bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Vasculogenic Potential and Endothelial Differentiation of Bone-Marrow-Derived Very Small Embryonic-like Stem Cells
Authors: Guerin Coralie L , Loyer Xavier , Vilar Jose , Cras Audrey , Mirault Tristan , Gaussem Pascale , Silvestre Jean Sebastien , Smadja David M 
Published: October 2019

Abstract
Objective: Very small embryonic-like stem cells (VSELs) are multipotent stem cells localized in adult bone marrow (BM) that may be mobilized into peripheral blood (PB) in response to tissue injury. We aimed to quantify VSELs in BM and PB of patients with critical limb ischemia (CLI) and to test their angiogenic potential in vitro as well as their therapeutic capacity in mouse model of CLI.
Approach and Results: We isolated BM VSELs from patients with CLI and studied their potential to differentiate into vascular lineages. Flow and imaging cytometry showed that VSEL counts were lower in BM (p<0.001) and higher (p<0.001) in PB from CLI patients compared to healthy controls, suggesting that ischemia may trigger VSELs mobilization in this patient population. Sorted BM-VSELs cultured in angiogenic media acquired a mesenchymal phenotype (CD90+, Thy-1 gene positive expression). VSEL-derived cells had a pattern of secretion similar to that of endothelial progenitor cells, as they released low levels of VEGF-A and inflammatory cytokines. Noteworthy, VSELs triggered post-ischemic revascularization in immunodeficient mice (p<0.05 vs PBS treatment), and acquired an endothelial phenotype either in vitro when cultured in the presence of VEGF-B (Cdh-5 gene positive expression), or in vivo in Matrigel implants (human CD31+ staining in neo-vessels from plug sections).
Conclusions: VSELs are a potential new source of therapeutic cells that may give rise to cells of the endothelial lineage in humans.

Disclosures
No relevant conflicts of interest to declare.
Isolation, Expansion and Characterization of BM-Mesenchimal Cells (MSCs) in Patients Affected By Chronic Myeloproliferative neoplasm (MPN)
Authors: Chiusolo Patrizia , Annunziata Francesca , Rossi Elena , Betti Silvia , Bellesi Silvia , De Stefano Valerio , Leone Giuseppe 
Published: October 2019

Abstract
Introduction MSCs constitute a pivotal cell type capable of shaping both the architecture of the microenvironment and modulating communication between the various cell types through effects on the extracellular matrix (ECM) and by secretion of various growth factors and cytokines. MSCs and hematopoietic stem cells are thought to share the same mesenchymal origin. Some data confirm that MSCs express a functional erythropoietin receptor and JAK2-transduction pathway, but their role in the development and evolution of MPN is still not well known so our aim was the isolation, expansion and characterization of MSCs in patients affected by MPN. Some data indicates that BM-MSCs of patients affected by MPN do not carry the JAK2-V617F mutation. We studied 20 patients affected by MPN with the following characteristics: M/F 12/8, median age 53years, 8 affected by PV, 8 by ET and 4 by PMF. 15 patients were positive for JAK2 V617F mutation, 1 pts for cMPL and 2 were CARL mutations carriers.
Methods: MSC were isolated by bone marrow fraction by gradient separation on Lympholyte cell separation media and expanded in culture with a specific medium (MesenCult) in plastic-adherent cultures up to the second passage. DNA was extracted from MSC using QIAmp DNA Mini kit and the study of recurrent alterations (JAK2, MPL and CARL gene mutations was performed).
Results: MCS were expanded in 14 on 21 patients. Flow citometry analysis confirmed the standard MSC phenotype (CD45 negative, CD73 positive, CD90 positive and CD105 positive). The molecular analysis of JAKV617F, cMPL and CARL mutations resulted negative in all analyzed samples both in patients carriers of mutations and in wild type ones.
Conclusions: We conclude that common mutations markers of MPN neoplasm are absent in the mesenchymal compartment of bone marrows of patients affected by MPN and are restricted to the neoplastic clone.
This research project was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)

Disclosures
No relevant conflicts of interest to declare.
Idiopathic Hepatitis Associated Aplastic Anemia
Authors: Rivera-Trujillo Alicia , Navarro-Escamilla Adolfo , Hernandez-Rodriguez Sonia , Campos-Cabrera Virginia , Campos-Cabrera Gregorio 
Published: October 2019

Abstract
Aplastic anemia (AA) in Mexico has an incidence of 3.5-4.0 x 106 (Hematology 2002;7:229-232). The presentation of idiopathic hepatitis associated aplastic anemia (IHAAA) in México is unknown due to data was not found on PubMed, but represents from 2-5% of all cases of AA in Europe and Far East (Virology 2011;8:87 and Br J Haematol 2010;149:890-895).
A previously healthy and normal family history 15 years old boy presented with epistaxis, pallor, jaundice, choluria and slightly hepato and splenomegaly, which were confirmed with full body CT scan, and no other alterations were detected. Remarkable results from AMA designated disease/organ panels were Hb 11.7 g/dL, adjusted reticulocytes 0.26%, neutrophils 0.931 K/µL, platelets 5.0 K/µL, ALT 1920 U/L, AST 2300 U/L, conjugated bilirubin 17 mg/dL, unconjugated bilirubin 15 md/dL, ferritin 1135 ng/mL. Supportive care was given and study for pancytopenia and hepatitis was started. Negative results from complete autoimmune panel including anti-LKM, anti-smooth muscle and anti-mitochondrial antibodies; panels for all hepatitis viruses, HIV, STORCH, EB, CMV, PVB19 and leptospira were negative. The patient was prepared for biopsies. Liver biopsy showed steatohepatitis, grade 2 fibrosis and lymphocyte infiltrates. Bone marrow biopsy showed 5% cellularity with absence of myeloid and megakaryocytes precursors, only erythroblasts and lymphoplasmocytoid cells; flow cytometry reported no abnormal cells and G-band karyotypes with and without mitomycin were normal. While the results from the biopsies the hepatic function improves but pancytopenia worsened to Hb 6.4 g/dL and neutrophils 0.124 K/µL. IHAAA was diagnosed and the patient continues with supportive care while results from siblings for allogeneic transplant arrive.
IHAAA is well described condition where secondary causes are ruled out. Autoreactive T lymphocytes and cytokines are implied in the pathophysiology as in conventional AA, affecting transiently the liver; and treatment is the same for both entities.
Figure 1 Figure 1.
Figure 2 Figure 2.
Figure 3 Figure 3.

Disclosures
No relevant conflicts of interest to declare.
Aberrant Overexpression and Regulatory Mechanism of Mir-21 in Diffuse Large B Cell Lymphoma
Authors: Fu Rong , Li Chunhong , Shao Zonghong 
Published: October 2019

Abstract
MicroRNAs (miRNAs) are critically responsible for lymphomagenesis. We found that miR-21 expression was significantly higher in diffuse large B cell lymphoma (DLBCL) line and paraffin-embedded tissue of primary lymphoma (n = 26) than that in normal lymph nodes (n = 10). To determine the functions of miR-21 in lymphomagenesis, we examined phosphatase and tensin homolog (PTEN) expression using immunohistochemical SP method in specimens of primary DLBCL. MiR-21 expression is negatively correlated with PTEN expression, but positively correlated with LDH. MiR-21 expression was significantly higher in stage III / IV patients than in stage I/II patients. Moreover, we examined the effects of antisense oligonucleotide (ASO) targeting miR-21 (ASO-21) in the DLCBL line overexpressing this miRNA. Electroporation was used to transfect ASO-21 into the cells, which showed slight endogenous miR-21 expression. Downregulating miR-21 expression resulted in increased incidence of apoptosis and PTEN upregulation. These results provide relevant new insight into the pathogenesis of DLBCL and suggest that targeting miR-21 may represent a useful approach for DLBCL treatment, and that high levels of miR-21 may be associated with increased poor prognosis for DLBCL patients.

Disclosures
No relevant conflicts of interest to declare.
Treatment of Acute Myeloid Leukemia with the NOPHO-AML 2004 Study in Chinese Children: A Single Center Study
Authors: Feng Xiaoqin , Li Chunfu 
Published: October 2019

Abstract
Objectives: The objective of the present study was to investigate the therapeutic efficacy and feasibility of NOPHO-AML 2004 study in the treatment of acute myeloid leukemia (AML; excluding acute promyelocytic leukemia) in Chinese children.
Methods: Thirty-one children with novo AML treated with the NOPHO-AML 2004 study were recruited from Jan. 2010 to Dec. 2013, and the clinical data were retrospectively analyzed. Among 31 AML children, their age were from 2-14 years old (median age 8 years old). There were 12,15 and 4 children classified in low risk group, intermediate risk group and high risk group by cytogenetic risk classification respectively. Eight children received concomitant hematopoietic stem cell transplantation. Kaplan Meier method with Log-Rank testing was employed for survival analysis.
Results: Follow-up was for a median 24 months (range: 5–50 months). The complete remission rate was 83.8%. The predicted 3-year leukemia free survival (LFS) rate was 53.8%. The LFS rate of low, intermediate and high risk group were 55.6%, 52.5% and 50.0% respectively. There was no significance in risk groups. The LFS rate of chemotherapy and chemotherapy concomitant HSCT were 42.7% and 87.5%, P<0.05. There were 2 cases of treatment related mortality including one case of sepsis and one case of ARDS.
Conclusions: NOPHO-AML 2004 study is clinically efficacious for the treatment of AML in Chinese children. HSCT treatment had better outcome than only chemotherapy in childhood with non low risk AML in CR1 phase.

Disclosures
No relevant conflicts of interest to declare.
Phase I-II Study of Sequential Therapy with Decitabine Followed By Clofarabine, Idarubicin, and Cytarabine (DAC-CIA regimen) in Relapsed/Refractory Acute Myeloid Leukemia (AML)
Authors: Jain Nitin , Ravandi Farhad , Garcia-Manero Guillermo , Borthakur Gautam , Kadia Tapan , Jabbour Elias , Pemmaraju Naveen , Daver Naval , DiNardo Courtney D. , Konopleva Marina , Pike Allison , Bivins Carol , Pierce Sherry , O'Brien Susan , Cortes Jorge E. , Kantarjian Hagop M. 
Published: October 2019

Abstract
Background: Patients (pts) with relapsed/refractory AML have dismal outcomes with currently available chemotherapy regimens. Preclinical and clinical evidence suggests that the use of hypomethylating agents such as decitabine prior to standard chemotherapy may be synergistic (Qin et al. Clin Can Res 2007; Scandura et al. Blood 2011; Clozel et al. Cancer Discov 2013).
Methods: Pts aged ≥18 to 65 years with relapsed or refractory AML (up to salvage 2) were eligible. Prior therapy with hypomethylating agents was allowed. The chemotherapy regimen was as follows: TableDoseDays INDUCTIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-9 (Dose level 1) Days 6-10 (Dose level 2)Idarubicin10 mg/m2 IVDays 6-8Cytarabine1 gm/m2 IVDays 6-10CONSOLIDATIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-8Idarubicin8 mg/m2 IVDays 6-7Cytarabine1 gm/m2 IVDays 6-8
Results: Eighteenpts (female, n=4) have been treated so far. Median age was 43 years (range 20-61). Majority of the pts (10/18, 56%) were in salvage 2. Four had a prior allogeneic stem cell transplant (SCT). Cytogenetics were diploid (n=4), complex (n=11), 11q abnormality (n=2), trisomy 8 (n=1). Five pts had a TP53 mutation and 3 pts had an NRAS mutation. Median number of cycles administered was 1 (range 1-2). Grade 3-4 non-hematological toxicity included grade 3 mucositis (DLT) in 2 pts during the induction cycle. Due to mucositis and prolonged cytopenias (prolonged cytopenias didn’t meet the DLT definition), dose level 2 was not pursued, and all patients were treated at dose level 1. Grade 3 transaminitis was seen in 4 pts. Fifteen pts had one or more infections. Six (33%) pts achieved CR, of whom 5 were able to proceed to SCT (one pt with CR opted not to pursue SCT). Median time to CR was 35 days. An additional 3 pts had a >50% decrease in bone marrow blast count (marrow response) and all three proceeded with SCT. All 4 patients with diploid cytogenetics achieved CR. Only 1/5 (20%) patients with mutated TP53 achieved a CR. Two patients have relapsed (one 3 months after SCT and the other after consolidation cycle 1). Six patients are alive (4 after stem cell transplant, 2 are receiving further salvage regimens after DAC-CIA failure). Median survival of the entire group is 7.2 months (see figure 1).
Conclusions: The sequential treatment of decitabine followed by chemotherapy is safe and effective with a CR rate of 33% and with 8/18 patients able to proceed to an allogeneic SCT. The phase II part of the study is enrolling patients at this time.
FIGURE 1 FIGURE 1.

Disclosures
Off Label Use: Decitabine and clofarabine are not approved for AML..
Diffusely Increased Bone Marrow 18F-FDG Uptake Is an Independent Predictor of Focal Bone Lesions in Patients with Newly Diagnosed Classical Hodgkin Lymphoma
Authors: Gormsen Lars C. , Wassberg Cecilia , Molin Daniel , Kamper Peter , Enblad Gunilla , d'Amore Francesco 
Published: October 2019

Abstract
Background: 18F-FDG PET/CT is recommended in the initial staging of patients with classical Hodgkin lymphoma (cHL). Whereas focal 18F-FDG uptake in the skeleton is considered to represent bone involvement, it is still unclear whether diffusely increased 18F-FDG bone marrow uptake (BMU) indicates lymphoma infiltration or merely reflects a state of general inflammation. This retrospective study was therefore performed to study the relationship between pre-therapeutic (PET0) 18F-FDG BMU and the presence of focal bone lesions.
Methods: A total of 139 patients (median age 44, range 8-83) referred to PET/CT between 2008 and 2014 for HL staging were included. All PET0 and post-therapeutic (PET2) images were reviewed and evidence of focal bone lesions was recorded (unifocal: ≤2 lesions, multifocal: >2 lesions). In addition, 18F-FDG uptake (SUVmax) was semiquantitatively measured in the vertebral bone marrow (SUVvertebra) and in the right lobe of the liver (SUVliver). BMU was calculated as SUVvertebra/SUVliver. The relationship between focal bone lesions on PET0 and BMU as well as age was subsequently analysed by logistic regression.
Results: In total 30/139 (22 %) patients had focal bone lesions at initial staging (10 unifocal, 20 multifocal). BMU at initial presentation was generally increased in all patients when compared with the post-therapeutic PET/CT (PET0: 1.22 +/- 0.03 vs. PET2: 0.95 +/- 0.03, p<0.001). In a logistic regression model diffusely increased BMU at PET0 (p=0.01) as well as age (p=0.01) were both independent predictors of focal bone lesions.
Conclusion: Diffusely increased 18F-FDG uptake is an independent predictor of skeletal bone lesions in patients with HL. Evidence of increased BMU might be evaluated as an additional outcome predictor in the pre-therapeutic risk assessment of patients with HL. With the purpose of validating these findings, we will analyze an independent cohort of Swedish cHL patients and joined data from both cohorts will be presented at the meeting.

Disclosures
No relevant conflicts of interest to declare.
BRG1 Expression in Diffuse Large B Cell Lymphoma (DLBCL) Is Associated with Advanced Disease Stage
Authors: Rehman Aseeb U , Nazeer Tipu , Wilner George D. , Laziuk Katsiaryna , Huho Albert N , Sheehan Christine S 
Published: October 2019

Abstract
Background: BRG1 is a component of the highly conserved multisubunit, 2.0-MDa mammalian transcriptional coactivator complex SWI/SNF. This chromatin-remodeling complex is critical for the regulation of gene transcription, thereby controlling diverse cellular processes including differentiation, proliferation, tumorigenesis and DNA repair. BRG1 gene is frequently down regulated or conversely, in some cases, up regulated in cancer cell lines and tumors, implicating that BRG1 may regulate cancer proliferation and progression. BRG1 is currently considered a potential selective therapeutic target. BRG1 expression level has been related to cancer cell migration and invasion and studies have suggested that BRG1 may serve as a prognostic marker in certain cancers. Few studies exist on expression of BRG1 in lymphoproliferative disorders and diffuse large B cell lymphoma (DLBCL) in particular. Our study was aimed at determining the immunohistochemical expression of the BRG1 protein in DLBCL and its potential association with clinicopathologic variables.
Design: Formalin-fixed, paraffin embedded sections from 49 Diffuse Large B-cell Lymphomas (DLBCL), were immunostained by a manual method (DAKO LSAB+ System-HRP) using rabbit monoclonal BRG1 (Abcam, Cambridge, MA) antibody. Nuclear and cytoplasmic immunoreactivity was semiquantitatively assessed in all cases. Scoring was based on staining intensity (weak, moderate, intense) and percentage of positive tumor cells (focal <= 10%, regional 11-50%, diffuse >50%). Results were correlated with clinicopathologic variables.
Results: BRG1 immunoreactivity was predominately nuclear. Intense diffuse nuclear BRG1 overexpression was observed in 22/49 (45%) cases and correlated with tumor stage [73% stage 4 vs 63% stage 3 vs 40% stage 2 vs 13% stage 1, (p=0.005)]. There were no other correlations that reached statistical significance.
Conclusion: BRG1 nuclear expression is increased in DLBCL and is associated with advanced tumor stage. This association with an important adverse prognostic indicator warrants further study of BRG1 expression and its potential as a selective therapeutic target in DLBCL.

Disclosures
No relevant conflicts of interest to declare.
Multiple Factors Analysis of B Cell Non-Hodgkin's Lymphoma Treatment-Related Interstitial Pneumonia
Authors: Zhao Jiali , Peng Yuna , Tan Huo 
Published: October 2019

Abstract
Objective To explore the related factors of interstitial pneumonia(IP) in B cell non-hodgkin's lymphoma (B - cNHL) patients who were treaded by chemotherapeutic drugs±RTX, which could provide certain references for clinical diagnosis and treatment .
Methods The clinical factors of 92 patients with B-cNHL enrolled from 2003 to 2013 in my hospitol were retrospectively studied, then cleared the high risk factors influencing the occurrence of IP.
Results The statistical analysis found that combined application of chemotherapeutic drugs and RTX was the only independent risk factor of IP,which have statistical Significance (OR=9.6; p<0.05) .While the other clinical factors, such as age, sex, past history of chronic lung disease and smoking, tumor’s clinical stage, International Prognostic Index (IPI) score, Eastern Cooperative Oncology Group-performance status(ECOG PS) score, complete blood cell count, LDH, bone marrowd and pulmonary parenchyma had nothing to do with the happening of the IP.Finally, compared chemotherapeutic drugs+RTX group and chemotherapeutic drugs group by survival analysis, the incidence of IP of the former was higher than the latter, and had statistical significance (P = 0.011).
Conclusion The incidence of IP of chemotherapeutic drugs+RTX group was obviously higher than chemotherapeutic drugs group. Addition of RTX to chemotherapy was identified as an independent risk factor for B-cNHL treatment-related IP. Once patients suffering from IP should Clinicians carefully identify IP caused by opportunistic pathogens and DIIP caused by RTX.

Disclosures
No relevant conflicts of interest to declare.
Coexpression of MYC and BCL-2 Predicts Inferior Survival in Pgi-DLBCL Treated with CHOP-like Regimen/Rituximab
Authors: Zhang Le , Xia Bing , Guo Shanqi , Li Xiaowu , Qu Fulian , Zhao Haifeng , Zhang Lianyu , Sun Baocun , Zhang Liang , Zhang Yizhuo 
Published: October 2019

Abstract
MYC protein expression has been identified to be associated with inferior overall survival (OS) and progression-free survival (PFS) when coexpressed with BCL-2 protein in patients with diffuse large B cell lymphoma (DLBCL). But the concurrent expression of MYC and BCL-2 proteins in primary gastrointestinal (PGI)-DLBCL has not been clearly understood. Here, we investigated whether this coexpression has prognostic significance in PGI-DLBCL patients and explored its associations with patients’ clinical parameters. We enrolled 60 PGI-DLBCL patients and 30 age- and sex-matched healthy controls. Expression levels of MYC and BCL-2 were detected from both protein and mRNA levels by immunohistochemistry and real-time RT-PCR. Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein were correlated with high MYC and BCL-2 mRNA expression, respectively (both p<0.05). We found that patients with advanced-stage disease (at IIE-IV) having higher MYC and BCL-2 coexpression levels (p<0.05). In addition, MYC+/BCL-2+ patients had more difficulty achieving complete remission than others (p<0.05). Presence of MYC protein expression only affected OS and PFS when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (p<0.05) even after adjusting for age, Lugano stage, IPI, and BCL-2 protein expression in a multivariable model. MYC+/BCL-2+ patients have poorer chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting prognosis of PGI-DLBCL patients.

Disclosures
No relevant conflicts of interest to declare.
Transdifferentiation of Malignant B-Cells into Macrophages in a Murine Model of Burkitt´s Lymphoma
Authors: Bruns Heiko , Mueller Sebastian , Bach Christian , Pasemann Shirin , Maurberger Anna , Mackensen Andreas , Gerbitz Armin 
Published: October 2019

Abstract
B-cell lymphomas, such as Burkitt's lymphoma, are malignant diseases of the hematopoietic system. They arise from transformed B-cells originating from diverse primary and secondary lymphatic tissues. Like in other cancers, the stroma of lymphomas is typically infiltrated by so-called tumor-associated macrophages (TAMs), which execute manifold tumor-specific functions. Interestingly it was shown, that mature B-cells could be efficiently re-programmed into macrophages by the overexpression of myeloid-specific transcription factors. Moreover, other studies observed in vitro that this lymphoid/myeloid plasticity might be also caused by oncogenes in cultured B-cells of murine lymphoma models. Therefore we consider, if lymphoma B-cells themselves might be a source of TAMs, besides the well-known infiltration of monocytic cells into the tumor environment. Based on the system of CD45.1/2 allotypes, a murine model of lymphoma was thus developed, which allows tracking of the conversion of lymphoma B-cells into TAMs.
It could be shown, that some lymphoma B-cells of the established model in fact spontaneously switched into a macrophage-like phenotype. Accordingly, they start to express typical macrophage markers, but seem to perform a transition into a myeloid-like expression profile on the level of transcription as well. Furthermore, analysis of the recombined immunoglobulin heavy chain confirmed the clonal identity of lymphoma b-cells and TAMs. Although these cells do not exhibit an overt immunological phenotype, they show elementary functional properties of macrophages, such as phagocytosis as well as a post-mitotic character. Moreover, transdifferentiated B-cells cells were resistant to chemotherapy and persist after treatment, while lymphoma B-cells were eradicated.
Which consequences the lymphoid/myeloid plasticity of lymphoma B-cells has for tumor development, progression, as well as for the outcome of therapy, and if these observations could be transferred to human tumors, will be object of future investigations.

Disclosures
No relevant conflicts of interest to declare.