bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Characterization of Human Multiple Myeloma Cell Lines by Genome-Wide Profiling.
Authors: Elosua Carolina , Catalina Purificacion , Palma Cristina , Walker Brian A , Dickens Nicholas J , Gonzalez David , Davies Faith E , Morgan Gareth J , Leone Paola E. 
Published: October 2019

Abstract
Abstract 1793
Poster Board I-819
Multiple Myeloma (MM) is a malignancy depicted by clonal expansion of plasma cells in the bone marrow. There are two broad genetic subtypes of multiple myeloma as defined as hyperdiploid multiple myeloma (H-MM), characterized by trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and nonhyperdiploid multiple myeloma (NH-MM) associated with primary translocations involving the immunoglobulin heavy chain (IgH). These two subtypes of multiple myeloma have two different molecular pathogenesis and characteristic changes of each have been already observed. In our study, we previously described the patterns of genetic lesions and molecular pathogenesis of 12 HMCLs with Affymetrix 500K Single Nucleotide Polymorphism-based mapping arrays, now we re-depict those patterns using the Illumina 1M array set and compare the two studies. These techniques allow the examination and identification of copy number changes, bi-allelic deletions and the identification of loss of heterozygosity (LOH) due to loss and uniparental disomy (UPD), as well as gene localization and identification. The 12 HMCLs utilized are characterized for their structural alterations and not by hyperdiploidy. In addition, so as to fulfill the selection criteria, a minimum of 3 cell lines must present the alterations cited below. Previously described gains were observed in 1q, 7q, 8, 11q, 18, 19, and 20q; but also found at 4q. The bi-allelic deletions were ascertained on 3p. Similarly, we identified the regions of mono-allelic deletions on 1, 2q, 6q, 8q, 9p, 11q, 12, 13q, 14q, 17p, and 20p. In addition, described regions of bi-allelic deletions were detected on 1p, 6q, 8p, 13q, 16q, and 22q, and furthermore located on 2q, 3, 4q, 9, 10q, 12p, and 20p. Finally, the UPD obtained were traced on 1q, 4q, 8q, 10q, and 22q. The use of the new platform has allowed us to re-identify, significantly increase in information above the original set and finely delimit the regions previously described. Taken together, the dysregulated genes from the myeloma genome indicate that the crucial pathways in myeloma include NF-kB, apoptosis, cell-cycle and critical intracellular signaling pathways including the JAK/STAT, Wnt signaling, RAS/RAF/MAPK and PI3k/AKT.

Disclosures
No relevant conflicts of interest to declare.
Molecular Profiling of Extramedullary and Medullary Plasmacytomas.
Authors: Mahindra Anuj , Amin Samir B , Motyckova Gabriela , Sohani Aliyah R. , Patel Kishan , Vallet Sonia , Chetri Gaurav , Ackerman Adam , Pozzi Samantha , Santo Loredana , Cirstea Diana , Toomey Christiana E. , Hochberg Ephraim P. , Cin Paola Dal , Hideshima Teru , Anderson Kenneth C. , Munshi Nikhil , Raje Noopur 
Published: October 2019

Abstract
Abstract 1806
Poster Board I-832
Plasmacytomas are rare clonal proliferations of plasma cells that though cytologically identical to plasma cell myeloma, present with osseous or extraosseous growth pattern. Understanding their molecular characteristics can provide crucial insights into their pathogenesis and risk of progression to multiple myeloma (MM). To investigate the differences between extramedullary (EMP) and medullary plasmacytomas (MP) and MM without plasmacytomas, we sought to molecularly profile these tumors by tissue microarrays, gene expression, microRNA, and FISH.
We identified 85 patients from our data base with a pathological diagnosis of plasmacytoma. Of the 85 patients, 13 patients presented with EMP, and 72 had MP. Among the patients with EMP (n=13), 2 patients presented with multiple lesions. Three of 13 (23%) patients progressed to develop MM at a median of 12 months. 72 patients presented with MP, of which 21 had solitary lesions and 27 (37%) progressed to MM at a median of 20.5months. There was a male preponderance (67% vs 33%) and the median age at diagnosis was 60.5 years (range 27.7-87.6). The mean overall survival for patients with EMP was 121 months (95% confidence interval[CI] 97-144 months) and for patients with MP was 102 months (95% CI 93-128 months) { p=0.025}
MicroRNA (miRNAs) profiling was performed on MP (n=19) and MM samples (n=66). Data was normalized using U6 endogenous control. Three hundred and one miRNAs out of a total 665 were significantly differentially expressed between MP vs MM samples. Gene expression profiling performed on MP will be correlated with the miRNA data to identify genes and transcripts of interest which will be functionally validated. Tissue microarrays were performed on 52 patients (8: EMP, 44: MP,) in whom paraffin-embedded tissue was available. Of samples analyzed, CD56 positivity was observed in 55% MP and 71% EMP samples (p=0.67). Additional staining for cyclin D1, Bcl 2 and FISH analysis will be reported.
Differential expression patterns of factors involved in proliferation, survival, adhesion, and stroma-tumor cell interactions may help explain plasmacytoma biology and identify factors responsible for progression to MM. These insights may help identify new therapeutic approaches and targets in the treatment of these plasma cell disorders.

Disclosures
Hochberg: Enzon: Consultancy, Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau. Anderson:Millennium: Research Funding. Raje:Celgene, Norvartis, Astrazeneca: Research Funding.
The Effect of the CXCR4 Inhibitors, AMD3100 and AMD3465, in Multiple Myeloma Cell Homing and Its Interaction with the Bone Marrow Microenvironment.
Authors: Runnels Judith M. , Azab Abdel Kareem , Pitsillides Costas , Farag Jonathan , Wu Juwell , Roccaro Aldo M. , Maiso Patricia , Lin Charles P. , Ghobrial Irene M. 
Published: October 2019

Abstract
Abstract 1826
Poster Board I-852
Patients with multiple myeloma (MM) typically present with the disease spread diffusely throughout the bone marrow (BM). This fact points to the role MM cell trafficking plays in disease progression. Like normal plasma cells, MM cell trafficking is directed by the cytokine, SDF-1 and its receptor, CXCR4. Using the small bicyclam molecule, AMD3100, to block the SDF-1/CXCR4 interaction, and in vivo flow cytometry to measure circulation time of MM cells in a xenograft model, we have previously shown that homing of injected AMD3100-treated MM cells to the bone marrow is perturbed. Soon after injection fewer AMD3100-treated than untreated MM cells are detected in mouse skull BM using in vivo fluorescence confocal microscopy. Furthermore, the combined treatment of established tumors with AMD3100 and bortezomib enhanced survival. Here we present data that the 2nd generation SDF-1/CXCR4 small monomacrocyclic inhibitor, AMD3465 behaves like its predecessor in blocking antibody binding to CXCR4 on MM cells, migration of MM cells toward SDF-1, and in vivo homing, but at concentrations 10-50 fold lower than AMD3100. Incubation with either 1uM AMD3465 or 50uM AMD3100 reduced antibody binding to CXCR4 on MM cells to isotype control levels. Likewise, treatment with AMD3465 reduced MM1S migration to 15% of that of untreated cells in a transwell migration assay. These in vitro effects translated in vivo into longer circulation times for AMD3465-treated MM cells than control cells. In vivo flow cytometry revealed that 40-50% of AMD3465-pre-treated cells remained in the circulation one hr after injection whereas untreated cells depleted to 20% of their original circulating cell count by that time. Future experiments will further describe the effect of AMD 3465 on MM cells in the BM microenvironment to answer whether AMD3465 can be used to mobilize MM cells from the BM environment or enhance survival when used in conjunction with therapeutic drugs.

Disclosures
Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
Impact of ABO Imcompatibility On Acute GvHD and Thrombotic Microangiopathy After Reduced-Intensity Cord Blood Transplantation.
Authors: Tsuji Masanori , Wake Atsushi , Uchida Naoyuki , Ishiwata Kazuya , Nakano Nobuaki , Takagi Shinsuke , Yamamoto Hisashi , Mori Yuki , Matsuno Naofumi , Masuoka Kazuhiro , Makino Shigeyoshi , Yoneyama Akiko , Taniguchi Shuichi 
Published: October 2019

Abstract
Abstract 2298
Poster Board II-275

Introduction:
Althouth ABO blood type is one of two antigen system for transplantation, the effect of ABO incompatibility on transplantation outcome still remains controversy. Furthermore, there is little data about ABO incompatibility on the outcome of unrelated cord blood transplantation following reduced-intensity conditioning (RI-CBT).

Design and Methods:
We retrospectively analyzed data of 155 patients who underwent RI-CBT performed at Toranomon Hospital from January 2005 to December 2008. The patients include 45 ABO-identical, 47 minor, 43 major, and 20 bidirectional ABO mismatched. All patients were performed using fludarabine-based reduced-intensity conditioning, and 114 patients (74%) were performed using TBI-containing regimen. Median age were 57 years-old and 94 patients (61%) were over 55 years-old. We evaluated the association between ABO incompatibility and neutrophil engraftment, one-year overall survival (OS) ; one-year non-relapsed mortality (NRM) ; and one-year relapse rate. We also analyzed the incidence of pre-engraftment immune reaction (PIR), acute graft-versus-host disease (GvHD) including severity, and thrombotic microangiopathy (TMA).

Results:
There were no significant differences in neutrophil-engraftment time, reticulocyte-engraftment time, and the incidence of PIR. The incidence of acute GvHD and grade 2-4 acute GvHD were significantly higher in major/bidirectional ABO-incompatible group than ABO-identical/minor ABO-incompatible group (respectively P=0.0008 and P=0.0116). The incidence of TMA tended to be higher in minor/bidirectional ABO-incompatible group than ABO-identical/major ABO-incompatible group (P=0.0637). There were no significant differences in one-year OS, NRM, and relapse rate. In multivariate analysis, risk factors of acute GvHD were age over 55, TBI-containing regimen, CD34-positive cells>0.7×10e5/kg, and major/bi-directional ABO incompatibility, and those of TMA were grade 3-4 acute GvHD and minor/bi-directional ABO incompatibility.

Discussion:
This study showed major-directional ABO incompatibility setting increased the incidence of acute GvHD. Sex incompatibility and HLA incompatibility were not significantly influenced the incidence of acute GvHD. The use of steroid for severe GvHD and the expression of ABO antigen on the surface of vascular endothelial cell may influence pathogenesis of TMA. Further studies including larger patients numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of RI-CBT.

Disclosures:
No relevant conflicts of interest to declare.
Higher Incidence of Relapse with Higher Doses of CD34+ Cells From Leukapheresis Products Infused in Adults with Acute Myelocytic Leukemia Autografted During the First Remission.
Authors: Gorin Norbert C , Labopin Myriam , Rocha Vanderson 
Published: October 2019

Abstract
Abstract 2315
Poster Board II-292

Purpose
The cell source for autologous stem cell transplantation has shifted from bone marrow (BM) to peripheral blood (PB). For patients with AML in CR1, we previously showed that the risk of relapse was greater with PB than BM and a poorer outcome was associated with a shorter interval from CR1 to PB transplantation (≦80 days) (JCO 2009 in press).
Leukemic and normal progenitors bear the CD34+ antigen and can be mobilized together; we questioned whether there was a relation linking the doses of CD34+ cells infused to the outcome.

Methods
Out of 1262 patients autografted with PB more than 80 days post CR1 and reported to the EBMT registry using MEDB form, the dose of CD34+ cells infused was available in 772.

Results
The CD34+ cell doses were categorized by percentiles to divide the whole group into five categories containing the same number of patients . We identified the fifth percentile (> 7.16 × 106/kg) as the cut off point for Relapse Incidence (RI) and Leukemia-Free survival (LFS). Patients receiving the highest dose had a higher RI (57+/-4%, vs. 44+/-2%; p=0.008) and a lower LFS (34+/-4% vs. 49+/-2%; p=0.007).
In a multivariate analysis adjusted for differences, RI was higher in patients receiving the highest CD34+ cell dose ((hazard ratio [HR], 1.48; 95% CI, 1.12-1.95; p = 0.005).and the LFS was worse (HR, 0.72; 95% CI, 0.55-0.93; p = 0.01).

Conclusion
For patients with AML in CR1 autografted with PB, risk of relapse is greater and LFS is lower in those receiving the highest doses of CD34+ cells.

Disclosures:
No relevant conflicts of interest to declare.
Pulmonary Infiltration by CLL/SLL in the Presence of Inflammation: Significant or Incidental Finding?.
Authors: Weil Andrew C , Kalaycio Matt E , Cook James R. 
Published: October 2019

Abstract
Abstract 2352
Poster Board II-329
Radiographically identified pulmonary infiltrates in patients with CLL are usually secondary to infectious causes. However, a subset of patients develop pathologic leukemic infiltrates. Lung biopsies containing both inflammation and CLL infiltrates are particularly problematic. It is unclear in such cases whether the CLL infiltrate represents a nonspecific “passenger effect” secondary to ongoing inflammation versus a pathologic leukemic infiltrate. Furthermore, it is unknown whether there are clinical factors that would help predict who is at higher risk for pulmonary infiltration by CLL. We retrospectively analyzed 45 transbronchial lung biopsies taken from 37 patients at the Cleveland Clinic between 1999 and 2008. We reviewed the biopsies for evidence of acute or chronic inflammation and involvment by CLL. Acute inflammation in our biopsies consisted of acute pneumonias. Cases displaying a lymphocytic infiltrate suspicious for CLL on routine H&E sections were further investigated by immunohistochemistry. The patients studied were 67.5% male with a median age of 67 (45-83) and a median absolute lymphocyte count of 2.75 (0.12 – 86.08). All patients at the time of diagnosis with CLL had flow cytometery of blood and/or bone marrow demonstrating CD5, CD19 positive B cells consistent with CLL. 72% of all patients were previously treated and 52% of patients had a RAI stage > 2 at the time of their diagnosis with CLL. CLL was identified in 20% of the biopsies. Of the 31.1% of biopsies showing acute inflammation, none had leukemia. CLL infiltration was found in association with and without chronic inflammation in 25% and 30.4% of the biopsies respectively. The median peripheral blood absolute lymphocyte count was 3.64 (1.33 – 86.08) in those with leukemic biopsies and 8.31 (0.12 – 79.12) in those without leukemic biopsies. Furthermore, only 33% of the patients with CLL positive biopsies had a RAI stage ≥ 3. At the time of biopsy, 7 previously treated patients were in remission; none of these cases displayed evidence of CLL in lung tissue. We found that the incidence of leukemic infiltration of lung biopsies did not increase in the presence of inflammation. In fact, the incidence of infiltration of biopsies with inflammation was lower than those without inflammation. These results demonstrate that leukemic infiltration on biopsies with inflammation is uncommon, and suggests that this phenomenon represents true, pathologic infiltration of the tissue by CLL and not a “passenger effect”. To the authors knowledge this is the largest study evaluating the association of inflammation and pathologic infiltration of pulmonary tissue by CLL.

Disclosures:
No relevant conflicts of interest to declare.
STAT3 Controls the Neutrophil Migratory Response to CXCR2 Ligands by Direct Activation of G-CSF-Responsive CXCR2 Expression and Via Modulation of CXCR2 Signal Transduction .
Authors: Nguyen-Jackson Hoainam , Panopoulos Athanasia , Zhang Huiyuan , Li Haiyan S. , Watowich Stephanie 
Published: October 2019

Abstract
Abstract 236
Neutrophil mobilization, the release of neutrophils from the bone marrow reserve into circulating blood, is important to increase peripheral neutrophil amounts during bacterial infections. Granulocyte colony-stimulating factor (G-CSF) and chemokines, such as MIP-2 (CXCL2), can induce neutrophil mobilization, but the mechanism(s) they employ remain unclear. The transcription factor STAT3 is the principal intracellular signaling molecule activated upon G-CSF-ligation of its receptor. Using a murine model with conditional STAT3 deletion in bone marrow, we demonstrated previously that acute G-CSF-responsive neutrophil mobilization and MIP-2-dependent neutrophil chemotaxis is mediated by STAT3. In this study, we show that STAT3 is also necessary for MIP-2-elicited neutrophil mobilization. STAT3 appears to function by regulating the amplitude of Raf/MEK/Erk activation by MIP-2, a signaling pathway that is important for MIP-2-mediated chemotaxis. In addition, we demonstrate that G-CSF stimulates the expression of the MIP-2 receptor via STAT3-dependent transcriptional activation of Il8rb. G-CSF treatment also induces changes in bone marrow chemokine expression levels in a STAT3-dependent manner, which may further affect neutrophil retention and release. Taken together, our study demonstrates that STAT3 regulates multiple aspects of chemokine and chemokine receptor expression and function within the bone marrow, indicating a central role in the neutrophil mobilization response.

Disclosures:
Nguyen-Jackson: Amgen, Inc: Research Funding. Panopoulos:Amgen, Inc: Research Funding. Zhang:Amgen, Inc: Research Funding. Li:Amgen, Inc: Research Funding. Watowich:Amgen, Inc: Research Funding.
Passive Transfer of Hepatitis B Core Antibody by Intravenous Immune Globulin in Patients with Immune Thrombocytopenic Purpura.
Authors: Arnold Donald M. , Carruthers Julie , DiTomasso Julie , Gagliardi Thea , Meyer Ralph M. , Crowther Mark A. , Kelton John G. 
Published: October 2019

Abstract
Abstract 2418
Poster Board II-395

Background:
Rituximab may reactivate remote hepatitis B infection. Thus, hepatitis B core antibody (HBcAb) seropositivity was an exclusion for a randomized trial of rituximab in patients with immune thrombocytopenic purpura (ITP) in Canada. During screening for this trial, we observed a high rate of HBcAb seropositivity at our centre. We investigated passive antibody transfer by intravenous immune globulin (IVIg) as a potential explanation.

Methods:
We performed a case-control study of consecutive ITP patients screened for eligibility for a randomized trial of rituximab. We compared the frequency of prior IVIg use and the IVIg product administered to patients who tested positive (n=11) and negative (n=13) for HBcAb. Total (IgG and IgM) HBcAb was tested using a microparticle enzyme immunoassay (MEIA) that measures the rate of inhibition compared with an internal cut-off value (AxSYM®, Abbott Laboratories, IL, USA). We calculated the odds ratio (OR) and 95% confidence interval (CI) for IVIg exposure. We also tested different lots of 2 IVIg products directly for HBcAb in the MEIA.

Results:
Of 24 consecutive patients with ITP screened, 11 (45.8%) were positive for HBcAb and thus were excluded from the randomized trial. The observed rate of HBcAb seropositivity in this cohort was 35 times higher than the expected seroprevalence in Canada of 1.3% (O'Brien Transfusion 2009). Of 11 HBcAb-positive patients, 10 (90.9%) had received prior IVIg [OR, 16 (95% CI, 1.54, 166.05)]. Of the 10 patients who received IVIg, 8 (80.0%) received Gamunex (10% human immune globulin, Talecris Biotherapeutics, Clayton, NC). HBcAb was repeated in 8 seropositive patients, of whom 4 were negative on repeat testing 7 to 104 weeks after the last dose of IVIg. Of the 13 HBcAb-negative patients, 5 (38.5%) had received prior IVIg; none were Gamunex. Seroconversion was documented in one patient serially tested after receiving Gamunex; MEIA rates decreased (became positive) rapidly, then gradually increased to normal after 7 weeks. Samples from 4 lots of Gamunex were reactive in the MEIA; whereas 3 lots of IGIVnex (Talecris Biotherapeutics) were non-reactive.

Conclusions:
False positive HBcAb results may occur due to the passive transfer of HBcAb from Gamunex, an IVIg product manufactured from donors who are not screened for HBcAb. HBcAb should be interpreted cautiously in any patient who received IVIg. We recommend HBcAb testing before IVIg administration so that treatments such as rituximab are not withheld unnecessarily.

Disclosures:
Arnold: Hoffman-LaRoche: Research Funding; Amgen: Consultancy, Honoraria. Meyer:The NCIC CTG is a clinical trials cooperative group. It receives its base grant support from the Canadian Cancer Society Research Institute. Many of its clinical trials include research support from industry. : Research Funding.
The Effects of Hyperthermia On Platelet Physiology.
Authors: Shi Quanwei , Wang Zhicheng , Yan Rong , Du Juan , Liu Jun , Ruan Changgeng , Dai Kesheng 
Published: October 2019

Abstract
Abstract 2422
Poster Board II-399

Introduction:
In some patients with fever or hyperthermia, hemorrhage is a significant pathological feature, which incurs severe or even fatal consequence. Although the mechanisms of hemorrhage in patients with hyperthermia or fever have been though to be complex, whether there is an association between hemorrhage and hyperthermia or fever is not well understood. Platelets play a central role in maintaining integrity of endothelium and biological hemostasis. Platelet count obviously reduces in most of patients with dengue fever or heatstroke, and reduced platelet aggregations have been found in patients with hemorrhage fever, raising the possibility that fever or hyperthermia incurs reduction of platelet count or function leading to hemorrhage.

Methods and Results:
To explore the effect of hyperthermia on platelet function, platelet-rich plasma (PRP) was isolated and incubated at hypothermia (22 degrees C), normothermia (37 degrees C) or hyperthermia (40 and 42 degrees C) for 1 or 2 hours, and then induced to aggregation by ADP. Platelet aggregation was significantly reduced with the growth of temperature in a time-dependent manner. To exclude the possible interference from plasma proteins, and to further investigate the effects of hyperthermia on platelet function, alpha-thrombin induced platelet aggregations were examined in washed platelets incubated at different temperatures for 1 or 2 hours. Washed platelets presented normal aggregation response to alpha-thrombin in platelets incubated at hypothermia, whereas alpha-thrombin induced platelet aggregations reduced gradually with the increase of temperature and time duration. Next, we investigated whether the reductions of platelet aggregation were resulted from platelet apoptosis under high temperature conditions. Hyperthermia gradually induced apoptotic events in platelets with the increase of temperature and time duration, including depolarization of mitochondrial inner transmembrane potential (ΔΨm), gelsolin cleavage, and phosphatidylserine (PS) exposure. Furthermore, hyperthermia incurs platelet glycoprotein (GP) Ibalpha ectodomain shedding.

Conclusions:
These results indicate that hyperthermia induces platelet apoptosis, thus suggesting the possible reason why platelet count or function was reduced in some patients with fever or hyperthermia. These findings not only have important implications for the pathogenesis of hemorrhage in some fever or hyperthermia-related diseases, but also suggest that attentions should be paid on platelet apoptosis under relative high temperature conditions, such as during hyperthermia therapy or platelet storage.

Disclosures:
No relevant conflicts of interest to declare.