBPα, NPM1, MLL-PTD, WT1, P53, DNMT3A, IDH1, IDH2 and ASXL1. Mutational analysis was performed with PCR-based assay followed by direct sequencing.

Results:
The results are summarized in Table 1. Fifteen patients with one mutated gene and 4 with two mutated genes at diagnosis remained unchanged at relapse, all the mutations detected were not present in the complete remission samples. Twenty-five patients without gene mutations at diagnosis did not acquire mutations at relapse. Six patients acquired gene mutations, 5 WT1 and one P53 mutations, indicating clonal evolution during leukemia relapse. Another 7 patients lost gene mutations including 2 FLT3-ITD, 2 FLT3-TKD, one NRAS, one JAK2V617F and one IDH1genes; notably, 4 of them harboring other mutated genes at relapse, suggesting outgrowth or clonal selection of these mutated clone(s) in relapse.

Conclusion:
Our study showed that gene mutation status in the majority of pediatric AML patients remained unchanged at both diagnosis and relapse, but acquisition or loss of gene mutations may occur at relapse.

Disclosures:
No relevant conflicts of interest to declare.
Constitutional Telomerase-Associated Gene Variants in Pediatric Acute Myeloid Leukemia (AML)
Authors: Gramatges M. Monica , Sasa Ghadir S. , Qi Xiaodong , Chen Julian J-L , Plon Sharon E , Bertuch Alison A. 
Published: October 2019

Abstract
Abstract 1408

Background:
Telomerase is an enzyme complex that maintains telomeric DNA, the TTAGGG repeats localized to chromosome ends. Defects in telomerase result in abnormally short telomeres in somatic cells, leading to early cell senescence, chemosensitivity, and susceptibility to genomic instability. Germline telomerase mutations are associated with a spectrum of disorders including idiopathic pulmonary fibrosis, familial liver disease, aplastic anemia, myelodysplastic syndrome (MDS), and dyskeratosis congenita, which confers a 90% lifetime risk for bone marrow failure, a 200-fold risk for AML, and a 2500-fold risk for MDS. These disorders have a variable clinical phenotype, but pronounced telomere shortening is a universal finding. Of note, enrichment of specific telomerase variants is observed in adults with hematologic malignancies. Our goal is to investigate the role of germline telomerase variants in pediatric AML development and treatment-related toxicities. We hypothesize that deleterious germline telomerase variants occur in children with AML and are associated with a telomere biology disorder phenotype. Exposure to chemotherapy and/or transplant may accelerate telomere shortening and manifestation of disease phenotype in affected individuals.

Methods:
This exploratory analysis will determine (1) the frequency of germline telomerase variants in our local pediatric AML population (2) the implication of these variants on telomerase function, and (3) whether variants are associated with a telomere biology disorder phenotype. We are sequencing the exons and flanking intronic regions of four telomerase-related genes, TERT, DKC1, TERC, and TINF2, in germline pediatric AML samples (n=100), and functionally characterizing all novel variants. We are reviewing all cases blinded to telomerase variant status for clinical evidence characteristic of a telomere biology disorder.

Results:
To date, out of the first 88 subjects sequenced, 12 constitutional heterozygous variants resulting in missense changes or deletions were found in 19 subjects (21.6%). Of the variants found, 7 are novel, and several represent rare variants observed in adult populations with hematologic malignancies. Among the 62 subjects that have undergone blinded chart review, clinical characteristics of telomere biology disorders were noted in subjects both with and without variants. In subjects with variants, the most predictive characteristics were (1) nail dysplasia, skin hyperpigmentation, and oral leukoplakia, (2) persistent liver or pulmonary disease of unknown etiology, and (3) delays in chemotherapy of more than 2 months due to cytopenias.

Conclusion:
Presence of deleterious telomerase variants may be susceptibility loci in pediatric AML. Our results suggest that further investigation of the disease phenotypes associated with these variants is warranted.

Disclosures:
No relevant conflicts of interest to declare.
Gene Expression Profiling (GEP) of Whole Bone Marrow Biopsies in Complete Remission (BMB-CR) of Multiple Myeloma (MM) Patients Treated On Total Therapy Protocols – Normalization of GEP Signature in Comparison with Normal Donor BMB (BMB-NL) and Consequences for Progression-Free Survival (PFS)
Authors: Heuck Christoph , Qu Pingping , Waheed Sarah , Usmani Saad Z , van Rhee Frits , Dhodapkar Madhav V. , Epstein Joshua , Zhang Qing , Johann Donald , Barlogie Bart 
Published: October 2019

Abstract
Abstract 198
GEP of purified plasma cells (PC) provides superb risk discrimination for PFS and overall survival (OS). It is well established that MM engages the BM micro-environment (ME) and subjugates it toward its survival and progression. International Myeloma Working Group- and flow-based CR have been linked to PFS and OS, but do not provide guidance vis-à-vis the duration of post-transplant consolidation and maintenance therapy. We reasoned that ME may still be altered in flow-CR as it may remain MM-impregnated long after CR is established; conversely, ME normalization may happen much earlier. In a first step, 20 BMB-NL were compared with 331 untreated patients with MM (BMB-MM), leading to the discovery of a 65 gene score (GEP-65), which was then applied to 83 patients with MGUS/asymptomatic multiple myeloma (AMM) and 88 MM patients in CR. GEP-65 risk scores were similar in BMB-CR and BMB-MGUS-AMM contrasting with significantly lower values for BMB-MM. Next we examined PFS for CR patients according to whether BMB-CR signature normalized (BMB-CR-NL, n=14) or failed to normalize (BMB-CR-MM, n=74). A borderline significantly superior PFS was observed in the former group suffering 2 events versus 31 in the remainder (p=0.08). We conclude that (1) BMB-MM differs markedly from BMB-NL, (2) BMB-CR resembles BMB-MGUS-AMM, and (3) BMB-CR-NL can be distinguished from BMB-CR-MM resulting in PFS differences. Availability of several hundred BMB-CR samples and nearly 100 BMB-NL will have been evaluated at the time of the meeting to address the following: (a) can these results be validated, (b) what is the time course of BMB-CR-NL and pattern to BMB-CR-MM and BMB-MM, (c) are there MM GEP molecular subgroup- and risk-dependent differences.

Disclosures:
Dhodapkar: Celgene: Research Funding; KHK: Research Funding.