bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular and Cytogenetic Risk Stratification For Core-Binding Factor-Positive Adult AML With Analysis Of Post-Remission Treatment Outcomes Including Transplantation
Authors: Yoon Jae-Ho , Kim Heeje , Shin Seung-Hwan , Jeon Young-Woo , Kim Jung-Ho , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Lee Seok , Min Chang-Ki , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Park Chong-Won 
Published: October 2019

Abstract
Core-binding factor (CBF)-positive acute myeloid leukemia (AML) is regarded as a favorable group with good complete remission (CR) rate after induction chemotherapy and is generally treated by repeated high-dose cytarabine consolidation or autologous hematopoietic stem cell transplantation (auto-HSCT). However, emerging molecular studies have recently identified the unfavorable CBF-AML subgroup which should be treated by further intensified treatments.
This single center retrospective study enrolled 264 adult CBF-AML patients from 2002 to 2011. Except 15 patients, 217 patients were treated by intensive induction chemotherapy and 32 were treated by reduced intensity treatment. After CR achievement, patients with available donor were treated by allogeneic (allo)-HSCT and the rest were treated by auto-HSCT or chemotherapy alone. We evaluated 206 patients who achieved CR after intensive chemotherapy regarding survival outcomes according to post-remission therapies and prognostic factors which affected the outcomes. The factors included cytogenetic study and subgroup analysis with additional chromosomes and normal karyotype (NK) mosaicism, c-kit mutation, minimal residual disease (MRD) qPCR level, BAALC and WT1 expression.
We achieved CR in 94.9% with intensive chemotherapy and 115 patients went on allo-HSCT and 72 were treated by auto-HSCT. There were no significant OS differences between CBF¥â/MYH11 and RUNX1/RUNX1T1 (p=0.173), and auto-HSCT showed favorable EFS (p=0.038) compared to allo-HSCT and chemotherapy alone. For cytogenetic analysis, inv(16) or t(16;16) with NK mosaicism showed the most favorable OS compared to t(8;21) with additional chromosome (¡Ã2) which showed the worst OS. c-kit mutation was a poor prognostic factor with lower reduction rate of post-induction MRD qPCR, however the effect was not definite after HSCT. For HSCT patients, we analyzed post-HSCT MRD qPCR and WT1 expression level. We found that undetected level of post-HSCT MRD qPCR and lower level of WT1 expression (<0.015) showed the most favorable OS with no relapse cases.
For CBF-AML, the role of auto-HSCT and allo-HSCT for selected patients should be re-evaluated by large prospective studies and the values like post-treatment MRD qPCR and WT1 expression level can be used for prediction of patients who might relapse with higher probability.

Disclosures:
No relevant conflicts of interest to declare.
Multi-Virus-Specific T-Cell Therapy For Patients After Hematopoietic Stem Cell and Cord Blood Transplantation
Authors: Hanley Patrick , Leen Ann , Gee Adrian P. , Leung Kathryn , Martinez Caridad , Krance Robert A. , Liu Hao , Brenner Malcolm K. , Heslop Helen E. , Rooney Cliona M. , Bollard Catherine M. 
Published: October 2019

Abstract
Cytomegalovirus, EBV and adenovirus are particularly problematic in patients after hematopoietic stem cell (HSCT) and cord blood transplantation (CBT) and are associated with significant morbidity and mortality. Deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders. We have developed two strategies to grow multivirus-specific donor-derived T-cells from peripheral blood (PB) and naive cord blood (CB). Using an adenoviral-vector expressing CMVpp65 to modify monocytes, DC and EBV-LCL we generated a single culture of PB or CB mononuclear cells that gave rise to multivirus-specific cytotoxic T-cells (CTL)(n=76). We have infused 34 patients with PB-derived CTL and 8 patients with CB-derived CTL. Patients received CTL infusions from 35 to 164days (median 84d) post HSCT or CBT at a median of 5x10e7 cells/m2. None developed >grade II GvHD or other toxicities over 3 months of safety monitoring after infusion. We observed up to a 5-fold increase in CMV- and EBV-specific T-cells by 4weeks post-CTL as measured by IFN-g ELISPOT assay. 33 viral reactivations were observed in patients before or immediately after CTL infusion. In the absence of conventional therapy, 8 of the 11 patients with CMV infection became negative for CMV in the blood within 7d of CTL infusion, with a corresponding rise in CMV-specific CTL in PB. Each of 10 patients with high EBV loads cleared their virus, as did 11 of 12 patients with adenoviral infections/disease. This study demonstrates that multivirus-specific CTL derived from the PB of seropositive donors as well as the CB of virus naive donors expand in vivo and are active against multiple viruses. Furthermore, by restoring immunity to multiple viruses simultaneously, the need for continued prophylaxis with pharmacotherapy is eliminated, thus, improving the efficiency and cost effectiveness of protecting HSCT and CBT recipients from these potentially lethal viruses.

Disclosures:
No relevant conflicts of interest to declare.
Pediatric Fanconi Anemia With Secondary AML: A Retrospective Outcome Report From The German AML-BFM Group
Authors: Beier Rita , Hoseini Sayed , Maecker-Kolhoff Britta , Schneppenheim Reinhard , von Neuhoff Christine , Ebell Wolfram , Schmid Hansjörg , Bader Peter , Ehlert Karoline , Sykora Karl-Walter , Creutzig Ursula , Kratz Christian , Chao Mwe Mwe , Reinhardt Dirk , Sauer Martin G. 
Published: October 2019

Abstract

Background
To date, allogeneic stem cell transplantation (SCT) is the only curative approach for patients with Fanconi anemia (FA) and myeloid malignancy (AML). No data exist on whether cytoreductive chemotherapy prior to SCT impacts outcome.

Methods
We retrospectively analyzed data retrieved from the AML-BFM database (Germany) regarding children with FA and AML.

Results
Between January 1993 and May 2013 14 patients were identified, in whom AML was diagnosed at a median age of 11.6 yrs [0.9-19.6] (n=13). In 10 patients (4 not available) the diagnosis FA preceded the occurrence of AML by a median of 32.3 months [0-161].
Six of 14 patients underwent SCT achieving a 5 year overall survival of 42%. Median time to transplant after the diagnosis of AML was 2 months. One patient died after relapse, one due to severe graft versus host disease (GvHD), another of unknown cause. Of the three surviving patients two had chronic GvHD (one limited, one extended). All three surviving patients received a radiation free preparative regimen (1. fludarabine (Flu) and cyclophosphamide (Cy); 2. busulfan (Bu) and Flu; 3. Bu, Flu and Cy.) including antibodies for intensive GVHD prophylaxis. In all three cases a high cell dose of either PBSC (30.1 x 10e6 CD34+) or BM (2.13 and 3.43 x 10e8 MNC) was infused. Two surviving patients received low dose cytoreductive therapy (thioguanin and cytarabin) to bridge time to SCT. The remaining patient did not receive pre-transplant therapy.
Eight of 14 patients did not receive a SCT. Median survival for these children was 40 days. Three of 8 patients received low intensity chemotherapy (thioguanin and/or cytarabin). Two were treated with more intensive combinations (e.g. cytarabin, adriamycin and etoposide). The latter all died of complications from long lasting aplasia.
Additionally to the 14 patients described above, another patient was identified, in whom AML developed 14 months after successful SCT for bone marrow failure. Blasts were of recipient origin and the patient died of progressive disease.

Conclusion
The data presented are subject to selection bias. Three of 14 patients survived and 2/3 surviving patients received low dose cytoreductive therapy for disease control before going to transplant. None of them achieved complete remission (CR) before SCT. Graft failure and chronic GVHD were the main complications after transplantation. FA patients with AML should proceed to SCT. Mild cytoreductive therapy with thioguanine and cytarabine may be useful. Achieving CR pre transplant might not be necessary for OS.

Disclosures:
No relevant conflicts of interest to declare.
Second Bacteremia During Antibiotic Treatment In Children With Acute Myeloid Leukemia: A Report From The Canadian Infections In AML Research Group
Authors: Tran Thai Hoa , Yanofsky Rochelle , Johnston Donna , Dix David , Gillmeister Biljana , Ethier Marie-Chantal , Portwine Carol , Price Victoria E. , Mitchell David , Cellot Sonia , Lewis Victor A. , Zelcer Shayna , Silva Mariana , Michon Bruno , Bowes Lynette , Stobart Kent , Brossard Josee , Beyene Joseph , Sung Lillian 
Published: October 2019

Abstract

Background
The risk of second bacteremia during antibiotic treatment for initial bacteremia is unknown in high-risk populations. Objectives were to describe the prevalence of second bacteremia during treatment and identify risk factors in children with acute myeloid leukemia (AML).

Methods
We conducted a retrospective, population-based cohort study that included children and adolescents with de novo, non-M3 AML who were diagnosed and treated between January 1, 1995 and December 31, 2004 at 15 Canadian centers. Patients were monitored for bacteremia during chemotherapy until completion of treatment, hematopoietic stem cell transplantation, relapse, refractory disease, or death.

Results
There were 290 episodes of bacteremia occurring in 185 (54.3%) of 341 children. Eighteen (6.2%) had a second bacteremia while receiving antibiotic treatment. Two episodes of second bacteremia were complicated by sepsis; there were no infection-related deaths. Eleven episodes (61.1%) had either an initial Gram-positive and subsequent Gram-negative bacteremia or initial Gram-negative followed by Gram-positive bacteremia. Days receiving corticosteroids (odds ratio (OR) 1.09, 95% confidence interval (CI) 1.07-1.12; P<0.0001), cumulative dose of corticosteroids (OR 1.04, 95% CI 1.00-1.08; P=0.035) and days of neutropenia from start of course to initial bacteremia (OR 1.07, 95% CI 1.02-1.12; P=0.007) were significantly associated with second bacteremia.

Conclusion
In pediatric AML, 6% will experience a second bacteremia during antibiotic treatment; duration of corticosteroid exposure and neutropenia are risk factors. These patients remain at high risk for second bacteremia after identification of the initial bacteremia and warrant continued broad-spectrum treatment during profound neutropenia.

Abbreviations
CONS: coagulase negative Staphylococcus ; VGS: viridans group Streptococcus; Amp: ampicillin; Cz: ceftazidime;
Cef: cefotaxime; Cipro: ciprofloxacin; Clin: clindamycin; Clox: cloxacillin; G: gentamicin; Metro: metronidazole; Mero: meropenem;
O: oxacillin; Pip: piperacillin; Ta: piperacillin/tazobactam; Tm:ticarcillin/clavulanate; To: tobramycin; V: vancomycin.

Disclosures:
No relevant conflicts of interest to declare.
Inhibition Of Inflammation Driven Leukemia Stem Cell Self-Renewal With a Selective JAK2 Antagonist
Authors: Court Recart Angela C , Sadarangani Anil , Chun Elizabeth , Mason Cayla N , Jiang Qingfei , Barrett Christian L , Wall Russell , Goff Daniel J , Geron Ifat , Shih Alice , Leu Heather S. , Ma Wenxue , Minden Mark D. , Frazer Kelly A , Marra Marco A. , Crews Leslie A , Jamieson Catriona HM 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) represents an important paradigm for identifying the molecular events that promote malignant reprogramming of progenitors into therapeutically recalcitrant leukemia stem cells (LSC) during blast crisis (BC) transformation. To elucidate mechanisms of human BC LSC generation, whole transcriptome RNA sequencing (RNA Seq), lentiviral BCR-ABL and JAK2 transduction, quantitative RT-PCR (qRT-PCR) and serial xenotransplantation studies were performed. In human BC LSC, RNA seq revealed extensive upregulation of inflammation-responsive genes in conjunction with JAK/STAT signaling pathway activation and splice isoform specific qRT-PCR uncovered a predilection for selective STAT5a isoform expression. While lentiviral BCR-ABL1 expression in cord blood progenitors enhanced JAK2 activation and expression of specific STAT5a splice isoforms, lentiviral human JAK2 overexpression globally activated inflammation-response genes and expression of adenosine deaminase RNA associated (ADAR1), a primate specific RNA editase previously shown to activate self-renewal in response to inflammation. Notably, inhibition of BC LSC self-renewal with dasatinib, a BCR-ABL inhibitor, combined with a potent JAK2 inhibitor, SAR302503, was associated with reduced STAT5a isoform expression and phospho-STAT5 activation as well as ADAR1 expression and activity. These results highlight a novel JAK/STAT pathway driven niche-responsive mechanism of human BC LSC generation that can be targeted, at least in part, with a selective JAK2 inhibitor and may be utilized as an RNA editing-based biomarker of cancer stem cell generation and therapeutic resistance.

Disclosures:
Jamieson: Sanofi: Consultancy.
Impaired Osteogenic Differentiation Of Mesenchymal Stem Cells Derived From Bone Marrow Of Patients With Low-Risk Myelodysplastic Syndromes
Authors: Chang Chunkang , Fei Chengming , Zhao Youshan , Guo Juan , Li Xiao 
Published: October 2019

Abstract

Background
The pathogenesis of MDS has not been completely understood, and insufficiency of the hematopoietic microenvironment can be an important factor. MSCs and osteoblasts are key components of the hematopoietic microenvironment. Studying osteoblastic differentiation of MSCs quantitatively may help to understand the pathogenesis of MDS.

Methods
38 patients with MDS and 15 normal donors were investigated in this study. Osteoblastic differentiation assays were performed in 16 MDS cases and 8 controls. The expression of osteogenic differentiation markers were measured by real-time PCR. Alkaline phosphatase staining was performed with Alkaline Phosphatase staining kit after 3,7,14 days of incubation. ALP activity was assessed at 3, 7, and 10 days after osteogenic differentiation. Mineralization analysis was performed at 7, 14 and 21 days of osteogenic induction. The areas of mineralization were measured by Image-Pro Plus 6.0 software.

Results
Both MDS-MSCs and normal cells displayed same fibroblast-like morphology and similar antigen expression. The expression level of RUNX2 was significantly decreased in MSCs from MDS, compaired with normal controls, especially in lower-risk MDS. After osteogenic induction, lower-risk MDS showed lower alkaline phosphatase activity, less intense alizarin red S staining, and lower gene expression of osteogenic differentiation markers, however, higher-risk MDS was normal.

Conclusions
We concluded that impaired osteogenic differentiation of MSCs was seen mainly in patients with lower-risk MDS. It may contribute to the ineffective hamatopoiesis of MDS.

Disclosures:
No relevant conflicts of interest to declare.
Spatial Epidemiology Of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma In The State Of Georgia
Authors: Bulka Catherine , Nastoupil Loretta J. , Switchenko Jeffrey , Ward Kevin , Bayakly Rana , Waller Lance , Flowers Christopher R. 
Published: October 2019

Abstract

Background
Exploring spatial patterns of disease incidence allows for the identification of areas of elevated or decreased risk. For chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), which have poorly understood etiologies, identifying spatial patterns through cluster analysis may provide insight about potential environmental and socio-demographic risk factors.

Methods
In order to investigate the spatial patterns of CLL/SLL incidence among adults (≥ 20 years), we linked cancer incidence data for the period 1999-2008 from the Georgia Comprehensive Cancer Registry (a CDC-supported a statewide population-based cancer registry collecting all cancer cases diagnosed among Georgia residents since 1995) with population data from the 2000 U.S. Census. CLL/SLL cases were aggregated to the census tract level. CLL/SLL incidence in Georgia was standardized indirectly by age, sex, and race to national rates obtained from SEER*Stat software. Choropleth maps were created to depict the ratio of observed to expected incidence (standardized incidence ratios [SIR]) by census tract using ArcGIS. Spatial Empirical Bayes smoothing was performed on the SIR values using GeoDa 1.01. To assess spatial correlation of SIRs, we conducted global and local cluster analyses by calculating global Moran’s I and local Moran’s I (also known as Local Indicators of Spatial Autocorrelation [LISA]) values. Cluster analyses were repeated, stratifying by age (20-59 years, 60+ years), sex, and race (Caucasian and African American). P-values less than 0.01 were considered statistically significant.

Results
765 incident CLL/SLL cases occurred among adults residing in Georgia between 1999 and 2008 (Table 1). There was a positive spatial autocorrelation for cases of CLL/SLL age 60 and older indicating these cases were geographically clustered (p = 0.0010) (Table 2). The LISA cluster map of the smoothed standardized incidence ratios shows the locations of “hot-spots” (high-high clusters) and “cold-spots” (low-low clusters) with clustering of high smoothed SIRs was found in the metro-Atlanta area, Albany, Macon, and outside of Augusta while cold-spots were mostly in the southern region of the state.

Conclusions
Despite the low number of cases of CLL/SLL in Georgia during the 10-year period studied, we found evidence of spatial clustering among adults 60 years and above. Hot-spots of smoothed SIRs were located in the metro-Atlanta area, Albany, Macon, and near Augusta, but these varied when stratified by age, sex, and race, suggesting confounding or effect modification that warrants further investigation.

Disclosures:
Flowers: Spectrum: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Genentech BioOncology: Consultancy; Sanofi: Research Funding; Janssen: Research Funding; Abbott: Research Funding.
Cost Analysis Of Stem Cell Transplantation In Developing Countries: Experience Of a Single Public Center In Mexico
Authors: León-Rodríguez Eucario , Guzmán-Uribe Patricia , Pérez-Álvarez Sandra Ileana , Cortina-Pastor Isabel 
Published: October 2019

Abstract

Introduction
Hematopoietic stem cell transplantation (HSCT) has become an important strategy for treatment of several diseases. However, in developing countries access is often limited by socioeconomic factors. The information about the costs of the procedure in Mexico is scarce which limits the development of public policies in the area.

Objective
Describe overall costs of HSCT as well as specific costs of resources used in a tertiary care center in Mexico City.

Material and Methods
Retrospective, descriptive, observational study. We calculated the median overall cost per transplant in the first 30 days and the median cost per resource category, using SPSS version 17.

Results
We evaluated a total of 50 TCPH from June 2010 to December 2012. Of all the procedures, 68% were autologous. The median cost for allo-HSCT was $ 24.910 USD, while for auto-HSCT was $14.742 USD. Specific charges were divided into the following areas: for allo-HSCT, conditioning chemotherapy and mobilization: $ 4.087 USD, hospitalization: $ 8.130 USD, laboratory studies: $ 3.922 USD, imaging: $ 1.012 USD, other medications: $ 5.278 USD, blood bank: $ 2.478 USD. For auto-HSCT, conditioning-mobilization: $ 4.997 USD, hospitalization $ 4.086 USD, laboratory $ 1.612 USD, imaging: $ 411 USD, other medications: $ 3.024 USD, blood bank: $ 611 USD. Estimated 5 year-overall survival for these patients was 71.6%.

Conclusions
These results contribute to the scarce information regarding costs of HSCT in our country. The cost of HSCT in INCMNSZ (government institution) is 10 times lower than in the U.S. with similar results regarding overall survival. These facts highlight the important role of non-profit institutions that contribute to the development of these programs.

Disclosures:
No relevant conflicts of interest to declare.
Systematic Review and Individual Patient Data Meta-Analysis Of Treatment-Related Risk Of Secondary Malignant Neoplasms After Hodgkin Lymphoma
Authors: Franklin Jeremy , Eichenauer Dennis A. , Becker Ingrid , Engert Andreas 
Published: October 2019

Abstract

Introduction
Secondary malignant neoplasms (SMN) are a major late effect of treatment for Hodgkin lymphoma (HL). Single trials have inadequate power to detect differences in SMN rates, while the many large-scale cohort-based studies of SMN after HL suffer from non-randomised, potentially biased comparisons of treatment strategies. The consequences of choice of first-line treatment for SMN risk remain unclear. We performed a Cochrane systematic review addressing this question based on our previous such review in 2000-2004.

Material and methods
Individual patient data (IPD) were collected from randomised controlled trials testing 5 currently relevant experimental strategies: avoidance of additional radiotherapy (RT) after chemotherapy (CT); reduction of RT field; reduction of RT dose; use of fewer CT cycles; intensification of CT regimen. All trials employed modern ABVD-like regimens and limited radiation fields, and recruited at least 50 patients per treatment group. Incidence of SMN, overall survival (OS) and progression-free survival (PFS) were analysed. Due to small numbers of events, SMN was analysed using Peto’s method.

Results and Discussion
Data from 16 of the 21 eligible trials were obtained, including 9498 patients. These trials recruited between 1984 and 2007 and randomised between 100 and 1351 patients each. Standard chemotherapy was predominantly ABVD, followed by COPP/ABVD and MOPP/ABV. Most frequent intensified chemotherapies were escalated BEACOPP and Stanford V. For each study question, key information and resulting odds ratios are shown in the table. Avoidance of additional RT significantly reduced the SMN risk (Peto odds ratio 0.433, 95% confidence interval (0.28; 0.82), p=0.010). Intensified chemotherapy regimens were associated with a consistent slightly higher risk but the effect was not significant. Other study questions showed no marked effects on SMN risk. Regarding solid tumors, follow-up is still too short: an update after 5 to 10 years is necessary.

Disclosures:
No relevant conflicts of interest to declare.