bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gadolinium Containing Contrast Agent Promotes Multiple Myeloma Cell Growth: Implication for Clinical Use of MRI in Myeloma.
Authors: Fulciniti Mariateresa , Sundararaman Swaminathan , Nanjappa Puru , Amin Samir B , Chevireddy Prajwal , Gokden Neriman , Hiatt Kim , High Whitney , Shammas Masood A , Prabhala Rao , Hideshima Teru , Tassone Pierfrancesco , Anderson Kenneth C. , Shah Sudhir V. , Munshi Nikhil C. 
Published: October 2019

Abstract
Abstract 1809
Poster Board I-835
Bone marrow infiltration by myeloma cells and osteolytic bone lesions are the major features of Multiple Myeloma. Magnetic Resonance Imaging (MRI) has been used in MM not only to image bone marrow (BM) and to identify lytic bone disease but to also evaluate therapeutic response and prognosis. Gadolinium (Gd)-based contrast agents are frequently used to enhance MRI resolution. We evaluated effect of the most common Gd-containing agent, Omniscan, on myeloma cells. We observed that Omniscan induced both time and dose dependent MM cell growth in vitro (8-20 fold increase relative to control). Importantly, the presence of BMSC enhanced the effect of Omniscan on growth of both MM cell lines and primary MM cells. However, Omniscan was not able to overcome cytotoxic effects of conventional and novel agents in MM. This growth promoting effects were not observed on normal BM stromal cells. Evaluating the molecular mechanism of action of Omniscan on MM cells, we observed time dependent ERK1/2 phosphorylation as well as reversal of growth promoting effects of Omniscan by specific inhibition of ERK signaling; however, Omniscan had no effect on STAT3 and AKT signaling pathways. Next, we investigated in vivo effect of Omniscan in a murine xenograft model of MM. Following detection of tumor, mice were treated with either iv Omniscan or PBS. Treatment with Omniscan significantly induced MM tumor growth compared to control mice (1042 ±243 mm3 vs 502 ±137 mm3 respectively; p=0.0001). Finally in autopsies in 8 MM patients with repeated exposure to Omniscan, we quantified gadolinium in various tissues using Inductively-coupled mass spectrometry. We observed massive quantities of gadolinium accumulation in tissues of these MM patients regardless of their renal function. These results, confirming both in vitro and in vivo growth promoting effects of Gd-containing contrast agent on MM, suggest the need for further analysis of the mechanism of its action on myeloma cells and careful analysis of its clinical impact in MM patients undergoing MRI evaluation.

Disclosures
No relevant conflicts of interest to declare.
A Clinically Usable Gene Expression Report for Risk Assessment and Identification of Possible Therapeutic Targets in Multiple Myeloma.
Authors: Meiβner Tobias , Seckinger Anja , Hielscher Thomas , Rème Thierry , Moreaux Jerome , Benner Axel , Bertsch Uta , Jauch Anna , Neben Kai , Möhler Thomas , Klein Bernard , Goldschmidt Hartmut , Hose Dirk 
Published: October 2019

Abstract
Abstract 1829
Poster Board I-855

Introduction
In addition to current clinical and cytogenetic risk factors, several highly predictive gene expression based risk stratifications have been proposed in multiple myeloma. At the same time, putative drugable targets have been identified which are only expressed in a subpopulation of myeloma patients (e.g. AURKA). Whereas assessment of both works well within a clinical trial or an experimental setting, they can currently not readily be applied to clinical routine.

Methods
As reference a group of 300 Affymetrix U133 Plus 2.0 DNA microarrays from patients with multiple myeloma is preprocessed using GC-RMA. Quality control of the DNA microarrays is implemented according to the MACQ-Project. Gene expression based prediction of sex, immunoglobulin- and light chain type is used as sample identity-test within a multicenter-setting. Gene expression based risk stratification (IFM-score, 70-gene high risk score, gene expression based proliferation index) and molecular classifications are assessed as published, as are individual target genes e.g. AURKA. To classify a patient within a prospective clinical routine setting, the documentation by value strategy (Kostka & Spang, 2008) was adapted for GC-RMA preprocessing and is used for documenting the quantitative preprocessing information of the reference group. The gene expression based report is developed in the open source language R, containing a GUI based on Gtk2, and the final report is created as a PDF-file.

Results
We present here our publicly available (http://code.google.com/p/gep-r) open source software-framework (GEP-R) that allows creating a gene expression based report from Affymetrix raw-data. The risk stratification of an individual patient is assessed and based on saved preprocessing information of a reference cohort by treating the individual patient's expression data as being part of this group, assuring comparable risk stratification. Results can be interpreted and commented within the report and a PDF based document be created. The generation of the report can be performed within short time on a standard computer.

Conclusion
Gene expression reporting allows validated assessment of risk and of individual therapeutic targets in myeloma patients within a clinical routine setting.

Disclosures
No relevant conflicts of interest to declare.
Significant Impact of IL-17A Gene Polymorphism On Transplant Outcomes After HLA-Fully-Matched Unrelated Bone Marrow Transplantation.
Authors: Takami Akiyoshi , Espinoza J. Luis , Onizuka Makoto , Kawase Takakazu , Katagiri Takamasa , Ohtake Shigeki , Morishima Yasuo , Fukuda Takahiro , Kodera Yoshihisa , Nakao Shinji 
Published: October 2019

Abstract
Abstract 2305
Poster Board II-282
IL-17 plays an active role in autoimmune diseases and organ transplant rejection through its mediating proinflammatory responses and inducing inflammatory cytokine and chemokine production. This study examined the impact of donor and recipient polymorphism in the IL-17A gene on the clinical outcomes in unrelated HLA-fully-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donor Program. The IL-17A polymorphism (rs2275913, G197A) was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. In patients with standard risk disease, the donor IL-17A-197A genotype was associated with significantly improved OS (adjusted HR, 0.32; 95% CI, 0.13-0.79; p=0.01) and reduced transplant related mortality (TRM) (adjusted HR, 0.27; 95% CI, 0.11-0.67; p=0.005), but no impact on disease relapse or the development of grades II-IV acute GVHD or chronic GVHD. Patients with standard risk disease receiving transplants from donors with the 197A genotype had better 5-year OS (71% vs. 40%, p=0.02; Figure) and lower 5-year TRM rate (27% vs. 60%, p=0.02). The IL-17A polymorphism did not significantly influence the transplant outcomes in patients with high risk disease. These results suggest transplantation from IL-17A-197A positive donor is advantageous in improving OS and reducing TRM after HLA-matched unrelated BMT for standard risk hematologic malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Autologous Transplantation for Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL).
Authors: Popat Uday , Hosing Chitra , Fanale Michelle , Medeiros L. Jeffrey , Alousi Amin M. , Giralt Sergio A. , de Lima Marcos J. , Qazilbash Muzaffar H. , Kebriaei Partow , Younes Anas , Khouri Issa , Andersson Borje , Champlin Richard , Anderlini Paolo 
Published: October 2019

Abstract
Abstract 2310
Poster Board II-287

Background:
NLPHL is an uncommon type of Hodgkin lymphoma characterized by nodules composed of large neoplastic B-cells (CD20+), lymphocyte predominant (LP) cells (previously known as L& H cells), associated with many small reactive B-cells. Patients with NLPHL typically have an indolent clinical course, but the disease can recur, often with histologic evidence of progression or transformation. Because of its rarity, limited information is available, mainly from retrospective studies. Very little information is available about salvage therapy particularly about the role of autologous transplantation in this disease. The purpose of this study was to evaluate outcomes of autologous transplantation in patients with relapsed or refractory NLPHL.
Patients and Methods: All patients with NLPHL who underwent autologous transplantation between January 1990 and December 2008 were included in this study. Pathology specimens were reviewed. The diagnosis of NLPHL was confirmed in all cases and, at time of transplant, many patients had histologic evidence of T-cell/histiocyte rich large B-cell lymphoma. During these 19 years, 26 patients (24 males) underwent autologous transplantation. Median age at transplantation was 35 years (range 13-51). At transplantation, 9 (35%) were in complete remission (CR); 13 (50%) were in partial remission (PR); and 4 (15%) had stable (SD) or progressive disease (PD). Median number of prior chemotherapy regimens was 3 (1-4). LDH was elevated in 10 (38%). Peripheral blood stem cells were used as stem cell source in 23 (86%) patients. Conditioning regimen were BEAM(10), BEAM-R(5), CBV(6), and other regimens in 5 patients. Peripheral blood stem cells were used as stem cell source in 23 (86%) patients.

Results:
Following transplant, 22 patients achieved complete remission. No treatment related mortality or treatment related MDS/AML occurred. Seven patients have relapsed. With a median follow up of 50 months (range, 2-138 months), the 5-year overall (OS) and event-free survival (EFS) were 76% (SE 9%) and 69%(SE 10%), respectively. For chemosensitive patients, The 5-year overall (OS) and event-free survival (EFS) were 82% (SE 10%) and 79% (SE 10%), respectively. Three out of 4 patients (75%) with chermoresistant disease relapsed compared to 4 out of 22 (18%) of patients with chemosensitive disease. Five patients died, all of recurrent disease.

Conclusion:
High-dose chemotherapy and autologous transplantation is highly effective in patients with refractory NLPHL or relapsed NLPHL including patients with histologic evidence of transformation to T-cell/histiocyte rich large B-cell lymphoma, and results in long term remission in most of patients.

Disclosures:
No relevant conflicts of interest to declare.
A Pathobiological Role of the Insulin Receptor in Chronic Lymphocytic Leukemia.
Authors: Malek Sami , Parkin Brian , Ouillette Peter , Kujawski Lisa , Erba Harry Paul , Campagnaro Erica L. , Kaminski Mark S. , Shedden Kerby , Saiya-Cork Kamlai 
Published: October 2019

Abstract
Abstract 2324
Poster Board II-301
The presence of genomic aberrations in CLL, including del17p and del11q, affects CLL patient survival, and thus an in-depth understanding of the genes influenced through these deletions is important. Further, genes affecting CLL disease progression that is observed in patients with recurrent genomic deletions, including del11q, remain incompletely characterized. Focusing therefore on del11q in CLL, we employed comparative expression array profiling (Affymetrix 133 2.0 plus arrays) of RNA from sorted CD19+ cells from 10 cases with and nine cases without del11q to identify stable transcriptome differences associated with del11q. Through these efforts we have identified for the first time differential expression of the insulin receptor (INSR) in CLL and predominant INSR expression in CLL with del11q. We have validated this finding in a cohort of 219 CLL cases. Our aggregate data suggest biologically and clinically meaningful INSR expression in a substantial subset of all CLL cases. INSR stimulation by insulin in CLL cells expressing the INSR resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated CLL cell apoptosis ex vivo. Clinically, CLL cases with INSR expression displayed larger lymphnodes and higher Rai stage at study enrollment and the disease progressed faster requiring repeat therapy earlier than CLL cases with low or absent INSR expression. This novel data provides the first description of a pathobiological role of the insulin receptor in CLL biology and disease progression, thus identifying a potential mediator and mechanism for del11q-associated CLL phenotypes. The identification of a transmembrane tyrosine kinase receptor with direct effects on CLL biology and clinical behavior offers opportunities for CLL prognostication and targeted therapy development and further strengthens the case for involvement of the INSR in cancer biology.

Disclosures:
Malek: Cephalon: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Affymetrix: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding.
Chronic Lymphocytic Leukaemia Drives the Production of T Regulatory Cells From the CD4+ CD25- Compartment with a CD27high/CD127 Low Phenotype.
Authors: Piper Karen , Karanth Mamtha , McLarnon Andrew , Kalk Emma , Khan Naeem , Murray Jim A , Pratt Guy , Moss Paul 
Published: October 2019

Abstract
Abstract 2330
Poster Board II-307
Patients with chronic lymphocytic leukaemia (CLL) have defects in both cellular and humoral immunity including changes in the numbers and function of T regulatory cells (Tregs). The identification of Tregs is an ever-evolving field and in this study we readdressed the phenotype using the markers CD25, FoxP3 and CD127-/lo and confirmed function by classical suppressor assays in CLL patients on and off treatment. Using the combination CD4 and FoxP3 we observed increased Treg frequencies in CLL patients, in particular with advanced disease, supporting previous studies showing an increase in Tregs in CLL. However in contrast to previous studies, there was no increase in the CD25+ FoxP3+ population in CLL patients rather the increase in FoxP3 expression occurred in the CD25- compartment of CLL patients. Interestingly CLL induced a 7-fold increase in the expression of FoxP3 in CD4+CD25- T cells following short-term co-culture. The T regulatory cells in CLL patients had a significantly higher expression of CD27 compared to healthy controls and although CD127 expression was low in both healthy and CLL patients it was significantly lower in CLL patients.
Fludarabine treatment initially induced increased expression of FoxP3 in the CD4+ T cell compartment but this declined gradually to reach levels below that pre-treatment. Here we propose that CLL drives the production of Tregs from the CD4+CD25- compartment as has been shown recently in Non-Hodgkins Lymphoma (NHL) and the mechanism of induction could provide alternative avenues for treatment.

Disclosures:
No relevant conflicts of interest to declare.
SHIP1 and PTEN Co-Inactivation and Akt Pathway Targeting in ALL.
Authors: Diccianni Mitchell B. , Barnhill Lisa M. , Lo Tony , Yu Alice L. 
Published: October 2019

Abstract
Abstract 2386
Poster Board II-363
Despite success in the treatment of Acute lymphoblastic leukemia (ALL), relapse and death continue to occur and in survivors, secondary malignancies due to the impact of aggressive chemotherapy negatively impact the quality and duration of life. Akt plays a central role in signal transduction and is negatively regulated by PTEN and, in cells of hematopoietic lineage, SHIP1; it is positively regulated by PIK3CA. Despite multiple levels of regulation, Akt is aberrantly activated in many cancers including ALL. To understand the mechanism behind Akt activation in ALL, PIK3CA, PTEN and SHIP1 genes were assessed in leukemia cell lines and primary samples. No sample harbored PIK3CA mutation. PTEN was expressed in just one-third of the cell lines analyzed, but in two-thirds of the primary ALL of both T- and B-lineage, though all were in the phosphorylated (inactivated) form. SHIP1 was expressed in all leukemia cell lines, except for Jurkat and K562 cell lines. In general, expression of SHIP1 protein was much higher in cell lines of the B-lineage than of the T-lineage. The Jurkat T-ALL cell line, long observed to lack SHIP1 protein, harbored biallelic inactivation by null mutation and a frame-shift deletion; no SHIP1 mutations were identified in the K562 cell line. In contrast to leukemia cell lines, no full length SHIP1 was detected in primary T-ALL, and only ∼20% of the primary B-precursor ALL expressed full length SHIP despite the expression of full length transcript. Both ALL lineages expressed truncated isoforms of SHIP, which cloning and sequence analysis revealed was due to premature termination resulting from the frame-shift and other translationally-inactivating alternative splicing. The co-inactivation of SHIP and PTEN may create therapeutic opportunities. The PI3KCA inhibitor LY294002 has been shown to sensitize glioblastoma and colon carcinoma to doxorubicin. To determine if these agents acted synergistically in T-ALL, cell lines Molt16 (SHIP1+/PTEN-), Jurkat (SHIP1-/PTEN-) and normal MNCs (SHIP1+/PTEN+) were subjected to various combinations of the PIK3CA inhibitor LY294002 and doxorubicin and cell proliferation and viability assessed. Normal cells were generally insensitive to both agents except at high concentrations. LY294002 and doxorubicin inhibited viability in Molt16 with IC50s of 10 uM and 0.1 ug/ml, respectively, with no evidence of synergy. Jurkat cells exhibited a similar IC50 to LY294002, but were more sensitive to doxorubicin (IC50s of 10 uM and 0.025 ug/ml, respectively), with the two agents demonstrating some synergy when added simultaneously at low concentrations. In summary, we present evidence of Akt pathway deregulation in T-ALL due to SHIP1/PTEN inactivation and suggest that agents targeting this pathway may provide new directions into the therapeutic treatment of T-ALL.

Disclosures:
No relevant conflicts of interest to declare.
Pseudonormokalemia in Patients with Thrombocytosis.
Authors: Goldman Raimonda , Steinberg Amir , Carreiro Jennifer , Panagopoulos Georgia , Cooper Marvin , Levine Randy L. 
Published: October 2019

Abstract
Abstract 2420
Poster Board II-397

Introduction:
Pseudohyperkalemia represents an artificial elevation in serum potassium concentration. It is well described that patients with thrombocytosis may have elevated serum but normal plasma potassium. The difference between serum and plasma potassium is felt to be due to potassium release from platelets during clotting. We propose that a similar mechanism will lead to “pseudonormokalemia,” where serum potassium appears to be in the normal range (3.5-5.0 MEq/L) despite below-normal levels in the plasma(<3.5 MEq/L).

Method:
The interim analysis of this study was sent for consideration to ASH Annual Meeting on November 2006 (108: 3964) We now present the final analysis by comparing 69 thrombocytosis patients (platelets>500,000/uL) to 68 control patients (platelets<500,000/uL). Patients were identified from a list of lab results generated by a computer search and serum and plasma potassium and CBC were then drawn simultaneously.

Results:
There was no statistically significant difference in sex distribution or age between the two groups. The average platelet count was 667,960/uL in the thrombocytosis group (SD 151,1 uL) and 286,790/uL (SD 103,9 uL) in the control group (p value <0.001). In both groups, serum potassium was higher than plasma potassium. The analysis comparing serum potassium levels between the two groups showed that serum potassium was significantly higher in the thrombocytosis group than in the control. In fact, we found a strong positive correlation (spearman's rho=0.61, p<.001) between platelet count and the difference in values in serum potassium minus plasma potassium. As the platelet count increases, so does the difference between the serum and plasma potassium. The thrombocytosis group was noted to have a difference between serum and plasma potassium of .51 MEq/L (SD .30 MEq/L) while the control group had a difference of .21 MEq/L (SD .20 MEq/L)

Conclusion:
Patients with thrombocytosis and normal serum potassium may actually be hypokalemic as this study demonstrates.

Disclosures:
No relevant conflicts of interest to declare.
The Quality and Accuracy of Hemophilia Information on the Internet.
Authors: Breakey Vicky R , Ignas Danial M , Denburg Avram E , Blanchette Victor S. 
Published: October 2019

Abstract
Abstract 244
The Internet has become a major source of health information for our patients, especially those with chronic illnesses. Hemophilia is an inherited bleeding disorder that is due to a deficiency of coagulation factor VIII (hemophilia A) or Factor IX (hemophilia B). There are many websites devoted to hemophilia, but currently there are no data on the quality of the information provided on the Internet. To assess the quality, accuracy and readability of information related to hemophilia that is available on the Internet, three reviewers (two physicians and one lay person with severe hemophilia A) reviewed the first three pages of hits for the search term “hemophilia” on the four most popular Internet search engines. The validated DISCERN rating instrument for written patient information was applied to assess the general quality of the information (Charnock et al. 1999). Content was assessed for breadth and accuracy using an adapted Checklist Rating System Instrument (Bichakjian et al. 2002). The World Federation of Hemophilia's “Guidelines for the Management of Hemophilia” were referenced as the gold standard of hemophilia information. Readability was assessed using the Flesch Reading Score and the Flesch-Kinkaid Grade level score. After omission of duplicates and inaccessible sites, a total of 31 websites were reviewed. The sites were 42% commercial, 29% institutional and 29% charitable. Reviewers showed good inter-rater reliability when assessing overall quality with the DISCERN tool, with a quadratic weighted kappa >0.6. Four websites (13%) contained a total of 15 inaccuracies. Readability of the five most highly-rated websites suggests that content is written at the equivalent of a grade 10/11 level, much higher than the grade 8 level suggested for patient education materials. In conclusion, the 31 websites containing hemophilia-related information varied widely in the content and quality of information with 13% of sites citing inaccuracies. Hemophilia treatment centers should be aware of the hemophilia resources available on the Internet and must guide patients in finding the most comprehensive and accurate information. Health care providers should be actively involved in the development of thorough and accurate web-based hemophilia education that is written at an appropriate level to meet the needs of our patients.

Disclosures:
Breakey: Baxter: Educational Grant for Hemophilia Patient Education. Blanchette:Baxter Healthcare Corporation: Educational Grant for Work in Hemophilia, Honoraria.