bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of Cord Blood T Regulatory Cells with Ruxolitinib Decreases Side Effects and Improves Survival in Xenogenic Graft Vs. Host Disease
Authors: Zeng Ke , Huang Meixian , Li Li , Lyu Mi-Ae , Ma Hongbing , Nishimoto Mitsutaka , Sadeghi Tara , Ahmed Sairah , Andersson Borje S. , Parmar Simrit 
Published: November 2020

Background: Recent approval of ruxolitinib (rux) for steroid refractory graft versus host disease (GvHD) has revolutionized the field and provided tremendous choice for the patients. However, the side effects including thrombocytopenia leads to dug discontinuation and intolerance. We have previously shown that adoptive therapy with cord blood (CB) derived T regulatory (Treg) cells can prevent and treat GvHD. We hypothesized that the addition of CB Treg therapy to rux based therapy can augment overall efficacy.
Methods: CellTrace Violet suppression assay was performed to evaluate the suppressor function of CB Treg cells in the presence or absence of rux. Xenogenic GvHD mouse model was utilized where the NSG mice underwent sublethal irradiation on day -1 followed by injection of 1x107 donor peripheral blood (PB) mononuclear cells (MNCs) on day 0. Oral rux at 1 mg daily was fed continuously to the mice in the presence or absence of 1x107 CB Treg cells, tagged with CellTrace Violet dye, administered on days +4, +7, +11, +18. Mice were followed every other day for weight, GvHD score and survival. Serial blood draws were performed to analyze for cell compartment and cytokine assays.
Results: We examine whether the addition of rux impacts the suppressor function of CB Treg cells. Varying concentration of rux including 0.01, 0.05, 0.1 and 0.5 µM were added at 24, 48 and 96 hours of the cell suppression assay. The addition of rux 0.05 µM at 48 hours of the cell suppression culture led to a restoration of poor cell function (Figure A). Lowest GVHD score was reported in the rux+CB Treg combination arms at day +14 when compared to rux alone or CB Treg alone arm which (Figure B) translated into a superior survival in the rux +CB Treg arm (Figure C). Furthermore, an increase in the hemoglobin level (Figure D) and the platelet count (Figure E) was demonstrated in the rux+CB Treg arm.
Addition of rux led to longer persistence of the injected CB Treg cells on day 14 (data not shown) which correlated with the increase in the plasma level of the pro-Treg cell signaling markers including IL-7 (Figure F) and IL-15 (Figure G). A decrease in the IL-4 production supported the increased Treg cell function (Figure H). A synergistic suppression of inflammatory cytokines including IL-17 (Figure I) and IL1A (Figure J) was evident in the rux+CB Treg arm.
Conclusion: The combination of CB Tregs with ruxolitinib leads to improved overall survival, decreased inflammatory cytokines and improved hematologic parameters. Such combination should be explored in a clinical setting
Figure

Disclosures
Sadeghi: Cellenkos Inc.: Current Employment. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
Traumatic Hyphema in a Type 1 Von Willebrand Patient: Clinical Case and Management
Authors: Lewis Jason , Dhami Jatinder , Langue Michael , Smink Gayle 
Published: November 2020

Von Willebrand disease (vWD) is the most common inherited congenital bleeding disorder. Type 1 is a deficiency, but not absence, of von Willebrand factor (vWF) and is the most common type. Bleeding episodes in patients with type 1 vWD vary and are related to the relative amount of von Willebrand factor produced. We report a case of a 15-year-old male with mild von Willebrand disease type 1 (vWF: 35%) who presented with a right eye grade lll hyphema and elevated intraocular pressure (IOP) following a traumatic injury. Despite medical management with Diamox, ophthalmic steroids, vWF replacement with Humate-P, the patient had a repeat bleeding event and worsening of his elevated intraocular pressure. Due to concern for corneal blood staining, the patient required surgical intervention with an anterior chamber washout. Von Willebrand factor replacement was given on presentation and prior to the procedure with goal von Willebrand factor (vWF) activity and Factor Vlll (FVlll) levels of 80-100 IU/dL. Factor replacement for a traumatic hyphema is necessary to reduce bleeding, but could lead to increased risk of thrombosis formation and increase risk of corneal staining. Balance between bleeding and thrombosis can lead to treatment challenges in patients with bleeding disorders including vWD.

Disclosures
Smink: Forma Therapeutics:Membership on an entity's Board of Directors or advisory committees;Highmark Insurance:Membership on an entity's Board of Directors or advisory committees.
Efficacy of Isatuximab on Surrogate Endpoints in Multiple Myeloma; A Systematic Review
Authors: Ammad Ud Din Mohammad , Hussain Syed Ather , Farrukh Hizra , Pasha Fajar , Abdullah Syed Maaz , Waris Imtisaal , Rehman Ebad , Setarehaseman Alireza , Ullah Asmat , Anwer Faiz 
Published: November 2020

Introduction:
Isatuximab (ISA) is an anti-CD38 monoclonal antibody that has shown benefit in patients with relapsed/refractory multiple myeloma (RRMM) in combination regimens. This study focuses on the clinical utility and tolerability of ISA based therapies in patients with ISS stage III disease.
Methods:
Literature search on PubMed, EmCare, Clinicaltrials.gov, Cochrane, and Google Scholar was performed from inception to July 1, 2020, for the use of ISA in MM patients. A total of five clinical trials, including phase Ib/II and phase III trials, were selected for a systematic review out of 109 studies (n=556 patients).
Results:
The median age was 61-71 years. The addition of ISA to pomalidomide-dexamethasone (PD) in previously treated patients was evaluated by Attal et al. (2019). International Staging System (ISS) stage III disease was present in 28% of the study population at baseline. Patients treated with ISA-PD had a meaningful increase in progression-free survival (PFS) (11.53 versus 6.47 months, P = 0.001, Hazard Ratio (HR): 0.596; 95% confidence interval (CI): 0.436-0.814. PFS benefit was maintained in subgroup analysis based on renal involvement, refractoriness to lenalidomide, and proteasome inhibitors. However, PFS benefit was not statistically significant in ISS stage III disease (HR: 0.64; CI: 0·36-1·11). Martin et al. (2017) evaluated the addition of ISA to lenalidomide and dexamethasone in 57 patients. 22% of the patients had ISS stage III disease. Mikeal et al. also included 9% and 37.1% of patients with ISS stage III MM in their phase Ib and II trials, respectively. All studies demonstrated a significant prolongation of PFS in patients refractory to lenalidomide with ISA administered at 10 mg/kg weekly/every two weeks. Iida et al. (2019) also reported statistically significant improvement in PFS with ISA monotherapy in heavily pretreated Japanese patients (PFS 4.7 months; 95% CI 3.75-NC). In patients with newly diagnosed MM, Ocio et al. (2017) showed encouraging results with an ISA based regimen in 17 patients. ISS stage III disease was present in 88% of the population. At the time of data cut-off, the overall response to treatment was 87%, and 82.4% continued to remain on treatment (see Table 1).
Conclusion:
ISA as monotherapy and in combination therapy improved surrogate endpoints without increased toxicity in patients refractory to previous lines of treatment. Limited data suggest an improvement in PFS for ISS stage III disease. Long-term results on efficacy in MM with high-risk cytogenetics are awaited.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
Photodynamic Therapy in Refractory Mycosis Fungoides: A Prospective, Open-Label Study
Authors: Brumfiel Caitlin M , Severson Kevin J , Patel Meera H , Cumsky Helen J L , Ginos Brenda F , Kosiorek Heidi E. , Janeczek Monica C , Besch-Stokes Jake , Rule William , DiCaudo David , Rosenthal Allison C. , Pittelkow Mark R , Mangold Aaron R 
Published: November 2020

Background:Case reports suggest photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an effective treatment for refractory mycosis fungoides (MF). No prospective trials have examined the use of ALA-PDT in MF.
Objective:We aimed to assess the efficacy of ALA-PDT in refractory MF.
Methods:This was a prospective study at Mayo Clinic in Scottsdale, Arizona in patients ≥ 18 years with plaque-stage treatment-refractory MF. Monthly sessions of ALA with blue light PDT were administered for up to six months. Responses were measured by Composite Assessment of Index Lesion Severity (CAILS) and Physician Global Assessment (PGA). Ad hoc analysis with modified CAILS (mCAILS) was performed, eliminating hyperpigmentation from scoring.
Results:Eleven patients (30 total lesions) were treated. Six patients completed the trial per protocol. Objective response rates were 36.4% by PGA (10.9-69.2%), 18.2% by CAILS (2.3-51.8%), and 36.4% by mCAILS (10.9-69.2%).
Limitations:Five patients did not complete all six PDT cycles per protocol, possibly accounting for reduced efficacy.
Conclusion:ALA-PDT with blue light irradiation was moderately effective and well tolerated in refractory plaque stage MF. Lower response rates compared to similar trials may be partially explained by utilization of strict lesional assessment criteria and other variations in methodology.

Disclosures
Mangold: MiRagen:Research Funding;Sun Pharma:Research Funding;Elorac:Research Funding;Kirin:Membership on an entity's Board of Directors or advisory committees;Solagenix:Research Funding.

OffLabel Disclosure:
Photodynamic therapy is a two-step therapy in which a drug that acts as a photosensitizer is administered to target a diseased tissue, followed by illumination with visible light to activate the drug and destroy the target tissue. PDT has been used to treat internal cancers as well as treatment of cancer and precancer of the skin.
DCE-MRI for Detection of Acute Myeloid Leukemia Derived Bone Marrow Vascular Dysfunction
Authors: Da Silva Gomes Ana , Siow Bernard , Passaro Diana , Bonnet Dominique 
Published: November 2020

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. While the clinical presentation is quite uniform, it is a highly heterogeneous disease at the genetic level. Using intravital two-photon microscopy in AML xenograft models, we have previously showed that AML patient-derived samples induced a common pathologic bone marrow (BM) vascular phenotype. To understand the translational potential of our findings we have optimized dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for the assessment of BM vascular dysfunction. We quantified non-model based parameters from DCE-MRI scans: Contrast Enhancement (CE); Wash-in Rate (WiR); and Wash-out Rate (WoR). CE reflects tissue vascular density and is a measurement of the proportion of fully functional vessels per pixel area, WIR reflects blood flow and tissue perfusion, and WoR reflects vascular permeability and tissue clearance capacity. We first measured DCE parameters in control mice. We observed no gender-related differences in BM DCE parameters, while we found significant age-related changes. As mice age, BM vascular density decreases together with increased vascular permeability and reduced tissue clearance capacity. When compared to age- matched controls, mice injected with AML cell lines showed decreased vascular density, decreased blood inflow, increased vascular permeability and reduced tissue clearance capacity. There was a progressive decline in BM vascular function as the disease burden increased, particularly in WiR and WoR parameters, with even low levels of leukemia significantly altering BM vascular function. When analyzing mice injected with AML patient samples, changes in BM vascular function were more dependent on the AML sample than on the engraftment. Low disease burden did not significantly change DCE vascular parameters. At high disease burden, patient-derived xenografts show different degrees of vascular disruption, spanning from global altered DCE parameters to milder phenotypes. Upon AraC treatment, altered vascular parameters remained unchanged in most of the cases, suggesting inability to fully rescue BM vascular function. In conclusion, we showed that DCE-MRI is able to detect consistent changes associated with BM vasculature induced by aging and leukemia. Despite the heterogeneous nature of the disease, our method captures different degrees of vascular alterations, with WIR having the highest diagnostic potential. Our results further suggest that the detection of a pathologic vascular phenotype in the BM of AML patients could be of use in the clinical scenario.

Disclosures
No relevant conflicts of interest to declare.
Fiirst-2: Prospective, Randomized Study Comparing Administration of Clotting Factor Concentrates with Standard Massive Hemorrhage Protocol in Severely Bleeding Trauma Patients
Authors: Da Luz Luis , Callum Jeannie L , Beckett Andrew , Peng Henry T , Engels Paul , Parry Neil , Tien Homer , Nathens Avery , Schwartz Bruce A. , Karkouti Keyvan 
Published: November 2020

Introduction: Acute trauma coagulopathy (ATC) is associated with severe hemorrhage. ATC etiology is often multifactorial, with acquired fibrinogen deficiency and consumption of clotting factors recognized as major factors. The FiiRST-2 study will determine the impact of early co-administration of fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) on the total number of allogeneic blood products (ABPs) transfused compared to the current standard of care (ratio-based plasma resuscitation).
Methods: FiiRST-2 is a multicenter (8 Canadian centers), pragmatic, randomized, parallel-control, superiority trial with a two-armed, two-stage design with an adaptive interim analysis. Research ethics board approval has been obtained and the study complies with the Declaration of Helsinki. Trauma patients &gt;16 years old at risk of massive hemorrhage will be randomized to receive FC + PCC or standard of care (ratio-based plasma resuscitation + FC in response to low fibrinogen levels) (Table 1) until all units in the second massive hemorrhage protocol (MHP) pack have been administered, or earlier if the MHP is terminated. The primary endpoint is to demonstrate superiority with respect to the number of ABP units (RBCs [red blood cells] + plasma + platelets) transfused within 24 hours of arrival at the trauma bay/emergency department. Secondary endpoints include RBC units transfused within 24 hours, incidence of thromboembolic events, and ventilator-free days up to Day 28. Safety endpoints include all adverse events (AEs) and serious adverse events (SAEs) up to Day 28. It is projected to enroll 360 patients depending on the results of the Interim analysis.
Results: An interim analysis will be performed after 120 patients have completed the study. The study is expected to start late 2020 and enrollment is expected to require about 2 years.
Conclusions: FiiRST-2 will determine if early hemostatic therapy with FC + PCC is superior to standard MHP packs in bleeding trauma patients. Results could have a major impact on clinical practice and improve management and outcomes in this high-risk group of patients.

Disclosures
Da Luz: Octapharma Canada: Research Funding. Callum:Octapharma: Research Funding; Canadian Blood Services: Research Funding. Schwartz:Octapharma: Current Employment. Karkouti:Canadian blood services: Research Funding; Octapharma: Research Funding.

OffLabel Disclosure:
PCC and fibrinogen concentrate for acquired coagulopathic bleeding (off-label in the USA)
Hematopoietic Jagged1 Is Required for the Transition of Hematopoietic Stem Cells from the Fetal Liver to the Adult Bone Marrow Niche
Authors: Shao Lijian , Paik Na Yoon , Pajcini Kostandin V. 
Published: November 2020

Notch signaling is known to play important roles in hematopoietic development and differentiation. Notch1 is required for emergence of the definitive hematopoietic stem cells (HSCs) from the hemogenic endothelium, and we have previously shown that Notch signaling is essential for survival and function of HSCs in the fetal liver. Activation of canonical Notch signaling requires direct cellular contact; thus, the identity of the ligand and the ligand-presenting cell during hematopoietic development would provide valuable information of the Notch signaling mechanism in HSCs as well as the identity of key niche cells that drive the expansion and cell fate decisions of embryonic HSCs. In the present study, we have taken a comprehensive approach to determine the ligands and cells that initiate Notch signaling in the mouse fetal liver. To this end, we have performed single-cell PCR analysis for all Notch signaling proteins in E14.5 fetal HSCs and compared the findings to the adult bone marrow HSCs. We also have analyzed fetal liver endothelial cells for surface expression of all Notch ligands. We determined that Jagged1 (Jag1) is highly expressed in both endothelial cells as well as in fetal HSCs but not adult HSCs. We have performed conditional loss-of-function analysis of Jag1 in fetal endothelial cells using inducible Ve-cadherinCreERT2 as well as in fetal hematopoietic lineages using constitutive VavCre. Our results indicate that while loss of endothelial Jag1 has severe effects in embryonic vascular development, loss of hematopoietic Jag1 allows for normal fetal morphology, yet severely impedes the functional ability of fetal liver HSCs to expand and differentiate both in vitro and in vivo. Fetal to adult transplantation of VavCre+Jag1f/f HSCs indicated a defect in reconstitution potential of fetal HSCs that lack Jag1 expression. Our findings indicate that hematopoietic Jag1 is essential for maturation of HSCs in the fetal liver and for homing and reconstitution potential of HSCs into the post-natal bone marrow microenvironment.

Disclosures
No relevant conflicts of interest to declare.
Development and Validation of a Risk Assessment Model for Early Infection during the First 3 Months in Patients with Newly Diagnosed Multiple Myeloma
Authors: Shang Yufeng , Wang Weida , Liu Minghui , Chen Xiaoqin , Xia Zhongjun , Zhou Fuling 
Published: November 2020

PurposeEarly infection was an important cause of mortality in patients with multiple myeloma (MM). The study aimed to assess factors affecting early infection and identify patients with high risk developing infection.
MethodsDuring January 2010 to June 2019, patients with MM were analyzed, retrospectively. The data was divided into training and independent validation cohort. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction, feature selection, and model building.
ResultsOf 745 confirmed MM patients, 540 eligible cases were included in final analyses. In total, 165 patients (30.6%) suffered infections, while 110 patients (20.4%) occurred early infections during the first 3 months after diagnosis. Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In training cohort, PS≥2, HGB&lt;100g/L, β2MG≥6.0mg/L and GLB≥80g/L were identified associated with early infections by LASSO regression. Based on the four factors, an early infection risk model of MM (IRMM) was established to define high- and low-risk groups, which showed significantly different rates of infection (35.3% vs. 9.4%,P&lt;0.001, HR=4.381 [95% CI, 2.802-7.221]). IRMM displayed good discrimination (AUC=0.756) and calibration (P=0.94).
ConclusionWe determined risk factors for early infection and established a predictive model to help clinicians identify patients with high-risk infection. It can help clinicians to determine whether to adjust monitoring and treatment strategies, or apply prophylactic interventions to high-risk patients.

Disclosures
No relevant conflicts of interest to declare.
Selectively and Efficiently Expanding Natural Killer Cells in Vitro
Authors: Lu Xuzhang , Liu Jie , Zhuxia Jia , Ouyang Xiaoqing , Chen Baoan 
Published: November 2020

Natural killer (NK) cells are the main innate immune cells, and have powerful antitumor activity in vitro, but NK cells based immunotherapy does not often get satisfactory results in clinical practice due to insufficient number and poor activity of NK cells.. Therefore, how to improve expansion efficiency and killing activity of NK cells in vitro is critical. Here we report an in vitro culture system culturing peripheral blood mononuclear cells (PBMC) with irradiated LCL as feeder cells in 10%FBS/RPMI1640 culture medium in the presence of 100U/ml IL-2 and 5ng/ml IL-15 for 14 days could selectively expand NK cells. With this culture system, the purity of NK cells increased from 11.5%± 7.01% to 75.3±10.9% (P&lt; 0.01), and the expansion efficiency was about 625±63 times than the original PBMC. Compared with the fresh NK cells isolated from PBMC, there was no significant change in the expression of inhibitory receptors on the surface of expanded NK cells, while the expression of activating receptors was significantly increased (p&lt;0.05). The cytotoxicity of expanded NK cells against leukemia cell line K562 was significantly higher than that of freshly isolated NK cells (72± 5.6% vs 8.7±2.3%, E: T=1, P&lt;0.01), expanded NK cells also showed stronger cytotoxicity to LCL (22±3.6%, E: T=1) and primary leukemia cells (42±5.2%, E:T=1). In summary, we could selectively expand NK cells with this in vitro culture system, the expanded NK cells gained higher expression of NCRs and NKG2D receptors, and displayed greater cytotoxicity against tumor cells, therefore could be readily applied to anti-tumor treatment in clinical treatment.
Figure

Disclosures
No relevant conflicts of interest to declare.