bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher TRAF6 and Fbxo 3 Expression Is With Progressive Multiple Myeloma and Blockage Of TRAF6 Inhibits Tumor Growth and Bone Resorption
Authors: Li Mingjie , Vardanyan Suzie , Gottlieb Jillian , Wang Cathy , Delijani Kevin , Halleluyan Ran , Ben-Zvi Joseph , Song Mitchell , Sanchez Eric , Bonavida Benjamin , Chen Haiming , Berenson James R. 
Published: October 2019

Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been implicated in regulating the NF-kB and JNK signal transduction pathways; and, thus, is likely to promote tumor cell proliferation and osteoclast formation. F-box proteins such as the E3 ligase component Fbxo3 and another F-box family member Fbxl 2, regulate TRAF protein signaling.
First, we investigated TRAF6 expression in bone marrow mononuclear cells (BMMCs) from multiple myeloma (MM) patients with progressive disease or in remission and healthy subjects. The results showed higher TRAF6 protein expression among MM patients with progressive disease than among those in remission or healthy subjects. Notably, changes in TRAF6 protein expression in MM BMMCs were found to correlate with response of individual patients to treatment with the proteasome inhibitors bortezomib or carfilzomib. We have previously reported inhibition of MM cell proliferation and increase of apoptosis through regulation of the NF-kB and JNK pathways using a silencing TRAF6 C-domain mRNA construct. In this study, we cloned a 167 amino acid (in residues 333 to 508) portion of the TRAF6 dominant negative (TRAF6dn) and synthesized decoy peptides of the TRAF6 interaction domain with CD40 and the TRAF6-RANK binding domain. Decreases in cell proliferation and increase in cell apoptosis in MM BMMCs treated with TRAF6dn occurred in a concentrationdependent fashion. We also found TRAF6dn markedly inhibited osteoclast cell formation of monocytes induced by RANKL and mCSF in a dose-dependent manner. Next, we examined the effect of TRAF6dn on NF-kB and JNK by determining phosphorylation of JUN kinase kinase (JNKK), which activates the MAP kinase homologues SAPK and JNK in response to IL-1 receptor stimulation. MM BMMCs exposed to the TRAF6dn fragment or TRAF6 decoy peptide showed reduced phosphoNF-kB protein and phosphorylation of JNKK. These studies suggest that the TRAF6dn or combined TRAF6 decoy and CD40 decoy peptide may be excellent agents to block both MM cell growth and osteoclast formation in MM.
We further investigated the protein expression of Fbxo 3, Fbxl 2 and TRAF6 in fresh BMMCs from MM patients with progressive disease or in remission. Results of Western blot analysis showed protein expression of Fbxo 3 and TRAF6 was increased and Fbxl 2 was decreased among patients with progressive disease compared to patients in remission.
Thus, these results may offer a new mechanism through which MM tumor cells are regulated and provide a new therapeutic approach to treat MM and reduce the clinical consequences resulting from enhanced bone loss that commonly occur in these patients.

Disclosures:
No relevant conflicts of interest to declare.
Regulatory T Cells Preserve Anti-Viral Immunity While Preventing Lethal Graft-Versus-Host Disease
Authors: Winkler Thomas H. , Seefried Martina , Kroeger Irena , Hoffmann Petra , Edinger Matthias , Ullrich Evelyn , Mach Michael 
Published: October 2019

Abstract
Graft-versus-host disease (GvHD) is a frequent and life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is therefore one of the main factors that limits the broad application of HSCT. Over the last decades, several studies have reported a clinical association between GvHD and reactivation of cytomegalovirus (CMV). Using a lethal murine GvHD model with major MHC mismatch (C57BL/6 -> Balb/c), we were able to demonstrate that recipients latently infected with murine CMV (MCMV) before transplantation showed recurrence of CMV infection concomitant with the manifestation of GvHD. Moreover, these preinfected recipients showed an accelerated mortality compared to recipients that were not preinfected. The therapeutic co-infusion of CD4+CD25+ regulatory T cells (Tregs) with conventional T cells (Tcons) prevented lethal GvHD in preinfected mice and, markedly reduced the recurrence of MCMV infection. Remarkably, these mice showed clearance of MCMV 5 weeks post transplantation in contrast to mice receiving only Tcons in which massive virus infection persisted. Enhanced reconstitution of T lymphocytes and establishment of an anti-MCMV antibody titer from donor B cells in these animals suggest that CD4+CD25+ Tregs do not interfere with an anti-viral response while suppressing Tcon-mediated GvHD. Therefore, our study revealed that the suppressive function of CD4+CD25+ Tregs is not affected by CMV reactivation and more importantly, that Tregs do not adversely affect the anti-viral immunity in the recipient. In sum, these results provide important information on the correlation of GvHD and CMV reactivation and underline the possible clinical benefit of Treg application in GvHD patients.

Disclosures:
No relevant conflicts of interest to declare.
Mobilization Scheme With Cytarabine In Poor Mobilizers Patients Diagnosed With Lymphoma
Authors: Calderón-Cabrera Cristina , González Magdalena Carmona , Martín Jesús , Herranz Eduardo Ríos , Novella Pilar Noguerol , De la Cruz Fátima , Carrillo Estrella , Espigado Ildefonso , Pérez-Simón Jose Antonio 
Published: October 2019

Abstract

Introduction
Mobilization regimens for hematopoietic stem cell transplantation have not undergone major changes except for the introduction of new drugs such as plerixafor. However, in patients receiving multiple lines of treatment, to obtain a suitable amount of hematopoietic progenitors (PH) is often difficult even with the addition of new drugs. We present our experience with a protocol of mobilization for poor mobilizer patients based on the use of cytarabine.

Material and Methods
From a total of 111 patients diagnosed with lymphoma who underwent autologous hematopoietic progenitors in our center from January 2005 to March 2013, 32 patients (35% of total) with previous mobilization failure, received cytarabine 400 mg/m2 /day x3 days + G-CSF (filgrastim or lenograstim) 10-16 mg /kg/day from day 7 to the end of collection. Cell blood cound and CD34 assays in peripheral blood were performed from day +11 postchemotherapy, and apheresis was started when CD34 > 10 x10e6/L.

Results
30 patients had non-Hodgkin lymphoma (NHL) (13 diffuse large B-cell lymphoma, 7 mantle cell lymphoma, 5 follicular lymphoma, 2 MALT lymphoma, 1 angioimmunoblastic lymphoma, 2 cutaneous lymphomas) and 2 Hodgkin's lymphoma (HL). Median age was 49 years (range 27-67). Median number of treatment lines prior to mobilization was 3 (1-5). In all 30 patients with NHL, an adequate amount of CD34 + cells was obtained. Only one patient with HL, who had previously received 5 lines of chemotherapy, did not mobilize. The average time from the end of chemotherapy to start of apheresis was 13.7 days (12-20). The average number of CD34 + cells circulating the starting day of apheresis was 41/μL (11-109). The mean of apheresis performed was 1.8 (1-3) with an average amount of CD34 obtained of 4.69 x10e6/kg (1.5-6.8). All patients received outpatient treatment and only 2 required hospitalization: one for short-term neutropenic fever and another due to a limited cutaneous hemorrhage during the neutropenia phase. All patients were transplanted without incidence and successfully engrafted. None required G-CSF early postransplant.

Conclusions
Mobilization with intermediate-dose cytarabine has proven to be a cost-effective regimen in lymphoma patients with prior mobilization failure.

Disclosures:
No relevant conflicts of interest to declare.
A Retrospective Analysis Of The Association Between Common Myeloablative Conditioning Regimens and Hepatotoxicity
Authors: Patel Rushang D. , Klumpp Thomas R. , Martin Mary Ellen , Kropf Patricia , Fasan Omotayo O. , Mangan Kenneth F. 
Published: October 2019

Abstract
High dose chemotherapy preceding stem cell transplant carries considerable risk of organ toxicity. Hepatic toxicity is one of the major causes of morbidity post transplant. The etiology is multi-factorial, with the common culprits being graft versus host disease as well as the agents used as part of the conditioning regimen. Evidence of pre-existing mild hepatic insufficiency demands an even more cautious approach while selecting a conditioning regimen prior to stem cell transplant. We analyzed the effect of various myeloablative conditioning regimens on post transplant liver function tests (LFT). CEP (cyclophosphamide, etoposide and cisplatin), BuCy (busulfan and cyclophosphamide), BEAM (carmustine, etoposide, cytarabine and melphalan) and Cy/TBI (cyclophosphamide with total body irradiation) were the four most commonly used regimens for autologous stem cell transplant (auto-SCT) at our center. A total of 404 patients were treated with CEP (210), BuCy (76), CyTBI (71) or BEAM (47) from 1988 to 2013. The majority of the patients underwent an auto-SCT for lymphoma (218 non-Hodgkin lymphoma, 98 Hodgkin’s lymphoma), while 67 transplant patients had leukemia. Patient age ranged from 17 to 73 years at the time of transplant, and the sex distribution revealed a male:female ratio of 1.5:1. We looked at the incidence of total bilirubin greater than 2 mg/dl, alkaline phosphatase greater than upper limit of normal, ALT greater than 126 U/L and AST greater than 82 U/L. The outcome of univariate analysis using chi-square test demonstrated statistically significant inter-group variability for three of the LFTs. CyTBI had the lowest incidence of hepatic insufficiency. Further analysis comparing CyTBI to the other three regimens, confirmed a highly significant statistical difference (p<0.01 by two-sided Fisher’s Exact test, see table below) in elevation of bilirubin, alkaline phosphatase as well as both the transaminases, favoring Cy/TBI as the safer regimen. This is an interesting finding given the common perception that TBI-based regimens are more toxic.CEP, BuCy and BEAMCy/TBIaffected/total (%)affected/total (%)p-valueTotal Bilirubin (≥ 2 mg/dl)27/263 (10.2 %)0/59 (0 %)0.007Alkaline Phosphatase (≥ upper limit of normal)97/262 (37 %)8/58 (13.7 %)0.0005ALT (≥ 126 U/L)39/263 (14.8 %)0/59 (0 %)0.0002AST (≥ 82 U/L)44/264 (16.7 %)2/59 (3.3 %)0.0065

Disclosures:
No relevant conflicts of interest to declare.
Impact Of Dysplasia On Outcome Of Patients With Acute Myeloid Leukemia and Response To Allogeneic Hematopoetic Stem Cell Transplantation
Authors: Farhan Shatha , Carroll Catherine , Pelland Danielle , Velasco Jose Carlos , Wautelet Susan , Ruemenapp Kenneth , Janakiraman Suseela M , Kuriakose Philip , Peres Edward , Janakiraman Nalini 
Published: October 2019

Abstract

Background
Myelodysplastic syndromes (MDS) are a heterogeneous group of malignancies characterized by dysplasia, cytopenia, ineffective hematopoiesis and by an increased risk of transformation to acute myeloid leukemia (AML). Recurrent aberrant karyotypes cannot entirely account for the genetic defects that are at the basis of the pathogenesis of MDS, as they are detected only in approximately 50% of patients.
Allogeneic hematopoietic cell transplantation (HCT) likely prolongs survival in patients with AML and MDS. In this report, we evaluated the impact of presence of dyspoesis in paients with AML with or without cytogenetic (CG) abnormality on outcome in our center.

Methods
We retrospectively reviewed all patients who were diagnosed with AML (non promyelocytic) in our center between 2002 and 2012. Primary objective was to study the impact of MDS with or without CG abnormalities on outcome of patients with AML. Demographics and disease-related variables were collected. OS was defined as the time from diagnosis to the time of death or last contact.

Results
Between 2002 and 2012, 123 patients with high or intermediate risk AML patients were treated at our center. Median age at diagnosis was 60 (range 19-89). Median OS for all patients was 368 days. Of 123 patients, 51 had MDS while 73 did not. CG abnormalities were present in 35 (68%) of patients with dyspoetic changes. Median age of AML patients with MDS was 59 while median age of AML without MDS patients was 55. Median number of blasts in bone marrow and peripheral blood in AML patients with MDS was 38% and 6% respectively. While median number of blasts in bone marrow and peripheral blood in AML patients without MDS was 67% and 39% respectively. Of 51 AML patients with MDS, 14 received HCT with median age of 56. Half of these received myeloablative regimen while the other half received reduced toxicity regimen.
The median survival time for AML patients without MDS was 401 days while the median survival time for AML patients with MDS was 278 days (p = 0.0201), Fig1.
For AML with MDS who received HCT, the median survival time was 586 days while it was 164.5 days for AML patient with MDS who did not receive HCT (p = 0.0013), Fig2.

Conclusion
In this small cohort from a single center, the results suggest that AML patients with dyspoetic changes do have a worse prognosis despite having lower percentage of blasts in bone marrow or peripheral blood. This can be explained by what Walter et al reprted, using next-generation sequencing, that the proportion of neoplastic marrow cells is indistinguishable in MDS and secondary-AML even with myeloblast count of zero. HCT can be performed in those patients including older patients with promising results.

Disclosures:
No relevant conflicts of interest to declare.
Autopsy Analysis On Epidemiology and Site of Involvement Of Invasive Fungal Infections (IFI) In Hematological Malignancies : A Retrospective Study at Hematologic Tertiary Care Department
Authors: Chierichini Anna , Monardo Francesca , Anaclerico Barbara , Borza Paola Anticoli , Bongarzoni Velia , Campagna Domenico , Cedrone Michele , Fenu Susanna , Norata Marianna , Paoloni Francesca , Ronci Benedetto , Annino Luciana 
Published: October 2019

Abstract

Background
Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be useful to monitor the local epidemiology ,the frequency and the disease patterns.

Aim
The aim of this retrospective analysis is to determinate the local epidemiology and the prevalence at autopsy of IFI, occurring in hematological malignancies at a single center over a eleven years period.

Methods
We have retrospectively reviewed 161 patients – median age 62,5 yrs, range 22 -83 - with hematological malignancies, who underwent autopsy between 2002 -2012. Acute Myeloid Leukemia (AML) were 77, Acute Lymphoid Leukemia (ALL) 11, Lymphoproliferative disorders (LPD) 56 and other disorders 17. Acute leukemia pts received systemic antifungal prophilaxis, whereas the others not absorbable prophilaxis. None patients received transplant procedures. An experienced pathologist evaluated the organ involvement and the IFI pathologic pattern. Fisher’s Exact test was used to recognize the IFI prevalence, the main occurring pathogens and the involved site; a p-value of <0.05 was considered statistically significant.

Results
The analysis of 161 consecutive autopsies identified 40 pts.(25%)resulting to have IFI; of these, 22 were AML (55%) ,6 ALL (15%),11LPD (28%) and 1 other. Aspergillus spp. infection was detected in 20 cases (50%), Mucor spp in 8 (20%) and Candida spp. in 12 (30%). Moulds were prevalent in acute leukemia pts. and Aspergillus spp. is the leading pathogen with respect to Candida and Mucor spp. (p 0,0396),with a statistically significant prevalence in ALL (p 0,0186).The site more involved resulted lung (p 0.0002). Whereas the standardized EORTC/MSG criteria applied in vivo were conclusive for IFI in 6 pts ( 15%) only, the postmortem findings revealed fungal infections in further 34 pts (85%).

Conclusion
This analysis confirms that the IFI diagnosis is still an unresolved issue in hematological malignancies. Acute leukemias remain the subset with the higher prevalence of mould infections. As in other largest studies, in our experience Aspergillus spp and lung proved to be the most recurrent pathogen and site of involvement. At now, the diagnostic methods are not still completely able to identify the underlying IFI, thus the autopsy rate should be increased to achieve a better knowledge of epidemiology and to critically review previous misdiagnosis.

Disclosures:
No relevant conflicts of interest to declare.
Synergism Between HOXA9 and Mutant JAK3 (M511I) Leads to Rapid Leukemia Development within an in Vivo Murine Bone Marrow Transplant Model
Authors: de Bock Charles E , Degryse Sandrine , Demeyer Sofie , Sweron Bram , Gielen Olga , Mentens Nicole , Geerdens Ellen , Cools Jan 
Published: October 2019

Abstract
Activation mutations in JAK3 occur in 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases, and co-occur frequently with HOXA cluster rearrangement. Genomic rearrangement of the HOXA cluster results in increased expression of HOXA9 and HOXA10. However it remains unclear if either HOXA9 or HOXA10 can cooperate with activating JAK3 mutations during oncogenic transformation and leukemogenesis. We have previously shown that JAK3 mutations lead to cell transformation and cause a long latency T-ALL in vivo using a mouse bone marrow transplant model. In this study we demonstrate that co-expression of the activating JAK3(M511I) protein with HOXA9 cooperate to develop leukemia within 30 days of transplant using an in vivo bone marrow transplant model. In our cooperative model, murine hematopoietic stem / progenitor cells were co-transduced with either both retroviral vectors encoding JAK3(M511I)/GFP and HOXA9/mCherry or each individually and then injected into sub-lethally irradiated recipient mice. Mice transplanted with bone marrow cells expressing JAK3(M511I) mutant alone developed T-ALL in 120 to 150 days. In sharp contrast, mice transplanted with cells expressing both JAK3(M511I) and HOXA9 showed rapid leukemia development within 30 days after transplant. Leukemia development was characterized by the rapid and specific increase in GFP-mCherry double positive cells. These animals showed high WBC, and splenomegaly and accumulation of immature CD8 single positive cells in the thymus. Similar experiments with HOXA10 did not show cooperation suggesting that HOXA9 is the more important oncogene in HOXA rearranged leukemias when a JAK3 activating mutation is present. To determine the underlying genetic mechanism for cooperation between HOXA9 and JAK3(M511I) the single positive JAK3 and double positive JAK3/HOXA9 expressing cells were isolated from thymi of leukemic mice for both epigenomic profiling using ATAC-seq and gene expression profiling. These analyses identified genetic pathways activated by the co-expression of HOXA9 and JAK3(M511I) mutation and provide mechanistic insight into the synergistic interaction between these two factors in driving leukemia development. Treatment of the animals with a JAK kinase inhibitor resulted in delayed leukemia development, confirming that the leukemia cells remain sensitive to the JAK inhibitor. This mouse model provides insight in the cooperation between oncogenes in leukemia development and provides a model for the study of targeted agents in this setting.

Disclosures
No relevant conflicts of interest to declare.
Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML
Authors: Hasle Henrik , Abrahamsson Jonas , De Bont Evelina S , de Haas Valerie , De Moerloose Barbara , Forestier Erik , Ha Shau Yin , Heldrup Jesper , Jahnukainen Kirsi , Jónsson Ólafur G , Lausen Birgitte , Palle Josefine , Reedijk Ardine , Saks Kadri , Zeller Bernward 
Published: October 2019

Abstract
Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)(p13q22), CBFB–MYH11, are considered as favorable risk factors in AML with superior event-free survival (EFS) and overall survival (OS). However, within the AML protocol from the Nordic society of pediatric hematology/oncology (NOPHO) from 2004 we observed a decrease in EFS for t(8;21) AML.
Material. We analyzed all children with t(8;21) or inv(16) treated on NOPHO-AML 93 and NOPHO-AML 2004 from Denmark, Finland, Iceland, Norway, and Sweden from 1993 to 2013 and patients from countries later joining the NOPHO-AML 2004 protocol; Estonia (2004), Hong Kong (2007), Belgium and the Netherlands (2010). The choice of anthracycline during induction changed from two courses including doxorubicin (75 mg/m2 in each course), Dox-Dox, in the NOPHO-AML 93 to idarubicin (36 mg/m2) and mitoxantrone (30 mg/m2), Ida-Mitox, in NOPHO-AML 04. After the observation of a decrease in EFS in patients with t(8;21) in late 2010 it was recommended to give fludarabine, cytarabine, and DaunoXome (liposomal daunorubicin 180 mg/m2) as second induction to patients with t(8;21); Ida-DNX.
Results. From 1993 to 2013 a total of 90 children, median age 9.1 years range 1-16, with t(8;21) AML were treated with Dox-Dox (n=25), Ida-Mitox (n=41), and Ida-DNX (n=24). Hematopoietic stem cell transplantation was given to 10 patients (11%), mostly with sibling donors in the NOPHO-AML 93 protocol (n=7). A reduction of the 3-year EFS was noted in patients treated with Ida-Mitox (41%) compared with Dox-Dox (64%). Those treated with Ida-DNX had significantly higher 3-year EFS of 87% (Figure). The events in t(8;21) AML on Ida-Mitox were relapses (n=20), death in CR1 (n=2), and secondary malignancy (n=2). The salvage rate for relapsed t(8;21) patients remained high and the overall favorable OS did not change significantly (Figure). From 1993 to 2013 a total of 58 children with inv(16) AML were treated with Dox-Dox (n=18) and Ida-Mitox (n=40). No significant changes in EFS (72% vs. 65%) or OS (89% vs. 79%) were observed for patients with inv(16).
Conclusion. Despite the overall favorable survival in t(8;21) the present study suggests that the choice of anthracycline during induction may be of major importance for the EFS in t(8;21) AML. Idarubicin and mitoxantrone during induction was associated with an inferior EFS compared with doxorubicin in t(8;21) AML. DaunoXome combined with fludarabine and cytarabine seemed to be particular effective during induction therapy in t(8;21) AML.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.