bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health Outcomes and Costs of Rituximab in Combination with Cyclophosphamide, Vincristine and Prednisolone in the Treatment of Patients with Advanced Follicular Lymphoma in Portugal.
Authors: Braga Paula , Carvalho Susana , Gomes Marília , Guerra Lurdes , Lúcio Paulo , Marques Herlander , Negreiro Filipa , Pereira Catarina , Silva Catarina , Teixeira Adriana 
Published: October 2019

Abstract
Abstract 2481
Poster Board II-458

Objective:
With the pressure on healthcare budgets, it has become increasingly important for healthcare decision makers to consider the value for money of the treatments they reimburse. The objective of this analysis was to evaluate the long term outcomes and costs of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP) versus CVP alone, in previously untreated patients with indolent Non-Hodgkin Lymphoma (NHL) from the Portuguese National Health System (NHS) perspective.

Methods:
Cost-effectiveness (Life Years Gained - LYG) and cost-utility analysis (Quality Adjusted Life years – QALYs) were performed for a time horizon of 10 years, according to a Markov economic model with three health states (“progression free survival”, “progression” and “death”) and monthly cycles for a population of previously untreated patients with indolent NHL. Data from a phase III clinical trial (Marcus 2007) was used and expanded to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a study in the UK performed in patients with follicular lymphoma. Resource consumption was estimated by a Portuguese expert panel (Delbecq Panel). Costs were calculated from the Portuguese NHS perspective through official data with prices updated to 2008. Only direct medical costs were considered. Costs and clinical outcomes were discounted at 5% per annum. Deterministic and probabilistic sensitivity analysis were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis.

Results:
The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€ 85,838) in comparison with R-CVP (€ 87,774). Life expectancy and quality-adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) than with CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 (8.7 months) in QALYs gained. The incremental cost per LYG was € 2,407 and the incremental cost per QALY gained was € 2,661. The probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results.

Conclusions:
This study demonstrates that the combination R-CVP in previously untreated non-Hodgkin lymphoma patients improves life expectancy and is a cost-effective alternative to CVP in Portugal.

Disclosures:
Braga: Roche Farmacêutica Química, Lda: Employment. Pereira:Roche Farmacêutica Química, Lda.: Employment.
Quality of Life in Non-Hodgkin Lymphoma: A Comparison Between Survivors of Indolent and Aggressive Disease.
Authors: Blaes Anne Hudson , Ma Linan , Peterson Bruce A. 
Published: October 2019

Abstract
Abstract 2494
Poster Board II-471

Introduction:
Few studies have examined the functional limitations, physical health, mental health, and general quality of life in cancer survivors with various types of non-Hodgkin lymphoma (NHL). Patients with aggressive NHL (AGG) require immediate chemotherapy for a potentially curable disease in contrast to patients with indolent NHL (IND) that is characterized by a chronic course with repeated relapses and progression despite therapy. This study examined the QOL in adult survivors of NHL >1 year from diagnosis and not currently on therapy; we hypothesized that fatigue and quality of life would be worse in patients with low grade NHL given the expectation of future progressive disease and repetition of multiple therapies.

Methods:
109 patients with NHL (58 AGG, 51 IND), more than one year from initial diagnosis, and at least three months from any active therapy, completed two health related quality of life assessments using the Medical Outcomes Study 36-Item Short-Form Healthy Survey (MOS SF-36) which assesses 8 subsets and 2 summary scores, and the Functional Assessment in Cancer Therapy – Fatigue (FACT-F). Physical and Mental SF-36 scores or FACT-F scores between IND and AGG were compared using a two sample t-test. Multiple linear regression* was performed to account for any potentially explanatory variables (age, use of chemotherapy, time from last treatment to survey).

Results:
Median age was 60 years [61 years (33-88) IND and 57 years (22-90) AGG]. 48.6% were female (52.9% IND, 44.8% AGG). 74.3% were in complete remission at the time of the survey (52.9% IND, 93.1% AGG) (p<0.001). 70.6% had received chemotherapy (43.1% IND, 94.8% AGG) and 55% had received immunotherapy (31.4% IND, 75.9% AGG). 17.6% of IND had received no therapy. The overall physical (PCS) and mental (MCS) component quality of life scores of the SF-36 did not differ between survivors with aggressive and indolent NHL; the median PCS was 51.8 (11.2-66.5) [56.8 IND, 51.4 AGG, p=0.192] and the median MCS was 54.2 (10.8-65.8) [54.6 IND, 53.3 AGG, p=0.239]. Examining the eight subcategories of the SF-36, physical function in survivors of IND was significantly better when compared with those of AGG NHL. Using the FACT-F, fatigue scores also did not differ between the two populations; the median FACT-F score was 45 (8-52) [47 IND, 43 AGG, p=0.114).

Conclusion:
While some other studies have reported a decreased quality of life in NHL survivors, our study reports a similar overall quality of life between survivors of IND and AGG NHL more than one year from initial diagnosis; this may be explained by a significant proportion of our IND patients having never received therapy or an acclimation to the need for future therapy. Physical function may be more impaired in survivors of AGG NHL and warrants further investigation.

Disclosures:
No relevant conflicts of interest to declare.
Statin Use Improves Overall Survival and Time to Treatment Failure in Patients with Primary CNS Lymphoma.
Authors: Ciminello Lauren , Toomey Christiana , Cobert Julien , Hochberg Fred H , Abramson Jeremy S. , Hochberg Ephraim 
Published: October 2019

Abstract
Abstract 2496
Poster Board II-473

Background:
HMG-CoA reductase inhibitors (statins) have been used to treat hypercholesterolemia and hyperlipidemia for over 20 years. Statins competitively inhibit HMG-CoA reductase thereby blocking the synthesis of mevalonate. They directly inhibit synthesis of steroid hormones and cholesterol but also indirectly inhibit prenylation and ubiqitination. As all currently marketed statins are lipophillic, with the exception of Pravachol (pravastatin), several therapeutic trials have attempted to exploit these indirect actions to treat both neoplastic (glioblastoma, anaplastic astrocytoma) and degenerative (Alzheimer's, Parkinson's) neurologic disease. We studied the impact of incidentally prescribed statins on high-risk patients with primary central nervous system diffuse large B cell lymphoma (PCNSL).

Methods:
We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, to identify all patients diagnosed with primary central nervous system lymphoma (PCNSL) between 1991 and 2007 (n=118). We excluded pediatric patients, patients who did not receive curative treatment and patients who failed to achieve a CR with initial therapy. Automated analysis of billing and medication administration records was used to identify the administration of statins to these patients. We compared the outcome of patients who were receiving statins to controls with PCNSL who did not receive statins. We excluded patients who did not receive statins within the time interval from 6 months prior to 2 years after their PCNSL diagnosis. As only a single statin pt was less than 50 we excluded all pts below this age from the cases and controls. All patients received high dose MTX based therapy. Overall survival (OS) was calculated from the date of first methotrexate.

Results:
Median age of statin patients was 66 yrs (range 52 – 76); median age of controls was 66 years (range 50 - 86). Nine patients were on atorvastatin, 9 were on simvastatin, 1 each were on pravastatin, rosuvastatin and fluvastatin. At a median follow-up of 47.5 months, concurrent statin therapy was associated with improved OS (62% vs. 37%)(p=0.04 Log-rank test). The median OS for all statin patients > 50 years old (n=21) was 60 months versus 37 months for all other patients > 50 years old (n=67) (p=<0.005 t-test two tailed).

Conclusions:
Concurrent prescription of HMG-CoA reductase inhibitors is associated with improved outcome in patients with high risk PCNSL compared to controls. Prospective controlled trials will be required to validate this observation.

Disclosures:
Hochberg: Amgen: Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Enzon: Speakers Bureau.
Treatment Does Not Correlate with Quality of Life in Children with Immune Thrombocytopenic Purpura: Results From the KIT International Cross-Cultural Validation Study.
Authors: Klaassen Robert , Grainger John D. , Riedlinger Arne , Blanchette Victor S. , Burke Tricia , Citrin Estela , Alvarez Gustavo Dufort y , Rachieru Petronella , Rakotonjanahary Josué , Gaedicke Gerhard , Wakefield Cindy D. , Young Nancy L. 
Published: October 2019

Abstract
Abstract 2501
Poster Board II-478

Introduction:
There is considerable controversy surrounding whether or not children with Immune Thrombocytopenic Purpura (ITP) should be treated if they present without bleeding. One of the potential benefits of treatment would be to improve the child's health-related quality of life (HRQoL).

Patients and Methods:
Variables including age, sex, type of ITP(acute versus chronic), treatment (observation, IVIG, Anti-D, and prednisone), platelet count and country of origin were analysed by multiple regression to determine their relationship to HRQoL as measured by the Kid's ITP Tools (KIT) child self-report version.

Results:
77 children from Uruguay (n=15), France (n=25), Germany (n=13) and the UK (n=24) self-completed the KIT. Mean platelet counts were: 6 for acute ITP patients (mean age 8.6 yrs) and 30 for chronic patients (mean age of 10.8 years). KIT scores by type of ITP and country are shown in the Figure. Multiple regression found that only the type of ITP (p=0.04) and the country of origin (p=0.029) were significantly associated with the KIT scores. Age, sex, platelet count and treatment were not correlated with KIT scores (p>0.16).

Conclusion:
The method of treatment did not have a significant impact on child-reported HRQoL. However, differences in HRQoL scores were found between acute and chronic groups and by country of origin.

Disclosures:
Klaassen: Cangene : Research Funding. Blanchette:Cangene: Research Funding. Young:Cangene: Research Funding.
Conditional Knockout of Sox4 Markedly Affects B Lymphopoiesis in Adult Mice.
Authors: Sun Baohua , Mallampati Saradhi , Gong Yun , Wang Donghai , You M. James , Amin Hesham M. , Ma Yupo , Rajewsky Klaus , Lefebvre Veronique , Sun Xiaoping 
Published: October 2019

Abstract
Abstract 2524
Poster Board II-501
B cells constitute an integral part of the immune system. The development of mature B cells from hematopoietic stem cells is a complex process that is regulated in a hierarchical order by various proteins, particularly transcription factors. Sox4 is a SRY-related HMG box containing transcription factor and is known to be involved in B cell development. However, the role of Sox4 in various stages of B cell development has not been systematically investigated. In this study we used a conditional knockout mouse strain and studied the effect of Sox4 deletion in B lymphopoiesis in adult mice. We crossed the Sox4-floxed mice with different Cre mouse strains that were expected to delete the floxed Sox4 gene at different B cell developmental stages. These Cre strains included Vav-iCre (expressed in hematopoietic stem cell stage, starting from early embryos), MX1-Cre (expression in hematopoietic stem cells, induced by pIpC injection in adults), MB1-Cre (expressed in B cells, starting from early progenitor cells in embryos), and CD21-Cre (expressed in mature B cells). We demonstrated that deletion of Sox4 caused an arrest of B lymphopoiesis at the transition from pre-pro-B cell (fraction A) stage to pro-B cell stage (fraction B): fraction A cells are slightly reduced in number whereas fraction B and later stage cells are nearly absent. The pre-pro-B cells from the Sox4 knockout mice retain a population of AA4.1+ cells, which are considered to be developed into B cells. Deletion of Sox4 in early embryonic stage (Vav-iCre) or in adults (Mx1-Cre) results in a similar phenotype on B lymphopoiesis, except that peritoneal B1 cells appear to be affected with Vav-iCre, but not with Mx1-Cre. MB1-Cre gave rise to similar results as did Vav-iCre, but the arrest was not as dramatic as with Vav-iCre. CD21-Cre produced no significant difference in B cell phenotype. These data suggested that Sox4 is required for early B cell development at the transition from pre-pro-B cells to pro-B cells and is not required for mature B cells. We are currently investigating the transcription program of this transcription factor in B cell development.

Disclosures:
No relevant conflicts of interest to declare.
A Recessive Embryonic Screen for Genes Regulating Hematopoietic Stem Cell and Blood Cell Generation and Function.
Authors: Papathanasiou Peter , Tunningley Robert , Pattabiraman Diwakar Ram , Ye Ping , Gonda Thomas J , Perkins Andrew Charles 
Published: October 2019

Abstract
Abstract 2527
Poster Board II-504
Identifying the genes that regulate the development, self-renewal and differentiation of stem cells is of vital importance for understanding normal organogenesis, tailoring tissue engineering for regenerative medicine, cellular reprogramming and cancer. A forward genetic screen for aberrant long-term hematopoietic stem cells and progenitors provides an unbiased and tractable approach to finding genes responsible for stem cell homeostasis and differentiation. Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome/mapping resources can identify genes essential for mammalian stem cells and blood development. A pilot flow cytometry-based recessive screen comprehensively analyzed nine subsets of hematopoietic stem, progenitor, and red cells in over one thousand mouse embryos at embryonic day (E) 14.5 from 34 pedigrees and recovered five strains with defects in early hematopoiesis. One mutant strain (Booreana - an Australian Aboriginal name meaning white) which has excess long-term hematopoietic stem cells and platelets but reduced myelo-erythroid progenitors was outcrossed and the genetic mutation mapped and identified as a novel mis-sense mutation in the transcription factor c-Myb. The mutation in the trans-activation domain (TA) completely ablates transcriptional activation in a reporter assay which contrasts with other TA domain mutants which are partly dysfunctional[TJG1] . Moreover, the Booreana (Boo) mutation completely abrogates interaction with the transcriptional co-activator, CBP. Boo/Boo homozygous mutant mice survive into adulthood, albeit with severe anemia and massively increased platelet counts, whereas c-Myb−/− mice die by E15.5 of development, suggesting c-Myb has essential functions in vivo which are independent of transcriptional activation. This ENU-generated mutation provides another allele of c-Myb with a phenotype in between the complete loss-of-function allele and previously identified mutant alleles from other ENU screens. ENU-generated point mutants such as the Booreana mutation can provide novel informative insights into key functional domains of proteins, and protein interactions and networks, which are missed in gene knockout mice. Other phenodeviants generated in our screen are currently being mapped and will be presented.
[TJG1]Not so in our hands, at least -– the Sandberg M303V is just as dead.

Disclosures:
No relevant conflicts of interest to declare.
Brain Imaginig in SCD Adults Patients: Correlation to TCD Image and Atoxic Contrast ( Microbubbles).
Authors: Bahia Paulo , Leite Ana , Veloso Orlando , Lobo Clarisse LOPES , Marcondes Jorge 
Published: October 2019

Abstract
Abstract 2555
Poster Board II-532

The purposes of this study were to evaluate the intracranial lesions in adults patients with sickle cell disease (SCD) using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). The patients were selected from the main hematological hospital of Rio de Janeiro state (HEMORIO). About 187 patients underwent neurological examination and Transcranial Doppler image (TCDi) with microbubbles. Eighty patients were chosen by an aleatory way to perform MRI and MRA, including those symptomatic and asymptomatic ones. MRI and the MRA were evaluated by two different neuroradiologists, in a blind way about the clinical aspects and TCD results. The middle age was 29 years and 81.3% of the patients had the homozygous form of the SCD. In the MRI, 50% of the patients showed intraparenchymatous lesions. Leukoencephalopathy was the most frequent abnormality in 47.5%, encephalomalacia in 16%, lacunar infarctation in 12.5% and atrophy in 12.5%. Of the encephalomalacia cases, the frontal and parietal lobes were the most affected in 85%. In the MRA study, 34% of the patients presented abnormalities, 26% with vascular stenosis and 19% with vascular occlusions. The anterior circulation was the most compromised in the stenotic cases and the carotid was the main affected artery in the occlusions cases. The silent lesions were observed in 45% of the MRI and 24% of the MRA. The prevalence of parenchymatous lesions and vascular stenosis in cases with genotype SS was significant. There was significant statistic relation between the leukoencefalophalopathy and the vascular stenosis with the medium basal hematocrit.

CONCLUSIONS:
The use of both methods (MRI and TCD image) demonstrated a powerful tool to study vascular lesions in SCD adults patients. The prevalence of silent infarcts in SCD adults patients was higher than previously estimated in literature (55%). This finding reinforces the prophylactic intervention study with TCD Imagining and prophylactic transfusion therapy in early stage of life.

Disclosures:
No relevant conflicts of interest to declare.
Relapsed Childhood High Hyperdiploid Acute Lymphoblastic Leukemia: Genome-Wide Screening Reveals the Presence of Preleukemic Ancestral Clones and the Secondary Nature of Microdeletions and RTK-RAS Mutations.
Authors: Davidsson Josef , Paulsson Kajsa , Lindgren David , Lilljebjörn Henrik , Chaplin Tracy , Forestier Erik , Andersen Mette K , Nordgren Ann , Rosenquist Richard , Fioretos Thoas , Young Bryan D , Johansson Bertil 
Published: October 2019

Abstract
Abstract 2591
Poster Board II-567
Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% relapse. This makes it important to identify these patients already at diagnosis to ensure proper risk-stratification. To identify changes associated with relapse and ascertain the genetic evolution patterns, SNP array and mutation analyses of FLT3, KRAS, NRAS, and PTPN11 were performed on 11 paired diagnostic/relapse samples. The “triples trisomies” +4, +10, and +17 were detected in 64%, a frequency similar to the one generally observed at diagnosis, thus questioning their favorable prognostic impact. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. Based on the genetic relationship between the paired samples, three groups were delineated: 1) identical genetic changes at diagnosis and relapse (18%), 2) clonal evolution with all changes at diagnosis being present at relapse (18%), and 3) clonal evolution with some changes conserved, lost or gained (64%), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern and perhaps necessary for overt leukemia.

Disclosures:
No relevant conflicts of interest to declare.
The AML Prognostic Marker, AF1q, Is Directly Regulated by MiR-29b.
Authors: Xiong Yin , Li Zejuan , Tan Aik Choon , Bemis Judson , Xie Xiuyan , Bunting Kevin D. , Chen Jianjun , Bemis Lynne , Tse William 
Published: October 2019

Abstract
Abstract 2603
Poster Board II-579
We have consistently shown that elevated expression of AF1q, an MLL fusion partner, is a poor prognostic biomarker for pediatric acute myeloid leukemia (AML), adult AML with normal cytogenetics (NC-AML), and adult myelodysplastic syndrome (MDS). However, the underlying mechanism of how AF1q is regulated in normal and abnormal hematopoiesis is still unclear. Our previous studies suggest that AF1q is highly regulated during hematopoietic cell differentiation and development and it is known that genes related to cell development and differentiation are likely to be regulated by various microRNAs. We used a variety of the web based programs to identify microRNA candidates that may potentially regulate AF1q based on the predicted targeting efficiency. We found the strongest predicted binder to the AF1q 3′untranslated region (3′UTR) was miR-29b, a member of the miR-29 family which has recently been characterized to regulate a member of the Bcl-2 family protein, Mcl-1 and other leukemia related oncogenes. We found that MiR-29b expression had a significantly inverse correlation (p<0.05) with AF1q expression in a cohort of more than 60 AML patients. This relationship is consistent with microRNA/AF1q regulation. In order to determine if miR-29b directly regulates AF1q, we chose H157 and SKMES1 lung cancer cell lines which were known to have high AF1q expression and high transfection efficiency to test if transfection of miR-29b into cells can suppress its endogenous AF1q expression. Our data showed that transfection of miR-29b into these two cell lines could indeed significantly suppress the AF1q expression both in H157 (p=0.001) and SKMES1 (p=0.004) cells. Then we wanted to determine if the miR-29b binding domain is specific in the AF1q 3′UTR region. Two reporter plasmids that contained the germline AF1q 3'UTR (GFP-A3U) and mutant AF1q 3′UTR in its microRNA binding site (GFP-A3U-Mutant) were constructed. We found that GFP readout was significantly suppressed in a stable transfection with native AF1q 3′UTR (GFP-A3U); in contrast, the GFP readout was not suppressed in a stable transfection with GFP-A3U-Mutant, suggesting that miR-29b is able to bind to the germline AF1q 3′UTR but not to the mutated 3′UTR (GFP-A3U-Mutant). These observations proved that miR-29b specifically regulates AF1q expression through its binding to the AF1q 3′UTR. Taking these observations together, we conclude that miR-29b directly regulates the leukemia associated gene AF1q. Elevated AF1q expression was found to have clinical significance in AML, thus, these findings warrant further investigation to determine if miR-29b will be able to serve as a prognostic biomarker for AML patients.

Disclosures:
No relevant conflicts of interest to declare.