bluuebunny/crossref_metadata_2025 huggingface dataset:
Lw-213 Synergizes with Rituximab to Inhibit Diffuse Large B-Cell Lymphomas By Upregulating CD20
Authors: Li Yuchen , Li Hui , Hui Hui , Xu Jingyan
Published: November 2021

Background：Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens.Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, since the remaining therapeutic options are limited. LW-213, a derivative of wogonin, is reported to possess antineoplastic properties in a variety of cancers, but whether it has effects on DLBCL is n-ot known. Studies have reported that upregulation of CD20 expression b-y either HDACi or silenced SOX2 expression showed sensitizing potential in Rituximab-induced cell death in malignant B cells. Our study was to explore whether LW-213 could sensitize DLBCL to Rixutimab thus improve therapeutic efficacy.

Methods： Two DLBCL cell lines, RI-1 (ABC subtype) and Su-DHL -8 (GCB subtype), were used in our study. RI-1 and Su-DHL-8 cells were treated with LW-213 at different doses and for different times, and their proliferation and viability were detected by Cell counting kit-8 (CCK8).Flow cytometry was used to determine surface CD20 expression. Western blotting and q-PCR were applied to examine the protein and mRNA levels of CD20, SOX2, Ace-H3 and Ace-H3K27. CDC assay was used to evaluate the synergistic effects of LW-213 and Rixutimab.

Results：We showed that LW-213 inhibited the proliferation of human DLBCL cell lines (Su-DHL-8、RI-1 ) in dose-and time-dependent manners with IC 50 values at the low μmol/L levels, meanwhile it potently inhibited primary lymphoma cells derived from peripheral blood of B-cel-l lymphoma patients. Furthermore, LW-213 significantly increased CD20 surface expression and the acetylation level of histone in DLBCL cell li-nes. Inversely，the SOX2 expression level remarkably decreased. Finally,Combination with LW-213 significantly synergized Rituximab-induced cell death in vitro.

Conclusion： The results demonstrate that LW-213 sensitizes DLBCL cells to Rituximab in vitro by upregulating CD20 expression and the SOX2/ace-H3K27/ace-H3 axis may plays a critical role in CD20 upregulation processing. Even though this strategy is important in vitro models,the upregulating CD20 expression therapy against DLBCL proposed in this study warrants further study in vivo and clinical trials .

Keywords：CD20 DLBCL Rituximab SOX2 Histone Deacetylation

Disclosures

No relevant conflicts of interest to declare.
Abelacimab Reduces Thrombus Propagation in a Baboon Model of Vascular Graft Thrombosis
Authors: Wallisch Michael , Khder Yasser , Hinds Monica T. , Tucker Erik I , Bloomfield Dan , Gruber Andras
Published: November 2021

Background: Factor XI (FXI) inhibition demonstrated strong efficacy in preventing thrombus formation in preclinical and clinical models of arterial and venous thrombosis. However, the effect of FXI inhibition in halting the progression of a formed clot remains largely unknown.

Aims: This study aims to test whether abelacimab, a dual-acting FXI and activated FXI (FXIa) monoclonal antibody, is effective in halting clot formation and downstream growth when administered before or during active clot formation in an established baboon femoral arterio-venous (AV) shunt model.

Methods: Three baboons had a chronic femoral AV shunt put in place; platelet and fibrin deposition inside and distal to collagen- or collagen + tissue factor (TF)-coated vascular grafts were measured at baseline (control), in a therapeutic setting, where abelacimab (1 mg/kg, intravenously) was administered 30 minutes after thrombus initiation, and in a preventative setting within the first 48 h and 1 week (144 - 216 h) post-administration. Pharmacodynamic effect was measured by activated partial thromboplastin time (aPTT).

Results: Consistent with its half-life of 20 to 30 days, single iv administration of abelacimab at a dose of 1 mg/kg resulted in long-lasting (> 4-week) aPTT prolongation (> 2-fold). Administration of abelacimab 30 minutes after initiation of thrombosis using grafts coated either with collagen or with collagen + TF quickly halted downstream propagation of platelet and fibrin deposition compared to control. Further, downstream propagation of platelet and fibrin deposition was markedly reduced when clotting was induced by collagen, or collagen + tissue factor after abelacimab administration.

Conclusions: These data suggest that abelacimab, a dual-acting anti-FXI/FXIa monoclonal antibody with a single long-lasting iv injection has the potential to slow down the growth and reduce the size of thrombi when admistered before or after clot induction. Data indicate a potential for therapeutic benefit of targeting FXI both in therapeutic and preventive settings.

Sponsored by: Anthos Therapeutics Inc., 55 Cambridge Parkway, Suite 103, Cambridge, MA 02142

Figure 1 Figure 1.

Disclosures

Wallisch: Aronora Inc,: Current Employment. Khder: Anthos Therapeutics: Consultancy; Novartis: Current equity holder in publicly-traded company, Other: Retiree. Bloomfield: Anthos Therapeutics: Current Employment. Gruber: Aronora Inc.: Current Employment, Current equity holder in publicly-traded company; Oregon Health and Science University: Current Employment.
The Application of Eltrombopag to Promote Platelet Engraftment after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Li Yahan , Yujie Jiang , Liu Xin , Li Ying , Wang Xianghua , Xu Hongzhi , Wang Xin , Fang Xiaosheng
Published: November 2021

Background :

Eltrombopag is an agonist of the thrombopoietin receptor, and it has achieved great efficacy in the treatment of immunologic thrombocytopenic (ITP) and reduction of platelets (PLT) after hematopoietic stem cell transplantation (HSCT), but it remains unclear whether Eltrombopag can promote PLT engraftment after HSCT.

Methods :

37 patients with HSCT were administered Eltrombopag 50 mg (qd) from +1 day until PLT >50x10^9/L or 1 month after HSCT. 45 patients in the same period applied TPO to promote PLT engraftment after HSCT and served as a control group. The engraftment time of PLT and WBC (white blood cell) as well as the GVHD incidence and adverse reaction were compared and analyzed in the two groups.

Results :

A total of 37 patients received Eltrombopag, 2 of the patients withdrew from the study due to intolerable gastrointestinal reactions. 35 patients eventually completed treatment with Eltrombopag. In Eltrombopag group, median time to WBC engraftment was 12 days (range, 10-17 days) and PLT engraftment was 15 days (range, 10-29 days). At the 1st month after HSCT, the median WBC was 3.93 x10 9/L (range, 0.87-40.01 x10 9/L) and the median PLT was 91 x10 9/L (range, 33-401 x10 9/L) in the Eltrombopag group. MKCs in the bone marrow were assayed at 1 month after HSCT. Median MKCs level was 40 (range, 2-345) in the Eltrombopag group. 13 (37%) patients developed grade II-IV aGVHD and 1 (2%) patient developed cGVHD in the Eltrombopag group. Of these 35 patients, 3 (8%) presented with elevated total bilirubin (TBIL), no patient had elevated alkaline phosphatase (ALP), 17（48%）developed proteinuria, 1 (2%) people with elevated blood urea nitrogen (BUN) and no patient showed elevated creatinine (CREA). A total of 45 patients were applied TPO during the same period. Among these patients, the median engraftment time for WBC and PLT was 12 days (range, 9-23 days) and 15 days (range, 9-41 days), respectively. At the 1st month after HSCT, the median number of WBC and PLT were 4.30 x10 9/L (range, 0.99-23.63 x10 9/L) and 79.5 x10 9/L (range, 5-512 x10 9/L), respectively. At the 1st month after transplantation, the median number of MKCs in the bone marrow were 44 (range, 2-788). 16 (35%) patients developed grade II-IV aGVHD and 6 (13%) patients developed cGVHD in the TPO group. Among these 45 patients, 7 (15%) presented with elevated TBIL, 5 (11%) had elevated ALP, 25 (55%) developed proteinuria, 4 (8%) people with elevated BUN and 1 (2%) patient showed elevated CREA. The engraftment time of PLT and WBC were same in the Eltrombopag group and the TPO group and the adverse reactions occurred similarly in both groups.

Conclusion :

Eltrombopag can be used to promote PLT engraftment after all-HSCT with acceptable adverse reaction.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Differential Activation of V γ4V δ1 and V γ9V δ2 Cord Blood Derived Gamma Delta T Cells upon Exposure to EBV-Lcl and K562 Cells
Authors: Ng Jeremy Wee Kiat , Lai Joey , Lim Tony Kiat Hon , Hwang William YK , Li Shang , Eaves Connie J. , Goh Yeow Tee , Cheung Alice
Published: November 2021

Gamma-delta (γδ) T cells have emerged as a promising candidate for adoptive cellular immunotherapy. To harness and maximize the anti-leukemia properties of these cells, we sort to comprehensively profile the transcriptomic signatures and immune repertoire of in vitro expanded γδ T cell products. Given the reported diverse TCR γδ repertoire and naïve nature of γδ T cells found in human cord blood (CB γδ), we serially track the molecular and cellular changes in these cells upon activation in expansion cultures. Based on the established viral reactivities of γδ T cell as well as prior studies showing their cross reactivities against leukemia and cancer cells, we had previously shown that stimulating CB γδ with an irradiated EBV-LCL feeder cell-based rapid expansion protocol (REP) is capable of generating cell products with potent and specific cytotoxicity against human AML cells. In the present study, using single cell RNA sequencing (scRNA-seq) coupled with single cell TCR γδ repertoire analysis, we compared the transcription signatures between our REP expanded γδ T cell (REP γδ) and non-manipulated γδ T cells reported in literatures, showing the progressive acquisition of an adult PB derived γδ T cell (PB γδ)-like cell states. Time course analysis demonstrated complex T cell activation and maturation trajectories correlating with variable level of clonal induction throughout the course of in vitro expansion. At the end of expansion, the harvested REP γδ are predominantly of the V γ4V δ1 subtype. Nevertheless, upon exposing REP γδ to target leukemia cell line K562, outgrowth of other non-V γ4V δ1 as well as the semi-invariant V γ9V δ2 cells were observed. Taken together, our data shows that as CB γδ expand and differentiate in culture, they adopt an adult PB γδ-like program. More importantly, our data highlights the rich clonal composition of in vitro expanded CB γδ, with different clonotypes being variably activated upon exposure to different stimuli. Such characteristics can potentially overcome the challenges of cancer heterogeneity and cell persistence, with the potential of improving outcomes in cell immunotherapy.

Disclosures

No relevant conflicts of interest to declare.
Fanci-FANCD2 Promotes Genome Stability and DNA Repair By Down-Regulating BLM Helicase Activity
Authors: Liang Fengshan , Nagarajan Arvindhan , Pillai Manoj M , Sung Patrick , Kupfer Gary M.
Published: November 2021

Background: Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure, developmental defects, and higher risk of cancer. Mutations in FA genes have been detected commonly in a large swath of cancers. In the FA DNA repair pathway, DNA damage induces the mono-ubiquitination of the FANCI-FANCD2 (ID2) heterodimer and this regulation licenses the execution of downstream DNA damage signaling and repair steps. In response to replication stress, FANCD2 also prevents replication fork collapse during S phase. Bloom syndrome (BS) is also a genomic instability disease, characterized by growth abnormalities and cancer predisposition. The single BS protein, BLM helicase, participates in DNA repair by promoting DNA end resection and double Holliday junction dissolution. It has been shown that BLM is involved in restart of stalled replication fork. FA and BS have functional interactions. In tumor DNA sequencing of the Yale Precision Tumor board, we identified a somatic 6 amino acid deletion in FANCD2 in a head and neck tumor, while a germline point mutation was found on the other allele. We have identified a FANCD2-L822A mutant with defective BLM binding, which was used to further investigate the role of FANCD2-BLM interaction in genome stability and DNA repair.

Methods: Highly purified proteins were used to investigate how ID2 affects helicase and DNA end resection activity of the BLM complex. HeLa, FANCD2-deficient, and FANCD2 corrected fibroblast cell lines were used to examine pRPA2 and RAD51 foci formation. We also used DNA fiber assay to detect end resection and isolation of proteins on nascent DNA (iPOND) assay to examine the RAD51 recruitment on replication fork.

Results: A somatic 6 amino acid deletion (p819-824) in FANCD2 was identified in a head and neck tumor. FA-D2 mutant cells expressing the mutant cDNA demonstrated defects in FANCD2 mono-ubiquitination and DNA damage hypersensitivity. A FANCD2-L822A mutant with defective BLM binding was identified (Figure A, B). We found that Bloom helicase and its DNA end resection activity within BLM-DNA2-RPA were negatively regulated by the heterodimer ID2 (Figure C, D). Both DNA and BLM binding of the ID2 are required for the inhibitory function. The premature DNA end resection and HU sensitivity in FANCD2 deficient and mutant cells are rescued by BLM knockdown. By iPOND assay, we discovered that FANCD2 antagonizes BLM to promote RAD51 recruitment on HU-stalled replication fork.

Conclusions: Our study suggests that the DNA end resection activity of BLM-DNA2 is tightly regulated by FANCD2 to ensure that the nuclease DNA2 normally resects the DNA intermediate needed for efficient DNA repair and RAD51 recruitment to protect replication forks. Our findings highlight that ID2-BLM interaction functions in DNA damage repair to maintain genome stability.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Single-Cell Sequencing Technology Reveals the Heterogeneity of the Immune Microenvironment and Key Molecules of Drug Resistance in Angioimmunoblastic T-Cell Lymphoma
Authors: Jin Hui , Fan Lei , Lu Xueying , Cao Lei , Wu Zijuan , Wang Luqiao , Zhu Huayuan , Li Jianyong
Published: November 2021

Objective:

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL). AITL is an aggressive malignancy with a poor prognosis, and its clinical manifestations vary greatly among individuals. The current chemotherapy regimens based on anthracycline show limited efficacy, and there is no best rescue treatment for patients with relapsed and refractory (RR) AITL. In addition, the lack of optimal AITL models in vitro greatly limits the basic research on the mechanism of disease occurrence and progression, and also hinders the development of new drugs and preclinical trials. Our study aims to deeply analyze the tumor heterogeneity and clonal evolution of AITL, discovering key molecules of drug resistance and potential theraputic targets.

Methods :

We detected fresh lymph node samples from newly diagnosed and relapsed/ refractory AITL patients using single-cell RNA sequencing, combined with imaging mass cytometry (IMC) and whole exome sequencing. IMC was performed to analyze the spatial position relationship and protein expression characteristics of different subgroups in the tumor microenvironment of AITL. In addition, AITL patient-derived organoid model was established to study the regulatory role of YY1 and its inhibitors in relapsed and refractory AITL.

Results :

ScRNA-seq revealed the significant differences in the tumor microenvironment of newly diagnosed and RR-AITL patients (Fig A,B). B cells and myeloid subgroups may play important roles in the development of AITL (Fig C). Transcription factor YY1, highly expressed in follicular helper T cell (Tfh) of RR-AITL patients, promoted the proliferation and drug resistance of AITL cells (Fig E,F). The proportion of CD8+ T cells in the RR-AITL sample was reduced, while the proportion of Treg was increased, as well as the depletion of T cells (Fig G,H). Furthermore, the stemness of B cells in RR-AITL was enhanced and exhibits significant malignant characteristics (Fig C,I-K). We also found decreased interaction in RR-AITL samples (Fig L,M). Moreover, for the first time, we established AITL patient-derived organoid models that can be stablely cultured in vitro (Fig N). On this basis, we could further clarify the important roles of transcription factor YY1 in the drug resistance of AITL, evaluate the cytotoxic effect of YY1 inhibitor NP-001 on AITL tumor cells.

Conclusion :

In conclusion, our study revealed the differences between newly diagnosed and relapsed /refractory AITL in terms of immune microenvironment, single-cell transcriptomes, and signal pathway activation. YY1 may serve as an novel target for drug resistance for RR-AITL patients. These findings may provide a theoretical foundation for improving the clinical treatment of AITL.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Comparison of Prophylactic and Preemptive Donor Lymphocyte Infusion in Patients with Very High Risk Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yang Luxin , Luo Yi , Huang He , Tan Yamin , Shi Jimin , Zhao Yanmin , Yu Jian , Lai Xiaoyu
Published: November 2021

Relapse remains to be the biggest problem for patients with very high risk acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor lymphocyte infusion (DLI) has been widely applied to the prevention and preemptive intervention of relapse post-transplantation. However, the optimal time to implement DLI in patients with a high risk of relapse remains controversial. During August 1, 2014 and August 30, 2020, four hundred and thirty-one consecutive acute leukemia patients with very high-risk features underwent allo-HSCT in our center. Ninety-five patients received prophylactic DLI (pro-DLI) while one hundred and fifty-five patients received preemptive DLI (pre-DLI). Patients were stratified into five risk groups by the disease-risk stratification system (DRSS) which recently introduced by European Society for Blood and Marrow Transplantation: low risk (N=44), intermediate-1 (N=67), intermediate-2 (N=60), high (N=36), and very high (N=43). In the very high group, patients who received pro-DLI achieved higher 3-year overall survival (OS) (50.8% versus 31.8%, P=0.05), leukemia-free survival (LFS) (52.5% versus 31.6%, P=0.03) and graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS) (47.9% versus 31.6%, P=0.04) compared with pre-DLI. Pro-DLI cohort was associated with a trend of lower 3-year cumulative rates of relapse (42.8% versus 57.9%, P=0.12) and non-relapse mortality (NRM) (4.6% versus 10.5%, P=0.43). In the subgroup of intermediate-2 and high (N=96), pro-DLI cohort was associated with superior survival and relapse rate, though without statistical significance. Further analysis was conducted separately between patients with positive minimal residual disease (MRD) and negative MRD pre-transplant in intermediate-2/high subgroup. In the patients with positive MRD before all-HSCT, pro-DLI achieved significant higher 3-year OS (66.7 % versus 26.2%, P=0.028), PFS (68.6 % versus 24.7%, P=0.015) and GRFS (68.6 % versus 14.4%, P=0.007), along with lower cumulative of relapse (31.4 % versus 59.3%, P=0.1) and NRM (0 versus 16%, P=0.1) compared with pre-DLI. However, pro-DLI patients was associated with inferior OS (52.7 % versus 77.8%, P=0.046), PFS(54.8 % versus 75.3%, P=0.247) and NRM (25% versus 3%, P=0.02) in patients with negative MRD. In addition, no difference was found in patients in the group of low and intermediate-1 risk. Taken together, we recommend early pro-DLI in patients of very-high risk group and positive MRD of intermediate-2/high group. Pre-DLI given timely after MRD turning positive achieved better outcome in the remaining patients.

Disclosures

No relevant conflicts of interest to declare.
Histopathologic Characterization of Vexas Syndrome
Authors: Barouqa Mohammad I. , Ravindran Aishwarya , Chen Dong , Oliveira Jennifer L , Olteanu Horatiu , Howard Matthew T , Zheng Gang , Patnaik Mrinal M. , Begna Kebede H. , Bock Allison M. , Go Ronald , Koster Matthew , Kourelis Taxiarchis , Mangaonkar Abhishek A. , Ryu Jay , Samec Matthew , Sartori Valinotti Julio C. , Warrington Kenneth , Reichard Kaaren K.
Published: November 2021

Introduction:

VEXAS syndrome (vacuoles, E1 ubiquitin ligase, X-linked, autoinflammatory, somatic) is a newly recognized inflammatory disorder caused by somatic mutations in the UBA1 gene. Bone marrows from these patients reveal a range of morphological changes in hematopoietic precursor cells. In this study, we aim to assess the laboratory indices and morphologic spectrum of bone marrow pathology in VEXAS syndrome.

Methods:

We identified 16 cases of VEXAS syndrome. All cases had confirmed UBA1 mutation. We reviewed bone marrow biopsies corresponding to the date of diagnosis. This study was approved by the Mayo Clinic Institutional Review Board.

Results:

All patients were male with a median age of 73 years - associated autoimmune disorders included Sweet syndrome, inflammatory arthritis, relapsing polychondritis and granulomatosis with polyangiitis.

14/16 patients had anemia with median hemoglobin of 10.4 (Range: 6.7- 14.1 g/dL). 15/16 had macrocytosis with median MCV 110.4 (Range: 94.8- 123.1 /fL). 5/16 had thrombocytopenia with median platelet count 174 (Range: 20- 500 x10^9/L). 7/16 had leukopenia with median WBC 3.65 (Range: 2.4- 11.6 x10^9/ L). The ESR and CRP medians were 61.0 mm/hr and 81.5 mg/L, respectively.

Karyotype was performed in 12 patients of which 11 were normal and the remaining case showed a complex karyotype. An NGS panel targeting the most frequent myeloid disorder associated gene mutations was negative in 10/15 cases. GS for myeloid mutations revealed pathogenic mutations in 5 patients, involving genes TET2 (2/5), DNMT3A (2/5), and TP53 (1/5).

Conclusions:

Bone marrow findings in VEXAS syndrome, in this series of 16 patients, are individually non-specific, yet when taken altogether in the overtly abnormal cases, are very suggestive when the clinical index of suspicion is high. In such scenarios, the combined clinical and bone marrow findings should prompt discussion and consideration for UBA1 mutation testing given the significant clinical implications for patient management and prognosis.

Disclosures

Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding.
Thrombotic Events in COVID-19 Patients Undergoing Convalescent Plasma Therapy: A Systematic Review
Authors: Yu Philip , Khalid Faran , Li Allen , Laureano Marissa , Crowther Mark
Published: November 2021

INTRODUCTION

Convalescent plasma therapy (CPT) has been proposed as a mechanism of passive immunization against COVID-19. Current guidelines on the efficacy of its use is not well delineated with limited studies analyzing the risk of thromboembolic events during treatment. The goal of this systematic review and meta-analysis was to assess the risk of arterial and venous thromboembolisms from CPT in patients with COVID-19.

METHODS

We conducted a comprehensive literature review of Ovid MEDLINE, Cochrane Central Registry of Controlled Trials (CENTRAL), and EMBASE from inception to June 2021. Title and abstract screening and full-text screening was done in duplicate by two independent reviewers. All randomized controlled trials and cohort studies that analyzed adult COVID-19 patients undergoing CPT were included for analysis. Editorials, conference abstracts, narrative reviews, case series, containing less than 100 patients were excluded. The primary outcome analyzed was the risk of thrombotic events in CPT + standard therapy vs standard therapy alone. Meta-analysis was done using a random-effects model using the Revman 5 software.

RESULTS

Of 1774 studies identified from our search, three randomized (n= 660 patients), and one non-randomized matched cohort study) (n = 96 patients) were included for analysis. The risk ratio for thrombotic events was 2.33, favoring the CPT group (95% CI, [0.70, 7.72], P = 0.17, I2 = 29%). Subgroup analyses showed that CPT + standard therapy was associated with a decreased risk of in-hospital mortality (RR = 0.70 [0.49, 0.98], P = 0.04, I2 = 0%). No significant difference in cardiovascular events (RR = 0.90 [0.67, 1.20], P = 0.48, I2 = 0%), hypertension (RR = 1.67 [0.56, 4.98], P = 0.35, I2 = 0%), and septic shock (RR = 0.97 [0.40, 2.35], P = 0.94, I2 = 41%) was found between CPT + standard therapy and standard therapy alone.

CONCLUSION

We found treatment of COVID-19 with standard therapy + CPT was not associated with an increase in the risk of thromboembolic events. CPT was associated with a decreased risk of in-hospital mortality but not of MACE, hypertension, or septic shock.

Disclosures

Crowther: Hemostasis reference laboratories: Honoraria; Bayer: Speakers Bureau; CSL Behring: Speakers Bureau; Precision Biologicals: Honoraria; Pfizer: Speakers Bureau; Syneos Health: Honoraria.
Epidemiology of Hospitalizations Due to Autoimmune Hemolytic Anemia in the United States
Authors: Mullangi Sanjana , Yadav Preeti , Kilinc Ekim , Gudivada Silpa , Khan Javaria , Anumolu Prathyusha , Khadka Shushmita , Goswami Ruchir , Patel Achint , Welaya Karim , Lekkala Manidhar Reddy
Published: November 2021

Introduction:

Autoimmune hemolytic anemia (AIHA) is an acquired immune disorder resulting in the production of cold and warm autoantibodies directed against red blood cell antigens; characterized by shortened red blood cell survival and a positive Coombs test. Types include primary disease (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immunosuppression with corticosteroids and other agents, Transfusion. There is not much recent data available on epidemiology of AIHA. We aim to estimate epidemiological trends and outcomes of AIHA as well as factors associated with poor outcomes by using the largest available national database from the United States.

Methods:

We derived a study cohort from the National Inpatient Sample (NIS) for the years 2007-2018 for hospitalizations due to AIHA by using International Classification of Diseases (9th/10th Editions) Clinical Modification diagnosis codes ICD-9-CM/ICD-10-CM). Other diagnosis and comorbidities were also identified by ICD-9/10-CM codes and Elixhauser comorbidity software. Our primary outcome was discharge disposition following AIHA hospitalization. We utilized multivariable survey logistic regression models to analyze and identify predictors of poor outcomes.

Results:

Between 2007-2018, a total of 52,814 hospitalizations occurred due to primary diagnosis of AIHA. Burden of hospitalizations remained stable from 4,254 (8.1%) in 2007 to 4,405 (8.3%) in 2018. AIHA patients in the study cohort were mostly above 65 years of age (48.6%) followed by 35-65 years of age (33.7%), females (58.3%) and Caucasians (69.1%). Overall in-hospital mortality of AIHA hospitalizations was 3.1%, and discharge to facility was 11.86%. Median length of stay for AIHA hospitalization was 4-days (interquartile range: 2-days to 6-days). Furthermore, in multivariable logistic regression analysis, increasing age (OR 1.2; 95%CI 1.1-1.3; p<0.001), male gender (OR 1.5; 95%CI 1.2-1.3; p:0.0024), vascular events (OR 1.5 ; 95%CI 1.1-2.0; p:0.0156), teaching hospitals (OR 3.1; 95%CI 1.5-6.5; p:0.002), plasmapheresis (OR 5.5; 95%CI 2.8-10.8; p:0.001) and intravenous immunoglobulins (OR 1.9; 95%CI 1.3-3.0; p:0.001) were associated with higher in-hospital mortality.

Conclusion:

Our study describes the epidemiology of hospitalizations due to AIHA in the United States from a nationally representative database. We observed that hospitalization burden due to AIHA have remained stable from 2007 to 2018. We also identified factors associated with higher in-hospital mortality and some of which are modifiable. Further studies are required to establish the causal association of these factors to poor outcomes and develop better risk stratification strategies to improve overall outcomes of AIHA.

Disclosures

No relevant conflicts of interest to declare.
Two Stage Intravital Imaging Mouse Model to Assess Venous Thromboembolism in Sickle Cell Disease
Authors: Brzoska Tomasz , Kaminski Tomasz W. , Tutuncuoglu Egemen , Gladwin Mark T. , Sundd Prithu
Published: November 2021

Sickle cell disease (SCD) patients have an increased risk of venous thromboembolism (VTE). Population-based studies demonstrated that VTE has a cumulative incidence rate of approximately 25% in adult SCD patients and is associated with higher risk of mortality. VTE in SCD is most commonly manifested as deep vein thrombosis (DVT) with associated pulmonary embolism (PE). Although autopsy studies have regularly discovered pulmonary thromboembolic lesions in SCD patients, the pathophysiology of VTE in SCD remains largely unknown mostly due to the lack of relevant animal VTE model. Understanding the mechanisms that promote VTE in SCD is imperative to identify its prevention and treatment measures.

To elucidate the cellular, molecular and biophysical mechanisms of VTE in SCD we developed an innovative two stage intravital imaging analysis experimental model in SCD mice. DVT in SCD mice was induced by surgical ligation of femoral vein. Venous thrombus formation was visualized using intravital multi-photon-excitation (MPE) microscopy. Venous thrombus took the form of a large mass of elliptical shape which extended in the long-axis direction of the femoral vein. It was composed of fibrin, erythrocytes and sparse platelets. Over time, thrombus was infiltrated by migrating neutrophils. To trigger acute PE, femoral vein ligation was removed and the venous thrombus was observed to spontaneously detach and travel to the SCD mouse lung. This method allowed real time visualization of acute PE in vivo using MPE microscopy of intact lung in live breathing mice. Acute PE involved embolization of the pulmonary arterioles and the arteriolar bottle-necks located at the junction of pulmonary arterioles and capillaries. The embolization of arteriolar circulation led to loss of blood flow in the arterioles and the down-stream capillaries.

Herein we introduce an intravital microscopy approach to probe VTE in SCD live mouse. Our model has potential application in investigating the molecular determinants of VTE associated with SCD as well as evaluating efficacy of new antithrombotic drugs.

Disclosures

Sundd: Bayer: Research Funding; CSL Behring Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Implementation of a High-Dose Cytarabine Outpatient Program for Acute Myeloid Leukemia Patients in a Limited-Source Setting
Authors: Haro Juan C , Espinoza-Morales Evelyn , Espino Johan , Jiménez-Mozo Fátima , Poma Nathaly , Casas Jhoisy , Castro-Mollo Melanie , Sandival Gustavo , Ortega Emperatriz , Roque Katia , Lopez Lourdes , Alcarraz Cindy , Lozano Sophia , Cervantes Elizabeth , Quintana Shirley , Vidaurre Tatiana , Enriquez Daniel J
Published: November 2021

Background: The management of acute myeloid leukemia (AML) patients usually requires long inpatient treatments that can affect the limited care facilities, the quality of life, and increases healthcare costs. Additionally, leukemia treating centers in developing countries face limited sources to deliver high-dose chemotherapies as inpatient treatments. Therefore, several reports have established the feasibility and safety of outpatient consolidation. We aimed to implement a high-dose cytarabine outpatient program for AML in a limited-source institution at a public center in Peru.Methods: We conducted a prospective pilot study starting in January 2019 and ending before the COVID-19 Pandemic in March 2020. Eligible patients were ≥ age 14, met inclusion criteria for inpatient induction regimens, were without active infection, and had the following: normal chest x-ray and biochemistry, complete remission after one cycle of 7+3 induction. Logistical requirements included a 3-hours distance residence near the treatment center, caregiver support, trained nursing staff, infusion room capacity, and participation in follow-up. Patients received prophylactic antimicrobials such as oral levofloxacin, fluconazole, and acyclovir and were admitted to the hospital for predetermined complications of therapy (fever, G3-4 toxicity, febrile neutropenia, bleeding or refractory thrombocytopenia). Risk stratification was based on conventional cytogenetics and multiplex PCR using Leukemia.net criteria.

Results: Forty-two patients were included during the study period. The median age was 38 years (16-63) and Female/Male ratio 4:3. According to Leukemia.net, 24% were classified as high, 50% intermediate and 26% as low risk group. Including FLT3 mutations in 26% of cases. Twenty-two and 20 subjects received 1-2 and 3-4 cycles of ambulatory HiDAC, respectively. About one-third of cases had emergency admissions during consolidation and 74% complete at least 3 cycles of cytarabine. Only 4 patients underwent sibling-donor allo-SCT. Sixty-four percent experienced relapses, and at 2 years follow-up only 21 subjects were alive. Median OS was 15 months, a better survival was shown among patients who received 3-4 cycles of ambulatory HiDAC (2-year OS 18 vs 23%, p=0.031).

Conclusion: Our pilot study shows the feasibility to deliver HiDAC as outpatient consolidation in selected AML cases in a limited setting. Additionally, a high rate of relapses and poor survival was noted in our cohort that requires further consideration.

Disclosures

No relevant conflicts of interest to declare.
Performance of Neutrophil-to-Lymphocyte Ratio (NLR) in Differentiating Vaso-Occlusive Crisis from Infection in Patients Presenting with Sickle Cell Crisis
Authors: Maharaj Satish , Chang Simone M , Xue Ruobing , Cisak Kamila I. , Sharma Vivek R.
Published: November 2021

Background:

Patients with sickle cell disease (SCD) are at increased risk of developing serious infections as a result of functional asplenia and altered humoral immunity. Nevertheless, presenting symptoms of sepsis such as fever and arthralgias are common in SCD and can occur with many sickle cell related conditions, including vaso-occlussive crises (VOC) and may not correlate with true infections. The neutrophil-to-lymphocyte ratio (NLR) is calculated as the absolute neutrophil count divided by the absolute lymphocyte count and represents an easily accessible value that has been found to correlate with inflammation and prognosis in several conditions. Few studies have evaluated NLR as a biomarker in sickle cell disease, and its utility in differentiating infection vs. VOC in patients presenting to the emergency room remains unknown.

Method: We conducted a retrospective review of 143 patients with SCD who presented to the emergency department with fever and painful crises. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=92) and patients with proven/possible infection (n=51). Inclusion criteria for both groups were patients with SCD, 17 years and older and complete blood count with differential on presentation; patients who had received antibiotics prior to presentation were excluded. Data collected on presentation included genotype, age, gender, complete blood count, hydroxyurea use. Data was analyzed between the two groups using descriptive statistics and receiver-operating characteristic (ROC) curve analysis.

Results: Demographics and clinical characteristics are summarized in the Table. The sample included primarily young adult males with 61% on hydroxyurea. Genotype HbSS (73%) was most prevalent followed by HbSC (23%) and HbSβ (4%). The mean Hb was around 8 g/dL. The VOC group had a lower mean white blood cell (WBC) count of 13.6, compare to 17.2 for patients with proven/possible infection. ROC analysis showed that NLR did correlate with infection, with a modest AUC 0.7 [95% CI (0.59-0.77)] that was significant (p=0.0002) when compared to the AUC=0.5 model. Maximum specificity and sensitivity in this sample was achieved with NLR = 4.5 (Specificity 75% and Sensitivity 59%).

Conclusion: In this sample, NLR on presentation significantly but only modestly correlated with infection as opposed to VOC. Optimal performance at NLR=4.5 achieved Specificity 75% and Sensitivity 59%. Despite modest performance, given the widespread availability and cost-effectiveness of NLR testing, further study in a larger sample may derive other variables that can combine with NLR to formulate a predictive model to improve care for these patients.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Evaluating the performance of propensity score matching based approaches in individual patient data meta-analysis
Authors: Johara Fatema Tuj , Benedetti Andrea , Platt Robert , Menzies Dick , Viiklepp Piret , Schaaf Simon , Chan Edward
Published: November 2021

Background

Individual-patient data meta-analysis (IPD-MA) is an increasingly popular approach because of its analytical benefits. IPD-MA of observational studies must overcome the problem of confounding, otherwise biased estimates of treatment effect may be obtained. One approach to reducing confounding bias could be the use of propensity score matching (PSM). IPD-MA can be considered as two-stage clustered data (patients within studies) and propensity score matching can be implemented within studies, across studies, and combining both.

Methods

This article focuses on implementation of four PSM-based approaches for the analysis of data structure that exploit IPD-MA in two ways: (i) estimation of propensity score model using single-level or random-effects logistic regression; and (ii) matching of propensity scores (PS) across studies, within studies or preferential-within studies. We investigated the performance of these approaches through a simulation study, which considers an IPD-MA that examined the success of different treatments for multidrug-resistant tuberculosis (MDR-TB). The simulation parameters were varied according to three treatment prevalences (according to studies, 50% and 30%), three levels of heterogeneity between studies (low, moderate and high) and three levels of pooled odds ratio (1, 1.5, 3).

Results

All approaches showed greater biases at the higher levels of heterogeneity regardless of the choices of treatment prevalences. However, matching of propensity scores using within-study and preferential-within study reported better performance compared to matching across studies when treatment prevalence varied across-studies. For fixed prevalences, a random-effect propensity score model to estimate propensity scores followed by matching of propensity scores across-studies achieved lower biases compared to other PSM-based approaches.

Conclusions

Propensity score matching has wide application in health research while only limited literature is available on the implementation of PSM methods in IPD-MA, and until now methodological performance of PSM methods have not been examined. We believe, this work offers an intuition to the applied researcher for the choice of the PSM-based approaches.
Effect of the “Normalized Epidemic Prevention and Control Requirements” on hospital-acquired and community-acquired infections in China
Authors: Chen Caiyun , Zhu Ping , Zhang Yongxiang , Liu Bo
Published: November 2021

Background

No studies have yet reported the effect of prevention and control measures, which were implemented to combat COVID-19, on the prevention and control of common HAIs. We aimed to examine the effect of the “Normalized Epidemic Prevention and Control Requirements” (implemented in May 2020) by comparison of hospital-acquired infections (HAIs) and community-acquired infections (CAIs) in China during 2018, 2019, and 2020.

Methods

Data of inpatients before and after implementation of new requirements were retrospectively analyzed, including infection rate, use of alcohol-based hand cleaner, anatomical sites of infections, pathogen species, infection by multi-drug resistant species, and use of different antibiotics.

Results

The HAI rate was significantly higher in 2020 than in 2018 and 2019 (P < 0.05), and the CAI rate was significantly higher in 2019 and 2020 than in 2018 (P < 0.001). Lower respiratory tract infections were the most common HAI during all years, with no significant changes over time. Lower respiratory tract infections were also the most common CAI, but were significantly more common in 2018 and 2019 than 2020 (P < 0.001). There were no changes in upper respiratory tract infections among HAIs or CAIs. Most HAIs and CAIs were from Gram-negative bacteria, and the percentages of fungal infections were greater in 2019 and 2020 than 2018. MRSA infections were more common in 2020 than in 2018 and 2019 (P < 0.05). The utilization rate and usage days of antibiotics decreased over time (P < 0.001) and the culture rate of microbial specimens before antibiotic usage increased over time (P < 0.001).

Conclusions

The new prevention and control requirements provided important benefits during the COVID-19 pandemic. However, their effects on HAIs were not obvious.
Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson’s disease trial
Authors: Hutchison R. Matthew , Evans Karleyton C. , Fox Tara , Yang Minhua , Barakos Jerome , Bedell Barry J. , Cedarbaum Jesse M. , Brys Miroslaw , Siderowf Andrew , Lang Anthony E.
Published: November 2021

Background

Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson’s disease (PD). Depending on the stage of progression, approximately 5–15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood.

Methods

The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis.

Results

In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]).

Conclusion

A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects.

Trial registration

ClinicalTrials.gov identifier: NCT03318523.

Date submitted: October 19, 2017.

First Posted: October 24, 2017.
Urban-rural differences in the associated factors of severe under-5 child undernutrition based on the composite index of severe anthropometric failure (CISAF) in Bangladesh
Authors: Anik Asibul Islam , Chowdhury Mohammad Rocky Khan , Khan Hafiz T. A. , Mondal Md Nazrul Islam , Perera Nirmala K. P. , Kader Manzur
Published: November 2021

Introduction

Severe undernutrition among under-5 children is usually assessed using single or conventional indicators (i.e., severe stunting, severe wasting, and/or severe underweight). But these conventional indicators partly overlap, thus not providing a comprehensive estimate of the proportion of malnourished children in the population. Incorporating all these conventional nutritional indicators, the Composite Index of Severe Anthropometric Failure (CSIAF) provides six different undernutrition measurements and estimates the overall burden of severe undernutrition with a more comprehensive view. This study applied the CISAF indicators to investigate the prevalence of severe under-5 child undernutrition in Bangladesh and its associated socioeconomic factors in the rural-urban context.

Methods

This study extracted the children dataset from the 2017–18 Bangladesh Demographic Health Survey (BDHS), and the data of 7661 children aged under-5 were used for further analyses. CISAF was used to define severe undernutrition by aggregating conventional nutritional indicators. Bivariate analysis was applied to examine the proportional differences of variables between non-severe undernutrition and severe undernutrition group. The potential associated socioeconomic factors for severe undernutrition were identified using the adjusted model of logistic regression analysis.

Results

The overall prevalence of severe undernutrition measured by CISAF among the children under-5 was 11.0% in Bangladesh (rural 11.5% vs urban 9.6%). The significant associated socioeconomic factors of severe undernutrition in rural areas were children born with small birth weight (AOR: 2.84), children from poorest households (AOR: 2.44), and children aged < 36 months, and children of uneducated mothers (AOR: 2.15). Similarly, in urban areas, factors like- children with small birth weight (AOR: 3.99), children of uneducated parents (AOR: 2.34), poorest households (APR: 2.40), underweight mothers (AOR: 1.58), mothers without postnatal care (AOR: 2.13), and children’s birth order ≥4 (AOR: 1.75), showed positive and significant association with severe under-5 undernutrition.

Conclusion

Severe undernutrition among the under-5 children dominates in Bangladesh, especially in rural areas and the poorest urban families. More research should be conducted using such composite indices (like- CISAF) to depict the comprehensive scenario of severe undernutrition among the under-5 children and to address multi-sectoral intervening programs for eradicating severe child undernutrition.