bluuebunny/crossref_metadata_2025_split huggingface dataset:
MGN1703, a Novel TLR9-Agonist - Results of a Phase 1 Clinical Trial in Patients with Metastatic Malignancies.
Authors: Weihrauch Martin R , Schmidt Manuel , Tschaika Marina , Richly Heike , von Bergwelt-Baildon Michael S , Hacker Ulrich , Shimabokuro-Vornhagen Alexander , Wittig Burghardt , Scheulen Max E 
Published: October 2019

Abstract
Abstract 4730

Background
The DNA-based immunomodulator MGN1703 stimulates the innate and cellular immune system mainly via the TLR9-receptor. The results of the recent in vivo experiments showed potent anti-tumor efficacy of MGN1703 in several mouse tumor models in prophylactic and therapeutic settings as well as a good safety profile in various animals. Two investigator-initiated pilot trials of MGN1703 as adjuvant in patients with metastatic solid tumors also showed good safety and tolerability of the drug as well as a positive effect on the response rate in patients treated with MGN1703.

Patients/Methods
In this Phase 1 clinical trial MGN1703 is administered subcutaneously in escalating doses (0.25 mg, 2 mg, 10 mg, 30 mg, and 60 mg; 3-6 patients per group) either in a single or in a multiple (2x / week over 6 weeks) dose regimen. Patients with metastatic tumors of the following entities are recruited for the study, if no other standard treatment options are available: Colorectal cancer, breast cancer, lung cancer, renal cell carcinoma and melanoma. Primary endpoints are evaluation of the safety and tolerability of escalating single doses and of escalating multiple doses of s.c. administered MGN1703, determination of the maximum tolerated dose (MTD) and dose limiting toxicity (DLT), and recommendation of a dose for a Phase 2 trial in patients.

Results
Currently, 12 patients have been treated and evaluated in the single dose groups of 0.25 mg, 2 mg, 10 mg and 30 mg (3 patients each). In the multiple dose group, 4 patients have been treated with 0.25 mg, 3 patients with 2 mg, 3 patients with 10 mg and 3 patients with 30 mg MGN1703, so far. Therapy was well tolerated except for sporadic transient symptoms as mild redness and induration of injection sites in two patients, increase of temperature to 38 °C in one patient, and fatigue in two patients. In the 0.25 mg group, one patient showed a stable disease (SD, according to RECIST) after 6 weeks of treatment, and in the 2 mg group, 3 of 3 patients showed a SD after 6 weeks. Treatment results of the last 2 dosing groups are pending. The four patients, who responded to the treatment with MGN1703, were treated with MGN1703 for further 6 weeks within an extension phase of this clinical trial. Two of them still had a SD after 12 weeks of treatment.

Conclusions
MGN1703 showed safety and tolerability at dosages up to 30 mg so far. The detailed evaluation of clinical and immunological responses is still ongoing. There has been no DLT at this point of the Phase 1 trial.

Disclosures:
Weihrauch: MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees. Schmidt:MOLOGEN AG: Employment. Tschaika:MOLOGEN AG: Employment. Wittig:MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees.
Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE.
Authors: Bruzzone Santina , Fruscione Floriana , Morando Sara , Poggi Alessandro , Garuti Anna , Selmo Martina , Ferrando Tiziana , Benvenuto Federica , Cea Michele , Soncini Debora , Moran Eva , Rocco Ilaria , Cirmena Gabriella , Zoppoli Gabriele , Ballestrero Alberto , Sordat Bernard , Patrone Franco , Uccelli Antonio , Nencioni Alessio 
Published: October 2019

Abstract
Abstract 4732
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866 mediated Nampt inhibition. As a consequence, impaired proliferation, reduced TNF-a production, ATP shortage, and, finally, autophagic cell demise result. We demonstrate that upregulation of the of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. We relate defective TNF-a production in response to FK866 to impaired SIRT6 activity. Finally, in line with its capacity to interfere with T lymphocyte function and survival, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly sirtuin inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.

Disclosures:
No relevant conflicts of interest to declare.
Risk Factors for Candidemia in Pediatric Oncology Patients.
Authors: Zaoutis Theoklis E , Prasad Priya A , Localio A. Russell , Reilly Anne , Bell Louis M , Walsh Thomas J , Gross Robert 
Published: October 2019

Abstract
Abstract 4735

Background
Candida species are among the most common causes of bloodstream infection and are associated with significant morbidity and mortality, particularly in oncology patients. Few studies have identified the risk factors for candidemia in pediatric oncology patients.

Methods
We conducted a nested case-control study within a cohort of pediatric patients admitted to the oncology unit at a children's hospital between 2001 and 2004. A case was defined as a patient with a positive blood culture for Candida spp. As time at risk is an important confounding variable in nosocomial studies assessing antibiotic risk factors, we selected two controls per case based on incidence-density sampling. Demographic and clinical data were collected by medical record review. Assessment of exposures was focused on the 2 weeks prior to the development of infection (case)/study entry (control). Conditional multivariate analyses were performed to determine independent risk factors for candidemia.

Results
We identified 45 oncology patients with candidemia during the study period. The most commonly isolated species were C. albicans (49%), C. parapsilosis (18%), C. glabrata (9%), and C. lusitaniae (9%). The median age of cases was 6.2 years (Interquartile Range (IQR): 2.9– 13.8 years). Median time to candidemia was 12 days (IQR: 4-22 days). There was no significant difference in mortality between cases (7%) and controls (7%). Independent risk factors for candidemia included receipt of aminoglycosides for >3 days (OR: 10.51, CI: 2.96, 64.43), receipt of total parenteral nutrition (OR: 13.82, CI: 2.48, 44.49), and Graft versus Host Disease (GVHD) (OR: 15.09, CI: 0.91, 250.24).

Conclusion
The receipt of aminoglycosides for >3 days, use of TPN, and GVHD were independently associated with candidemia in pediatric oncology patients. These results may inform targeted interventions to reduce the risk of candidemia in pediatric oncology patients.

Disclosures:
Zaoutis: Merck & Co.: Research Funding; Cephalon: Research Funding; Enzon: Research Funding.
Combined Phosphoepitope Specific Flow Cytometry and MHC-Multimer Staining - A New Tool to Monitor Antigen-Specific Signaling in CMV-Specific T-Cells.
Authors: Kapp Markus , Thiele Rainer , Baumeister Elke , Fick Kerstin , Stuhler Gernot , Opitz Andreas , Einsele Hermann , Grigoleit Götz Ulrich 
Published: October 2019

Abstract
Abstract 4737
Flow cytometry has become a routine method in both clinical and basic immunological research. Its ability to differentiate between distinct populations of cells by surface staining of various parameters is a main advantage since we have the possibility to identify antigen-specific T-cells by flow cytometry through the development of soluble multimeric peptide–MHC complexes. Nevertheless, surface staining does not provide information about the functionality of the analyzed cell populations. Hence, further methods have been described to define cells by detection of intracellular epitopes. These assays include the intracellular staining of distinct cytokines or phosporylated signaling molecules (Phosflow). MHC-multimer approaches combined with intracellular cytokine staining are routinely used, whereas the detection of intracellular p-kinases under MHC-multimer staining applying the Phosflow-protocols has not been realized so far. The use of phosphoepitope analysis in antigen-specific T-cells is of high interest in infections or especially during immunosuppressive drug treatment. Therefore, we aimed to establish a dual multimer-phospho-staining protocol to provide a method to get insight into the biochemical signaling processes in antigen-specific T-cells. We chose CTL responses against CMV as model system due to well established epitopes and high frequency in healthy donors. The original Phosflow-protocols did not turn out to be suitable for a combination with MHC-multimer staining. The very harsh fixation and permeabilization procedures largely or completely abrogated the antigen-specific staining. We have been able to stain both the CMV-specific T-cell-receptor and phosphorylated kinases following polyclonal stimuli (e.g. PMA, IL-2 etc.) using different protocols for some p-kinases (ERK, STAT5, NfKB, p38). These protocols allow a combination of specific T-cell-receptor staining with that of intranuclear phosphoepitopes after polyclonal stimulation. In preliminary experiments, we have also been able to show a specific phosphorylation of the ERK molecule after stimulation with CMV-specific artificial antigen-presenting cells or antibody-coated plates. As mentioned above, the use of phosphoepitope analysis in antigen-specific T-cells may offer the possibility to correlate immunological anergy with distinct signaling processes in defined clinical situations, e.g. in immunosuppressed patients post alloSCT.

Disclosures:
No relevant conflicts of interest to declare.
Multicentric prospective Study of Differential Treatment for Elderly Patients Affected by Aggressive Non Hodgkin Lymphoma Based On a Geriatric Multidimensional Analysis.
Authors: Gini Guido , Olivieri Attilio , Bocci Caterina , Catarini Massimo , Visani Giuseppe , Montanari Mauro , Guiducci Barbara , Isidori Alessandro , Brunori Marino , Alesiani Francesco , Giuliodori Luciano , Marcellini Massimo , Offidani Massimo , Caraffa Patrizia , Stronati Andrea , Capelli Debora , Trappolini Silvia , Leoni Pietro 
Published: October 2019

Abstract
Abstract 4775
From November 2002 to March 2006 in the centres of the region Marche participating in the study have been diagnosed 91 new cases of lymphoma B diffuse large cells in patients aged 65 years or more.
All the 91 patients enrolled prospectively in our study were assessed on the basis of multidimensional geriatric evaluation (MGE).
MGE analysed in detail the following aspects of elderly: Functional status, Socio-economic conditions, State cognitive, State emotional, Therapy pharmacology, State nutritional and every geriatric syndromes.
On the basis of MGE we have identified 3 groups. The first group was composed of the patients who had no disability and that they could receive a standard chemotherapy with CHOP-Rituximab scheme.
The second group of patients had at most 2 co-morbidities of moderate grade in the absence of geriatric syndromes. These patients have received a therapy chop-like with anthracycline liposomal peghilated (Caelyx).
The third group composed of “frail patients” showed over the 85 years, 3 or more co-morbidities ADL <6 and one or more geriatric syndromes. These patients run therapy with chop scheme with reducing dose of 50%.
54 patients (59%) were allocated to the first group, 22 (25%) in the second and 15 (16%) in the third. In the first group, after the treatment, 82% has obtained the complete remission, and in the second and third group is obtained respectively in 64% and 60%. It was observed 1 death toxic to the first and third group and 2 in the second. Currently with a median follow-up of 55 months are live in complete remission 31 patients (57%) of the group 1, 7 patients (32%) of the group 2 and 3 patients (20%) of the group 3. The MGE has proven a useful instrument for an objective evaluation of elderly patients and has been possible to guide to the choice of therapy more appropriate also in patients that showed relevant co-morbidities.

Disclosures:
Offidani: Celgene: Honoraria; Janssen Cilag: Honoraria.
Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia.
Authors: Sun Jenny , Xu Lian , Tseng Hsiuyi , Ciccarelli Bryan , Fulciniti Mariateresa , Hunter Zachary , Maghsoudi Kaveh , Hatjiharissi Evdoxia , Zhou Yangsheng , Yang Guang , Zhu B. , Liu Xia , Gong Ping , Ioakimidis Thea , Sheehy Patricia , Manning Robert , Hanzis Christina , Lewicki Megan , Patterson Christopher J , Chauhan Dharminder , Rodig Scott J. , Munshi Nikhil C. , Anderson Kenneth. C , O'Connor Owen O , Treon Steven 
Published: October 2019

Abstract
Abstract 4785
Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM.

Disclosures:
No relevant conflicts of interest to declare.
Low-Dose Bexarotene Alone or in Combination for the Treatment of Relapsed or Refractory Cutaneous T-Cell Lymphoma.
Authors: Beltran Brady , Paredes Antonio , Moises Celia , Sanchez Gadwin , Sokol Lubomir , Castillo Jorge 
Published: October 2019

Abstract
Abstract 4790

Introduction
Selective ligands of retinoid X receptor (i.e. bexarotene) are used in the treatment of early and advanced stages of cutaneous T-cell lymphoma (CTCL). The objective of this study is to report a Peruvian single-institution experience on 13 cases of relapsed or refractory CTCL who were treated with low-dose bexarotene alone or in combination with phototherapy or interferon alfa-2a.

Methods
From 2002 to 2008, thirteen patients with relapsed or refractory CTCL were treated with bexarotene at low dose (75-300 mg/day) as monotherapy (BEX; 3 cases) or in combination with interferon alfa-2a (INF) at 3-9 million units subcutaneously three times a week (5 cases) or phototherapy (PT; 4 cases). Therapy was continuously administered until progression of disease or unacceptable toxicity. Eight patients with mycosis fungoides (MF), two patients with aggressive epidermotropic CD8+ cytotoxic lymphoma (AECL), two patients with Sezary Syndrome (SS) and one with smoldering adult T-cell leukemia/lymphoma (ATLL) were included in this study.

Results
Mean age was 57 years (range 26 to 74 years). In average, patients were exposed to three prior lines of therapy (range 1 to 5). From the 8 cases of MF, 3 cases were treated with BEX monotherapy, achieving 1 complete response (CR), 1 partial response (PR) and 1 progressive disease (PD); 3 cases were treated with BEX and PT, obtaining 1 CR and 2 PR; and 2 cases were treated with BEX and IFN, both showing PD. From the 2 cases with AECL, 1 case received BEX/PT achieving a PR and 1 case received BEX/IFN showing PD. From the 2 cases with SS, both were treated with BEX/IFN achieving a PR. The case of ATLL achieved a PR with BEX/PT. The overall response for the entire group was 69.2% (9/13) with a mean duration of response of 15 months (range 2 to 67 months). From the therapy point of view, BEX alone achieved a 66% overall response rate (ORR), BEX/IFN showed a 40% ORR and BEX/PT showed a 100% ORR with a 20% CR. Most common adverse events were mild, seven patients experienced grade 1–2 hypercholesterolemia, and hypertriglyceridemia grade 1–2 was seen in seven patients and grade 3 in two cases. Four patients developed grade 1–2 hypothyroidism.

Conclusions
Low-dose BEX alone or in combination with INF or PT is effective in the treatment of patients with relapsed or refractory CTCL and is associated with mild toxicity. Prospective studies, if possible, are needed to further investigate novel therapeutic approaches in these hard-to-treat patients.

Disclosures:
No relevant conflicts of interest to declare.
Artesunate,a Antimalarial Agent,Exhibits Potent Anti-Leukemia Activities in Vitro and Inbibit Wnt/b-Catenin Pathway.
Authors: Xu Na , Xiaoli Liu , Du Qingfeng , Liu Zhi , Li Rong , Yang Jun , Wang Shuang , Zhong Min , Wang Yu 
Published: October 2019

Abstract
Abstract 4822
Artesunate (ART), a remarkable antimalarial agent, its antitumor effect was widely studied recently. But whether the antitumor mechanisms of ART involves in Wnt/b-catenin signalling, a major oncogenic pathway have yet been poorly understood. In address this question,we treated human leukemia cell lines,such as K562 cells, HL-60 cells,U937cells and KG1a cells with 12.5ug/ml,50ug/ml, 100 ug/ml and 200ug/ml ART for 24h, 48h and 72h respectively. Determined by the Cell Counting Kit-8 and flow cytometry analysis on apoptosis, we found that ART suppressed the leukemia cells proliferation and promoted the apoptosis of leukemia cells in a time- and concentration-dependent manner. Furthermore, we detected the mRNA level and protein expression of b-catenin and Wnt/b-catenin target genes c-myc and cyclinD1 by QRT-PCR and western blotting when the above leukemia cell lines treated with ART for 48h. The results demonstrated that the the mRNA level and protein expression of c-myc and cyclinD1 was lower in ART groups than in the contorl groups,and in concentration-dependent manner. on the other hand, there was no significant difference in the mRNA level and protein expression of b-catenin in the ART groups compare to the contorl groups. Moreover, we observed b-catenin by immunofluorescence technology, the Bioluminescent imaging demonstrated that ART translocated b-catenin from nucleus to adherent junctions of membrane,and binding to E-cadherin on the cell membrane. Our results provide the vitro evidence for the anti-luekemia mechanism of ART correlated to the inhibition of hyperactive Wnt/b-catenin signaling pathway. Combination With the present studies, the antitumor mechanism of ART is invoved in multiple signaling pathways, and the well known low toxicity. We thus speculate that ART might be a promising candidate drug for the treatment of leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia After Hematopoietic Cell Transplantation.
Authors: Barker Collin C. , Agovi Manza- A , Logan Brent , Gupta Vikas , Lazarus Hillard M. , Ballen Karen K , Hale Gregory A. , Frangoul Haydar , Rizzo J. Douglas , Pasquini Marcelo C. 
Published: October 2019

Abstract
Abstract 652
Prevalence of obesity in children has been rapidly rising in the last decade in the US and other industrialized countries (US prevalence, ages 2-19, 16%, NHANES, 2008) and it represents a serious health concern. The impact of recipient's weight on mortality after hematopoietic cell transplantation (HCT) for non-malignant diseases is not well characterized. We studied the effect of body mass (BMI) on transplant outcomes in 1,281 patients aged 2-19 years who underwent HCT for severe aplastic anemia from 1990-2005. The study population was divided in five groups based on age-adjusted BMI percentiles. Patients in the <5th, 5-25th, 26-75th, 76-95th and >95th percentile BMI were classified as underweight, at risk for underweight, normal weight, at risk for overweight, and overweight respectively. Cox proportional hazards regression models for survival and acute graft-versus-host disease grade III-IV (aGVHD) were performed using BMI groups as the main effect and the normal weight (26-75th percentile) as the baseline comparison. Two-year overall survival was lower for overweight children (p<0.001, table). The risk of death, adjusted for significant covariates was higher for overweight compared to normal weight children (p=0.001, table). BMI groups were not associated with excess risk for aGVHD. Other significant factors associated with mortality include race and region of US, donor type, performance score at HCT, recipient age, and year of transplant. Risk of death was higher in African American patients (1.84, p=0.009) compared to Caucasians in the US, donors other than HLA-matched sibling and patients who received HCT before 2002. Among recipients of HLA-matched sibling grafts, use of busulfan-containing regimens (3.13, p<0.001) or cyclophosphamide without antithymocyte globulin (ATG) (1.92, p=0.03) had a higher risk of death compared to recipients of cyclophosphamide and ATG. Conditioning regimens in recipients of unrelated donor HCT were not associated with mortality. Among the reported causes of death, organ failure and infections occurred more frequently in overweight patients compared to the other BMI groups. In conclusion, overweight children with severe aplastic anemia have a higher risk of death after HCT independent of other factors analyzed in the study.BMI percentileN100 day mortality Probability (95% CI)2-y OS Probability (95% CI)RR of death (95% CI)p26-75th152515 (10-20)76 (70-82)1.00-<5th10812 ( 7-19)77 (68-84)1.01 (0.65-1.57)0.975-25th19611 ( 9-14)77 (74-81)1.38 (0.99-1.91)0.0676-95th30417 (13-21)73 (68-78)1.22 (0.93-1.61)0.14>95th14229 (22-36)59 (51-67)1.71 (1.24-2.35)0.0011Baseline group

Disclosures:
No relevant conflicts of interest to declare.