bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship of Myeloma Cells, Stromal Cells and Monocytes Under Bone Marrow Microenvironment
Authors: Ikeda Hiroshi , Aoki Yuka , Nojima Nasanori , Yasui Hiroshi , Hayashi Toshiaki , Ishida Tadao 
Published: October 2019

Abstract
Abstract 4987
The Bone marrow (BM) microenvironment plays crucial role in pathogenesis of Multiple myeloma(MM). Myeloma cells contacts with bone marrow stromal cells (BMSCs), which secrete factors/cytokines, promoting tumor cell growth and survival. Paracrine secretion of cytokines(i. e., interleukin-6 (IL-6) insulin-like growth factor-1, inflammatory protein-1a) in BM stromal cells promotes multiple myeloma cell proliferation and protects against drug-induced cytotoxicity. These cytokines provide stimulatory signals for multiple myeloma growth and survival.
Bone involvement is a common feature in MM patient, solid and hematologic cancers. MM localizes to the bone in nearly all patients ranges between 40% and 75%. Disease-related skeletal complications result in significant morbidity due to pain, pathologic fractures and spinal cord compression. The bone microenvironment creates a supportive niche for tumor growth. Osteoclasts and bone marrow stromal cells, along with extracellular matrix and cytokines stimulate tumor cell proliferation and confer chemoresistance. Therefore, the reciprocal interactions between tumor cells, osteoclasts, osteoblasts, and bone marrow stromal cells present an important.
In current study, monocyte can directly promote mesenchymal stem cells osteogenic differentiation through cell contact interactions, thus resulting in the production of osteogenic factors by the monocytes. This mechanism is mediated by the activation of STAT3 signaling pathway in the mesechymal stem cells that leads to the upregulation of Osteoblasts-associated genes such as Runx2 and alkaline phosphatase (ALP), and the down-regulation of inhibitors such as DKK1 to drive the differentiation of mesechymal stem cells into osteoblasts.
In this study, we examined the role of monocyte, component of BM cells, as a potential niche component that supports myeloma cells. We investigated the proliferation of MM cell lines cultured alone or co-cultured with BM stromal cells, monocytes, or a combination of BM stromal cells and monocytes. Consistently, we observed increased proliferation of MM cell lines in the presence of either BM stromal cells or monocytes compared to cell line-only control. Furthermore, the co-culture of BM stromal cells plus monocytes induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, BMSCs and monocytes decreased the rate of apoptosis of myeloma cells. Our results therefore suggest that highlights the role of monocyte as an important component of the BM microenvironment.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Significance of Cell of Origin Subclassification in Diffuse Large B Cell Lymphoma
Authors: Dawod Muath , Gomez-Gelvez Juan , Mattour Ahmad , Inamdar Kedar V. , Janakiraman Nalini 
Published: October 2019

Abstract
Abstract 5081

Background:
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease that has been divided into three different prognostic subgroups: Germinal Center B cell-like (GC), Activated B cell-like (ABC) and type 3 according to gene expression profile using cDNA. Immunohistochemistry (IHC) has been used as surrogate to identify these cell-of-origin subgroups. Data about the prognostic value of IHC has been conflicting.

Patients and methods:
In this retrospective study, we reviewed the charts of 252 patients diagnosed with DLBCL at Henry Ford Hospital from 1999 to 2012. We excluded patients with HIV, transformed lymphomas and unavailable samples. Data was collected on a total of 157 patients. The following data was gathered: age, sex, race, IPI score, disease stage, hemoglobin, white blood and platelet counts, best response achieved and dates of treatment start, relapse, death or last follow up. Tissue microarray slides with the following IHC stains (CD10, MUM1, Bcl6) were prepared and reviewed when needed. Using Hans Algorithm, samples were divided into two major groups (GC-like and non-GC-like). 3-year progression free and overall survivals were compared between all subgroups using a log-rank test. Continuous variables were reported as median and range, and compared using Wilcoxon rank-sum tests. Categorical variables were reported as median and range, and compared using Chi-square tests. Statistical significance was set at p<0. 05.

Results:
Eighty patients (51%) were classified as GC-like, and 77 patients (49%) as non-GC-like. GC-like subgroup had a significantly longer 3-year progression free survival (90% vs 74%, P=0. 024), as compared with the non-GC-like subgroup. There was a trend toward longer overall survival but it didn't reach statistical significance (74% vs 67%, P=0. 161). For all patients, IPI stands as a strong prognostic index with 3-year overall survival of (85% and 46%, P=<. 001) in patients with low IPI (0 to 2) and high IPI (3 to 5) respectively. Interestingly, in patients with low IPI, cell of origin stands as a prognostic factor with 3-year progression free survival of (96% and 81%, P=0. 032) in GC-like and non-GC-like groups respectively. While in patients with high IPI, there was no significant difference in progression free survival in cell-of-origin subgroups.

Conclusion:
Cell of origin subclassification as determined by IHC surrogate markers predict for better progression free survival in GC-like subgroup but not for overall survival. While this prognostic value was maintained in patients with low IPI, there was no prognostic significance in patients with high IPI. IPI is still a valuable prognostic tool in patients with DLBCL.

Disclosures:
No relevant conflicts of interest to declare.
Variability in Exposure of Epitope G40-R43 of Domain I in Commercial Anti-β2-Glycoprotein I IgG Elisas Influences the Diagnosis of the Antiphospholipid Syndrome
Authors: Pelkmans Leonie , Kelchtermans Hilde , Ninivaggi Marisa , Lindhout Theo , de Groot Philip G , Pengo Vittorio , De Laat Bas 
Published: October 2019

Abstract
Abstract 632

Introduction.
Diagnosis of the antiphospholipid syndrome (APS) depends on the detection of autoantibodies against phospholipid-bound β2-glycoprotein I (β2GPI), the most prominent antigen in APS. One of the main problems faced is the high variability observed between different commercially available anti-β2GPI assays. Anti-β2GPI antibodies constitute a heterogeneous population, but predominantly antibodies reacting to a cryptic epitope Glycine40-Arginine43 (G40-R43) in domain I of β2GPI are associated with a strong risk to develop thrombosis. b2GPI is present in blood in a native conformation (either circular or S-shaped). After interaction with anionic surfaces it opens up (J-shaped conformation), resulting in exposure of the epitope G40-R43 in domain I. It is therefore important that in diagnostic assays b2GPI is presented in the open conformation enabling antibodies to react with the G40-R43 epitope. We hypothesize that the high variability between different commercial anti-b2GPI ELISA assays arise from variation in exposure of the G40-R43 epitope of b2GPI.

Methods.
Two patient-derived monoclonal antibodies P2-6 and P1-117 were tested for their reactivity towards β2GPI in different conformations. Using both antibodies, we compared exposure of epitope G40-R43 on β2GPI in five different commercial anti-β2GPI IgG assays. 10 patient samples selected for their low to high positivity towards epitope G40-R43, were tested in two anti-β2GPI IgG assays.

Results.
Using neutral versus anionic ELISA plates, we have shown that antibody P1-117 specifically reacts with epitope G40-R43, exposed only in the open conformation, while antibody P2-6 recognizes β2GPI irrespective of its conformation (Fig. 1). In one of the tested anti-β2GPI assays, both antibodies showed equal reactivity towards β2GPI, indicating that all the coated β2GPI exposes epitope G40-R43. In this assay, all ten anti-domain I positive patients tested positive. In other assays P1-117 displayed lower reactivity towards β2GPI than P2-6, demonstrating a reduced exposure of G40-R43. Only 3 out of the 10 patients tested positive in such assay, illustrating that a significant number of patients can be falsely assigned negative in assays characterized by a reduced exposure of epitope G40-R43.

Conclusions.
The exposure of epitope G40-R43 on β2GPI is highly variable in commercial anti-β2GPI assays, and influences the diagnosis of APS. Our results have major implications for the diagnosis of APS, as it provides suitable controls to ensure sufficient exposure of the G40-R43 epitope or suggests the development of alternative assays coating only domain I of β2GPI.

Disclosures:
No relevant conflicts of interest to declare.
New Insights in Development and Function of Human Innate Lymphoid Cells
Authors: Spits Hergen , Bernink Jochem , Peters Charlotte , Mjosberg Jenny 
Published: October 2019

Abstract
Abstract SCI-19
Innate lymphoid cells (ILC) are immune cells that lack a specific antigen receptor, yet possess the capacity to produce an array of effector cytokines that in variety matches that of T-helper-cell subsets. Innate lymphoid cells function in lymphoid organogenesis, tissue remodeling antimicrobial immunity and inflammation, particularly at barrier surfaces. The ability of ILCs to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. ILCs are also involved in repair of tissue damage inflicted by pathogenic microbes. The scientific session presentation will include data on developmental requirements, lineage relationship and effector functions of human ILCs. Two families of innate lymphoid cells will be discussed: Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity and inflammation, and Type 2 innate lymphoid cells that are important for helminth immunity. In addition, evidence will be presented for the existence of a novel ILC population that is dedicated to producing interferon-γ and which we call type 1 ILC. The potential roles of ILC in the pathology of immunity-mediated inflammatory and infectious diseases, including allergic diseases, will be discussed.

Disclosures:
No relevant conflicts of interest to declare.
The Impact Of Oxidative Stress On The Immune Compartment Of Chronic Lymphocytic Leukemia Patients
Authors: Jitschin Regina , Bricks Juliane , Berger Jana , Eckart Michael J , Mackensen Andreas , Mougiakakos Dimitrios 
Published: October 2019

Abstract
Reactive oxygen species (ROS) such as hydrogen peroxide or superoxide are highly reactive and hyperpermeable. They are continuously produced by mainly the mitochondria during oxidative phosphorylation. Immune cells of especially myeloid origin contribute additionally to the ROS production via the membrane-bound NADPH-oxidase. During inflammation or “inflammatory-like” conditions as often seen in neoplasias ROS production is highly increased. The physiological redox-buffers are overwhelmed leading to the metabolic condition termed oxidative stress. Immune cells, especially NK- and T-cells are very sensitive towards ROS-induced cell death resulting from mitochondrial depolarization. Furthermore, ROS can interfere with nuclear NF-kB translocation thus leading to reduced activation, cytokine production, and cytotoxic activity of immune cells. Functional immune defects at several levels as well as significant shifts in the balance of immune populations have been related to oxidative stress in patients suffering from mainly solid malignant diseases. In this study we sought out to investigate the presence of oxidative stress in patients with chronic lymphocytic leukemia (CLL) and its potential effects on their cellular immune compartment.
Peripheral blood and serum from 65 patients with untreated CLL was collected upon informed consent. Oxidative stress was measured based on the concentration of so-called ROS-surrogate markers in the patients' sera. Therefore oxidized lipids, proteins, and DNA bases were quantified by ELISA. The immune compartment was evaluated using multicolor flow cytometry and the analyses included T-, NK-, myeloid-, and dendritic-cell subsets.
ROS levels were increased in CLL patients. Based on the concentration of ROS-modified molecules we were able to group our patient cohort into a ROShi and ROSlo group. The ROShi group exhibited lower levels of T-cell activation, while there was a shift of the CD56bright/CD56dim NK-cell balance towards the CD56bright subset. We could not detect significant differences in the myeloid- and dendritic-cell compartment or alterations of T- and NK-cell maturation.
Our results implicate that ROS belongs to the tumor immune escape mechanism present in CLL. The use of redox modifying agents in combination with the steadily emerging immune-based approaches could potentially boost their therapeutic efficacy.

Disclosures:
No relevant conflicts of interest to declare.
Kinetics Of Chronic Lymphocytic Leukemia Cells In Tissues and Blood During Therapy With The BTK Inhibitor Ibrutinib
Authors: Wodarz Dominik , Garg Naveen , Komarova Natalia L. , Benjamini Ohad , Keating Michael J. , Wierda William G. , Kantarjian Hagop M. , James Danelle F. , O'Brien Susan M. , Burger Jan A. 
Published: October 2019

Abstract
Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor (BCR) signaling, is blocked by ibrutinib, a BTK inhibitor that is clinically active in patients with chronic lymphocytic leukemia (CLL). Characteristically, ibrutinib causes CLL cell redistribution from tissue sites into the peripheral blood during the initial weeks of therapy, resulting in a transient surge in lymphocytosis. This activity of ibrutinib is thought to be important for the anti-leukemia activity of ibrutinib in CLL, because it removes CLL cells from the tissue microenvironment and consequently deprives the leukemia cells from growth- and survival-promoting cellular and molecular signals that are present in the tissues. However, clinically it has been noted that the magnitude of lymphocytosis during ibrutinib therapy is lesser than what would be expected from the rapid reduction in overall tissue disease burden, seen during the early weeks of ibrutinib therapy, especially in patients with bulky lymph nodes.
Therefore, we aimed to quantify the relative amount of tissue CLL cells redistributed into the peripheral blood, and to better characterize the dynamics of this redistribution phenomenon. Crucial kinetic parameters were estimated by fitting a two-compartment mathematical model to clinical data that document serial blood lymphocyte counts of CLL patients as well as changes in total tissue burden, calculated from radiological measurements of lymph node and spleen volumes during ibrutinib therapy. This was done in a cohort of ten relapsed CLL patients, treated with single-agent ibrutinib, 420 mg PO daily on the Phase 1b/2 ibrutinib study at MD Anderson Cancer Center. We found that during ibrutinib therapy, on average 1.7 ± 1.1% of the cells die per day in the blood, while in tissue 2.7% ± 0.99% of the cells die per day. These death rates during treatment are approximately 5 times higher than those estimated in previous studies in the absence of treatment. The average fraction of the tissue CLL cells that was redistributed into the blood during ibrutinib therapy accounted for 23.3 ± 17% (range: 1.9% to 52.6%) of the calculated total tissue disease burden, with an average time for achieving a 50% reduction in tissue CLL cells of 20.3 ± 3.6 days. These findings indicate that generally a relatively small fraction of the total tissue CLL cell burden is re-distributed into the blood during ibrutinib therapy, and that a significant amount of drug-induced cell death occurs in tissue compartments.

Disclosures:
Off Label Use: Ibrutinib for CLL therapy. James:Pharmacyclics: Employment, Equity Ownership. O'Brien:Pharmacyclics: Research Funding. Burger:Pharmacyclics: Research Funding.
Role Of PET/CT In The Management Of Burkitt Lymphoma
Authors: Carrillo Estrella , De la Cruz Fatima , Marín Víctor , Solé María , Borrego Isabel , Quiroga Eduardo , Manzanares Marina , Capote Francisco Javier , Ramirez María José , Espigado Ildefonso , Vázquez Ricardo , Jose Antonio Pérez-Simón 
Published: October 2019

Abstract

Introduction
Burkitt lymphoma (BL) is a highly aggressive and chemosensitive B cell non-Hodgkin lymphoma derived from germinal or post-germinal center B cells, which affects commonly extranodal sites. Although studies have described 100% of 18F-FDG avidity in BL, PET/CT is not routinely used in those patients being only recommended in the context of a clinical trial. The aim of the present study is to evaluate retrospectively, the role of PET/CT instead of CT scan alone both to stage newly diagnosed BL patients as well as to evaluate disease response after chemotherapy.

Patients and Methods
53 PET/CT (20 PET/CT at diagnosis, 28 after first line treatment and 5 to monitor residual disease detected in response assessment PET/CT) were performed in 32 patients, between 2006 y 2012. Locations of involved areas were registered comparing staging CT and PET/CT and were classified as discrepancy or not.

Results
Patientxs baseline characteristics are summarized in table 1. At diagnosis, abdominal adenopathies had the highest SUVmax with a mean of 14,83 (3,5-35). Discrepancies were found in 64,7% of patients who had both imaging test available at diagnosis (n=17), almost all of them in extranodal sites. These findings upstaged 12% patients from localized to advanced disease. Sensitivity of PET/CT and CT was 100% and 53%, respectively. Regarding the response assessment, in 5 patients out of 13 (38%) who had both imaging test, the PET/CT after first-line treatment was negative whereas the CT demonstrated residual masses. No relapses were observed in those patients. Among 28 patients with a PET/CT available after first-line treatment, CR was attained in 22 patients; one true-positive and 5 false-positive lesions (FP) (1 nodal and 4 extranodal) were detected after completing treatment. SUVmax of FP single nodal site was 2,6 as compared to a mean of 14,9 for the positive lesions at diagnosis while the mean SUVmax of false-positive extranodal sites was 4,4 as compared to 12,1 at diagnosis. NPV was 100% and PPV 16%. SUVmax value of FP lesion was<60% of diagnosis in all cases. Thus, with a cut-off value SUVmax above 60% of that of diagnosis, the PPV is also 100%.

Conclusion
as compared to CT scan, a more accurate staging in BL can be obtained using PET/CT. Regarding response assessment, NPV reaches 100% and, using a cut-off value for the SUVmax of 60% below the value of diagnosis, also a 100% PPV is observed.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Characteristics and Outcomes Of Waldeyer’s Ring Lymphoma: Nation-Wide Study In Korea
Authors: Shin Ho-Jin , Suh Cheolwon , Il Lee Soon , Kim Won Seog , Lee Won Sik , Kim Hyo Jung , Choi Chul Won , Kim Jin Seok 
Published: October 2019

Abstract
There has been published several papers that analyzed Waldeyer’s ring lymphoma. However, so far, Asian data was rare and WHO classification was not used for classifying subtype of malignant lymphoma.
328 patients who were diagnosed as non-Hodgkin’s lymphoma involved Waldeyer’s ring (WR-NHL) were analyzed retrospectively in Korea.
Male was slightly predominant compared to female. Low risk disease (low to low intermediate by International prognostic index) was 76.8% and localized disease was 64.9%. Most patients had normal level of serum lactate dehydrogenase (85.4%) and were not absent of B symptoms (85.1%). Bone marrow involvement was seen in only 30 patients (9.1%). Diffuse large B cell lymphoma (DLBCL) (73.2%) was most popular, and peripheral T cell lymphoma, NK/T cell lymphoma, and marginal zone B-cell lymphoma were also frequently involved Waldeyer’s ring. Almost subtype of lymphoma including DLBCL involved tonsil most frequently (199/328, 60.7%). Frequently involved extra-Waldeyer’s ring sites were bone marrow, G-I tract, lung/plerura/pericardium, and bone. In DLBCL, 169 patients (70.4%) received chemotherapy, 50 patients (20.8%) received chemotherapy plus radiotherapy, thirteen patients (5.4%) received surgical resection +/- chemotherapy or radiotherapy, and six patients (2.5%) received radiotherapy alone. Surgical resection showed improved PFS, DFS, and OS compared to chemotherapy +/- radiotherapy. In localized disease, all patients who received surgical resection still alive until now and chemotherapy or chemotherapy plus radiotherapy was better PFS and OS than radiotherapy alone (5-year PFS rates, 83.2% and 89.3% vs 66.7%; 5-year OS rates, 77.0% and 75.4% vs 58.9%). PFS, DFS and OS of B-cell lymphoma exhibited improved compared to T-cell lymphoma.
In conclusion, DLBCL was most frequent subtype and tonsil was frequently involved site of WR-NHL. In localized disease, surgical resection should be tried as possible for achieving long-term survival. Especially, in T-cell lymphoma patients, more aggressive treatment was required due to poor outcomes compared with B-cell lymphoma.

Disclosures:
No relevant conflicts of interest to declare.
Ifosfamide, Methotrexate, Etoposide, and Prednisolone (IMEP) Plus L-Asparaginase As a First-Line Therapy Improves Outcomes In Stage III/IV NK/T-Cell Lymphoma, Nasal Type (NTCL)
Authors: Kim Miso , Kim Ki Hwan , Keam Bhumsuk , Lee Se-Hoon , Kim Dong-Wan , Lee Jong Seok , Heo Dae Seog , Kim Tae Min 
Published: October 2019

Abstract

Background
The prognosis of NTCL patients presenting in stage III/IV is extremely poor and there is no standard chemotherapy. Although L-asparaginase (L-asp) is known to be effective for NTCL, its significance has not been well demonstrated in a relatively homogenous subset. In addition, there were few studies to evaluate treatment outcomes and prognostic factors in stage III/IV NTCL. This study was undertaken to evaluate the efficacy of L-asparaginase-based combination chemotherapy (IMEP plus L-asp) and prognostic factors in stage III/IV NTCL.

Methods
A total of 70 patients with newly diagnosed NTCL at stage III/IV were enrolled from 3 Korean centers between Jan 2000 and Feb 2013. All patients received IMEP plus L-asp (N=22) regimens or combination chemotherapy without L-asp (N=48) as a first-line treatment. Recurrent cases were excluded. Clinical prognostic factors, treatment outcomes, and prognostic scores were compared between the groups. Independent prognostic factors for survivals were identified using multivariate analyses.

Results
The median age was 48.5 years (range, 18-73 years) with a male-to-female ratio of 2.2:1. After a median follow-up period of 12.8 months (range, 1.1-186.6 months), median progression-free survival (PFS) and overall survival (OS) were 5.6 months and 12.3 months, respectively. Clinical factors and treatment outcomes were compared between IMEP plus L-asp and chemotherapy without L-asp groups (Table 1). Higher response rate (RR) and complete response (CR) rates were observed in patients treated with IMEP plus L-asp compared with those treated with chemotherapy without L-asp (RR 90.0% vs. 34.8%, P< 0.0001; and CR rates 65.0% vs. 21.7%, P = 0.001). In addition, PFS and OS were significantly higher for IMEP plus L-asp group compared with chemotherapy without L-asp group (Table 1). Use of chemotherapy without L-asp (hazards ratio [HR]=2.29, 95% confidence interval [CI] 1.22-4.29; P = 0.010) and poor performance status (HR=2.10, 95% CI 1.23-3.59; P = 0.007) were independent predictors for reduced PFS. Independent factors adversely affecting OS were poor performance status (HR=1.99, 95% CI 1.08-3.65; P = 0.027), 2 or more extranodal sites (HR=2.91, 95% CI 1.25-6.77; P = 0.013), and chemotherapy without L-asp (HR=3.51, 95% CI 1.53-8.06; P= 0.003).

Conclusions
L-asparaginase-based combination chemotherapy (IMEP plus L-asp) is active against stage III/IV NTCL and an independent predictor for improved survivals. L-asp containing regimen might be useful as a first-line treatment for stage III/IV NTCL.

Disclosures:
No relevant conflicts of interest to declare.