bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic Accuracy of Age-Adjusted D-Dimer Cutoff in Suspected Cases of Pulmonary Embolism
Authors: Dhakal Prajwal , Iftikhar Harris Mian , Wang Ling , Panthi Sagar , Shrotriya Shiva , Rayamajhi Supratik 
Published: October 2019

Abstract
Introduction
Current guidelines recommend use of clinical pretest probability scores, d-dimer assay, and imaging studies in the diagnosis of pulmonary embolism (PE). Studies have shown that normal d-dimer levels with low-intermediate probability in Wells score can safely exclude PE in most cases. Usually, d-dimer level of less than 500 µg/L is used to decide that no further imaging studies such as computed tomography pulmonary angiography (CTPA) or ventilation perfusion (V/Q) scan) are required. However, the conventional cutoff of 500 µg/L may not be as specific in all patients as d-dimer levels increase with age. Thus, use of age-adjusted d-dimer cutoff has been advocated which is defined as (age × 10) µg/L in patients 50 years or older.
Objective
To study if age-adjusted d-dimer is helpful in decreasing imaging studies without missing the diagnosis of PE in suspected cases.
Methods
We did an observational retrospective study of all consecutive adult patients who presented to the emergency department from January 2014 to December 2016. The patients who were clinically suspected with PE and underwent subsequent workup along with d-dimer assays were included for analysis. The number of imaging studies performed for PE diagnosis were recorded.
Results
We included 3,197 patients in the study. Median age was 55 years, and 67% were females (Table 1). Total 2,937 (92%) patients had elevated d-dimer levels based on conventional d-dimer cutoff compared to 2,526 (79%) patients based on age-adjusted d-dimer cutoff. The age-adjusted d-dimer cutoff was more specific (21% vs 8%, p-value<0.0001) but less sensitive (100% vs 95%, p-value= 0.15) than conventional cutoff (Table 2). The use of age-adjusted d-dimer cutoff would have avoided 409 (13% of total) imaging studies (Table 3). However, 2 cases (0.7% of total) with PE, which would have underwent imaging study with conventional cutoff, would have been missed with age-adjusted d-dimer cutoff. The Wells score was 3, intermediate pretest probability, for both cases of PE.
Conclusion
Age-adjusted d-dimer cutoff can significantly decrease the number of imaging studies performed in cases of suspected PE. However, as shown in our study, there is a chance of missing cases with actual PE. Thus, clinicians should always be aware of a rare probability of false negative result with age-adjusted d-dimer levels. Further stratification of the probability risk or the prompt use of imaging studies in cases with higher clinical suspicion can help in accurate diagnosis of PE.

Disclosures
No relevant conflicts of interest to declare.
Ultra-Deep Sequencing Leads to Earlier and More Sensitive Detection of Known or Novel Mutations of BCR-ABL1 in Chronic Myeloid Leukemia
Authors: Xiao Hongli , Wang Heng , Lou Jin , Chen Weihong , Zhang Qiaoxia , Du Xin 
Published: October 2019

Abstract
Detection of BCR-ABL1 mutations that inhibit tyrosine kinase inhibitors is important for the treatment of CML patients. Sanger sequencing (SS) technique is considered the gold standard for mutation detection in a clinical laboratory. We analyzed 40 clinical samples from 22 CML patients with TKI resistance by ultra-deep sequencing (UDS) and compared the results with classical SS-based tests. UDS facilitates the detection of low levels of mutations (<20% allele frequencies) that SS does not detect. In subgroups of cases with multiple mutations, UDS was also able to determine whether two mutations were on same BCR-ABL1 allele (compound) or not (polyclonal). We found a pair of compound mutations unreported: F359C/E450 which confer high-level resistance to first-generation TKI imatinib, second-generation TKIs dasatinib and nilotinib, third-generation TKI ponatinib and a new TKI GZD824. UDS provides a reliable method for identifying low levels of BCR-ABL1 mutations.

Disclosures
No relevant conflicts of interest to declare.
The Platelet Isoform of Phosphofructokinase in Acute Myeloid Leukemia: Clinical Relevance and Prognostic Implication
Authors: Luo Xiaodan , Zheng Dantian , Zheng Runhui , Wang Chunyan , Xu Lihua , Tan Huo 
Published: October 2019

Abstract
Background: Phosphofructokinase (PFK), a key enzyme of the glycolytic pathway, has L (liver), M (muscle), and P (platelet) isoforms with different tissue distributions. The Platelet Isoform of PFK (PFKP) plays an important role in regulating aerobic glycolysis and macromolecular biosynthesis to support cell growth. Up-regulation of PFKP is associated with progression and metastasis of varied kinds of solid organ tumor. However, less is known about the association between PFKP and hematology malignancy. Here, we investigated the role of PFKP in acute myeloid leukemia (AML).
Methods: To characterize PFKP mRNA expression in AML, we performed qRT-PCR on bone marrow cells (BMCs) from 55 newly diagnosed AML patients with the median age of 47 years (range 16-82 years). The FAB type is M0 (2/55), M1 (3/55), M2 (15/55), M3 (11/55), M4 (11/55) and M5 (11/55). Two patients were diagnosed with myelodysplastic syndromes related AML. We screened for mutations in a selected panel of genes (NPM1, CEPBA, FLT3, KIT, WT1 and TP53), based on which patients were further categorized into standard (19/55), intermediate (21/55) and poor (15/55) cytogenetic risk groups. Patients were categorized into PFKPhigh and PFKPlow groups according to the median mRNA expression of PFKP. Complete remission (CR) rate was compared between two groups after 1 cycle and 4 cycles of chemotherapy. One year-relapse rate, overall survival rate (OS) and disease free survival rate (DFS) was also compared between PFKPhigh and PFKPlow groups.
Results: PFKP mRNA expression of AML patients was significantly higher than that of the normal control (P<0.05). PFKP expression in different cytogenetic risk groups were evaluated and the result showed that the mRNA expression in poor risk group was much higher than that in standard or intermediate group (P<0.05). According to the median mRNA expression of PFKP, patients were categorized into PFKPhigh (28/55) and PFKPlow (27/55) groups. The CR rate after the first cycle of treatment was higher in PFKPlow group, but did not differ significantly after another 3 cycles of chemotherapy were finished. PFKP mRNA expression was decreased after patients received CR (P<0.05). In 32 out of 55 patients, autologous hematopoietic stem cell transplantation (HSCT) (N=20) or allogeneic HSCT (N=12) was performed after 4 cycles of chemotherapy. In 20 patients post auto-HSCT, 1 year-relapse rate was higher and OS and DFS was decreased significantly in PFKPhighgroup compared to PFKPlow group. However, results showed no difference between two groups for patients post allo-HSCT.
Conclusions: PFKP expressions were increased in AML especially patients in poor cytogenetic risk group. PFKP might be a prognostic factor of poor clinical outcome of AML.

Disclosures
No relevant conflicts of interest to declare.
Russian Experience of Bosutinib Use in Chronic Myeloid Leukemia Patients in Routine Clinical Practice
Authors: Shuvaev Vasily , Vinogradova Olga , Martynkevich Irina , Natalya Novitskaya , Fominykh Mikhail , Tsareva Svetlana , Shikhbabaeva Dzhariyat , Pankrashkina Maria , Chernikov Mikhail , Sharkunov Nikolay , Zotova Irina , Udaleva Vera , Motyko Ekaterina , Voloshin Sergei 
Published: October 2019

Abstract
Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance.
Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results.
Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30.
Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR).
Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia.

Disclosures
No relevant conflicts of interest to declare.
Direct Oral Anticoagulants in Patients with Myeloproliferative Neoplasms: A Single Institution Retrospective Study
Authors: Deloughery Emma P. , McBane Robert D. , Ashrani Aneel A. , Tefferi Ayalew , Slusser Joshua P , Pruthi Rajiv K. 
Published: October 2019

Abstract
Introduction: Myeloproliferative neoplasms (MPN) are associated with an increased risk of venous (VTE) and arterial (ATE) thromboembolic events (TE). Anticoagulation needs to be balanced between the risk of incident and recurrent TE and risk of hemorrhage. While data on outcomes of anticoagulation with warfarin in patients with MPN are available, data on safety and efficacy of direct oral anticoagulants (DOACs) in this subgroup are not. Herein, we present outcomes of use of DOACs in patients with MPN at our institution.
Methods: In this retrospective cohort study, we searched the Mayo Clinic clinical databases for patients meeting the WHO criteria for MPN who had been prescribed a DOAC between 2011 and 2017. The MPN diagnosis had to have predated the DOAC prescription. Medical records of consenting patients meeting study criteria were reviewed and data on demographics, diagnosis of MPN, indication for DOAC prescription, and their efficacy (incident or recurrent TE) and safety (hemorrhagic events) were abstracted.
Results: Over the study period, 19 patients (female = 10) met inclusion criteria. The median age of patients at MPN diagnosis was 67 years (35-83), and 73 years (53-86) at initiation of DOAC. Prescribed DOACs included rivaroxaban (n=12), apixaban (n=6), and dabigatran (n=2) (one patient received rivaroxaban and was switched to apixaban). MPN diagnoses included polycythemia vera (PV) (n=9), essential thrombocythemia and chronic myeloproliferative neoplasm NOS (3 each), chronic myeloid leukemia and myelofibrosis (2 each). Indications for DOAC included thromboembolism (n=13; 68%) (arterial:2 and venous:11), and atrial fibrillation (afib) (n=6; 31%). The median duration of DOAC therapy was 241.5 days (range 13-1879). Five patients were switched from warfarin to rivaroxaban (n=4) and apixaban (n=1) at patient and/or provider preference; the rest were initiated on the DOAC de novo based on provider preference.
Of the 19 patients, one patient each experienced a major hemorrhagic and TE event. One patient with PV who was on rivaroxaban for afib required hospitalization for gastrointestinal hemorrhage due to gastritis; DOAC was discontinued following this episode. One other patient with PV had a non-ST elevation myocardial infarction while on rivaroxaban for afib and prior stroke; DOAC was continued. There were no deaths attributable to DOAC use.
Discussion: Our limited data suggests that use of DOACs in patients with MPN is feasible with an acceptable balance between risk of hemorrhage and recurrent thrombosis. Additional data on long term outcomes of DOACs in MPNs are needed.

Disclosures
No relevant conflicts of interest to declare.
Study on Use of CAR-T Cells in Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Liu Jun , Tan Xu , Ying-Ying Ma , Mai-Hong Wang , Liu Yao , Lei Gao , Peiyan Kong , Zhang Cheng , Zhang Xi , Zeng Defu 
Published: October 2019

Abstract
Background: The chimeric antigen receptor T (CAR-T) cells have showed strong anti-leukemia role, which can treat or prevent relapse by targeting minimal residual disease for patients undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). The infusion of allogeneic CAR-T cells may cause the graft-versus-host disease, which could limit its use during and after allo-HSCT. It is still unclear whether CAR-T cells can be used during and after allo-HSCT. In this study, the use of CAR-T cells in these situation was explored.
Methods: Two patients with relapsed/refractory acute lymphoblastic leukemia (ALL) received allo-HSCT, the CAR-T cells was used as a reduced-intensity conditioning regimen. Another three patients with high-risk ALL received preventive infusion of CAR-T cells on days +60 after allo-HSCT.
Results: For patients undergone allo-HSCT, the time of peak CAR-T cell proliferation was detected after the first infusion of CAR-T cells on day 7. The engraftment and full donor cell engraftment were established. The disease was in complete remission with negative minimal residual disease, which was undetectable by flow cytometry. No graft-versus-host disease and serious cytokine release syndrome was found. For patients received preventive infusion of CAR-T cells, the CAR-T cells continually survival. No graft-versus-host disease and serious cytokine release syndrome was found. The disease is complete remission for 1-6 months.
Conclusion: It is safety and effective for CAR-T cells used in allogeneic hematopoietic stem cell transplantation.

Disclosures
No relevant conflicts of interest to declare.
Primary Extranodal Diffuse Large B-Cell Lymphomas Are Enriched for Mutations in MYD88 and CD79B.
Authors: Weissinger Stephanie Ellen , Moeller Peter , Marienfeld Ralf , Bloehdorn Johannes , Viardot Andreas 
Published: October 2019

Abstract
Introduction: Diffuse large B-cell lymphomas (DLBCLs) with mutations in MYD88 and CD79B are a distinct molecular subentity according to recent analysis ("MCD-type" according to R. Schmitz et al., N Engl J Med 2018; and partially "cluster 5" according to B. Chapuy et al., Nature Medicine 2018). Both mutations were found particularly in specific anatomical localizations.
Methods: To evaluate the incidence of MYD88 and CD79B mutations in primary extranodal DLBCL, we analyzed 111 tumor specimens of 99 patients. We performed targeted resequencing analysis to detect MYD88, CD79B, CARD11 and BTK mutations.
Results: MYD88 mutations were frequently found in primary CNS lymphoma (67%), lymphoma of Waldeyer´s ring and paranasal sinuses (ENT) (44%), breast (75%), testicular (60%) and cutaneous (50%); the majority of mutations (89%) were located on L265P. CD79B mutations were frequent in CNS lymphoma (57%), lymphoma of ENT (52%) and breast lymphoma (50%). Both mutations occur simultaneously in CNS lymphoma (48%) and ENT lymphoma (33%). CARD11 mutations were frequently found in CNS lymphoma (33%) and in ENT lymphoma (26%). BTK mutations were found rarely, with the highest frequency (11%) in ENT lymphoma.
Conclusion: Both, mutations in CD79B and MYD88 are frequent in primary extranodal lymphoma particularly in CNS lymphoma, lymphoma of Waldeyer's ring and paranasal sinuses, testicular, cutaneous and breast lymphoma. These findings may contribute to establish targeted therapeutic intervention of B-cell signaling in this subentity.

Disclosures
Weissinger: Bristol-Myers Squibb: Research Funding. Viardot:BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria; Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.
Prognostic Impact of Deletion 17p Clone Size on Outcome in Chronic Lymphocytic Leukemia Patients (A Real Life Routine Practice Perspective in Brazil)
Authors: Bigni Ricardo , de Souza Fernandez Teresa , Rego Mayara , Luise Ingrid , Abdelhay Eliana , Fernandez Cecilia , Araujo Keyla 
Published: October 2019

Abstract
Objectives: Chronic lymphocytic leukemia (CLL) presents a heterogeneous clinical course. Treatment mainly aims to control clinical manifestations and improving survival. Some biological markers have significant prognostic value. Cytogenetic studies in CLL have central role to refine the follow-up of disease evolution, to guide treatment options and monitoring response. Due to low mitotic index in conventional cytogenetic studies, fluorescence in situ hybridization (FISH) became an indispensable tool. The main objective of this study was analyze the presence of del(17p13) using FISH and the percentage of positive cells that have impact on survival, along with clinical characteristics from CLL patients. Methods: Seventy-one CLL patients were studied from 2010 to 2017. Median age was 57 years old and male patients were 56,4%. FISH analysis was performed using peripheral blood samples from patients and TP53 spectrum srange/CEP 17 spectrum green probe (Vysis). Statistical analysis was performed with SPSS20.0 software. Results: Twenty-eight of 71 patients had positive FISH for del(17p13) and the evidence of more than 20% del(17p13) cells was related to a worse overall survival (p<0,05). No difference in survival was observed between negative FISH patients and those with less than 20% del(17p13) cells. Conclusions: Patients presenting del(17p13) in more than 20% of cells had worse prognosis with reduced survival. Our results suggest the prognostic relevance of deletion17p clone size detected by FISH in CLL patients.

Disclosures
Bigni: Janssen: Honoraria, Research Funding.
Akt-Mediated Platelet Apoptosis and Its Therapeutic Implications in Immune Thrombocytopenia
Authors: Yan Rong , Chen Mengxing , Dai Kesheng 
Published: October 2019

Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with anti-platelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIba autoantibodies. Consistent with these findings, anti-GPIba monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIba antibody binding activates Akt which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIba antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling, or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal new pathogenic mechanisms of ITP with anti-GPIba autoantibodies, more importantly, suggest novel therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.

Disclosures
No relevant conflicts of interest to declare.
Toward a Proteome-Complete Computational Model of the Human Red Blood Cell
Authors: Yurkovich James T , Yang Laurence , Palsson Bernhard O 
Published: October 2019

Abstract
The human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for metabolism and macromolecules. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms-such as hemoglobin binding and the formation and detoxification of reactive oxygen species-and account for sequence variations between individuals, allowing for personalized physiological predictions. This model allows for direct computation of the oxyhemoglobin curve as a function of model species and a more accurate computation of the flux state of the metabolic network. More broadly, this work represents another step toward building increasingly more complete systems biology whole-cell models.

Disclosures
No relevant conflicts of interest to declare.