bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Venous Thromboembolism in Hospitalized Patients with Acute Ischemic Stroke Versus Other Neurological Conditions
Authors: Dhanesha Nirav , Garg Aayushi , Shaban Amir , Samaniego Edgar , Chauhan Anil K , Leira Enrique 
Published: November 2021

Abstract
Background
The mechanism of increased risk of venous thromboembolism (VTE) after acute ischemic stroke (AIS) is unclear. In this study, we aimed to evaluate the risk of VTE in hospitalizations due to AIS as compared to those due to non-vascular neurological conditions. We also aimed to assess any potential association between VTE risk and the use of intravenous thrombolysis (rtPA) among hospitalizations with AIS.
Methods
In this case-control study, data were obtained from the Nationwide Inpatient Sample 2016-2018. Propensity score matching was used to adjust for the baseline differences between the groups. Logistic regression analysis was used to compare the risk of VTE.
Results
We identified 1,541,685 hospitalizations due to AIS and 1,453,520 hospitalizations due to non-vascular neurological diagnoses that served as controls. After propensity score matching, 640,560 cases with AIS and corresponding well-matched controls were obtained. Hospitalizations due to AIS had higher odds of VTE as compared to the controls [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.40-1.60, P&lt;0.001]. Among hospitalizations with AIS, 184,065 (11.9%) got rtPA. The odds of VTE were lower among the AIS hospitalizations that received rtPA as compared to those that did not (OR 0.89, 95% CI 0.79-0.99, P0.035).
Conclusion
Hospitalizations due to AIS have a higher risk of VTE as compared to the non-vascular neurological controls. Among AIS cases, the risk of VTE is lower among patients treated with rtPA. These epidemiological findings support the hypothesis that the risk of VTE after AIS might be partly mediated by an intrinsic pro-coagulant state.

Disclosures
No relevant conflicts of interest to declare.
Idiopathic Erythrocytosis: Vascular Complications
Authors: Malas Abdullah , Bufalino Shams , Hancock Christie , Bitran Jacob D. 
Published: November 2021

Abstract
Idiopathic Erythrocytosis (IE) is a diagnosis of exclusion once primary and secondary causes have been eliminated; yet IE remains an enigmatic disorder. Published series from decades ago (Modan & Modan J. Hematol [1968] 14:375; Pearson & Wetherly-Mein, Clin.Lab Hematol. [1974] 1:189) have reported high rates of vascular complications (46%) and advise phlebotomy to keep the hematocrit to less than 45%. A More recent series (McMullin B.J. Hematol. [2005] 130:174) advise no need for phlebotomy in patients with no co-morbidities such as vascular disease, diabetes, or hypertension. In an attempt to determine some practice guidelines, we undertook a retrospective analysis of patients identified with IE within our practice and to quantify the rates of vascular complications, if any.
From January 1, 2016 to December 31. 2020 99 patients were referred because of erythrocytosis. Twenty of these 99 patients had polycythemia rubra vera and 77 had secondary erythrocytosis ( 64 males, 13 females, median age 61 years). Of these 77 patients with secondary erythrocytosis, 40 had obstructive sleep apnea, 10 men abused testosterone, and 1 patient each was either post splenectomy or post kidney transplant, 1 patient had a renal cell carcinoma, and 1 patient had familial erythrocytosis. Twenty patients were identified as having IE and all 20 did not have a JAK2 mutation. There 13 males and 7 females with a median age of 63 years (range 31-76). The median hemoglobin was 17.2 gm/dl and the median hematocrit was 51.2 (range 15.0 to 18.4 and 49% to 55% respectively). The median erythropoietin level was 9.9 mu/ml (range 5-38.5). Two of the 20 patients underwent therapeutic phlebotomy and developed no vascular complications. Eighteen patients were simply followed with phlebotomy despite having comorbidities of hypertension, increased BMI, type II diabetes, and none developed vascular complications. IE remain an enigmatic disorder that requires uniform diagnostic criteria as well as uniform practice guidelines; however, given our retrospective review, we do not believe that therapeutic phlebotomy is justified.

Disclosures
No relevant conflicts of interest to declare.
Prevention of Fetal/Neonatal Alloimmune Thrombocytopenia in a Preclinical Model By Monoclonal Anti-HPA-1a Antibody Prophylaxis: Structural and Functional Properties of Antibody Variant Isoforms
Authors: Mørtberg Trude Victoria , Zhi Huiying , Vidarsson Gestur , Foss Stian , Michaelsen Terje E , Skogen Bjørn , Stuge Tor Brynjar , Andersen Jan Terje , Newman Peter J. , Ahlen Maria Therese 
Published: November 2021

Abstract
Maternal alloantibodies to paternally inherited platelet antigens can cause fetal/neonatal alloimmune thrombocytopenia (FNAIT), rendering the fetus or newborn prone to bleeding and intracranial hemorrhage (ICH) with risk of lifelong disabilities or death. In Caucasians, the vast majority of cases are due to antibodies to the Human Platelet Antigen (HPA)-1a epitope on glycoprotein (GP)IIIa. To date, there are neither any means to prevent or reduce the risk of alloimmunization and subsequent FNAIT, nor safe and efficient treatment during affected pregnancies. Thus, a prophylactic regimen by administration of monoclonal antibodies to women at risk would be highly beneficial. Knowledge about the optimal functional design of prophylactic monoclonal antibodies for antenatal or post-natal use is however still limited. We have previously isolated and characterized a fully human anti-HPA-1a monoclonal antibody, mAb26.4. In the current study we have explored the prophylactic potential of this antibody by testing a panel of different IgG1 designs, including the wild-type mAb26.4, variants with modified Fc-region N-glycans, as well as an effector silent variant. We performed analyses of properties relevant for immunosuppression: in vitro Fc-receptor binding and capacity to induce phagocytosis, in vivo half-life measurements in humanized FcRn mice and platelet clearance in a recently developed transgenic mouse strain with a recreated HPA-1a epitope on murine GPIIIa. The prophylactic capacity by antibody-mediated immune suppression in vivo, were further tested in the FNAIT pre-clinical murine model, in which BALB/c females can be immunized by transfusion of HPA-1a-expressing platelets from the transgenic mice and where subsequent breeding of pre-immunized mice with transgenic males cause thrombocytopenia in off-springs mimicking FNAIT. By intravenous administrations of mAb26.4 variants prior to platelet transfusions, the mice generated no or low anti-platelet responses compared to control mice, and normal platelet counts in pups upon subsequent breeding. Our data thus successfully demonstrates efficient immunosuppression and prevention of FNAIT by anti-HPA-1a human monoclonal variants, providing further support for potential use in humans.

Disclosures
Skogen: Prophylix Pharma AS: Current holder of individual stocks in a privately-held company. Newman: Rallybio: Consultancy, Research Funding.
Flow Cytometry Based Identification of CD26+ Leukemic Stem Cells in the Peripheral Blood Has a Potential Role in the Rapid Diagnosis of Chronic Myeloid Leukemia
Authors: Sharma Praveen , Sachdeva Man Updesh Singh , Naseem Shano , Sreedharanunni Sreejesh , Das Reena , Malhotra Pankaj , Varma Neelam 
Published: November 2021

Abstract
Background: Demonstration of t(9;22)(BCR-ABL1) fusion is gold standard for the diagnosis of chronic myeloid leukemia (CML). We performed a flowcytometric assay to identify CD26+ CML leukemic stem cells (LSCs) for its value as a standalone diagnostic investigation for the diagnosis of CML and its utility for detection of residual disease in CML patients on therapy.
Methods: Patients of CML/ CML on follow-up were included and peripheral (PB) and/or bone marrow (BM) samples were utilized for flowcytometric analysis. PB and/or BM of patients with diseases other than CML were used as controls. Under 'lyse-wash-stain-wash' sequence, the sample was incubated with a pre-titrated custom-made antibody cocktail in a 'test' tube containing CD45, CD34, CD38 and CD26 mo-abs. Acquisition was carried out on BD FACS Canto II and analysis was done with Diva Software. Clinical data including demographic details, complete blood count and BM findings were also noted.
Results: A total of 104 samples (63 PB and 41 BM) from 64 patients [confirmed & treatment naïve CML (n=30), CML on follow-up (n=15), non-CML (n=19)] were tested. The median (range) time for reporting of PB/BM examination, molecular genetic studies and flow cytometry for CD26+ CML LSCs was 5 (3-11 days), 4 (3-6 days) and 1 (0-1 day) respectively. CD26+ LSCs were identified in all patients with a confirmed diagnosis of CML (Median=0.07%, range 0.002%-26.79%), and also in 8/15 patients of the follow-up group, who also reported persisting levels of BCR-ABL1. None of the patients in the non-CML group and follow-up CML patients with negative RT-PCR results showed the presence of CD26+ LSCs. Also, there was a strong correlation between CD26+ CML LSCs in the PB and BM (r=0.917).
Conclusion: Flow cytometric assessment for CD26+ LSCs is quick with reporting time of even less than an hour. Flow cytometric identification of CD26+ LSCs in the peripheral blood can be a cheap, rapid, robust and potential diagnostic tool for the diagnosis of CML compared to available testing methods. It is independent of BCR-ABL1 transcript type and its role in residual disease monitoring needs further investigation.

Disclosures
No relevant conflicts of interest to declare.
Expression of Paraoxonase-2 in Different Stages of Cutaneous T Cell Lymphoma: Is It a Potential Biomarker for Aggressiveness?
Authors: Morsia Erika , Rupoli Serena , Molinelli Elisa , Sartini Davide , Offidani Anna Maria , Emanuelli Monica , Salvolini Eleonora , Olivieri Attilio , Goteri Gaia 
Published: November 2021

Abstract
Introduction: Paraoxonase 2 (PON2) is an intracellular membrane protein that belong to the PON gene family. This enzyme exerting a crucial role against production of reactive oxygen species within mithochondrial respiratory chain. Some reports provided clinical evidence for a link between PON2 and different types of malignancies and recently a growing attention has been focused on exploring the role of PON2 in cancer. Moreover, in contrast to solid tumors, a low expression levels of PON2 protein were detected in hematological malignancies like acute myeloid leukemia and B-cell lymphomas. The aim of this study was to investigate the role of PON2 in the cutaneous T cells Lymphoma (CTCL).
Methods: We performed an immunohistochemistry analysis of PON2 protein expression at various stages CTCL. We analyzed PON2 protein using skin biopsies from stage I (n= 3) and stage II (n= 6) Mycosis Fungoides (MF) and stage III/IV (n= 5) erythrodermic MF/Sézary Syndrome (SS) and control (n=6) tissues. Values were expressed as percentage of PON2-positive staining cells, whereas the intensity of PON2 positivity was semi-quantitatively scored from negative to -/+/+++. Subsequent statistical analysis was carried out to explore the existence of correlations between intra-tumor enzyme level and clinical-pathological features at diagnosis.
Results: In our preliminary study, results showed PON2 down-expression in SS compared to controls. Among CTCL, we found significant differences in enzyme levels between MF and erythrodermic MF/SS; in fact, PON2 expression was higher in patients with not erythrodermic MF compared to patients with erythrodermic MF/SS. (Table I) Moreover, we found no significant differences in enzyme levels between MF patients and controls.
Conclusion: Our study is the first to demonstrate downregulation of PON2 intra-tumoral in SS patients while protein levels were higher in stage I and II MF patients. These findings seem to suggest that PON2 expression levels could be negatively related with tumor aggressiveness in CTCL: an interesting phenomenon where PON2 is upregulated in the early stages and downregulated in the late stages of CTCL. Further, in vitro studies are needed to clarify the mechanism related to PON2 expression.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Role of Daratumumab in Relapsed and Refractory Multiple Myeloma Patients: Meta-Analysis and Literature Review
Authors: Abodunrin Faith O , Tauseef Abubakar , Silberstein Peter 
Published: November 2021

Abstract
Introduction:
In 2015, U.S. Food and Drug Administration granted daratumumab approval, based on two phase II studies, as monotherapy (16 mg/kg in heavily treated patients) for MM patients who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or patient's double refractory to these agents [1]. Daratumumab is a human IgG1 monoclonal antibody targeting CD38, expressed at high levels on malignant cells in multiple myeloma (MM) [2].
METHODS AND METHODOLOGY:
This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per PRISMA guidelines and its summary is given in Figure 1. Two authors (AA and MZ) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane library using the medical search terms: "daratumumab, refractory, relapsed, multiple myeloma". Three of the totals of 679 articles reviewed were selected as having identical primary and secondary outcomes
Results:
A total of 3 studies including 1533 patients (849 in Daratumumab treatment group while 684 patients in control group) were included in the study (Figure I). Mean age was 65 years in both groups. 54.4% had a progression free survival in daratumumab group as compared to 8% in control. Overall response rate, very good partial response, and complete response favors treatment group while minimal and partial response outcome favored control group. Adverse effects were more common in treatment group as compared to treatment group.
Discussion:
In ELOQUENT-3 trial, role of Elotuzumab was studied in RRMM patients which showed ORR of 53% in treatment group in comparison to our study which showed ORR of 85.2% with significant p-value of &lt;0.001 [3]. Similar kind of results were seen with Eloquent-2 trial which showed overall response rate of 79 % respectively [4].
References:
1. Overdijk MB, Jansen JH, Nederend M, Lammerts van Bueren JJ, Groen RW, Parren PW. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking. 2016;197(3):807-13.
2. Dima D, Dower J, Comenzo RL, Varga C. Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy. Cancer management and research. 2020;12:7891-903.
3. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822.
4. Zhang T, Wang S, Lin T, Xie J, Zhao L, Liang Z, et al. Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed/refractory multiple myeloma. Oncotarget. 2017;8(20):34001-17.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Platelet Mediated Monocyte/Macrophage Immune Training
Authors: Li Chen , Maurya Preeti , Nieves-Lopez Benjamin , Ture Sara , Morrell Craig N. 
Published: November 2021

Abstract
Platelets are essential mediators of vascular and immune homeostasis as well as mediators of thrombosis. Platelet functions in hemostasis and thrombosis have received great attention in both basic and clinical research, however, emerging research indicates platelets are also critical components of the immune system. Platelets have important roles in many inflammation-associated diseases including sepsis, atherosclerosis, and peripheral artery disease.
In recent years, much interest has focused on the acute outcomes of interactions between platelets and monocytes/macrophages in immune responses to bacterial infections, as several studies have demonstrated that platelets contribute to bacteria clearance and inflammation resolution by regulating monocyte/macrophage responses and their immune differentiation. However, macrophages are long-lived cells and past stimulation and immune interactions can change their responses to future stimuli - a concept termed 'innate immune memory'. Whether platelet interactions with monocytes/macrophages alters their inflammatory responses to secondary stimuli in a long-lasting manner remains unclear.
We have now found that platelet interactions with monocytes and macrophages as a first stimulus, changed their responses to secondary stimuli, such as lipopolysaccharide (LPS) and unmethylated cytosine-phosphate-guanine (CpG). We incubated monocytes or macrophages with control buffer or platelets overnight and then removed the platelets prior to the addition of LPS or CpG as secondary stimulation. LPS and CpG induced IL-6 and TNFα were reduced by platelet pre-incubation compared to platelet naïve macrophages. Despite reduced cytokine secretion, platelet pre-incubation increased monocyte and macrophage proliferation in response to secondary stimuli. Furthermore, the platelet mediated macrophage secondary stimuli phenotype was preserved for several days after platelet exposure indicating a genetic reprogramming mediated mechanism. Circulating monocytes from platelet deficient TPOR -/- mice and adult mice made platelet deficient also had higher Il6 expression and secrete more IL-6 in response to stimulation compared to monocytes from WT mice indicating in vivo platelet mediated monocyte immune-training. Furthermore, the genetic reprogramming may be dependent on a HIF1α dependent process, as platelet pre-incubation increased macrophage Hif1α expression, a known mediator of trained immunity.
Monocytes and macrophages, are 'immune plastic' and adapt to their environment in a functional manner. These novel data indicate that platelets 'reprogram' monocytes/macrophages and shape their responses to future stimulation.

Disclosures
No relevant conflicts of interest to declare.
Platelets up-Regulate Tumor Cell Programmed Death-Ligand 1 through Epidermal Growth Factor Receptor Signal Transduction
Authors: Guo Qiuchen , Malloy Michael W , Roweth Harvey G. , Italiano Joseph E. , Battinelli Elisabeth 
Published: November 2021

Abstract
Introduction: Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are important immune checkpoint proteins in cancer immunotherapy and targeted therapies against PD-L1 have significantly prolonged many patients' lives. Recently, high baseline platelet to lymphocyte ratio was reported to be associated with decreased patient response rate to immune checkpoint inhibition (ICI) therapies, including anti-PD-L1 therapy, suggesting the potential role of platelets in tumor immunity. Platelets express PD-L1 on their surface, and platelets binding to PD-L1 negative tumor cells can "decorate" tumor cells with PD-L1 and protect against T cell-mediated cytotoxicity. However, whether platelet can affect PD-L1 expression on tumor cells is still unknown.
Methods: In this study, we designed platelet-tumor cell co-culture systems to investigate whether direct or indirect exposure to platelets affects tumor cell PD-L1 surface expression. Considering platelets can be artificially activated by commonly used cell culture medium, the co-culture was performed in platelet resuspension buffer (HEPES, NaCl, KCl, MgCl2, NaHCO3, Glucose, pH7.4) supplied with fetal bovine serum and L-glutamine. After 24 hours of co-culture, platelets were washed out and fresh culturing medium was added to tumor cells and cultured for another 24 hours. At the end of the experiments, tumor cells were harvested and the PD-L1 expression analyzed by flow cytometry and RT-qPCR.
Results and discussion: Here we report that direct co-culture of platelets with either breast cancer cell line MDA-MB-468 or lung cancer cell line A549 increased tumor cell PD-L1 surface expression by up-regulating PD-L1 transcription. This platelet-induced tumor cell PD-L1 up-regulation can be partly reduced by pre-treating platelets with antiplatelet agents such as aspirin and ticagrelor, suggesting platelet activation contributes to platelet induced tumor cell PD-L1 up-regulation. The up-regulation of tumor cell PD-L1 by platelets was not due to abundant platelet cytokines such as C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C motif chemokine 5 (CXCL5). However, both an epidermal growth factor (EGF) neutralizing antibody and cetuximab (EGFR neutralizing monoclonal antibody) decreased the platelet-induced increase in tumor cell PD-L1, suggesting that platelets initiate tumor cell PD-L1 transcription through the EGF signaling pathway. Our data indicate a novel function of platelets in tumor immunity and warrant further investigation to determine if targeting platelets offers a novel adjuvant approach to improve ICI therapy.

Disclosures
Italiano: Sierra Oncology: Consultancy; PlateletBio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Carrick Therapeutics: Consultancy.
The Prognostic Impact of Abnormal Protein Bands in Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Low Soon Khai , Ho Matthew , Jamshed Saad 
Published: November 2021

Abstract
Introduction: The detection of abnormal protein bands (APB) different from the original monoclonal protein in patients with multiple myeloma (MM) who underwent stem cell transplantation and/or chemotherapy has been reported. These atypical serum immunofixation patterns may be monoclonal (also termed secondary monoclonal gammopathy of undetermined significance) or oligoclonal bands (OB). The prognostic significance of this phenomenon remains controversial. This systematic review and meta-analysis aimed to summarize and analyze the evidence for the association between APB with survival in MM patients.
Methods: A systematic search of PubMed, Cochrane, Google Scholar, Medline-Ovid, CINAHL, and ERIC, was conducted using relevant search terms. All studies were screened using predefined selection criteria and critically appraised for quality assessment following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All studies that described the presence of APB, defined as monoclonal spike with heavy or light chain immunoglobulin distinct from the original paraprotein at initial diagnosis of MM, and its associations with survival were included. Studies that reported multivariate adjusted hazard ratios (HR) were further included for meta-analysis. Random-effects model was used to synthesize the pooled HR estimate for the association of APB with survival. Cochran's Q statistics and I2 tests were used to evaluate statistical heterogeneity.
Results: A total of 24 out of 181 eligible studies were included for qualitative synthesis. Four studies (including 1115 patients) that reported HR estimates were included in the final meta-analysis. The random-effect summary HR for the progression-free survival among patients with APB was 0.44 (95% CI, 0.31-0.65) with no statistical heterogeneity (I2=0%, p=0.93). The pooled HR for the association with overall survival was 0.31 (95% CI, 0.14-0.66) with moderate statistical heterogeneity (I2=45%; p=0.16) for patients with APB. One study (Silva et al, 2017) only included patients with at least very good partial response while the other three studies reported similar findings of higher occurrence of APB with complete response (Tovar et al, 2013; Jo et al, 2014; Zou et al, 2014). These results are also consistent with the presumed association of APB with complete response as suggested in other studies included in qualitative review.
Conclusions: This study indicated a potential prognostic value of APB for favorable outcomes in the context of both overall and progression-free survival in MM patients after treatment. Further research is needed to evaluate the prognostic impact of the sole emergence of APB irrespective of treatment response.
Figure 1 Figure 1.

Disclosures
Jamshed: Takeda: Honoraria.