bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome after Autologous Stem Cell Transplantation for Multiple Myeloma in Patients with Preceeding Plasma Cell Disorders.
Authors: Kumar Shaji , Dingli David , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis K. , Rajkumar S. Vincent , Litzow Mark R. , Gertz Morie A. 
Published: October 2019

Background: Nearly a third of patients with newly diagnosed myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or plasmacytoma. While high dose therapy improves survival in patients with myeloma, it is not clear if patients with preceding PCPD have a different outcome.
Methods and Results: We identified 151 patients with preceding PCPD from among 804 patients undergoing high dose therapy at our institution. These included 59 patients (7.3%) who had a preexisting diagnosis of MGUS, 88 (11%) patients, in whom the diagnosis of MM was preceded by SMM, including 23 patients who also had a preceding MGUS or plasmacytoma. In addition, 27 (3.4%) patients gave a preceding history of plasmacytoma. The median duration from the first diagnosis of a PCPD to that of myeloma was 32.4 months (range, 6.1 to 31 years), and was longer for patients with an initial diagnosis of MGUS compared to those with out preceding MGUS. While response rates including complete responses were generally similar between the two groups of patients, those with any preceding PCPD had a median TTP of 24.2 months (95% CI; 20, 28.3) compared to 17.3 (95% CI; 15.7, 18.8) months for those with no previous history (De novo Myeloma); p = 0.01 (Figure 1). The median OS from transplant for patients with previous history was 63.7 months (95% CI; 50.2, 77.4) compared to 48.3 months (95% CI; 39.7, 56.9) for the de novo group, p = 0.01 (Figure 2). These differences were most striking for those with a preceding diagnosis of MGUS; who had a longer time to progression (27.6 months vs. 17.7 months; p = 0.02), and longer OS from transplant (80.2 months vs. 49.3 months, p = 0.046) compared to those without any preceding MGUS. In a multivariate analysis, transplant within 12 months of diagnosis, lower serum M-protein at transplant, PCLI <1%, absence of cytogenetic abnormalities, achievement of CR, and presence of any preexisting monoclonal disorder prior to diagnosis of myeloma were independently prognostic for risk of post transplant relapse.
Conclusion: Patients with preexisting PCPD at the time of myeloma diagnosis undergoing HDT has a better outcome reflecting more indolent disease and a favorable biology than those presenting with de novo myeloma and no antecedent plasma cell dyscrasia.
Figure Figure Figure Figure
Polyclonal Hypergammaglobulinemia in a Randomized Sample of Ghanaian Adult Males.
Authors: Buadi Francis , Katzmann Jerry A. , Pfeiffer Ruth M. , Hsing Ann W. , Yeboah Edward D. , Biritwum Richard B. , Dispenzieri Angela , Kyle Robert , Rajkumar Vincent , Landgren Ola 
Published: October 2019

Abstract
Introduction Diffuse or polyclonal hypergammaglobulinemia has been associated with multiple medical conditions such as autoimmune diseases, infections, and chronic liver diseases. However, the possibility of differences in gamma globulin levels in different races and its association with environmental and socioeconomic factors is not well studied.
Method A randomized sample of 917 adult males (50–74 years) in an urban community in Ghana underwent in-person interview and health examination. Serum from all persons was analyzed by electrophoresis performed on agarose gel. Those found to have a monoclonal protein (n=54) were excluded from further analysis. Gamma globulin levels were measured in the remaining 863 samples. Associations between selected characteristics and gamma globulin levels were assessed by Chi-square test and logistic regression models.
Results The median gamma globulin level was 1.86 gm/dl. Seventy three percent of the study population had gamma globulin levels above the 1.6 gm/dl reference level and will be considered to have hypergammaglobulinemia. Surprisingly, 25% had gamma globulin levels above 2.17 gm/dl. In univariate analysis increased gamma globulin levels were associated with older age within the study population. Only 54% of the males aged 60 yrs or younger had gamma globulin levels above 1.6 gm/dl compared to 69% in those older than 60 yrs (p=0.007). Higher education level was associated with a low prevalence of hypergammaglobulinemia 51% compared with 74% in those with less than high school education (p <0.0001). Smoking was not associated (p=0.16) with gamma globulin levels. Although a higher proportion (71%) of people with history of alcohol use had hypergammaglobulinemia compared to the control (63%) this was not statistically significant (p=0.07). Self-reported history of genital warts, genital herpes and meningitis was associated with hypergammaglobulinemia, whereas syphilis, malaria, cholera, gonorrhea, hepatitis, measles and tuberculosis had no association with gamma globulin levels in univariate analysis.
Conclusion Three quarters of this randomized sample of Ghanaian adult males has hypergammaglobulinemia based on current laboratory definitions. More work is needed to uncover underlying causes for the observed high gamma globulin levels in this population. Further evaluation of a younger population with less environmental influence may help explain whether this is due to genetic differences, environmental exposures, or a combination.
MicroRNA Expression Contributes to Hypoxia-Inducible Factor-1a-Induced Differentiation of Myeloid Leukemic Cells.
Authors: He Ming , Zhang Bo , Yin Qianqian , Guo Meng , Zhao Qian , Chen Guo-Qiang 
Published: October 2019

Abstract
Abstract 1007
Poster Board I-29
In our previous study, we showed that the hypoxia or hypoxia-mimetic agents induces differentiation of myeloid leukemic cells. During this event, hypoxia-inducible factor-1a (HIF-1a) exerts a critical role in its transcriptional activity-independent manner. MicroRNAs (miRNAs) regulate the expression of 30% of the transcripts of human genome on a posttranscriptional level. Recent work on miRNA has shed light on the possible involvement of miRNA genes in biological processes such as cell proliferation, differentiation and hematopoiesis. To reveal the miRNA expression profile and related roles in HIF-1a-induced differentiation of myeloid leukemic cells, miRNA expression profiling was analyzed by microarray in HIF-1a-expressing U937T cells (U937Tclone) and HIF-1a-absent cells (U937Tempty) in 0 day, 2 days and 4 days after tetracycline removal. The differentially expressed miRNAs, as verified by quantitative real-time RT-PCR and Northern blot, were subjected to gene ontology (GO) analysis and pathway analysis. The upregulated and downregulated miRNAs in U937Tclone cells in three time points after tetracycline removal were 11 miRNAs and 7 miRNAs, respectively. The differential expression of miR-26a, -107, -19b, -20a, -17, -92a, -92b and -106a was validated. On the basis of bioinformatic analysis, we focused on the changed components of miRNA 17-92 cluster and miRNA 106a-92 cluster, mostly considered as oncomirs, which have the similar downregulated expression profile. The results showed that miR-17 was significantly depressed by 40% and 70% in 2 and 4 days after tetracycline removal in U937Tclone. And miR-20a was significantly depressed by 60% and 80%, respectively. High-enrichment GOs containing differentiation-related targeted genes and miRNA-gene networks revealed STAT3 as one of the highest degree of target genes, which was targeted by the three changed components of miR-17 family (miR-17, -20a and -106a). STAT3 protein was validated to be upregulated in U937Tclone after tetracycline removal by Western blot, and no fluctuation in STAT3 mRNA levels was observed, which may uncover the critical role of miR-17 family in the cell differentiation induced by HIF-1a. In summary, significantly different miRNA profiles were seen in U937Tclone cells as compared to U937Temptycells. The downregulation of the components of miRNA 17-92 and 106a-92 cluster may contribute to HIF-1a-induced myeloid leukemic cell differentiation by targeting STAT3 or other signaling pathways. Further functional study of these miRNAs will be carried out by overexpression and knockdown experiments. These data would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of acute myelogenous leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Differential Down-Regulation of RPL35a in Human Bone Marrow Progenitors Demonstrates a p53 Independent Mechanism Mediating the Diamond Blackfan Anemia Phenotype.
Authors: Caywood Emi , Farrar Jason E. , Lipton Jeffrey Michael , Arceci Robert J. 
Published: October 2019

Abstract
Abstract 1096
Poster Board I-118
We have previously reported the first known mutations in a gene that encodes a large ribosomal subunit protein, Rpl35a that are linked to Diamond Blackfan Anemia (DBA), a congenital pure red cell aplasia. We have demonstrated that down-regulation of RPL35a results in decreased cellular proliferation, increased apoptosis, impaired ribosomal RNA processing and defective ribosome biogenesis. In order to examine the mechanisms by which defects in RPL35a lead to the development of DBA, we have developed a lentiviral system containing shRNA to down-regulate RPL35a and RPS19, a gene encoding a small ribosomal protein known to be defective in about 25% of DBA cases. Defects in these cellular processes have been linked to disruption of cell cycle progression through activation of nucleolar associated regulatory mechanisms. Cell cycle analysis of the normal human bone marrow progenitors transduced with the specific shRNA demonstrates a G1 arrest when compared to cells transduced with a luciferase shRNA control construct. Similar findings were made in the p53-mutant cell line, TF-1. In contrast, cell cycle analysis of the p53-mutant UT-7/Epo cell line demonstrates a primarily G2/M arrest. To further investigate the mechanism of the cell cycle arrest in bone marrow progenitors, p53 expression was analyzed by Western Blot. Only a nearly complete knockdown resulted in increased p53 expression; shRNA affecting a haploinsufficient state had no evidence of increased p53 expression. However, clonogenic studies of human bone marrow progenitors transduced with shRNA constructs that approximate haploinsufficiency demonstrate a selective absence of erythroid colonies compared to myeloid colonies, thus mimicking the phenotype of DBA. In contrast, bone marrow progenitors transduced with shRNA that causes near complete absence of expression of RPL35a have neither myeloid nor erythroid clonogenic potential consistent with a stem cell catastrophe. These data may suggest a p53 independent pathway can mediate the effects of ribosomal protein deficiency in DBA as well as demonstrate a model for further understanding abnormalities in ribosomal proteins that result in an in vitro phenocopy of altered DBA hematopoiesis.

Disclosures
No relevant conflicts of interest to declare.
Exposure to Novel Agents Increases Post Relapse Survival in Patients with High Risk Myeloma Defined by Early Relapse (<12 months).
Authors: Venner Christopher P. , Connors Joseph M. , Sutherland Heather J. , Shepherd John D. , Hamata Linda , Mourad Yasser Abou , Barnett Michael J , Forrest Donna L. , Hogge Donna E. , Nantel Stephen H. , Narayanan Sujaatha , Nevill Thomas J. , Nitta Janet , Power Maryse M , Toze Cynthia L. , Smith Clayton , Song Kevin 
Published: October 2019

Abstract
Abstract 2872
Poster Board II-848

Intro:
Relapse within 12 months of stem cell transplant is an important clinically relevant prognostic factor predicting poor outcome for patients with multiple myeloma (MM). Little is known about the use of novel agents (NA) in this setting and their impact on survival. In British Columbia autologous stem cell transplantation (ASCT) as a part of initial treatment is the standard of care for patients who are eligible. The use of NA is largely restricted to the relapsed setting thus providing a large cohort of patients to assess the impact of these drugs.

Patients:
We reviewed our experience with 418 patients with MM treated with ASCT diagnosed between 1985 and 2008. 307 have relapsed. Although thalidomide was available starting in 1999, the other novel agents, bortezomib and lenalidomide, were not available until after 2004, permitting division into two groups before and after Dec 2004.

Methods:
The cohort was separated into four groups based upon year of relapse (pre and post 2004) and remission duration post ASCT. Early relapse was defined as recurrence within 12 months (m) of ASCT. Four groups were defined: Group A, late relapse after 2004 (n=138); B, early relapse after 2004 (n=70); C, late relapse before 2004 (n=58); D, early relapse before 2004 (n=41). We examined the impact of NA exposure on post relapse survival (PRS).

Results:
Median overall survival from diagnosis of myeloma of the whole cohort was 79.9 months (95% CI; 70, 89). Median PRS was 31.0m (95% CI; 25, 36). Exposure to novel agents conferred a better PRS (35.7m, 95% CI; 30, 42 vs. 9.1m, 95% CI; 4, 13; p < 0.001). Results comparing the various groups are summarized in table 1. Kaplan-Meier curves of the four groups are shown in figure 1.

Conclusion:
Post relapse survival for patients with MM treated with ASCT has improved with the introduction of novel agents. Although relapse within 12m of ASCT remains an important clinical prognostic factor predicting worse outcome, the introduction of bortezomib and lenalidomide after 2004 correlates with a 24 month improvement in post relapse survival in these patients.

Disclosures:
Connors: Roche Canada: Research Funding.
Recurrent Thromboembolism in a Tertiary Care Pediatric Center.
Authors: Rajpurkar Madhvi , Zia Ayesha N. , Sabo Cynthia , Thomas Ronald , Chitlur Meera B. , Frey Mary Jane , Lusher Jeanne M. 
Published: October 2019

Abstract
Abstract 2987
Poster Board II-963

Background:
Thrombosis in children, though rare, is being increasingly recognized in pediatric tertiary care centers. Most data on children have largely been extrapolated from adults. Comprehensive data about the incidence and risk factors for recurrence of pediatric thrombosis are scarce.

Aim:
1) To estimate the incidence of recurrence of thrombosis at a single pediatric tertiary care center and 2) To determine the risk factors for recurrent thrombosis in children.

Methods:
After local IRB approval, charts of patients (pts) with documented venous or arterial thrombosis admitted or referred to the hematology service from 2001-2008, were reviewed and pertinent data obtained. Data were analyzed using the 17.0 version of SPSS.

Results:
Preliminary analysis revealed 238 pts (ages 0-30 years) with 183 deep venous (DVT, 75%), 53 arterial (22%) and 2 combined (0.8%) episodes of thrombosis at initial presentation. Of the 183 pts with DVT there were 110 females, 128 males; of pts with arterial strokes there were 21 females, 32 males. Overall 11 pts (4.6%, 6 females, 5 males) had a recurrence, with 91% venous and 9% arterial. Three (27%; 2 females, 1 male) out of the 11 pts had a third recurrence, which were all venous. Sites for recurrence were lower extremity (82%), neck (9%) and thorax (9%).
Risk factors for recurrence were positive family history of DVT (7/11; 63.6%), elevation in factor VIII (5/11; 45.5%), proximal lower extremity thrombosis as primary site (5/11; 45.5%), obesity (4/11; 36.4%), the presence of PTTLA (4/11; 36.4%) and the presence of inflammatory bowel disease (27.3%). Heterozygous factor V Leiden and congenital AT III deficiency was present in one pt each (9%) with recurrence. Other congenital thrombophilia traits were not seen in patients with recurrent events. Interestingly, gender, duration of treatment and residual clot after treatment (partial resolution) were not significantly associated with risk of recurrence.

Conclusion:
Recurrent thrombosis is infrequent in children and a positive family history, elevated factor VIII, and other acquired factors such as obesity and inflammatory bowel disease were identified as risk factors for recurrence. Inherited thrombophilia and partial resolution of thrombosis were not associated with recurrence in this series of patients. Larger multi-center trials are needed to identify risk factors for recurrence in children. To our knowledge this is the first pediatric study that has systematically evaluated the incidence and risk factors associated with recurrent pediatric thrombosis.

Disclosures:
No relevant conflicts of interest to declare.
PAX5-PML Acts as a Dual Dominant-Negative Form of Both PAX5 and PML.
Authors: Kurahashi Shingo , Hayakawa Fumihiko , Miyata Yasuhiko , Minami Yosuke , Abe Akihiro , Naoe Tomoki 
Published: October 2019

Abstract
Abstract 3070
Poster Board III-7
PAX5 is a transcription factor expressed in B lymphoid lineage from pro-B cell to mature B cell, and is required for B-cell development and maintenance. De-regulated and reduced PAX5 activity has been implicated in B cell malignancies both in human disease and mouse models. Recently, approximately 30% of childhood and adult B cell acute lymphoblastic leukemia have aberrancies in PAX5 gene such as deletions, point mutations, or chromosomal translocations. Chromosomal translocation t(9;15)(p13;q24) was found in 2 cases of childhood acute lymphoblastic leukemia and resulted in an in-frame fusion of PAX5 to PML gene. PAX5 moiety of PAX5-PML retains its DNA binding domain but loses its transactivation domain suggesting PAX5-PML will be a dominant negative form of PAX5. PML is originally found as a fusion partner of RARαa in PML-RARαa, an oncoprotein found in acute promyeloid leukemia (APL), and is now thought to be a tumor suppressor and a pro-apoptotic factor. PML-RARαa dominant-negatively affects PML function by disrupting PML nuclear bodies (NBs) where PML exerts its function and gives APL cells survival advantage. These findings give rise a speculation that PAX5-PML not only causes differentiation block by transcriptional repression of PAX5 target genes but also confers a survival advantage by inhibition of PML function. However, no functional analysis has been done for PAX5-PML.
Here, we demonstrate that PAX5-PML had a dominant negative effect on both PAX5 and PML. PAX5-PML inhibited transcriptional activity of PAX5 in luciferase reporter assay. PAX5-PML expression also suppressed expression of CD19, one of the transcriptional targets of PAX5, in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA binding activity in electro mobility shift assay although it retains DNA binding domain of PAX5, suggesting that inhibition of PAX5 DNA binding by occupation of PAX5 binding sites would not be the mechanism for PAX5-PML to inhibit PAX5 transcriptional activity. On the other hand, co-expression of PAX5-PML inhibited PML sumoylation, an essential post-translational modification for PML to form NBs, and altered PML localization from NB pattern to diffuse nuclear pattern. Furthermore, treatment with arsenic trioxide, a therapeutic reagent for APL which induces enhancement of PML sumoylation, reconstitution of PML NBs, and apoptosis in APL cells, induced recovery of PML sumoylation and reconstitution of PML NBs also in cells expressing PAX5-PML. More importantly, arsenic trioxide treatment of PAX5-PML expressing HeLa cells, which showed resistance to PML dependent apoptosis, overcame anti-apoptotic effect of PAX5-PML. These data suggest the involvement of this fusion protein in the leukemogenesis of B-ALL in dual-dominant negative manner and the possibility that some cases of ALL can be treated with arsenic trioxide.

Disclosures
Naoe: Kyowa Hakko Kirin, Wyeth and Chugai: Research Funding.
A Prospective Study of Iron Overload in Patients Undergoing Ablative Stem Cell Transplantation.
Authors: Armand Philippe , Rhodes Joanna , Kim Haesook , Cutler Corey , Ho Vincent T. , Koreth John , Alyea Edwin P , Soiffer Robert J , Antin Joseph H 
Published: October 2019

Abstract
Abstract 3332
Poster Board III-220

Introduction
Iron overload is a recently recognized problem for patients undergoing hematopoietic stem cell transplantation (HSCT). Hyperferritinemia is common and is associated with significantly increased treatment-related mortality (TRM) and poorer overall survival after HSCT. However, serum ferritin may be a poor surrogate for total body iron burden, and no prospective study of parenchymal iron overload has yet been reported. We initiated a prospective study of adult patients with acute leukemia or myelodysplastic syndrome (MDS) undergoing myeloablative HSCT, in order to estimate the prevalence of iron overload in this population. We measured pre-HSCT serum ferritin, C-reactive protein (CRP), iron, total iron binding capacity, and genotyped patients for HFE mutations. All patients also underwent liver and cardiac MRI with measurement of T2*, from which liver iron content (LIC) and cardiac iron loading were inferred.

Results
41 of 45 planned patients have been enrolled to date. Median age was 46 years (range, 18-63). 24 patients had AML, 11 had ALL, and 6 had MDS. They had received a median of 2 prior chemotherapy courses (range, 0-6). Among the 39 patients with available transfusion history, the median number of prior RBC transfusions was 19 (range, 0-59). 88% of patients had a pre-HSCT serum ferritin above normal; the median value was 1432 (range, 20-6989). Higher ferritin values were associated with more advanced disease stage, number of prior chemotherapy regimens, and number of transfusions. The median LIC was 3 g/g dry weight (g/gdw) (range, 0.6-12.9). 85% of patients had an LIC above the upper limit of normal (1.8 g/gdw), and 17% had an LIC above 7 g/gdw. Only 1 patient had cardiac iron overload (cardiac T2*<20 msec). Pre-HSCT LIC correlated best with serum ferritin (r=0.7), although it also correlated with transfusion history (r=0.56) and with transferrin saturation (r=0.50). The correlation improved further (r=0.76) when ferritin was divided by log(CRP), when CRP was above normal (see Figure).
Median follow-up after HSCT is 4.5 months (range, 0.2-13.5), precluding full analysis of clinical outcomes at this point.

Conclusion
Hepatic iron overload is very common in patients with acute leukemia or MDS undergoing HSCT, and is strongly correlated with transfusion history. Cardiac iron overload is rare. Pre-HSCT serum ferritin, adjusted for CRP, is a good surrogate marker for hepatic iron overload. This close relationship lends support to prior studies that used serum ferritin to assess the impact of pre-HSCT iron overload on transplantation outcome. Moreover, it provides the basis for the assessment of iron chelation strategies to reduce TRM.

Disclosures
Armand: Novartis: Consultancy, Research Funding.