bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Blood Graft Cellular Content in Myeloma (MM) Patients and Non-Hodgkin Lymphoma (NHL) Patients Mobilized with Chemotherapy Plus G-CSF with or without Plerixafor
Authors: Jantunen Esa , Varmavuo Ville , Silvennoinen Raija , Valonen Piia , Kuittinen Taru , Nousiainen Tapio , Mäntymaa Pentti 
Published: October 2019

Abstract
Abstract 4414

Background:
Cellular composition of blood graft collected to support high-dose therapy may have important implications in regard to hematopoietic and immune reconstitution after high-dose therapy. Mobilization method used may have effect on graft composition as well as previous therapy given to the patients.

Methods:
We have retrospective analyzed by flow cytometry cellular composition of freezed blood grafts in 34 patients with NHL (chemotherapy + G-CSF mobilization 15, add-on plerixafor 19 patients) and compared the observations with those of 17 MM patients mobilized either with low-dose cyclophosphamide + G-CSF (n=12) or with add-on plerixafor (n=5). The analyses were performed from the first graft collected from the chemomobilized patients or from the first draft collected after the plerixafor injection, respectively. Antibodies used included CD34, CD38, CD133 in regard to CD34+ subclasses and CD3, CD4, CD8, CD19 and CD3CD16/CD56 to analyze lymphocyte subsets. In addition, 7-aminoactinomycin D staining was used to assess the amount of nonviable CD34+ and lymphoid cells.

Results:
In regard to the patients mobilized without plerixafor, MM patients had higher content of CD34+ cells (4.9 vs. 2.0 × 106/kg, p=0.009) as well as lower proportion of more primitive stem cells (0.8 vs. 1.9 % of all CD34+ cells, p=0.075) when compared to NHL patients. The amount of B-lymphocytes was also significantly higher in MM patients (0.5 × 106/kg vs. 0.0, p< 0.001). No differences were observed in the total amount of T (CD3+) cells, NK cells or in the proportion of nonviable CD34+ or lymphoid cells. Of the plerixafor treated patients, the amount of B-lymphocytes was higher in MM patients (1.8 × 106/kg vs. 0.0, p<0.001) as well as CD4/CD8 ratio (2.56 vs. 1.0, p=0.004) when compared to NHL patients.

Conclusion:
As there appears to be differences between MM and NHL patients mobilized with or without plerixafor, it might be advisable to analyze separately effects of mobilization therapy to graft content and post-transplant outcomes in these diseases. Apparently the type and intensity of previous therapy given to the patients (e.g. rituximab) has important effects on graft cellular composition.

Disclosures:
Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria. Silvennoinen:Genzyme: Consultancy.
Double and Triple Hit Diffuse Large B Cell Lymphomas and First Line Therapy
Authors: Jaglal Michael V. , Peker Deniz , Tao Jianguo , Cultrera Jennifer L. 
Published: October 2019

Abstract
Abstract 4885

Background:
B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL) or Burkitt like lymphoma is a high grade lymphoma, with a high proliferation index and a complex karyotype mostly involving MYC and BCL-2 genes, so called “double hit” as well as BCL-6 genes, so called “triple hit”. This high grade lymphoma shows an aggressive behavior for which the most appropriate therapeutic approach is not established.

Methods:
This was a single center retrospective review of patients with a confirmed diagnosis of B cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL from 2006 to 2012. The definitive diagnosis in all cases was based on morphological and phenotypic features, and genetic abnormalities involving MYC, BCL-2, and BCL-6. Clinicopathological data was extracted including age, gender, primary disease location, phenotypic subtype, genetic abnormalities by FISH, IPI scores, treatment regimens and survival data. Descriptive statistical analyses were utilized. Kaplan-Meier method was used to estimate OS and log rank test was used to compare the groups. All data were analyzed using SPSS version 19.0 statistical software.

Results:
31 patients with “Double or Triple Hit” lymphomas were identified between 2006 and 2012. The age range at diagnosis was 33–87 years with median age of 71. 23 of 31 patients (74 %) were ≥ 60 years old. Male to female ratio was 1.58:1 (19:12). The median ECOG PS was 1. No patients had HIV. A majority of patients presented with extranodal disease 21 out of 31 patients and only 10 patients presented with nodal disease. The mean overall survival of the entire cohort was 28 months with ranges 3 to 40 months. 20 of 31 patients (65%) are currently alive. RCHOP was the most utilized treatment regimen in the cohort of alive patients 13 out of 20 patients (65%). Patients who presented with CNS disease had a worse prognosis when compared to the entire cohort with a mean overall survival of 13 months versus non CNS disease overall survival was 32 months (p=0.014). In patients treated with RCHOP for first line therapy the overall survival was 33 months versus 17 months for non RCHOP regimens first line (p=.048). The non RCHOP regimens included Hyper CVAD, ESHAP, and RICE.

Conclusions:
RCHOP was the most utilized treatment regimen in the cohort of alive patients. The treatment regimen with the best efficacy in this retrospective study was RCHOP in first line treatment of “Double or Triple Hit” lymphomas. CNS disease is associated with worse prognosis in patients with “Double or Triple Hit” lymphomas in this retrospective study.

Disclosures:
No relevant conflicts of interest to declare.
Cytotoxic Effect of Bendamustine Combined with Kinase Inhibitors in Hematologic Cell Lines
Authors: Hagiwara Kazumi , Kojima Yuki , Miyata Yasuhiko , Nagai Hirokazu 
Published: October 2019

Abstract
Abstract 4912
Bendamustine, a kind of alkylating agent, has demonstrated a favorable anti-tumor activity both alone and in combination with rituximab in low grade B cell lymphoma. Because the kinase cascades, including B-cell receptor signaling, are necessary for the proliferation and survival of the lymphoma cells, the kinase inhibitors have been developed as molecular target agents of malignant lymphomas. We investigated the cytotoxic effect of bendamustine, both as a single agent and in combination with these new kinase inhibitors in human lymphoid cell lines. We used three B-cell lines, BALL-1 (acute lymphoblastic leukemia), SKLY16 (B-cell lymphoma) and DHL4 (diffuse large B cell lymphoma), and T-cell line THP-6 in this study. These cells were treated with bendamustine alone or combined with enzastaurin (a PKC-β inhibitor), CAL-101 (a p110δ PI3K inhibitor), PCI-32765 (a Btk inhibitor) or R406 (a Syk inhibitor) for 48 hours. Drug-induced cytotoxicity was evaluated using the MTT assay. Cell viability in each experiment was normalized using untreated controls. The treatment with bendamustine alone decreased cell viability in a dose-dependent manner on these three B-cell lines. In contrast, T-cell line THP-6 showed the resistance to bendamusitine. For the combination study, cells were exposed to bendamustine (10μM) and one of these kinase inhibitors at various concentrations simultaneously for 48 hours. CAL-101 and PCI-32765 did not enhance the cytotoxic effect on all of B-cell lines. In BALL-1 and SKLY16 cells, the combination with enzastaurin or R406 resulted in a higher cytotoxic activity than that induced by bendamustine alone. In DHL4 cells, the treatment combined with R406 inhibited cell growth effectively, but not with enzastaurin. To evaluate whether these drug combinations are synergistic, a combination index (CI) was calculated and normalized isobolograms were constructed from non-constant ratio drug combinations using Calcusyn software. The CI values were less than 0. 7 in SKLY16 cells treated with bendamustine and enzastaurin, indicating that these produced synergistic cytotoxic effects in cell line-dependent manner. Our results show that enzastaurin might potentiate the cytotoxic activity of bendamustine in vitro and be a good candidate for the combination with bendamustine.

Disclosures:
No relevant conflicts of interest to declare.
Derivation and Drug Screening of Growth Factors- and Stroma-Dependent Human Multiple Myeloma Cells
Authors: Shieh Jae-Hung , Su Tsann-Long , Shieh Jason , Moore Malcolm A.S. 
Published: October 2019

Abstract
Abstract 5020
Multiple myeloma (MM) is the second most common hematological malignancy in the U. S. MM is treatable but not curable with a median survival of 5–7 years with advanced treatment. There are several established human MM cell lines that grow in the absence of any cytokine dependence or stromal interaction. However, most primary MM patient specimens are difficult to maintain or to expand in vitro for pathophysiology investigation and drug screening. To address this issue, we systemically evaluated effects of various culture parameters on the growth of primary MM cells. A serum-free MS-5 cell (a murine bone marrow stromal cell line) co-culture system containing cytokine cocktail is capable of expanding purified CD138+ cells from primary MM specimens in vitro. Optimal expansion of the MM CD138+ cells requires a combination of stromal cells, human interleukin (IL-6) and human hepatocyte growth factors (hHGF). These MM cells can be maintained and repeatedly recovered following cryopreservation. The in vitro effect of five novel alkylating agents (BO-1055, −1090, 1099, −1393 and −1509) was evaluated for an inhibition of proliferation of the MM cells, and on human mesenchymal stem cells (hMSC), murine MSC (MS-5 cells and Op9 cells), human bone marrow derived endothelial cells (BMEC), and human cord blood (CB) CD34+ cells, as well as for a week 5 Cobblestones area forming cells (CAFC; an in vitro surrogate assay for hematopoietic stem cells) assay with CB CD34+ cells. BO-1055 shows a promising therapeutic window between the MM cells and other normal tissues. For the MM cells, IC50 was ∼1. 02 μM. In contrast, IC50 of BMEC, MSC, CB CD34+ cells and CAFC was >10, >25, 8, and >5 μM, respectively. Therefore, our stromal culture system supports human primary MM cells and closely recapitulates the growth of MM cells in their niche in vivo. We also identified a novel BO-1055 molecule that inhibits primary MM cells but is well-tolerated by other normal tissues. This in vitro stromal co-culture system provides a powerful tool to dissect the pathophysiology of human MM, and to screen new drugs for MM therapy.

Disclosures:
No relevant conflicts of interest to declare.
Modulation of Proinflammatory Cytokines and Insulinlike Growth Factor-1 (IGF-1) in Human Immunodeficiency Virus-1 Smoldering Multiple Myeloma (HIVSMM) Patients
Authors: McPherson Eugene , Tassy Philippe 
Published: October 2019

Abstract
Abstract 5043
Multiple myeloma is a B-cell malignancy involving germinal center B cells characterized by blood and urinary monoclonal proteins, osteolytic bone lesions and infiltration of bone marrow with plasma cells wit pathology involving aberrant chromosomal translocation with increased glucose uptake (Warburg Phenomena). This glucose transporter (GLUT) is activated and over expressed along with proinflammatory cytokines produced by malignant plasma cells both smoldering and multiple myeloma (MM). These cytokines may control growth, progression and dissemination. Interleukin-6 (IL-6) is a major cytokinetic growth factor in MM but IGF-1 is a more prominent growth factor that binds to IGF-1 receptor (IGF-1R) and is a strong indicator of prognosis which can augment anti-apoptotic effects of IL-6. Modulation of IGF-1 and proinflammatory cytokines in HIVSMM patients with ritonavir-based highly active antiretroviral therapy (RTV-based HAART) may suppress nuclear factor kappa b (NF Kb) and inhibit the overexpression of GLUT-1–4 required for HIVSMM growth and viability. A selenium adjuvant RTV-based HAART abrogates GLUT activity with specificity for GLUT-4 (prominent growth factor in MM cells. We present a 44 YOF with an with HIV disease, anemia, CD4 cell count of 74/cumm, viral load > 1 million copies/ml, SMM with IgG kappa/lambda 3. 68 grams/L, a hypocellular bone marrow biopsy with > 60 % plasma cell (polytypic) and with an increase in immature forms. Her serum free light chains (SFLC) on diagnosis was 324 mg/dl/121 mg/dl kappa/lambda ratio of 2. 68, bone scan with no evidence of lytic lesions and beta-2-microglobulin (B2MG) of 14. 40 mg/L: soluble interleukin-2 receptor (sIL2R) of 10, 833. 47 pg/ml; IGF-1 was 346 ng/ml (Nl = 94–250 ng/ml); selenium level was 137 mg/dl; C-reactive protein (CRP) of 38 mg/dl. After three years of selenium-RTV-based-HAART therapy her proinflammatory markers trended downward. CD4 cell count now is 348/cumm; viral load of 25. 7 copies/ml; SMM IgG 0. 972 grams/L; SFLC of 35. 9mg/dl/35mg/dl kappa/lambda ratio of 1. 03; B2MG of 2. 24 mg/L; sIL2R of 6546. 14 pg/ml; IGF-1 of 128 ng/ml; selenium of 150mg/dl; and CRP of 0. 26 mg/dl.

Conclusions:
Modulation of myeloma proinflammatory cytokines with protease inhibitor RTV, selenium adjuvant based HAART in HIVSMM patients may suppress the GLUT OVEREXPRESSION activity and prevent development TUMORGENESIS OF MM.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Value of Interim PET/CT in Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL). Experience of the Spanish Geltamo Group
Authors: Coronado Mónica , Pardal Emilia , Couto Rosa , de la Cruz Fatima , Panizo Carlos , Grande Carlos , Arranz Reyes , Ramirez María José , Hernández Roberto , Martin Alejandro , Caballero Dolores 
Published: October 2019

Abstract
Abstract 5076

Background:
Interim FDG-PET appears to be useful to guide risk stratification of patients with DLBCL, but remains controversial because the absence of consensus criteria for assessment. The reduction of maximum Standardized Uptake Value (SUVmax) between baseline and interim PET improves the accuracy and reproductibility of this method (Casasnovas, Blood 2011).

Patients and Methods:
A prospective non randomized phase II trial (EudraCT:2006-005254-68) was undertaken in young patients (pts) newly diagnosed of poor risk DLBCL. Therapy was changed after 3 cycles of R- MegaCHOP based on PET (using local assesment and visual scale); pts with positive PET received early salvage therapy. Primary end points were Progression free survival (PFS) and Overalll survival (OS). Retrospectively, central review was done by three experts using visual assessment (Deauville criteria) and semiquantitative asessment. Baseline and interim SUVmax, and ΔSUVmax were evaluated (cutt off ΔSUVmax: 66%). Significance of PET parameters in OS was analyzed.

Results:
71 pts were enrolled and central review was possible in 50 pts, from which 80% have complete follow up (mean 37, 6 months, 3. 4–56. 4). OS was significantly influenced by interim PET result, using visual (p=0. 046) but mainly by semiquantitative analysis (p=0. 0008). ΔSUVmax had impact on the overall survival (p=0. 007) whereas basal SUVmax did not.

Conclusions:
Our preliminary results show that outcome of DLBCL pts with a positive interim PET is worse despite change of therapy. Semiquantitative PET evaluation seems to be necessary, being ΔSUVmax a good prognostic parameter.

Disclosures:
No relevant conflicts of interest to declare.
HIF-1α Induces a Chemoresistance Phenotype in a Non-Hodgkin‘s Lymphoma Cell Line Via up-Regulation of Bcl-xL
Authors: Hernandez-Luna Marco A , Rocha-Zavaleta Leticia , Vega Mario I , Huerta-Yepez Sara 
Published: October 2019

Abstract
Abstract 5091
Non-Hodgkin's Lymphoma (NHL) is one of the most common cancers in childhood. The development of chemoresistance in tumor cells is one of the principal causes of treatment failure. This resistance has been associated to different mechanisms, being the overexpression of anti-apoptotic proteins such as Bcl-xL. It has been shown that this protein is regulated by the transcription factor HIF-1α, which is overexpressed in several tumors, including NHL, and the overexpression of both proteins may result in resistance to chemotherapy. We investigated the role of HIF-1α in resistance to chemotherapy via the induction of the Bcl-xL expression in NHL cell lines, using a pharmacological modulation of HIF-1α. Our data showed that treating the Ramos cell with ethyl 3, 4-dihydroxybenzoate, the inhibitor of prolylhydroxylase, induces accumulation of HIF-1α and this correlates with an increase of Bcl-xL as well as resistance to apoptosis after the exposition to chemotherapeutics drugs. In contrast, the treatment of Ramos cells with 2-methoxyestradiol, the inhibitor of HIF-1α activity, induced downregulation of the Bcl-xL expression, and this correlates with the sensitization of tumor cells to chemotherapeutic drugs. This data demonstrated that the up-regulation of the anti-apoptotic protein Bcl-xL in NHL cells correlates with HIF-1α expression and activity, through which induces a phenotype of chemoresistance.

Disclosures:
No relevant conflicts of interest to declare.
Anemia in Lymphoma: The Role of Cytokines
Authors: Shao Zonghong , Wang Ting , Tu Meifeng , Zhu Jun , Zheng Wen 
Published: October 2019

Abstract
Abstract 5103

Purpose
This study was to investigate the role that cytokines play in the pathogenesis of lymphoma associated anemia.

Methods
IFN-γ, IL-6, TNF-α, IL-1β and EPO in plasma samples from 45 lymphoma patients and 12 controls were analyzed using enzyme-linked immunosorbent assays and EPOR on their bone marrow cells were detected by flow cytometry. Their bone marrow CFU-E were cultured in vitro also.

Results
Of 45 initial lymphoma patients, 25 (55. 6%) had anemia before diagnosis, 13(28. 9%) had anemia during therapy, 7(15. 5%)never had anemia. Plasma IFN-γ and TNF-α levels were significantly higher in severe and moderate anemia patients than those in mild anemia patients, no anemia patients and controls. Patient's plasma EPO, IL-6 and IFN-γlevels showed an inverse correlation to their Hb. Lymphoma without anemia patients had significantly high bone marrow EPOR level than that of lymphoma associated anemia patients and controls. Patients bone marrow CFU-E showed positive correlation to their Hb and EPOR.

Conclusion
Increased plasma IFN-γ, TNF-α and IL-6 might contribute to anemia in lymphoma, EPO and EPOR levels were elevated to balance such negetive effects and maintain hemotopoiesis.

Disclosures:
No relevant conflicts of interest to declare.
Incidental Venous Thromboembolism in Kidney Cancer Patients: A Retrospective Case-Control Study
Authors: Yokom Daniel W , Ihaddadene Ryma , Le Gal Gregoire , Carrier Marc 
Published: October 2019

Abstract
Abstract 5134

Introduction:
The incidence of venous thromboembolism (VTE) in kidney cancer patients has been reported at 1. 2–3. 2% with an estimated hazard ratio for death of 1. 3–3. 2. Computed Tomography (CT) scans are used frequently to stage cancer, and as the resolution of the scans increases more incidentally discovered asymptomatic VTE are being diagnosed. Currently, it is unclear if incidentally found VTE have the same effect on survival as symptomatic VTE in kidney cancer patients.

Methods:
We undertook a retrospective case-control analysis of all kidney cancer patients treated at our institution between January 1, 2005 and July 1, 2012. Cases with VTE were matched in a ratio of 1:2 to controls by gender, age and stage at cancer diagnosis. All charts were reviewed for comorbidities at cancer diagnosis, cancer type, stage, and treatment plan. We reviewed imaging studies to identify the location of the VTE and whether it was unsuspected – which was defined as a VTE found on a CT which was indicated for cancer staging.

Results:
From a cohort of 1166 primary kidney cancer patients we identified 68 (5. 8%) patients who developed a VTE. There were 30 cases of pulmonary embolism (PE), 24 lower extremity deep vein thrombosis (DVT), 5 DVT of the upper extremity and neck and 9 intra-abdominal VTE. Of these, 35% were discovered incidentally and 65% were symptomatic.
Compared to matched controls, all patients with VTE did not have worsened survival (hazard ratio [HR] = 0. 87; 95% CI: 0. 54–1. 42). As demonstrated in Figure 1, symptomatic and incidentally discovered VTE were at no increased risk of death compared to controls (HR = 0. 72; 95% CI: 0. 40 – 1. 31 and HR = 1. 12; 95% CI: 0. 61 – 2. 27 respectively). Also, when looking specifically at symptomatic and incidentally discovered pulmonary embolisms, no difference in survival was detected (HR = 1. 44; 95% CI: 0. 68 – 3. 06 and HR = 0. 78; 95% CI: 0. 31 – 1. 97 respectively).

Conclusions:
In this analysis of kidney cancer patients we found a high rate of VTE (5. 8%) of which 35% were found incidentally on CT staging. The results from this study show that kidney cancer patients with VTE do not have worse survival outcomes than those without VTE. Moreover, the difference in survival between patients with any symptomatic VTE or PE does not differ from incidentally found VTE or PE.

Disclosures:
No relevant conflicts of interest to declare.