bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pro-Angiogenic Mir-296 Is Frequently Overexpressed and Is Associated with Advanced Stage Disease in Diffuse Large B-Cell Lymphoma
Authors: Borges Natália Morais , de Conti Marina Lourenço , de Andrade Tathiana Azevedo , Macedo Marina Petaccia , de Souza Begnami Maria Dirlei Ferreira , Alves Antônio Corrêa , Colleoni Gisele Wally Braga 
Published: October 2019

Abstract
Abstract 1570

Introduction:
MicroRNAs (miRNAs) are a class of endogenous short non-coding RNAs that control gene expression by acting on target mRNAs for promoting either their degradation or translational repression. Some of them have involvement in regulating various aspects of angiogenesis, including proliferation, migration and morphogenesis of endothelial cells, which are important in regulating cardiovascular development and cancer. The term “angiomiR” is used to define the miRNAs that control angiogenesis. They are classified into pro-angiomiRs, those that promote angiogenesis, and anti-angiomiRs, those that inhibit angiogenesis. The identification of angiomiRs as the key to regulating angiogenesis has opened new paths in the treatment of vascular and oncology diseases.

Aims:
This study aims to analyze the expression angiomiRs in diffuse large B-cell lymphoma (DLBCL) and to correlate them with clinical and histological features to identify possible biomarkers and prognostic factors.

Patients and Methods:
We studied 93 samples of de novo DLBCL diagnosed between 2000 and 2010. All the cases were HIV-negative. MicroRNAs were obtained from paraffin embedded tumor samples using RecoverAll™ Total Nucleic Acid Isolation Kit for FFPE Tissues (Applied Biosystems). Four angiomiRs (miR-378, miR-296, miR-210 and miR-126) were analyzed. RNU44 and U18 were used as endogenous controls for quantitative PCR (TaqMan®Small RNA Assays). We set a threshold of a 1.5-fold difference in angiomiRs expression compared to controls (palatine tonsil).

Results:
miR-378, miR-296, miR-210 and miR-126 overexpression were observed in 43%, 47%, 22% and 5%, respectively. Considering that miR-378 and miR-296 were frequently overexpressed in DLBCL, we further analyzed the following variables: age (<=60 versus >60 years), Ann Arbor Staging System (I-II versus III-IV), International Prognostic Index (0–2 versus 3–5), DLBCL classification (NOS versus subtypes), tumor origin according to Hans (2004) algorithm (GCB versus non-GCB). We observed higher median miR-296 expression in DLBCL classified as stage III-IV (p = 0.0415, Mann-Whitney). For the other variables, were did not find any statistically significant difference between groups.

Conclusions:
miR-296, that directly decreased the levels of hepatocyte-growth factor regulated tyrosine kinase substrate (HGS) and indirectly upregulate VEGFR2 and PDGFRβ, was overexpressed in almost 50% of de novo DLBCL and was associated with advanced stage disease. Our study brings new information about the role of microRNA importance in DLBCL development and can be explored as prognostic and therapeutic target for patients suffering from this prevalent malignancy (Supported by FAPESP 2010/17668-6).

Disclosures:
No relevant conflicts of interest to declare.
Lymphoma Occurring Over the Age of 90: Clinical Presentation and Outcome
Authors: Trebouet Adrien , Marchand Tony , Lemal Richard , Gyan Emmanuel , Broussais Florence , Guillermin Yann , Monjanel Hélène , Salles Gilles , Le Gouill Steven , Boulanger Stephanie , Leguyader Sandra , Collignon Albert , Rossille Delphine , Thieblemont Catherine , Lamy Thierry , Houot Roch 
Published: October 2019

Abstract
Abstract 1582

Background
Lymphoma occurring in very elderly patients (i.e. >90 years of age) is not uncommon and its incidence is expected to increase due to prolongation of life expectancy. Its management raises therapeutic as well as ethical considerations. However, no reports are currently available in this population of patients rendering their management particularly challenging. The purpose of our study is to describe the clinical presentation, management and outcome of patients diagnosed with lymphoma at the age of 90 or over.

Methods
In a retrospective, multicenter study, we analyzed 234 patients with Non-Hodgkin (NHL, n=227) and Hodgkin (HL, n=7) lymphoma diagnosed at the age of 90 or over, between 1990 and 2012.

Results
Histologic incidence of lymphoma subtypes was evaluated using 3 epidemiologic cancer registries, accounting for 128 patients. In this cohort, 55% of the patients presented with aggressive NHL, 42% with indolent NHL and 3% with HL. The most frequent histologies were diffuse large B cell lymphoma (46%), follicular lymphoma (9.5%), lymphoplasmacytic lymphoma (8%) and marginal zone lymphoma (5.5%).
Clinical characteristics, management and outcome were collected for 169 patients among several institutions. At diagnosis, median age was 92 [range 90–100]. Most patients were female (66%) and still living at home (73%). Charlson index was low (i.e. ≤2) in 68% of the patients. Forty-five percent of the patients had a low (i.e. ≤1) performance status (PS).
The majority of the patients (63.5%) received a treatment (Fig. 1).
Median overall survival (OS) for the entire cohort was 6.9 months. OS was significantly shorter in patients with aggressive lymphoma (OS = 5.2 vs 19.2 months, p<0.001, Fig. 2), poor (i.e. ≥2) PS (OS = 4.1 vs 16.6 months, p=0.001), advanced (i.e. III-IV) Ann Arbor stage (OS = 2.3 vs 7.1 months, p=0.04), low (i.e. ≤36g/L) albumin level (OS = 4.6 vs 13.8 months, p=0.002) and in the absence of treatment (OS = 4.5 vs 9 months, p=0.05).
Causes of death were: lymphoma in 58% of cases, anti-lymphoma treatment in 8.5% of cases and other causes in 33.5% of cases.

Conclusions
Lymphoma occurring over the age of 90 is more frequently aggressive than indolent. Most of the patients die of lymphoma rather than from toxicities of the treatment. This suggests that a subset of patients may benefit from adapted therapies in spite of their very advanced age. Management of these patients may be guided by prognostic factors such as histologic subtype, PS, Ann Arbor stage and albumin level.

Disclosures:
No relevant conflicts of interest to declare.
Survival and Clinicopathological Characteristics of EBV-Positive Diffuse Large B-Cell Lymphoma
Authors: Beltran Brady E , Cotacallapa Erick , Castillo Jorge J 
Published: October 2019

Abstract
Abstract 1588

Background:
EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients.

Methods:
Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test.

Results:
A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001).

Conclusions:
Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS.

Disclosures:
No relevant conflicts of interest to declare.
Preferential Acquision of N-Glycosylation Sites in the VDJ Region in Germinal Center B-Cell-Like Difusse Large B-Cell Lymphoma
Authors: Alcoceba Miguel , Sebastián Elena , Balanzategui Ana , Marín Luis , Montes-Moreno Santiago , Flores Teresa , Puig Noemí , Sarasquete M. Eugenia , Chillón M. Carmen , Jiménez Cristina , Corral Rocío , González-Barca Eva , Caballero M. Dolores , Miguel Jesús F. San , García-Sanz Ramón , González Marcos 
Published: October 2019

Abstract
Abstract 1589

Introduction:
Acquired potentially N-glycosylation sites are produced by somatic hypermutation (SHM) in the immunoglobulin (Ig) variable region. This phenomenon is produced in ∼9% of normal B-cells and seems to be related to certain B-cell lymphoproliferative disorders (B-LPDs) such as follicular lymphoma (FL, 79%), endemic Burkitt lymphoma (BL, 82%) and diffuse large B-cell lymphoma (DLBCL, 41%). These data suggest that new potential N-glycosylation sites could be related to germinal center B (GCB)-LPDs. By contrast, in other B-LPDs, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), MALT lymphoma, Waldenström macroglobulinemia (WM) or multiple myeloma (MM), these modifications have not been analyzed in deep.

Aims:
To evaluate the acquisition of potential N-glycosylation sites in B-LPDs, including immunohystochemical DLBCL subtypes (GCB and non-GCB) and specific non-GCB-LPDs, such as hairy cell leukemia (HCL), splenic marginal-zone lymphoma (SMZL), CLL, MCL, ocular extranodal marginal zone lymphoma (OAEMZL), MM and WM.

Patients:
A total of 953 sequences (203 from our group and 750 previously published sequences) of B-LPDs were included. Diagnosis distribution was as follows: DLBCL (n=235), MCL (n=235), CLL (n=166), MM (n=96), OAEMZL (n=82), SMZL (n=68), WM (n=38) and HCL (n=33).

Methods:
Acquired N-glycosylation sites were counted according to the sequence Asn-X-Ser/Thr, where X could be any amino acid except Pro. Natural motifs in germline sequences of IGHV1–08, IGHV4–34 e IGHV-5a were not considered. Fisher test was used to perform comparisons between groups. To distinguish DLBCL biological subtypes (GCB and non-GCB DLBCL), Hans' algorithm was used.

Results:
A total of 83 out of the 235 DLBCL cases acquired at least a new N-glycosylation site, a higher value than in normal B-cells (35% vs. 9%, p<0.0001). Higher incidence of these motifs in the group of GCB as compared to non-GCB DLBCL were observed (52% vs. 20%, p<0.0001). Those cases diagnosed of HCL, CLL, MCL, MM, WM, OAEMZL and SMZL presented a reduced number of new N-glycosylation sites, showing similar values than normal B-cells (range 3–18%, p=ns).

Conclusions:
We described for the first time the pattern of N-glycosylation in HCL, SMZL, OAEMZL and in the immunohystochemical DLBCL subtypes, where the GCB-DLBCL showed a higher number of new N-glycosylation sites with respect to non-GCB DLBCL and other non-GCB-LPDs. The presence of novel N-glycosylation sites in FL, BL and in GCB-DLBCL strongly suggests that these motifs are characteristic of the germinal center B-LPDs.

Disclosures:
No relevant conflicts of interest to declare.
Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with Immunochemotherapy. R-BMD Geltamo 08 Trial
Authors: Peñalver Francisco Javier , Márquez José Antonio , Durán Soledad , Giraldo Pilar , Montalban Carlos , Ramírez María José , Sancho Juan Manuel , Terol María José , Capote Francisco Javier , Gutiérrez Antonio , Sánchez Blanca , Canales Miguel , Caballero María Dolores 
Published: October 2019

Abstract
Abstract 1639

Objectives
To evaluate the efficacy and safety of rituximab-bendamustine-mitoxantrone-dexamethasone (R-BMD) in patients with relapsed or refractory follicular lymphoma, (R/R FL) to first-line therapy with R-chemotherapy (R-ChemoT), followed by maintenance with R.

Methods
Phase II trial including 61 patients with R/R LF, after a 1st R-ChemoT line. Induction treatment: Rituximab 375 mg/m2 iv, day 1; bendamustine 90 mg/m2 iv, days 1 and 2; mitoxantrone 6 mg/m2/day iv, day 1; oral dexamethasone 20 mg / day, days 1 to 5. Cycles of 28 days. Evaluation of response after 3rd cycle. If stable disease or progression: withdrawal from the study. If complete response (CR) or complete response unconfirmed (CRu): administration of a 4th cycle. If partial response (PR): administration up to 6 cycles. If CR, CRu or PR at the end of induction: patients receive maintenance with R 375 mg/m2/day every 12 weeks for 2 years. Primary objective: Complete responses (CR + CRu). Results are presented as valid % and median [range].

Results
Results from 46 patients who completed induction period. 52.2% women, age 63 [32–76] years. Ann Arbor stage III / IV 75.6% (31/41) and III / IV-B 22.6% (7/31). FLIPI: intermediate risk 28.9% (11/38); high-risk 23.7% (9/38). Number of administered cycles: 4 [1–6]. Overall response 93.5% (43/46); CR: see Table 1. Progression Free Survival –median (CI95%)-: 14.5 (11.6-NA) months. The most relevant grade 3/4 toxicity: neutropenia 52% (n = 24; 17 patients received G-CSF) and thrombocytopenia 4.3% (n = 2). Infections grade 3/4: 6.5% (n = 3). One patient died due to CMV reactivation. No skin reactions were reported. There are maintenance available data from 15 patients: 3 patients sustained CR at the end of this period, and 2 patients progressed.

Conclusions
R-BMD is a treatment schedule effective and a safe alternative for patients with R/R FL, after a 1st line with R-ChemoT. No skin reactions were reported, possibly due to the inclusion of dexamethasone in the treatment scheme. Additional follow up is required to achieve more conclusive findings.

Disclosures:
No relevant conflicts of interest to declare.
Progressive Peripheral Arterial Occlusive Disease and Other Vascular Events During Nilotinib Therapy in Chronic Myeloid Leukemia
Authors: Levato Luciano , Cantaffa Renato , Kropp Mariagrazia , Magro Domenico , Piro Eugenio , Molica Stefano 
Published: October 2019

Abstract
Abstract 1679
Recent data suggest that second-generation tyrosine-kinase inhibitor (TKI) dasatinib and nilotinib can be responsible for increased non-hematologic adverse events in comparison to imatinib. In particular, there are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving nilotinib. With this in mind we retrospectively evaluated incidence of PAOD or other vascular occlusive events in our cohort including 82 consecutive chronic myeloid leukemia (CML) patients treated at our institution with imatinib alone (n=55) or nilotinib as first-line (n=17) or second-line treatment after imatinib failure (n=10). After a median time of exposition to nilotinib of 24 months (range, 7–34 months) 4 (14.8%) out of 27 patients developed an episode of severe and previously unrecognized PAOD or other vascular occlusive events (2 PAOD, 1 myocardial infarction, 1 ictus). All 4 patients were more than 60 years old and 3 out of 4 were male while obesity was never observed. A history of nicotine abuse could be found in 2 out of 4 patients. The same applied when we looking for the presence of arterial hypertension (2/4) or dyslipidemia (2/4). When 55 patients treated with imatinib were analyzed for PAOD or other vascular occlusive event incidence we detected only one patient who experienced myocardial infarction after 135 months of therapy.
We then evaluated the likelihood of developing PAOD in the subset of patients treated only with imatinib and in those who received nilotinib, respectively. The projected 10-year actuarial probability of remaining PAOD-free was 100% in the imatinib group and 67% in the nilotinib group (HR, 14.6; P=0.0008). Interestingly, the two patient cohorts were alike with respect to age (P=0.76), gender (P=0.80), number cardiovascular risk factors (P=0.62) and body mass index (P=0.59). The only difference we observed was a significantly longer exposition to drug among patients treated only with imatinib in comparison to those who received nilotinib (P<0.001).
In conclusion this study although hampered by the relatively small patient number suggests that in CML front-line and second-line treatment should be adapted to the individual situation in each patient. Parameters related to risk of developing TKI-associated adverse PAOD events should be considered before choosing a second-generation TKI.

Disclosures:
No relevant conflicts of interest to declare.
Genetic Predisposition to Molecular Response in Patients with Myeloproliferative Neoplasms Treated with Hydroxycarbamide
Authors: Angona Anna , Bellosillo Beatriz , Alvarez-Larrán Alberto , Martinez-Aviles Luz Maria , Camacho Laura , Pairet Silvia , Fernández Concepción , Besses Carles 
Published: October 2019

Abstract
Abstract 1738

Introduction:
Hydroxycarbamide (HC) is an antimetabolite used as first-line therapy in high risk essential thrombocythemia (ET) and polycythemia vera (PV). In treatment-naive patients, HC achieves complete hematological and partial molecular response in 80% and 50% of patients, respectively. Genetic factors involved in the pharmacokinetics of HC, as well as in the acquisition of the JAK2V617F mutation, could play a role in the variability among these patients in achieving a molecular response.

Objective:
To assess the influence of 46/1 JAK2 haplotype and urea transporters polymorphisms on the molecular response in JAK2V617F-positive PV and ET patients treated with HC.

Methods:
JAK2V617F allele burden was measured by quantitative PCR at diagnosis and every 6 months during follow-up in 53 PV patients and in 41 ET patients receiving HC therapy. Molecular response to HC treatment was defined according to European LeukemiaNet (ELN) criteria. SNPs rs12340895 and rs12343867 were used to determine 46/1 haplotype status and SNPs rs2298720 (SLC14A1), rs9960464 (SLC14A2), were used to genotype urea transporters. The rate of molecular response was compared according to 46/1 JAK2 haplotype status (negative, heterozygous, homozygous), and genotype of 2 urea transporters: SLC14A1 (GG, GA, AA) and SLC14A2 (GG, GA, AA). The study was approved by the local Ethics Committee and informed consent was obtained according to the Declaration of Helsinki.

Results:
Overall, molecular response (CR or PR) was achieved in 48 patients (51%), corresponding to 46% and 57% in PV and ET patients, respectively (p=0.3). In ET patients, there were no significant differences in the proportion of patients achieving a molecular response according to 46/1 JAK2 haplotype or to the different transporter genotypes. PV patients with the GG genotype in transporter SLC14A2 obtained more frequently a molecular response than those with AA or GA genotype (71% versus 36%, p=0.03). No significant differences in molecular response were observed in PV patients according to transporter SLC14A1 and 46/1 JAK2 haplotype.

Conclusion:
46/1 JAK2 haplotype status did not influence molecular response in PV or ET patients treated with HC. Polymorphisms in urea transporters showed a minimal effect on the rate of molecular response in these patients.

Disclosures:
No relevant conflicts of interest to declare.
PDE4 Inhibitors Block TLR7 and TLR9-Driven Signaling, Proliferation and Cytokine Secretion in CLL Cells As Well As Proliferation Driven by Exposure to Apoptotic Cells
Authors: Tan Ying , Watkins Amanda A. , Rifkin Ian R. , Lerner Adam 
Published: October 2019

Abstract
Abstract 1774
A growing body of literature supports the concept that at least a subset of chronic lymphocytic leukemia (CLL) B cell-receptors (BCRs) are reactive with antigens exposed on apoptotic cells. Work done in the autoimmunity field suggests that through their BCRs, autoreactive B cells can internalize RNA and DNA-containing autoantigens, thereby activating endosomal Toll-like receptor (TLR) 7 and TLR9, respectively, with subsequent TLR-mediated signaling, proliferation and cytokine secretion. cAMP signaling modulates inflammatory signaling in immune system cells and our prior studies have shown that PKA, EPAC and CREB-mediated cAMP signaling can be potently induced in CLL cells with inhibitors of the cyclic nucleotide phosphodiesterase (PDE) PDE4 family in the absence of additional exogenous stimulators of adenylate cyclase. We therefore examined the ability of PDE4 inhibitor-mediated cAMP signaling to regulate TLR7 and 9-mediated signaling in CLL cells. Treatment of CLL cells with the TLR7 and 9 agonists R848 and CpG-B oligonucleotide, respectively, induced IRAK1 degradation and activation of three signaling pathways known to be downstream of TLR7 and 9: the transcription factors NFkB and IRF5 as well as the MAP kinase JNK. The prototypic PDE4 inhibitor rolipram inhibited R848-induced TLR7 and CpG-B-induced TLR9 signaling in CLL cells as judged by Western analysis and immunofluorescent studies of NFkB and IRF5 nuclear translocation as well as JNK phosphorylation. Rolipram also blocked R848 and CpG-B-induced CLL proliferation and TNF secretion. In contrast, rolipram augmented R848 and CpG-B-induced CLL IL-10 synthesis, in keeping with prior studies documenting cAMP response elements in the IL-10 promoter. To test whether RNA and/or DNA antigens exposed in apoptotic cells might induce proliferation in CLL cells through BCR-mediated internalization and subsequent activation of TLR7 and TLR9, we irradiated CLL cells and added them in a graded fashion to live autologous CLL cells. Such exposure to irradiated cells undergoing apoptosis drove CLL proliferation in a manner that was sensitive to TLR7 and TLR9 antagonists, IRAK4 kinase inhibitors and the PDE4 inhibitor rolipram. Our work supports the concept that BCR and TLR-driven responses to apoptotic RNA and DNA-containing complexes may drive proliferation in CLL cells and that PDE4 inhibitors and other agents that target TLR signaling may prove to be effective therapeutic agents in this disease.

Disclosures:
No relevant conflicts of interest to declare.