bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK Cells of Acute Myeloid Leukemia Patients Exhibit Exhausted Phenotype with Impaired Functional Activity
Authors: Zhigarev Dmitry , MacFarlane Alexander W. , Drenberg Christina Diane , Nejati Reza , Varshavsky Asya , Campbell Kerry S. 
Published: November 2021

Abstract
Acute myeloid leukemia (AML) accounts for about one third of all leukemias, with half of all leukemia deaths. The low 5-year survival rate and manifestation of this deadly disease in old age reinforce the need for new safe and effective AML therapies. Considering the exceptional role of immune cells in the recognition and elimination of tumor cells, one of these methods is immunotherapy. However, for the development of immunotherapeutic approaches, it is necessary to clearly understand the role of certain effector cells in the pathogenesis of the disease, as well as to have the knowledge about the phenotypic characteristics of these cells.
Natural killer (NK) cells play important roles in innate cancer immunosurveillance, and some published data indicate that the antitumor function of NK cells is reduced in AML patients. To expand upon previous work, we performed a comprehensive analysis of the phenotypic and functional characteristics of NK cells in previously untreated AML patients that took into account a wide variety of biomarkers. The goals of this study were to define the phenotypic and functional differences in NK cells from AML patients and healthy donors and determine how these parameters affect outcome of the disease.
We used 14-color flow cytometry to assess more than 30 measurable markers on NK cells from the peripheral blood of 33 untreated AML patients and age-matched healthy controls. In addition, NK cells were tested for interferon-γ responses under antibody-dependent cellular cytotoxicity conditions. Results in AML patients were then compared to healthy donors.
We found that the NK cells of patients with AML have a significantly lower capacity to secrete IFN-γ and showed numerous signs of an exhausted phenotype, as compared to healthy controls. These included increased surface expression of CD39, PD-1, and LILRB1 on NK cells from AML patients. Interestingly, surface expression of the TIGIT checkpoint receptor did not differ between AML patients and healthy donors, but surface expression of the activating receptor DNAM-1, which shares the same ligands on tumor cells, was decreased. All of these data confirm that the NK cells of AML patients are functionally impaired.
We also noted that the frequency of CD57 + NKG2C + KIR + memory-like "adaptive" NK cells was greater in the blood of AML patients. The proportion of adaptive NK cells did not correlate with the age of donors. Phenotypic features of this cell subpopulation from the AML patients included significantly increased expression levels of CD56 and significantly lower expression of the activating receptor DNAM-1.

Disclosures
Zhigarev: Janssen R&D: Research Funding; Immunitas Therapeutics: Consultancy; Tavotek Biotherapeutics: Consultancy. Drenberg: Janssen R&D: Current Employment. Campbell: Janssen R&D: Research Funding.
Anti-Leukemic Properties of the Kinase Inhibitor OTSSP167 in T Cell Acute Lymphoblastic Leukemia
Authors: Bridges Cory Seth , Chen Taylor J , Puppi Monica , Lacorazza H. Daniel 
Published: November 2021

Abstract
The remission rates of T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy in children, have improved through the years. Despite this advance, 10-20% of the patients do not respond to current therapy, and relapse leukemia is the leading cause of death in children with cancer. Our previous work showed aberrant activation of the actionable MAP2K7-JNK pathway in pediatric T-ALL and proposed this pathway as a target for pharmacological inhibition. Here we demonstrate the anti-leukemic capacity of the kinase inhibitor OTSSP167 in T-ALL via MAP2K7 inhibition. OTSSP167, a MELK inhibitor shown to also inhibit MAP2K7, showed a dose-dependent cytotoxicity in a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM). OTSSP167 induced apoptosis and G2/M cell cycle arrest that correlated with increased cleavage of PARP and caspase 3 and elevated levels of cyclin B1 and phosphorylated CDC2. Immunoblot blot analysis shows OTSSP167 treatment inhibited the MAP2K7-JNK-ATF2 pathway, in addition to MELK, in a panel of T-ALL cell lines. Biochemical kinase assay shows inhibition of MAP2K7 kinase activity with an IC50 of 160 nM. Furthermore, OTSSP167 was able to inhibit MAP2K7 activated by treatment of T-ALL cells with sorbitol. This kinase inhibitor shows low toxicity in mice (10 mg/Kg) and controls leukemia burden in cell-based xenograft model with significant reduction on the expansion of KOPT-K1 cells and improved survival (P=0.003). Furthermore, OTSSP167 was able to control leukemia in patient-derived xenograft (PDX) model and to target leukemia-initiating cells in the NOTCH1-induced T-ALL mouse model. Altogether, OTSSP167 is a potent MAP2K7 inhibitor with low toxicity that emerges as a potential adjuvant drug to increase treatment response and reduce relapses in pediatric T-ALL.

Disclosures
No relevant conflicts of interest to declare.
Decitabine Combined with Minimally Myelosuppressive Therapy for Induction of Remission of Pediatric High-Risk Acute Myeloid Leukemia with Chromosome 5q Deletion. a Report of Three Cases
Authors: Cheng Shengqin , Xiao Peifang , Wang Juxiang , Gao Li , Zheng Jiajia , Hu Yixin , Ding Xin , Ling Jing , Lu Qin , Pan Jian , Li Bohan , Lu Jun , Wang Yi , Ribeiro Raul C , Hu Shaoyan 
Published: November 2021

Abstract
Cases of pediatric acute myeloid leukemia (AML) with complex karyotypes including chromosome 5 abnormalities are rare and have a dismal prognosis. Management of AML with monosomy 5/del(5q) has not been uniform. We treated three adolescents with this AML subtype with combined low-dose cytarabine and mitoxantrone, concurrent with decitabine and G-CSF, for remission induction. Decitabine was also included in the conditioning regimen before hematopoietic cell transplantation (HCT). All three patients attained complete remission after treatment with this combination. The treatment was well tolerated, and the patients are alive and free of disease at 3.6, 3.2, and 3.0 years after HCT, respectively. Our experience suggests that HCT is required for the eradication of pediatric AML, and possibly MDS, with complex karyotypes including del(5q). Decitabine combined with regimens of low myelotoxicity for remission induction represents an alternative approach to decrease the risk of complications associated with post-remission chemotherapy before HCT.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Fecal Microbiota Transplantation As a Therapeutic Option for Graft-Versus-Host-Disease: A Systematic Review and Future Directions
Authors: Aslam Hafiz muhammad , Veeraballi Sindhusha , Hashmi Shahrukh K. 
Published: November 2021

Abstract
Introduction:
In recent years, there has been an expanding focus on interplay between intestinal microbiotal diversity and outcome of acute graft versus host disease(GVHD) in hematopoietic stem cell transplantation (HCT) recipients. One of the compelling intervention to maintain healthy gut microbiota for better outcome of GVHD in HCT recipients is Fecal microbial transplantation(FMT). Several non randomized small clinical studies and case reports on the efficacy and safety of FMT were reported so far. However, the ultimate role of FMT as a therapeutic option to treat GVHD is yet to be determined due to lack of randomised, large scale, statistically significant studies. Here in, we report a systemic review of literature available so far in an effort to establish a definite role of FMT.
Methodology: A systemic literature search was conducted using various electronic databases. The case reports, case series and clinical studies related to FMT were used as a therapeutic or preventative modality specifically for GVHD are included.
Results: Upon pooling of data, 87 patients from 6 studies and 5 case reports were included in the study in which complete remission(CR) occured in 43.7% and partial remission(PR) occured in 20.7% patients which is equivalent to 64.4% overall response rate in treating GVHD. Furthermore, out of all the species in fecal matter, clostridium was found to be the most valuable species in decreasing the rates of GVHD re-occurrence. Only a limited number of patients had treatment-related mortality
(TRM) from GVHD while few showed mild GI-related (abdominal pain/distention, nausea, regurgitation) and non-GI adverse reactions including infections, anemia, thrombocytopenia, paroxysmal, and atrial fibrillation. We emphasize that the most of the patients did not have any major complications after FMT.
Conclusion:
We conclude that the FMT is a safe and effective strategy for the management of GVHD based on our study. The establishment of gut diversity along with the patient's intrinsic factors like fucosyltransferase 2 (FUT2) secretor status and baseline gut microbial diversity play a major role in the success of FMT. Given the restricted size and absence of randomized data, one cannot portray FMT as a standard of care yet, however, the low or absent toxicity along with improvement in survival justifies this modality to be tested in a randomized fashion. We strongly encourage the transplant community to enroll patients in innovative trials utilizing FMT, as this may be a one of the safest strategies for both prevention and treatment of GVHD

Disclosures
No relevant conflicts of interest to declare.
Anti-HNA-3a Alloantibodies Can Cause Differential Endothelial Damage through a Direct Neutrophil Activation Pathway
Authors: Radenkovic Filip , Chiaretti Sara , Burton Mark , Hassell Penny , Bui Xuan , Flower Robert , Tung John-Paul 
Published: November 2021

Abstract
INTRODUCTION: The human neutrophil antigen (HNA) 3a/b is associated with a single amino acid substitution (R 154Q polymorphism) on the first extracellular loop of choline transporter-like protein 2 (CTL2). Antibodies against HNA-3a have been associated with severe and fatal transfusion-related acute lung injury (TRALI). Epitope mapping suggests the existence of two types of HNA-3a antibodies. Type I antibodies only require first extracellular loop of the CTL2 for expression of the antigen, type II antibodies require at least the first 3 extracellular loops of CTL2 in a native configuration (i.e. expressed on a cell membrane). This study aimed to evaluate the activity of type I and type II anti-HNA-3a antibodies in an in vitro TRALI model.
STUDY DESIGN & METHODS: The granulocyte agglutination test (GAT) and granulocyte immunofluorescence test (GIFT) were used to confirm anti-HNA-3a activity in two donor sera (Q49 and Q50). Flow cytometry was used to confirm antibody binding to freshly isolated human or mouse neutrophils. A rabbit polyclonal antibody against an epitope in the third extracellular loop of CTL2's was coated onto the wells of an ELISA plate and neutrophil HNA-3a antigen was captured and sera tested. For the TRALI model, human lung microvascular endothelial cells (HLMVECs) were grown to confluence before being treated with lipopolysaccharide (LPS). Freshly isolated neutrophils from HNA-3aa homozygote donors were then added with 10% Q49 or Q50. Microscopic counting of Trypan blue staining was used to measure rate HLMVEC death. Significance was determined using a one-way ANOVA (p&lt;0.05), followed by Dunnett's post-hoc test.
RESULTS AND DISCUSSION: GAT and GIFT confirmed that both Q49 and Q50 contained an anti-HNA-3a antibody, and that neither contained antibodies against any other HNA or HLA molecules. In flow cytometry, both Q49 and Q50 bound to human neutrophils, but only Q49 bound to mouse neutrophils. In the ELISA, signal was detected only for Q49. These data provided evidence that Q49 was a type I antibody and Q50 was a type II antibody. Within the TRALI model, HLVMEC death was observed with both Q49 and Q50 only in the presence of LPS and neutrophils (Table 1). Previously reported HLMVEC permeability in the absence of neutrophils (Bayat et al. Arterioscler Thromb Vasc Biol. 2013) was not observed as in this study the outcome measured was HLMVEC death. In the present study, the effect for Q49 (type I) was significantly larger than for Q50 (type II; Table 1; p-value &lt;0.0001).
CONCLUSIONS: In this model, LPS and neutrophils were required for anti-HNA-3a mediated HLMVEC death thought to reflect events involved in the initiation of TRALI. The observation that type I antibodies elicited a stronger response provides a direction for further research.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
PI3K δ /γ Inhibition Enhances the Expansion and Anti-Tumor Cytotoxicity of CART Cells for CLL Patients
Authors: Wang Shuhua , Funk Christopher R. , Ravindranathan Sruthi , Chen Kevin , Waller Edmund K. 
Published: November 2021

Abstract
Background:
While CD19-targeted chimeric antigen receptor (CAR) based T cell therapy has shown promise in the treatment of chronic lymphocytic leukemia (CLL), overall efficacy is limited due to impaired T-cell fitness. We have previously shown that dual inhibition of PI3Kδ and PI3Kγ enhanced mitochondrial mass and ex vivo expansion of central and stem cell memory T cells from CLL patients(Funk, 2019,Journal for Immunotherapy of Cancer). In this study, we hypothesized that pharmacological inhibition of these pathways during ex vivo culture would increase the expansion and in vivo anti-tumor cytotoxicity.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of CLL patients by ficol hypaque centrifugation. T cells were negatively selected using MACS beads and transduced with CD19 CAR lentivirus (encoding CD28 or 41BB co-stimulatory domains) and stimulated with anti-CD3/CD28 beads in media containing 30 U/mL interleukin-2 with or without the PI3Kδ/γ inhibitor duvelisib (Duv) for 15 days. NOG mice were engrafted with the OSU-CLL cell line for 14 to 18 days with tumor burden measured by flow cytometry of blood samples from the mice, comprising a mean 0.15% of peripheral nucleated cell content. Control-CART or Duv-CART were injected by tail vein injection. Frequencies of CART, OSU-CLL cells and immune checkpoint molecule expression of CART or T cells in blood were measured by serial flow cytometry. Kaplan-Meier survival plots were represented as recipient survival on the indicated days
Results: Treatment with either CD28 or 4-1BB Duv-CART cells led to significantly prolonged survival relative to control-CART (Figure 1, P&lt;0.05). Recipients of Duv-CART cleared circulating OSU-CLL faster than control CART (Figure 2. P&lt;0.05 at day26 for CD28 CART) and exhibited greater peak expansion and persistence of total CART and CD8+ CART. Recipients of Duv-CART cells had significantly greater in vivo persistence and expansion of total CART and CD8+ CART (Figure 3, P&lt;0.001, day14 after CART were infused). Consistent with improved survival, both CD28 Duv-CART and 4-BB Duv-CART show reduced expression of LAG3, TIM3 and PD1 in the CD4 (Figure 4) and CD8+ subsets at earlier time point in vivo. (* p&lt;0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001).
Conclusions: Inhibition of PI3Kd/g during CART cell culture decreased the expression of immune checkpoint molecules and enhanced in vivo expansion leading to greater efficacy in eliminating CLL.
Figure 1 Figure 1.

Disclosures
Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.
Acute Myeloid Leukemia : Clinical Characteristics and Survival Outcomes in Lebanese Patients
Authors: Nasr Fadi , Diab Saada , Ghauche Ahmad , Yehia Intissar , Nasr Lewis 
Published: November 2021

Abstract
Context The molecular characteristics of this disease remain widely unknown in Lebanon.
Cytogenetics and molecular testing in AML are becoming routine practice for disease classification and prognosis. In Lebanon, a nationwide study showed an incidence of 1.1% among all cancers in 2003, slightly more predominant in males.

Objective The aim of this study was to describe patient's characteristics and outcome in Lebanese patients.

Design 80 patients from a single Lebanese center were included. We reviewed disease characteristics of patients diagnosed with AML between January 2008 and December 2020. Medical files were reviewed and SPSS software was used for statistical analysis.

Results 48.1 % of patients were males, with a median age of 61 years at diagnosis. Cytopenia was present at 30% of patients. Diagnosis was confirmed by bone marrow aspirate in 95% of the patients. Karyotype was missing in 48% of patients. When available, 13%, 54% and 33% were respectively in the low, intermediate, and high risk group. FLT3 was positive in 47.4% of tested cases and NPM1 in 16.7%. No patient was found to have t (16;16) and 5.4% have inversion 16. PML-RARA was positive in 2% of patients. Idarubicin-cytosar was given as induction treatment for 82% of patients. 58% achieved complete remission, 2% were in partial remission and 40% were primary refractory. 51.7% relapsed after remission. PFS was 11 months with a median OS of 17 months. No significant statistical correlation was found between Karyotype on diagnosis and survival [P = 0.3].
Conclusion Our study is the first to describe AML characteristics in Lebanon. Multicenter studies are needed to elaborate a clinical and epidemiological data register for leukemia patients in Lebanon.

Disclosures
No relevant conflicts of interest to declare.
CAR-T Therapy Followed By Unrelated Cord Blood Transplantation for the Treatment of Children and Young Adults Relapsed/Refractory B-Cell ALL: Superior Survival but Relatively High Post-Transplant Relapse
Authors: Sun Guangyu , Tang Baolin , Wan Xiang , Yao Wen , Song Kaidi , Geng Liangquan , Qiang Ping , Wu Yue , Zhu Lijun , Wang Dongyao , Wu Yun , Liu Huilan , Sun Zimin , Zhu Xiaoyu 
Published: November 2021

Abstract
Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) has poor long-term survival even after chimeric antigen receptor (CAR)-T cell therapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies supported that CAR-T therapy followed by allo-HSCT is benefit for improving long-term leukemia free survival (LFS). Since probably a stronger graft versus leukemia (GVL) effect of unrelated cord blood transplantation (UCBT), it is uncertain whether consolidative UCBT is suitable for R/R B-ALL after CAR-T therapy. Here, we conducted a retrospective comparative study for R/R B-ALL patients receiving UCBT in our transplantation center. Totally 43 cases with R/R B-ALL who underwent UCBT were assigned to CAR-T group (patients achieved CR or CRi by CAR-T cell therapy before bridging to UCBT, n = 21) or non-remission (NR) group (n = 22). The median time from CAR-T infusion to UCBT was 62 (range, 42-185) days. All patients achieved neutrophil engraftment by day 42 in CAR-T group. The 180-day cumulative incidence of platelet engraftment was higher in CAR-T group than in NR group (90.5% vs 65.7%, P = 0.16). Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) were 28.6% and 23.8% in CAR-T group, which were both tendency lower than in NR group (45.5% and 31.8%, P = 0.32 and P = 0.63, respectively). No patient suffered from extensive chronic GVHD in CAR-T group, which was lower than in NR group (9.1%, P = 0.23). Lower 2-year cumulative incidence of transplant-related mortality (TRM), and higher probabilities of 2-year overall survival, leukemia free survival (LFS), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) were found in CAR-T group (4.8% vs 28.2%; 75.0% vs 37.7%; 49.8% vs 23.0%; 42.4% vs 14.8%; P = 0.037, 0.005, 0.028 and 0.017; respectively). However, 2-year cumulative incidence of relapse was comparably high between CAR-T and NR group (26.7% vs 38.3%; P = 0.41). CAR-T therapy followed by UCBT has a superior survival for R/R B-ALL, but remains relatively high post-transplant relapse rate. Prevention of relapse after UCBT is warranted in this patient cohort.

Disclosures
No relevant conflicts of interest to declare.
Kikuchi-Fujimoto Disease: A Case Report
Authors: Hickman Jonathan , An Joseph 
Published: November 2021

Abstract

Kikuchi-Fujimoto: A Case Report
Hickman, JD. MD LT MC USN and An, Joseph, DO. LCDR MC USN
Naval Medical Center Portsmouth
620 Johns Paul John Cir, Portsmouth VA
757-953-2223
The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
We are military service members and employees of the U.S. Government. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.
Kikuchi-Fujimoto disease is a rare benign disorder often presenting with tender cervical lymphadenopathy, fever, and malaise. While first described in Japan, its distribution is worldwide and predominantly seen in young adults. Diagnosis is based on characteristic histopathologic findings of patchy necrosis occupied by karyorrhectic debris and abundant histiocytes on node biopsy. The origin is unclear but associated with a preceding viral illness as well as cutaneous lupus erythematosus. Treatment is generally supportive and focused on managing tender lymph nodes.
We present a case of a 28-year-old female presenting with a 2 month history of night sweats, fever, and weight loss in the setting of painful neck swelling. CT and PET/CT imaging demonstrated numerous hypermetabolic and enlarged nodes in the bilateral cervical and axillary regions. Lab studies were notable for leukopenia, anemia, and elevated inflammatory markers. A COVID-19 screening was negative. Excisional biopsy of a cervical node revealed extensive cortical necrosis and apoptotic debris with scattered histiocytes and plasmacytoid dendritic cells in absence of neutrophils or a monoclonal B cell or T cell population. Treatment was initiated with NSAIDs and close monitoring. The patient exhibited a complete response after two months.
Our case is an important reminder that lymphadenopathy, fever, and night sweats in a young adult are not pathognomonic for lymphoma. Nonetheless, a high suspicion for lymphoma should be maintained and followed with an expedited workup. Kikuchi-Fujimoto can certainly mimic Hodgkin lymphoma or other serious conditions like lupus erythematosus and tuberculosis. The diagnosis is largely one of exclusion following a careful examination of a lymph node histopathology and must be considered in young previously healthy adults to avoid misdiagnosis and unnecessary escalation of treatment.

Disclosures
No relevant conflicts of interest to declare.