bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiotherapy in Stage I and II Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT): Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database
Authors: Olszewski Adam J. , Desai Amrita 
Published: October 2019

Abstract
Abstract 2053

Background:
External beam radiotherapy (RT) is the treatment of choice for many patients with localized (stage IE-IIE) MALT lymphoma, primarily based on single-institution case series. There are no specific factors favoring surgical management or addition of systemic therapy in these cases. The purpose of this study was to evaluate the association of RT used as the initial treatment strategy with survival outcomes in a population-based cohort.

Methods:
We analyzed 6,111 cases of st I/IIE MALT lymphoma of the most common anatomical locations included in the SEER database, diagnosed between 1998 and 2009. Cases identified through autopsy or death certificate only, as well as those with unknown stage or RT status were excluded. RT was recorded only if administered as part of the initial treatment strategy within 12 months of diagnosis. 5-year relative survival was summarized for treated and untreated patients. For multivariate regression, flexible parametric Royston-Parmar models for overall survival were fitted for each site, adjusting for clinical and socioeconomic confounders. Age and surgical excision of the primary site were always included as variables. No records of progression-free survival, alternative or subsequent systemic treatments or watchful waiting strategy were available.

Results:
There were significant differences in the rates of RT utilization, baseline clinical characteristics and survival outcomes. Median age varied from 57 years (cutaneous lymphoma) to 69 years (breast). In multivariate models, RT was associated with improved survival in patients with ocular, cutaneous or gastric localization with no significant association for the pulmonary, intestinal, salivary, mammary and thyroid sites. The hazard ratio in gastric MALT was non-proportional and increased from 0.45 at 6 months to 0.97 at 24 months form diagnosis. Long-term prognosis for ocular, salivary and cutaneous thyroid lymphomas was excellent, but was less favorable for the gastrointestinal or pulmonary locations.

Conclusions:
The survival benefits of RT in early-stage MALT lymphoma are most evident for ocular and cutaneous sites of origin, and this modality can be advocated for treatment. The relative survival of 99–100% in those anatomical subtypes may indicate curative potential in patients who receive RT. In gastric MALT lymphoma the benefit is limited to the early period of two years of follow up. Inferior survival despite local radiotherapy in pulmonary and intestinal locations may suggest higher rates of occult disseminated disease and potential value of systemic therapy.

Disclosures:
No relevant conflicts of interest to declare.
Thymocyte Reprogramming by the Scl, Lmo1 and Notch1 Oncogenes
Authors: Gerby Bastien , Tremblay Cedric Stevens , Tremblay Mathieu , Rojas-Sutterlin Shanti , Hoang Trang 
Published: October 2019

Abstract
Abstract 207
Normal thymic progenitors are devoid of self-renewal capacity, which is a distinctive stem cell property. These thymic progenitors progress into the thymus through several stages of differentiation (DN1, DN2-4, DP) before giving rise to CD4+ or CD8+ immunocompetent cells that are released into the periphery. Therfore, thymic output requires continuous seeding from stem cell-derived progenitors. T cell acute lymphoblastic leukemia (T-ALL) is a common cancer in children. Almost 25% of childhood T-ALL involve the SCL transcription factor and/or its nuclear partners LMO1/2 and more than 50% harbour gain of function mutations of NOTCH1. Using a transgenic mouse model that reproduces the human disease, we previously showed that activation of SCL, LMO1 and Notch1 in the thymus is sufficient to transform thymocyte progenitors and induce T-ALL (Tremblay M et al., 2010). Here, we explore the mechanism of transformation by these three oncogenes in primary thymocytes during the pre-leukemic stage. Our results indicate that the SCL and LMO1 oncogenes collaborate to confer an aberrant self-renewal potential to a subset of pre-leukemic thymocytes, via induction of a stem cell gene signature that also distinguishes primary T-ALL patient samples in which LMO2 is expressed. Furthermore, our clonality and functional analyses indicate that only a few clones of preleukemic thymocytes from Scl-Lmo1 mice are able to colonize the thymus of recipient mice in transplantation assays and produce mature T-cells during the pre-leukemic stage. Precisely, we show that self-renewal activity is enriched in DN3 thymocytes which eventually acquire Notch1 gain of function mutations and leukemia initiating activity. On the other hand, the Notch1 oncogene by itself does not confer self-renewal properties to thymocytes. Rather, we show that the Notch1 oncogene enhances the activity of the SCL-LMO1 oncogene to increase the frequency of pre-Leukemic Stem Cells (pre-LSCs) without modifying the clonal expansion of individual pre-LSC when transplanted at limiting dilutions. These results indicate that the Notch1 oncogene modifies the self-renewal activity enforced by the SCLtgLMO1tg oncogenes into a self-renewal of expansion, typical of a transformed state. Furthermore, NOTCH1 confers an invasive potential to SCLtgLMO1tg thymocytes that become thymus-independent and acquire the capacity to develop in peripheral organs. Therefore, our observations are consistent with the view that the SCL-LMO1 oncogenic transcription factors reprogram DN3 thymocytes to acquire self-renewal potential, thereby establishing a pre-leukemic state. Finally, NOTCH1 activation provides a strong signal that collaborates with the SCL-LMO1 oncogenes to induce T-ALL by favoring self-renewal divisions in pre-LSC together with an invasive capacity.

Disclosures:
No relevant conflicts of interest to declare.
Relationship Between vitamin D Deficiency and Bone Fragility in Sickle Cell Disease: A Cohort Study of 56 adults.
Authors: Arlet Jean-Benoît , Courbebaisse Marie , Chatellier Gilles , Eladari Dominique , Souberbielle Jean-Claude , Friedlander Gerard , De Montalembert Mariane , Prié Dominique , Pouchot Jacques , Ribeil Jean-Antoine 
Published: October 2019

Abstract
Abstract 2103

Background:
Recent studies suggest that patients with sickle cell disease (SCD) have profound vitamin D (VD) deficiency. Limited data exist on the effect of VD deficiency on bone fragility in these patients.

Objectives:
To assess the prevalence of VD deficiency in adults with SCD and its consequences on bone metabolism and fragility.

Methods:
This prospective study included 56 SCD adult patients (mean age 29.8 ± 9.5 years), in a clinically steady state. Clinical and laboratory data were recorded. Bone mineral density (BMD) was measured using dual X-ray absorptiometry. Fracture history, BMD, avascular osteonecrosis, H-shaped vertebra and markers of mineral metabolism were compared between two groups of patients presenting very low (≤6 ng/ml, n=26) (group 1) and low (>6 ng/ml, n=26) (group 2) 25(OH)D concentration, respectively.

Results:
Median 25(OH)D concentration was 6 ng/mL. VD deficiency (25(OH)D <10 ng/mL) was found in 42 out of 56 patients (75%) and secondary hyperparathyroidism in 40 (71.4%). History of fracture was documented in 17 patients (30.3%), osteopenia and/or ospeoporosis in 39.6% of patients. Overall, patients of group 1 were more likely to have sustained a fracture (42.8%) compared to patients of group 2 (17.8%) (p=0.04). These patients had also lower body mass index and significantly higher parathyroid hormone, C-terminal telopeptides of type I-collagen and bone-specific alkaline phosphatase serum levels. There was no difference between group for BMD, avascular osteonecrosis history, H-shaped vertebra, and disease severity markers.

Conclusion:
This study suggests that VD deficiency is a key feature in SCD-bone disease. It is highly prevalent and associated with hyperparathyroidism, bone resorption markers, and history of fracture. The optimal supplementation regimen remains to be determined.

Disclosures:
No relevant conflicts of interest to declare.
The Biological Effects and Mechanisms of Interleukin-34 in the U937 Human Leukemic Cell Model.
Authors: Booker Burthia E , Adunyah Samuel E. 
Published: October 2019

Abstract
Abstract 2155
Interleukin-34 (IL-34) is a cytokine consisting of a 39kD homodimer employing the Macrophage Colony Stimulating Factor (MCSF/CSF-1) receptor; recently identified through functional proteomics experiments. Among its physiological activities, IL-34 has been shown to promote monocyte viability and proliferation; promote the differentiation of bone marrow cells into macrophage progenitors and induce pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, and GM-CSF in human whole blood. All of the published work on IL-34 involves its effects on hematopoietic and osteoclast progenitors; however, it is not known whether IL-34 has the ability to induce any of these physiological responses in cancer cells. The purpose of this study is to evaluate the biological effects of IL-34 in the U937 leukemia cell line while deducing the signaling mechanisms associated with these effects. Thus far, we have evaluated IL-34 on U937 cells for cell growth and proliferation, induction of cytokines, migration, differentiation and apoptosis. Congruently, we are also exploring the JAK/STAT and PI3K/Akt signaling pathways for activation. In U937 cells, we have noted that while IL-34 does not induce cell growth or proliferation, there is a reduction in cells in the S phase of the cell cycle at 48hours, post treatment. Additionally, we note a differential induction of a number of Th1/Th2/Th17 and pro-inflammatory cytokines, namely IL-1α, IL-1b, IL-6, IL-8 and G-CSF. Our results also show that IL-34 influences the migration of monocytes by the possible induction of chemoattractant cytokines in media. Furthermore, we report that IL-34 is able to differentiate the human leukemic cellular model, U937, from monoblastic precursor cells towards monocyte- and macrophage-like cells. Accompanying this differentiation appears to be a selective induction of apoptosis in undifferentiated U937 cells, supported by the induction of cleaved Caspase-3. To our knowledge, this is the first report that IL-34 induces differentiation in human leukemic cellular model, let alone any cancer model. Exploration of the JAK/STAT signaling pathway has identified TYK2 and JAK 1 as mediators of the IL-34 signal through in U937 cells, while identification of its associated STAT proteins is currently ongoing. Interestingly, the evaluation of the PI3K/Akt pathway has demonstrated a reduction of phosphorylated Akt, suggesting an influence of PTEN, which is currently being evaluated. This research may provide insight into the influence of IL-34 in the cancer microenvironment as compared to the normal cell microenvironment, resulting in potential therapies targeting its mechanistic actions.

Disclosures:
No relevant conflicts of interest to declare.
Cleaved High Molecular Weight Kininogen Induces Endothelial Progenitor Cell Senescence by Stimulation of JNK/FOXO4/MnSOD Pathway.
Authors: Zhu Xuemei , Colman Robert W. , Wu Yi 
Published: October 2019

Abstract
Abstract 2181

Objectives:
High molecular weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), and is cleaved to its active form (HKa) upon the activation of this system. Although the KKS activation is widely involved in a variety of pathological settings, the activities of its activation product HKa remain largely unknown. Recently we have reported that HKa accelerates the onset of endothelial progenitor cell (EPC) senescence by induction of reactive oxygen species (Arterioscler Thromb Vasc Biol. 2011;31:883), whereas the mechanism is not clear. In this study, we investigated whether HKa induces EPC senescence via stimulation of c-Jun N-terminal kinases (JNK)-related pathway.

Methods:
Human EPCs were treated with HKa in different concentrations for 72 hours, which were followed by the measurement of phospharylation of JNK at Thr183/tyr185 and transcription factor FOXO4 at Thr451, as well as expression of Mn-superoxide dismutase (MnSOD) at protein and mRNA level. To narrow down the functional domain of HKa, recombinant proteins of human HK heavy chain (HC, 19–380aa) and light chain (LC, 390–644aa) were generated for determining which domain(s) mediates the effect of HKa.

Results:
In a concentration-dependent manner, HKa treatment induced phosphorylation of JNK at Thr183/Tyr185, and its downstream phosphorylation of transcription factor FOXO4 at Thr451. Concomitantly, HKa upregulated the expression of MnSOD at protein and mRNA levels as measured by Western blot and real time RT-PCR. However, it did not affect the expression of catalase. Similar to HKa, the heavy chain (HC), but not the light chain, increased the percentage of senescent EPCs (63%±6.6 for HC v.s. 77.5%±6.02 for HKa). Moreover, HC at 100 nM increased FOXO4 phosphorylation at Thr451 and the expression of MnSOD in EPCs. Besides, both of HKa and its HC stimulated the production of intracellular H2O2.

Conclusion:
These above results demonstrate that HKa accelerates the onset of EPC senescence by stimulating JNK/FOXO4/MnSOD pathway, and its effect is mediated by the HC.

Disclosures:
No relevant conflicts of interest to declare.
Identification of a Novel Exosite (Glu634-Arg639) in the Spacer Domain of ADAMTS13 Required for Recognition of Von Willebrand Factor.
Authors: Casina Veronica , Hanby Hayley , Lyalenko Anastasia , Zheng X. Long 
Published: October 2019

Abstract
Abstract 2214
Exosite binding plays a key role in cleavage of VWF by ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13). Two exosites that are evolutionarily conserved from zebra fish to mammals have been identified in the spacer domain by sequence alignment. Previous studies have shown that exosite 3 in the spacer domain plays a critical role for substrate recognition (Blood 115:2300–10, 2010), and modification of this exosite generates ADAMTS13 variants with improved specific activity but reduced autoantibody binding (Blood 119:3836–43, 2012). In the present study, using a site-directed mutagenesis approach, we identified a novel exosite near exosite 3 in the spacer domain, termed exosite 4, a region between residues Glu634 and Arg639. A partial (ΔEx4a:deletion of Leu632-Asp635 or ΔEx4b:deletion of Arg636-Arg639) or complete deletion of the exosite (ΔEx4) significantly impaired proteolytic activity towards peptidyl VWF73 and multimeric VWF. Moreover, substitution of all surface exposed residues in Ex4A (LTED/AAAA) or Ex4b (RLPR/AAAA) with alanine had a similarly detrimental effect on proteolytic activity. Further studies demonstrated that the residues Asp635 and Arg636 in exosite 4 play a critical role for substrate recognition. We conclude that the region between residues Glu634 and Arg639 is a novel exosite necessary for recognition and cleavage of VWF.

Disclosures:
No relevant conflicts of interest to declare.
Matched Cohort Analysis of Allogeneic Hematopoietic Cell Transplantation (HCT) with Total Marrow Irradiation/Fludarabine/Melphalan (TFM) Versus Fludarabine/Melphalan (FM) Conditioning for Acute Leukemia
Authors: Rosenthal Joseph , Wong Jefrrey , Stein Anthony Selwyn , Stiller Tracy , Palmer Joycelynne , Forman Stephen J. 
Published: October 2019

Abstract
Abstract 222
We have previously reported the feasibility and safety of augmenting the reduced-intensity regimen (RIC) of FM by addition of total marrow irradiation, a targeted form of TBI, using a helical tomotherapy (HT) device (Rosenthal, Blood. 2011;117(1):309–315). In this study we compared outcomes in patients with acute leukemia undergoing HCT receiving either TFM or FM.

Patients and Methods:
We analyzed 72 patients with acute leukemia or MDS who received either FM (N=36) or TFM (N=36) HCT. Eligibility criteria for TFM were age > 50 years of age or compromised organ function (COF); high-risk remission or marrow blasts ≤10%. TFM patients were matched to a set of FM patients based on age, gender, diagnosis and disease risk (low, intermediate, high). All patients received FM with fludarabine 25 mg/m2/d × 5 days and melphalan140 mg/m2/d × 1 day, and TMI was delivered at 150cGy/fraction in 8 fractions over 4 days in the TFM group. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines for both groups.

Results:
Demographic characteristics were similar, including gender (20 females, 55.6%) and age (median 58 years, range: 22–68 in TFM and 20–68 in FM). The proportions of patients by diagnoses were similar: AML (n=27), ALL (n=7), MDS (n=2). Disease risk assignments in both groups were: Low risk (n=15), intermediate (n=6), high (n=15). There were 15 and 13 pts with active disease in FM and TFM, respectively. HLA-identical siblings (n=16, 44.4%) or matched unrelated donor (n=20, 55.6%) were used in each group. Outcomes are reported for the TFM and FM recipients, respectively as follows: myeloid recovery was documented on day 13.5 (9–24) and 15 (8–20). Transplant-related toxicities were limited to grade 3 or less in both groups. The most common grade 3 toxicities were: mucositis, n=9 and n=7 and bacterial infection, n=10 and n=11, respectively. Acute GvHD grade II-IV occurred in 20 pts (55%) and 19 (53%). Extensive chronic GVHD was documented in 24 (67%) and 20 (56%) pts. Twenty-one and 18 patients are alive at a median of 30.2 months and 35.3 months in the TFM and FM, respectively. The relapse cumulative incidence at 2 years post HCT was 11.1% (TFM) compared to 30.6% (FM) (p=0.06) (insert ). With a median follow-up of 31.7 months (4.1 – 62.5) for alive patients, the 2-year overall and progression-free survival estimates are 57.2 % (95% CI, 46.6–66.4) -TFM, and 62.8% (95% CI, 51.8–72.0) -FM, and 57.7% (95% CI, 47.2–67.0) -TFM, and 48.5% (95% CI, 40.2–56.3) -FM, respectively.

Conclusion:
The addition of TMI at a dose of 1200 cGy to FM is safe and tolerable and may decrease the risk of relapse related mortality.

Disclosures:
No relevant conflicts of interest to declare.
Recombinant B-Domain Deleted Porcine Factor VIII (OBI-1) Safety and Efficacy in the Treatment of Acquired Hemophilia A: Interim Results.
Authors: Louis Jean St. , Kruse-Jarres Rebecca , Greist Anne , Shapiro Amy D. , Smith Hedy , Drebes Anja B , Lozier Jay N. , Gomperts Edward D. 
Published: October 2019

Abstract
Abstract 2224

Introduction
OBI-1 is an investigational B-domain deleted recombinant porcine factor VIII (FVIII) with low cross-reactivity to anti-human FVIII antibodies. Acquired hemophilia A (AHA) is caused by autoantibodies (inhibitors) against human FVIII. Patients are predominantly elderly and have co-morbidities. Current pharmacologic treatment of bleeds is guided by clinical assessment alone as there is no laboratory surrogate for efficacy. Importantly, OBI-1 efficacy can be monitored by FVIII levels in addition to clinical assessment.

Methods
Accur8 Auto-antibody trial (NCT01178294) is a prospective, open label, Phase 2/3 study. The primary objective is to evaluate efficacy of OBI-1 treatment for serious (life- or limb-threatening) bleeds in patients ≥18 years with AHA. FVIII levels are obtained before and within 10–20 min following initial OBI-1 dose (200U/kg) and at 2–3 h. Additional OBI-1 doses (≤400U/kg every 2–3 h) are administered to achieve target FVIII levels. The primary efficacy outcome is the control of bleeding 24 h after starting OBI-1.

Results
As of July, 2012, fifteen patients with severe bleeds were entered into the trial along with one individual treated under compassionate use and all had successful control of hemorrhage at 24 h and subsequent resolution of the bleed. Therapeutic FVIII activity levels were achieved and maintained with intermittent
OBI-1 administration based on FVIII levels. Six serious adverse events were reported including four deaths after treatment was discontinued, all being unrelated to OBI-1 as determined by the investigators. Antibodies to OBI-1 developed in two subjects indicated with an * in the table below. However, both responded toOBI-1.

Conclusions
These interim results provide support for the safety and efficacy of OBI-1 in the treatment of serious bleeding episodes in AHA. Additional confirming data could establish OBI-1 as a useful treatment option for AHA.

Disclosures:
St. Louis: Inspiration Biopharmaceuticals Inc: Research Funding. Kruse-Jarres:Inspiration Biopharmaceiticals Inc: Research Funding. Greist:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Research Funding. Smith:Inspiration Biopharmaceuticals Inc: Research Funding. Drebes:Inspiration Biopharmaceuticals Inc: Research Funding. Gomperts:Inspiration Biopharmaceuticals Inc: Consultancy.
Recombinant Human Soluble Thrombomodulin Safely and Effectively Rescues Acute Promyelocytic Leukemia Patients From Disseminated Intravascular Coagulation.
Authors: Ikezoe Takayuki , Takeuchi Asako , Kim Tsukie , Akabuki Kazuki , Sakai Mizu , Taniguchi Ayuko , Togitani Tazuto , Yokoyama Akihito 
Published: October 2019

Abstract
Abstract 2226
Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) with a high mortality rate, mostly attributable to intracranial hemorrhage caused by disseminated intravascular coagulation (DIC). Almost all patients with APL develop DIC. The introduction of all-trans retinoic acid (ATRA) into the induction chemotherapy regimen has revolutionized the treatment of individuals with APL, with nearly 90% of newly diagnosed APL patients achieving complete remission and over 70% of patients surviving longer than 5 years. However, population-based studies have shown that the early death-rate during induction chemotherapy remains extremely high with nearly 30% incidence and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required.
Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of TM, and inactivates coagulation. A phase III trial comparing efficacy and safety between rTM and low-dose heparin showed that rTM significantly improved DIC associated with hematological malignancies or infections. This clinical trial excluded almost all patients with APL, because concomitant use of ATRA was prohibited. The use of rTM for the treatment of DIC was approved in Japan in be 2008.
In this study, we treated individuals for DIC caused by APL (n=9) using rTM in combination with ATRA and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Percentage change of FDP and change of fibrinogen were significantly higher in the rTM group than the control group (repeated measures ANOVA, p=0.041 and p=0.045, respectively). Interestingly, treatment with rTM significantly reduced the transfusion units of FFP required to maintain plasma levels of fibrinogen above 150 mg/dl (0.63 ± 0.93 U/d vs. 4.3 ± 1.6 U/d, p=0.001). Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL.

Disclosures:
No relevant conflicts of interest to declare.