bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparin Forms Macromolecular Complexes with Protamine and Lysozyme.
Authors: Chudasama Shalini , Espinasse Benjamin , Wiesner Mark R , Arepally Gowthami M 
Published: October 2019

Abstract
Abstract 1316
Poster Board I-340
The immune response in Heparin-Induced Thrombocytopenia (HIT) is directed to and initiated by large multimolecular complexes of Platelet Factor 4 (PF4) and heparin. We, and others, have previously shown that PF4 and heparin multimolecular assembly occurs through colloidal interactions, wherein heparin, a negatively charged polymeric compound, facilitates macromolecular assembly by binding and neutralizing PF4's positive charge (Suvarna, Blood 2007). In these same studies, we also demonstrated that changes in the molar ratios of the two reactants result in PF4/heparin (PF4:H) complexes with markedly altered biophysical properties and immunogenicity. Because PF4:H electrostatic interactions are non-specific, we hypothesized that other positively charged proteins would exhibit similar colloidal interactions with heparin. To test this hypothesis, we selected two positively charged proteins (protamine and lysozyme) and studied heparin-dependent complex formation by spectrophotometry (A280nm), and zeta potential (Zeta Sizer, Malvern, UK). Protamine sulfate (250, 125, 62.5, 31.2, 15.6 and 7.8 mcg/mL; Mw 5.1kDa) and lysozyme (1000, 500, 250 and 125 mcg/mL; Mw 14.3kDa) were mixed with various heparin concentrations (0-160 U/mL; activity 140U/mg; Mw 12kDa) and biophysical properties characterized by both instruments. Both protamine and lysozyme showed heparin-dependent complex formation, with peak particle formation occurring over a range of heparin concentrations (2-25 U/mL ) for both compounds. For protamine, particle formation was maximal at protamine:heparin (Pr:H) molar ratios of ∼2.5-3:1, whereas lysozyme formed peak particles at lysozyme;heparin (Ly:H) molar ratios of ∼5:1 (See figure). As with PF4:H complexes, size of complexes was dependent on mass amounts of protamine or lysozyme, with particle size increasing or decreasing in proportion to the amounts of protamine or lysozyme available for complex formation. These findings indicate that heparin is capable of forming macromolecular complexes with other proteins through charge dependent interactions. Additional in vitro and in vivo studies are underway to determine if Pr:H or Lys:H complexes exhibit cross-reactivity with PF4/heparin antibodies and if complex formation is associated with immunological consequences.

Disclosures
No relevant conflicts of interest to declare.
ATP Acts as Danger Associated Molecular Pattern and Enhances Acute Graft-Versus-Host Disease Severity Via P2×7-R.
Authors: Wilhelm Konrad , Müller Tobias , Ganesan Jayanthi , Dürr Christoph , Gerlach Ulrike , Zerweck Alf , Finke Jürgen , Idzko Marco , Zeiser Robert 
Published: October 2019

Abstract
Abstract 1336
Poster Board I-358
Conditioning prior allogeneic hematopoietic cell transplantation causes local tissue injury. Cellular molecules that are released upon cell stress, injury or cell death can act as potent danger associated molecular patterns (DAMP). Nucleotides like ATP are ideal candidates to serve as such indicators of cell damage, since they are present in the extracellular environment in the nanomolar range under physiological conditions but are released upon unphysiological cell death which causes activation of purinergic receptors. The role of purinergic signaling in alloantigen driven immune responses such as graft-versus-host disease (GvHD) is unclear. We found that ATP levels in the peritoneal fluid increased when GvHD was present in human and mice. Detection of extracellular ATP with a luciferase based in vivo detection system demonstrated early ATP release from the gastrointestinal tract. Blockade of multiple purinergic receptors on T cells or ATP neutralization during GvHD development reduced disease severity and proinflammatory cytokine production significantly. Gene expression analysis of different P2R in GvHD target organs identified the P2X7(R)receptor to be increasingly expressed. P2X7R−/− recipients developed less severe GvHD as compared to wildtype mice. This was paralleled by the induction of STAT5 signaling with increased numbers of Foxp3 positive regulatory T cells while STAT1 phosphorylation and IFN-γ production was reduced. Despite P2X7R blocking, T cells were still able to reconstitute the lymphoid compartment with a polyclonal intact TCR repertoire analyzed by spectratyping DNA sequence analyses of the CDR3 region and to reject established B-cell lymphoma. Therefore, DAMPs such as endogenous nucleotides may not be required for anti-tumor activity but dominantly trigger acute GvHD. Blockade or genetic deficiency of P2X7R in BMT recipients conferred GvHD protection without loss of GvL effects, which has important clinical implications given the availability of P2X7R inhibitors.

Disclosures
No relevant conflicts of interest to declare.
Mutual Activation and Expansion of Donor CD4 + T Cells and B Cells in Transplants Play a Critical Role in the Initiation of Chronic Graft-Versus-Host Disease.
Authors: Young James Sundblom , Zhao Dongchang , Yi Tangsheng , Liu Hongjun , Zeng Defu 
Published: October 2019

Abstract
Abstract 1342
Poster Board I-364
Chronic graft versus host disease (GVHD) is an autoimmune-like disease, in which both donor CD4+ T and B cells play important roles in the pathogenesis. However, it is unclear how donor CD4+ T and B cells interact in the context of chronic GVHD. In our current studies, we found that, in a new chronic GVHD model of MHC-matched DBA/2 donor to BALB/c host, depletion of donor CD4+ T cells in transplants prevented donor B220+ B cell upregulation of co-stimulatory molecules (i.e. B7.1, B7.2, and MHC II), prevented donor B cell differentiation into syndecan+ IgG anti-dsDNA autoantibody-producing plasma cells, and prevented the induction of chronic GVHD. In addition, we found that donor CD4+ T cells were able to drive both marginal zone B (AA4.1−B220+CD1dhiCD23lo) and follicular B (AA4.1−B220+CD23hiCD1dlo) cells to become IgG autoantibody-producing cells. On the other hand, depletion of donor B220+ B cells in transplants prevented expansion of donor-type CD4+ T cells that proliferated in response to donor DC stimulation, prevented the skewing of TCR CDR3-length of the donor CD4+ T cells as revealed by TCR spectratyping, and prevented induction of chronic GVHD. These results indicate that donor CD4+ T and B cells mutually activate each other in the chronic GVHD recipients; alloreactive donor CD4+ T cells activate and drive donor B cell differentiation into IgG autoantibody producing cells, in turn, donor B cells mediate the expansion and TCR-spreading of autoreactive donor CD4+ T cells. Therefore, donor CD4+ T and B cells in transplants orchestrate the development of chronic GVHD. This work is supported by NIH R01 AI066008.

Disclosures
No relevant conflicts of interest to declare.
Elevated Pre-Treatment Serum Immunoglobulin Free Light Chains (FLC) Are Associated with Poor Event-Free and Overall Survival in Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Maurer Matthew J , Micallef Ivana N , Katzmann Jerry A , Nikcevich Daniel , Witzig Thomas E 
Published: October 2019

Abstract
Abstract 136

Background:
The serum free light chain (FLC) assay quantitates free kappa and free lambda immunoglobulin light chains. This assay has prognostic value in MGUS, multiple myeloma (MM), solitary plasmacytoma, and AL amyloidoisis, and has been incorporated in response criteria for both MM and AL amyloidosis. A percentage of non-Hodgkin's lymphoma (NHL) patients also present with abnormal FLC concentrations and recent data suggest that AIDS patients with elevated serum FLC are at higher risk of developing NHL. Here we assess the impact of FLC in a cohort of patients with diffuse large B-cell lymphoma (DLBCL) enrolled on a cooperative group clinical trial.

Methods:
Newly diagnosed DLBCL patients were treated with epratuzumab + R-CHOP (ER-CHOP) on NCCTG clinical trial N0489. Serum FLC was quantitated prior to treatment and after cycles 2 and 6 using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Patients were followed per clinical trial protocol for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively).

Results:
107 patients were enrolled on the trial. 80 patients had a pre-treatment serum draw and a central pathology confirmed diagnosis of DLBCL, of which 47 had a post-cycle 2 sample (C2) and a 54 had a post-cycle 6 sample (C6). At a medium follow-up of 25 months (range 7-39), 22 patients (28%) had an event and 17 patients died (21%). Prior to treatment 23 patients (29%) had abnormal kappa concentrations (all elevated), 16 (20%) had abnormal lambda concentrations (11 elevated, 5 decreased), and 9 (11%) had an abnormal kappa/lambda ratio. FLC concentrations were significantly reduced in patients during treatment, with a median reduction in kappa (C2: 46%, C6: 64%) and lambda (C2: 44%, C6: 49%), all p<0.0001. Elevated FLC prior to treatment was highly associated with both OS (logrank p=0.009) and EFS (logrank p=0.006); these associations remained significant after adjusting for IPI (both p = 0.01).

Conclusions:
A significant percentage of DLBCL patients present with abnormal FLC concentrations. Kappa and lambda are significantly reduced for most patients during treatment. Elevated pre-treatment FLC concentrations are associated with inferior EFS and OS in DLBCL and this association is independent of the IPI. A follow-up study of FLC and prognosis is currently underway in a cohort of 1500 NHL patients from the Mayo Clinic and University of Iowa SPORE.

Disclosures:
No relevant conflicts of interest to declare.
The C677T Methylenetetrahydrofolate Reductase Polymorphism and Insulin Resistance in Childhood Cancer Survivors.
Authors: Bishop Lisa Ann , Steffen Lyn M , Tsai Alex , Hanson Naomi , Baker K. Scott , Dengel Donald R. , Kelly Aaron , Sinaiko Alan R. , Petryk Anna , Moran Antoinette , Perkins Joanna Lee , Lundsford-Lee Jill , Steinberger Julia 
Published: October 2019

Abstract
Abstract 1400
Poster Board I-422

Introduction:
Childhood cancer survivors have increased risk for cardiovascular disease and insulin resistance. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and low folate are associated with higher levels of homocysteine and changes in methylation status; these factors, in particular the TT and CT genotypes have been associated with insulin resistance in animal and human models. The CT genotype is present in about 25 % of the healthy US population. Vitamin B12 is an important co-factor in this association. The homocysteine/methionine ratio has been used as an indirect marker of methylation status and MTHFR function.

Population and Methods:
This analysis includes children (n=156) who survived ≥ 5-yrs following diagnosis of acute lymphoblastic leukemia (ALL) (n=55), acute myeloid leukemia (AML) (n=4), and non-Hodgkin's lymphoma (NHL) (n=13), central nervous system tumors (38) and other cancers (n=46). Mean age at diagnosis was 10.3 yrs (5.7-15.8) and mean age at evaluation was 15.0 yrs (9.9-17.9). Anthropometric measurements, blood pressure (BP), fasting glucose, insulin, lipids, folate, vitamin B12, homocysteine, and methionine were collected. Insulin resistance was assessed by euglycemic hyperinsulinemic clamp, adjusted for lean body mass (low Mlbm represents insulin resistance, less than 50% of distribution). Genetic polymorphisms, of MTHFR CC (wildtype) CT (heterozygous) and TT (homozygous) were identified; comparisons between MTHFR polymorphisms were adjusted for age, gender, and Tanner stage.

Results:
CC genotype was present in 44%, CT in 47.3 %, and TT in 8.7 % of survivors. Folate and B12 levels were lowest in the TT group, although not statistically significant (P value >0.05). Insulin resistance was most prevalent in the CT group and least prevalent in the TT group. The homocysteine/ methionine ratio was lowest in the CT group and highest in the TT group. Measures of adiposity were similar in all three groups (Table).

Conclusion:
This study suggests an increased frequency of the CT genotype in this study population of childhood cancer survivors compared to the healthy US population. Insulin resistance was most prevalent in the CT group; however, this was not associated with low levels of folate, B12, or high homocysteine/methionine ratio. The low frequency of insulin resistance in the TT group likely reflects the small number of participants with this genotype. Further study of these variables in larger populations is needed to provide sufficient power in assessing these relationships in childhood cancer survivors.

Disclosures:
No relevant conflicts of interest to declare.
Inpatient Geriatric Assessment Detects Impairment Among Older Adults Receiving Induction Chemotherapy for Acute Myelogenous Leukemia.
Authors: Klepin Heidi D , Geiger Ann M , Williamson Jeff , Kritchevsky Stephen , Tooze Janet A , Ellis Leslie Renee , Levitan Denise , Isom Scott , Powell Bayard L. 
Published: October 2019

Abstract
Abstract 1401
Poster Board I-423

Background:
Acute myelogenous leukemia (AML) is a disease which largely affects older adults, for whom optimal therapy is unclear. Evidence-based strategies to identify those older adults who may tolerate and benefit from standard therapies are lacking.

Objective:
Test the utility of a bedside geriatric assessment (GA) to detect impairment in multiple geriatric domains among older adults initiating induction chemotherapy for AML.

Methods:
Ongoing prospective study of patients ≥60 years of age with newly diagnosed AML and planned induction chemotherapy admitted to Wake Forest University. Bedside geriatric assessment (GA) was performed during inpatient work-up for AML. GA measures included the Modified Mini-Mental Status Exam (3MS), Center for Epidemiologic Studies Depression Scale (CES-D), Distress thermometer, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), Pepper Assessment Tool for Disability ([PAT-D], includes self- reported activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility questions), Short Physical Performance Battery ([SPPB], includes timed 4-meter walk, chair stands, standing balance), and grip strength.

Results:
26 of 29 eligible patients enrolled between 1/2009 and 8/2009. The median age was 68 (range 60-82) years, and 42.3% were female. Prior myelodysplastic syndrome was present in 34.6%, with intermediate or poor-risk cytogenetics in 95.6%. Baseline laboratory measures included white blood cell count (mean 17.3×103/mm3, SD 25.0×103), hemoglobin (mean 9.2g/dl, SD 1.5), lactate dehydrogenase (mean 282.4 U/L, SD 168.8). Mean baseline GA scores included: 3MS 83.0 (SD 14.7), CES-D 9.4 (SD 9.3), Distress 3.8 (SD 3.4), HCT-CI 1.3 (SD 1.6), PAT-D 1.4 (SD 0.7), SPPB 7.1 (SD 3.9), grip strength 32.4 kilograms (SD 9.2). Although 84.6% of subjects had an Eastern Cooperative Oncology Group (ECOG) Performance score <2, a substantial proportion met criteria for impairment in multiple geriatric domains.

Conclusions:
GA measures detect abnormalities which are not adequately reflected by the ECOG performance score in older adults with AML. Future analyses from this ongoing study will evaluate whether these abnormalities are independently associated with treatment-related morbidity and survival.

Disclosures:
No relevant conflicts of interest to declare.
Diet, Lifestyle and Venous Thromboembolism (VTE) in Thai Population.
Authors: Rojnuckarin Ponlapat , Bhoopat Lantarima , Hiransuthikul Narin , Intragumtornchai Tanin 
Published: October 2019

Abstract
Abstract 1414
Poster Board I-437

Introduction:
Previous studies demonstrated that the incidence of venous thromboembolism (VTE) was very low among Thais (Lancet. 1975; 1: 1357-8, Arch Intern Med. 1988; 148: 1349-53). However, recent investigations in Asian countries strongly indicated that VTE is currently much more common, approaching rates in the western countries. Meanwhile, the latest National Health Surveys showed the inadequate vegetable and fruit intakes, as well as an obvious rise in prevalence of obesity in Thai population. Therefore, changing diet and behaviors are suspected to contribute to this marked increase in the VTE incidence.

Patients and Methods
The case-control study was conducted. Cases were objectively confirmed venous thromboembolism. Patients with underlying cancer, antiphospholipid syndrome and arterial thrombosis were excluded. Controls are age- and sex-matched healthy volunteers. Body mass indices, history of alcohol intake, smoking and exercise were obtained. Food consumptions were interviewed using a food frequency questionnaire modified from the Thailand National Health Examination Survey III previously validated in Thai population.

Results:
There were 97 cases and 195 controls. The mean age was 54.6 yr, ranging from 17-93 yr, and 70% were female. VTE was significantly associated with low vegetable intakes (below 3.5 standard servings per day) compared with controls (Odd ratio [OR] 2.5, 95% confidence interval [CI] 1.37-4.67), while there was no difference in fruit consumption (p values =0.53). Notably, low fish intakes (below 0.1 serving per day, OR 3.9, 95%CI 1.58-9.71) and having spicy food less than once a week (OR 1.9, 95%CI 1.15-3.18) also increased the risk. The meat, fat, carbohydrate, fast food or alcohol consumptions were similar. In addition, VTE was associated with overweight (OR 2.1, 95%CI 1.21-3.62) and obesity (OR 3.1, 95%CI 1.46-6.74, p values = 0.002 and 0.001, respectively). Furthermore, estrogen uses also increased the risk of VTE (OR 3.7, 95% CI 1.05-13.20, p=0.02), while smoking and lack of exercise did not.

Conclusions:
Low vegetable, fish and spicy food intakes, as well as obesity and hormonal uses, are the risk factors for VTE in Thai population.

Disclosures:
No relevant conflicts of interest to declare.
Impact of Physician to Physician Interactions Utilizing Case Based Learning Workshops to Accelerate Accrual to Lymphoma Trials.
Authors: Eckardt John , Ku Nora , DeMaggio Annemieke , Peracha Omair , Levonyak Nick , Reese Merrick H. , Levonyak Mark , Jain Vinay 
Published: October 2019

Abstract
Abstract 1418
Poster Board I-441

Introduction:
Seventy percent of clinical trials in the United States are delayed by one to six months due to enrollment challenges. Barriers to accrual are site specific as well as protocol specific. Site specific challenges include perceptions of patient ineligibility and cumbersome screening processes. Protocol barriers include complexity of inclusion and exclusion criteria. Coomis et al (J Onc Prac 2009; 5:50) reported that 73% of overall clinical trial awareness was generated by physician interest. Therefore, the familiarity of investigators with each trial is crucial to optimizing patient accrual. The standard protocol initiation process relies on investigators and staff to attend an investigator's meeting. However, this approach does not focus on actual clinical patient presentations to determine trial eligibility or exclusion. As a result, many investigators may overlook key criteria for eligibility thus losing patients to enrollment. We have previously shown that interventions directly with PIs to increase PI awareness of inclusion/exclusion criteria of a clinical trial results in improved trial accrual (ASCO 2009, abs 6613).

Methods:
Investigator focused Accrual Workshops (AW) are used to increase patient enrollment to oncology clinical trials. While a standard investigator meeting includes protocol review, AW first create a compelling scientific story to re-engage the investigators in the trial. The key to these AW is the use of case-based learning to highlight the clinical and scientific rationale of the trial as opposed to general protocol review.

Results:
Between May 2008 and May 2009, 14 AW were conducted for 5 separate studies including 2 lymphoma trials. The AW with less than 120 days of follow up (n=5) show no significant impact although there was a trend toward increased accrual. In those with more than 120 days of follow up (n=9), the mean increase in accrual was 108% with increased accrual following every AW (Figure 1). After those 9 AW, patient accrual per month increased 1.65 fold on average. Analysis of the 2 lymphoma clinical trials demonstrates a significant increase in accrual following AW of 230% and 40%, respectively.

Conclusion:
AW using physician to physician clinical case-based learning provide an effective means of educating investigators and research staff in the identification of patients who meet the criteria for participation in clinical trials. The impact of AW on clinical trial accrual is best seen over time and they are effective in lymphoma clinical trials as well as others. After every AW with more than 120 day follow up, accrual was accelerated.

Disclosures:
No relevant conflicts of interest to declare.
Arterial and Venous Thrombosis in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma: A Population-Based Study.
Authors: Kristinsson Sigurdur Y , Pfeiffer Ruth , Bjorkholm Magnus , Goldin Lynn R , Schulman Sam , Blimark Cecilie , Mellqvist Ulf-Henrik , Wahlin Anders , Turesson Ingemar , Landgren Ola 
Published: October 2019

Abstract
Abstract 1872
Poster Board I-897

Background
Patients with multiple myeloma (MM) have an increased risk of venous thrombosis. Additionally, MM has been associated with arterial thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of undetermined significance (MGUS).

Methods
Using population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18,627 MM and 5,326 MGUS patients, compared to 70,991 and 20,161 matched controls, respectively. Hazard ratios for thrombosis, at 1, 5, and 10 years follow-up were calculated using Cox proportional hazard models.

Results>
At 1, 5 and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4–8.9), 4.6 (4.1–5.1), and 4.1 (3.8–4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8–2.1), 1.5 (1.4–1.6), and 1.5 (1.4–1.5). At 1, 5 and 10 years after MGUS diagnosis, hazard ratios were 3.6 (2.6–4.9), 2.2 (1.8–2.6), and 2.1 (1.8–2.5) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5–1.9), 1.3 (1.2–1.4), and 1.3 (1.3–1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis with hazard ratios 4.5 (2.8–7.2) and 1.6 (1.3–1.9) 1 year and 2.2 (1.7–2.8) and 1.2 (1.1–1.4) 5 years after diagnosis. Risks for thrombosis did not vary by M-protein concentration (above/below 10.0 g/L) at diagnosis. MGUS patients with (versus without) thrombosis had no excess risk of MM progression.

Conclusion
In this large study including more than 5,000 MGUS patients and 18,000 MM patients, and their matched controls, we found that both MGUS and MM patients had an increased risk of venous as well as arterial thrombosis. Among MGUS patients, an excess risk of thrombosis was observed in patients with IgG/IgA MGUS, but not IgM. Future studies are needed to clarify underlying mechanisms of our findings. Such efforts will be of relevance for physicians managing MGUS and MM patients and have potential implications for the development of better thrombosis prophylaxis strategies.

Disclosures:
Mellqvist: Johnson and Johnson: Research Funding; Celgene: Speakers Bureau; Jansen-Cilag: Speakers Bureau.