bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole Exome Sequencing Defines the Genetic Differences Between Pediatric and Adult Follicular Lymphoma
Authors: Ondrejka Sarah Lynn , Jaffe Elaine S , Gong Shunyou , Rajagopalan Deepthi , Love Cassandra , Dave Sandeep 
Published: October 2019

Abstract
Follicular lymphoma (FL) is the most common low grade lymphoma in adults, but uncommon in children. While the two diseases are similar in morphology and immunophenotype, pediatric-type FLs manifest higher grade histology with most cases being localized and curable with standard therapy. Pediatric-type FLs are thought arise from germinal center B cells and typically demonstrate higher expression of the germinal center B cell markers BCL6 and CD10.
While the genetic basis of adult FL has been studied previously, the genetic basis of pediatric-type FL remains largely unknown. In this study, we sought to define the gene coding mutations occurring in pediatric FL and compared them to those of 48 adult FLs, as well as other adult lymphomas derived from germinal center B cells including 88 GCB DLBCLs and 67 cases of BL that we, and others, have published previously.
We obtained a total of 32 pediatric-type FLs along with paired normal tissue. The median age wa 8 years with 62% male patients. We performed whole-exome sequencing for these cases using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes (CCDS database), as well as ~700 human miRNAs from miRBase (v13). In all, we generated over 6 GB of sequencing data using high throughput sequencing on the Illumina platform.
Using bioinformatics approaches that we have described previously, we identified 26 candidate cancer genes that were recurrently somatically mutated in pediatric FL. We found that the genes mutated in pediatric FLs were from three predominant ontologies/pathways. These included DNA damage repair (40%, ATM, RB1), chromatin modification (34%, SETD2, SMARCA4 and TET2) and alternative splicing (12%, SF3B1). We also noted IRF4 translocations and TNFRSF14 mutations in 10% of the cases as has been described previously.
We further compared pediatric FLs to other germinal center B cell derived lymphomas and, in particular, FLs occurring in adults. We found that the mutations that characterize adult FLs including MLL2, CREBBP, and GNA13 were absent in pediatric FLs. There was only one pediatric FL case with an EZH2 mutation, which otherwise occur commonly in germinal center B cell derived lymphomas.
Thus, pediatric FLs are genetically unlike both adult FLs and other germinal center B cell derived lymphomas. Our data provide new clues to the distinctive genetic basis of these tumors and their clinical behavior.

Disclosures
No relevant conflicts of interest to declare.
The Homeobox Gene VENTX Collaborates with AML1-ETO in Inducing an Acute Leukemia in Mice
Authors: Gentner Eva , Vegi Naidu , Mulaw Medhanie A. , Quintanilla-Fend Leticia , Döhner Hartmut , Döhner Konstanze , Buske Christian , Rawat Vijay P.S. , Feuring-Buske Michaela 
Published: October 2019

Abstract
Homeobox genes are key factors in the development of acute leukemias. So far, little is known about the role of non-clustered homeobox genes such as VENTX. The Vent-like homeobox gene VENTX is a member of the Vent gene family in mammals and is the mammalian homolog of the Xenopus xvent gene. Our group has previously shown that VENTX promotes myeloid differentiation when overexpressed in normal CD34+ human stem - and progenitor cells and shows high and aberrant expression in human acute myeloid leukemia (AML) characterized by the AML1-ETO (AE) fusion (Rawat et al., PNAS 2010). To prove the functional relevance of aberrant VENTX expression in this AML genotype, we set up in vitro assays and a murine bone marrow transplantation model, mimicking high expression of VENTX by retrovirally engineered expression of the gene in murine bone marrow progenitor cells. In the CFU-S assay coexpression of both genes significantly increased the frequency of spleen colonies 14-fold and 7-fold compared to VENTX and AE, respectively (p<0.02), and more than 7-fold compared to the control (p<0.001). Most importantly and in contrast to AE alone, coexpression of AE and VENTX induced an acute leukemia after a median latency of 11.3 months post transplant. All leukemias evaluated were rapidly transplantable with a median latency until leukemia induced death of 40 days. The median blast percentage in primary recipient mice was 66% (range 35-100%, n=24). Of note, massive expansion of the red pulpa was documented with the appearance of erythroblasts in the spleen. Furthermore, blasts in the bone marrow expressed CD19, partly in combination with Sca1 and Gr1, pointing to an aberrant expression of this antigen in the AE/VENTX leukemias. Ex vivo, leukemic cells grew permanently generating AE/VENTX positive cell lines. RNA-Seq analyses from CD34+ cord blood transduced with VENTX documented 279 differentially expressed genes compared to the GFP control, hitting 7 pathways (Hematopoietic cell lineage, Cytokine-cytokine receptor pathway, Jak-STAT signaling pathway, Porphyrin and Chlorophyll Metabolism, Asthma, Thyroid cancer and Endocytosis) in the KEGG-Analysis and showed a downregulation of genes necessary for terminal erythroid differentiation such as the EPO-receptor and GATA1. Taken together, these data characterize VENTX as an important contributing factor to AE positive leukemias. Importantly, coexpression of AE and VENTX allows the generation of a murine AE model, which in contrast to all other published mouse models mimics aberrant expression of CD19 in human AE positive AML, a hallmark of this AML genotype.

Disclosures
Buske: CELLTRION, Inc.: Consultancy, Honoraria.
Lmo2's Oncogenic Function in T-Cell Leukemia Requires Ldb1
Authors: Li Liqi , Layer Justin H. , Warzecha Claude , Tripathi Rati , Love Paul , Dave Utpal P. 
Published: October 2019

Abstract
LIM domain Only-2 (LMO2) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). LMO2 encodes a small protein with 2 LIM domains that is part of a large multiprotein complex in hematopoietic stem and progenitor cells, where it is required for HSC specification and maintenance. Many of LMO2's protein partners in HSPCs are expressed in T-ALL implying that protein complexes similar to those nucleated by LMO2 in HSPCs also play a role in leukemia. In this study, we analyzed a critical component of the LMO2 associated complex, LIM domain binding1 (LDB1). LDB1 appears to be an obligate partner of LMO2 in HSPCs but it is not required for T-cell development from committed progenitors. LDB1 is concordantly expressed with LMO2 in human T-ALL although its expression is more widespread than LMO2. To further define Ldb1's role in leukemia, we induced its conditional knockout in CD2-Lmo2 transgenic mice. CD2-Lmo2 transgenic mice develop T-ALL with high penetrance and closely model the human disease. We discovered that Lmo2-induced T-ALL was markedly attenuated in penetrance and latency by Ldb1 deletion. Since Lmo2 induces a distinct differentiation arrest in T-cell progenitors prior to leukemic transformation, we analyzed the differentiation of T-cell progenitors in CD2-Lmo2 transgenic/floxed-Ldb1/Lck-Cre mice and in non-Lmo2 transgenics: floxed-Ldb1/Lck-Cre mice. Ldb1 deletion by Lck-Cre was efficient in double negative and double positive T-cell progenitors. In striking contrast, Ldb1 deletion could not be induced in CD2-Lmo2 transgenic T-cell progenitors. Consistent with this finding, T-ALLs that developed in CD2-Lmo2/floxed-Ldb1/Lck-Cre mice had incomplete deletion of Ldb1. These results imply that Ldb1 is a required factor for Lmo2 to induce T-ALL. Lastly, gene expression analysis of Lmo2-induced T-ALLs and ChIP-exonuclease analysis of Ldb1 occupancy in T-ALL suggested that the Lmo2/Ldb1 complex enforced a gene signature similar to that seen in HSPCs and in Early T-cell Precursor ALL. In conclusion, Ldb1 is a required partner for Lmo2 to induce T-ALL. Additionally, the HSPC function of Lmo2/Ldb1 complexes may be recapitulated in T-cell progenitors prior to T-ALL.

Disclosures
No relevant conflicts of interest to declare.
Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma
Authors: Porrata Luis , Ristow Kay , McPhail Ellen D. , Macon William , Maurer Matthew J , Nowakowski Grzegorz S. , Ansell Stephen , Witzig Thomas E. , Markovic Svetomir , Habermann Thomas M. 
Published: October 2019

Abstract
The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB
Figure 1. Figure 1.

Disclosures
Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..
Racial Disparities in Incidence and Survival for Patients with Multiple Myeloma in the United States
Authors: Radhakrishnan Lakshmi , Lonial Sagar , Nooka Ajay K. 
Published: October 2019

Abstract
Background: Over the past two decades the incidence of myeloma has been gradually increasing in the United States. The incidence rates are higher in men than women, and higher in blacks than whites. Similar to the differential incidence, overall survival rate between blacks and whites are also dissimilar; a difference that is not completely explained and may be attributable to genetic variations between the two groups.
Methods: Using data from 18 SEER registries, we examined differences in incidence, mortality and survival from 1973-2012 for 89,867 myeloma patients (68,701 white, 16,364 black and 4,802 others) by race, gender and age-stratification. ICD-O-3 and morphologic (9732/3) codes were used to identify cases. Age-adjusted incidence and mortality rates, regression analysis and survival curves were calculated by race. Statistics were computed using the National Cancer Institute SEER*Stat software, version 8.2.0. and SAS software, version 9.4 (SAS Institute Inc, Cary, NC).
Results: Median age at diagnosis was 70 years (range 20-100 years) for the overall population (blacks: 66 years; whites: 71 years, and others: 69 years (P<0.01). The age-adjusted incidence rates per 100,000 populations were: blacks- 11.9 (95% CI 11.6, 12.1, P-value<0.05); whites- 5.1 (95% CI 5.0, 5.2) and others- 3.7 (95% CI 3.6, 3.9). The incidence rates were higher for black males, 14.2 (95% CI 14, 14.7) followed by black females, 10.3 (95% CI 10, 10.6, P-value<0.05). Using white male as reference, incidence rate ratios for black males and females are 2.20 (95% CI 2.12, 2.28) and 1.60 (95% CI 1.54, 1.65) respectively. The 2-year relative survival rates (RSR) for the study population were: whites- 60.4%, blacks: 64.1% and others: 68.4%, respectively. The 5-year RSR by race and gender are included in figure 1. On the survival analysis, black race is an independent factor to have improved survival (HR=0.884, P-value<0.0001). This was corroborated on regression analysis, showing decreased hazard ratios for blacks (HR 0.856 95% CI 0.834, 0.878) compared to whites (P-value<0.001).
Conclusions: Black patients are diagnosed younger than whites and other races. The IRRs for black males are twice compared to white males. While the 5-year RSRs are improving for all races and genders, black race is an independent factor to have improved survival. Further population-based studies focused on the exploring the underlying biological mechanisms of disease may explain the earlier presentation with disease and better overall survival among black patients.
Figure 1. Figure 1.

Disclosures
Lonial: Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy.
Predictors of Increase in Emergency Room (ER) Visits and Hospitalizations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Chemotherapy
Authors: Feinberg Bruce , Schenkel Brad , McBride Ali , Ellis Lorie , Bhor Menaka , Radtchenko Janna , Lal Lincy S 
Published: October 2019

Abstract
Background: Acute care interventions negatively impact patients' quality of life and represent one of the major cost drivers in oncology care. Understanding the predictors for increased healthcare resource utilization is essential for better management of patients with CLL. This study evaluated predictors for ER visits and hospitalizations in patients with CLL treated with chemotherapy.
Methods: Using claims data (MORE2 Registry®), patients receiving chemotherapy for CLL were retrospectively identified by ICD-9 codes (204.1X) during a 48-month period (August 2009-2013). Patients with secondary malignancies, pregnancy codes, and age <18 were excluded. Univariate regression analysis was conducted to determine covariates associated with an increase in ER visits and hospitalizations. Results for significant variables were reported as odds ratio/p-value. Odds ratio >1 indicates increase in chance of event.
Results: A total of 2,013 patients with CLL were identified. Median age at diagnosis was 72 years, 61% were male, 34% were treated in the relapsed setting, 42% had ER visits, and 39% were hospitalized throughout their treatment history. Significant increases in ER visits and hospitalizations were associated with the following variables (OR/p-value): age (ER: 1.015/.001, hospitalization: 1.001/.038), Charlson comorbidity index (ER: 1.253/.013, hospitalization: 1.038/.018), supportive care use (ER: 2.087/<.001, hospitalization: 2.429/<.001), number of CLL related adverse events (ER: 12.311/<.001, hospitalization: 29.467/<.001), chemotherapy duration (ER: 1.001/<.001, hospitalization: 1.001/<.001), bendamustine use (ER: 1.404/.001, hospitalization: 1.381/.002), fludarabine use (ER: 1.405/<.001, hospitalization: 1.395/.001), Northeast region of the United States (ER: 1.293/.008, hospitalization: 1.321/.005), and treatment following relapse (ER: 3.413/<.001, hospitalization: 4.018/<.001). Significant covariates associated with a decrease in hospitalizations or ER visits were not found.
Conclusions: This retrospective study demonstrated that patient demographic and clinical characteristics as well as chemotherapy choice were associated with ER visits and hospitalizations in patients with CLL. ER visits and hospitalizations have similar drivers. These data warrant consideration of age and comorbidity-adjusted treatment choice in CLL patients who need active treatment with antineoplastics.

Disclosures
Feinberg: Janssen Scientific Affairs, LLC: Consultancy. Schenkel:Janssen Scientific Affairs, LLC: Employment. McBride:Janssen Scientific Affairs, LLC: Consultancy. Ellis:Janssen Scientific Affairs, LLC: Employment. Bhor:Janssen Scientific Affairs, LLC: Consultancy. Radtchenko:Janssen Scientific Affairs, LLC: Consultancy. Lal:Janssen Scientific Affairs, LLC: Consultancy.
The Dysfunction of Platelets in Paroxysmal Nocturnal Hemoglobinuria
Authors: Fu Rong , Meng Yinping , Wang Yihao , Liu Hui , Liu Yi , Li Lijuan , Ding Shaoxue , Ruan Erbao , Wang Huaquan , Wang Guojin , Song Jia , Shao Zonghong 
Published: October 2019

Abstract
Introduction Thrombosis is one of the most dangerous complications in PNH, which can cause high mortality. However, its underlying mechanism remains unclear. To explore the mechanism of thrombosis in PNH, the function of platelets and complements were investigated in our study.
Material and Methods Serum level of terminal complement complex (sC5b-9) was detected by ELISA. The quantities of C5b-9,CD61 and CD62p on the membrane of platelets were detected by flow cytometry. Clinical tests were collected, including D-Dimer and platelet aggregation rates induced by adenosine diphosphate (ADP) and arachidonic acid (ARA).
Results The serum sC5b-9 level was significantly lower in the PNH/PNH-AA group than that in the control group (p<0.01). The deposition of C5b-9 on CD59- platelets (17.53%±6.27%) was higher than those on CD59+ platelets in PNH/PNH-AA patients(11.33%±5.03%) and normal controls(10.88%±3.58%) (p<0.01). D-dimer was significantly higher in PNH/PNH-AA patients (485ng/dL) than that in normal controls (311ng/dL)(p<0.05),especially in patients with LDH>1000U/L(789ng/dL). CD61 and CD62p expression on CD59+ platelets in PNH patients (76.87%,39.99%) were significantly lower than those in normal controls(98.41%,64.21%)(p<0.05,p<0.01).CD62p expression on CD59- platelets (40.07%) was significantly lower than normal controls(p<0.01). Platelet aggregation stimulated by agonists ADP (37.54±24.25)% and ARA (24.60%) were lower in the PNH/PNH-AA group than that in the control group(59.20±23.30)%, (14.54%) (p < 0.05). Interestingly,CD61 expression on CD59+ platelets in PNH patients was higher in the patients with higher type II PNH clone.
Conclusions The function of platelets was inversely inhibited,especially CD59+ platelets even if hypercoagulation continuously exists in PNH/PNH-AA.

Disclosures
No relevant conflicts of interest to declare.
Significant Improvement of Survival By T2* Cardiovascular Magnetic Resonance in Thalassemia Major
Authors: Pepe Alessia , Meloni Antonella , Del Vecchio Giovanni Carlo , Romeo Maria Antonietta , Gamberini Maria Rita , Bonetti Federico , Neri Maria Giovanna , Chiodi Elisabetta , Positano Vincenzo , Maggio Aurelio , Borgna-Pignatti Caterina 
Published: October 2019

Abstract

Background: In 2004 seven Italian centers reported survival data for patients with thalassemia major (TM) and showed that heart disease due to iron overload was the most common cause of death (Borgna et al Haematologica 2004). In the same years the accurate and noninvasive assessment of cardiac siderosis was made possible in Italy by the introduction of the T2* cardiovascular magnetic resonance (CMR).
Purpose: We aimed to evaluate if the deployment of T2* CMR had an impact on the mortality rate.
Methods: Four centers contributed to the present study, updating the data of the enrolled patients until August 31, 2010. For the patients who died, the date of the death represented the end of the study. 577 patients (264 females and 313 males) were included.
Results: One-hundred and fifty-nine (27.6%) patients died, 124 of whom (77.9%) died before the year 2000.
The Table shows the comparison between dead patients and survivors. Dead patients were significantly younger and they were more frequently males. Dead patients started chelation therapy significantly later. HIV, arrhythmias and heart failure were significantly more frequent in dead patients. According to the Cox model, the following variables were identified as significant univariate prognosticators for the death: male sex (HR=1.87, 95%CI=1.34-2.60, P<0.0001), HIV (HR=2.55, 95%CI=1.25-5.20, P=0.010) and heart failure (HR=8.86, 95%CI=6.37-12.31, P<0.0001).
MRI was not performed in 406 patients (70.4%) and no patient had been scanned before his/her death. Among the survivors, MRI was not performed in the 59% of the cases (P<0.0001). The absence of an MRI scan was a significant univariate prognosticator for death (HR=43.25, 95%CI=11.32-165.33, P<0.0001).
The study was restricted to the patients dead after 2004 (19/159=12%) or followed until August 2010 (N=357). In this subgroup of 376 patients, MRI was not performed in the 52.4% of the survivors and in all dead patients (P<0.0001). The absence of a MRI exam was reconfirmed as a strong predictive factor for death (HR=49.37, 95%CI=1.08-2263.24, P=0.046). The Kaplan-Meier curve is showed in Figure 1. The log-rank test revealed a significant difference in the curves (P<0.0001).
Conclusions: Our data suggests that the use of T2* CMR, that enables individually tailored chelation regimes reducing the likelihood of developing decompensated cardiac failure, allowed the reduction of cardiac mortality in chronically transfused TM patients.
Table 1. Table 1. Figure 1. Figure 1.

Disclosures
Pepe: Novartis: Speakers Bureau; Chiesi: Speakers Bureau; ApoPharma Inc: Speakers Bureau.