bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Management of Cardiovascular Diseases in Patients with Hemophilia: The French Coche Registry
Authors: Guillet Benoit , Wibaut Benedicte , Falaise Céline , Lebreton Aurelien , Castet Sabine , Gautier Philippe , Claeyssens Ségolène , Schved Jean-François , Cayla Guillaume 
Published: October 2019

Abstract
Introduction: Over the last decades, life expectancy of patients with hemophilia (PWH) has significantly improved and therefore, age-related comorbidities like cardiovascular disease (CVD) are now common features. Using antithrombotic and antiplatelet agents, as needed for managing CVD, proves complex in PWH given that these drugs, along with the often required invasive procedures, interfere with hemostasis; general recommendations are not applicable as such.
Method: To collect data on current real-life practices in this patient population, the COCHE registry (COmorbidités Cardiovasculaires chez les patients HEmophiles) has been implemented back in July 2011. This French observational study sought to describe prospectively the management of CVD in PWH who require treatment with antiplatelet agents, antithrombotics, or both.
Results: By January 2018, this registry had prospectively included 67 PWH: 59 hemophilia A and 8 hemophilia B patients (47 mild, 10 moderate, and 10 severe), with a median age of 65±12.5 years. Overall, 52 patients were included for coronary artery disease (CAD) and 16 for atrial fibrillation (AF), with one patient presenting both CAD and AF. Among the 67 patients enrolled, 49 were receiving on-demand replacement therapy. Identified cardiovascular risk factors were arterial hypertension (n=44), overweight or obesity (n= 35), dyslipidemia (n=30; four tested positive for human immune deficiency virus [HIV]), smoking (n=17), family coronary disease history (n=11), non-insulin dependent diabetes mellitus (NIDDM) (n=11), and insulin dependent diabetes mellitus (IDDM) (n=3).
Conclusion: The proposals discussed herein are largely based on the experience we gained whilst managing PWH with CVD from the COCHE registry. To us, a multidisciplinary approach appears paramount.

Disclosures
Lebreton: Sobi: Consultancy, Research Funding.
Chromatin Organization By SATB1 Regulates HSP70 Induction in Early Erythropoiesis and Lost in Diamond Blackfan Anemia
Authors: Wilkes Mark C , Takasaki Kaoru , Youn Minyoung , Chae Hee-Don , Narla Anupama , Sakamoto Kathleen M. 
Published: October 2019

Abstract
Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome. The disease usually presents within the first year of life and is associated with anemia, congenital abnormalities, and an increased risk of developing cancer. The most prevalent mutations are found in the ribosomal protein RPS19, accounting for over 25% of cases but approximately 70% of DBA patients carry mutations in ribosomal genes. Downregulation of GATA1 has been attributed to the disease, but the upstream mechanisms leading to aberrant erythropoiesis is only beginning to be elucidated.
SATB1 is highly upregulated in lymphocytes (especially thymocytes) and steadily downregulated in all myeloid ineages during differentiation. However the more modest expression of SATB1 in early progenitors is required for self-renewal of HSCs and globin switching in early erythropoiesis. Using transcriptomics, we identified SATB1 expression is prematurely lost in RPS19-insufficient erythropoiesis and that over a third (16/42) of RPS19-sensitive early erythroid genes were rescued upon SATB1 re-expression. One of the most deregulated transcripts encode the chaperone HSP70.
GATA1 is an essential master regulator in erythroid differentiation and high GATA1 protein levels are required for efficient erythropoiesis. In DBA, GATA1 protein expression is drastically diminished. Two mechanisms contribute to this. At the translational level, GATA1 transcripts fail to be translated adequately due to ribosomal inefficiency at binding short, unstructured 5'UTRs. At the protein level,HSP70 loss leads to reduced GATA1 protein stability. During healthy erythropoiesis HSP70 genes are drastically upregulated (3.21, 4.18 and 1.37- fold) and this is lost in RPS19 insufficiency. Here we report that upregulation of HSP70 in healthy erythropoiesis requires SATB1. SATB1 binds to 3 sites within a 40kb region surrounding the HSP70 gene loci and recruits a distal predicted enhancer element to the proximal promoters via formation of two chromatin loops. During RPS19-insufficiency this chromatin organization is lost, but SATB1 re-expression restores chromatin looping and HSP70 expression, stabilizing GATA1 and promoting efficient erythropoiesis. As with HSP70, it is likely that permissive chromatin organization is essential for other RPS19-sensitive erythroid genes rescued by SATB1 re-expression.

Disclosures
No relevant conflicts of interest to declare.
Supplementation with Selenium As Prevention for the Development of Mucositis in Patients Undergoing HSCT. Results of a Pilot Study
Authors: Cantu Rodriguez Olga , Gomez-Almaguer David , Gutierrez Aguirre Cesar Homero , Mancias Consuelo , Tarín Arzaga Luz del Carmen , Gómez-De León Andrés , Herrera-Rojas Miguel , Garza-Ocañas Lourdes , Hawing Jose Angel 
Published: October 2019

Abstract
Introduction:
Numerous clinical trials have been conducted in order to reduce or prevent the appearance of mucositis in patients undergoing cancer treatment and some of these have appeared in the clinical guidelines as recommendations (Keefe,DM Cancer 2007). However, to date no molecule has been shown to prevent appearance of this kind of lesions. Selenium, a trace element in the organism, cofactor of multiple biological processes, has been used previously for mucositis chemoprevention in head and neck tumors. We conducted a study to know if selenium supplementation has an impact on the development of mucositis.
Objective:
We aim to know the impact of Selenium in patients undergoing hematopoietic stem cell transplantation, in the presentation and duration of mucositis comparing against placebo.
Methods: We performed a double blind clinical trial in a single center pilot study approved by our ethics committee. All patients candidates for autologous or allogeneic HSCT above 18 years were submitted for our study previous informed consent by our institution. Patients were randomized into one of two arms: a) selenium methionine, b) placebo.
Previously randomized, patients were administered supplementation with oral selenium methionine at a dose of 400mcg/day or placebo starting 7 days prior transplantion. We determined a baseline measurement of serum and urinary selenium. Subsequent measurements were made each week for a total of 28 days. Evaluations were made with validated SMAQ questionnaires which also included scales of mucositis severity, using the WHO mucositis scale. All of them performed by an observer blinded to what supplementation were being administered to each patient.
Results: We have recruited a total of 31 patients, of whom 16 were allogeneic and 15 autologous. We observed that 38.7% developed some degree of mucositis, most of them on the allogeneic arm (10 patients). Selenium consumption arm was associated with a median decrease of 32% (1.9 vs 2.8) in the WHO scale in the severity of mucositis compared to the placebo arm (p=0.046), however we didn't find difference in mucositis resolution time between groups (p=0.162). On the other hand, selenium supplementation was associated with shorter platelet engraftment time (p=0.041), without any significant difference in neutrophil engraftment time. With a follow up of 112 days, there are no difference about mortality or other analized variables.
Conclusions: Supplementation with selenium was associated with a slight decrease in the severity of mucositis in comparison with placebo. Without any relevant findings in relation to mortality or other variables analized.

Disclosures
Gomez-Almaguer: Novartis: Consultancy; AbbVie: Consultancy. Herrera-Rojas:Janssen: Employment.
Role of Bone Marrow Infiltration and POD 24 in Follicular Lymphoma
Authors: Rivas-Vera Silvia , Acosta-Maldonado Brenda Lizeth , Estrada-Martínez Lizeth Elisua 
Published: October 2019

Abstract
Follicular lymphoma (FL) is the most common indolent lymphoma with a median survival approaching 20 years. However, there is significant clinical heterogeneity with subsets of patients experiencing transformation, early recurrence or refractory disease. Some authors found that progression of disease within 24 months of diagnosis, in patients treated with chemoimmunotherapy (POD24), is associated with poor overall survival (OS).
OBJECTIVE
Evaluate the POD24 as an early clinical endpoint in FL and evaluate FL international prognostic index (FLIPI), and other baseline risk factors at diagnosis for overall survival and relapse.
METHODS
We conducted a retrospective and observational study in which 160 patients with follicular lymphoma who received R-CHOP at National Institute of Cancerology, Mexico from 2011 to 2017. We analyze with Kaplan Meier curves, log rank test and logistic regression model.
RESULTS
We analyze 160 patients, median of age was 53 years (26- 88), with a female : male ratio of 1.17:1. In this group: 86% had hemoglobin >12 mg/dL, LDH was normal in 62%, 1-4 nodal areas were affected in 64%, 56% of patients had high FLIPI score, 27% had B symptoms and we found bone marrow infiltration in 30% of cases; grade 2 Follicular lymphoma was the most common histological subtype (40.5%). Most of patients achieved complete response (81%), 12% partial response after the first line therapy. Only 13 patients (8%) presents relapse. Sixty four percent received maintenance. Only 13 of patients relapsed, 10 after 24 months and only 3 in first 24 months from diagnostic (POD 24). Fig. 1
Overall survival in our population was 89% to 8 years, the factors with statistical significance in the bivariate analysis were the more nodal regions affected (1-4), high FLIPI score and POD 24
POD 24, adjusted to FLIPI score, was an independent predictor of survival in regression analysis (p<0.041, HR:35 IC 95% 1.15-1060.21). The bone marrow infiltration at diagnosis was the only independent predictor for relapse (p<0.007, HR: 6.9, IC 95% 1.7- 28.2).
CONCLUSION:
In our study group, POD 24, was an important predictor of overall survival, and bone marrow infiltration at diagnosis was the only predictor factor for relapse.

Disclosures
No relevant conflicts of interest to declare.
Rituximab Combined with Donor Lymphocyte Infusion Cured Immunohemolysis after Refractory Hematopoietic Stem Cell Transplantation
Authors: Liao Jianyun , Peng Zhiyong , Liu Huaying , He Yuelin , Li Chunfu 
Published: October 2019

Abstract
Background
Immuno-hemolytic anemia is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT). Primary or secondary reaction between recipient lymphocytes and donor RBC antigens was considered as one of cause of post-transplantation immune-hemolysis (PTI). Different treatments can be administered according to the donor cell chimeric status and antibody titer of blood types of the donor in recipient.
Objective:
To find the ways of treatment of PTI after HSCT.
Methods:
A retrospective analysis about the complications of 707 patients underwent HSCT in our center from January 2010 to July 2017 was made. Of them, PI occurred in 28 patients with positive direct Coomb's test. By donor cell chimerism status, the 28 patients with PTI were divided into two groups. In group 1 (n=11), the patients presented full donor chimerism and received rituximab or/and steroid treatment only; In group 2 (n=17), the patients presented mixed chimerism and received rituximab and gradually decreasing immunosuppressive agents with/without, thereafter, donor lymphocyte infusion (DLI).
Results: A total of 28 patients was cured after treatment. Of 11 cases in group 1, five patients developed grade 1-2 acute GVHD and four of which developed pancytopenia. Of 17 patients with mixed chimerism (75-99.5%) in group 2, four had post-HSCT pure red blood cell aplasia and the major blood type incompatibility between the donor and recipients. In group 2, six patients with PTI were cured by rituximab and gradually decreasing immunosuppressive therapy only; 11 patients had no respond to the treatment of these treatments, and were cured after combined with DLI.
Conclusion:
When PTI occurred, chimerism status may help us to determine how to treat PTI. For patients with full donor cell chimerism, it may be fit to give rituximab and to reduce immunosuppressive agent gradually. DLI may be given to the patients with mixed chimerism and no responding to the combined therapy of rituximab and immunosuppressive agent reduction.

Disclosures
No relevant conflicts of interest to declare.
Observations from the First 1,000 Suspected aHUS Patients, Tested By a Rapid aHUS Genetic (NGS) Panel: Causative Genes Identified in a Subpopulation of Our Database
Authors: Anderson-Furgeson James , Kain Jamey , Venkataramani Sujatha , Lim Jooeun , Ero Mike , Lewis Bradley 
Published: October 2019

Abstract
Atypical Hemolytic Uremic Syndrome (aHUS) is a life-threatening, progressive genetic disease. aHUS results from uncontrolled activation of the complement system, which then targets endothelial cells, leading to thrombotic microangiopathy (TMA). The disease commonly progresses to kidney failure and death. Currently, aHUS is diagnosed by ruling out other diseases which cause TMA. Treatment is often performed with eculizumab, a terminal inhibitor of complement, which is expensive. Due to the severity of aHUS and the expense of treatment, rapid diagnosis of the disease is desirable. With a genetic sequencing assay for aHUS with a turnaround time of two days, we have gained comprehensive genetic understanding of a population of patients displaying acute clinical presentation of aHUS. The genes sequenced for the assay are CFH, MCP (CD46), CFI, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, THBD, PLG, and DGKE, alongside deletion/duplication analysis for CFHR1-3 and CFHR1-4. Currently, over 1000 patients have been tested using this panel. We reviewed de-identified aggregate results for a subset of patients tested using this panel (416 patients). We tabulated the frequency of clear-cut causative genetic variants in each of the genes among the patients tested positive for aHUS. The most common variant among the positives tabulated is the large deletion in CFHR1, at 23%. 23% of positives have a variant in MCP, 15% in CFH, 10% in THBD, 9% in CFI, 6% in C3, 6% in PLG, 5% in CFB, 3% in CFHR5, and 1% in DGKE. Furthermore, we report the frequency of positive, equivocal and negative results, breakdown of rare variant types per gene, frequency of patients with multiple rare variants, frequency of novel variants in the genes sequenced, frequency of deletion-duplication events in CFHR1-3 and CFHR1-4, and the CFH and MCP/CD46 risk polymorphisms. These data may provide the largest overview to date of genetic variants in risk-factor genes in patients where an aHUS diagnosis is suspected.

Disclosures
No relevant conflicts of interest to declare.
High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients
Authors: Sashihara Junji , Tanaka-Taya Keiko , Tanaka Shinya , Amo Kiyoko , Miyagawa Hiromi , Hosoi Gaku , Taniguchi Tomokuni , Fukui Takafumi , Kasuga Naoki , Aono Toshiya , Sako Masahiro , Hara Junichi , Yamanishi Koichi , Okada Shintaro 
Published: October 2019

AbstractHuman herpesvirus 6 (HHV-6) infection in recipients of cord blood stem cell transplants (CBSCTs) was estimated by semiquantitative and real-time quantitative polymerase chain reaction (PCR) and reverse-transcription PCR. Of the CBSCT recipients, 7 (70%) of 10 had active HHV-6 infection after transplantation, and all 7 were inferred from their age to have already had a primary infection. Because HHV-6 DNA is seldom detected in cord blood, these cases were considered likely to represent reactivation. In contrast, the 3 patients without HHV-6 infection were all believed to be naive regarding HHV-6 primary infection because of their age and the results of PCR assays given before the transplantation procedure. The incidence of HHV-6 infection after transplantation was significantly higher (P < .05) than after bone marrow (BM) transplantation and peripheral blood stem cell (PBSC) transplantation, when recipients without primary HHV-6 infection prior to transplantation were excluded (CBSCT, 100%; BMT/PBSCT, 56.3%). Real-time PCR revealed a higher level of viral DNA in the peripheral blood mononuclear cells from CBSCT recipients than from BMT/PBSCT recipients or patients with exanthem subitum (P < .05). HHV-6 mRNA of the U79/80gene was also detected by reverse-transcription PCR in all analyzed patients with HHV-6 infection. Its detection was correlated with the emergence of viral DNA in the plasma and symptoms such as fever and rash. Thus, HHV-6 infection was more frequent and the viral load was higher in CBSCT recipients with prior primary infection.
Liposomal Amphotericin B (L-AMB) Is Superior to Amphotericin B Deoxycholate (AmB-d) in Preventing Breakthrough Fungal Infections in Patients with Prolonged Neutropenia and Fever: Results of a Sub-Group Analysis of an Empirical Antifungal Therapy Trial.
Authors: Cordonnier Catherine , Walsh Thomas J. , Bresnik Mark 
Published: October 2019

Abstract
In a trial of empirical antifungal therapy in persistently febrile neutropenic patients, L-AMB was shown to be comparable in overall efficacy with significantly less nephrotoxicity and infusion-related reactions when compared to AmB-d. In addition, significantly fewer proven breakthrough invasive fungal infections (IFI) occurred in the L-AMB treatment group. (Walsh TJ, et al, NEJM1999; 340: 764–71). In order to better evaluate the maximum efficacy benefit of L-AMB in a higher risk patient subset, a sub-group analysis was performed on those patients with duration of neutropenia greater than or equal to the median duration for the entire study population. The results of this sub-group analysis are presented.
Methods: From the original data set, the median duration of neutropenia from the time of treatment initiation was determined. Clinical success (defined by a composite endpoint), frequency of proven breakthrough IFI and all cause mortality were reported by treatment group for patients with duration of neutropenia greater than or equal to the median. Investigator-reported proven breakthrough IFI were reviewed and verified by an independent, blinded expert.
Results: A total of 687 patients were enrolled in the trial. Median duration of neutropenia following initiation of antifungal therapy was 7 days (range 1–50). 392 patients had neutropenia >/= 7 days, (L-AMB=205), (AmB-d=187). Clinical success: L-AMB: 128/205 (62.4%); AmB-d: 112/187 (59.9%), and all cause mortality: L-AMB: 19/205 (9.3%); AmB-d: 24/187 (12.8%) were not significantly different. The frequency of proven breakthrough IFI favored L-AMB: L-AMB: 7/205 (3.4%); AmB-d: 18/187 (9.6%), p=0.01. Organisms isolated: L-AMB: 2 Candida spp (blood); 4 Aspergillus spp. (3 pneumonia, 1 wound); 1 Mucor sp (pneumonia). AmB-d: 9 Candida spp (8 blood, 1 pneumonia); 7 Aspergillus spp (4 pneumonia, 1 sinus, 1 pericarditis, 1 wound); 1 Cryptococcus albidus (blood); 1 unclassified mould (pneumonia). The difference in emergent proven IFI for the patients with neutropenia <7d trended in favor of L-AMB, but was not statistically significant: L-AMB 3/138 (2.2%); AmB-d 8/157 (5.1%).
Conclusions: Overall clinical success and all cause mortality remained equivalent for the 2 treatment arms in the subset of patients with prolonged neutropenia. However, L-AMB significantly reduced the frequency of proven breakthrough IFI in this high-risk patient population. These data support the efficacy of L-AMB as empirical therapy, particularly for persistently neutropenic patients at higher risk for invasive fungal infections.
In Vivo Downregulation of Bcl-2 by G3139 (G) Enhances Rituximab (R) Anti-Tumor Activity: Effect of Sequential Versus Concurrent G3139 Administration on Survival in a Lymphoma-Bearing SCID Mouse Model.
Authors: Ramanarayanan Jeyanthi , Hernandez-Ilizaliturri Francisco J. , Czuczman Myron S. 
Published: October 2019

Abstract
Bcl-2 over expression has been associated with poor prognosis and chemoresistance in various hematologic and solid tumor malignancies. G, an antisense oligonucleotide (ASO) targeting Bcl-2, downregulates Bcl-2 expression favoring apoptosis in cancer cells. Previously, we have demonstrated that G enhances R anti-tumor activity in various lymphoma pre-clinical models. Clinical trials are being conducted to evaluate the safety and efficacy of G3139 combined with R in relapsed/refractory NHL patients. However, the optimal sequence of administration of G and R is unknown. Our main objective was to determine the optimal anti-tumor schedule to administer G in combination with R. Six 8-week old SCID mice were inoculated via tail vein injection with Raji cells (1 x 106 on day 0). After five days, to allow for tumor engraftment, mice were assigned to receive placebo [P], G, R, R followed by G [R→G], G followed by R [G→R] or G preceding each dose of R [G+R]. In addition, other control groups consisted of lymphoma-bearing mice treated with G3622 (ASO control) [reverse sequence, RS], trastuzumab (isotype) [I] and R in combination with G3622 [R+RS]. Antibodies were administered vial tail vein injection at a dose of 10mg/kg/dose x 4 doses and ASO were administered intraperitoneally at 5mg/kg/dose x 8 doses. The end-point of the study was survival. Survival analysis was performed by Kaplan-Meier curves and p values calculated using log rank test. Differences in survival of lymphoma-bearing SCID mice were noted according to the schedule of G/R administration. Synergistic activity was observed in animals treated with [G+R]. A modest improvement in the mean survival was noted in animals treated with [G] (26 days) or [G→R] (28 days) when compared to control mice (20 days) (P < 0.001). Anti-tumor activity was observed in SCID mice treated with R (mean survival 34 days) and was improved by the sequential addition of G [R→G] (median survival 48 days, P = 0.038). Concomitant administration of G and R resulted in the highest anti-tumor activity as measured by the longest survival (mean 80 days, P < 0.001). Our data demonstrates differences in R/G anti-tumor activity depending on the schedule of administration of G and R. Sequential administration of R followed by G resulted in a better disease control than G followed by R. However, concurrent G and R administration was shown to be superior to sequential strategies in improving survival of lymphoma-bearing SCID mice. Our pre-clinical data suggest the importance of a concurrent administration of these agents in clinical trials whereby, down-regulation of Bcl-2 by G allows enhancement of rituximab-associated anti-tumor activity.