bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Alterations and Their Clinical Implications in Older Patients with Acute Myeloid Leukemia
Authors: Tsai Cheng-Hong , Hou Hsin-An , Chou Wen-Chien , Lin Chien-Chin , Chen Chien-Yuan , Tang Jih-Luh , Yao Ming , Li Chi-Cheng , Huang Shang-Yi , Ko Bor-Sheng , Hsu Szu-Chun , Lin Chien-Ting , Wu Shang-Ju , Tsay Woei , Tien Hwei-Fang 
Published: October 2019

Abstract
Introduction
Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited.
Methods and Materials
A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315).
Result
Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival.
Conclusion
Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated.

Disclosures
Tang: Novartis: Consultancy, Honoraria.
CD163+ Tumor Associated Macrophages Predict Inferior Outcome in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP
Authors: Zeng Hong , Wei Yongqiang , Xie Muchen , Yang Lei , Huang Fen , Wei Xiaolei , Hao Xiaoxiao , Wei Qi , Feng Ru 
Published: October 2019

Abstract
Tumor-associated macrophages (TAMs), as the major component in tumor microenvironment, have been reported to correlate with the prognosis in diffuse large B-cell lymphoma (DLBCL). However due to the different subtypes of TAMs and the given therapy regimen, the prognostic value of TAMs in DLBCL patients remains controversial. To explore the prognostic significance of different TAMs subtypes in DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), we retrospectively analyzed 77 de novo DLBCL patients in present study.
TAM markers including CD68 and CD163 were evaluated by immunohistochemistry. The cutoff value of CD68, CD163 and CD163/CD68 ratio was determined by receiver operating characteristic curve. In a total of 77 patients, CD68 high expression was found in71.4 %( 55/77) DLBCL patients and CD163 high expression in 51.4 %( 40/77 patients. Patients with high CD163 expression were more present with extranodal sites (P =0.049). However other clinical parameters including age, gender, Ann Arbor stage, performance stage, B symptoms, LDH and international prognostic index (IPI) showed no difference in patients with high and low CD68 or CD163 expression (P >0.05). CD68 expression has less effect on overall survival (OS) and event-free survival (EFS) (P =0.852, 0.782). However, high CD163 expression showed poor OS and EFS in DLBCL patients (P =0.006, 0.004) and also high CD163/CD68 ratio (P <0.001, 0.001). The multivariate analysis revealed that the high CD163 expression and CD163/CD68 ratio remained unfavorable factors for both OS (P =0.094, 0.002) and EFS (P =0.044, 0.016) independent of IPI. In conclusion, our date suggest that high CD163+ TAMs in tumor microenvironment may imply poor outcome in DLBCL patients treated with R-CHOP, but not CD68+ TAMs.

Disclosures
No relevant conflicts of interest to declare.
Aspirin-Platelet Sensitivity in Patients with Essential Thrombocythemia: Role βfibrinogen G-455-a Gene Polymorphism
Authors: Cacciola Rossella Rosari , Cacciola Gentilini Elio , Cacciola Emma 
Published: October 2019

Abstract
Essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet activation and thrombotic risk. Aspirin (ASA) is the standard therapy to normal platelet hyperaggregation and to prevent the thrombosis. It is reported that thrombocythaemic patients are ASA insensitive. It is debated if inherited thrombophilia increases the thrombocythemic platelet activation and, hence, the ASA platelet insensitivity. Therefore, we evaluated βFibrinogen G-455-A gene polymorphism, as thrombophilic molecular mutation associated with increased platelet aggregation, platelet count, β-thromboglobulin (β-TG) and platelet factor 4(PF4) as markers of platelet activation, fibrinogen (Fg), platelet functional activity (PFA), as indicator of ASA platelet sensitivity, clot formation time (CFT) and the maximum clot firmness (MCF), as indicators of aspirinated platelet contribution to clot firmness. We studied 40 patients (24 men, 16 women; mean age 56 years, range 37-77) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. The βFibrinogen G455-A genotype was determined using a commercialized polymerase chain reaction kit with sequence-specific primers. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. PFA, CFT and MCF were measured by Platelet Function Analyzer (PFA-100) and by ROTEM delta, respectively. All patients had heterozygous βFibrinogen G455-A. The mean platelet count was 441±72x109/L. All patients had normal Fg (244±47 mg/dl) high β-TG and PF4 (244±15 IU/ml vs 20±11 IU/ml and 162±56 IU/ml vs 6±2 IU/ml, respectively) (p<.0001 and p<.0001, respectively), prolonged C/EPI closure time (CT, unit: s, n.v. 84-160 s) (252±48 s), normal CFT (CFT, unit: s, n.v. 30-110 s) (50±7s) and MCF (MCF, unit: mm, n.v. 50-72 mm) (71±2 mm). These findings suggest that βFibrinogen G-455-A gene polymorphism does not affect the clonal platelet hyperaggregation in ET.

Disclosures
No relevant conflicts of interest to declare.
A Rapid and Simple Assay for the Determination of Adamts-13 Activity
Authors: Binder Nikolaus B. , Griffiths Margaret , Vetr Helga 
Published: October 2019

Abstract
In recent years the determination of ADAMTS-13 activity in plasma has become an important diagnostics test in the differentiation of Thromobocytopenic Purpura (TTP) patients from those with other forms of Thrombotic micoangiopathies (TMA). Moreover, it is also useful for monitoring the effectiveness of treatment in such patients.
The standard laboratory test for ADAMTS-13 Activity is an ELISA assay, which has an assay which requires 4 hours to process. This assay tends to be performed by specialized laboratories, so samples are usually batch tested. Therefore for a physician to receive a patient ADAMTS-13 activity result can range from 24 hours to as much as one week. This delay in reporting could have a negative impact on patient care.
We have developed a rapid and simple assay which would allow the physician to have an initial reportable result for ADAMTS-13 Activity within 1 hour from the blood draw.
The assay is based on flow through technology, which allows for simple, rapid processing. Plasma samples are pre-incubated with a substrate which is cleaved by ADAMTS-13 present in the plasma. This pre-treated sample is applied to the single test unit which contains a membrane with immobilized antibodies specific for the cleaved substrate. As the sample flows through the membrane into an absorbent pad the cleaved substrate binds to capture antibody. A secondary biotinylated antibody is used to detect the membrane bound complex. Using a Streptavidin-gold conjugate a red colour is produced. The colour intensity is proportional to the level of ADAMTS-13 activity in the plasma sample and compared with a colour standard card, allowing semi-quantitative analysis of the patient sample.
The assay can be performed at room temperature without specialized laboratory equipment and minimal training is needed to perform the test. The assay processing time is under 30 minutes. The test is designed for evaluation of a single patient sample, with a positive control run in parallel.
The designed assay cut-off value of 10% ADAMTS-13 Activity is clinically relevant for differentiation of TTP patients. A 100% correlation was observed when TTP patient samples (n=20) were run in the TECHNOZYM ADATMS-13 ELISA and this assay, as summarized in the figure below.
This rapid and simple assay is versatile and suitable as a cost effective screening assay enabling quick turn-around for ADAMTS-13 activity reporting.
Figure Shows a graphically representation of the method comparison between single test and ELISA results. Figure. Shows a graphically representation of the method comparison between single test and ELISA results.

Disclosures
Binder: Technoclone Herstellung von Diagnostika und Arzneimitteln GmbH: Employment. Griffiths:Technoclone Herstellung von Diagnostika und Arzneimitteln GmbH: Employment. Vetr:Technoclone Herstellung von Diagnostika und Arzneimitteln GmbH: Employment.
The Embt Risk Score Predicts the Outcome of Patients with Leukaemia Receiving Single Umbilical Cord Blood Transplantation
Authors: Zhu Xiaoyu , Tang Baolin , Zheng Changcheng , Liu Huilan , Geng Liangquan , Tong Juan , Zhang Lei , Zhang Xuhan , Yao Wen , Song Kaidi , Wang Xingbing , Ding Kaiyang , Sun Zimin 
Published: October 2019

Abstract
Aim The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes following allogeneic haematopoietic stem cell transplantation (allo-HSCT). However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). The aim of this study was to assess the capacity of the EBMT risk score in predicting the outcomes of patients with leukaemia receiving sUCBT. Methods We retrospectively analysed 218 consecutive patients with leukaemia who received sUCBT at our centre between February 2011 and December 2015. Sixty-eight of the 218 patients had AML, 137 had ALL, 10 had CML, 2 had mixed phenotype AL, and only one patient had plasma cell leukaemia. The median age was 12 years (range, 1-46 years), and the median weight was 40 kg (range, 10-100 kg). All of the patients received an intensified myeloablative conditioning regimen with cyclosporine A (CsA) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis. All of the patients were followed until 31 March 2016, with a median follow-up of 10.7 months (range, 0.5-58.9 months). Results The overall survival (OS) and leukaemia-free survival (LFS) of the entire cohort were 66.8% and 55.4%, respectively, whereas the cumulative incidences of relapse rate and non-relapse mortality (NRM) were 22.4% and 18.0%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS, worse LFS, lower NRM and higher relapse rate, ranging from 80.2%, 74.5%,7.5% and 18.0%, respectively, for patients with a score of 1 to 21.8%, 17.0%, 27.3% and 55.7%, respectively, for patients with a score of 5/6. Hazard ratios of the four indexes all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM and relapse was maintained in the multivariate analysis. Moreover, considering the importance of allele-level HLA matching, we developed a modified sUCBT-EBMT risk score using HLA matching situations instead of donor type and found that the modified score could also be used as a predictor for patient outcomes following sUCBT. Conclusions The EBMT risk score is a good predictor of outcomes of patients with leukaemia following sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.

Disclosures
No relevant conflicts of interest to declare.
Haploidentical Hematopoietic Stem Cell Transplant Compared with Matched Sibling and Unrelated Transplants in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia in First Complete Remission
Authors: Liu Qifa , Han Lijie , Fan Zhiping , Huang Fen , LI Xuan , Xu Na , Lin Ren , Sun Jing 
Published: October 2019

Abstract
Matched-sibling donor (MSD) and matched unrelated donors (MUD) hematopoietic stem-cell transplantation (HSCT) have been recommended for the adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1). However, it is not defined for this portion of patients whether HLA haploidentical donor (HID) transplants can achieve equivalent outcomes compared to MSD and MUD transplants. From 2009 to 2014, 379 adult patients with Ph-negative ALL in CR1 underwent HID HSCT (n = 159), or MSD HSCT (n = 135), or MUD HSCT (n = 85). Among HID, MSD and MUD transplants, the 100-day incidences of acute graft-versus-host disease (aGVHD) Grade Ⅲ-IV were 11.0%, 8.4% and 10.6% respectively (P>0.05), and 2-year chronic GVHD (cGVHD) were 38.9%, 28.5% and 35.6% respectively ( P>0.05 ). At 5 years, the incidences of relapse were 19.0%, 24.0% and 23.4% in HID, MSD and MUD transplants respectively (P>0.05). The 5-year transplant related mortality (TRM) of HID was higher than MSD transplants (16.5% vs 10.9%, P = 0.032), and no difference compared with MUD transplants (16.5% vs 18.1%, P > 0.05). However, the 5-year overall survival (OS), disease-free survival (DFS) did not differ among HID, MSD and MUD transplants (OS 70.9%, 72.0%, 65.4% respectively, P > 0.05; DFS 67.3%, 66.0%, 62.0%, respectively, P > 0.05).
Our results indicate that outcomes of adult patients with Ph-negative ALL in CR1 from HID transplants are comparable to MSD and MUD transplants.

Disclosures
Lin: National Natural Science Foundation of China 81400141: Research Funding; National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding.
Comparison of Disposition and Complications in Geriatric (≥ 65 years) and Non-Geriatric (50-64 years) Cancer Patients Receiving Hematopoietic Stem Cell Transplantation
Authors: Guddati Achuta Kumar , Kumar Gagan , Lewis Robert David , Shapira Iuliana 
Published: October 2019

Abstract
Background:.The disposition and complications of hematopoietic stem cell transplant (HSCT) in the geriatric population has not been extensively studied and compared with younger patients. We have analyzed a database with nationwide representation for outcomes of HSCT in these patients over a 12 year period.
Methods: Data regarding patients who underwent HSCT was extracted from the Nationwide Inpatient Sample (NIS) from 2000 to 2011 using ICD-9-CM codes. HSCT hospitalizations were classified into allogeneic transplantation, autologous transplantation, subsequent hospitalization (s/p transplant) with graft versus host disease (GVHD) and subsequent hospitalization (s/p transplant) with other complications. NIS variables were used to identify in-hospital complications and discharge disposition. Chi square test and Wilcoxon rank test were used to compare categorical and continuous variables respectively.
Results: The proportion of elderly patients (≥ 65 years) receiving autologous transplants and being discharged to nursing homes has increased over the past decade when compared to a younger patient population. Notably, the rate of major complications: mechanical ventilation, tracheostomy and requirement of new dialysis are similar in both the patient populations. The trends from 2000 to 2011 are summarized in Table 1.
Conclusion: Although the rate of transplant-associated complications are similar in geriatric and non-geriatric populations, a higher percentage of geriatric cancer patients who receive HSCT are discharged to nursing homes. These rates have not significantly changed over the past decade (p > 0.05). More medical services and resources will be required to support the growing elderly population undergoing HSCT.
Table 1 Table 1.

Disclosures
No relevant conflicts of interest to declare.
LNK (SH2B3) Deficiency Ameliorates Hematopoietic Stem Cell Defects in Fanconi Anemi
Authors: Balcerek Joanna , Jiang Jing , Jiang Qinqin , Lyu Kaosheng , Greenberg Roger , Tong Wei 
Published: October 2019

Abstract
Fanconi Anemia (FA) is one of the most common inherited bone marrow failure (iBMF) syndromes. Although initially identified over 85 years ago, FA remains a fatal genetic disease. Nineteen FA genes cooperate in a genome stability pathway that is essential for repair of DNA damage and tolerance of replication stress. Cells derived from FA patients are hypersensitive to DNA interstrand crosslink (ICL)-inducing agents, such as Mitomycin C (MMC), and exhibit DNA damage checkpoint and mitosis defects. Mutations in FA genes result in hematopoietic stem cell (HSC) defects, bone marrow failure and cancer predisposition. Importantly, interventions to mitigate HSC defects do not exist, aside from allogeneic bone marrow transplantation (BMT).
HSCs deficient for FancD2, a central component of the FA signaling pathway, are markedly compromised in reconstituting the hematopoietic system in murine BMT models. Remarkably, we found that loss of the adaptor protein Lnk (also called Sh2b3) restores HSC function in FancD2 knockout mice without accelerating neoplastic transformation. LNK negatively regulates HSC self-renewal, in part by attenuating cytokine signaling-activated JAK2 signaling in HSCs (J Clin Invest. 2008;118(8):2832-2844). Fancd2-/-;Lnk-/- (DKO) mice exhibit increased phenotypic HSCs in comparison to wildtype (WT) animals, and DKOHSC function is also largely restored to WT levels in serial transplantation assays. Primary DKOHSC and progenitors (HSPCs) are still sensitive to MMC, indicating that LNK does not play an overt role in ICL repair. Instead, Lnk deficiency notably reduces spontaneous DNA damage and genome instability. This is in agreement with recent studies that reveal a requirement for FA proteins in replication stress, which is a separable function from their role in DNA repair (Cell. 2011;145(4):529-542; Cancer Cell. 2012;22(1):106-116). Strikingly, we demonstrated that Lnk deficiency mitigates replication stress by stabilizing stalled replication forks, and that this effect is dependent upon cytokine signaling.
Together, our data demonstrate that Lnk deficiency ameliorates FA HSPC defects by alleviating replication stress associated DNA damage and genome instability. To our knowledge, this is one of the first examples of in vivo genetic suppression of FA-associated HSPC defects. Our work sheds light on mechanisms underlying the origin of bone marrow failure in FA patients and has implications for new therapeutic strategies to treat FA associated bone marrow failure.

Disclosures
No relevant conflicts of interest to declare.
Osteoclasts Promote Immune Suppressive Microenvironment in Multiple Myeloma: Therapeutic Implication
Authors: An Gang , Acharya Chirag , Feng Xiaoyan , Wen Kenneth , Zhong Mike , Zhang Li , Munshi Nikhil C , Qiu Lugui , Tai Yu-Tzu , Anderson Kenneth C. 
Published: October 2019

Abstract
Purpose: The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesion in patients with multiple myeloma (MM). Mechanisms remain elusive whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment.
Methods: We examined if OCs could modulate T cell-mediated anti-MM immunity; Inhibitory immune molecules expression during osteoclastogenesis; The impact of APRIL on PDL1 expression in MM and the pathway; The impact of Anti-CD38 mAb on osteoclastogenesis and T cell response;
Results: Here, we first show that OCs significantly protect MM cells against T cell-mediated cytotoxicity via direct inhibition of proliferating CD4+and CD8+ T cells. The immune checkpoint molecules PDL1, Galectin-9, HVEM, and CD200, as well as T cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO) and CD38 are significantly up-regulated during osteoclastogenesis. Importantly, levels of these molecules, except CD38, are higher in OCs than MM cells. Anti-PDL1 monoclonal antibody and IDO inhibitor partly overcome OC-inhibited T cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), mainly secreted by OCs, are significantly up-regulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PDL1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly up-regulated during osteoclastogenesis. When targeted by an anti-CD38 monoclonal antibody, suppressive T cell function by OCs is alleviated, associated with down-regulation of HVEM and IDO.
Conclusion: Taken together, these results define expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support combination of targeting these molecules to improve anti-MM immunity.

Disclosures
Anderson: Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.