bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity in Infants with Acute Myeloid Leukemia: Retrospective Analysis of a Japanese Nationwide Survey
Authors: Shimada Akira , Tomizawa Daisuke , Kinoshita Akitoshi , Hamamoto Kazuko , Tsukimoto Ichiro , Ogawa Atsushi , Taga Takashi , Imamura Toshihiko , Tawa Akio , Horibe Keizo , Taki Tomohiko , Hayashi Yasuhide , Adachi Souichi 
Published: October 2019

Abstract
Abstract 1477

Introduction:
When compared to older patients, infants with acute leukemia exhibit distinct cytogenetic features, such as higher prevalence of MLL gene rearrangement (MLL-R), and are known to have higher vulnerability to intensive cytotoxic therapy, such as hematopoietic stem cell transplantation. In contrast to acute lymphoblastic leukemia (ALL), there have been few reports on acute myeloid leukemia (AML) in infants. To develop more appropriate therapeutic strategies for infants with AML, it is necessary to elucidate the distinct clinical features of this subgroup. We therefore performed a retrospective analysis on infant AML in Japan. Patients: Infants with AML, aged less than 1 year at diagnosis, registered in any of the 6 Japanese AML clinical trials between 1991 and 2010 (TCCSG M91-13, TCCSG M96-14, AML99, CCLSG9805, CCLSG9805RE, and JPLSG AML-05) were included in this study. Patients with Down syndrome were excluded. Results: A total of 122 infant AML patients were included in the present analysis, which comprised approximately 10% of all pediatric AML patients. The most frequent FAB classification type was M5 (28.7%), followed by M7 (22.9%) and M4 (10.8%). About 30% of patients had 11q23 abnormalities/MLL -R, but there was no impact on prognosis. Several cases with normal karyotype were revealed to be MLL -R on FISH analysis or on MLL -fusion chimeric transcript analysis by RT-PCR. t(8;21), inv(16) and t(15;17) cases were very rare among the infant cohorts. Furthermore, 7.8% had t(1;22)(p13;q13), and 2.5% had t(7;12)(q36;p13). Genetic mutation results could be obtained in 11 cases in the AML99 study; only one case each was confirmed to have NRAS, KRAS or KIT gene mutation. No cases with FLT3-ITD were detected among the 11 cases in the AML99 or the 44 cases in the AML-05 study. Survival rate varied based on treatment received; 5-year OS rate was 58.3% to 71.4%, and 5-year EFS rate was 49.4% to 64.2%. Discussion: Survival rate in infant AML was identical to that in older pediatric AML. However, there was a possible underestimation of MLL -R patients based on sole chromosome analysis; the prevalence of MLL -R was less than 50% in infant AML patients, without any prognostic impact. Other well-known genetic alterations in pediatric AML also had no effect on outcome of infant AML. Infant AML is a heterogeneous subgroup of pediatric AML, and further studies, as well as novel biomarkers, will be necessary to fully understand its biology.

Disclosures:
No relevant conflicts of interest to declare.
hsTRAIL/Apo2L Induces Apoptosis in Enteropathy-Associated T-Cell Lymphoma
Authors: Radersma Marijn , de Baaij Laura R , Hijmering Nathalie J , Ossenkoppele Gert , Meijer Chris JLM , Mulder Chris JJ , Cillessen Saskia AGM 
Published: October 2019

Abstract
Abstract 1665
EATL is an intestinal tumor of aberrant intraepithelial T-lymphocytes (IELs) and may be preceded by refractory celiac disease type II (RCD II). Current therapies include surgery, chemotherapy and autologous and/or allogeneic stem cell transplantation. Despite these therapies, the overall outcome of EATL is very poor with 1- and 5-year survival rates in the range of 31–39% and 8–20%, respectively. Therefore, new therapeutic options are needed. Human soluble tumor necrosis factor-related apoptosis-inducing ligand, hsTRAIL/Apo2L, a member of the TNF family, has proven to selectively kill tumor cells via an alternative, death-receptor mediated apoptosis pathway. In this present study we evaluated if hsTRAIL/Apo2L induces apoptosis in both isolated lymphoma cells of EATL biopsies and isolated cells of RCD II biopsies.
hsTRAIL/Apo2L induced apoptosis in isolated EATL lymphoma cells. RCD II cells were less sensitive to hsTRAIL/Apo2L compared to EATL cells. hsTRAIL/Apo2L induced apoptosis in EATL cells was caspase-9 dependent, but unexpectedly active caspase-8 involvement could not be detected. RT-MLPA analysis on EATL samples confirmed this observation by showing increased levels of c-Flip in EATL cells, which suggests a blockage in the extrinsic apoptosis pathway. Both EATL and RCDII cells showed expression of TRAIL receptors R1 and R2 and almost no expression of R3 and R4.
In conclusion, our study showed that hsTRAIL/Apo2L induces apoptosis in EATL cells through the intrinsic apoptosis pathway. Moreover, we showed that TRAIL receptor R1 and R2 are expressed in EATL cells. Based on these results, hsTRAIL/Apo2L may be a new therapeutic option for EATL patients.

Disclosures:
No relevant conflicts of interest to declare.
Antisense Oligonucleotide Mediated Depletion of Factor XI Prevents Vascular Occlusion in An Experimental Thrombosis Model in Primates
Authors: Crosby Jeff R. , Marzec Ulla M , Zhao Chenguang , Gao Dacao , Revenko Alexey S , Matafonov Anton , Gailani David , MacLeod Robert , Gruber Andras , Hanson Stephen , Monia Brett P. 
Published: October 2019

Abstract
Abstract 2250
It has recently been demonstrated that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents. Furthermore, FXI deficiency is not associated with spontaneous bleeding in humans, and deficiency of a contact factor does not cause abnormal bleeding. We have previously shown that treatment with FXI Antisense Oligonucleotides (ASOs) produces potent, dose-dependent antithrombotic activity in various venous and arterial murine thrombosis models. In the current study we characterize the antithrombotic effects of FXI ASOs in a non-human primate model. Subcutaneous administration of FXI ASOs in cynomologus monkeys resulted in a dose-and time-dependant decrease in FXI mRNA levels in liver (up to 90%), decreased FXI protein and activity levels measured in plasma, and prolonged activated partial thromboplastin times (aPTT). Importantly, FXI depletion in monkeys was not associated with an increased risk of bleeding. Recent studies demonstrated that complete inhibition (>99%) of FXI by a monoclonal antibody reduced thrombin generation and prevented vascular occlusion in a collagen-coated graft inserted into a baboon arteriovenous shunt (Tucker et al., Blood 2009). In the present study, we set out to determine the relationship between FXI levels and antithrombotic activity, and in particular, the minimal level of FXI reduction required to produce an antithrombotic effect in a baboon thrombosis model. Using the FXI monoclonal antibody, we demonstrate that ∼50% inhibition of FXI levels produces antithrombotic activity in baboons. Next we applied baboon-specific FXI ASOs and demonstrated reductions in FXI protein levels and activity, with corresponding increases in aPTT levels. Baboons were then treated with FXI ASOs in a manner that would produce ∼50% reduction of FXI protein levels and measured anti-thrombotic activity. Similar to the antibody approach, ASO-mediated reduction of FXI plasma levels ≥ 50% resulted in a potent antithrombotic effect. Furthermore, reductions in FXI levels do not increase bleeding times in baboons. These results further support the development of FXI ASOs for antithrombotic therapy with the potential for a superior safety profile compared to currently available anticoagulants.

Disclosures:
Crosby: Isis Pharmaceuticals: Employment. Zhao:Isis Pharmaceuticals: Employment. Gao:Isis Pharmaceuticals: Employment. Revenko:Isis Pharmaceuticals: Employment. MacLeod:Isis Pharmaceuticals: Employment. Gruber:Aronora, LLC: Consultancy, Equity Ownership. Monia:Isis Pharmaceuticals: Employment.
Family History of Venous Thromboembolism (VTE) and the Risk of VTE Recurrence in Patients with a First Unprovoked VTE: A Multicenter Prospective Cohort Study
Authors: Gauthier Karine , Sabri Elham , Kahn Susan R. , Wells Philip S , Anderson David , Gal Gregoire Le , Solymoss Susan , Crowther Mark A. , Perrier Arnaud , White Richard H. , Kovacs Michael J. , Carrier Marc , Rodger Marc A. 
Published: October 2019

Abstract
Abstract 2299

Introduction:
The duration of anticoagulation after unprovoked venous thromboembolism (VTE) has been characterized as the most important unanswered question in clinical thrombosis management. This has led to research to identify predictors of recurrent VTE to identify high-risk patients who might warrant indefinite anticoagulation. Many clinicians assume that a family history of VTE is a predictor of recurrent VTE. This study aims to assess the value of family history as a predictor for recurrent VTE.

Methods:
Prospective multi-center multi-national cohort study recruited patients with a first objectively proven unprovoked VTE who completed 5 to 7 months of anticoagulation therapy. A detailed family history of VTE was completed for every subject. The information recorded included the number of affected relatives, whether they were first or second degree relatives and if the VTE was unprovoked or secondary. Patients were then followed for recurrent VTE.

Results:
664 subjects were enrolled between October 2001 and March 2006, 649 subjects were followed for a mean duration of 3.8 years (3.6–3.98 95% C.I.). The mean age of subjects in this cohort was 53 years (min-max 18–95) and 49% of subjects were females. A family history of VTE in at least 1 first-degree relative was recorded for 112 (17.3%) subjects. A total of 142 (21.9%) suspected VTE events were adjudicated as recurrences. The recurrence rate was 5.94% (4.89–7.15 95% C.I.) per patient-year for patients without any family history of VTE, and it was 4.82% (3.02–7.30 95% C.I.) per patient-year in patients with a family history of VTE in at least 1 first-degree relative. In secondary analyses, neither a family history of unprovoked VTE, multiple unprovoked VTE, in first-degree nor second-degree relatives was a predictor of recurrent VTE. A multivariate analysis was performed to adjust for known risk factors for VTE recurrence, but the adjusted hazard ratios were again not significantly different.

Conclusion:
A family history of VTE is not a predictor for recurrent VTE, and therefore should not be used to segregate unprovoked VTE patients in high- and low-risk categories.

Disclosures:
No relevant conflicts of interest to declare.
Unlike Heparins Newer Oral Anticoagulants Do Not Interact with HIT Antibodies and Maybe Useful in the Longterm Anticoagulant Management of Heparin Compromised Patients
Authors: Lewis Bruce E , Aranda Christopher , Lewis Mary , Hoppensteadt Debra , Walenga Jeanine M. , Fareed Jawed 
Published: October 2019

Abstract
Abstract 2317

Introduction:
Heparin and low molecular weight heparins such as enoxaparin and dlateparin are widely used in the management of thrombosis and cardiovascular disorders. However these anticoagulants are capable of producing the generation of HIT antibodies and their use is not recommended in patients with previous history of HIT. More recently several new oral anticoagulants have been approved around the world. These include the oral anti-Xa agents namely, Apixaban (Bristol-Myers Squibb), Rivaroxaban(Bayer Healthcare) and anti-IIa agents, dabigatran (Boehringer-Ingelheim). All of these represent synthetic low molecular weight compounds. Apixaban and Rivaroxaban are active agents where as Dabigatran requires endogenous activation. The purpose of this investigation was to determine the relative effects of the newer anticoagulants and enoxaparin on HIT antibody mediated platelet aggregation and other interactions with platelets.

Materials:
Rivaroxaban was obtained in powdered form from Bayer Healthcare (Wuppertal, Germany) Apixaban and Dabigatran were of synthetic origin. Enoxaparin was obtained from Sanofi-Aventis (paris, France). All drugs were dissolved in appropriate solutions and a working solution of 100 ug/ml was prepared in buffered saline. Pooled HIT sera was prepared by pooling clinically symptomatic HIT patients with high titers of anti-heparin platelet factor 4 antibodies.

Method:
Whole blood samples drawn from normal healthy volunteers were supplemented with each of these agents at a graded concentration of 0–100 ug/ml for 60 minutes to determine the relative release of platelet factor 4. To test the interaction of HIT antibody with each of these agents 50 ul of PRP samples were mixed with 150 ul HIT positive heat inactivated sera/plasma or plasmapheresis fliud (collected from symptomatic HIT patients). Graded amounts of each of these new anticoagulants at 0.1, 1.0 and 10 ug/ml were added to test the platelet aggregation response at a period of 60 minutes.

Results:
In contrast to enoxaparin which produced an increase in the platelet factor 4 release upon 60 minute incubation 25.6+3.1 ng/ml), none of the new oral anticoagulants produced an increase in the PF4 <15.0 ng/ml. Enoxaparin also produced a strong HIT antibody mediated response, whereas none of these newer oral agents produced any aggregation responses.

Conclusion:
These studies demonstrate that –enoxaparin the newer oral anticoagulant drugs do not interact with HIT antibody to mediate plarelet aggregation responses. Moreover, these newer agents do not promote platelet factor 4 release. Thus, these agents can be used in the long term anticoagulant management of heparin compromised patients.

Disclosures:
No relevant conflicts of interest to declare.
Therapeutic Implications of Ventx in Acute Lymphocytic Leukemia
Authors: Gao Hong (Jenny) , Wu Xiaoming , Zhu Zhenglun (Jerry) 
Published: October 2019

Abstract
Abstract 2457
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, representing about a third of all pediatric cancers. Despite significant progress in ALL treatment over the past decades, relapse occurs in about 20% cases, which are often resistant to conventional chemotherapy. The canonical Wnt/b-catenin signaling has been implicated in pathogenesis of ALL, and has been a target of intensive investigation for its potential application in cancer prevention and treatment. During our recent studies, using methods of reverse genetics and developmental modeling of Xenopus embryogenesis, we identified VentX as a novel Wnt antagonist and a putative tumor suppressor in lymphocyte leukemia. On the basis of our prior findings that VentX inhibit proliferation of lymphoblastic leukemic cells, our current studies are designed to explore the potential role of VentX as a novel therapeutic target of ALL and its underlying mechanisms.
Using lymphoblastic cell model and real-time RT-PCR technique, we found that VentX expression can be induced by chemotherapeutic agents. We found that elevated expression of VentX caused a senescence phenotype in lymphoblastic leukemic cells and importantly, down-regulation of VentX expression by RNA interference technique led to strong attenuation of the cytotoxic effects of chemotherapeutic agents. Mechanistically, we found that VentX binds to the promoter and p53 and p16 and transactivates the p53/p21 and the p16/pRb senescence pathways, which have been implicated in pathogenesis of ALL. We found further that VentX control these two senescence pathways in primary B lymphocytes and that inactivation of both pathways rather than one is required to abolish the inhibitory effects of VentX on the proliferation of lymphoblastic leukemia cells.
In summary, the results of our investigation suggest that VentX is a novel therapeutic target of ALL. We found that VentX poised as a pivotal link between the oncogenic Wnt signaling pathway and the tumor suppressing senescence pathway. Given the implications of Wnt and senescence pathway in leukemia stem cells, a resource of chemo-resistance and relapse, targeting VentX may present novel opportunities for managing refractory cases of ALL and the eventual cure of the diseases.

Disclosures:
No relevant conflicts of interest to declare.
The t(14;18)(q32;q21) Confers Resistance to Apoptosis-Induced by Smoothened Inhibitors In Diffuse Large B-Cell Lymphoma That Can Be Restored by Functional Inhibition of BCL2
Authors: Kunkalla Kranthi , Qu Changju , Liu Yadong , Singh Rajesh , Vega Francisco 
Published: October 2019

Abstract
Abstract 2479
Generally in cancers, high expression of anti-apoptotic proteins induced by oncogenic signaling pathways is a major cause for treatment failure. Previously, we have demonstrated that Hedgehog (Hh) signaling is activated and functional in diffuse large B-cell lymphoma (DLBCL) and that its inhibition, using the Smoothened (SMO) inhibitor cyclopamine-KAAD, induces apoptosis in cell lines of DLBCL of activated B-cell (ABC) subtype and cell cycle arrest (G1-phase) in those of germinal center (GC) subtype. Induction of apoptosis in ABC-DLBCL was due to decrease of BCL2 expression (protein and mRNA levels), a direct target of Hh signaling (Leukemia 2010;24:1025–36). We also found that BCL2 is upregulated in the tumor cells in the presence of stroma and that Hh inhibition abrogates this upregulation (Oncogene 2011, in press). Here, we explored the possibility of overcoming resistance to apoptosis-induced by Hh inhibition in GC-DLBCL using a combination of the SMO inhibitor “Hh antagonist” (Genentech Inc) with the BH3 mimetic ABT-737 (Abbot laboratories) in a panel of 5 GC type DLBCL cell lines, 4 of them with the t(14:18)(q32;q21) (DOHH2, SUDHL4, Toledo and OCI-LY19) and one without the translocation (HT). ABT-737 is a functional inhibitor of three major anti-apoptotic proteins of the BCL2 family (BCL2, BCL-xL and BCL-W). Combinatorial treatments were performed with increasing concentrations of the Hh antagonist (2.5, 5.0 and 7.5 μM) and with variable but minimal lethal doses of ABT-737 (inducing cell death less than 20%). Using cell viability, apoptosis (annexin-V) and cell cycle based assays, we found that the combined treatments resulted in a additive/synergistic decrease of cell viability and increase of apoptosis in comparison to the treatment with the Hh antagonist alone. In contrast to ABC type DLBCL cell lines, in DLBCL cells with t(14;18), Hh antagonist did not result in decrease expression of BCL2, BCL-xL and BCL-W indicating that the additive effect of ABT-737 was due to their functional inhibition and not by suppressing expression levels of these proteins. On the other hand, treatments with the Hh antagonist resulted in a concentration dependent decrease of BCL2 protein levels in HT cells. In summary, our data confirm that in the presence the t(14;18), inhibition of SMO does not result in decrease of BCL2 expression. In these cases, concomitant inhibition of BCL2 function and SMO is needed to induce apoptosis. Combined inhibition of Hh signaling and BCL2 function may have a therapeutic value for lymphomas with the t(14;18)(q32;q21).

Disclosures:
No relevant conflicts of interest to declare.
The Prognosis of Children Acute Lymphoblastic Leukemia (ALL) with Minimal Residual Disease (MRD) ≥10-2 After Induction (TP1) Depends on the Prephase Response and on the Level of the MRD After Consolidation (TP2): Results of the 58951EORTC Trial
Authors: Bertrand Yves , Suciu Stefan , Grardel Nathalie , Bakkus Marleen , Mazingue Francoise , Yacouben Karima , Uyttebroeck Anne , Lutz Patrick , Plantaz Dominique , Girard Sandrine , Dastugue Nicole , Benoit Yves , Cavé Hélène 
Published: October 2019

Abstract
Abstract 2571

Background:
In our previous EORTC 58881 trial in childhood ALL, we have shown the prognostic impact of the MRD, quantitated by polymerase chain reaction assay. Patients with TP1 MRD ≥10–2 (D35), had a higher risk of relapse than those with TP1 MRD<10-2 (Cavé et al, NEJM, 1998). For these patients hematopoietic stem cell transplantation (HSCT) with an HLA matched donor was recommended in our subsequent EORTC 58951 trial. Here we report on the patients with MRD ≥10-2 (TP1) in the 58951 trial.

Methods:
Between December 1998 and July 2008, 1955 children (1y-18y) with ALL were enrolled in the 58951 trial, 1459 being evaluable for the MRD (TP1) by PCR (rearrangements of the T-cell receptor and immunoglobulin heavy chain genes). Seventy-nine patients with Phi-negative ALL had a TP1 MRD ≥10-2, and 69 of them achieved a complete hematological remission after induction. Here we report on the outcome of these 69 patients.

Results:
At a median follow-up of 7.6 years, the overall 5-years EFS and OS rates for the 69 patients were 56.1% (SE 6.0%) and 62.0% (SE 5.9%) respectively. Prephase good responders (PGR) (<1000 blasts/mm3 D8) (N=40) had a better OS rate as compared to prephase poor responders (PPR) (N=29): 72.2% (SE 7.1%) vs 48.0% (SE 9.3%) (hazard ratio=0.43, p = 0. 002). In B-lineage ALL patients the OS was similar between PGR (N=32) and PPR (N=6) subgroups, whereas in T-ALL patients there was a better OS for PGR (N=8) than for PPR (N=23) subgroup. Of note, all the patients with hyperdiploidy > 51 chromosomes were PGR.
TP2 MRD (after consolidation) was assessed in 59 pts. All patients but one (1/13) with TP2 MRD ≥10-2 died. In PGR patients, those with TP2 MRD < 10-3 (N=18) had a significant better OS rate at 5 years than those with TP2 MRD ≥10-3 (N=17): 88.9% (SE 7.4%) vs 52.3 % (SE 12.3%), hazard ratio=0.17, p=0.009. We observed no relapses among patients with hyperdiploidy > 51 chromosomes and TP2 <10-3. PPR patients had a poor 5-year OS, independent of TP2 level (MRD <10-3 (N=8) or MRD ≥10-3 (N=16)).

Conclusions:
The prognosis of children ALL with TP1 MRD ≥10-2 has improved with early intensification of the treatment as compared to the one observed in our previous 58881 study. However the outcome of these patients was still heterogeneous and the prephase response was still of prognostic importance. Patients with GPR and TP2 <10-3 had a favourable prognosis and for those patients HSCT is not mandatory.
For other patients with PPR and/or TP2 ≥10-3 the prognosis was worse and these patients may benefit from alternative therapy and/or intensification with HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Implications of PET-Negative Residual Disease At the Completion of Chemotherapy for Diffuse Large B-Cell Lymphoma
Authors: Dabaja Bouthaina S. , Phan Jack , Medeiros L. Jeffrey , Hagemeister F.B. , Chuang Hubert , Fayad Luis , Shihadeh Ferial , Allen Pamela , Wogan Christine , Rodriguez Maria A. 
Published: October 2019

Abstract
Abstract 2695

Purpose:
To evaluate potential differences in overall survival (OS) and progression-free survival (PFS) according to PET and CT disease status at completion of chemotherapy for patients with Diffuse Large B-cell lymphoma.

Patients and Methods:
Subjects were 303 patients with histologically confirmed DLBCL treated between January 2001 and December 2007; no patient received radiation therapy. We evaluated: age, sex, Ann Arbor stage, bulky disease, International Prognostic Index score, Ki-67 expression, PET standardized uptake values (SUVs), disease status after chemotherapy and at last follow-up.

Results:
Median age was 61 years; 149 men; 81 (27%) had stage I-II, 242 (73%) stage III-IV. A total of 248 patients (82%) completed 6–8 cycles of doxorubicin-based therapy. On multivariate analysis, both OS and PFS were significantly influenced by: the presence of PET negative residual mass on CT at completion of therapy (P < 0.001 for OS and P < 0.001 for PFS) (Figure 1); number of cycles and type of chemotherapy (P < 0.001 for OS and P < 0.001 for PFS); Combined presence (p=0.01 for OS and P=0.003 for PFS) of high Ki 67, high PET SUV, and bulky disease; and IPI score (P = 0.001 for OS and P < 0.001 for PFS). Same factors remained significant when replacing response to therapy with size of the residual mass on CT (Figure 2), or number of residual sites (Figure 3) (p<0.0001 OS and p<0.0001 PFS).

Conclusion:
Presence of a residual mass on CT at the completion of chemotherapy has both prognostic and predictive value in patients with DLBCL. These patients should be considered for biopsy and further consolidative therapy.

Disclosures:
No relevant conflicts of interest to declare.