bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of F-18 FDG PET/CT for the Diagnosis and Therapeutic Management of Extranodal Natural Killer (NK)/T-Cell Lymphoma, Nasal Type
Authors: Xu Bing , Li Rongwei , Shi Pengcheng , Dong Huijuan , Guo Xutao , Fan Zhiping , Huang Fen 
Published: October 2019

Abstract
Background: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is quite rare in Western populations, but relatively common in East Asia (especially China) and Latin America. ENKTL is an aggressive disease with poor prognosis, requiring risk stratification. Similar symptoms, such as nasal obstruction and purulent nasal discharge, are found in patients with nasal NKTL and in patients with chronic rhinosinusitis. The images from contrast-enhanced computed tomography (CT) frequently show no prominent mass. As a result, the diagnosis is often delayed because it is frequently misdiagnosed as sinusitis. F-18 FDG PET/CT is a powerful imaging tool for diagnosis, staging, and evaluation of therapeutic effect in oncology.
Aims: This study was designed to investigate the value of FDG PET/CT in the therapeutic management of extranodal natural killer (NK)/T-cell lymphoma, nasal type.
Methods: A total of 26 patients with NK/T-cell lymphoma, nasal type were diagnosed according to morphologic and immunophenotypic criteria as specified
in the World Health Organization (WHO) classification. All patients underwent FDG PET/CT and clinical information was obtained by review of medical records.
Results: In 26 cases, all nasal/extranasal lesions were FDG-avid evidented to be neoplasm on CT scan and histopathological examinations. FDG-avid lesions in nasal/maxillary areas were uniformly more localized than demonstrated on CT scan, suggesting soft tissue masses on CT were partly due to inflammatory reaction. Among the 26 patients with definite diagnosis, 9 patients were re-staged on the basis of F18 FDG PET/CT with 5 patients down-staged and 4 patients up-staged. Statistical difference of the standardized uptake values (SUV) after 6 courses of chemotherapy and/or radiotherapy between the complete remission (CR) group and the partial remission (PR) group can be found (4.1±2.3 versus 7.8±1.7,P=0.006). The SUV value between pre-reatment and post-treatment were also of statistical significance in 22 patients (11.4±6.2 versus 5.6±2.1,P = 0.000).At a follow up of 18 months, patients got CR had a longer survival time than those got PR, stable disease (SD) or progress disease (PD) in 20 patients out of 26 patients.(median survival:310 days vs 284 days,(95% CI: 0.7156 to 1.365, p<0.05).
Conclusions: Our preliminary study suggests that FDG PET/CT can provide more accurate information on the diagnosis, staged and therapeutic response assessment in extranodal natural killer (NK)/T-cell lymphoma, nasal type. FDG PET/CT can be an invaluable imaging modality in this clinical setting. Further investigation with large patients enrollment is warranted.

Disclosures
No relevant conflicts of interest to declare.
Long-Term Remission (>3 years) after Rituximab Monotherapy Used for Patients with Relapsed Indolent Non-Hodgkin Lymphomas (NHL)
Authors: Michallet Anne-Sophie , Beckerich Florence , Bouafia-Sauvy Fadhela , Espinouse Daniel , Salles Gilles , Coiffier Bertrand 
Published: October 2019

Abstract
Background:
Rituximab has demonstrated significant clinical efficacy in the treatment of NHL, particularly in combination with chemotherapy, and its use has dramatically changed the treatment and outcome of both indolent and aggressive B-cell NHL over the past decade. Furthermore, consistent toxicity data have been obtained with a safe and tolerable profile in a large majority of patients.
Aim:
The objective of this retrospective study is to evaluate the long-term efficacy of rituximab monotherapy (4 weekly infusion at induction followed by 4 infusion every 2 months as consolidation) used for patients with relapsed indolent NHL.
Results:
From May 1998 through January 2011, Among 919 patients with indolent NHL treated in our department, 488 (53%) relapsed and were treated with rituximab alone (first and later relapse). 126 (26%) responded and were still in response 2 years later. These 126 patients (68 (54%) males and 58 (46%) females with a median age of 61 y; range: 17-94) are the subject of our analysis. 24% were over 70 years old, 45% were in first relapsed and 25% in later relapsed. Only 16% of the population have more than one co-morbidities (cardiac and or renal respectively); 79% a normal PS (0-1) with only 4 patients having a PS >2; 80% no bulky disease but 72% a disseminated disease (73% stage III and IV). In this study, 60 (48%) patients had a follicular lymphoma with 50% at an intermediate risk group according to the FLIPI score ; 20 (16%) a marginal zone lymphoma, and 43 (34%) a small lymphocytic or lymphoplasmacytic lymphoma and 3 patients other characteristics of lymphoproliferative disorders. After rituximab monotherapy, 55% of the entire cohort was in complete response (CR) and 31% in CRu or partial response and 5% in stable disease. Among these 126 patients, 74% progressed later than 3 years (38% later than 5 years). With a median follow-up of 6.5 years, 4-year and 8-year PFS were 70% and 30%, respectively. 18% had transformation into Richter syndrome and 12 patients have died.
Conclusion: Rituximab monotherapy is an effective therapy in selected relapsed indolent NHL and allows long-term response. This strategy could be used as “spare of chemotherapy” which is an important question today, especially in indolent not curable disease.

Disclosures
No relevant conflicts of interest to declare.
Enhancing Natural Killer Cell-Mediated Lysis of Lymphoma Cells By Combining Therapeutic Antibodies with CD20-Specific Immunoligands Engaging NKG2D or NKp30
Authors: Peipp Matthias , Kellner Christian , Günther Andreas , Humpe Andreas , Repp Roland , Klausz Katja , Derer Stefanie , Valerius Thomas , van de Winkel Jan G.J. , Parren Paul W.H.I. , Gramatzki Martin 
Published: October 2019

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) represents a major effector function of many therapeutic antibodies. Thus, enhancing ADCC is a promising approach to further improve antibody therapy. Here, the CD20-specific immunoligands ULBP2:7D8 and B7-H6:7D8, which engage the stimulatory NK cell receptors natural killer group 2 member D (NKG2D) and NKp30, respectively, were compared for their abilities to boost ADCC in an attempt to design an effective antibody combination strategy.
The immunoligands are designed as single chain molecules, with a single chain fragment variable (scFv) of the CD20 antibody 7D8 fused to UL16-binding protein (ULBP) 2 or B7 homologue 6 (B7-H6), which are ligands of the activating NK cell receptors NKG2D and NKp30, respectively. By binding to lymphoma cells the immunoligands designated as ULBP2:7D8 and B7-H6:7D8 mimicked an induced self phenotype and thereby triggered NK cells to kill lymphoma and leukemia cells. Both immunoligands augmented ADCC by NK cells synergistically when combined with the lymphoma-directed antibodies rituximab or daratumumab recognizing CD20 and CD38, respectively. Antibody combinations with ULBP2:7D8 resulted in higher cytotoxicity (up to 10-fold lower EC50-values) in comparison to combinations with B7-H6:7D8, which in individual experiments failed to boost ADCC. Thus, NK cells were triggered more efficiently when NKG2D rather than NKp30 was co-ligated together with FcγRIIIA. Although a combination of ULBP2:7D8 and B7-H6:7D8 produced synergistic effects, no significant improvements were obtained by combining the three agents rituximab, B7-H6:7D8 and ULBP2:7D8. Enhancement of ADCC by the immunoligands was also achieved when NK cells from lymphoma or leukemia patients were analyzed as effector cells. ULBP2:7D8 in particular increased lysis not only of allogeneic but also of autologous tumor cells.
In summary, co-targeting of NKG2D was more effective in promoting NK cell-mediated ADCC than co-ligation of NKp30 and may represent a promising approach to further enhance the efficacy of therapeutic antibodies. Based on these results we propose a ‘dual-dual-targeting’ concept by co-targeting of two surface antigens on tumor cells and concomitant engagement of two different activating NK cell receptors.

Disclosures
van de Winkel: Genmab BV: Employment, Patents & Royalties. Parren:Genmab: Employment, Equity Ownership.
Whole-Genome Epigenomic Analysis in Multiple Myeloma Reveals DNA Hypermethylation of B-Cell Specific Enhancers
Authors: Agirre Xabier , Castellano Giancarlo , Pascual Marien , Health Simon , Kulis Marta , Segura Victor , Bergmann Anke , Esteve Anna , Merkel Angelika , Raineri Emanuele , Agueda Lidia , Blanc Julie , Richardson David , Clarke Laura , Russiñol Nuria , Queirós Ana C. , Beekman Renée , Rodriguez-Madoz Juan R. , San José-Enériz Edurne , Fang Fang , Gutierrez Norma Carmen , García-Verdugo José M , Robson Michael I. , Schirmer Eric C. , Guruceaga Elisabeth , Martens Joost H.A. , Gut Marta , Calasanz María José , Flicek Paul , Siebert Reiner , Campo Elias , San Miguel Jesus F. , Melnick Ari M , Stunnenberg Hendrik G. , Gut Ivo G. , Prosper Felipe , Martín-Subero Jose Ignacio 
Published: October 2019

Abstract
Analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed regional DNA hypermethylation embedded in extensive global hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM as compared to normal plasma cells were located outside CpG islands and were unexpectedly associated with intronic enhancer regions active in normal B cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with downregulation of its host genes. ChIP-seq and DNAseI-seq further revealed that DNA hypermethylation in these regions was related to enhancer decommissioning. Hypermethylated enhancer regions overlap with binding sites of B-cell specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation suggesting that MM cells reacquire epigenetic features of undifferentiated cells upon loss of expression of B-cell specific TFs. Overall, we have identified DNA hypermethylation of developmentally-regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.

Disclosures
No relevant conflicts of interest to declare.
Epigenetic Signature of Leukemia Stem Cells Defines Subgroups Associated with Clinical Outcome and Cell of Origin in AML
Authors: Jung Namyoung , Dai Bo , Gentles Andrew J. , Murakami Peter , Majeti Ravindra , Feinberg Andrew P. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a hematologic malignancy initiated by leukemia-initiating or leukemia stem cells (LSC) which can differentiate into clonally related leukemic blast cells. This leukemia stem cell model proposes that functional properties of LSC and their blast progeny must be derived by epigenetic differences. Here, we examined genome wide DNA methylation of LSC-enriched populations and blast cells from 15 AML patients, along with 6 well-defined hematopoietic stem and progenitor cell (HSPC) populations from 5 normal controls using Illumina Infinium Human Methylation 450 BeadChip array. Strikingly, LSC-enriched populations exhibited global hypomethylation compared to non-engrafting blast cells, demonstrating that epigenetic change could drive the functional difference of LSC and their blast progeny. We defined an LSC epigenetic signature by integrating DNA methylation and gene expression analysis. The signature independently predicted overall survival of patients in both DNA methylation and gene expression data sets. Finally, we identified that LSC-enriched populations formed two major clusters when compared to normal HSPC: a granulocyte-macrophage progenitor (GMP)-like and a lymphoid-primed multipotential progenitor (L-MPP)-like subgroup that may reflect the cell of origin for these cases. These subgroups showed strong association with cytogenetic abnormalities and molecular mutations associated with the cell of origin. These results provide the first evidence for epigenetic variation between LSC and their blast progeny that are prognostic, and for epigenetically defined cell of origin of AML LSC.

Disclosures
No relevant conflicts of interest to declare.
Absolute Lymphocyte Counts at the End of Induction Is a Prognostic Indicator in Childhood Acute Lymphoblastic Leukemia
Authors: Hasegawa Daiichiro , Hirase Satoshi , Takahashi Hironobu , Saito Atsuro , Kozaki Aiko , Ishida Toshiaki , Yanai Tomoko , Kawasaki Keiichiro , Yamamoto Noriyuki , Kubokawa Ikuko , Mori Takeshi , Hayakawa Akira , Nishimura Noriyuki , Iijima Kazumoto , Kosaka Yoshiyuki 
Published: October 2019

Abstract
BACKGROUND: Recently, several studies have demonstrated that absolute lymphocyte counts (ALC) after induction therapy predicted treatment outcome. To address this issue, we here assessed the impact of the ALC at the end of induction therapy on outcomes in childhood ALL.
METHODS: We reviewed 141 cases of pediatric ALL with 1-21 years of age treated on the Japan Association Childhood Leukemia Study group ALL-02 series of treatment trials between 2002 and 2013. Patients with Philadelphia chromosome-positive ALL were excluded. Variables retrospectively analyzed included ALC at several time points during remission induction, age at diagnosis, gender, initial white blood cell count (WBC), cytogenetics, immunological phenotype, stratified risk, treatment response for bone marrow (the percentage of blasts at day 15), and outcome. Events in the analysis of event-free survival (EFS) included induction failure, death, relapse and secondary malignant neoplasm. The comparison of categorical variables between groups was performed by chi-square test. The probability of EFS and overall survival (OS) were analyzed with the use of the Kaplan–Meier method and a stratified log-rank test. A multivariate analysis of survival was performed with the use of a Cox proportional-hazard model to evaluate the treatment effect with adjustment for stratification factors.
RESULTS: The subjects included 121 of B-precursor ALL, 10 of T cell ALL, and 4 of acute mixed lineage leukemia/ acute unclassified leukemia. We found high WBC count at diagnosis (>100K/microL) and slow early responder for bone marrow at day 15 to be an unfavorable prognostic indicator, and also the ALC at the end of induction (day29) to be a statistically significant predictor of improved OS and EFS in our cohort. Patients with ALC ≥ 800/microL had a superior 5-year overall survival (100 ± 1.7% vs 88.1 ± 4.3 %, p=0.0001) and EFS (98.3 ± 1.7% vs 81.8 ± 5.0 %, p=0.0001). Multivariate analysis demonstrated that ALC at day29 was an independent, clinically significant predictor of improved EFS and OS after controlling WBC at diagnosis, gender, age at diagnosis, and cytogenetics. Multiple regression analysis adjusting for initial WBC count, peripheral blast counts at day8, and cytogenetics, also revealed an independent relationship (p=0.005) between treatment response (the percentage of blasts at day 15) and ALC at day29.
CONCLUSIONS: ALC is a simple, statistically significant prognostic factor in childhood ALL that may refine current risk stratification algorithms.

Disclosures
No relevant conflicts of interest to declare.
Embryologic Origin of Functional Granulopoiesis
Authors: McGrath Kathleen E , Palis James , Fegan Katherine H. , Catherman Seana C 
Published: October 2019

Abstract
The first progenitors with granulocyte potential arise in the murine yolk sac beginning at embryonic day 8.5 (E8.5), 48 hours before hematopoietic stem cells (HSCs) are formed. These granulocyte progenitors are part of a wave of definitive erythro-myeloid progenitors (EMPs) that display a unique immunophenotype. By E10.5, we observe EMPs in the bloodstream and enriched in the liver, the site of fetal hematopoiesis, consistent with previous reports of GM-CFC presence in the early embryo. HSCs begin to colonize the fetal liver between E11.5 and E12.5, where they subsequently expand and differentiate. Thus, the presence of maturing blood cells at this time-point likely represent the output of EMP that colonize the fetal liver before HSCs. In vitro culture of purified EMPs results in the complete myeloid repertoire found in the adult, including neutrophils, basophils, eosinophils and mast cells. To see which of these potentials is actually realized in the embryo, we examined myelopoiesis in the liver at E11.5- E12.5. There was no morphological evidence of eosinophils, basophils or mast cells in the early fetal liver, and there were no lineage specific transcripts for these cells types (EPX, FCepsilonR) detected by qPCR before E15.5. However, rare cells with neutrophil morphology were found in the fetal liver and in the bloodstream at E12.5. We utilized flow cytometry to enumerate granulocytes (GF1+, Mac1+) in both liver and the bloodstream during early embryogenesis. In order to rule out contamination from maternal cells, we analyzed embryos generated from GFP+ male mice mated with wild-type females. Per embryo equivalent, we consistently found a small number of granulocytes already present in both fetal liver and circulation at E11.5. The number of granulocytes increases to over one hundred at E12.5 and thousands by E13.5. We used imaging flow cytometry to examine the maturational state of the granulocytes in the fetal liver. Consistent with their recent differentiation, fetal liver granulocytes were predominately at the most immature stages as compared to bone marrow samples. Interestingly, at E11.5 and E12.5, a large proportion the circulating granulocytes were maternal derived (GFP-). The presence of these maternal granulocytes could not be accounted for by contamination of maternal blood given the levels of maternal RBCs in the samples. These data indicate that both maternal- and embryonic EMP-derived neutrophils co-circulate in the early embryo. Furthermore, when fetal blood was stimulated with bacteria-like BioParticles, fetal derived (GFP+) and maternal granulocytes (GFP-) each responded with oxidative bursts. Taken together, these data indicate that the early mammalian embryo utilizes both yolk sac-derived transient definitive progenitors and maternal granulocytes to provide host defense before HSC-derived hematopoiesis is established.

Disclosures
No relevant conflicts of interest to declare.
Quantitative Assessment of Translocation Transcript Ratio Predicts for Relapse Free Survival Among Patients with Core Binding Factor Acute Myeloid Leukemia
Authors: Hoang Thuyvan , Qiao Wei , Cortes Jorge E. , Patel Keyur , Ravandi Farhad , Kadia Tapan M. , Brandt Mark , Luthra Raja , Kantarjian Hagop M. , Borthakur Gautam 
Published: October 2019

Abstract
Presence of unique translocation events allows us to monitor minimal residual disease by quantitative polymerase chain reaction (qPCR) in patients with core binding factor acute myeloid leukemia (CBF-AML) that includes Inversion(16), t(16;16) and t (8;21) cytogenetic abnormalities. Fludarabine based regimens; Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) and FLAG, idarubicin (FLAG-Ida) have been two consecutive regimens used as front-line therapy for all new patients with CBF-AML presenting to MD Anderson Cancer Center since 2007. MRD has been monitored by baseline and periodic qPCR studies from bone marrow samples during induction/consolidation and follow up. Based on recent literature we investigated whether time to achievement of lowest qPCR value or the lowest qPCR value are important to predict for relapse free survival (RFS) in a multi-variate analysis.
Between 2007 and early 2014, 89 patients (pts) have achieved remission with frontline induction regimens; FLAG-GO=41 (46%) and FLAG-Ida=48 pts (54%); 44 patients with Inv (16) and 45 pts with t(8;21). Median presenting WBC count is 12.5x 106/L (range 1.9-97.2) and median qPCR ratio with ABL1 as control at presentation is >100. Median lowest qPCR following induction/consolidation is 0 (range 0-15.9) and is the same for inv (16) and t(8;21) (p=0.14). The median lowest qPCR value by regimen is 0 for FLAG-GO and the same for FLAG-Ida is 0.01 (p=0.003). RFS with a median follow up of more than 3 years is 80% and is not different among regimens (p=0.5). Because of infrequency of events, the analysis was mostly done using both cytogenetic groups and both regimens together.
Median time to lowest qPCR was 7 months for both cytogenetic subgroups as well as for both FLAG-GO and FLAG-Ida regimens (range 1-28 months). In a univariate analysis that included age, log WBC and platelet counts, cytogenetics, regimen, time to lowest qPCR value and the log lowest qPCR value as variables; log lowest qPCR is the only variable significantly predicting for RFS (p<0.01) while time to lowest qPCR is not (p=0.7).
Conclusion: RFS remains high among patients treated with FLAG-GO or FLAG-Ida and lowest qPCR value rather than the time to achieve lowest qPCR.

Disclosures
No relevant conflicts of interest to declare.
Erythroid Cells Adapt to L-Leucine Scarcity By Reducing Hemoglobin Production Via the mTORC1/4E-BP Pathway
Authors: Chung Jacky , Bauer Daniel E. , Ghamari Alireza , Nizzi Christopher P. , Deck Kathryn M. , Kingsley Paul D. , Yien Yvette Y. , Huston Nicholas C. , Chen Caiyong , Wittig Johannes G. , Palis James , Orkin Stuart H. , Lodish Harvey F. , Eisenstein Richard S. , Cantor Alan B. , Paw Barry H. 
Published: October 2019

Abstract
In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. Here, we find that maturing erythroid cells increase L-leucine uptake via transcriptional up-regulation of the L-leucine transporter, LAT3. Inadequate L-leucine uptake by L-leucine starvation or LAT3 inhibition triggers a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells via the mTORC1/4E-BP pathway. CRISPR-mediated deletion of 4E-BPs in murine erythroid cells renders them resistant to mTORC1 and LAT3 inhibition, markedly restoring hemoglobinization. Our complementary results demonstrate that globins are direct translational mTORC1 targets during normal development. This pathway is distinct from the previously reported translational regulatory mechanisms mediated by the heme-regulated inhibitor (HRI) kinase or by severe amino acid deprivation via the general control nonderepressible 2 (GCN2) kinase. We propose that, in red cells, mTORC1 serves as a homeostatic sensor coupling hemoglobin production to sufficient L-leucine uptake.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.