bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development Of a New Regimen Function For Cancer Chemotherapy With a Computerized Physician Order Entry System Aimed At Reducing The Burden On Doctors In Japan
Authors: Komatsu Tsunehiko , Kimura Yuko Nishide , Takaba Yuji , Okubo Kensuke , Ishii Tomotaka , Yuji Koichiro , Nakagawa Masahiko 
Published: October 2019

Abstract

Background
Physician overwork has long been a problem in Japanese society. Mean weekly working durations are reportedly 70.6 hours. The working hours of hematologists are estimated to be especially long. In addition, there is no payment system for specialist medical care in Japan and there is no difference in payments for treatment between specialists and general physicians. The average hourly wage is $30 for both specialists and general physicians in Japan, while the respective values are $100 and $70 in the United States. Given this situation, we advocate that working hours of Japanese hematologists be reduced by improving their work efficiency. One of the problems lies in dose calculations for anticancer drugs. With the conventional ordering system, the method of rounding the dose fractions varies among physicians and there is a potential risk of incorrect administration. We developed an anticancer drug administration system designed to reduce hematologists’ workloads and improve the appropriateness of anticancer drug dosing. We then examined its efficacy.

Methods
EGMAIN-GX (Fujitsu Ltd., Japan) version 2 is an electronic medical record system incorporating an ordering function. We developed a drug administration system named Regimen version 4 in order to update the EGMAIN-GX version 2 ordering system. The new system allows dose calculation with a rounding function in which the dose is automatically rounded off to the nearest whole number. Seven hematologists were asked to order five regimens (IDR/araC, Flu/ivBU, R-CHOP, hyper-CVAD, R-ESAHP）for a patient (165 cm in height and weighing 52 kg) using the new and old systems. Times required for ordering and prescribed doses of anticancer drugs were compared between the two systems. Statistical analysis was performed using Student’s t test.

Results
The mean time and standard deviation (seconds) for ordering are shown in Table 1.
The time was significantly reduced with version 4 as compared to version 2, except for R-CHOP. The cumulative time was reduced by 54% with version 4. As to the prescribed doses of anticancer drugs, significant differences between the two systems were found in busulfan (42.0 mg vs. 40.7 mg, p < 0.0001; figures rounded off to the nearest whole number in the present system, i.e., 42.0 mg) and rituximab (529 mg vs. 583 mg, p= 0.002; figures rounded down to the nearest 100 in the present system, i.e., 500 mg).

Conclusions
The new drug administration system significantly reduced the time required for ordering and facilitated appropriate anticancer drug dosing. These results show that the new drug administration system can reduce hematologists’ workloads and also reduce the risk of incorrect administration of anticancer drugs.

Disclosures:
No relevant conflicts of interest to declare.
Disparities In Receipt Of Radiotherapy and Survival By Age, Sex and Ethnicity Among Patients With Localized Diffuse Large B-Cell Lymphoma
Authors: Shah Binay K. , Bista Amir 
Published: October 2019

Abstract

Background
Combination therapy with 3 cycles of chemotherapy followed by involved field radiotherapy has been a standard of care for treatment of localized diffuse large B-cell lymphoma (Miller TP NEJM 1998). This population based study evaluated ethnic disparities in receipt of radiotherapy (RT) and its effect on survival in patients with localized diffuse large B cell lymphoma (DLBCL) in the United States.

Methods
The Surveillance, Epidemiology, and End Results database was reviewed to identify patients with stage I DLBCL diagnosed between 1998 and 2008. We used unadjusted and adjusted odds ratio (OR) to analyze association of receipt of radiotherapy with age (<60 and 60+ years), sex and ethnicity (White, Black and Others). We calculated relative survival rates for different cohorts using SEER*Stat software. We used cox’s proportional hazard model to investigate the impact of age, sex and ethnicity on survival rates.

Results
A total of 11763 patients with localized DLBCL as the only primary malignancy were included in the study. Of the cohort, 38.2% received radiotherapy. Receipt of radiotherapy varied significantly by patient ethnicity - whites were more likely to receive RT compared to blacks and others. Similarly, age <60 years and females were more likely to receive radiotherapy compared with older patients and males (Table – 1).
The 1- and 5- year relative survival rates for patients receiving RT were higher compared to those who did not receive RT: 88.3±0.5% vs 73.4±0.6%, p-value <0.0001 at 1-year and 77.8±0.8% vs 62.5±0.7%, p-value <0.0001 at 5-years. Among patients who received RT, 1- and 5- year relative survival rates were significantly higher in whites compared to black or other- race patients.

Conclusions
This population based study showed that only 38.2% of patients with localized DLBCL received radiotherapy. White patients were more likely to receive RT compared to blacks and others. Survival rates are significantly higher for patients who received RT.

Disclosures:
No relevant conflicts of interest to declare.
Heterozygous Mutation Of Dynamin 2 Expands The Pool Of IL-7 Responsive Leukemic Stem Cells In T-Cell Acute Lymphoblastic Leukemia
Authors: Curtis David J. , Brown Fiona C. , Collett Michael , Lucas Sarah E. , Saw Jesslyn , Robinson Phillip J. , Tremblay Cedric Stevens 
Published: October 2019

Abstract
Early thymocyte progenitor T-cell acute lymphoblastic leukemia (ETP-ALL) is a poor prognosis malignancy that has a distinct genetic basis characterized by activating mutations of the IL-7 signaling pathway. Recurrent mutations spanning Dynamin 2 (Dnm2), a gene encoding a large GTPase required for clathrin-mediated endocytosis, have been identified in ETP-ALL although why these mutations are enriched in ETP-ALL remains obscure. We have utilized the Lmo2 transgenic mouse model to define the role of DNM2 mutations in ETP-ALL. Sequencing of 11 cases of Lmo2-derived T-ALL identified two novel Dnm2 mutations, a frameshift (Serine126fs) and a premature stop (Isoleucine135stop) mutation within the GTPase domain, which confirmed the relevance of this mouse model for studying Dnm2 mutations. We mated Lmo2 mice with mice carrying a germ-line missense mutation of Dnm2 in the GTPase domain (V235G), which impairs GTPase activity. This Dnm2 mutation had two important biologic effects on Lmo2-derived T-ALL: an increased penetrance (90% compared with 50% by 12 months of age; p<0.05) and a more immature phenotype (DN1-3 compared with ISP8). To address the mechanism of these effects, we examined the phenotype and expression profile of early leukemic stem cells harboring the Dnm2 mutation. The major abnormality was an expansion of IL-7 responsive leukemic stem cells with increased proliferation and survival. Intriguingly, the presence of Dnm2 mutations sensitized leukemic cells to killing by a small molecule inhibitor of Dnm2. Together, our data provide the first experimental evidence that Dnm2 mutations are enriched in ETP-ALL by expanding the pool of IL-7 responsive leukemic stem cells. Furthermore, our data supports further testing of Dynamin inhibitors in this subset of poor prognosis T-ALL.

Disclosures:
No relevant conflicts of interest to declare.
Persistence of Minimal Residual Disease Assessed By Multi-Parameter Flow Cytometry (MFC) at 30 and 90 Days after Achieving Complete Remission Predicts Outcome in Patients with Acute Myeloid Leukemia
Authors: Pinnamaneni Pramod , Jorgensen Jeffrey L. , Kantarjian Hagop M. , Jabbour Elias , Pierce Sherry R. , Brandt Mark , Wang Sa A. , Konoplev Sergej , Konopleva Marina , Kornblau Steven M. , Kadia Tapan , DiNardo Courtney D. , Pemmaraju Naveen , Andreeff Michael , Estrov Zeev , Garcia-Manero Guillermo , Cortes Jorge E. , Ravandi Farhad 
Published: October 2019

Abstract
Purpose – To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) after achieving initial response to therapy, in predicting outcome in patients with acute myeloid leukemia (AML)
Methods – We investigated the predictive value of MRD assessment by MFC in 191 patients with newly diagnosed AML treated between February 2010 and April 2014 at our institution who had available MRD assessment. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR and at approximately 30 days and 90 days after achieving CR. Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype.
Results – Of the 191 patients, 167 (87%) achieved complete remission (CR) or CR without platelet recovery (CRp). Their median age was 58 years (Range, 17-85). 84 (44%) were older than 60 years. Median WBC at presentation was 3.2 x 109/L(Range, 0.5-100.2 x 109/L) and median bone marrow blast percentage was 43% (Range, 11-96%). Cytogenetics was favorable risk in 4 (2%), intermediate risk in130 (68%) and adverse risk in 57 (30%). Treatment included cytarabine plus anthracycline in 170 (89%) and hypomethylating agents-based strategies in 21 (11%). 48 patients had available samples at 30 days post CR and 32 (67%) became MRD negative. Achieving MRD negative status was associated with a statistically significant improvement in CR duration (p=0.02) and overall survival (OS) (p=0.0005). 56 patients were evaluated for MRD status at 90 days and 45 (80%) were negative. Again, achieving MRD negative status was associated with a significant improvement in CR duration (p=0.002) and OS (p=0.0009).
Conclusion – Achieving MRD negative status by MFC at 30 and 90 days post CR is associated with an improved outcome in patients with AML
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Comprehensive Genetic Characterization of Pediatric T-Cell Acute Lymphoblastic Leukemia
Authors: Karrman Kristina , Castor Anders , Behrendtz Mikael , Forestier Erik , Olsson Linda , Ehinger Mats , Biloglav Andrea , Fioretos Thoas , Paulsson Kajsa , Johansson Bertil 
Published: October 2019

Abstract
A comprehensive genetic characterization comprising conventional chromosome banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) array analyses as well as large-scale sequencing of 75 genes were performed on a consecutive series of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. An abnormal karyotype was identified in 46% of the cases. Recurrent cytogenetic aberrations comprised T-cell receptor (TCR) translocations and deletions of 6q and 9p. FISH analyses of TCR rearrangements were positive in 26% of the investigated cases. The vast majority (37/39; 95%) of cases analyzed by SNP arrays displayed aberrations, with a median of 3 changes (range 0-11) per case. The genes recurrently deleted were CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. One case displayed chromothripsis involving 6q. No case had a whole chromosome uniparental isodisomy (wUPID); in fact, only one T-ALL of 123 informative cases in the literature has had a wUPID. However, segmental UPIDs (sUPIDs) were seen in 44% of the present cases, with most being sUPID9p. CDKN2A was homozygously deleted in all cases with sUPID9p, with a heterozygous deletion occurring prior to the sUPID9p in all instances. There was no evidence for chromosomal instability when comparing diagnostic and relapse samples. Among the genes sequenced, 14 were mutated in 28 cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse, showing that such mutations also can be secondary events. These findings support a multistep leukemogenic process.

Disclosures
No relevant conflicts of interest to declare.
Late Effects: An Evaluation of Contrasting Physical and Psychological Experiences Between Child and Adult Hodgkin Survivors
Authors: Sarker Shah-Jalal , George Gincy Elsa , Chowdhury Kashfia , Levitt Gill , Kingston Judith , Lister Andrew , Gribben John G. , Korszun Ania 
Published: October 2019

Abstract
Purpose
A retrospective study to assess the effect of age at diagnosis (AD) of patients with Hodgkin’s Lymphoma (HL) on the development of physical late effects (secondary malignancies, hyperthyroidism, fatigue), depressive symptoms and quality of life (QOL) using the Impact of Cancer (positive and negative scales) Questionnaire.
Methods
280 Hodgkin’s Lymphoma (HL) survivors from St. Bartholomew’s Hospital, London were divided into two groups; 57 Childhood (AD≤17 years) Hodgkin’s Lymphoma (CHL) and 223 Adult (AD≥18 years) Hodgkin’s Lymphoma (AHL). Chi-square/Fisher’s exact tests and logistic regression analyses were conducted to identify the effect of AD on late effects; adjusting for histological subtype (HS) and treatment modality (TM). For IOC, two separate hierarchical linear regression analyses were conducted to examine the combined association of; (i) AD, HS and TM (ii) AD, HS, TM and the late effects on IOC.
Results
CHL survivors were four times more likely to develop a secondary malignancy than AHL survivors (P=0.011). AD was not associated with hyperthyroidism, fatigue or depression. Higher negative IOC scores were significantly associated with lower levels of social support and two or more medical co-morbidities (P≤0.001). Although there was no significant association between AD and negative IOC, lower positive IOC scores were significantly associated with CHL (P=0.040).
Conclusions
CHL survivors may benefit from more vigorous screening for secondary malignancies to enable their early detection and treatment. QOL varies in different groups and those with less social support and more medical co-morbidities would benefit from interventions to reduce negative IOC. An early psychological intervention to increase positive IOC and resilience for young people with HL may also improve their future QOL as long-term CHL survivors.

Disclosures
Gribben: Celgene: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria.
The Role of ADAMTS13-Specific Circulating Immune Complexes in Prediction of Recurrence of Acquired Thrombotic Thrombocytopenic Purpura
Authors: Ferrari Barbara , Valsecchi Carla , Pontiggia Silvia , Mancini Ilaria , Lotta Luca Andrea , Mikovic Danijela , Meloni Giovanna , Peyvandi Flora 
Published: October 2019

Abstract
Introduction. Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. We recently developed and validated a new ELISA method for the detection of ADAMTS13-specific circulating immune complexes (CICs) in acquired TTP patients. This study aims at investigating the clinical relevance of ADAMTS13-specific CICs at disease presentation in a large cohort of acquired TTP patients.
Methods. We measured ADAMTS13-specific CICs by ELISA in 51 patients from the Milan TTP Registry, at the first episode of acquired TTP. All patients presented anti-ADAMTS13 autoantibodies by western blotting and severe ADAMTS13 deficiency (i.e., <10% of normal) by FRETS-VWF73 or CBA assays. We studied the associations between ADAMTS13-specific CICs levels and (i) ADAMTS13-related measurements (i.e., ADAMTS13 antigen, anti-ADAMTS13 IgG), (ii) clinical and laboratory markers of disease severity (i.e., muco-cutaneous bleeding, neurological, renal and cardiovascular symptoms, number of platelets, LDH, hemoglobin, creatinine), (iii) short- and long-term clinical outcomes (i.e., number of plasma exchange procedures required to attain remission, recurrence). Statistical analyses were performed using linear, logistic and Cox regression models.
Results. The prevalence of ADAMTS13-specific CICs in patients experiencing a first episode of acquired TTP was 39% (95% confidence intervals [CI]: 26-52%). ADAMTS13-specific CICs were only associated with ADAMTS13 antigen levels at regression analyses (beta per 10% increase in ADAMTS13 antigen, 95% CI: 0.05, 0.02-0.08). The presence of ADAMTS13-specific CICs was associated with more than a four-fold increase in the risk of recurrence at 2 years after the first TTP episode (hazard ratio, 95%CI: 4.2, 1.1-16.4).
Conclusions. ADAMTS13-specific CICs are neither a biomarker of disease severity, nor a predictor of clinical outcome during acute phase. Conversely, ADAMTS13-specific CICs seem to have relevance in predicting the recurrence of acute TTP episodes.

Disclosures
Peyvandi: NovoNordisk: Research Funding; Kedrion : Research Funding; NovoNordisk: Speakers Bureau; CSL Behring : Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau.
A Two-Site Interaction Underpins TRIM25 Activation of the RIG-I Anti-Viral Response
Authors: D'Cruz Akshay A , Kershaw Nadia J , Linossi Edmond M , Chiang Jessica J , Wang May K , Dagley Laura F , Croker Ben A , Zhang Jian-Guo , Gack Michaela U , Nicola Nicos A , Babon Jeffrey J , Nicholson Sandra E 
Published: October 2019

Abstract
SPRY/B30.2 domain-containing proteins are found in 103 human proteins that regulate numerous cellular processes including RNA processing, histone methylation, red blood cell membrane integrity, terminal erythroid cell differentiation and innate immune responses. Despite an increased understanding of SPRY/B30.2 domain function, some confusion remains as to the precise domain boundaries, the number and location of binding sites, and importantly how activation of these domains contribute to signal transduction. The B30.2 domain of tripartite motif 25 (TRIM25) interacts with the viral RNA sensor retinoic acid-inducible gene I (RIG-I), facilitating the formation of a RIG-I tetramer, which is required for activation of the innate immune response against RNA viruses such as influenza A, measles, HIV and hepatitis C. Here we have investigated the biochemical and structural changes associated with the activation of TRIM25 in the context of RIG-I binding. We solved a 1.8 Å crystal structure of the TRIM25 B30.2 domain and identified a putative RIG-I-binding site, which was confirmed by mutagenesis and functional analyses. Further mutagenesis identified a second site on the opposing face of the B30.2 domain that also specifically interacts with RIG-I. While the CARD1 domain of RIG-I is known to interact with the B30.2 domain of TRIM25, our data suggest that a conformational change within the CARD2 domain of RIG-I enables it to also interact with the B30.2 domain of TRIM25. We propose that both RIG-I CARDs interact with sites on opposing sides of the TRIM25 B30.2 domain to form a TRIM25/RIG-I complex that facilitates RIG-I tetramerisation and activation. The characterization of a dual binding mode for the TRIM25 B30.2 domain is a first for the SPRY/B30.2 domain family. Disease-associated polymorphisms of Pyrin, involved in Familial Mediterranean Fever, and mutational analyses of TRIM5a, required for HIV restriction, suggest that a second binding site may be a characteristic feature of other B30.2-containing TRIM proteins, and may facilitate the formation of large oligomeric complexes that are important for inflammasome function and HIV capsid destruction.

Disclosures
No relevant conflicts of interest to declare.
Proteomic Analysis Identifies Outcome-Predictive Clusters in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified
Authors: Ludvigsen Maja , Pedersen Martin Bjerregaard , Hamilton-Dutoit Stephen Jacques , Bendix Knud , Møller Michael Boe , Nørgaard Peter H. , Poulsen Tim Svenstrup , Besenbacher Søren , d'Amore Francesco , Honoré Bent 
Published: October 2019

Abstract
Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of mature T-cell lymphomas, probably composed by different biologically related subsets that have not yet been conclusively identified. In the WHO classification, PTCL-NOS accounts for 25-30% of all mature T-/NK-cell malignancies. The clinical outcome is generally poor with a 5-yr overall survival of 30-35% after conventional treatment strategies. The aim of the study was to apply proteomic analysis in PTCL-NOS and to use the protein expression profiles to characterize clinically relevant subsets within this heterogeneous entity by means of unsupervised cluster analysis.
Methods: Archival frozen tumor tissue samples from 20 patients diagnosed with PTCL-NOS from 1991 to 2010 were analyzed for protein expression by high-resolution two-dimensional gel electrophoresis. Individual protein spots were visualized with fluorescence staining and the expression profiles were identified. All patients were homogeneously treated with curatively intended anthracycline-containing combination regimens. Clinico-pathological features were obtained from the Danish Lymphoma Registry (LYFO) and from patient records. Hyperplastic tonsils from healthy adults were included as reference tissue (n=8). Principal component analysis and unsupervised hierarchical cluster analysis were performed on the basis of the protein expression profiles. Differentially expressed (two-fold or higher, Mann-Whitney U-test) proteins between the detected clusters were identified by liquid chromatography - tandem mass spectrometry.
Results: Unsupervised cluster analysis defined three distinct clusters: one containing all reference samples and two additional ones further subdividing the PTCL-NOS cases in two separate subsets. Patients from these two PTCL-NOS subsets had significantly different responses to treatment and survival (p = 0.001). The differentially expressed proteins were primarily involved in (i) promotion of tumor growth, (ii) regulation of cellular metabolism, and (iii) immune responses.
Conclusion : Proteomic analysis identified shared protein expression patterns and potential prognostic markers in subsets of PTCL-NOS.

Disclosures
No relevant conflicts of interest to declare.